Synthesis and Reactivity of Model Intermediates Proposed for the Pd-Catalyzed Remote C-H Functionalization of N-(2-Haloaryl)acrylamides

Article abstract of DOI:10.1021/acs.organomet.7b00702

We have studied the possible reaction pathways operating in the Pd-catalyzed remote C-H functionalization of N-(2-haloaryl)acrylamides from an organometallic approach. We have isolated and characterized several proposed reaction intermediates, such as σ-a

Full text of DOI:10.1021/acs.organomet.7b00702

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Cite This: Organometallics XXXX, XXX, XXX-XXX
Synthesis and Reactivity of Model Intermediates Proposed for the
Pd-Catalyzed Remote C−H Functionalization of N‑(2-
Haloaryl)acrylamides
Marta Perez-Gomez,† Leticia Navarro,† Isabel Saura-Llamas,† Delia Bautista,‡ Mark Lautens,*,§
́
́
and Jose-Antonio García-Lopez*,†
́
́
†Grupo de Química Organometal
‡SAI, Universidad de Murcia, 30100, Murcia, Spain
́ ́
ica. Dpto. Química Inorganica, Universidad de Murcia, Campus de Espinardo, 30100, Murcia, Spain
§Davenport Research Laboratories, Department of Chemistry, University of Toronto, Toronto, Ontario M5S 3H6, Canada
S
* Supporting Information
ABSTRACT: We have studied the possible reaction pathways
operating in the Pd-catalyzed remote C−H functionalization of
N-(2-haloaryl)acrylamides from an organometallic approach. We
have isolated and characterized several proposed reaction
intermediates, such as σ-alkyl-Pd complexes and spiro C,C-
palladacycles, and evaluated the role of the base and the auxiliary
ligands coordinated to Pd in the remote C−H activation process.
In addition, the reactivity of these intermediates toward different
unsaturated species such as benzyne, alkynes, and isocyanides has
been studied in order to gain further insight into the reaction
mechanism leading to functionalized spiro-oxoindoles.
conveniently designed substrates to avoid β-hydrogen elimi-
nation.
INTRODUCTION
■
The functionalization of unreactive remote C−H bonds has
become an emerging research topic, since this approach opens
up new routes and molecular disconnections in organic
synthesis.1,2 These transformations have generally been
performed through the installation of suitable directing groups
in the core substrate, which guide regioselectively a transition
metal toward the desired C−H position, forming a C−metal
bond, which can be further functionalized. For instance, several
synthetic methods involving the use of palladium have been
recently developed by introducing coordinating groups, such as
8-aminoquinoline, substituted pyridines, and tethered cyanides,
into the molecular structure of the starting material.2,3 These
protocols allow the functionalization (i.e. arylation, alkenyla-
tion, acetoxylation, etc.) of C−H positions previously thought
inaccessible, such as meta2b,g and para2d positions in aromatic
rings or δ2a and γ2e,f positions in aliphatic chains.
Palladium-catalyzed cascade reactions represent a comple-
mentary approach for the functionalization of remote C−H
moieties (Scheme 1).4,5 In these processes, an organopalladium
intermediate is able to add regioselectively to a tethered
unsaturated moiety, such as an alkene or alkyne, leading to a
new organometallic species in which the palladium atom
becomes closer to a formerly remote C−H moiety, therefore
enabling its activation by the metal and its subsequent
functionalization. Those cascade reactions involving the
carbopalladation of alkenes are mainly carried out in
Our research groups6−8 and others9 have recently developed
new methodologies based on this last approach, such as the
synthesis of complex spirocyclic heterocycles in a straightfor-
ward manner through the coupling of simple alkenylated
building blocks and arynes, alkynes, or α-diazocarbonyl
compounds. Furthermore, a remote alkylation employing
alkyl halides in these types of cascade reactions was reported
by one of our research groups.10
These strategies have been successfully applied to the
synthesis of functionalized spiro-oxoindoles, a molecular
scaffold that has attracted great interest due to its presence in
natural products and pharmaceuticals.11 We have now studied
in detail the synthesis and reactivity of some of the key
intermediates proposed in this new type of remote C−H
functionalization in order to gain further insight into the
reaction pathway.
Taking the remote arylation of the N-(2-iodophenyl)-
acrylamide 1 with benzyne as a representative example of
transformations based on the carbopalladation of tethered
alkenes (Scheme 2),6,7a two possible reaction pathways can be
envisioned for the overall remote C−H functionalization (paths
a and b, depicted in the Scheme 2). Both pathways share some
Received: September 13, 2017
© XXXX American Chemical Society
A
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Pd(II) intermediate of type 2.12 This species could react with
the corresponding coupling partner (benzyne in this case) to
give a new intermediate 3, followed by a C−H activation step
and a final C−C coupling process (path a, Scheme 2).
Alternatively, the intermediate 2 can give a spiro-palladacycle of
type 4, where the insertion of the unsaturated coupling partner
would take place, giving rise to the functionalization of both
C−Pd bonds.
Scheme 1. Directing-Group-Assisted and Cascade-Type
Remote C−H Functionalizations
The synthesis of a type 4 complex was recently reported as
part of the mechanistic studies in remote cascade C−H
arylation leading to spiro-biaryl scaffolds (Scheme 2).7a It was
found that complex 4a could react with benzyne to give the
expected spiro-biaryl 7, upon decomposition of the correspond-
ing carbopalladated species (Scheme 3). A similar assay carried
out soon thereafter where benzyne was replaced by an α-
diazocarbonyl compound as the coupling partner, also provided
the spirocyclic oxoindole 8 (Scheme 3).8 Both results support
the generation of intermediates of type 4 in the overall catalytic
arylation or alkylation, respectively. Nevertheless, the feasibility
of the alternative path a (Scheme 2), in which the coupling
partner reacts first with the σ-alkyl intermediate 2, has not yet
been assessed from an organometallic approach.
RESULTS AND DISCUSSION
■
First, we focused on the stepwise synthesis of both types of
intermediates starting from the N-(2-iodophenyl)acrylamide 1,
a model substrate which we have previously functionalized by
means of Pd-catalyzed remote C−H activation protocols: the σ-
alkyl Pd(II) complex of type 2 and the C,C-spiropalladacycle of
type 4. The N-(2-iodophenyl)acrylamide 1 was reacted with an
equimolar amount of Pd(dba)2 in the presence of 2 equiv of
PPh3 in CH2Cl2 at room temperature under an inert
common intermediates. For instance, the oxidative addition of a
haloarene to a Pd(0) complex (either preformed or generated
in situ from Pd(OAc)2 and PPh3) would render an aryl-Pd(II)
species, which in turn could evolve through the intramolecular
carbopalladation of the tethered alkene, generating a σ-alkyl
a
Scheme 2. Remote Arylation of N-(2-Iodophenyl)acrylamide with Benzyne and Its Possible Reaction Pathways
a
B represents a generic base.
B
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plausible explanation for this behavior could rely on the
dissociation of one of the phosphine ligands caused by a high
steric hindrance around the metallic center, giving rise to a
complex such as 9 (broad signal at 40.2 ppm, Figure 1) and free
PPh3 (broad signal at −4.5 ppm).
Scheme 3. Reported Reactivity of the C,C-Palladacycle 4a
with Arynes and α-Diazocarbonyl Compounds
The Pd center present in the proposed complex 9 could
interact with the nearby aryl group to complete its coordination
sphere. A similar σ-alkyl complex where the Pd atom
coordinates to the phenyl ring was fully characterized and
crystallized by Cam
́
pora et al.14a Nevertheless, the species 9
could evolve to give a new intermediate 10, where a more
stable C,O-palladacycle was generated (signal at 37.7 ppm).
Finally, the oxidation of the free phosphine would produce
OPPh3 (signal at 29.3 ppm). An additional peak at 12.4 ppm
was attributed to [PdI2(PPh3)2], arising from further
decomposition processes, and it gained in intensity over time.
According to path b, depicted in the Scheme 2 for the
catalytic reaction, complex 2a should be able to generate the
C,C-palladated intermediate 4a under the right conditions.
When complex 2a was heated in toluene at 80 °C for 4 h, traces
of 4a could hardly be detected in the31P NMR spectrum of the
crude reaction mixture. Nevertheless, when the same experi-
ment was run in MeCN, we observed the consumption of the
starting material and the formation of a mixture of products
containing the palladacycle 4a, which could be easily identified
by 31P NMR, since its spectrum shows two characteristic
doublets at 25.6 and 24.8 ppm (corresponding to the two
distinct phosphine ligands). Likely, the generation of 4a from
2a under base-free conditions might be related to the
generation of ill-defined side decomposition products that can
act as bases to remove the HI formed upon the C−H activation
step. Moreover, complex 4a was the main product of the crude
atmosphere for 2 h (Scheme 4). A pale gray solid could be
isolated upon addition of Et2O to the reaction mixture, whose
31P NMR spectrum showed a main signal at 33.1 ppm
(attributed to the expected complex 2a), along with two smaller
and much broader signals at 40.2 and −4.5 ppm (Figure 1).
The chemical equivalence of the phosphine ligands in 2a
indicated their mutually trans disposition, in agreement with
the high transphobia for P/C-donor ligands.13 A solution of this
solid in CDCl3 was monitored by 1H NMR at room
temperature for 14 h. We found that two new singlets appeared
at 37.7 and 29.3 ppm and gained intensity at the expenses of
the first three signals (40.2, 33.1, and −4.5 ppm, Figure 1). A
Scheme 4. Synthesis of the σ-Alkyl Pd Complex 2a and Its Evolution under Different Conditions: Protonolysis of the Complex
4a
C
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1
Figure 1. Stacking of the H NMR spectra of a CDCl3 solution of complex 2a at 25 °C at increasing times. The different species are marked as
follows: 9, red circles (40.2 ppm); 10, green stars (37.7 ppm); 2a, black triangles (33.1 ppm); OPPh3, blue squares (29.3 ppm); [PdI2(PPh3)2],
orange circles (12.4 ppm); PPh3, white circle (−4.5 ppm).
mixture when an analogous reaction was carried out in MeCN
in the presence of Cs2CO3 (61%, NMR yield). Therefore, the
addition of Cs2CO3 was not essential for the C−H activation to
proceed in MeCN, but its presence was beneficial for the
overall process. The intermediate 4a could be better prepared
in good yield and in a single step by reacting 1 with 1 equiv of
[Pd(PPh3)4] in toluene at 80 °C in the presence of Cs2CO3
(Scheme 4), as reported previously by one of us.7a
In an attempt to isolate an analogous complex to 10, we
carried out the partial protonolysis of the C(sp2)−Pd bond15
(present in intermediate 4a) by adding carefully a small amount
of a saturated solution of HCl in CH2Cl2 to a solution of 4a in
CH2Cl2 at room temperature (Scheme 4). Via this method, we
could isolate complex 11, whose 31P NMR spectrum showed a
singlet at 37.8 ppm, very close to that of the complex 10. The
X-ray crystal structure of 11·CH2Cl2 could be successfully
determined, confirming the nature of the C,O-palladacycle
(Figure 2). The palladium atom was in a slightly distorted
The addition of an excess of HCl to a solution of 4a
provoked the protonolysis of both C−Pd bonds, affording the
oxoindole 12 (Scheme 4).
Next, we attempted the synthesis of intermediates of type 2
that were easier to handle and study, by switching the ligand
from PPh3 to N,N,N′,N′-tetramethylethylenediamine
(TMEDA) or 4,4′-di-tert-butyl-2,2′-bipyridyl (t-bipy). The
oxidative addition of the N-(2-iodophenyl)acrylamide 1 to
Pd(dba)2 in the presence of either of these nitrogen ligands
afforded the corresponding σ-alkyl Pd(II) complexes 2b,c in
good yields (Scheme 5). These complexes were sufficiently
stable to be fully characterized, and 2b could be conveniently
crystallized to study its crystal structure by X-ray diffraction
(Figure 3). The palladium atom was in an almost perfect
square-planar environment, with a mean deviation of the Pd(II)
coordination plane of 0.003 Å and a dihedral angle of 0.7°
between the planes N(1)−Pd(1)−N(2) and C(1)−Pd(1)−
I(1). The N(1)−Pd(1)−N(2) angle is 77.94(7)°, quite smaller
than the standard value of 90° for an ideal square-planar
complex, due to the steric constraints imposed by the bite angle
of the bipyridine ligand.
We can conclude that the first two steps of the catalytic cycle
operating in the remote C−H functionalization reactions
(Scheme 1), i.e., the oxidative addition of the C−I bond to
Pd(0) and the intramolecular carbopalladation of the tethered
olefin, took place smoothly at room temperature regardless of
the nature of the ligand (PPh3 or N,N-chelating donors).
At this point we explored the thermal evolution of the σ-alkyl
Pd(II) complex bearing N,N-chelating ligands. When a solution
of complex 2b in MeCN was heated to 80 °C for 8 h, a mixture
of the starting material 2b, the C,C-palladacycle 4b (arising
from the C−H activation), and the organic product 13
(2b:4b:13 ratio 1:1.7:0.7) was obtained (Scheme 5). The
product 13 arises from a C−I coupling process in the σ-alkyl
Pd(II) complex and represents formally a carboiodination of
the initial double bond present in the N-(2-iodophenyl)-
acrylamide 1.5e,16 The palladacycle 4b was isolated in good
yield when we performed the reaction in the presence of
Cs2CO3.
Figure 2. Thermal ellipsoid plot (50% probability) of 11 along with
the labeling scheme. Hydrogen atoms have been omitted for clarity.
square-planar environment, with a mean deviation of the Pd(II)
coordination plane of 0.066 Å and a dihedral angle of 6.5°
between the planes Cl(1)−Pd(1)−P(1) and O(1)−Pd(1)−
C(1). The C,O-chelated ligand formed a five-membered
metallacycle, with an envelope conformation.
The crystal structure of complex 4b·C3H6O was solved by X-
ray diffraction studies (Figure 4). The palladium atom was in a
distorted-square-planar environment, with a mean deviation of
D
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Scheme 5. Synthesis of Complexes 2b,c and Their Evolution under Different Conditions
angles N(1)−Pd(1)−N(2) and C(1)−Pd−C(11) are far from
the optimal value of 90° (79.98(7) and 77.20(5)°, respectively)
due to the steric constraints imposed by the bite angles of both
chelated ligands. The Pd(1)−N bond lengths are not
2
significantly different (Pd(1)−N(1) trans to Csp
=
3
2.1107(14) Å; Pd(1)−N(2) trans to Csp = 2.1190(14) Å),
indicating in this case a similar trans influence of both the
C(sp2) and the C(sp3) donor atoms. The discrete molecules of
4b·C3H6O are associated through C−H···O hydrogen bonds,
giving zigzag chains along the b axis (details, including
symmetry operations, are given in the Supporting Information).
The crystal structure of 4b·C3H6O resembles the structural
features previously reported for 4a.7a
Once again, the addition of Cs2CO3 suppressed the
generation of the secondary byproducts (12 and 13, Scheme
5). It is worth noting that the product 13, arising from the C−I
coupling process, was only observed in the decomposition
process of complexes 2b,c (containing N,N-chelating ligands),
and not in the case of 2a (containing PPh3). This observation
might be closely related to the fact that the N,N-chelating
ligands force a cis geometry of the iodide and the alkyl moiety
around the Pd atom.
Figure 3. Thermal ellipsoid plot (50% probability) of 2b along with
the labeling scheme. Hydrogen atoms have been omitted for clarity.
In CHCl3 solution at 65 °C, the complex 2c evolved to give a
mixture of the products 12 and 13 (Scheme 5). The oxoindole
12 is the result of an alternative reaction pathway which
3
presumably involves the protonolysis of the Csp −Pd bond.
Likely, the absence of a base in the reaction mixture allows the
3
protonolysis of the Csp −Pd bond to proceed.
The Cs2CO3 assists the palladation reaction, and it can
operate through different mechanisms: (i) removing the iodo
ligand from the coordination sphere of palladium, hence
avoiding the C−I bond formation, and (ii) providing a base to
facilitate the abstraction of the proton either intra- or
intermolecularly.17 To further evaluate the role of Cs2CO3 in
the remote C−H activation process, we synthesized complexes
14b,c by reacting the σ-alkyl Pd(II) complexes 2b,c with
AgOTf in MeCN at room temperature (Scheme 6). We
intended to replace the iodine moiety by a far less coordinating
ligand, such as the triflate anion. The cationic complexes 14b,c
were obtained. The crystal structure of complex 14c was
Figure 4. Thermal ellipsoid plot (50% probability) of 4b along with
the labeling scheme. Hydrogen atoms have been omitted for clarity.
the Pd(II) coordination plane of 0.064 Å and a dihedral angle
of 6.8° between the planes N(1)−Pd(1)−N(2) and C(1)−
Pd(1)−C(11). The palladium atom is simultaneously coordi-
nated to two chelated ligands: an N,N- and a C,C-moiety. The
E
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Scheme 6. Synthesis of Cationic Complexes 14b,c
Scheme 7. Formation of 4b from 14b
determined by X-ray diffraction (Figure 5) and showed the
intramolecular chelation of the oxygen atom from the amide
precursors, the formation of a stable C,O-chelated intermediate,
such as 14b or 14c, could take place, precluding the rotation of
the alkyl-Pd moiety, the placement of the metal in a
conveniently close position to the neighboring phenyl ring,
and therefore the metalation. The neutral precursor could bear
either the initial iodide or a carbonate ligand. Furthermore,
when complex 14b was heated in MeCN at 80 °C in the
presence of Cs2CO3 (Scheme 7), the formation of the
palladacycle 4b was observed (30%, NMR yield).
Once we had assessed the synthesis of the intermediates of
type 2 and their evolution to give 4 with different ligands, we
continued our study by exploring their behavior toward
unsaturated species. We carried out the reactions of the σ-
alkyl Pd(II) complexes 2a,b with two different coupling
partners: (a) in situ generated benzyne and (b) an α-
diazocarbonyl compound (Scheme 8). The intermediate 2a
gave the corresponding organic products 7 and 8 in moderate
yields. However, when 2b was used as the starting material, a
complex mixture of products was obtained, where 7 and 8
could not be detected by either 1H NMR or HPLC-MS
(Scheme 8). The outcome of these reactions indicates that the
nature of the ligands in the Pd coordination sphere plays a key
Figure 5. Thermal ellipsoid plot (50% probability) of 14c along with
the labeling scheme. Hydrogen atoms and the triflate anion have been
omitted for clarity.
moiety to Pd(II). The palladium atom was in a slightly
distorted-square-planar environment, with a mean deviation of
the Pd(II) coordination plane of 0.041 Å and a dihedral angle
of 7.5° between the planes N(1)−Pd(1)−N(2) and C(1)−
Pd(1)−O(1). The palladium atom is simultaneously coordi-
nated to two chelated ligands: the TMEDA (angle N(1)−
Pd(1)−N(2) = 85.22(12)°) and the anionic C,O-moiety (angle
O(1)−Pd(1)−C(1) = 84.48(11)°). The Pd(1)−N(1) bond
length (2.167(3) Å) is significantly longer than the Pd(1)−
N(2) bond length (2.054(3) Å), reflecting the greater trans
influence of the C-donor atom. The organic cation is associated
with the triflate anion through a C−H···O hydrogen bond
(details, including symmetry operations, are given in the
Supporting Information). The cationic nature of complexes
14b,c in solution was confirmed by measuring the values of
their molar conductivity in acetone.
Scheme 8. Reactivity of the Complexes 2a,b with Different
Coupling Partners
We hypothesized that the exchange of the iodo by a triflate
ligand would lead to an enhancement in the electrophilic
character of Pd(II), promoting the C−H activation step.17a,18
Nevertheless, complexes 14b,c were very stable in solution and
did not evolve to give the corresponding palladacycles 4b,c,
respectively, when they were heated at 80 °C in MeCN for 16 h
(Scheme 7). This behavior is in contrast with that observed for
the neutral complexes 2a,b, which did undergo partially the
cyclometalation in MeCN, even in the absence of an external
base (Scheme 5). These results might indicate that the C−H
activation is facilitated by the generation of a coordination
vacancy, upon ligand dissociation from Pd(II), to afford species
such as 9 (Scheme 4). This dissociation would take place more
easily from a neutral complex; otherwise, for cationic
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role in the overall transformation: the strongly chelating
bipyridine ligand blocks the process, while a more labile ligand
such as PPh3 allows the reaction to proceed.
Scheme 10. Reported Catalytic Reaction from Substrate 15
None of the results, at this stage, can be used to discard
either of the two possible reaction pathways for the
intermediate 2a (paths a and b, Scheme 2), since, as discussed
above, the remote metalation of 2a to give 4a can take place in
MeCN. When the reaction of 2a and the α-diazocarbonyl
compound was performed in toluene in the absence of Cs2CO3
(conditions that disfavored the formation of 4a, vide supra), a
complex mixture of products was observed where only traces of
8 were present (Scheme 9). This result does not exclude
Scheme 9. Reactivity of the Complexes 2a and 4a toward the
α-Diazocarbonyl Coupling Partner
which of its two distinct Pd−C bonds was functionalized at
first, to get a detailed picture of the complete reaction from the
N-(2-iodophenyl)acrylamide 1 to the final organic product. Our
goal was the isolation of any of the organometallic
intermediates arising from the insertion of unsaturated coupling
partners, such as benzyne, alkynes, carbon monoxide, and
isocyanides, into either of the two Pd−C bonds present in 4a.
Vicente’s group reported the isolation of several aryl-Pd
complexes arising from the insertion of benzyne into the
Pd−C bond of six-membered palladacycles.19 Following a
similar method, we set the reaction of 4a with benzyne
generated in situ at room temperature, but even under these
mild conditions the organic product 7 (arising from the C−C
coupling) was detected: that is, the plausible organometallic
intermediate arising from the insertion of the aryne
decomposed rapidly (Scheme 11). A similar behavior was
found when a reactive alkyne such as dimethyl acetylenedi-
carboxylate (DMAD) was used instead of benzyne (Scheme
11). This reaction was monitored by 1H NMR, which
confirmed the finding that the concentration of possible
insertion species was quite low, and only starting materials or
the organic product 17 arising from the decomposition could
be detected. Other alkynes such as diphenylacetylene and 3-
hexyne proved to be unreactive. Related insertion reactions of
completely the possibility of generating 8 from a hypothetical
alkyl-Pd(II) intermediate arising from the insertion of the α-
diazocarbonyl compound into 2a (since there is no presence of
an external base to assist the subsequent C−H activation).
However, we know that (1) 2a reacts with the α-diazocarbonyl
compound in MeCN, under base-free conditions, to give 8
(Scheme 8), but the same reaction does not happen in toluene
and (2) 4a reacts with the α-diazocarbonyl compound in
toluene in the absence of an external base to afford 8 (75%,
NMR yield; Scheme 9). Hence, the overall transformation
seems to proceed via the generation of the key C,C-
spiropalladacycle 4a from 2a, and its subsequent reaction
with the coupling partner (path b, Scheme 2), rather than the
alternative direct reaction from the σ-alkyl Pd(II) 2a (path a,
Scheme 2).
Complementarily to the stoichiometric studies we report in
this paper, one of our research groups designed a different
approach to check the feasibility of the reaction path a (Scheme
2).7a The oxidative addition of the model substrate 15 to Pd(0)
(Scheme 10) would provide a similar intermediate to 3 (path a,
Scheme 2), arising from the benzyne insertion into the σ-alkyl
Pd(II) 2a. Nevertheless, the submission of the substrate 15 to
the Pd(0) catalysis did not provide the expected spiro-biaryl
scaffold 7 but the product 16 arising from the coupling with
MeCN. It is noteworthy that the formation of this last product
was not observed in the catalytic reaction.
2
3
alkynes into five-membered Csp ,Csp -palladacycles and -nickela-
cycles have been reported in the literature.14b−d Similarly to our
case, no seven-membered metallacyclic intermediates arising
from the insertion of the alkyne into the Pd−C bond could be
isolated from the reaction mixtures.
There are numerous examples in the literature regarding the
insertion of carbon monoxide or isocyanides into the Pd−C
bond of palladated arenes, which render isolable acyl or
iminoacyl complexes.13c,15b,19c,20 Nevertheless, the palladacycle
4a was quite robust toward CO insertion, since no reaction was
observed after 16 h under CO atmosphere (1.5 atm) at either
room temperature or 90 °C. The reaction of 4a with xylyl
isocyanide (XyNC) at room temperature afforded complexes
18 and 19, arising from the displacement of one or two of the
phosphine ligands from the coordination sphere, depending on
the stoichiometry of the reaction (Scheme 12).21 No iminoacyl
derivatives from the insertion of the isocynide were observed.
Forcing the reaction conditions with an excess of XyNC (3
equiv) at 100 °C led to a complex mixture of products. It is
worth noting that the products 18 and 19 contain a palladium
center bonded simultaneously to sp-, sp2-, and sp3-hybridized
Focusing on the generation of the diverse spirocyclic organic
products from the intermediate 4a, we attempted to determine
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strained [4,5]-spirocycle 20 (Scheme 13). Very likely, the
oxidant promoted the formation of a Pd(IV) intermediate in
Scheme 11. Attempts To Isolate Organometallic
Intermediates Arising from the Insertion of Benzyne and
DMAD
Scheme 13. Oxidative C−C Coupling Promoted by
PhI(OAc)2
the course of the reaction, which evolved through an oxidative
C−C coupling process to afford 20, rather than undergoing a
C−O coupling event. The catalytic synthesis of similar [4,5]-
spirocyclic scaffolds was reported to occur via a Pd(0)/Pd(II)
cycle when a bulky phosphine such as P(tBu)3 was used as
ligand.9
CONCLUSION
■
In conclusion, we have synthesized several of the organo-
metallic intermediates operating in the Pd-catalyzed cascade
remote C−H functionalization of N-(2-halophenyl)-
acrylamides. According to the results presented in this study,
these types of catalytic reactions proceed successfully when the
σ-alkyl Pd(II) complex generated upon the intramolecular
carbopalladation is prone to undergo a C−H activation on the
formerly remote phenyl moiety of the substrate. The feasibility
of the palladation step is affected by the auxiliary ligands
present on the coordination sphere of the metal, the solvent of
choice, and the presence of a base. Labile ligands such as PPh3,
in MeCN as the solvent and in the presence of Cs2CO3, favor
the formation of the key C,C-spiropalladacycle intermediate,
which in turn reacts with a coupling partner to render the
corresponding spirocyclic organic skeletons. When the reaction
conditions hamper the C−H metalation (and subsequently the
formation of the spiropalladacycle intermediate), the overall
remote functionalization is blocked. These results indicate that
an alternative reaction pathway in which the σ-alkyl Pd(II)
complex reacts with the unsaturated species at first is unlikely to
happen in the catalytic transformations. Furthermore, the final
steps of the catalytic remote arylation cycle (i.e., insertion of the
aryne or activated alkyne into the Pd−C bond of the C,C-
spiropalladacycle intermediate and subsequent C−C bond
fomation leading to the spiro-oxoindole scaffold) are not the
rate-limiting steps of the cycle, since they take place rapidly at
room temperature.
Scheme 12. Reactions of Complex 4a with XyNC
C-donors. For complex 18 we propose that the XyNC ligand is
EXPERIMENTAL SECTION
■
coordinated trans to the aryl group, similarly to other Pd(II)
Infrared spectra were recorded on a PerkinElmer Spectrum 100
spectrophotometer. High-resolution ESI mass spectra were recorded
on an Agilent 6220 Accurate Mass TOF LC/MS spectrometer.
Melting points were determined using a Reichert apparatus and are
uncorrected. Nuclear magnetic resonance (NMR) spectra were
recorded on a 300 or 400 MHz Bruker NMR spectrometer in
13d
2
complexes containing a Csp -donor, PPh3, and an isocyanide.
In addition to the reactivity of the intermediate 4a toward
unsaturated species, we investigated the behavior of this
complex toward an oxidant such as PhI(OAc)2. The reaction
of 4a with PhI(OAc)2 at room temperature gave rise to the
H
DOI: 10.1021/acs.organomet.7b00702
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Article
CDCl3 at 298 K (unless stated otherwise). All chemical shift values are
reported in parts per million (ppm) with coupling constant (J) values
reported in Hz. All spectra were referenced to TMS for 1H NMR and
the CDCl3 solvent peak for 13C{1H} NMR. Anhydrous MeCN was
purchased from commercial sources and used as received. TLC tests
were run on TLC Alugram Sil G plates and visualized under UV light
at 254 nm. Chromatographic separations were carried out on silica gel.
Synthesis of Complex 2a. Pd(dba)2 (240 mg, 0.41 mmol) and
PPh3 (220 mg, 0.83 mmol) were added to a solution of N-(2-
iodophenyl)acrylamide 1 (150 mg, 0.41 mmol) in dry CH2Cl2 (30
mL) in a Carius tube under a nitrogen atmosphere. The tube was
sealed, and the mixture was stirred at room temperature for 2.5 h. The
resulting solution was filtered over a Celite pad. The solvent of the
filtrate was partially removed to leave ca. 4 mL, and Et2O (20 mL) was
added. The resulting suspension was filtered, and the solid was washed
with Et2O (2 × 2 mL) and air-dried to give compound 2a as a gray
solid. Yield: 137 mg, 0.14 mmol, 33%. The complex 2a is not stable in
solution and gives rise to other species such us 9, 10, and PPh3; for this
reason only the representative 1H NMR signals are described. 1H
NMR (400.9 MHz, CDCl3): δ = 6.99−6.93 (m, 2H), 6.81 (d, J = 8.0
Hz, 1H), 3.36 (s, 3H), 2.03 (d, J = 9.3 Hz, 1H), 1.55 (br dd, J = 9.3,
5.4 Hz, 1H). 31P NMR (121.50 MHz, CDCl3): δ 33.1 (s). HR-MS
(+ESI): m/z calcd for C52H44NOP2Pd [M − I]+ 866.1933, found
866.1941. We could not obtain an adequate elemental analysis of the
complex 2a, probably due to the precipitation of small amounts of 9,
10, and/or PPh3 along with 2a.
cm−1): ν(CO) 1692 (s). Anal. Calcd for C22H30IN3OPd·1/2H2O: C,
44.42; H, 5.25; N, 7.06. Found: C, 44.23; H, 5.33; N, 6.85.
Synthesis of Complex 4b. A Carius tube was charged with the
substrate 2b (300 mg, 0.41 mmol), dry Cs2CO3 (199 mg, 0.62 mmol),
and a magnetic stirrer. The tube was rapidly set under a nitrogen
atmosphere, and dry CH3CN was added (12 mL). The tube was
sealed, and the mixture was stirred at 75 °C for 16 h. After the tube
was cooled, the crude product was diluted with CH2Cl2 (30 mL) and
filtered through a Celite plug. The filtrate was concentrated to ca. 1
mL, Et2O (15 mL) was added, and the mixture was stirred in a cold
bath for 30 min. A yellow solid precipitated slowly. The suspension
was filtered, and the solid was washed with ether (2 × 3 mL) and air-
dried to give 4b·0.75CH2Cl2 as a yellow solid. Yield: 167 mg, 0.25
mmol, 60%. Mp: 130−132 °C. 1H NMR (400.9 MHz, CDCl3): δ 9.20
(d, J = 5.6 Hz, 1H), 8.42 (d, J = 6 Hz, 1H), 8.01 (dd, J = 10.0, 1.6 Hz,
2H), 7.91 (dd, J = 7.6 Hz, 0.8, 1H), 7.59 (td, J = 5.6, 2 Hz, 2H), 7.33
(dd, J = 5.6, 1.6 Hz, 1H), 7.17 (td, J = 7.6, 1.2 Hz, 1H), 7.02 (td, J =
7.2, 1.2 Hz, 1H), 6.92 (td, J = 7.2, 0.8 Hz, 1H), 6.88−6.83 (m, 2H),
6.46 (dd, J = 7.6, 1.2 Hz, 1H), 5.30 (crystallization CH2Cl2, 1.1H),
3.30 (s, 3H), 2.91 (d, J = 8.4 Hz, 1H), 2.20 (d, J = 8.4 Hz, 1 H), 1.47
(s, 9H), 1.40 (s, 9H). 13C NMR (75.4 MHz, CDCl3): δ 181.7 (s, Cq),
162.29 (s, Cq), 162.25 (s, Cq), 161.8 (s, Cq), 161.5 (s, Cq), 155.4 (s,
Cq), 155.1 (s, Cq), 150.6 (s, CH), 149.5 (s, CH), 142.9 (s, Cq), 139.5
(s, Cq), 135.2 (s, CH), 126.3 (s, CH), 124.9 (s, CH), 124.4 (s, CH),
123.5 (s, CH), 123.1 (s, CH), 122.7 (s, CH), 122.2 (s, CH), 121.9 (s,
CH), 118.2 (s, CH), 118.0 (s, CH), 107.0 (s, CH), 65.4 (s, Cq), 35.4
(s, Cq), 35.3 (s, Cq), 34.4 (s, CH2), 30.4 (s, CH3), 30.3 (s, CH3), 26.2
(s, CH3). IR (Nujol, cm−1): ν(CO) 1698 (s). Anal. Calcd for
C34H37N3OPd·0.75CH2Cl2: C, 61.94; H, 5.76; N, 6.24. Found: C,
61.72; H, 5.83; N, 6.20. Single crystals of 4b, suitable for an X-ray
diffraction study, were obtained by slow diffusion of n-pentane into a
solution of 4b in acetone.
Synthesis of Complex 2b. Pd(dba)2 (914 mg, 1.59 mmol) and
4,4′-tert-butyl-2,2′-bipyridine (427 mg, 1.59 mmol) were added to a
solution of N-(2-iodophenyl)acrylamide 1 (577 mg, 1.59 mmol) in dry
CH2Cl2 (30 mL) in a Carius tube, under a nitrogen atmosphere. The
tube was sealed, and the mixture was stirred at room temperature for 3
h. The resulting solution was filtered over a Celite pad, the filtrate was
concentrated to ca. 1 mL, and Et2O (20 mL) was added. The resulting
suspension was filtered, and the solid was washed with Et2O (2 × 5
mL) and air-dried to give compound 2b as a yellow solid. Yield: 877
Synthesis of Complex 11. A saturated solution of HCl in
dichloromethane (600 μL), prepared by bubbling HCl gas through
dichloromethane, was added to a solution of 4a (200 mg, 0.23 mmol)
in commercial dichloromethane (30 mL). The resulting mixture was
stirred at room temperature for 16 h. The solution was concentrated
to ca. 1 mL, and Et2O (15 mL) was added. The resulting suspension
was filtered, and the solid was washed with Et2O (2 × 3 mL) and air-
dried to afford 11 as a yellow solid. Yield: 83 mg, 0.13 mmol, 56%.
1
mg, 1.19 mmol, 71%. Mp: 188 °C. H NMR (400.9 MHz, CDCl3): δ
9.42 (d, J = 6.0 Hz, 1H), 8.66 (d, J = 6.0 Hz, 1H), 7.86 (dd, J = 6.4, 2.0
Hz, 2H), 7.70−7.60 (m, 2H), 7.59 (dd, J = 7.6, 0.8 Hz, 1H), 7.38 (dd,
J = 6.0, 2.0 Hz, 1H), 7.33 (dd, J = 6.0, 2.0 Hz, 1H), 7.21−7.17 (m,
2H), 7.13−7.07 (m, 2H), 6.85 (td, J = 7.6, 0.8 Hz, 1H), 6.71 (d, J = 7.2
Hz, 1H), 3.37 (d, J = 8.9 Hz, 1H), 3.12 (s, 3H), 2.61 (d, J = 8.9 Hz,
1H), 1.41 (s, 9H), 1.38 (s, 9H). 13C NMR (100.8 MHz, CDCl3): δ
179.3 (s, Cq), 162.5 (s, Cq), 162.4 (s, Cq), 155.8 (s, Cq), 153.6 (s, Cq),
152.4 (s, CH), 148.7 (s, CH), 143.1 (s, Cq), 142.7 (s, Cq), 135.0 (s,
Cq), 127.8 (s, CH), 127.7 (s, CH), 127.5 (s, CH), 126.9 (s, CH),
126.2 (s, CH), 123.4 (s, CH), 122.8 (s, CH), 121.3 (s, CH), 118.2 (s,
CH), 117.7 (s, CH), 107.4 (s, CH), 58.8 (s, Cq), 35.4 (s, Cq), 35.3 (s,
Cq), 30.3 (s, CH3), 30.2 (s, CH3), 26.4 (s, CH3), 19.3 (s, CH2). IR
(Nujol, cm−1): ν (CO) 1699 (s). Anal. Calcd for C34H38N3OPdI: C,
55.33; H, 5.19; N, 5.69. Found: C, 55.65; H, 5.13; N, 5.67.
1
Mp: 154−156 °C. H NMR (300.1 MHz, CDCl3): δ 7.57−7.48 (m,
5H), 7.46−7.39 (m, 5H), 7.36−7.30 (m, 9H), 7.23−7.06 (m, 2 H),
6.97−6.95 (m, 2 H), 6.81 (d, J = 9.3 Hz, 1 H), 3.39 (s, 3 H). 1.83 (d, J
= 9.6 Hz, 1H), 1.24 (dd, J = 9.6, 6.3 Hz, 1H). 13C NMR (75.4 MHz,
CDCl3): δ 192.0 (s, Cq), 144.1 (s, Cq), 141.7 (s, Cq), 134.5 (d, J = 11.7
Hz, CH), 130.6 (d, J = 54.9 Hz, Cq), 130.6 (d, J = 2.4 Hz, CH), 129.0
(s, CH), 128.4 (s, CH), 128.2 (d, J = 11.2 Hz; CH), 127.2 (s, CH),
126.2 (s, CH), 124.2 (s, CH), 123.2 (s, CH), 109.9 (s, CH), 66.4 (s,
Cq), 32.0 (s, CH2), 27.4 (s, CH3). One Cq signal is overlapped or not
observed. 31P NMR (121.5 MHz, CDCl3): δ 37.8 (s). IR (cm−1): 1705
ν(CO) 1704 (s). HR-MS (+ESI): m/z calcd for C34H29NOPPd [M −
Cl]+ 604.1022, found 604.1031. Single crystals of 11, suitable for an X-
ray diffraction study, were obtained by slow diffusion of n-pentane into
a solution of 11 in dichloromethane. No satisfactory elemental analysis
could be obtained for this compound, probably due to its tendency to
crystallize with variable amounts of solvent. The bulk purity of this
compound was assessed by 1H, 13C, and 31P NMR, and the spectra are
provided in the Supporting Information.
Synthesis of Complex 2c·1/2H2O. Pd(dba)2 (524 mg, 0.911
mmol) and TMEDA (136 μL, 0.911 mmol) were added to a solution
of N-(2-iodophenyl)acrylamide 1 (331 mg, 0.911 mmol) in dry
CH2Cl2 (30 mL) in a Carius tube, under a nitrogen atmosphere. The
tube was sealed, and the mixture was stirred at room temperature for 3
h. The resulting solution was filtered over a Celite pad, the filtrate was
concentrated to ca. 3 mL, and Et2O (20 mL) was added. The
suspension was filtered, and the solid was washed with Et2O (2 × 5
mL) and air-dried to give compound 2c·1/2H2O as an orange solid.
Synthesis of Compound 12. An excess of a saturated solution of
HCl in dichloromethane (1 mL), prepared by bubbling HCl gas
through dichloromethane, was added to a solution of 4a (50 mg, 0.06
mmol) in commercial dichloromethane (15 mL). The resulting
mixture was stirred at room temperature for 16 h, and Et2O (15 mL)
was added. The suspension was filtered, and the solid was washed with
Et2O (2 × 3 mL) and air-dried to give [PdCl2(PPh3)] (10.5 mg, 0.015
mmol), which was identified by 31P NMR (δ 23 ppm (s)). The solvent
was removed from the filtrate, and the crude product was purified by
preparative TLC (silica gel, petroleum ether/EtOAc (10/1)) to give
compound 12 as a pale yellow oil. Yield: 8.3 mg, 0.04 mmol, 58%. 1H
NMR (300.1 MHz, CDCl3): δ 7.35 (dd, J = 7.8, 1.6 Hz, 1H), 7.30−
1
Yield: 341 mg, 0.573 mmol, 63%. Mp: 160 °C dec. H NMR (300.1
MHz, CDCl3): δ 8.17 (d, J = 7.5 Hz, 1H), 7.60 (d, J = 7.2 Hz, 1H),
7.28−7.14 (m, 5H), 7.10 (td, J = 7.5, 0.9 Hz, 1H), 6.77 (d, J = 7.8 Hz,
1H), 3.19 (s, 3H), 2.87 (d, J = 8.7 Hz, 1H), 2.67−2.31 (m, 14H), 2.11
(br s, 2H), 1.87 (d, J = 8.7 Hz, 1H). 13C NMR (100.8 MHz, CDCl3):
δ 180.0 (s, Cq), 143.9 (s, Cq), 143.5 (s, Cq), 135.7 (s, Cq), 127.7 (s,
CH), 127.3 (br s, CH), 127.2 (s, CH), 126.3 (s, CH), 121.4 (s, CH),
107.8 (s, CH), 62.0 (br s, CH2), 61.5 (s, Cq), 57.7 (br s, CH2), 52.6
(br s, CH3), 50.4 (br s, CH3), 49.3 (br s, CH3), 48.5 (br s, CH3), 26.6
(s, CH3), 18.2 (s, CH2). Some 13C signals are overlapped. IR (Nujol,
I
DOI: 10.1021/acs.organomet.7b00702
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Article
7.20 (m, 5H), 7.18−7.17 (m, 1H), 7.09 (td, J = 7.5, 0.9 Hz, 1H), 6.91
(d, J = 7.8 Hz, 1H), 3.24 (s, 3H), 1.79 (s, 3H). 13C NMR (75.4 MHz,
CDCl3): δ 179.4 (s, Cq), 143.2 (s, Cq), 140.8 (s, Cq), 134.8 (s, Cq),
128.5 (s, CH), 128.1 (s, CH), 127.2 (s, CH), 126.6 (s, CH), 124.2 (s,
CH), 122.7 (s, CH), 108.3 (s, CH), 52.1 (s, Cq), 26.5 (s, CH3), 23.7
(s, CH3). IR (Nujol, cm−1): 1716 ν(CO) (s). HR-MS (+ESI): m/z
calcd for C16H15NO [M + H]+ 238.1226, found 238.1234. These data
are in agreement with those reported previously in the literature.22
Thermal Decomposition of Complex 2c To Give Com-
pounds 12 and 13. A solution of complex 2c·1/2H2O (180 mg,
0.303 mmol) in CHCl3 (10 mL) was heated for 36 h under a nitrogen
atmosphere at 70 °C in a sealed Carius tube. The resulting suspension
was filtered through a Celite pad, and the solvent was removed from
the filtrate. The residue was purified by preparative TLC (silica gel,
petroleum ether/Et2O (11/1)) to give the compounds 12 (12 mg,
0.05 mmol, 16%) and 13 (23 mg, 0.065 mmol, 21%). Data for 13 are
Calcd for C23H30F3N3O4PdS·1/4CH2Cl2: C, 44.38; H, 4.89; N, 6.68;
S, 5.09. Found: C, 44.28; H, 4.93; N, 6.65; S, 5.07.
Synthesis of Compound 17. Dimethyl acetylenedicarboxylate
(7.5 μL, 0.06 mmol) was added to a solution of 4a (50 mg, 0.06
mmol) in dry dichloromethane (15 mL). The mixture was stirred at
room temperature for 16 h. The solvent was removed, and the residue
was purified by preparative TLC chromatography (silica gel, petroleum
ether/EtOAc 7/1) to afford compound 17 as a white solid. Mp: 76−
78 °C. Yield: 17.4 mg, 0.05 mmol, 77%. 1H NMR (300.1 MHz,
CDCl3): δ 7.33−7.31 (m, 1H), 7.29−7.22 (m, 4H), 6.96 (td, J = 7.8,
1.2 Hz, 1H), 6.91 (d, J = 7.5 Hz, 1H), 6.87−6.84 (m, 1H), 4.03 (s,
3H), 3.76 (s, 3H), 3.35 (s, 3H), 3.24 (d, J = 17.1 Hz, 1H), 2.94 (d, J =
17.1 Hz, 1H). 13C NMR (75.4 MHz, CDCl3): δ 179.3 (s, Cq), 169.5
(s, Cq), 166.7 (s, Cq), 142.6 (s, Cq), 142.2 (s, Cq), 137.2 (s, Cq), 133.5
(s, Cq), 132.3 (s, CH), 130.7 (s, Cq), 129.7 (s, CH), 129.3 (s, CH),
128.2 (s, CH), 127.0 (s, CH), 124.7 (s, CH), 124.3 (s, Cq), 124.2 (s,
CH), 109.6 (s, CH), 53.7 (s, CH3), 53.4 (s, CH3), 52.7(s, Cq), 33.7(s,
CH2), 27.6 (s, CH3). IR (Nujol, cm−1): 1722 ν(CO) (br). HRMS
(+ESI): m/z calcd for C22H20NO5 [M + H]+ 378.1336, found
1
as follows. Pale yellow oil. H NMR (300.1 MHz, CDCl3): δ 7.45−
7.39 (m, 4H), 7.33−7.27 (m, 3H), 7.19 (td, J = 7.5, 0.9 Hz, 1H), 6.93
(d, J = 7.8 Hz, 1H), 4.03 (d, J = 9.8 Hz, 1H), 3.77 (d, J = 9.8 Hz, 1H),
3.24 (s, 3H). 13C NMR (75.4 MHz, CDCl3): δ 176.1 (s, Cq), 144.0 (s,
Cq), 137.7 (s, Cq), 130.8 (s, Cq), 129.1 (s, CH), 128.8 (s, CH), 128.0
(s, CH), 127.1 (s, CH), 124.9 (s, CH), 122.7 (s, CH), 108.6 (s, CH),
56.6 (s, Cq), 26.5 (s, CH3), 10.5 (s, CH2). IR (Nujol, cm−1): ν(CO)
1697 (m). HRMS (+ESI): m/z calcd for C16H15INO [M + H]+
364.0193, found 364.0183. The bulk purity of the compound 13 was
1
378.1331. The bulk purity of the compound 17 was assessed by H
and 13C NMR, and the spectra are provided in the Supporting
Information.
Synthesis of Complex 18·1/2Et2O. A solution of xylyl isocyanide
(30 mg, 0.23 mmol) in dichloromethane (15 mL) was added dropwise
to a solution of 4a (200 mg, 0.23 mmol) in dichloromethane (20 mL),
and the mixture was stirred at room temperature for 16 h. The solvent
was removed under reduced pressure, and Et2O was added (15 mL).
The resulting mixture was stirred in a cold bath for 30 min. The
suspension was filtered, and the solid was washed with Et2O (2 × 3
mL) and air-dried to give complex 18·1/2Et2O as a yellow solid. Yield:
1
assessed by H and 13C NMR, and the spectra are provided in the
Supporting Information.
Synthesis of Complex 14b·1/2MeCN. AgOTf (18 mg, 0.068
mmol) was added to a solution of 2b (50 mg, 0.068 mmol) in CH3CN
(15 mL). The resulting mixture was stirred in the dark for 12 h. The
suspension was filtered through a Celite pad, the filtrate was
concentrated to ca. 2 mL, and Et2O (15 mL) was added. The
resulting suspension was filtered, and the solid was washed with Et2O
(2 × 5 mL) and air-dried to give complex 14b·1/2MeCN as an off-
1
129 mg, 0.17 mmol, 73%. Mp: 118−120 °C. H NMR (300.1 MHz,
CDCl3): δ 7.82 (td, J = 7.3, 1.5 Hz, 1H), 7.71−7.64 (m, 1H), 7.57 (dd,
J = 7.5, 1.0 Hz, 1H), 7.55−7.46 (m, 6H), 7.30−7.27 (m, 4H), 7.24−
7.23 (m, 3H), 7.21−7.20 (m, 1H), 7.17−7.15 (m, 2H), 7.04 (d, J = 7.5
Hz, 2H), 6.98 (dd, J = 7.5, 1.0 Hz, 1H), 6.95−6.91 (m, 1H), 6.87 (td, J
= 7.2, 1.2 Hz, 1H), 6.77 (d, J = 7.5 Hz, 1H), 6.59−6.55 (m, 1H), 3.22
(s, 3H), 2.36 (dd, J = 7.2, 1.2 Hz, 1H), 2.14 (s, 6H, Me, Xy), 1.76 (“t”,
J = 10.4 Hz, 1H). 13C NMR (100.8 MHz, CDCl3): δ 180.9 (s, Cq),
168.5 (s, Cq), 167.4 (s, Cq), 159.8 (s, Cq), 142.3 (s, Cq), 139.2 (s,
CH), 138.7 (s, Cq), 134.5 (s, Cq), 133.6 (d, J = 13.0 Hz, CH), 132.7
(d, J = 34.4 Hz, Cq‑ipso), 131.6 (d, J = 9.9 Hz, CH), 129.4 (s, CH),
128.3 (s, CH), 127.8 (d, J = 9.6 Hz, CH), 127.3 (s, CH), 125.8 (s,
CH), 124.7 (d, J = 8.3 Hz, CH), 123.8 (d, J = 7.4 Hz, CH), 122.5 (d, J
= 3.0 Hz, CH), 121.3 (s, CH), 106.6 (s, CH), 67.9 (d, J = 7.6 Hz, Cq),
65.3 (s, CH2, crystallization Et2O), 39.8 (d, J = 8.2 Hz, CH2), 25.7 (s,
CH3), 18.1 (s, CH3), 14.8 (s, CH3, crystallization Et2O). 31P NMR
(162.3 MHz, CDCl3): δ 23.3 (s). IR (Nujol, cm−1): ν(CN) 2147 (s),
ν(CO) 1708 (s). Anal. Calcd for C43H37N2OPPd·1/2Et2O: C, 69.99;
H, 5.48; N, 3.62. Found: C, 69.80; H, 5.33; N, 3.37.
white solid. Yield: 44 mg, 0.056 mmol, 82%. Mp: 155 °C dec. ΛM
=
117.0 Ω−1 cm2 mol−1. 1H NMR (400.9 MHz, acetone-d6): δ 8.68 (d, J
= 6.0 Hz, 1H), 8.62 (d, J = 1.6 Hz, 2H), 8.55 (d, J = 5.6 Hz, 1H),
7.78−7.73 (m, 4H), 7.41−7.34 (m, 4H), 7.32−7.26 (m, 1H), 7.19−
7.41 (br m, 2H), 3.51 (br s, 3H), 2.53 (br s, 2H), 2.15 (br s, 1.5H;
crystallization MeCN), 1.44 (s, 9H), 1.42 (s, 9H). 13C NMR (100.8
MHz, acetone-d6): δ 166.2 (s, Cq), 166.1 (s, Cq), 157.7 (s, Cq), 153.6
(s, Cq), 152.3 (s, CH), 149.2 (s, CH), 145.0 (s, Cq), 142.2 (s, Cq),
129.7 (s, CH), 129.2 (s, CH), 128.4 (s, CH), 127.3 (s, CH), 125.4 (s,
CH), 125.3 (s, CH), 122.2 (s, CH), 121.1 (s, CH), 36.6 (s, Cq), 36.5
(s, Cq), 30.3 (s, CH3), 30.2 (s, CH3). Some signals are overlapped or
not observed. IR (Nujol, cm−1): ν(CO) 1711 (s). Anal. Calcd for
C35H38F3N3O4PdS·1/2MeCN: C, 55.39; H, 5.06; N, 6.27; S, 4.10.
Found: C, 55.26; H, 4.69; N, 6.68; S, 4.38.
Synthesis of Complex 14c·1/4CH2Cl2. AgOTf (56 mg, 0.217
mmol) was added to a solution of 2c·1/2H2O (127 mg, 0.213 mmol)
in CH3CN (30 mL). The resulting mixture was stirred in the dark for
12 h. The suspension was filtered through a Celite pad, and the solvent
was removed from the filtrate under vacuum. The residue was
dissolved in CH2Cl2 (2 mL), and Et2O (10 mL) was added. The
resulting suspension was filtered, and the solid was washed with Et2O
(2 × 5 mL) and air-dried to give 14c·1/4CH2Cl2. Yield: 92 mg, 0.151
Synthesis of Complex 19. A solution of xylyl isocyanide (24 mg,
0.18 mmol) in dichloromethane (10 mL) was added dropwise to a
solution of 4a (50 mg, 0.06 mmol) in dichloromethane (15 mL), and
the mixture was stirred at room temperature for 16 h. The solvent was
partially removed from the mixture to leave ca. 2 mL, Et2O (15 mL)
was added, and the suspension was filtered to remove solid impurities.
The filtrate was concentrated to ca. 2 mL, and n-pentane (15 mL) was
added. The suspension was filtered, and the solid was washed with n-
pentane (2 × 5 mL) and air-dried to give 19 as a yellow solid. Yield: 20
mg, 0.03 mmol, 55%. Mp: 164−166 °C. 1H NMR (400.9 MHz,
CDCl3): δ 7.81 (dd, J = 7.6, 1.2 Hz, 1H), 7.54 (dd, J = 7.2, 0.8 Hz,
1H), 7.30−7.17 (m, 5H), 7.08 (d, J = 7.6 Hz, 2H), 7.01 (td, J = 7.6, 0.8
Hz, 1H), 6.94 (td, J = 7.2, 1.2 Hz, 1H), 6.87 (td, J = 7.2, 1.2 Hz, 1H),
6.85 (d, J = 7.6 Hz, 1H), 6.51 (dd, J = 7.6, 1.2 Hz, 1H). 3.29 (s, 3H),
2.64 (d, J = 10.4 Hz, 1H), 2.57 (s, 6H; Me, Xy), 2.36 (s, 6H; Me, Xy),
2.32 (d, J = 10.4 Hz, 1H). 13C NMR (100.8 MHz, CDCl3): δ 181.7 (s,
Cq), 165.8 (s, Cq), 160.3 (s, Cq), 142.8 (s, Cq), 140.2 (s, CH), 139.3
(s, Cq), 135.4 (s, CH), 135.1 (s, CH), 132.9 (s, Cq), 129.3 (s, Cq),
129.2 (s, Cq), 128.1 (s, CH), 127.9 (s, CH), 126.6 (s, CH), 125.2 (s,
CH), 124.5 (s, CH), 124.2 (s, CH), 122.9 (s, CH), 122.2 (s, CH),
107.2 (s, CH), 67.9 (s, Cq), 34.5 (s, CH2), 26.3 (s, CH3), 19.1 (s,
1
mmol, 68%. Mp: 151 °C dec. ΛM = 124.3 Ω−1 cm2 mol−1. H NMR
(400.9 MHz, CDCl3): δ 7.61−7.59 (m, 2H), 7.46−7.42 (m, 2H),
7.38−7.34 (m, 1H), 7.31 (dd, J = 7.6, 0.8 Hz, 1H), 7.27−7.25 (m,
1H), 7.16 (td, J = 7.6, 0.8 Hz, 1H), 6.92 (d, J = 8 Hz, 1H), 5.30 (s,
0.2H, crystallization CH2Cl2) 3.35 (s, 3H), 3.02−2.95 (m, 1H), 2.79−
2.77 (m, 1H), 2.73−2.2.71 (m partially obscured, 1H) 2.70 (s, 3H),
2.69 (s, 3H), 2.68 (s, 3H), 2.65−2.58 (m, 1H), 2.56 (s, 3H), 1.82 (d, J
= 8.4 Hz, 1H), 1.71 (d, J = 8.4 Hz, 1H). 13C NMR (100.8 MHz,
CDCl3): δ 194.5 (s, Cq), 143.6 (s, Cq), 141.3 (s, Cq), 134.1 (s, Cq),
129.2 (s, CH), 128.4 (s, CH), 128.0 (s, CH), 125.6 (s, CH), 125.5 (s,
CH), 123.5 (s, CH), 110.6 (s, CH), 66.5 (s, Cq), 64.3 (s, CH2), 57.4
(s, CH2), 53.4 (s, CH3), 51.7 (s, CH3), 48.7 (s, CH3), 47.3 (s, CH3),
27.3 (s, CH3), 21.4 (s, CH2). IR (Nujol, cm−1): ν(CO) 1600 (s). Anal.
J
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CH3), 18.8 (s, CH3). Some 13C signals are overlapped. IR (Nujol,
cm−1): ν(CN) 2167 (s), 2141, ν(CO) 1698 (s). Anal. Calcd for
C34H31N3OPd: C, 67.60; H, 5.17; N, 6.95. Found: C, 67.64; H, 5.27;
N, 6.82.
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Synthesis of Compound 20. PhI(OAc)2 (39 mg, 0.12 mmol)
was added to a solution of 4a (100 mg, 0.12 mmol) in
dichloromethane (25 mL), and the mixture was stirred at room
temperature for 16 h. The solvent was removed, and the residue was
purified by preparative TLC chromatography (silica gel, petroleum
ether/EtOAc 5/1) to provide compound 20 as a white solid. Yield: 21
mg, 0.09 mmol, 74%. Mp: 124−126 °C. 1H NMR (300.1 MHz,
CDCl3): δ 7.35−7.28 (m, 2H), 7.26−7.20 (m, 2H), 7.11 (ddd, J = 7.2,
1.2, 0.3 Hz, 1 H), 7.02 (td, J = 7.5, 0.9 Hz, 1H), 6.91−6.85 (m, 2H),
3.77 (d, J = 13.5 Hz, 1H), 3.46 (d, J = 13.5 Hz, 1H), 3.29 (s, 3H). 13C
NMR (75.4 MHz, CDCl3): δ 176.9 (s, Cq), 144.3 (s, Cq), 143.9 (s,
Cq), 143.8 (s, Cq), 130.6 (s, Cq), 128.8 (s, CH), 128.5 (s, CH), 128.0
(s, CH), 123.2 (s, CH), 123.0 (s, CH), 122.6 (s, CH), 121.6 (s, CH),
108.0 (s, CH), 55.8 (s, Cq), 42.8 (s, CH2), 26.5 (s, CH3). IR (Nujol,
cm−1): 1717 ν(CO) (s). HR-MS (+ESI): m/z calcd for C16H14NO [M
+ H]+ 236.107, found 236.1068. These data are in agreement with
those reported previously in the literature.23
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ASSOCIATED CONTENT
* Supporting Information
■
S
(4) (a) Grigg, R.; Fretwell, P.; Meerholtz, C.; Sridharan, V.
Tetrahedron 1994, 50, 359−370. (b) Metal catalyzed cascade reactions;
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.7b00702.
Muller, J. J. T., Ed.; Springer: Berlin, 2006; Topics in Organometallic
̈
Chemistry 19. (c) Ruck, R. T.; Huffman, M. A.; Kim, M. M.; Shevlin,
M.; Kandur, W. V.; Davies, I. W. Angew. Chem., Int. Ed. 2008, 47,
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A.; Wang, Q.; Neuville, L.; Zhu, J. Angew. Chem., Int. Ed. 2013, 52,
1H, 31P, and 13C-APT or 13C NMR spectra of the new
compounds, crystallographic data, and details of hydro-
gen bonds (including symmetry operators) (PDF)
Accession Codes
CCDC 1574286−1574289 contain the supplementary crystal-
lographic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
12385−12389. (h) Mehta, V. P.; García-Lop
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ez, J.−A. ChemCatChem
2017, 9, 1149−1156.
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(a) Fan, J.-H.; Wei, W.-T.; Zhou, M.-B.; Song, R.-J.; Li, J.-H. Angew.
Chem., Int. Ed. 2014, 53, 6650−6654. (b) Davis, D. C.; Walker, K. L.;
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AUTHOR INFORMATION
Corresponding Authors
*E-mail for M.L.: mlautens@chem.utoronto.ca.
*E-mail for J.-A.G.-L.: joangalo@um.es.
■
Ed. 2016, 55, 9714−9718. Qiu, Y.; Yang, B.; Zhu, C.; Backvall, J.-E.
̈
Angew. Chem., Int. Ed. 2016, 55, 6520−6524. (d) Frutos-Pedreno, R.;
̃
́
García-Lopez, J.-A. Adv. Synth. Catal. 2016, 358, 2692−2700.
(e) Petrone, D. A.; Franzoni, I.; Ye, J.; Rodríguez, J. F.; Poblador-
ORCID
Bahamonde, A. I.; Lautens, M. J. Am. Chem. Soc. 2017, 139, 3546−
3557. (f) Qiu, Y.; Yang, B.; Jiang, T.; Zhu, C.; Backvall, J.-E. Angew.
̈
Isabel Saura-Llamas: 0000-0001-8335-6747
Chem., Int. Ed. 2017, 56, 3221−3225.
Jose-Antonio García-Lopez: 0000-0002-8143-7081
́
́
́ ́ ́
(6) Perez-Gomez, M.; García-Lopez, J.-A. Angew. Chem., Int. Ed.
Notes
2016, 55, 14389−14393.
The authors declare no competing financial interest.
(7) (a) Yoon, H.; Lossouarn, A.; Landau, F.; Lautens, M. Org. Lett.
2016, 18, 6324−6327. (b) Yoon, H.; Rolz, M.; Landau, F.; Lautens, M.
̈
ACKNOWLEDGMENTS
Angew. Chem., Int. Ed. 2017, 56, 10920.
■
(8) Per
́ ́ ́
ez-Gomez, M.; Hernandez-Ponte, S.; Bautista, D.; García-
Financial support from MINECO (grant CTQ2015-69568-P)
Lopez, J.-A. Chem. Commun. 2017, 53, 2842−2845.
́
and Fundacion
́
Sen
́
eca (grant 19890/GERM/15) is gratefully
(9) (a) Zheng, H.; Zhu, Y.; Shi, Y. Angew. Chem., Int. Ed. 2014, 53,
11280−11284. (b) Shao, C.; Wu, Z.; Ji, X.; Zhou, B.; Zhang, Y. Chem.
Commun. 2017, 53, 10429.
acknowledged. M.L. thanks NSERC Canada, Alphora Inc., and
the University of Toronto for financial support. We thank Prof.
Vicente Soler, Dr. Ivan Franzoni, and Mr. Hyung Yoon for
useful comments and discussion.
(10) Ye, J.; Shi, Z.; Sperger, T.; Yasukawa, Y.; Kingston, C.;
Schoenebeck, F.; Lautens, M. Nat. Chem. 2016, 9, 361−368.
(11) (a) Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007,
46, 8748−8758. (b) Rottmann, M.; McNamara, C.; Yeung, B. K. S.;
Lee, M. C. S.; Zou, B.; Russell, B.; Seitz, P.; Plouffe, D. M.; Dharia, N.
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