Palladium-Mediated Functionalization of Benzofuran and Benzothiophene Cores

Article abstract of DOI:10.1021/acs.organomet.8b00682

The palladation reactions of 2-heteroaromatic primary phenethylamines bearing a benzofuran and benzothiophene nuclei have been studied. We have assessed the reactivity of the corresponding dimeric six-membered palladacycles (arising from C-H metalation) toward neutral ligands and unsaturated species. The insertion reactions of isocyanides into the Pd-C bond of the aforementioned palladacycles allowed the isolation of the corresponding iminoacyl intermediates, which could later be decomposed to give the amidine derivatives containing these relevant heterocyclic cores. In contrast, the carbonylation and alkenylation reactions led to straightforward formation of lactams and alkenylated organic derivatives. Interestingly, an unusual hydrogen-bond-promoted E-to-Z isomerization equilibrium of the resulting olefins was observed. Furthermore, we have studied the conditions to perform the alkenylation of the N-Boc derivatives of these substrates in a catalytic fashion. All the organometallic complexes (arising from the C-H activation of the heteroaromatic cores and insertion of isocyanides) and organic products (arising from the decomposition reactions) have been fully characterized, including the X-ray crystal structures of several organometallic and organic derivatives.

Full text of DOI:10.1021/acs.organomet.8b00682

Article
pubs.acs.org/Organometallics
Cite This: Organometallics XXXX, XXX, XXX−XXX
Palladium-Mediated Functionalization of Benzofuran and
Benzothiophene Cores
†
†
,†
́
́
́
́
́
Marta Perez-Gomez, Sergio Hernandez-Ponte, Jose Antonio García-Lopez,*
†
‡
,†
†
́
̃
Roberto Frutos-Pedreno, Delia Bautista, Isabel Saura-Llamas,* and Jose Vicente
†
́
́
Grupo de Química Organometalica, Departamento de Química Inorganica, Facultad de Química, Universidad de Murcia, 30100
Murcia, Spain
‡SAI, Universidad de Murcia, 30100 Murcia, Spain
S
* Supporting Information
ABSTRACT: The palladation reactions of 2-heteroaromatic primary
phenethylamines bearing a benzofuran and benzothiophene nuclei have
been studied. We have assessed the reactivity of the corresponding dimeric
six-membered palladacycles (arising from C−H metalation) toward neutral
ligands and unsaturated species. The insertion reactions of isocyanides into
the Pd−C bond of the aforementioned palladacycles allowed the isolation of
the corresponding iminoacyl intermediates, which could later be
decomposed to give the amidine derivatives containing these relevant
heterocyclic cores. In contrast, the carbonylation and alkenylation reactions
led to straightforward formation of lactams and alkenylated organic
derivatives. Interestingly, an unusual hydrogen-bond-promoted E-to-Z
isomerization equilibrium of the resulting olefins was observed. Furthermore, we have studied the conditions to perform the
alkenylation of the N-Boc derivatives of these substrates in a catalytic fashion. All the organometallic complexes (arising from
the C−H activation of the heteroaromatic cores and insertion of isocyanides) and organic products (arising from the
decomposition reactions) have been fully characterized, including the X-ray crystal structures of several organometallic and
organic derivatives.
neurotransmitters (i.e., dopamine or triptamine), amino acids
(i.e., phenylalanine or tryptophan), or marketed psychoactive
drugs (i.e., the phenethylamine scaffold family). For these
reasons, we set to study the functionalization of the benzofuran
and benzothiophene cores bearing a 2-ethylamino substituent
at the 3-position by means of a C−H palladation/
functionalization sequence.
To our knowledge, very few palladacycles derived from the
benzofuran or benzothiophene cores have been isolated, and
they are mainly metalated at the 3-position of the
heteroaromatic ring (see Chart 1 in the Experimental Section
for the numbering scheme). These examples included: (1) For
the benzofuran nucleus: (1a) C,N-,9 C,S-,10,11 or C,Se-five-
membered palladacycles10 metalated at the C3 position; and
(1b) C,N-six-membered palladacycles metalated at C3.12 (2)
For the benzothiophene nucleus: (2a) C,N-five-membered
palladacycles metalated at C3, where the nitrogen atom
belongs to an imine13 or a pyridine moiety,14 (2b) S,C,N-
pincer derivatives containing two five-membered rings,15 and
(3b) C,N-five- or six-membered palladacycles metalated at the
C2 position, being the nitrogen part of an imine fragment.12,16
In this article, we (1) describe the synthesis of
unprecedented palladacycles containing 2-aminoethyl-benzo-
INTRODUCTION
■
Heteroaromatic compounds occupy a privileged position
within the chemical sciences because of their numerous
applications in functional materials and medicinal chemistry.
More specifically, benzofuran and benzothiophene cores have
attracted great attention due to their widespread presence in
natural products, biologically active compounds, and pharma-
ceuticals.1 For instance, these nuclei are present in compounds
that exhibit anti-inflamatory, antimicrobial, antidepressant, or
anticancer activities to name a few. Some marketed drugs
include raloxifene, zileuton, or amiodarone.
The importance of these heteroaromatic cores has prompted
the development of synthetic methodologies to either
construct these scaffolds from different precursors or function-
alize the different positions within the heteroaromatic nuclei.
As happens in many other aspects of chemistry, transition-
metal-mediated or -catalyzed reactions constitute an extra-
ordinarily useful tool to achieve a wide structural diversity in
the substitution pattern of benzofuran and benzothiophene
cores. Palladium has proven especially versatile to perform a
broad range of cross-coupling reactions involving these
heteroaromatic scaffolds.2−6
We are particularly interested in the functionalization of
arene/heteroarene nuclei bearing a tethered 2-aminoethyl
moiety (ArCH2CH2NH2),7,8 since this type of structure is
present in many compounds with biological relevance, such as
Received: September 17, 2018
© XXXX American Chemical Society
A
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furan and benzothiophene and (2) study the reaction of the
new metallacycles with unsaturated molecules such as CO,
isocyanides, and alkenes. In all cases, decomposition of the
organometallic intermediates arising from the insertion of the
unsaturated species into the Pd−C bond afforded interesting
organic derivatives. Finally, we reported also the catalytic
alkenylation of the N-Boc protected starting amines.
(B·HCl) was reacted with Pd(OAc)2 in a 1:1 molar ratio, in
acetonitrile, at room temperature, to render HOAc and the
cyclometalated complex [Pd2{κ2C,N-(C8H4S)CH2CH2NH2-
3}2(μ-Cl)2]·2MeCN (2b·2MeCN; Scheme 2). Complex 2b·
Scheme 2. Synthesis of Cyclopalladated Derivatives of 2-
(Benzothiophene-3-yl)ethanamine
RESULTS AND DISCUSSION
■
Synthesis of the Cyclometalated Complexes Con-
taining the Benzofuran and Benzothiophene Cores.
The cyclopalladation of 2-(benzofuran-3-yl) and 2-(benzo-
thiophene-3-yl) ethanamines occurred under mild conditions,
if the appropriate starting materials were selected. In both
cases, the corresponding ammoniums salts (triflate for the
amine containing the benzofuran nucleus and chloride for the
benzothiophene core) underwent C−H activation at the 2-
position of the heteroaromatic ring when treated with
Pd(OAc) in acetonitrile, at room temperature.
2-(Benzofuran-3-yl)ethanaminium triflate (A·HOTf) re-
acted with Pd(OAc)2 in a 1:1 molar ratio to give HOAc and
the cyclometalated solvento-complex [Pd{κ2C,N-(C8H4O)-
CH2CH2NH2-3}(NCMe)2]OTf (1a; Scheme 1), which
2MeCN reacted with neutral ligands (L) in a 1:2 molar ratio to
give the mononuclear adducts [PdCl{κ2C,N-(C8H4S)CH2-
CH2NH2-3}(L)] (L = PPh3, 3b; 4-pic, 6b; tBuNC, 7b; XyNC,
8b; Scheme 2).
As mentioned in the Introduction, no palladacycles derived
from a primary arylalkylamine containing either the benzofuran
or the benzothiophene ring have been described previously.
Moreover, there are only two precedents of similar C,N-
palladacycles with the metal at the C3 position of the
benzothiophene ring, and in both cases, the nitrogen atom
belongs to an imine fragment.12,16
Scheme 1. Synthesis of Cyclopalladated Derivatives of 2-
(Benzofuran-3-yl)ethanamine
Structure of the Cyclometalated Complexes Contain-
ing the Benzofuran and Benzothiophene Cores. The 1H
and 13C{1H} NMR spectra of complexes 1a and 2a,b clearly
1
showed that cyclometalation had taken place. Thus, the H
NMR signal corresponding to H2 of the starting material (A·
HOTf: 7.88 (s); B·HCl: 7.59 (s) ppm) disappeared upon
metalation.
The crystal structures of complexes 3a·Et2O, 3b, 4a, 6b·1/
6CH2Cl2, 7b, and 8b·1/4CH2Cl2·1/4Et2O (Figures 1−6) have
been determined by X-ray diffraction. The asymmetric unit of
the crystal structures of complexes 6b·1/6CH2Cl2, 7b, and 8b·
1/4CH2Cl2·1/4Et2O contain two (8b) or three independent
molecules (6b and 7b), along with some crystallization solvent.
In all cases, the palladium center displayed a square-planar
geometry (almost perfect for 3a·Et2O, 7b, and 8b·1/4CH2Cl2·
1/4Et2O, and slightly distorted for 3b, 4a, 6b·1/6CH2Cl2).
The metal is coordinated to the carbon (C1) and nitrogen
(N1) atoms of the chelated arylalkylamino ligand, forming a
six-membered metallacycle with an envelope (4a, 6b·1/
6CH2Cl2, 7b, and 8b·1/4CH2Cl2·1/4Et2O) or a twist-boat
conformation (3a·Et2O, 3b). For complexes 3a·Et2O, 3b, 6b·
1/6CH2Cl2, 7b, and 8b·1/4CH2Cl2·1/4Et2O, the coordination
sphere of the metal is completed with a chloro (Cl1) and the
donor atom of a neutral ligand (P1, N11, C11A, or C12A). In
all cases, the monodentate ligands are placed in a trans position
to the NH2 group, which is the expected geometry according
to the transphobia scale for C-/N-donor, C-/P-donor, and C-/
C-donor pairs of ligands.17
further reacted with NaCl to afford a yellow solid that
precipitated from the reaction mixture. The IR and H NMR
1
spectra of this solid suggested the formulation [Pd2{κ2C,N-
(C8H4O)CH2CH2NH2-3}2(μ-Cl)2]·2MeCN (2a·2MeCN),
although other formulations cannot be ruled out. Complex
2a was obtained in analytically pure form by recrystallization of
2a·2MeCN from acetone. Complex 2a·2MeCN reacted with
PPh3 in a 1:2 molar ratio to give the mononuclear phosphino
adduct [PdCl{κ2C,N-(C8H4O)CH2CH2NH2-3}(PPh3)] (3a).
For the synthesis of cationic derivatives, complex 1a was used
as starting material. Thus, when 4-methyl-pyridine (4-pic) or
tBuNC was added to a solution of 1a (molar ratio 2:1) in
acetonitrile or CH2Cl2, the complex [Pd{κ2C,N-(C8H4O)CH2-
CH2NH2-3}(L)2]OTf was isolated in moderate to good yield
t
(L = 4-pic (4a; 62%), BuNC (5a; 74%); Scheme 1).
The availability of the crystal structures of four complexes
which only differed in the neutral ligand coordinated in the
trans position with respect to the amino group allows us to
To prepare analogous complexes containing the benzothio-
phene ring, 2-(benzothiophene-3-yl)ethanaminium chloride
B
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Figure 1. X-ray thermal ellipsoid plot of 3a·Et2O (50% probability)
along with the labeling scheme. The solvent molecule and the
hydrogen atoms bonded to carbon have been omitted for clarity.
Selected bond lengths (Å) and angles (deg): Pd(1)−N(1) =
2.1176(15), Pd(1)−Cl(1) = 2.3707(4), Pd(1)−P(1) = 2.2501(5),
Pd(1)−C(1) = 1.9656(17); N(1)−Pd(1)−Cl(1) = 84.55(4), Cl(1)−
Pd(1)−P(1) = 95.609(17), P(1)−Pd(1)−C(1) = 90.76(5), C(1)−
Pd(1)−N(1) = 88.99(7).
Figure 3. X-ray thermal ellipsoid plot of the cation of 4a (50%
probability) along with the labeling scheme. The hydrogen atoms
bonded to carbon have been omitted for clarity. Selected bond
lengths (Å) and angles (deg): Pd(1)−N(1) = 2.0565(13), Pd(1)−
N(11) = 2.1305(13), Pd(1)−N(21) = 2.0359(13), Pd(1)−C(1) =
1.9619(15); N(1)−Pd(1)−N(11) = 88.14(5), N(11)−Pd(1)−N(21)
= 91.10(5), N(21)−Pd(1)−C(1) = 91.76(6), C(1)−Pd(1)−N(1) =
89.01(6).
Figure 2. X-ray thermal ellipsoid plot of 3b (50% probability) along
with the labeling scheme. The hydrogen atoms bonded to carbon
have been omitted for clarity. Selected bond lengths (Å) and angles
(deg): Pd(1)−N(1) = 2.0994(11), Pd(1)−Cl(1) = 2.3699(4),
Pd(1)−P(1) = 2.2599(4), Pd(1)−C(1) = 1.9797(13); N(1)−
Pd(1)−Cl(1) = 86.66(3), Cl(1)−Pd(1)−P(1) = 92.029(15),
P(1)−Pd(1)−C(1) = 93.37(4), C(1)−Pd(1)−N(1) = 88.35(5).
Figure 4. X-ray thermal ellipsoid plot of one (molecule 1) of the three
independent molecules of the complex 6b·1/6CH2Cl2 (50%
probability) along with the labeling scheme. The crystallization
solvent and the hydrogen atoms bonded to carbon have been omitted
for clarity. Selected bond lengths (Å) and angles (deg): Pd(1)−N(1)
= 2.041(4), Pd(1)−Cl(1) = 2.4314(13), Pd(1)−N(11) = 2.051(4),
Pd(1)−C(1) = 1.991(5); N(1)−Pd(1)−Cl(1) = 86.35(12), Cl(1)−
Pd(1)−N(11) = 91.85(12), N(11)−Pd(1)−C(1) = 92.63(18),
C(1)−Pd(1)−N(1) = 89.27(18). X-ray thermal elipsoid plots and
selected bond lengths (Å) and angles (deg) for the other two
independent molecules present in the asymmetric unit (molecules 2
and 3) are given in the Supporting Information.
compare the Pd−N bond lengths (Table 1), which increased
along the sequence 6b·1/6CH2Cl2 < 7b ≈ 8b·1/4CH2Cl2·1/
4Et2O < 3b following the trend normally observed for the trans
influence of these ligands: N-donor < C(sp)-donor < P-
donor.18
In the cationic complex 4a, the metal completes its
coordination sphere with the nitrogen atoms (N11 and N22)
of two picoline ligands. Both pyridine rings are almost
perpendicular to the metal coordination plane (88.2° and
75.5°) to avoid steric hindrance. Similarly, for complex 6b·1/
6CH2Cl2, the aromatic ring of the 4-picoline is also rotated
with respect to the coordination plane of the metal (angle of
59−90°, for the three independent molecules in the
asymmetric unit). However, in complex 8b·1/4CH2Cl2, the
xylyl ring of the isocyanide ligand is almost coplanar with the
coordination plane of the metal (1° and 1.7° for both
molecules in the asymmetric unit). This feature allows the
existence of intermolecular π−π stacking interactions between
the C6H4 and Xy rings. The geometrical parameters of the π−π
interactions are given in the Supporting Information.
Stoichiometric Functionalization of 2-(Benzofuran-3-
yl)- and 2-(Benzothiophene-3-yl)ethanamines. The
pharmaceutical relevance of the benzofuran and benzothio-
phene cores has prompted the development of several
methodologies for the functionalization of these moieties via
transition-metal-mediated or -catalyzed reactions.19 Specially
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Unsaturated species, such as isocyanides, carbon monoxide,
and alkenes, readily insert into the Pd−C bond of aryl-
complexes to afford organometallic iminoacyl,21 acyl-,22 and
alkyl-derivatives23 or organic compounds upon further
decomposition.21,24 The accepted mechanism of these
insertion reactions into the Pd−C bond involves (1)
coordination of the unsaturated molecule to the metal center
and (2) migratory insertion of the aryl group to the
coordinated ligand.25,26 These organometallic intermediates
can be stable enough to be isolated or evolve through a
reductive elimination process to afford the corresponding
organic derivatives.21,24
We have previously applied this methodology (formation of
a Pd−C bond, reaction with an unsaturated molecule, and
decomposition of the formed organometallic compound) to
the stoichiometric synthesis of amidines and amidinium salts,
lactams, and alkenylated compounds derived from primary
benzyl and phenethylalkylamines.23,27,28 Noteworthy, for these
reactions, the catalytic cycle seems to fail, since ortho
palladation of primary arylalkylamines does not occur (or is
extremely slow) when an excess of the amine is present.7 Due
to their interesting properties, we sought to extend this
methodology to the synthesis of heteroarylalkyl amine
derivatives containing the benzofuran and benzothiophene
nuclei.
Insertion Reactions of Isocyanides into the Pd−C Bond.
The dimeric C,N-palladacycles reacted easily with RNC to
afford mononuclear complexes with the isocyanide ligand
coordinated in a cis position relative to the aryl group. Under
adequate reaction conditions (depending on the electronic and
steric properties of both the palladacycle and the isocya-
nide),21,26 these compounds could evolve to the corresponding
iminoacyl complexes, arising from the insertion of the
isocyanide into the C−Pd bond. In order to get one of such
complexes, we carried out the reaction of palladacycle 2b with
4 equiv of XyNC (molar ratio Pd:RNC = 1:2; Scheme 3).
When XyNC was added to a suspension of 2b in CH2Cl2 at
room temperature, an orange solution was observed, which
quickly changed its color to red, and then to yellow. From the
last solution, a yellow solid (X) could be isolated, that proved
to be a mixture of three products (by 1H NMR; Figure 7): the
coordination complex 8b, the iminoacyl complex 9b
(characterized by X-ray studies, see below), and [Pd2Cl2-
(CNXy)4] (which showed a very characteristic signal at δ 2.52
ppm). The latter compound was the only one isolated when
additional XyNC (4 equiv) was added to the original yellow
solution.27,29
As we have stated in the previous section, complex 8b could
be isolated in good yield by reacting the starting palladacycle 2·
2MeCN with 2 equiv of XyNC at 0 °C (Scheme 1; 74%). At
higher temperatures, a variable amount of di-inserted complex
9b was always obtained. The easy insertion of the isocyanide
into the Pd−C bond of 8b resembles the behavior of the
reported palladacycle derived from benzyl methyl sulfide,30
which underwent rapid isocyanide insertion at room temper-
ature. However, all of our attempts to isolate pure complex 9b
were fruitless. Thus, the reaction of complex 8b with 1 equiv of
XyNC (under different experimental conditions; Scheme 4)
always afforded a mixture of complexes 8b, 9b, and
[Pd2Cl2(CNXy)4] (4:2:1, after 48 h at room temperature).
Slow diffusion of Et2O into a solution of this mixture in
CH2Cl2 led to the formation of two different types of crystals,
which were manually separated: yellow needles, corresponding
Figure 5. X-ray thermal ellipsoid plot of one (molecule 1) of the three
independent molecules of the complex 7b (50% probability) along
with the labeling scheme. The hydrogen atoms bonded to carbon
have been omitted for clarity. Selected bond lengths (Å) and angles
(deg): Pd(1)−N(1A) = 2.0659(19), Pd(1)−Cl(1A) = 2.3984(5),
Pd(1)−C(11A) = 1.943(2), Pd(1)−C(1A) = 1.985(2); N(1A)−
Pd(1)−Cl(1A) = 88.21(5), Cl(1A)−Pd(1)−C(11A) = 87.78(6),
C(11A)−Pd(1)−C(1A) = 94.01(9), C(1A)−Pd(1)−N(1A) =
90.00(8). X-ray thermal elipsoid plots and selected bond lengths
(Å) and angles (deg) for the other two independent molecules
present in the asymmetric unit (molecules 2 and 3) are given in the
Supporting Information.
Figure 6. X-ray thermal ellipsoid plot of one (molecule A) of the two
independent molecules of the complex 8b·1/4CH2Cl2·1/4Et2O (50%
probability) along with the labeling scheme. The crystallization
solvent and the hydrogen atoms bonded to carbon have been omitted
for clarity. Selected bond lengths (Å) and angles (deg): Pd(1A)−
N(1A) = 2.0609(16), Pd(1A)−Cl(1A) = 2.4073(5), Pd(1A)−
C(12A) = 1.9439(18), Pd(1A)−C(1A) = 1.9900(17); N(1A)−
Pd(1A)−Cl(1A) = 86.56(5), Cl(1A)−Pd(1A)−C(12A) = 90.51(5),
C(12A)−Pd(1A)−C(1A) = 93.62(7), C(1A)−Pd(1A)−N(1A) =
89.28(7). X-ray thermal elipsoid plot and selected bond lengths (Å)
and angles (deg) for the other independent molecule present in the
asymmetric unit (molecule B) are given in the Supporting
Information.
interesting are those transformations involving the direct
functionalization of a C−H bond of the heteroaromatic
core,5,6,20 via the formation of an M−C bond that subsequently
reacts with a coupling partner, for instance, an unsaturated
molecule.
D
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Table 1. Selected Bond Lengths (Å) and Angles (deg) within the Coordination Sphere of Pd(II) for Complexes 3a·Et2O, 3b,
6b·1/6CH2Cl2, 7b, and 8b·1/4CH2Cl2·1/4Et2O
bond lengths (Å)
Pd−C(1)
angles (deg)
compound
3a·Et2O (L = P1)
3b (L = P1)
6b·1/6CH2Cl2 (L = N11)
7b (L = C11)
8b·1/4CH2Cl2·1/4Et2O (L = C12)
Pd−N(1)
Pd−L
Pd−Cl(1)
C(1)−Pd−N(1)
2.1176(15)
2.0994(11)
2.041(4)
2.0659(19)
2.0609(16)
1.9656(17)
1.9797(13)
1.991(5)
2.2501(5)
2.2599(4)
2.051(4)
2.3707(4)
2.3699(4)
2.4314(13)
2.3984(5)
2.4073(5)
88.99(7)
88.35(5)
89.27(18)
90.00(8)
89.28(7)
1.985(2)
1.943(2)
1.9900(17)
1.9439(18)
Scheme 3. Reaction of XyNC with the Palladacycle Derived
from 2-(Benzothiophene-3-yl)ethanamine
to complex 8b, and a few orange blocks, corresponding to the
iminoacyl complex 9b, whose crystal structure was determined
by X-ray diffraction studies (Figure 8). The seven-membered
metallacycle adopted a twist-boat conformation. The palladium
center was coordinated to Cl (Cl1), the NH2 group (N1), the
terminal carbon atom of the isocyanide ligand (C12), and the
carbon atom of the inserted isocyanide (C11), in a slightly
distorted square-planar geometry (mean deviation from the
coordination plane of Pd(II), 0.043 Å). Both Xy rings are
almost parallel (angle between planes of 8°), and rotated 54.7°
and 62.3° with respect to the Pd(II) coordination plane,
avoiding steric hindrance. Similar features are observed in
related iminoacyl derivatives.28 The discrete molecules of
complex 9b are associated through N−H···Cl hydrogen bonds,
giving dimers (details, including symmetry operations are given
in the Supporting Information).
1
Figure 7. H NMR spectra (1−5 ppm; CDCl3) of (a) the iminoacyl
complex 9b (signals denoted by red circles); (b) the yellow solid X,
obtained by reaction of complex 2b and 4 equiv of XyNC; and (c)
complex 8b (signals denoted by blue triangles). The green square
corresponds to the signal of [Pd2Cl2(CNXy)4], and the black asterisks
indicate the resonances corresponding to traces of solvents.
AgOTf (OTf = O3SCF3) and heated in toluene, the amidinium
salt 10b was obtained (50% yield; Scheme 4), along with
metallic palladium. The NMR spectra of compound 10b were
in agreement with the proposed structure. Additionally, the
crystal structure of 10b was determined by X-ray diffraction
studies (Figure 9). It corresponded to the Z isomer, reflecting
the thermodynamic stability of this geometry. The six-
membered aza-ring adopted a twisted boat conformation,
and the atoms C(10), N(1), C(11), N(2), and C(12) were
almost coplanar (mean deviation from the plane 0.021 Å).
Delocalization of electron density between the atoms N(1),
C(11), and N(2) was confirmed by the similar N(1)−C(11)
and N(2)−C(11) bond distances (1.324(4) and 1.323(4) Å,
respectively) and the angles around both nitrogen atoms
(C(10)−N(1)−C(11), 121.8(3)°; C(11)−N(2)−C(12),
128.9(3)°). In compound 10b, the cationic units were
connected between them and to the triflate groups through
hydrogen bonds, giving layers (see the Supporting Informa-
tion).
The 1H NMR of the collected orange blocks, which
happened not to be completely separable, corresponded to a
mixture of complex 9b and [Pd2Cl2(CNXy)4]. In complex 9b,
steric hindrance prevents rotation around the Xy−N bond of
the inserted isocyanide, and the two Me groups become
unequivalent, as well as the meta protons and the meta and
ortho carbon atoms of the xylyl ring (as observed in its 1H and
13C{1H} NMR spectra).
Our original goal was to employ the iminoacyl complex 9b
to obtain the corresponding amidinium salt, via thermal
depalladation. However, as we could not develop an adequate
synthesis for 9b, we tried an alternative method to prepare this
type of N-heterocycle derivative. When complex 7b, which
t
contained coordinated BuNC, an isocyanide less prone than
XyNC to undergo polyinsertion reactions, was treated with
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Scheme 4. Insertion of RNC into the Pd−C Bond of
Cyclopalladated Derivatives of 2-(Benzofuran-3-yl) and 2-
(Benzothiophene-3-yl)ethanamines
Figure 9. X-ray thermal ellipsoid plot of the cation of compound 10b
(50% probability) along with the labeling scheme. The hydrogen
atoms bonded to carbon have been omitted for clarity. Selected bond
lengths (Å) and angles (deg): N2−C12 = 1.500(4), N2−C11 =
1.315(2), N1−C11 = 1.323(4), N1−C10 = 1.475(4), C1−C11 =
1.460(4); C11−N2−C12 = 128.9(3), C11−N1−C10 = 121.8(3),
N1−C11−N2 = 124.6(3), N1−C11−C1 = 115.4(3), N2−C11−C1 =
120.0(3).
Scheme 5. Insertion of CO into the Pd−C Bond of
Cyclopalladated Derivatives of 2-(Benzofuran-3-yl) and 2-
(Benzothiophene-3-yl)ethanamines
Figure 8. X-ray thermal ellipsoid plot of 9b (50% probability) along
with the labeling scheme. The hydrogen atoms bonded to carbon
have been omitted for clarity. Selected bond lengths (Å) and angles
(deg): Pd(1)−Cl(1) = 2.4026(8), Pd(1)−N(1) = 2.106(2), Pd(1)−
C(11) = 2.002(3), Pd(1)−C(12) = 1.929(3), C(11)−N(2) =
1.273(4), C(12)−N(3) = 1.154(4); Cl(1)−Pd(1)−N(1) =
90.02(7), N(1)−Pd(1)−C(11) = 86.37(10), C(11)−Pd(1)−C(12)
= 89.28(11), C(12)−Pd(1)−Cl(1) = 94.47(8), C(1)−C(11)−N(2)
= 116.3(2), C(11)−N(2)−C(21) = 124.3(2), Pd(1)−C(11)−N(2) =
126.8(2), Pd(1)−C(12)−N(3) = 179.7(3), C(12)−N(3)−C(31) =
171.7(3).
The compounds 11a and 11b were characterized by IR and
NMR spectroscopy and high-resolution mass spectrometry
(HR-ESIMS). The NMR data supported the structures of
these compounds, depicted in Scheme 5. The 1H NMR spectra
of both lactams exhibited one signal between 6.40 and 6.72
ppm (δ: 6.72 (11a), 6.46 ppm (11b)), corresponding to the
NH proton. In the 13C{1H} NMR spectra, the CO group
appeared between 161 and 164 ppm (δ: 161.2 (11a), 163.9
ppm (11b)). In addition, the IR spectra of both compounds
showed bands in the region of 1652−1685 cm−1, attributed to
ν(CO).
To prepare the N-heterocycles derived from the benzofuran
ring, the cationic complex 5a was a more effective starting
material. Complex 5a, heated in toluene at 120 °C for ca. 18 h,
evolved to the amidinium salt 10a and metallic palladium
(Scheme 4).
Insertion of Carbon Monoxide into the Pd−C Bond. The
reaction of 2b, in CH2Cl2 at 65 °C, with CO in the presence of
NEt3, afforded Pd(0), HNEt3Cl, and 3,4-dihydro[1]-
benzothieno[2,3-c]pyridin-1(2H)-one (11b; Scheme 5) in
moderate yields (54%). The NEt3 played a double role in
the reaction: it coordinated to Pd(II), improving the solubility
of the starting material, and reacted with the HCl formed
during the coupling process.
Chapman et al. reported the synthesis of lactam 11b in 1970
through cyclization of N-ethoxycarbonyl-2-(3-benzo[b]-
thienyl)ethanamine with P2O5 and POCl3 (Bischler−Napier-
alski reaction), although no NMR data were provided.31
Curiously, in spite of its structural interest, no other synthesis
has been published since then. To our knowledge, no synthesis
of compound 11a has been reported.
Insertion of Methyl Acrylate into the Pd−C Bond. When
complex 1a reacted with methyl acrylate (molar ratio 1:4) in
CHCl3, at 65 °C for 18 h, decomposition to metallic palladium
took place and the alkenyl derivative E-12a was isolated in
moderate yield (56%; Scheme 6). In acetone solution, E-12a
underwent an isomerization process to render a mixture of E-
To prepare the lactam derived from the benzofuran ring, the
cationic complex 1a was used as starting material. The
solvento-complex 1a reacted with CO and NEt3 in CHCl3
for ca. 18 h to afford 11a and metallic palladium (Scheme 5).
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insolubility in the reaction media (CHCl3), as isomerization
took place in solution (acetone) at room temperature. Both
isomers were distinguished by a NOESY experiment carried
out on the mixture E/Z-12a, which showed a correlation
between the hydrogen atoms of the double bond for the Z
isomer (Scheme 6). No correlation was observed for the E
isomer.
Scheme 6. Insertion of Methyl Acrylate into the Pd−C Bond
of the Palladacycles Derived from 2-(Benzofuran-3-yl) and
2-(Benzothiophene-3-yl)ethanamines
For disubstituted alkenes, generally E isomers are more
stable than Z isomers,32 and are also the standard outcome
products of the Heck-coupling reactions.33 Thus, this isomer-
ization seemed surprising. We developed optimized 3D
molecular structures for the cations of E- and Z-12a with the
software Spartan 14 (Figure 11), and the model predicted the
12a and Z-12a (final ratio E-12a:Z-12a ca. 1:3, after 18 h at 65
°C; Scheme 6 and Figure 10). The isolation of the E isomer,
the kinetically favored product, could be attributed to its
Figure 11. Optimized 3D molecular models obtained with the
software Spartan 14 for the cation of (a) E- and (b) Z-12a. In Z-12a,
the possible hydrogen bonds involving the NH3 group are depicted as
dashed green lines.
E isomer to be ca. 29.6 kJ mol−1 more stable than the Z form.
However, the proximity of the OMe substituent on the alkenyl
moiety to the NH3 group in Z-12a could lead to the formation
of hydrogen bonds, which would stabilize this configuration.
Noteworthy, the 1H NMR spectra of both isomers in acetone-
d6 were quite similar, although the CH2N group in Z-12a
appeared at higher frequencies than the one of E-12a (Z-12a:
4.24 ppm; E-12a: δ 3.59−3.69 ppm), which supported the
existence of hydrogen bond involving the adjacent NH3 group
in the former. Unfortunately, the NH3 groups were not
1
observed in the H NMR after some time in acetone solution.
A logical reaction pathway for the isomerization (Scheme 7)
would involve: (1) proton transfer from the ammonium group
to the carbonyl moiety, rendering a carbocation that could be
stabilized by the benzofuranyl group; (2) rotation of the σ C−
C bond; and (3) regeneration of the ammonium group and
restoration of the double CC bond with Z configuration. We
have described a similar E to Z isomerization process
promoted by intramolecular hydrogen bond interactions.34
We tried an analogous alkenylation with the palladacycle
containing the benzothiophene core. Thus, we carried out the
reaction between complex 2b·2MeCN and AgOTf, and after
removing the AgCl formed, we added methyl acrylate (molar
ratio Pd:alkene 1:2) and heated the mixture in CHCl3, at 65
°C for 48 h. In the reaction media, the alkenyl derivative E-12b
1
Figure 10. H NMR spectra (6.3−8.1 ppm; acetone-d6) of complex
12a: (a) the crude of the reaction (only E isomer); (b) recrystallized
product from acetone/Et2O (2:1 mixture of E/Z isomers); (c) after
ca. 4 h at room temperature dissolved in acetone-d6 (1:1 mixture of
E/Z isomers); (d) after 18 h at 65 °C dissolved in acetone-d6 (1:3
mixture of E/Z isomers). The red and blue circles correspond to the
alkenylic protons of the E and Z isomers, respectively. Spectra a, b,
and c were recorded in a 300 Mz spectrometer, while spectrum d was
recorded in a 400 Mz spectrometer.
1
(identified by H NMR in acetone-d6) precipitated along with
metallic palladium. Similarly to what happened to E-12a, in
acetone solution, E-12b isomerizated to render a mixture of E-
12b and Z-12b (final ratio E-12b:Z-12b ca. 1:1.3, after 24 h at
65 °C; Scheme 6). This process was slower for 12b than for
12a, likely due to the nature of the heteroatom in the ring.
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Scheme 7. Proposed Mechanism for the Isomerization of
12a
Scheme 8. Synthesis of N-Boc Derivatives
Scheme 9. Optimized Conditions for the 2-Alkenylation of
a
Substrates 13
Catalytic Alkenylation of N-Substituted Derivatives
of 2-(Benzofuran-3-yl)- and 2-(Benzothiophene-3-yl)-
ethanamine. The Pd-catalyzed arylation and alkynylation at
the C2 position of benzofuran and benzothiophene nuclei
assisted by suitable directing groups (such as carboxylic acids
or thioamides at the 3-position of the heteroarene) have been
reported.4,5,35 Nevertheless, there are no precedents for related
directed alkenylation. Furthermore, none of the published
studies include substrates containing a tethered directing
amino group at the 3-position of the heterocycle. Notwith-
standing, the strong coordination ability of primary amines to
Pd hampers the development of catalytic methodologies of
substrates containing alkyl-NH2 moieties as directing groups.7
Only some specific aryl substrates bearing bulky alkyl groups
on the primary amine have been successfully functionalized
under Pd-catalysis.36 On the other hand, the nondirected Pd-
catalyzed alkenylation at the C2 position of benzothiophene
and benzofuran rings via oxidative coupling with olefins has
indeed been reported to occur in a range of different
conditions.3,6 In order to attempt the catalytic alkenylation
of the 3-aminoethyl-substituted benzofuran and benzothio-
phene cores, we converted the amines A and B into their
corresponding N-Boc derivatives 13a and 13b (Boc = tert-
butoxycarbonyl; Scheme 8).
We attempted the Pd-catalyzed C−H alkenylation of
substrate 13a in a range of different conditions (see the SI).
A 77% yield of the alkenylated product 14a was obtained when
the reaction was carried out using a 10 mol % of Pd(OAc)2 in
1,2-dichloroethane at 100 °C in the presence of 2 equiv of
Cu(OAc)2 as the oxidant and 2 equiv of methyl acrylate
(Scheme 9). Other combinations of solvents (MeCN, HOAc,
or toluene) and oxidants (AgOAc or 1,4-benzoquinone)
afforded lower yields of the desired compound 14a. The
catalytic alkenylation of substrate 13b worked better using
acetonitrile as solvent instead of 1,2-dichloroethane. The yields
of these catalytic transformations are comparable to those
reported for the undirected alkenylation of benzofuran and
benzothiophene cores.3,6
a
For 13a, solvent = 1,2-dichloroethane, and for 13b, solvent =
acetonitrile. The reported yields were determined by 1H NMR, using
an internal standard.
CONCLUSION
■
In conclusion, we have investigated the functionalization of
benzothiophene and benzofuran cores bearing a tethered
aminoethyl moiety, through the palladation of the C−H bond
at the C2 position of the ring. The palladation reactions,
assisted by the coordination of the pending primary amine
moiety, take place under mild conditions if the appropriate
ammonium salts were used as starting materials. The insertion
reactions of isocyanides and carbon monoxide into the Pd−C
bond of the six-membered palladacycles led, upon decom-
position of the organometallic intermediates formed, to cyclic
amidines and lactams. Under the right conditions, the
iminoacyl intermediates arising from the reactions with
isocyanides could be isolated. The alkenylation of the starting
substrates was studied stoichiometrically, and later carried out
catalytically for the N-Boc protected amines. Interestingly, the
isolated E-alkenylated products arising from the Heck-type
coupling reactions on the cyclopalladated primary amines
evolved to the Z isomers in acetone solution.
EXPERIMENTAL SECTION
■
General Considerations, Materials, and Instrumentation.
Unless otherwise noted, all preparations were carried out at room
temperature under atmospheric conditions. Synthesis grade solvents
were obtained from commercial sources. All other reagents were
obtained from commercial sources and used as received.
H
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Unless otherwise stated, NMR spectra were recorded in CDCl3 on
Bruker Avance 300 or 400 spectrometers at 298 K. Chemical shifts are
DMSO-d6): δ 3.12 (br s, 2 H, CH2N), 3.17−3.22 (m, 2 H, CH2Ar),
7.40 (m, 2 H, H5 + H6), 7.59 (s, 1 H, H2), 7.90 (m, 1 H, H4), 7.98
(m, 1 H, H7), 8.35 (br s, 3 H, NH3). 13C{1H} NMR (75.5 MHz,
DMSO-d6): δ 25.9 (s, CH2Ar), 38.2 (s, CH2N), 121.6 (s, CH4) 123.0
(s, CH7), 123.9 (s, CH2), 124.2 (s, CH5), 124.5 (s, CH6), 131.7 (s,
C3), 138.3 (s, C3a) 139.7 (s, C7a).
1
referenced to internal TMS. Signals in the H and 13C{1H} NMR
spectra of all complexes were assigned with the help of APT, HMQC,
and HMBC techniques. The groups 2-(benzofuran-3-yl)ethanamine
and 2-(benzo[b]thiophen-3-yl)ethanamine are denoted by Ar or by
C8H4O and C8H4S, respectively. Inserted and coordinated XyNC are
denoted by XyNCi and XyNCc, respectively. Melting points were
determined on a Reichert apparatus and are uncorrected. Con-
ductivities were measured with a Crison Micro CM2200 conduc-
tometer. Elemental analyses were carried out with a Carlo Erba 1106
microanalyzer. Infrared spectra were recorded in the range 4000−200
cm−1 on a PerkinElmer Spectrum 100 spectrophotometer, using
Nujol mulls between polyethylene sheets. High resolution ESI mass
spectra were recorded on an Agilent 6220 Accurate-Mass TOF LC/
MS.
Synthesis of [Pd{κ2(C,N-(C8H4O)CH2CH2NH2-3}(NCMe)2]OTf
(1a). A solution of A·HOTf (500 mg, 1.61 mmol) in CH3CN (15
mL) was added to a solution of Pd(OAc)2 (360 mg, 1.61 mmol) in
CH3CN (10 mL), and the resulting mixture was stirred at room
temperature overnight. The mixture was filtered through a plug of
Celite, the filtrate was concentrated to ca. 1 mL without heating, and
Et2O was added (25 mL). The suspension was filtered, and the solid
was washed with Et2O (2 × 5 mL) and air-dried to afford complex 1a
as a yellow solid. Yield: 700 mg, 1.40 mmol, 87%. Anal. Calcd for
C15H16F3N3O4SPd (497.79 g/mol): C, 36.19; H, 3.24; N, 8.44; S,
6.44. Found: C, 36.41; H, 3.15; N, 8.35; S, 6.45. Mp: 108 °C. ΛM
(Ω−1 cm2 mol−1): 113 (5.0 × 10−4 M in acetone). IR (cm−1): ν(NH)
3270 s, 3233 s, 3156 s; ν(CN) 2337 m, 2320 m, 2309 m, 2292 m. 1H
NMR (400.9 MHz, DMSO-d6): δ 2.37 (s, 6 H, MeCN), 2.67−2.69
(m, 2 H, CH2N), 2.81 (“t”, 2 H, CH2Ar, 3JHH = 5.6 Hz), 4.98 (br s, 2
H, NH2), 7.10−7.13 (m, 2 H, H5 + H6), 7.39−7.41 (m, 1 H, H4),
7.44−7.46 (m, 1 H, H7). 13C{1H} NMR (100.8 MHz, DMSO-d6): δ
1.1 (s, Me), 23.1 (s, CH2Ar), 40.9 (s, CH2N), 110.0 (s, CH7), 115.4
Chart 1 gives the numbering schemes for the new palladacycles and
the organic derivatives.
Chart 1. Numbering Schemes for the New Palladium(II)
a
Complexes and the Organic Derivatives
1
(s, C3), 117.4 (s, CH4), 120.7 (q, CF3SO3, JCF = 317.2 Hz), 121.8
(s, CH6 or CH5), 122.2 (s, CH6 or CH5), 128.1 (s, C3a), 149.0 (br
s, C2), 156.3 (s, C7a). 19F NMR (282.4 MHz): δ −78.02 (CF3SO3).
Synthesis of [Pd2(μ-Cl)2{κ2(C,N-(C8H4O)CH2CH2NH2-3}2]·
2MeCN (2a·2MeCN). The ammonium triflate A·HOTf (500 mg,
1.606 mmol) was added to a suspension of Pd(OAc)2 (366 mg, 1.630
mmol) in CH3CN (50 mL). The resulting mixture was stirred at
room temperature overnight and filtered over a plug of Celite.
NaHCO3 (1 g, 11.90 mmol) was added to the filtrate; the resulting
suspension was stirred for 1 h and then filtered over a plug of Celite.
NaCl (1 g, 17.11 mmol) was added to the filtrate, and the suspension
was stirred for 1 h. The solvent was removed from the mixture to ca.
10 mL, and the suspension was filtered. The solid was washed with
H2O (3 × 5 mL) and Et2O (3 × 5 mL) and air-dried to give a first
crop of complex 2a·2MeCN as a pale yellow solid (140 mg). The
filtrate was concentrated to ca. 5 mL and H2O (3 mL) was added.
The suspension was filtered and the solid was washed with H2O (3 ×
5 mL) and Et2O (3 × 5 mL) and air-dried to give a second crop of
complex 2a·2MeCN as a pale yellow solid (280 mg). Yield: 420 mg,
0.61 mmol, 76%. An analytically pure sample of complex 2a was
obtained by recrystallization from acetone/CH2Cl2. Anal. Calcd for
C20H20Cl2N2O2Pd2 (604.098 g/mol): C, 39.76; H, 3.34; N, 4.64.
Found: C, 39.86; H, 3.23; N, 4.59. Dec pt: 180 °C. IR (cm−1):
ν(NH) 3313 m, 3297 m, 3248 s, 3228 m; δ(NH2) 1578 m. NMR data
a
For the convenience of the reader, the notation of the free ligands is
maintained in the cyclopalladated complexes.
Synthesis of (C8H5O)CH2CH2NH3OTf (A·HOTf). Trifluorome-
thanesulfonic acid (547 μL, 6.20 mmol) was added dropwise to a cold
solution of 2-(benzofuran-3-yl)ethanamine (1000 mg, 6.20 mmol) in
ether (20 mL) in an ice bath. The suspension was stirred for 10 min at
0 °C and filtered. The solid was washed with Et2O (2 × 5 mL) and
air-dried to afford A·HOTf as a colorless solid. Yield: 1708 mg, 5.49
mmol, 88%. Anal. Calcd for C11H12F3NO4S (311.277 g/mol): C,
42.44; H, 3.89; N, 4.50; S, 10.30. Found: C, 42.55; H, 3.98; N, 4.38;
S, 10.32. Mp: 165 °C. ΛM (Ω−1 cm2 mol−1): 114 (5.0 × 10−4 M in
acetone). IR (cm−1): ν(NH) 3202 br, vs 1H NMR (300.1 MHz,
3
DMSO-d6): δ 2.94 (t, 2 H, CH2Ar, JHH = 6.9 Hz), 3.13 (m, 2 H,
CH2N), 7.31 (m, 2 H, H6 + H5), 7.56−7.59 (m, 1 H, H4), 7.66−7.69
(m, 1 H, H7), 7.76 (br s, 3 H, NH3), 7.88 (s, 1 H, H2). 13C{1H}
NMR (100.8 MHz, DMSO-d6): δ 21.3 (s, CH2Ar), 38.2 (s, CH2N),
111.4 (s, CH4), 115.5 (s, C3), 119.6 (s, CH7), 120.6 (q, CF3SO3,
1JCF = 319.4 Hz), 122.6 (s, CH2), 124.5 (s, CH5), 127.3 (s, C3a),
143.0.3 (s, CH6), 154.8 (s, C7a).
1
for 2a·2MeCN: H NMR (300.1 MHz, DMSO-d6): δ 2.06 (s, 3 H,
Synthesis of (C8H5S)CH2CH2NH3Cl (B·HCl). Under a nitrogen
atmosphere, a Carius tube was charged with 3-cyanomethyl-
benzothiophene (2.5 g, 14.4 mmol), dry THF (15 mL), and BH3·
THF (20 mL of solution 1 M in TFH, 20 mmol), and the mixture was
stirred at room temperature for 3.5 h. The reaction mixture was
cooled to 0 °C in an ice bath, and methanol was added dropwise until
bubbling stopped (ca. 20 mL). The solvent was removed, aqueous
HCl (40 mL of solution 0.5 M) was added to the residue, and the
mixture was heated at 100 °C for 1 h. The solvent was evaporated to
ca. 20 mL, and the resulting suspension was washed with Et2O (2 ×
30 mL). The aqueous phase was basified with NaOH (solution 1 M)
until pH = 12, and extracted with ethyl acetate (2 × 20 mL). The
organic layers were combined, the solvent was removed, and
concentrated HCl was added (5 mL). The water was removed, a
4:1 mixture of Et2O/acetone (30 mL) was added to the residue, and
the suspension was vigorously stirred. The suspension was filtered,
and the solid was washed with a 4:1 mixture of Et2O/acetone (3 × 5
mL) and vacuum-dried to give B·HCl as a colorless solid, which was
stored protected from moisture. Yield: 1.82 g, 8.52 mmol, 59%. Anal.
Calcd for C10H12ClNS (213.73 g/mol): C, 56.20; H, 5.66; N, 6.55; S,
15.00. Found: C, 56.30; H, 5.74; N, 6.44; S, 14.97. Mp: 204 °C. IR
3
MeCN), 2.63 (m, 2 H, CH2N), 2.77 (“t”, 2 H, CH2Ar, JHH = 5.4
Hz), 4.88 (br s, 2 H, NH2), 7.05−7.14 (m, 2 H, C6H4), 7.32−7.35
(m, 2 H, C6H4). 13C{1H} NMR (75.5 MHz, DMSO-d6): δ 1.1 (s,
MeCN), 22.9 (s, CH2Ar), 39.8 (s, CH2N, partially obscured by the
signal corresponding to the DMSO-d6), 109.9 (s, CH), 113.6 (s, C3),
117.2 (s, CH), 121.4 (s, CH), 121.7 (s, CH), 128.6 (s, C3a), 156.2 (s,
C7a), 157.1 (s, C2). The 13C{1H} signal corresponding to the CN
group was not observed.
Synthesis of [Pd2(μ-Cl)2{κ2(C,N-(C8H4S)CH2CH2NH2-3}2]·
2MeCN (2b·2MeCN). The ammonium salt B·HCl (525 mg, 2.34
mmol) was added to a suspension of Pd(OAc)2 (500 mg, 2.34 mmol)
in acetonitrile (50 mL), and the mixture was stirred for 24 h. A yellow
precipitate was slowly formed. The suspension was filtered, and the
solid was washed with Et2O (2 × 3 mL) and dried under vacuum to
afford the complex 2b·2MeCN as a yellow solid. Yield: 689 mg, 0.96
mmol, 82%. Anal. Calcd for C20H20Cl2N2Pd2S2·2CH3CN (718.334 g/
mol): C, 40.13; H, 3.65; N, 7.80; S, 8.93. Found: C, 40.02; H, 3.62;
N, 7.72; S, 9.05. Mp: 210 °C. IR (cm−1): ν(NH) 3207 s, 3133 s;
1
ν(CN) 2318 m, 2290 w; δ(NH2) 1595 m; ν(Pd−Cl) 318 m. H
NMR (300.1 MHz, DMSO-d6): 2.06 (s, 3 H, MeCN), 2.65 (br s, 2 H,
(cm−1): ν(NH) 3340 br; δ(NH2) 1603 m. H NMR (300.1 MHz,
CH2N), 2.91 (“t”, 2 H, CH2Ar, 3JHH = 5.4 Hz), 4.60 (br s, 2 H, NH2),
1
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7.05 (b t, 1 H, H6, 3JHH = 7.2 Hz) 7.15 (b t, 1 H, H5, 3JHH = 7.2 Hz),
ΛM (Ω−1 cm2 mol−1): 120 (5.0 × 10−4 M in acetone). IR (cm−1):
ν(NH) 3291 m, 3216 m, 3146 s; ν(CN) 1618 s, 1595 s. 1H NMR
(400.9 MHz, acetone-d6): δ 2.40 (s, 3 H, Me), 2.45 (s, 3 H, Me),
2.96−3.03 (m, 4 H, CH2N + CH2Ar), 4.63 (br s, 2 H, NH2), 6.95−
7.08 (m, 3 H, H5 + H6 + H7), 7.34 (dd, 1 H, H4, 3JHH = 6.8 Hz, 3JHH
= 0.8 Hz), 7.43 (d, 4 H, m-H, pic, 3JHH = 6.0 Hz), 8.70 (d, 2 H, o-H,
3
3
7.47 (br d, 1 H, H4, JHH = 7.8 Hz), 7.65 (br d, 1 H, H7, JHH = 7.8
Hz). 13C{1H} NMR (75.5 MHz, DMSO-d6): δ 1.1 (s, Me, MeCN),
28.4 (s, CH2Ar), 41.1 (s, CH2N), 119.0 (s, CH4), 120.7 (s, CH7),
121.1 (s, CH6), 122.2 (s, CH5), 126.6 (s, C3), 132.5 (C2), 138.7 (s,
C3a), 143.2 (s, C7a).
Synthesis of [Pd{κ2(C,N-(C8H4O)CH2CH2NH2-3}Cl(PPh3)]·Et2O
(3a·Et2O). PPh3 (115 mg, 0.438 mmol) was added to a suspension of
2a·2MeCN (150 mg, 0.218 mmol) in CH2Cl2 (10 mL), and the
mixture was stirred for 15 min at room temperature. The solution was
filtered through a plug of MgSO4, solvent was removed from the
filtrate to ca. 2 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 afford 3a·Et2O as a pale yellow solid. Yield: 212 mg, 0.332
mmol, 76%. Anal. Calcd for C28H25ClNOPPd·C4H10O (638.464 g/
mol): C, 60.20; H, 5.53; N, 2.19. Found: C, 60.14; H, 5.52; N, 2.04.
pic, JHH = 5.6 Hz), 8.81 (d, 2 H, o-H, pic, JHH = 6.4 Hz). 13C{1H}
NMR (100.8 MHz, acetone-d6): δ 20.9 (s, Me, pic), 21.0 (s, Me, pic),
24.2 (s, CH2), 42.3 (s, CH2), 110.4 (s, CH5 or CH7), 115.2 (s, C3 or
C3a), 117.8 (s, CH4), 122.0 (s, CH5 or CH7), 122.2 (s, CH6), 122.2
(q, CF3SO3, 1JCF = 319.4 Hz), 127.4 (s, m-CH, pic), 127.6 (s, m-CH,
pic), 129.9 (s, C3 or C3a), 150.8 (s, o-CH, pic), 152.5 (s, C−Me,
pic), 152.9 (s, o-CH, pic), 156.2 (S, C2), 157.9 (s, C7a).
3
3
Synthesis of [Pd{κ2(C,N-(C8H4O)CH2CH2NH2-3}(CNtBu)2]OTf
t
(5a). A solution of BuNC (68 μL, 0.60 mmol) in CH2Cl2 (15 mL)
was added dropwise to a solution of 1a in CH2Cl2 (10 mL), and the
mixture was stirred at room temperature for 2 h. The suspension was
filtered through a plug of Celite, the filtrate was concentrated to ca. 2
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 afford 5a
as a light yellow solid. Yield: 129 mg, 0.22 mmol, 74%. Anal. Calcd for
C21H29F3N3O4SPd (581.08 g/mol): C, 43.34; H, 4.85; N, 7.22; S,
5.51. Found: C, 43.20; H, 4.90; N, 7.17; S, 5.64. Mp: 135 °C (dec).
ΛM (Ω−1 cm2 mol−1): 128 (5.0 × 10−4 M in acetone). IR (cm−1):
1
Mp: 208 °C (dec). IR (cm−1): ν(NH) 3248 w, 3211 m, 3124 m. H
3
NMR (400.9 MHz): δ 1.25 (t, 6 H, MeCH2O, JHH = 7.2 Hz), 2.93
(“t”, 2 H, CH2Ar, 3JHH = 5.6 Hz), 3.06 (m, 2 H, CH2N), 3.52 (q, 4 H,
CH2O, 3JHH = 7.2 Hz), 3.53 (br s, 2 H, obscured by the signal of the
3
CH2O, NH2), 6.55 (d, 1 H, H7, JHH = 8.0 Hz), 6.88 (td, 1 H, H6,
4
3
4
3JHH = 7.6, JHH = 1.2 Hz), 7.04 (td, 1 H, H5, JHH = 7.4, JHH = 0.8
Hz), 7.27−7.35 (m, 7 H, H4 + m-H of PPh3), 7.36−7.43 (m, 3 H, p-
H, PPh3), 7.66−7.75 (m, 6 H, o-H, PPh3). 13C{1H} NMR (100.8
MHz): δ 15.2 (s, MeCH2O), 24.6 (s, CH2Ar), 40.0 (s, CH2N), 65.8
(s, CH2O), 109.5 (s, CH7), 114.7 (s, C3), 116.5 (s, CH4), 121.0 (s,
CH5), 121.2 (s, CH6), 127.8 (d, m-CH, PPh3, 3JCP = 11.0 Hz), 128.7
1
ν(NH) 3235 s, 3152 m; ν(CN) 2243 s. H NMR (400.9 MHz): δ
1.63 (s, 9 H, tBu), 1.70 (s, 9 H, tBu), 2.93 (t, 2 H, CH2Ar, 3JHH = 6.0
Hz), 3.04−3.08 (m, 2 H, CH2N), 4.22 (br s, 2 H, NH2), 7.15−7.17
(m, 2 H, H6 + H7), 7.27−7.29 (m, 1 H, H5), 7.38−7.40 (m, 1 H,
4
(s, C3a), 130.2 (s, p-CH, PPh3, JCP = 2.0 Hz), 131.6 (d, i-C, PPh3,
t
H4). 13C{1H} NMR (75.5 MHz): δ 23.7 (s, CH2Ar), 29.8 (s, Bu),
1JCP = 53.1 Hz), 134.5 (d, o-CH, PPh3, JPH = 11.6 Hz), 156.4 (d,
2
29.9 (s, tBu), 40.6 (s, CH2N), 109.8 (s, CH5), 116.1 (s, C3), 117.9 (s,
CH4), 121.7 (s, CH7), 122.8 (s, CH6), 127.8 (s, C3a), 157.4 (s,
C7a), 160.9 (s, C2). The 13C{1H} signal corresponding to the OTf
group was not observed. 19F NMR (282.4 MHz): δ −77.9 (s, OTf).
Synthesis of [Pd{κ2(C,N-(C8H4S)CH2CH2NH2-3}Cl(4-pic)] (6b).
4-Picoline (135 μL, 1.39 mmol) was added to a suspension of 2·
2MeCN (500 mg, 0.70 mmol) in CH2Cl2 (40 mL), and the resulting
mixture was stirred for 30 min. The solution was filtered through a
plug of MgSO4, the filtrate was concentrated to ca. 3 mL, and Et2O
(30 mL) was added. The suspension was filtered, and the solid was
washed with Et2O (2 × 3 mL) and dried under vacuum to give
complex 6b as a pale yellow solid. Yield: 423 mg, 1.03 mmol, 72%.
Anal. Calcd for C16H17ClN2PdS (411.244 g/mol): C, 46.73; H, 4.17;
N, 6.81; S, 7.80. Found: C, 46.43; H, 4.19; N, 6.56; S, 7.68. Dec pt:
218 °C. IR (cm−1): ν(NH) 3252 m, 3191 m, 3123 m; ν(CN) 1616
C7a, JCP = 3.5 Hz), 158.3 (d, C2, JCP = 5.3 Hz). 31P{1H} NMR
(162.3 MHz): δ 38.9 (s, PPh3). Single crystals suitable for an X-ray
diffraction study were obtained by slow diffusion of Et2O into a
solution of 3a·Et2O in CH2Cl2.
4
3
Synthesis of [Pd{κ2(C,N-(C8H4S)CH2CH2NH2-3}Cl(PPh3)]·Et2O
(3b). PPh3 (100 mg, 0.38 mmol) was added to a suspension of 2b·
2MeCN (130 mg, 0.18 mmol) in CH2Cl2 (30 mL), and the resulting
mixture was stirred for 30 min. The solution was filtered through a
plug of MgSO4, the filtrate was concentrated to ca. 3 mL, and n-
pentane (30 mL) was added. The suspension was filtered, and the
solid was washed with n-pentane (2 × 3 mL) and dried under vacuum
to obtain complex 3b as a yellow solid. Yield: 136 mg, 0.23 mmol,
65%. Anal. Calcd for C28H25ClNPPdS (580.406 g/mol): C, 57.94; H,
4.34; N, 2.41; S, 5.52. Found: C, 57.88; H, 4.45; N, 2.47; S, 5.56. Mp:
1
164 °C. IR (cm−1): ν(NH) 3240 m, 3200 m, 3060 m. H NMR
1
(400.9 MHz): δ 2.75 (m, 2 H, CH2N), 3.22 (“t”, 2 H, CH2Ar, 3JHH
5.6 Hz), 3.48 (m, 2 H, NH2), 7.00 (ddd, 1 H, H6, 3JHH = 8.0, 3JHH
7.2, 4JHH = 1.2 Hz), 7.19 (ddd, 1 H, H5, 3JHH = 8.0, 3JHH = 7.2, 4JHH
=
=
=
m. H NMR (300.1 MHz): δ 2.17 (s, 3 H, Me), 3.03−3.11 (m, 4 H,
CH2N + CH2Ar), 4.19 (br s, 2 H, NH2), 6.37 (d, 2 H, m-H, pic, 3JHH
= 6.0 Hz), 7.19 (m, 1 H, H6), 7.30 (m, 1 H, H5), 7.52 (d, 1 H, H4,
3JHH = 8.1 Hz), 7.63 (d, 1 H, H7, 3JHH = 7.8 Hz), 8.24 (“d”, 2 H, o-H,
pic, 3JHH = 6.6 Hz). 13C{1H} NMR (75.5 MHz): δ 21.0 (s, Me), 28.4
(s, CH2Ar), 41.4 (s, CH2N), 119.5 (s, CH4), 121.4 (s, CH7), 122.1
(s, CH6), 123.2 (s, CH5), 125.6 (s, m-CH, pic), 128.6 (s, C3), 134.3
(s, C2), 139.6 (s, C3a), 142.1 (s, C7a), 150.0 (s, p-C, pic), 152.7 (s, o-
CH, pic). Single crystals suitable for an X-ray diffraction study were
obtained by slow diffusion of Et2O into a solution of 6b in CH2Cl2.
Synthesis of [Pd{κ2(C,N-(C8H4S)CH2CH2NH2-3}Cl(CNtBu)]
1.2 Hz), 7.29−7.34 (m, 6 H, m-H, PPh3), 7.37−7.40 (m, 3 H, p-H,
PPh3), 7.42 (“d”, 1 H, H7, 3JHH = 8.0 Hz), 7.55 (“d”, 1 H, H4, 3JHH
=
8.0 Hz), 7.61−7.65 (m, 6 H, o-H, PPh3). 13C{1H} NMR (75.5 MHz):
3
δ 31.5 (s, CH2Ar), 37.5 (d, CH2N, JPC = 6.3 Hz), 119.1 (s, CH4),
121.1 (s, CH6), 121.4 (s, CH7), 122.7 (s, CH5), 128.1 (d, m-CH,
PPh3, 3JPC = 11.0 Hz), 129.3 (s, C3), 130.6 (d, p-CH, PPh3, 4JPC = 2.0
Hz), 130.9 (d, i-C, PPh3, 1JPC = 52.5 Hz), 134.8 (d, o-CH, PPh3, 2JPC
4
= 11.6 Hz), 138.3 (s, C2), 143.6 (s, C3a), 144.1 (d, C7a, JPC = 2.7
t
Hz). 31P{1H} NMR (162.3 MHz): δ 34.6 (s, PPh3). Single crystals
suitable for an X-ray diffraction study were obtained by slow diffusion
of n-pentane into a solution of 3b in CHCl3.
(7b). A solution of BuNC (62.9 μL, 0.56 mmol) in CH2Cl2 (15
mL) was added dropwise (ca. 15 min) to a suspension of 2·2MeCN
(200 mg, 0.28 mmol) in CH2Cl2 (15 mL). The resulting yellow
solution was stirred for 15 min and filtered through a plug of MgSO4.
The filtrate was concentrated, without heating, to ca. 1 mL, and Et2O
(20 mL) was added. A colorless solid appeared when the solvent from
the mixture was evaporated to ca. 5 mL. Et2O (15 mL) was added,
and the resulting suspension was filtered, and the solid was washed
with cold Et2O (2 × 3 mL) and air-dried, to give a first crop of
complex 7b as a colorless solid (133 mg). The filtrate was
concentrated to ca. 5 mL, the resulting suspension was filtered, and
the solid was washed with cold Et2O (2 × 3 mL) and air-dried to give
a second crop of complex 7b as a colorless solid (52 mg). Yield: 185
mg, 0.46 mmol, 83%. Anal. Calcd for C19H19ClN2PdS (401.248 g/
mol): C, 44.90; H, 4.77; N, 6.98; S, 7.99. Found: C, 44.88; H, 4.74;
Synthesis of [Pd{κ2(C,N-(C8H4O)CH2CH2NH2-3}(4-pic)2]OTf
(4a). The ammonium triflate A·HOTf (125 mg, 0.40 mmol) was
added to a solution of Pd(OAc)2 (90 mg, 0.40 mmol) in CH3CN (50
mL). The resulting mixture was stirred at room temperature
overnight. 4-Picoline (80 μL, 0.80 mmol) was added and the solution
was stirred at room temperature for 2 h. The suspension was filtered
through a plug of Celite, the filtrate was concentrated to ca. 1 mL, and
Et2O (25 mL) was added. The suspension was filtered, and the solid
was washed with Et2O (2 × 5 mL) and air-dried to afford 4a as a pale
yellow solid. Yield: 150 mg, 0.25 mmol, 62%. Anal. Calcd for
C23H24F3N3O4SPd (601.05 g/mol): C, 45.89; H, 4.02; N, 6.98; S,
5.33. Found: C, 45.87; H, 4.10; N, 6.88; S, 5.35. Mp: 180 °C (dec).
J
DOI: 10.1021/acs.organomet.8b00682
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
N, 6.79; S, 7.86. Mp: 120 °C. IR (cm−1): ν(NH) 3250 s, 3202 m,
3130 m; ν(CN) 2213 vs 1H NMR (300.1 MHz): δ 1.36 (s, 9 H, Me,
H, Xyi), 6.62 (“d”, 2 H, m-H, Xyi, 3JHH = 6.4 Hz), 7.02 (“d”, 2 H, m-H,
3
Xyc, JHH = 7.6 Hz), 7.13−7.20 (m, 1 H, p-H, Xyc), 7.38−7.45 (m, 2
H, H5 + H6), 7.82−7.87 (m, 2 H, H4 + H7). 13C{1H} NMR (100.8
MHz): δ 18.6 (s, Me, Xyc), 19.4 (s, Me, Xyi), 30.4 (s, CH2Ar), 41.7
(s, CH2N), 121.9 (s, CH4), 122.6 (s, CH7), 123.5 (s, p-CH, Xyi),
124.2 (s, CH5), 126.4 (s, CH6), 127.0 (s, C−Me, Xyi), 127.7 (s, m-
CH, Xyc), 127.8 (s, m-CH, Xyi), 129.5 (s, p-CH, Xyc), 133.2 (s, C3),
135.3 (s, C−Me, Xyc), 139.6 (s, C3a), 141.3 (s, C7a), 141.8 (s, C2),
151.8 (s, i-C, Xyi), 167.0 (s, CN). The signals corresponding to the
CN group and the i-C of the coordinated isocyanide were not
observed. Single crystals of 9b suitable for an X-ray diffraction study
were obtained by slow diffusion of Et2O into a solution of C in
CH2Cl2.
3
tBu), 2.98 (m, 2 H, CH2N), 3.10 (“t”, 2 H, CH2Ar, JHH = 5.1 Hz),
3.79 (br s, 2 H, NH2), 7.19 (m, 1 H, H6), 7.27 (m, 1 H, H5), 7.58 (d,
3
3
1 H, H4, JHH = 7.8 Hz), 7.75 (d, 1 H, H7, JHH = 7.8 Hz). 13C{1H}
t
NMR (75.5 MHz): δ 28.7 (s, CH2Ar), 29.5 (s, Me, Bu), 40.7 (s,
CH2N), 58.5 (s, CMe3), 119.7 (s, CH4), 121.1 (s, CH7), 122.2 (s,
CH6), 123.1 (s, CH5), 127.5 (s, C3), 132.7 (s, C2), 138.7 (s, C3a),
143.3 (s, C7a). The signal corresponding to the CN group of the
coordinated isocyanide was not observed. Single crystals suitable for
an X-ray diffraction study were obtained by slow diffusion of n-
pentane into a solution of 7b in Et2O.
Synthesis of [Pd{κ2(C,N-(C8H4S)CH2CH2NH2-3}Cl(CNXy)] (8b).
A solution of XyNC (86 mg, 0.66 mmol) in CH2Cl2 (10 mL) was
added dropwise (ca. 7 min) to a suspension of 2·2MeCN (240 mg,
0.33 mmol) in CH2Cl2 (10 mL) at −15 °C. The resulting solution
was stirred for 3 min at −15 °C and filtered through a plug of MgSO4.
The filtrate was concentrated under vacuum, without heating, to ca. 1
mL, and Et2O (20 mL) was added. The resulting suspension was
filtered, and the solid was washed with Et2O (2 × 3 mL) and air-dried
to give a first crop of complex 8b as a colorless solid (205 mg). The
filtrate was concentrated to ca. 5 mL, the resulting suspension was
filtered, and the solid was washed with cold Et2O (2 × 3 mL) and air-
dried to give a second crop of complex 8b as a colorless solid (22
mg). Yield: 227 mg, 0.51 mmol, 76%. Anal. Calcd for C19H19ClN2PdS
(449.292 g/mol): C, 50.79; H, 4.26; N, 6.23; S, 7.14. Found: C,
50.84; H, 4.26; N, 6.12; S, 7.15. Mp: 193 °C. IR (cm−1): ν(NH) 3272
Synthesis of N-(3,4-Dihydrobenzofuran[2,3-c]pyridin-1(2H)-
ylidene)butan-1-aminium Triflate (10a). A solution of 5a (90 mg,
0.15 mmol) in toluene was stirred at 120 °C overnight in a Carius
tube. The suspension was filtered through a plug of Celite, the solvent
was removed from the filtrate, and the residue was dried under
vacuum to give the compound 10a as a yellow oil. Yield: 18 mg, 0.04
mmol, 29%. ESI-HRMS: calcd for C15H19N2O [(M − OTf)+]
1
243.1492, found 243.1488. IR (cm−1): ν(NH) 3270 m br. H NMR
(400.9 MHz): 1.54 (s, 9 H, tBu), 3.03 (t, 2 H, CH2Ar, 3JHH = 7.6 Hz),
3.93 (t, 2 H, CH2N, 3JHH = 8.0 Hz), 7.07 (br s, 1 H, NH), 7.32 (br t,
3
1 H, H5, 3JHH = 8.4 Hz), 7.47 (ddd, 1 H, H6, JHH = 8.0, 3JHH = 7.2,
4JHH = 1.2 Hz), 7.57−7.59 (m, 2 H, H4 + H7), 8.42 (br s, 1 H, NH).
t
13C{1H} NMR (100.8 MHz): δ 18.9 (s, CH2Ar), 27.9 (s, Me, Bu),
41.0 (s, CH2N), 112.5 (s, CH7), 121.6 (q, CF3SO3, 1JCF = 319.0 Hz),
121.3 (s, CH4), 124.8 (s, CH5), 127.8 (s, C3), 129.3 (s, CH6), 137.8
(s, C2), 148.9 (s, C3a), 156.2 (s, C7a).
1
m, 3203 m, 3132 m; ν(CN) 2192 s. H NMR (400.9 MHz): δ 2.41
(s, 6 H, Me, Xy), 3.04 (m, 2 H, CH2N), 3.13 (“t”, 2 H, CH2Ar, 3JHH
=
4.8 Hz), 3.90 (br s, 2 H, NH2), 7.00 (d, 2 H, m-H, Xy, 3JHH = 7.6 Hz),
7.07 (m, 1 H, H6), 7.15 (m, 1 H, H5), 7.16 (t, 1 H, p-H, Xy, 3JHH
Synthesis of N-(3,4-Dihydrobenzothiophen[2,3-c]pyridin-
1(2H)-ylidene)butan-1-aminium Triflate (10b). AgOTf (58 mg,
0.22 mmol) was added to a solution of complex 7b (90 mg, 0.22
mmol) in CHCl3 (30 mL). The mixture was protected from light and
stirred for 24 h. The suspension was filtered through a plug of MgSO4,
and the yellow filtrate was refluxed for 72 h. Decomposition to
metallic palladium was observed. The solvent was eliminated from the
mixture, and acetone (20 mL) was added to the residue. The
suspension was filtered to remove the metallic palladium. The
solution was filtered again through a plug of MgSO4, the filtrate was
concentrated to ca. 1 mL, and Et2O (15 mL) was added. The solvent
was completely removed, and Et2O (15 mL) was added to the
residue. The mixture was stirred for 24 h, the suspension was filtered,
and the solid was air-dried to give crude compound 10b as an off-
white solid (46 mg). Pure complex 10b was obtained by preparative
TLC, in silica gel with a fluorescent indicator. The solid was dissolved
in acetone (2 mL), and a 9:1 mixture of CH2Cl2/MeOH was used as
eluent. The second least retained fraction was collected. The product
was extracted from the silica gel using a 8:1 mixture of CH2Cl2/
MeOH. The solvent was removed, acetone (15 mL) was added to the
residue, the resulting suspension was filtered, and the solvent was
removed from the filtrate to afford pure compound 10b as a colorless
solid. Yield (crude 10b): 46 mg, 0.11 mmol, 50%. Mp: 160 °C. IR
(cm−1): ν(NH) 3256 s; ν(CN) 1627 s, 1574 s. ESI-HRMS:
calculated exact mass for C15H19N2S, 259.1269 [(M − CF3SO3)+];
=
8.0 Hz), 7.45 (“d”, 1 H, H4, 3JHH = 8.0 Hz), 7.62 (“d”, 1 H, H7, 3JHH
= 7.4 Hz). 13C{1H} NMR (100.8 MHz): δ 19.0 (s, Me, Xy), 28.7 (s,
CH2Ar), 40.7 (s, CH2N), 119.4 (s, CH4), 121.0 (s, CH7), 122.3 (s,
CH6), 123.2 (s, CH5), 125.8 (br s, i-C, Xy), 127.4 (s, C3), 127.9 (s,
m-CH, Xy), 129.7 (s, p-CH, Xy), 132.8 (s, C2), 136.3 (s, C−Me, Xy),
138.3 (s, C3a), 140.1 (s, CN), 143.4 (s, C7a). Single crystals of 8b·1/
4CH2Cl2·1/4Et2O suitable for an X-ray diffraction study were
obtained by slow diffusion of Et2O into a solution of 8b in CH2Cl2.
Synthesis of [Pd{κ2(C,N-(C(NXy)C8H4S)CH2CH2NH2-3}Cl-
(CNXy)] (9b). A solution of XyNC (42 mg, 0.32 mmol) in CH2Cl2
(5 mL) was added dropwise (ca. 8 min) to a solution of complex 8b
(150 mg, 0.33 mmol) in CH2Cl2 (10 mL) at 0 °C. The mixture was
stirred at 0 °C for 1.5 h. Several changes in its color were observed
until eventually it turned yellow. An aliquot (ca. 1 mL) was extracted
from the reaction, the solvent was removed, and the residue was
dissolved in CDCl3. The 1H NMR spectrum of this solid proved it to
be a mixture of 8b (the starting material) and 9b (4:1 ratio). The
1
reaction mixture was stirred at room temperature for 20 h. The H
NMR analysis of a new aliquot showed a similar mixture to the
previous one (ratio 8b/9b = 2:1). After 24 h more, this ratio did not
change. The solution was concentrated to ca. 2 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 a yellow solid
C (121 mg). The 1H NMR of this solid proved it to be a mixture ca.
4:2:1 of complexes 8b, 9b, and [Pd2Cl2(NCXy)4]. This yellow solid C
was dissolved in CH2Cl2 (6 mL), the solution was distributed in three
test tubes, and Et2O was slowly added to them (Et2O/CH2Cl2 ratio =
4:1). After 48 h, the formation of two types of crystals was observed:
pale yellow needles and yellow-orange blocks. Both types of crystals
were manually separated with the help of a glass capillary. The yellow
needles corresponded to complex 8b previously characterized. The
yellow-orange blocks corresponded to complex 9b, whose crystalline
structure could be determined by X-ray diffraction studies. Enough
orange crystals were collected to register their 1H and 13C{1H} NMR
spectra. Apart from complex 8b, the sample also contained small
amounts of [PdCl2(CNXy)41]. The NMR data of complex 9b were
extracted from the mixture. H NMR (400.9 MHz): δ 2.12 (s, 6 H,
Me, Xyc), 2.19 (s, 6 H, Me, Xyi), 3.05 (m, 2 H, NH2), 3.30 (m, 2 H,
CH2N), 4.31 (“t”, 2 H, CH2Ar, 3JHH = 5.6 Hz), 6.77−6.85 (m, 1 H, p-
1
t
found, 259.1268. H NMR (300.1 MHz): δ 1.65 (s, 9 H, Me, Bu),
3
3
3.35 (t, 2 H, CH2N, JHH = 7.2 Hz), 4.03 (br t, 2 H, CH2Ar, JHH
=
7.2 Hz), 7.61 (m, 2 H, H7 + H6), 8.05 (m, 1 H, H4), 8.10 (m, 1 H,
H5), 8.10 (br s, 1 H, NH, overlapped with H5), 8.70 (br s, 1 H, NH).
t
13C{1H} NMR (75.5 MHz): δ 22.7 (s, CH2Ar), 28.4 (s, Me, Bu),
41.5 (s, CH2N), 55.8 (s, CMe3), 124.0 (s, CH5), 124.3 (s, CH4),
126.6 (s, CH7), 129.8 (s, CH6), 137.5 (s, C3a), 142.4 (s, C7a), 145.1
(s, C3), 154.7 (s, C2). The 13C{1H} resonances corresponding to the
CN and the triflate groups were not observed. Single crystals
suitable for an X-ray diffraction study were obtained by slow
evaporation of a solution of 10b in CHCl3.
Synthesis of 4-Dihydro[1]benzofuran[2,3-c]pyridin-1(2H)-
one (11a). NEt3 (5 mL, 35.87 mmol) was added to a solution of
1a (150 mg, 0.3 mmol) in CHCl3 (5 mL) under a CO atmosphere
(1.5 atm), and the mixture was stirred at room temperature overnight.
The resulting suspension was filtered through a plug of Celite, and the
K
DOI: 10.1021/acs.organomet.8b00682
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
3
4
solvent was removed from the filtrate. The residue was purified by
flash chromatography using a 3:97 mixture of n-hexane/ethyl acetate
as eluent. The solvent was removed, and the residue was vacuum-
dried to afford pure lactam 11a as a colorless solid. Yield: 15 mg, 0.08
mmol, 27%. Mp: 146 °C. IR (cm−1): ν(CO) 1685 s. ESI-HRMS calcd
Hz), 7.57 (dt, 1 H, H7, JHH = 7.2, JHH = 1.2 Hz), 7.70 (d, 1 H, 
CH, 3JHH = 15.3 Hz), 7.86 (ddd, 1 H, H4, 3JHH = 8.4, 4JHH = 1.5, 4JHH
= 0.9 Hz), 7.90 (br s, 3 H, NH3, overlapped with the corresponding
signal of the E isomer). 13C{1H} NMR (75.5 MHz, acetone-d6): E
isomer (minor isomer, extracted from the 1:3 equilibrium mixture of
E/Z isomers): δ 22.2 (s, CH2Ar), 40.9 (s, CH2N), 52.0 (s, Me), 112.1
(s, CH7), 119.1 (s, CH), 120.6 (s, C3), 121.5 (s, CH4), 124.3 (s,
CH5), 128.1 (s, CH6), 129.5 (s, CH), 150.1 (s, C2), 155.7 (s,
C7a), 167.1 (s, CO). The 13C{1H} resonance corresponding to C3a
was not observed or overlapped with the corresponding signal of the
Z isomer. Z isomer (major isomer, extracted from the 1:3 equilibrium
mixture of E/Z isomers): δ 22.4 (s, CH2Ar), 48.2 (s, CH2N), 52.0 (s,
Me), 112.2 (s, CH7), 119.2 (s, CH), 120.6 (s, C3), 121.4 (s,
CH4), 124.4 (s, CH5), 128.2 (s, CH6), 129.2 (s, C3a), 129.4 (s, 
CH), 150.1 (s, C2), 155.6 (s, C7a), 167.1 (s, CO).
1
for C11H10NO2, 188.0706 [(M + H)+]; found, 188.0712. H NMR
3
(400.9 MHz): δ 3.04 (t, 2 H, CH2Ar, JHH = 7.2 Hz), 3.75 (td, 2 H,
3
4
CH2N, JHH = 7.2, JHH = 2.8 Hz), 6.72 (br s, 1 H, NH), 7.30−7.34
(m, 1 H, H5), 7.42−7.46 (m, 1 H, H6), 7.58−7.60 (m, 2 H, H7 +
H4). 13C{1H} NMR (75.5 MHz): δ 20.5 (s, CH2Ar), 41.2 (s, CH2N),
112.6 (s, CH7), 120.9 (s, CH4), 123.5 (s, CH5), 125.1 (s, C3), 125.8
(s, C3a), 127.4 (s, CH6), 143.6 (s, C2), 155.7 (s, C7a), 161.2 (s,
CO).
Synthesis of 3,4-Dihydro[1]benzothieno[2,3-c]pyridin-
1(2H)-one (11b). NEt3 (146 μL, 1.05 mmmol) was added to a
suspension of 2b·2MeCN (188 mg, 0.26 mmol) in CHCl3 (15 mL),
in a Carius tube. A CO atmosphere (1.2 atm) was established, and the
mixture was stirred for 48 h at 65 °C. Decomposition to metallic
palladium was observed. The solvent was eliminated from the mixture,
and acetone (20 mL) was added to the residue. The suspension was
filtered to collect a black solid (98 mg) which was a mixture of
metallic palladium and NHEt3Cl. The filtrate was again filtered
through a plug of MgSO4, the filtrate was concentrated to ca. 1 mL,
and Et2O (15 mL) was added. The resulting suspension was filtered,
and the colorless solid was air-dried and identified as NHEt3Cl (60
Synthesis of (E)-2-(2-(3-Methoxy-3-oxoprop-1-enyl)benzo-
[b]thiophen-3-yl)ethanaminium Triflate (12b). AgOTf (107 mg,
0.42 mmol) was added to a suspension of 2b·2MeCN (150 mg, 0.21
mmol) in acetone (20 mL). The mixture was protected from light and
stirred for 24 h. The suspension was filtered through a plug of MgSO4,
the solvent was removed from the filtrate, and CHCl3 (40 mL) was
added. The suspension was transferred to a Carius tube, methyl
acrylate (75 μL, 0.832 mmol) was added, and the mixture was stirred
for 48 h at 65 °C. Decomposition to metallic palladium was observed.
The solvent was removed, and acetone (20 mL) was added. The
suspension was filtered to collect a black solid. The filtrate was filtered
again through a plug of MgSO4. The filtrate was concentrated to ca. 1
mL, and Et2O (20 mL) was added. The suspension was filtered, and
the solid was washed with CH2Cl2 (3 × 5 mL) and Et2O (3 × 5 mL)
1
mg) by H NMR. The filtrate was concentrated to ca. 1 mL, and n-
pentane (15 mL) was added. A sticky solid was formed. The solvent
was removed, and the residue was vacuum-dried to afford crude
lactam 11b as a cream-colored solid (58 mg). Crude 11b was purified
by flash chromatography using a 15:85 mixture of n-hexane/ethyl
acetate as eluent. The solvent was removed, and the residue was
vacuum-dried to afford pure lactam 11b as a colorless solid. Yield
(crude 11b): 58 mg, 0.29 mmol, 54%. Yield (pure 11b): 25 mg, 0.13
mmol, 23%. Mp: 150 °C. IR (cm−1): ν(NH) 3211 br m; ν(CO) 1651
s. ESI-HRMS: calculated exact mass for C11H10NOS, 204.0483 [(M +
1
and air-dried to afford crude compound E-12b (by H NMR) as a
brown solid (100 mg). Yield (crude 12b): 100 mg, 0.24 mmol, 58%.
Mp: 210 °C. IR (cm−1): ν(NH) 3162 m; ν(CO) 1711 s; ν(CC)
1617 m. ESI-HRMS: exact calculated mass for C14H16NO2S,
262.0896 [(M + 1)+]; found, 262.0895. 1H NMR (300.1 MHz,
acetone-d6): E isomer: δ 3.52−3.60 (br m, 2 H, CH2N), 3.63−3.71
(m, 2 H, CH2Ar), 3.77 (s, 3 H, Me), 6.33 (d, 1 H, CH, 3JHH = 15.6
Hz), 7.43−7.51 (m, 2 H, H5 + H6), 7.92−7.96 (m, 1 H, H7), 8.04−
8.08 (m, 1 H, H4), 8.06 (d, 1 H, CH, 3JHH = 15.3 Hz). The signal
corresponding to the NH3 group was obscured by resonances of the
aromatic protons. Z isomer (extracted from the 1:1.3 equilibrium
mixture of E/Z isomers): δ 3.63−3.69 (m, 2 H, CH2Ar, overlapped
with the corresponding signal of the E isomer), 3.77 (s, 3 H, Me,
overlapped with the corresponding signal of the E isomer), 4.16 (t, 2
1
1)+]; found, 204.0481. H NMR (400.9 MHz): δ 3.09 (“t”, 2 H,
3
3
3
CN2Ar, JHH = 7.2 Hz), 3.75 (td, 2 H, CH2N, JHH = 7.2, JHH = 2.4
Hz), 6.46 (br s, 1 H, NH), 7.42−7.49 (m, 2 H, H5 + H6), 7.74−7.76
(m, 1 H, H4), 7.89−7.92 (m, 1 H, H7). 13C{1H} NMR (75.5 MHz):
δ 22.9 (s, CH2Ar), 41.2 (s, CH2N), 122.9 (s, CH4), 123.4 (s, CH7),
124.7 (s, CH5), 126.9 (s, CH6), 131.0 (s, C2), 137.5 (s, C3a), 140.0
(s, C3), 141.9 (s, C7a), 163.9 (s, CO).
Synthesis of 2-(2-(3-Methoxy-3-oxoprop-1-enyl)benzo[b]-
furan-3-yl)ethanaminium Triflate (12a). Methyl acrylate (108
μL, 1.20 mmol) was added to a solution of 1a (150 mg, 0.30 mmol)
in CHCl3 (3 mL), and the mixture was stirred at 65 °C overnight.
3
3
H, CH2N, JHH = 7.8 Hz), 6.33 (d, 1 H, CH, JHH = 15.6 Hz),
7.43−7.52 (m, 2 H, H5 + H6, overlapped with the corresponding
signals of the E isomer), 7.92−7.96 (m, 1 H, H7, overlapped with the
1
3
The resulting suspension was filtered to give crude E-12a (by H
corresponding signal of the E isomer), 8.02 (d, 1 H, CH, JHH
=
NMR) as a gray solid (80 mg). Crude E-12a was dissolved in acetone,
and the mixture was filtered through a plug of Celite. The filtrate was
concentrated to ca. 0.5 mL, and Et2O was added (15 mL). The
solvent was partially removed to ca. 10 mL, and Et2O (10 mL) was
added. The suspension was filtered, and the solid was washed with
Et2O (2 × 3 mL) and air-dried to give a 2:1 mixture of E/Z-12a as a
colorless solid. Yield (E/Z-12a): 33 mg, 0.083 mmol, 28%. Mp: 204
°C. ΛM (Ω−1 cm2 mol−1): 108 (5.0 × 10−4 M in acetone). IR (cm−1):
ν(NH) 3162 br m; ν(CO) 1705 s. ESI-HRMS calcd for C14H16NO3,
15.6 Hz), 8.04−8.08 (m, 1 H, H4, overlapped with the corresponding
signal of the E isomer). The signal corresponding to the NH3 group
was obscured by resonances of the aromatic protons. 13C{1H} NMR
(75.5 MHz, acetone-d6): E isomer: δ 24.1, 24.2 (s, CH2Ar), 48.2, 40.3
(s, CH2N), 51.1 (s, Me), 119.7 (s, CH), 122.6 (s, CH4 or CH7),
122.8 (s, CH4 or CH7), 125.1 (s, CH5 or CH6), 127.0 (s, CH5 or
CH6), 134.6 (s, CH), 134.8 (s, C3 or C3a), 135.9 (s, C2), 139.1
(s, C7a), 139.5 (s, C3 or C3a), 166.0 (s, CO). The signal
corresponding to the methylene carbons of isomer E-12b appeared
split, probably because the presence in solution of an equilibrium (for
instance, deprotonation of the aminium group) or two different
species generated by hydrogen bonding in solution. This splitting is
1
246.1130 [(M − OTf)+]; found, 246.1129. H NMR (300.1 MHz,
acetone-d6): E isomer: δ 3.48−3.52 (m, 2 H, CH2Ar), 3.59−3.69 (br
m, 2 H, CH2N), 3.77 (s, 3 H, Me), 6.52 (d, 1 H, CH, 3JHH = 15.6
Hz), 7.33 (ddd, 1 H, H5, 3JHH = 8.4, 3JHH = 7.6, 4JHH = 1.2 Hz), 7.46
(td, 1 H, H6, 3JHH = 7.4, 4JHH = 1.2 Hz), 7.56 (dt, 1 H, H7, 3JHH = 7.2,
4JHH = 1.2 Hz), 7.71 (d, 1 H, CH, 3JHH = 15.3 Hz), 7.85 (ddd, 1 H,
1
not due to the E/Z isomerization, as checked by the H NMR of the
sample, which correspondes to the pure E isomer.
Synthesis of tert-Butyl 2-(Benzo[b]furan-3-yl)-
ethylcarbamate (13a). Na2CO3 (205 mg, 1.93 mmol) was added
to a solution of A·HOTf (200 mg, 0.64 mmol) in CH2Cl2 (10 mL),
and the mixture was stirred at room temperature for 1 h. Di-tert-butyl
dicarbonate (Boc2O; 154 mg, 0.70 mmol) was added, and the mixture
was stirred for 12 h at room temperature. CH2Cl2 (30 mL) and
distilled water (30 mL) were added, and the organic phase was
collected and dried over MgSO4. The suspension was filtered, and the
solvent was completely removed from the filtrate to give 13a as a
3
4
4
H4, JHH = 8.4, JHH = 1.5, JHH = 0.9 Hz), 7.90 (br s, 3 H, NH3). Z
isomer (extracted from the 1:3 equilibrium mixture of E/Z isomers):
δ 3.48−3.56 (m, 2 H, CH2Ar, overlapped with the corresponding
signal of the E isomer), 3.77 (s, 3 H, Me, overlapped with the
corresponding signal of the E isomer), 4.24 (t, 2 H, CH2N, 3JHH = 7.2
3
Hz), 6.52 (d, 1 H, CH, JHH = 15.6 Hz, overlapped with the
corresponding signal of the E isomer), 7.33 (ddd, 1 H, H5, 3JHH = 8.4,
4
3
4
3JHH = 7.6, JHH = 1.2 Hz), 7.47 (td, 1 H, H6, JHH = 7.4, JHH = 1.2
L
DOI: 10.1021/acs.organomet.8b00682
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
dense yellow oil. Yield: 157 mg, 0.60 mmol, 94%. Anal. Calcd for
C15H19NO3 (261.136 g/mol): C, 68.94; H, 7.33; N, 5.36. Found: C,
68.85; H, 7.34; N, 5.22. IR (cm−1): ν(NH) 3430 vs, 3357 vs; ν(CO)
removed from the filtrate to afford crude 14b as a yellow oil. Crude
14b was dissolved in CH2Cl2 (2 mL) and purified by column
cromatography using aluminum oxide and eluting with a 4:1 mixture
1
1
t
of petroleum ether/ethyl acetate. Yield: 57% (by H NMR). Isolated
1698 s. H NMR (400.9 MHz): δ 1.43 (s, 9 H, Bu), 2.88 (t, 2 H,
3
yield: 36 mg, 0.10 mmol, 40%. ESI-HRMS calcd for C19H23NNaO4S,
CH2Ar, JHH = 6.8 Hz), 3.45 (m, 2 H, CH2N), 4.65 (s, 1 H, NH),
1
384.1245 [(M + Na)+]; found, 384.1239. H NMR (300.1 MHz): δ
7.22 (td, 1 H, H5 or H6, 3JHH = 7.6, 3JHH = 1.2 Hz), 7.29 (td, 1 H, H5
or H6, 3JHH = 7.6, 3JHH = 1.6 Hz,), 7.45 (s, 1 H, H2), 7.47 (br s, 1 H,
1.43 (s, 3H, tBu), 3.20 (t, 2 H, CH2Ar, 3JHH = 6.0 Hz), 3.35−3.42 (m,
3
H4), 7.56 (br d, 1 H, H7, JHH = 7.6 Hz). 13C{1H} NMR (100.8
2 H, CH2N), 3.81 (s, 3 H, Me), 4.64 (br s, 1 H, NH), 6.32 (d, 1 H,
3
MHz): δ 24.3 (s, CH2Ar), 28.4 (s, Me, tBu), 39.9 (s, CH2N), 79.3 (s,
CMe3), 111.5 (s, CH4), 117.3 (s, C3), 119.5 (s, CH7), 122.4 (s,
CH5), 124.3 (s, CH6), 127.9 (s, C3a), 141.8 (s, CH2), 155.4 (s,
C7a), 155.8 (s, CO).
CH, JHH = 15.3 Hz), 7.37−7.40 (m, 2 H, H4 + H5), 7.76−7.80
(m, 2 H, H6 + H7), 7.56−7.62, 7.98 (d, 1 H, CH, 3JHH = 15.6 Hz).
13C{1H} NMR (75.5 MHz): δ 27.4 (s, CH2Ar), 28.3 (s, tBu), 40.9 (s,
CH2N), 51.8 (s, Me), 79.4 (s, CMe3), 119.0 (s, CH), 122.5 (s,
CH6 or CH7), 122.9 (s, CH6 or CH7), 124.8 (s, CH4 or CH5),
126.6 (s, CH4 or CH5), 135.1 (s, C2), 135.3 (s, CH), 137.6 (s,
C3), 139.3 (s, C7a), 139.9 (s, C3a), 155.8 (C-Boc), 167.0 (s, CO).
Single Crystal X-ray Structure Determinations. Relevant
crystallographic data, details of the refinements, and details (including
symmetry operators) of hydrogen bonds for compounds 3a·Et2O, 3b,
4a, 6b·1/6CH2Cl2, 7b, 8b·1/4CH2Cl2·1/4Et2O, 9b, and 10b are
given in the Supporting Information. Data Collection. Crystals suitable
for X-ray diffraction were mounted in inert oil on a glass fiber and
transferred to a Bruker D8 QUEST diffractometer. Data were
recorded at 100(2) K, using graphite-monochromated Mo-Ka
radiation (λ = 0.71073 Å), and ω- and ϕ-scan mode. Multiscan
absorption corrections were applied for all complexes. Structure
Solution and Refinements. Crystal structures were solved by a dual
method, and all non-hydrogen atoms were refined anisotropically on
F2 using the program SHELXL-2014/7 (3a·Et2O, 3b, 4a, 6b·1/
6CH2Cl2, 7b, 9b, and 10b)37 or SHELXL-2016/6 (8b·1/4CH2Cl2·1/
4Et2O)38 Hydrogen atoms were refined as follows: Compounds 3a·
Et2O, 6b·1/6CH2Cl2, 7b, 9b, and 10b: NH2, free with SADI; methyl,
rigid group; all others, riding. Complex 3b: NH2, free with DFIX; all
others, riding. Complex 4a: NH2, free; methyls, rigid group; all others,
riding. Complex 8b·1/4CH2Cl2·1/4Et2O: NH2, free with DFIX;
ordered methyl, rigid group; all others, riding. Special features: For 3b:
A region of residual electron density could not be interpreted in terms
of realistic solvent molecules, even allowing for possible disorder. For
this reason the program SQUEEZE, which is part of the PLATON
system,39 was employed to remove mathematically the effects of the
solvent. Standard deviations of refined parameters should be
interpreted with caution. The void volume per cell was 594 Å3 with
a void electron count per cell of 146. This additional solvent was not
taken into account when calculating derived parameters such as the
formula weight, because the nature of the solvent was uncertain. For
6b·1/6CH2Cl2: An ill-defined region of residual electron density over
an inversion center was interpreted as half a molecule of dichloro-
methane, disordered over two positions, with a ca. 37:13 occupancy
distribution. For 8b·1/4CH2Cl2·1/4Et2O: A poorly resolved region of
residual electron density was interpreted as the superposition of half a
molecule of dichloromethane and half a molecule of Et2O. The
carbon and the oxygen atoms of the Et2O were refined as isotropic.
Synthesis of tert-Butyl 2-(Benzo[b]thiophen-3-yl)-
ethylcarbamate (13b). Na2CO3 (496 mg, 4.68 mmol) was added
to a suspension of B·HCl (500 mg, 2.34 mmol) in CH2Cl2 (50 mL).
The suspension was stirred for 2.5 h at room temperature, and di-tert-
butyl dicarbonate (Boc2O; 562 mg, 2.57 mmol) was added. After 24
h, the mixture was washed with distilled water (3 × 50 mL). The
organic phase was dried over MgSO4, the suspension was filtered, the
solvent was removed from the filtrate, and n-pentane (20 mL) was
added to the colorless residue. The solvent was again removed, n-
pentane (20 mL) was added, and the suspension was vigorously
stirred. The suspension was filtered, and the solid was air-dried to give
pure compound 13b as a colorless solid. Yield: 558 mg, 2.01 mmol,
86%. Mp: 59 °C. IR (cm−1): ν(NH) 3364 s; ν(CO) 1694 s. ESI-
HRMS: exact calculated mass for C15H19NNaO2S, 300.1034 [(M +
Na)+]; found, 300.1026. 1H NMR (400.9 MHz): δ 1.44 (s, 9 H, Me,
3
tBu), 3.05 (“t”, 2 H, CH2Ar, JHH = 6.8 Hz), 3.49 (m, 2 H, CH2N),
4.63 (br s, 1 H, NH), 7.16 (s, 1 H, H2), 7.37 (m, 2 H, H5 + H6), 7.77
3
(br d, 1 H, H4, JHH = 8.0 Hz), 7.86 (m, 1 H, H7). 13C{1H} NMR
t
(100.8 MHz): δ 28.4 (s, Me, Bu), 29.1 (s, CH2Ar), 40.1 (s, CH2N),
79.3 (s, CMe3), 121.6 (s, CH4), 122.4 (s, CH2), 122.9 (s, CH7),
124.0 (s, CH5), 124.3 (s, CH6), 133.5 (s, C3), 138.8 (s, 3a), 140.5 (s,
C7a), 155.8 (s, CO).
Synthesis of (E)-Methyl 3-(3-(2-(tert-Butoxycarbonyl)ethyl)-
benzo[b]furan-2-yl)acrylate (14a). In a Carius tube, Pd(OAc)2
(10 mg, 0.043 mmol), Cu(OAc)2 (78 mg, 0.43 mmol), and methyl
acrylate (77.2 μL, 0.86 mmol) were added to a solution of 13a (112
mg, 0.43 mmmol) in 1,2-dichloroethane (3 mL), and the mixture was
refluxed for 16 h. CH2Cl2 (25 mL) was added to the resulting
suspension, and the mixture was washed with aq. NH3 (10%; 2 × 20
mL). The organic layer was collected, dried over a plug of MgSO4,
and filtered. The solvent was removed from the filtrate to afford crude
14a. Crude 14a was dissolved in CH2Cl2 (2 mL) and purified by
preparative TLC in silica gel with a fluorescent indicator, eluting with
a 7:1 mixture of petroleum ether/ethyl acetate. The most retained
fraction was collected, and the product was extracted from the silica
gel using ethyl acetate (50 mL). The solvent was removed to give
compound 14a as a yellow oil. Yield: 77% (by 1H NMR). IR (cm−1):
ν(NH) 3372 br w; ν(CO) 1714 s, 1635 m. ESI-HRMS calcd for
1
C19H23NNaO5, 368.1468 [(M + Na)+]; found, 368.1472. H NMR
t
3
(300.1 MHz): δ 1.43 (s, 9 H, Bu), 3.02 (t, 2 H, CH2N, JHH = 6.6
Hz), 3.39−3.44 (m, 2 H, CH2Ar), 3.81 (s, 3 H, Me), 4.64 (br s, 1 H,
NH), 6.57 (d, 1 H, CH, 3JHH = 15.6 Hz), 7.22−7.28 (m, 1 H, H5),
7.34−7.40 (m, 1 H, H6), 7.44−7.48 (m, 1 H, H7), 7.56−7.62 (br s, 1
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.8b00682.
3
H, H4), 7.59 (d, 1 H, CH, JHH = 15.6 Hz). 13C{1H} NMR (75.5
MHz): δ 24.5 (s, CH2Ar), 28.3 (s, tBu), 40.5 (s, CH2N), 51.7 (s, Me),
79.4 (s, CMe3), 111.4 (s, CH7), 117.8 (s, CH), 120.3 (s, CH4),
121.9 (s, C3), 123.1 (s, CH5), 126.8 (s, CH6), 128.9 (s, CH),
128.9 (s, C3a), 149.0 (s, C2), 154.9 (s, C7a), 155.7 (s, C-Boc), 167.2
(s, CO).
1H and 13C{1H}-APT NMR spectra of compounds 10−
14, crystallographic data for compounds 3a·Et2O, 3b, 4a,
6b·1/6CH2Cl2, 7b, 8b·1/4CH2Cl2·1/4Et2O, 9b, and
10b, and details of hydrogen bonds (including symmetry
operators) (PDF)
Synthesis of (E)-Methyl 3-(3-(2-(tert-Butoxycarbonyl)ethyl)-
benzo[b]thiophen-2-yl)acrylate (14b). In a Carius tube, Pd-
(OAc)2 (5.6 mg, 0.025 mmol), Cu(OAc)2 (45 mg, 0.25 mmol), and
methyl acrylate (135 μL, 1.50 mmol) were added to a solution of 13b
(70 mg, 0.25 mmol) in acetonitrile (3 mL), and the mixture was
heated 110 °C for 48 h. Solvent was removed to ca. 1 mL, and
CH2Cl2 (25 mL) was added to the resulting suspension. The mixture
was washed with aq. NH3 (10%; 2 × 30 mL). The organic layer was
collected, dried over a plug of MgSO4, and filtered. The solvent was
Accession Codes
CCDC 1866905, 1866907, and 1866924−1866929 contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
M
DOI: 10.1021/acs.organomet.8b00682
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
(8) (a) Vicente, J.; Saura-Llamas, I.; Cuadrado, J.; Ramírez de
Arellano, M. C. Ortho-Metalated Primary Amines. 6. The First
Synthesis of Six-Membered Palladacycles from Primary Amines
Containing Electron-Withdrawing Substituents: End of the Limiting
Rules of Cope and Friedrich on Cyclopalladation of Benzyl- and
Phenethylamines. Organometallics 2003, 22, 5513−5517. (b) Vicente,
J.; Saura-Llamas, I.; Bautista, D. Regiospecific Functionalization of
Pharmaceuticals and Other Biologically Active Molecules Through
Cyclopalladated Compounds. 2-Iodination of Phentermine and L-
Tryptophan Methyl Ester. Organometallics 2005, 24, 6001−6004.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: joangalo@um.es (J.A.G.-L.).
*E-mail: ims@um.es (I.S.-L.).
ORCID
́
(c) Vicente, J.; Saura-Llamas, I.; García-Lopez, J. A.; Calmuschi-Cula,
́
́
Jose Antonio García-Lopez: 0000-0002-8143-7081
Isabel Saura-Llamas: 0000-0001-8335-6747
B.; Bautista, D. Ortho Palladation and Functionalization of L-
Phenylalanine Methyl Ester. Organometallics 2007, 26, 2768−2776.
́
(d) Vicente, J.; Saura-Llamas, I.; Oliva-Madrid, M. J.; García-Lopez, J.
Notes
A.; Bautista, D. A New Method for High-Yield Cyclopalladation of
Primary and Secondary Amines. Atom-Efficient Open-to-Air Inex-
pensive Synthesis of Buchwald-Type Precatalysts. Organometallics
2011, 30, 4624−4631.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(9) Nonoyama, M.; Nakajima, K. Cyclometallation of 2-(2-
pyridyl)benzo[b]furan and1-(2-pyridyl and 2-pyrimidyl)indole with
palladium(II) and rhodium(III). Structures of unexpectedly formed
nitropalladium(II) complexes. Polyhedron 1998, 18, 533−543.
(10) Nonoyama, M.; Nakajima, K.; Mizuno, H.; Hayashi, S.
Cyclometallation of N,N-dimethylbenzo[b]furan-2-carbothio (and
seleno) amides with palladium(II), ruthenium(II) and rhodium(III).
Inorg. Chim. Acta 1994, 215, 91−101.
This paper is dedicated to Professor Ernesto Carmona on the
occasion of his 70th birthday. We thank the Spanish Ministerio
́
de Economıa y Competitividad (grant CTQ2015-69568-P)
́
́
and Fundacion Seneca (grant 19890/GERM/15) for financial
support.
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