Insertion reactions on carbopalladated benzyne: From eight- to nine- and ten-membered palladacycles. Applications to the synthesis of N-heterocycles

Article abstract of DOI:10.1021/om500772p

The ortho-metalated complexes [Pd{C,N-C₆H₂CH₂CH₂NH₂-2,(OMe)₂-4,5}(Br)]₂ (A) and [Pd{C,N-C₆H₄CH₂CMe₂NH₂-2}(Cl)]₂ (B), derived from homoveratrylamine and phentermine, respectively, react with benzyne generated in situ, to afford the previously reported eight-membered palladacycles 1a and 1b, respectively, arising from the insertion of one molecule of the aryne into the Pd-C_aryl bond. Complexes 1 react with isocyanides RNC (R = Xy, ^tBu) in 1:4 molar ratio to give the nine-membered iminoacyl palladacycles [Pd(C,N-C(=NR)-C₆H₄{C₆H₂CH₂CH₂NH₂-2(OMe)₂-4,5)-2})Br(CNR)] (R = Xy (2a), R = ^tBu (3a)) and [Pd(C,N-C(=NXy)-C₆H₄{C₆H₄CH₂CMe₂NH₂-2)-2})Cl(CNR)] (R = Xy (2b), R = ^tBu (3b)). Complex 2a decomposes in refluxing toluene to afford palladium(0) and 7,8-dihydro-10,11-dimethoxy-5-[(2,6-dimethylphenyl)imino]dibenzo[c,e]azocinium triflate (4a). When 1b reacts with TlOTf and XyNC (molar ratio 1:2:2), 7,8-dihydro-5-[(2,6-dimethylphenyl)imino]-7,7-dimethyldibenzo[c,e]azocinium triflate (4b) is obtained, resulting from an isocyanide insertion/C-N reductive coupling sequence. The amidinium triflates 4a and 4b present E/Z isomerism in CHCl₃ solution. The stoichiometric carbonylation of dinuclear complexes 1 renders, after depalladation, the lactams 7,8-dihydro-10,11-dimethoxydibenzo[c,e]azocin-5(6H)-one (5a) and 7,8-dihydro-7,7-dimethyldibenzo[c,e]azocin-5(6H)-one (5b) or the previously reported ester derivative [2-MeO₂CC₆H₄C₆H₂CH₂CH₂NH₃-2-(OMe)₂-4,5]Br (6a) or [2-MeO₂CC₆H₄C₆H₄CH₂CMe₂NH₃-2]Cl (6b), depending on the reaction conditions. The eight-membered palladacycles 1 react with alkenes to afford complexes [PdCl₂(biarylamine)₂] (7a, 7b, 8b), containing the Heck-type functionalized phenethylamines. The reaction of 1b with ^tBuOK in toluene at 95 °C, under a N₂ atmosphere, affords 6,7-dihydro-6,6-dimethyl-5H-dibenz[b,d]azepine (9b), resulting from a C-N reductive coupling process. The crystal structures of compounds [Pd(C,N-C(=NXy)-C₆H₄{C₆H₂CH₂CH₂NH₂-2(OMe)₂-4,5)-2})Br(CNXy)]·CH₂Cl₂·1/2H₂O (2a·CH₂Cl₂·1/2H₂O), [Pd(C,N-C(=NXy)-C₆H₄{C₆H₄CH₂CMe₂NH₂-2)-2})Cl(CNXy)]·0.72Et₂O·0.28CHCl₃ (2b·0.72Et₂O·0.28CHCl₃), and 7,8-dihydro-10,11-dimethoxydibenzo[c,e]azocin-5(6H)-one (5a) have been determined by X-ray diffraction studies.

Full text of DOI:10.1021/om500772p

Article
pubs.acs.org/Organometallics
Insertion Reactions on Carbopalladated Benzyne: From Eight- to
Nine- and Ten-Membered Palladacycles. Applications to the
Synthesis of N‑Heterocycles
†
†
,†
‡
́ ́ ́
María-Jose Oliva-Madrid, Jose-Antonio García-Lopez, Isabel Saura-Llamas,* Delia Bautista,
,†
and Jose
́
Vicente*
†
́ ́
Grupo de Química Organometalica, Departamento de Química Inorganica, Facultad de Química, Universidad de Murcia, E-301001
Murcia, Spain
‡
SAI, Universidad de Murcia, E-30100 Murcia, Spain
S Supporting Information
*
ABSTRACT: The ortho-metalated complexes [Pd{C,N-
C H CH CH NH -2,(OMe) -4,5}(μ-Br)] (A) and [Pd{C,N-
6
2
2
2
2
2
2
C H CH CMe NH -2}(μ-Cl)] (B), derived from homovera-
6
4
2
2
2
2
trylamine and phentermine, respectively, react with benzyne
generated in situ, to afford the previously reported eight-
membered palladacycles 1a and 1b, respectively, arising from
the insertion of one molecule of the aryne into the Pd−C
aryl
t
bond. Complexes 1 react with isocyanides RNC (R = Xy, Bu)
in 1:4 molar ratio to give the nine-membered iminoacyl
palladacycles [Pd(C,N-C(NR)-C H {C H CH CH NH -2-
6
4
6
2
2
2
2
t
(
OMe) -4,5)-2′})Br(CNR)] (R = Xy (2a), R = Bu (3a))
2
and [Pd(C,N-C(NXy)-C H {C H CH CMe NH -2)-2′})Cl-
6
4
6
4
2
2
2
t
(
CNR)] (R = Xy (2b), R = Bu (3b)). Complex 2a decomposes
in refluxing toluene to afford palladium(0) and 7,8-dihydro-10,11-dimethoxy-5-[(2,6-dimethylphenyl)imino]dibenzo[c,e]-
azocinium triflate (4a). When 1b reacts with TlOTf and XyNC (molar ratio 1:2:2), 7,8-dihydro-5-[(2,6-dimethylphenyl)imino]-
7
,7-dimethyldibenzo[c,e]azocinium triflate (4b) is obtained, resulting from an isocyanide insertion/C−N reductive coupling
sequence. The amidinium triflates 4a and 4b present E/Z isomerism in CHCl solution. The stoichiometric carbonylation of
3
dinuclear complexes 1 renders, after depalladation, the lactams 7,8-dihydro-10,11-dimethoxydibenzo[c,e]azocin-5(6H)-one (5a)
and 7,8-dihydro-7,7-dimethyldibenzo[c,e]azocin-5(6H)-one (5b) or the previously reported ester derivative [2′-
MeO CC H C H CH CH NH -2-(OMe) -4,5]Br (6a) or [2′-MeO CC H C H CH CMe NH -2]Cl (6b), depending on the
2
6
4
6
2
2
2
3
2
2
6
4
6
4
2
2
3
reaction conditions. The eight-membered palladacycles 1 react with alkenes to afford complexes [PdCl (biarylamine) ] (7a, 7b,
2
2
t
8
b), containing the Heck-type functionalized phenethylamines. The reaction of 1b with BuOK in toluene at 95 °C, under a N
2
atmosphere, affords 6,7-dihydro-6,6-dimethyl-5H-dibenz[b,d]azepine (9b), resulting from a C−N reductive coupling process.
The crystal structures of compounds [Pd(C,N-C(NXy)-C H {C H CH CH NH -2(OMe) -4,5)-2′})Br(CNXy)]·CH Cl ·1/
6
4
6
2
2
2
2
2
2
2
2
0
H O (2a·CH Cl ·1/2H O), [Pd(C,N-C(NXy)-C H {C H CH CMe NH -2)-2′})Cl(CNXy)]·0.72Et O·0.28CHCl (2b·
2
2
2
2
6
4
6
4
2
2
2
2
3
.72Et O·0.28CHCl ), and 7,8-dihydro-10,11-dimethoxydibenzo[c,e]azocin-5(6H)-one (5a) have been determined by X-ray
2 3
diffraction studies.
INTRODUCTION
Recently we have reported the synthesis and isolation of
eight- or ten-membered palladacycles (Scheme 1) through the
■
The palladium-catalyzed coupling reactions using benzyne (two
or three components, homo- or heterocoupling reactions) have
attracted great interest because arynes are highly reactive
species for the synthesis of biaryls and condensed aromatic
structures, which are present in a large number of interesting
products of biological relevance, such as terpenes, coumarines,
flavonoids, tannins, and alkaloids. One of the proposed
mechanisms for these reactions involved the formation of a Pd-
aryl complex, followed by the insertion of one or two molecules
of the aryne into the Pd−C bond, and the subsequent
insertion of, respectively, 1 or 2 equiv of benzyne, generated in
6
situ, into the Pd−C bond of six-membered C,N-pallada-
1
,2
aryl
∧
∧
cycles [Pd(C N)(μ-Y)]2 (Y = Br, C N = C,N-
∧
C H CH CH NH -2,(OMe) -4,5 (A); Y = Cl, C N = C,N-
6
2
2
2
2
2
C H CH CMe NH -2 (B); Scheme 1), derived from homo-
6
4
2
2
2
7
8
9,10
veratrylamine and phentermine, respectively.
They
3
,4
represented the first isolated metallacycles obtained by direct
carbometalation of an aryne. These complexes could be
Received: July 29, 2014
2
,5
decomposition of the organometallic intermediate.
©
XXXX American Chemical Society
A
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Scheme 1. Insertion of Benzyne into the Pd−C Bond of Six-
or Eight-Membered Palladacycles
Depalladation of the eight-membered palladacycles 1a,b or
the complexes resulting from the insertion of unsaturated
molecules into their Pd−C bond has allowed the synthesis of
seven- and eight-membered N-heterocycles resulting from a
C−N coupling process, such as dibenzazepine, dibenzazocine,
and dibenzazocinone derivatives (Chart 1). The N-heterocyclic
Chart 1. Biaryl Skeletons Containing Seven- or Eight-
Membered Rings
considered models for the intermediates proposed in the
cascade palladium-catalyzed reactions involving arynes, if we
can prove that the Pd−C bond is still reactive toward
unsaturated molecules. The literature includes only a few
eight-membered C,N-palladacycles, most of them arising from
the insertion of one molecule of alkene into the Pd−C bond in
11,12
ortho-palladated arylalkylamines
or derived from the
systems containing biaryl units have received considerable
attention due to their pharmacological properties. For instance,
the dibenz[b,f]azepine skeleton exhibits a wide range of
biological activity, including antidepressive, analgesic, anti-
monoinsertion of symmetrical and nonsymmetrical alkynes
13
into six-membered ring complexes, containing chelating
1
4
12
amides, or phenethylamines.
15
The main target of this work is to systematically explore the
reactivity of the mentioned eight-membered palladacycles 1
toward several unsaturated species. We have preliminarily
psychotic, and antihistaminic properties. The dibenzo[c,e]-
azocine skeleton is structurally analogous to apogalanthamine,
which is well known for its antihypotensive and antiserotonin
9
16
reported the only previous work on this topic (Scheme 2). As
activities. Other apogalanthamine analogues are found to act
17
as α-adrenergic blocking agents or show high activity against
18
Scheme 2. Our Previously Reported Reactivity of Benzyne-
the Herpes simplex virus. Finally, the eight-membered biaryl
9
19
Inserted Eight-Membered Palladacycles
lactams exhibit moderate albeit significant cytotoxicities.
RESULTS AND DISCUSSION
Synthesis and Structure of Nine-Membered Iminoacyl
Palladacycles. Dimer 1a or 1b reacted with 2 equiv of XyNC
■
(
molar ratio Pd/XyNC = 1:1) to give a mixture of the starting
palladacycle 1a or 1b, the iminoacyl derivative 2a or 2b
Scheme 3), and another unidentified complex, likely, the
(
mononuclear derivative with the XyNC coordinated to the
metal center. Both iminoacyl complexes 2a and 2b could be
isolated in good to moderate yields (58% and 77%,
respectively) by reactions of 1a and 1b with 4 equiv of
XyNC in CH Cl , at room temperature (molar ratio Pd/XyNC
2
2
=
1:2), which means that insertion occurs only after
coordination of the isocyanide. Dimers 1 also reacted with
t
an extension, we report here the reactions of complexes 1 with
BuNC (molar ratio 1:4; Scheme 3) to give the iminoacyl
(
1) isocyanides, to afford nine-membered iminoacyl pallada-
complexes 3. In this case, the insertion reaction took place in
t
cycles, which can decompose through a C−N coupling process
to give the corresponding dibenzazocines derivatives; (2) CO,
to give, depending on the reaction conditions, dibenzazoci-
spite of the presence of an electron-donating group ( Bu) in the
2
0,21
isocyanide that hampered the process.
The insertion of isocyanides into the Pd−C bond is
described by a two-step mechanism that involves (1)
coordination of the ligand to the metal center and (2) insertion
7
nones or the methyl esters of N -amino acids; and (3) alkenes,
to give the coordination complexes [PdCl (biarylamine) ],
2
2
2
0−24
which contain the Heck-type functionalized phenethylamines
and exhibit axial chirality. Finally, one of the palladacycles
of the coordinated isocyanide into the aryl−Pd bond.
The
rate of the second step increases when increasing the
electrophilicity of the coordinated isocyanide and decreasing
t
derived from benzyne monoinsertion reacts with BuOK, to
2
0,21
afford Pd(0) and a tetrahydro-dibenzazepine.
its steric hindrance.
The behavior of complexes 1 toward
B
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Scheme 3. Reactions of Eight-Membered Palladacycles with
Isocyanides
Figure 1. X-ray thermal ellipsoid plot of one (A) of the two
independent molecules of complex 2a·CH Cl ·1/2H O (50%
2
2
2
probability) along with the labeling scheme. The solvent molecules
and the hydrogen atoms have been omitted for clarity. Selected bond
lengths (Å) and angles (deg) are given for both independent
molecules (A and B) in Table 1.
the insertion of the isocyanide is similar to that of the six-
7
membered palladacycles derived from homoveratrylamine or
23
benzyl methyl sulfide, which underwent rapid isocyanide
insertion at room temperature.
Complexes 2 and 3 were fully characterized by elemental
1
analyses and NMR and IR spectroscopic techniques. The H
NMR spectra of all these complexes indicated the diaster-
eotopic nature of the NH and CH protons (2a, 2b, 3a, 3b)
2
2
and the CMe methyl groups (2b, 3b), likely due to the stable
2
conformation of the nine-membered ring, which did not change
on the NMR time scale at room temperature. In agreement
Figure 2. X-ray thermal ellipsoid plot of complex 2b·0.72Et
O·
2
0
.28CHCl (50% probability) along with the labeling scheme. The
3
1
13
solvent molecules and the hydrogen atoms have been omitted for
clarity. Selected bond lengths (Å) and angles (deg) are given in Table
with the proposed structures, the H and C NMR spectra of
complexes 2a and 2b revealed the restricted rotation of the Xy
group of the inserted isocyanide moiety, probably caused by
steric hidrance. For this reason, inequivalent signals for
inserted-Xy methyl groups were observed. The IR spectra of
the iminoacyl complexes displayed one intense absorption in
1
.
CH Cl ·1/2H O, there were two independent molecules in the
2
2
2
asymmetric unit (A and B). The structures displayed the
−1
the region 2180−2194 cm (2a: 2180, 2b: 2183, 3a: 2194, 3b:
palladium atoms coordinated to Br or Cl, the NH group, the
2
−
1
2
194 cm ), which could be assigned to ν(CN) of the
terminal carbon atom of the isocyanide ligand, and the carbon
atom of the inserted isocyanide (C15) in geometries between
square-planar and distorted square-planar, with mean deviations
of the coordination planes of Pd(II) between 0.04 and 0.017 Å
(2a·CH Cl ·1/2H O: (A): 0.040 Å, (B) 0.017 Å; 2b·0.72Et O·
coordinated isocyanide. They also exhibited one or two bands
in the range 1582−1645 cm (2a: 1582, 1605; 2b: 1584, 1607;
a: 1607, 1645; 3b: 1622, 1640 cm ), one of which should
−1
−1
3
correspond to the ν(CN). For all these complexes, we
propose that the coordinated isocyanide is trans to the amino
group, because this is the normal behavior for palladacycles
2
2
2
2
0.28CHCl : 0.107 Å) and dihedral angles of 3.9−10.8° between
3
the planes N−Pd−C and C(NR)−Pd−X (2a·CH Cl ·1/
2
2
1
1,21,22,24−26
containing arylalkylamines,
and this is in accord-
2H O: (A) 7.7°, (B) 3.9°; 2b·0.72Et O·0.28CHCl : 10.8°).
2
2
3
ance with the well-established transphobia between C-donor
The nine-membered metallacycles adopted a skewed-boat-boat
2
7
28
ligands.
The crystal structure of the iminoacyl complexes 2a·CH Cl ·
conformation. The mean planes of both Xy rings formed an
angle between 10° and 17.5° (2a·CH Cl ·1/2H O: (A) 14.2°,
2
2
2
2
2
1
/2H O and 2b·0.72Et O·0.28CHCl were determined by X-
(B) 10.0°; 2b·0.72Et O·0.28CHCl : 17.5°), and the two rings
2
2
3
2 3
ray diffraction (Figures 1 and 2, respectively). For complex 2a·
of the biaryl unit planes are almost perpendicular (2a·CH Cl ·
2 2
C
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1
8
/2H O: (A) 83.5°, (B) 85.8°; 2b·0.72Et O·0.38CHCl :
Scheme 4. Isomerism for Exocyclic Amidinium Salts 4 in
2
2
3
a
2.5°).
CDCl at Room Temperature
3
Table 1. Selected Bond Lengths and Angles for Complexes
2
a·CH Cl ·1/2H O and 2b·0.72Et O·0.28CHCl
2
2
2
2
3
a
2
a·CH Cl ·1/2H O
2
2
2
2
b·0.72Et O·
2
A
B
0.28CHCl3
Bond Lengths (Å)
b
Pd(1)−X(1)
2.5790(12)
2.109(5)
2.018(5)
1.938(5)
1.275(6)
1.156(6)
2.5697(14)
2.106(5)
2.039(5)
1.936(5)
1.266(6)
1.153(7)
2.4565(7),
2.126(2)
2.021(2)
1.929(3)
1.269(3)
1.152(3)
Pd(1)−N(1)
Pd(1)−C(15)
Pd(1)−C(31)
C(15)−N(2)
C(31)−N(3)
Angles (deg)
b
X(1)−Pd(1)−N(1)
N(1)−Pd(1)−C(15)
C(15)−Pd(1)−C(31)
90.48(13),
88.88(18)
92.5(2)
89.86(12),
90.93(19)
92.9(2)
94.03(6),
89.64(9)
90.22(10)
86.40(8)
114.9(2)
125.5(2)
124.94(19)
173.3(2)
169.0(3)
a
1
The molar ratio was determined by the NH integral ratios in the H
b
C(31)−Pd(1)−X(1)
87.69(15)
116.0(4)
125.1(4),
125.0(4)
171.8(5)
167.6(5)
86.14(15)
116.2(4)
123.6(4)
126.5(4)
171.3(4)
172.3(5)
NMR spectra.
C(1)−C(15)−N(2)
C(15)−N(2)−C(21)
Pd(1)−C(15)−N(2)
Pd(1)−C(31)−N(3)
C(31)−N(3)−C(32)
NMR spectra, which exhibited an NOE to the exocyclic NH
1
signal (XyNH). When the H NMR spectrum of the amidinium
triflate 4a or 4b was recorded in DMSO-d , it exclusively
6
revealed the Z isomer. Therefore, the equilibrium observed for
E/Z-4 was solvent dependent, as described for other amidinium
salts.
The compounds 4, containing the 7,8-dihydrodibenzo[c,e]-
azocine skeleton, are structurally related with the apogalanth-
amine (Chart 1), a biaryl subunit with a fused eight-membered
N-heterocyclic ring system.
a
Selected lengths and angles are given for both independent molecules
b
present in the asymmetric unit (A and B). X = Br (2a·CH Cl ·1/
2
21,32
2
2
H O) or Cl (2b·0.72Et O·0.28CHCl ).
2 2 3
In both complexes, the discrete molecules are associated
through hydrogen bonds, giving dimers (2b·0.72Et O·
2
0
.28CHCl ) or dimers of dimers (2a·CH Cl ·1/2H O; details,
Reactions of the Eight-Membered Palladacycles with
CO. Synthesis and Structure of 7,8-Dihydrodibenz[c,e]-
azocin-5(6H)-ones. Treatment of complexes 1, derived from
the monoinsertion of benzyne into the Pd−C bond, with CO in
3
2
2
2
including symmetry operations, are given in the Supporting
Information).
Only a few examples of isolated nine-membered pallada-
cycles have been previously reported that are not stabilized by
the coordination of an internal double bond.
Synthesis and Structure of 7,8-Dihydro-5-[(2,6-
dimethylphenyl)imino]dibenzo[c,e]azocinium Triflates.
It is well known that iminoacyl derivatives can be decomposed
under suitable conditions to afford the corresponding amidine
the presence of a base (1a: Na CO ; 1b: NEt ), in CHCl , at 65
2 3 3 3
2
9,30
°C (1a) or room temperature (1b), afforded Pd(0) and the
corresponding lactams (5a, 70%, or 5b, 40%; Scheme 5) in
Scheme 5. Synthesis of Lactams 5 and Esters 6
2
4,30
or amidinium derivatives.
When the nine-membered
iminoacyl palladacycle 2a was treated with TlOTf (TlCF SO )
3
3
in a molar ratio of 1:1 and heated in toluene, the azocinium
triflate 4a was obtained in moderate yield (45%; Scheme 3),
along with metallic palladium. The analogous azocinium salt 4b
was better prepared by the reaction of the six-membered
palladacycle 1b with thallium triflate and XyNC and then
heating the mixture in toluene (Scheme 3; 90%). We have
previously used this synthetic route to prepare 2-amino-
isoindolinium, 3,4-dihydroisoquinolinium, or hexahydro-3-
24
21,31
benzo[d]azocinium salts derived from five-, six-,
eight-membered C,N-palladacycles.
or
11,30
The spectroscopic data of compounds 4 are in agreement
1
with the proposed structures. The H NMR spectrum of 4a or
4
b in CDCl at room temperature displayed two sets of signals,
3
which were attributed to a mixture of the isomers Z/E, as a
result of the partially double character of the exocyclic C−N
bond in the amidinum salts. For both salts, the Z isomer was
the major component (molar ratio Z-4a:E-4a = 5:1, Z-4b:E-4b
=
6.6:1; Scheme 4), easily distinguished by the resonance
1
corresponding to H10′ (Scheme 4) of the fused ring in their H
D
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Organometallics
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good to moderate yields. A few examples of eight-membered
MeO CC H C H CH CMe NH -2]Cl (6b), which was the
methyl ester derivative of an N -amino acid.
2
6
4
6
4
2
2
3
12
33
7
lactams arising from alkene/CO or alkyne/CO sequential
insertion reactions into the Pd−C bond have been reported.
This method constitutes a new synthetic route to prepare biaryl
lactams, which exhibit moderate albeit significant cytotoxicities
and may serve as structural models for future medicinal
Reactions of the Eight-Membered Palladacycles with
Alkenes. When a solution of 1a (CHCl , 65 °C) or a
3
suspension of 1b (CH Cl , RT) reacted with ethyl acrylate in
2
2
1:2 molar ratio, the coordination complex trans-[PdY {2′-
2
1
9,34
chemistry developments.
Previous syntheses of similar
EtO CCHCH-C H C H CH CH NR -2-X -4,5} ] (Y = Br,
2
6
4
6
2
2
2
2
2
2
dihydro-dibenzazocinones are carried out by cyclization of o-
R = H, X = OMe (7a); Y = Cl, R = Me, X = H (7b); Scheme 6)
3
5
(
2′-carboxylphenyl)phenylalanine or by azidotrimethylsilane-
mediated Schmidt rearrangements using oximes as starting
Scheme 6. Synthesis of Complexes 7 and 8b
3
6
materials.
The organic derivatives 5a and 5b have been characterized by
IR and NMR spectroscopy and high-resolution mass
spectrometry (HRESIMS). The NMR data support the
1
structures of these compounds, shown in Scheme 5. The H
NMR spectrum of the lactams exhibited one signal between
5
.60 and 6.00 ppm (δ: 5.92 (5a), 5.62 ppm (5b)),
1
3
corresponding to the NH proton. In the C NMR spectra
the CO group appeared between 172 and 174 ppm (δ: 174.0
(
5a), 172.4 ppm (5b)). In addition, the ν(CO) band in the
−1
IR spectrum appears in the region of 1632−1663 cm . The
crystal structure of 7,8-dihydro-8,9-dimethoxydibenz[c,e]-
azocin-5(6H)-one (5a) was solved by X-ray diffraction studies
(
Figure 3). The eight-membered lactam ring adopted a twist-
Figure 3. Thermal ellipsoid plot (50% probability) of compound 5a
along with the labeling scheme. The hydrogen atoms bonded to
carbon have been omitted for clarity. Selected bond lengths (Å) and
angles (deg): N(1)−C(7) = 1.336(2), C(7)−C(10) = 1.496(2),
C(10)−C(15) = 1.407(3), C(15)−C(5) = 1.498(3), C(5)−C(6) =
1
.396(3), C(6)−C(8) = 1.510(3), C(8)−C(9) = 1.521(3), N(1)−
was obtained in excellent to moderate yields (7a: 62%; 7b:
95%) along with metallic palladium. Similarly, the reaction of
C(9) = 1.456(2), C(7)−O(1) = 1.243(2); N(1)−C(7)−C(10) =
1
=
=
17.49(15), C(7)−C(10)−C(15) = 122.85(16), C(10)−C(15)−C(5)
121.90(15), C(15)−C(5)−C(6) = 125.79(16), C(5)−C(6)−C(8)
125.85(17), C(6)−C(8)−C(9) = 117.52(16), C(8)−C(9)−N(1) =
13.23(16), C(9)−N(1)−C(7) = 123.92(17), N(1)−C(7)−O(1) =
22.37(17), O(1)−C(7)−C(10) = 120.09(16).
1b (CHCl , 65 °C) with styrene led to complex trans-
3
[PdCl {2′-PhCHCH-C H C H CH CH NMe } ] (8b,
2
6
4
6
2
2
2
2 2
1
1
6
0%; Scheme 6). However, the reaction between 1a and
styrene (molar ratio = 1:2) afforded Pd(0) and a complicated
mixture that seemed to contain the coupling product, although
it could not be separated by fractional crystallization nor by
chromatographic techniques. We also tried the reaction of 1a
and 1b with 2-norbornene (molar ratio = 1:2), but in both
cases intractable mixtures were obtained.
37
boat conformation. The molecules of compound 5a are
connected through hydrogen bond interactions giving double
layers parallel to the bc plane (see the Supporting Information).
9
As we have reported previously, complex 1a or 1b also
reacted with CO in MeOH (Scheme 5) to give metallic
palladium and a rare 2,2′-functionalyzed biaryl containing an
alkylamino and a carboxymethyl substituent, [2′-MeO CC H -
Formation of complexes 7 and 8b could be explained
assuming that alkene (ethyl acrylate or styrene) inserts into the
Pd−C bond of 1 to give a ten-membered palladacycle (I;
Scheme 6). For this intermediate, we propose that the R′ group
2
6
4
C H CH CH NH -2-(OMe) -4,5]Cl (6a) or [2′-
6
2
2
2
3
2
E
dx.doi.org/10.1021/om500772p | Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
is at the carbon atom bonded to Pd(II), because (1) this is the
regiochemistry that explains the formation of the internal
olefins coordinated to Pd(II) in complexes 7 and 8b, and (2)
this is the most frequent regioisomer found in the insertion of
electron-poor alkenes into the Pd−C bonds of neutral
Scheme 7. Synthesis of Dibenzazepine 9b
1
1,12,38,39
complexes.
Nevertheless, we cannot discard the
presence of the other regioisomers in the reaction media,
especially in the case of 7a and 8b, as the final products were
isolated in only a 60−62% yield. The ten-membered pallada-
cycle I quickly undergoes a β-hydride elimination to generate
2
an η -olefin-hydrido complex of Pd(II) (II; Scheme 6), which
evolves to a dinuclear intermediate (III). Finally, III
decomposes to give H , Pd(0), and complex 7 or 8b. This
2
last step is different from that postulated in the classical Heck−
Mizoroki cross-coupling reaction involving other C,N-pallada-
2
5,39,40
cycles,
probably because of the existence in our case of
the strong H N−Pd bond. Our research group has previously
2
reported that some olefins insert into the Pd−C bond of ortho-
palladated primary arylalkylamines to give stable complexes
containing the corresponding coordinated ortho-vinylated
The dibenzazepine structural skeleton is present in many
44
1
1
natural products, which possess a significant potential as
amines.
45−48
drugs in the medical field.
The most commonly employed
When 2-norbornene was used, the ten-membered pallada-
cycle intermediate analogous to I could form, but since a β-
elimination process was not possible, other decomposition
pathways operated and Pd(0) and very complicated mixtures
were obtained.
synthesis of dibenzazepines involves intramolecular cyclization
49
47
via radical mechanisms, condensation reactions, electro-
46,48,50
philic aromatic substitutions,
or Heck-type coupling
48,51
processes.
The complexes 7 and 8b have been characterized by IR and
NMR spectroscopy and elemental analyses. In their H NMR
CONCLUSION
1
■
In summary, the Pd−C bond of the eight-membered
metallacycles obtained by the reaction of benzyne and ortho-
metalated homoveratrylamine and phentermine is still reactive
toward unsaturated molecules and undergoes the insertion of
RNC, CO, alkenes (this work), or benzyne (see ref 10) to
afford (1) enlarged nine- or ten-membered palladacycles, (2)
spectrum, each olefinic hydrogen appears as a doublet with a
3
coupling constant of ca. J = 16 Hz, which is in agreement
HH
with the trans geometry of the double bond. In the NMR
spectra of complexes 7 and 8b some signals appeared split,
which can be assigned to the presence of two different
diastereomeric complexes arising from two distinct pairings of
the two enantiomers of the complexes 7 and 8b (R R or S S
a a
[
PdCl (amine) ], which contains a functionalized biarylamine
2 2
a
a
and exhibits axial chirality, or (3) after depalladation, the
organic products resulting from C−N coupling. The synthesis
of dibenzazepines, dibenzazocines, or dibenzazocinone deriva-
tives is reported.
vs R S or S R ). The chirality in these complexes arises from
a
a
a a
the hindered rotation about the single C−C bond of the biaryl
ligand, caused by the bulky substituents at the ortho-positions
4
(
Figure 4). This axial chirality is observed in many natural
EXPERIMENTAL SECTION
Caution! Special precautions should be taken in handling thallium(I)
compounds, which are toxic.
■
General Procedures. Infrared spectra, C, H, N, and S analyses,
conductance measurements, and melting point determinations were
7
conducted as described previously. Unless otherwise stated, NMR
spectra were recorded in CDCl via a 200, 300, or 400 spectrometer.
3
1
13
1
Chemical shifts are referenced to TMS ( H and C{ H}). Signals in
1
13
the H and C NMR spectra of all complexes were assigned with the
help of APT, HMQC, and HMBC techniques. Reactions were carried
out at room temperature without special precautions against moisture,
unless otherwise indicated.
Figure 4. Axial chirality for diortho-substituted biaryls 7 and 8b.
9
The palladacycles 1a and 1b were prepared as previously reported.
products that exhibit remarkable bioactivities, such as the
t
t
HTfO, BuOK, NEt , XyNC, BuNC, CO, Na CO , ethyl acrylate,
3
2
3
4
1
antibiotic vancomycin or some compounds related to 1-
phenylanthraquinone, which have recently shown good
styrene, and 2-norbornene were used as received. TlOTf was prepared
by reaction of Tl CO and HTfO (1:2) in water and recrystallized
2
3
4
2
43
antimalarial and antitumor activities.
Synthesis and Structure of 6,7-Dihydro-6,6-dimethyl-
H-dibenz[b,d]azepine. The reaction of 1b with BuOK in
toluene at 95 °C, under a N2 atmosphere, afforded the
dibenzazepine 9b in good yield (70%; Scheme 7). Unfortu-
nately, when a similar reaction was carried out starting from 1a,
although decomposition to Pd(0) was observed, a complicated
mixture was obtained from which no pure organic compounds
could be isolated.
from acetone/Et O. Chart 2 gives the numbering scheme for the new
2
palladium complexes and the organic compounds.
Synthesis of 2a. XyNC (47 mg, 0.361 mmol) was added to a
t
5
solution of palladacycle 1a (80 mg, 0.090 mmol) in CH Cl (25 mL),
2
2
and the resulting solution was stirred for 1 h. The mixture was filtered
through a plug of Celite, the filtrate was concentrated to ca. 2 mL, and
Et O (30 mL) was added. The suspension was filtered, and the solid
2
was washed with Et O (2 × 5 mL) and air-dried to afford complex 2a
2
as a yellow solid. Yield: 72 mg, 0.104 mmol. An analytically pure
sample of complex 2a was obtained by recrystallization from CH Cl /
2
2
F
dx.doi.org/10.1021/om500772p | Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
1
30.2 (s, CH, C6), 130.6 (s, CH, C6′), 131.8 (s, CH, C3 or C5), 134.3
Chart 2. Numbering Schemes for the New Palladium(II)
Complexes and the Organic Derivatives
(
1
s, C1), 135.5 (s, o-C, coordinated Xy), 138.2 (s, C1′), 142.9 (s, C2′),
43.1 (s, C2), 149.9 (s, i-C, inserted Xy), 179.5 (s, CN). The
resonances corresponding to the methyl groups of the inserted XyNC
as well as the CN of coordinated XyNC were not observed. Single
crystals of 2b·0.72Et O·0.28CHCl suitable for an X-ray diffraction
study were obtained by slow diffusion of Et O into a solution of 2b·
H O in CHCl .
2
3
2
2
3
t
Synthesis of 3a. BuNC (41 μL, 0.361 mmol) was added to a
solution of complex 1a (80 mg, 0.090 mmol) in CH Cl (25 mL), and
2
2
the resulting solution was stirred for 1 h. The mixture was filtered
through a plug of Celite, the filtrate was concentrated to ca. 2 mL, and
n-pentane (30 mL) was added. The suspension was filtered, and the
solid was washed with n-pentane (2 × 5 mL) and air-dried to afford
complex 3a as a yellow solid. Yield: 60 mg, 0.098 mmol, 55%. An
analytically pure sample of complex 3a was obtained by recrystalliza-
tion from CH Cl /n-pentane and drying the sample in a vacuum oven
2
2
at 60 °C for 16 h. Mp: 134 °C. Anal. Calcd for C H BrN O Pd
2
6
36
3
2
(
608.915): C, 51.28; H, 5.96; N, 6.90. Found: C, 51.07; H, 5.88; N,
−1
7
1
1
.07. IR (cm ): ν(NH) 3305 w, 3253 w; ν(CN) 2173 s, ν(CN)
1
t
607 s. H NMR (400.91 MHz): δ 1.33 (s, 9 H, Me, coordinated Bu),
Et O and drying the sample in a vacuum oven at 60 °C for 16 h. Mp:
2
t
.57 (s, 9 H, Me, inserted Bu), 1.62−1.67 (m, partially obscured by
1
5
3
42 °C. Anal. Calcd for C H BrN O Pd (692.992): C, 57.19; H,
33 36 3 2
1
t
2
−
the Bu signal, 1 H, NH ), 2.56 (br d, 1 H, CH Ar, J = 11.2 Hz),
.24; N, 6.06. Found: C, 57.19; H, 5.11; N, 5.82. IR (cm ): ν(NH)
2 2 HH
1
2.74−2.81 (m, 2 H, 1 H of CH Ar + 1 H of NH ), 2.98−3.02 (m, 1 H,
305 w, 3253 w; ν(CN) 2180 s; ν(CN) 1606 s. H NMR (600
2
2
CH N), 3.42−3.46 (m, 1 H, CH N), 3.82 (s, 3 H, MeO), 3.89 (s, 3 H,
MHz, −50 °C): δ 1.16 (br s, 2 H, NH ), 2.47 (br s, 3 H, Me, inserted
Xy), 2.54 (s, 6 H, Me, coordinated Xy), 2.57 (br s, 3 H, Me, inserted
2
2
2
MeO), 6.65 (s, 1 H, H6), 6.77 (s, 1 H, H3), 7.05 (m, 2 H, H3′ + H6′),
3
3
7.18−7.22 (“t”, 1 H, H5′, J = 6.4 Hz), 7.26−7.32 (m, partially
Xy), 2.81 (br d, 1 H, CH Ar, J = 10.8 Hz), 3.10−3.33 (m, 2 H, 1 H
HH
2
HH
1
3
1
obscured by the CHCl signal, 1 H, H4′). C{ H} NMR (100.81
CH Ar + 1 H of CH N), 3.51−3.60 (m, 1 H, CH N), 3.91 (s, 3 H,
3
2
2
2
t
MHz): δ 30.0 (s, Me, inserted Bu), 30.2 (s, CH Ar), 30.3 (s, Me,
inserted Bu), 31.1 (s, Me, coordinated Bu), 44.2 (s, CH N), 55.8 (s,
MeO), 4.00 (s, 3 H, MeO), 6.91 (s, 2 H, H6 + H3), 7.02−7.51 (m, 10
2
t
t
13
1
H, H4′ + H3′ + H5′ + H6′). C{ H} NMR (100.81 MHz, −50 °C):
δ 19.1 (s, Me, coordinated Xy), 19.2 (s, Me, inserted Xy), 19.8 (s, Me,
inserted Xy), 31.7 (s, CH Ar), 44.9 (s, CH N), 55.9 (s, MeO), 56.0 (s,
2
MeO), 56.0 (s, MeO), 108.5 (s, CH, C6), 114.4 (s, CH, C3), 125.5 (s,
CH, C3′), 126.0 (s, CH, C5′), 127.0 (s, CH, C4′), 130.7 (s, CH, C6′),
2
2
1
35.3 (s, C1), 135.6 (s, C2), 144.5 (s, C1′), 144.6 (s, C2′), 146.7 (s,
MeO), 113.6 (s, CH, C6), 123.4 (s, CH, C3), 125.8 (s, o-C, inserted
Xy), 125.9 (s, C1), 126.2 (s, o-C, inserted Xy), 127.0 (s, m-CH,
inserted Xy), 127.4 (s, m-CH, inserted Xy), 127.4 (s, p-CH, inserted
Xy), 127.9 (s, p-CH, coordinated Xy), 128.0 (s, m-CH, coordinated
Xy), 128.7 (s, CH, C3′), 129.7 (s, CH, C5′), 129.9 (s, CH, C4′), 131.6
13
C4), 148.7 (s, C5), 173.3 (s, CN). The C NMR resonance
corresponding to the CN group was not observed.
t
Synthesis of 3b·H O. BuNC (49 μL, 0.437 mmol) was added to a
2
solution of complex 1b (80 mg, 0.109 mmol) in CH Cl (25 mL), and
2
2
the resulting solution was cooled at 0 °C for 30 min. The mixture was
filtered through a plug of Celite, the filtrate was concentrated to ca. 2
(
s, CH, C6′), 134.9 (s, C2), 135.4 (s, i-C, inserted Xy), 135.6 (s, o-C,
13
coordinated Xy), 146.9 (s, C4 or C5), 148.7 (s, C4 or C5). The
C
mL, and Et O (30 mL) was added. The suspension was filtered, and
NMR resonances corresponding to the CN, CN, and i-C inserted
in the XyNC group, and C1′ and C2′, were not observed. Single
crystals of 2a·CH Cl ·1/2H O suitable for an X-ray diffraction study
were obtained by slow diffusion of n-pentane into a solution of 2a in
CH Cl .
2
the solid was washed with Et O (2 × 5 mL) and air-dried to afford
2
crude complex 3b·H O as a yellow solid. Yield: 56 mg, 0.102 mmol,
2
2
2
2
4
7%. An analytically pure sample of complex 3b·H O was obtained by
2
recrystallization from CH Cl /Et O and drying the sample in a
2
2
2
2
2
vacuum oven at 70 °C for 16 h. Mp: 167 °C. Anal. Calcd for
Synthesis of 2b·H O. XyNC (45 mg, 0.343 mmol) was added to a
2
C H ClN Pd·H O (550.472): C, 56.73; H, 6.96; N, 7.63. Found: C,
solution of palladacycle 1b (50 mg, 0.068 mmol) in CH Cl (10 mL),
and the resulting bright yellow solution was stirred for 3 h. The
solution was concentrated to ca. 1 mL, and Et O (20 mL) was added.
The suspension was filtered, and the yellow solid was washed with
26 36
3
2
2
2
−1
5
2
7.00; H, 6.75; N, 7.69. IR (cm ): ν(NH) 3305 w, 3253 w; ν(CN)
1
193 s, ν(CN) 1640 m. H NMR (300.1 MHz): δ 1.28 (s, 9 H, Me,
2
t
coordinated Bu), 1.49 (s, 3 H, CMe ), 1.50 (s, 3 H, CMe ), 1.55 (s, 9
2
2
t
H, Me, inserted Bu), 1.58 (br s, 2 H, H O), 1.84 (br d, 1 H, NH ,
JHH = 10.8 Hz), 2.39 (br d, 1 H, CH Ar, J = 15.0 Hz), 2.51 (br d, 1
H, CH Ar, JHH = 14.7 Hz), 2.86 (br d, 1 H, NH , JHH = 10.2 Hz),
Et O (2 × 5 mL) and air-dried to give the complex 2b·H O. Yield: 61
2
2
2
2
2
2
mg, 0.094 mmol, 69%. Dec pt: 190 °C. Anal. Calcd for C H ClN Pd·
2
HH
3
4
36
3
2
2
H O (646.568): C, 63.16; H, 5.92; N, 6.50. Found: C, 63.38; H, 5.76;
2
2
2
−1
2
N, 6.40. IR (cm ): ν(NH) 3292 m, 3169 m, 3099 m; ν(CN) 2182
7.00 (br d, 1 H, Ar, JHH = 7.8 Hz), 7.18−7.25 (m, 3 H, Ar), 7.26−7.33
13 1
1
vs; ν(CN) 1606 s. H NMR (400.91 MHz): δ 1.41 (s, 3 H, Me,
(m, partially obscured by the CHCl
signal, 4 H, Ar). C{ H} NMR
3
t
CMe ), 1.42 (br s, partially obscured by the resonance of CMe , 3 H,
(100.81 MHz): δ 30.0 (s, Me, inserted Bu), 30.3 (s, Me, coordinated
Bu), 33.3 (s, Me, CMe ), 33.9 (s, Me, CMe ), 40.1 (s, CH Ar), 55.0
2 2 2
2
2
t
Me, inserted Xy), 1.57 (s, 3 H, Me, CMe ), 1.62 (br s, 2 H, H O), 2.07
2
2
(
br s, 3 H, Me, inserted Xy), 2.28 (s, 6 H, Me, coordinated Xy), 2.35
(s, CMe ), 125.8 (s, CH, C4), 125.9 (s, CH, C3′), 126.2 (s, CH, C4′),
2
2
(
br d, 1 H, NH , J = 11.6 Hz), 2.43 (br m, 1 H, NH ), 2.54 (d, 1 H,
127.1 (s, CH, C3 or C5), 128.1 (s, CH, C5′), 130.0 (s, CH, C6), 132.7
(s, CH, C3 or C5), 133.7 (s, C1), 136.3 (s, C1′), 143.7 (s, C2′), 143.8
2
HH
2
2
2
CH Ar, J = 14.4 Hz), 2.68 (d, 1 H, CH Ar, J = 14.4 Hz), 6.75−
6
2
HH
2
HH
13
.85 (m, 3 H, p-H + m-H, inserted Xy), 7.06 (d, 2 H, m-H,
(s, C2), 171.4 (s, CN). The C NMR resonance corresponding to
3
3
4
coordinated Xy, J = 7.6 Hz), 7.13 (dd, 1 H, H6′, J = 7.6, J
=
=
the CN group was not observed.
HH
HH
HH
3
1
7
7
.2 Hz), 7.20 (m, 1 H, p-H, coordinated Xy), 7.30 (td, 1 H, H4, J
Synthesis of 4a. TlOTf (51 mg, 0.144 mmol) was added to a
suspension of complex 2a (100 mg, 0.144 mmol) in acetone (20 mL),
and the resulting solution was stirred for 30 min. The mixture was
filtered through a plug of Celite, the solvent from the filtrate was
removed, and toluene (10 mL) was added. The mixture was heated at
110 °C for 16 h. Decomposition to metallic palladium was observed.
The resulting suspension was filtered through a plug of Celite, the
solvent was removed from the filtrate, and the residue was vigorously
HH
4
.2, J = 2.0 Hz), 7.36−7.46 (m, 5 H, H3 + H4′ + H5 + H5′ + H6),
HH
3
4
13
1
.73 (dd, 1 H, H3′, J = 8.0, J = 1.6 Hz). C{ H} NMR (100.81
HH
HH
MHz): δ 18.8 (s, Me, coordinated XyNC), 31.3 (s, Me, CMe ), 34.9
2
(
s, Me, CMe ), 43.8 (s, CH Ar), 56.0 (s, CMe ), 123.1 (s, p-CH,
2 2 2
inserted Xy), 125.3 (s, o-C, inserted Xy), 126.2 (s, i-C, coordinated
Xy), 126.5 (s, CH, C4), 126.7 (s, CH, C3′), 127.0 (s, CH, C4′), 127.7
(
s, CH, C3 or C5), 127.8 (s, CH, C5′), 127.9 (s, m-CH, coordinated
Xy), 128.0 (s, m-CH, inserted Xy), 129.5 (s, p-CH, coordinated Xy),
stirred in Et O (30 mL). The resulting suspension was filtered, and the
2
G
dx.doi.org/10.1021/om500772p | Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
solid was washed with Et O (2 × 5 mL) and air-dried to afford
1 H, CH Ar), 2.95 (m, 1 H, CH Ar), 3.35 (m, 1 H, CH N), 3.46 (m, 1
2
2
2
2
compound 4a as an orange solid. Yield: 35 mg, 0.065 mmol, 45%. Λ
H, CH N), 3.83 (s, 3 H, MeO), 3.90 (s, 3 H, MeO), 5.92 (“t”, 1 H,
M
2
−1
2
−1
−4
3
(Ω
cm mol ) = 64 (1.5 × 10 M). Mp: 104 °C. HRESIMS: exact
NH, J = 6.4 Hz), 6.65 (s, 1 H, H10), 6.76 (s, 1 H, H7), 7.28−7.29
HH
+
13
1
mass calcd for C H N O 387.2073 [(M − OTf) ]; found 387.2033.
(m, 1 H, H7′), 7.41−7.53 (m, 3 H, H8′ + H9′ + H10′). C{ H}
25
27
2
2
−1
1
IR (cm ): ν(NH) 3195 br m; ν(CN) 1636 s. H NMR (300.1
NMR (75.45 MHz): δ 34.4 (s, CH Ar), 41.3 (s, CH N), 55.9 (s,
2
2
MHz, DMSO-d ): δ 1.38 (s, 3 H, Me, Xy), 2.26 (s, 3 H, Me, Xy),
MeO), 56.0 (s, MeO), 126.9 (s, CH, C8′), 127.1 (s, C10a), 127.8 (s,
CH, C9′), 129.7 (s, CH, C7′), 130.0 (s, CH, C10′), 132.1 (s, C6a),
135.8 (s, C5), 139.3 (s, C6), 147.4 (s, C8), 148.5 (s, C9), 174.0 (s,
CO). Single crystals suitable for an X-ray diffraction study were
obtained by slow diffusion of n-pentane into a solution of 5a in
CH Cl .
6
2
.83−2.91 (m, 2 H, CH Ar), 3.20−3.27 (m, partially obscured by the
2
H O signal, 1 H, CH N), 3.39−3.45 (m, partially obscured by the
MeO signal, 1 H, CH N), 3.73 (s, 3 H, MeO), 3.78 (s, 3 H, MeO),
2
2
2
6
7
7
.70 (s, 1 H, H7), 6.89 (s, 1 H, H10), 7.10−7.14 (m, 1 H, p-H, Xy),
3
.21−7.28 (m, 2 H, m-H, Xy), 7.58 (d, 1 H, H10′, J = 7.5 Hz),
HH
2
2
.72−7.74 (m, 2 H, H8′ + H9′), 7.81−7.86 (m, 1 H, H7′), 9.07 (“t”, 1
Synthesis of 5b. Et N (50 μL, 0.359 mmol) was added to a
3
3
13
H, CH NH, J = 5.7 Hz), 11.14 (s, 1 H, XyNH). C NMR (100.81
solution of palladacycle 1b (120 mg, 0.164 mmol) in CHCl (15 mL)
2
HH
3
MHz, DMSO-d ): δ 15.5 (s, Me, Xy), 17.3 (s, Me, Xy), 33.0 (s,
in a Carius tube, and CO was bubbled through the solution. The
pressure of CO was increased to 1 atm, the tube was sealed, and the
mixture was stirred for 12 h. Decomposition to metallic palladium was
observed. The suspension was filtered through a plug of Celite, and the
6
CH Ar), 42.2 (s, CH N), 55.9 (s, MeO), 55.9 (s, MeO), 114.9 (s, CH,
2
2
C7 + C10), 127.4 (s, CH, C9′), 127.4 (s, C10a), 128.4 (s, CH, C8′),
28.8 (s, C5), 128.9 (s, m-CH, Xy), 129.0 (s, p-CH, Xy), 129.2 (s, m-
CH, Xy), 130.3 (s, CH, C10′), 130.3 (s, C6a), 130.5 (s, i-C, Xy), 132.7
1
filtrate was extracted with water (2 × 15 mL) to remove the Et NHCl
3
(
1
s, CH, C7′), 135.1 (s, o-C, Xy), 135.2 (s, o-C, Xy), 147.5 (s, C8),
formed. The organic layer was dried over MgSO , and the mixture was
4
49.1 (s, C9), 164.2 (s, CN).
filtered. The filtrate was concentrated to ca. 1 mL, and n-pentane (20
mL) was added. The suspension was filtered, and the solid was washed
with n-pentane (2 × 5 mL) and dried in a vacuum oven at 60 °C for
16 h to afford lactam 5b as a colorless solid. Yield: 33 mg, 0.131 mmol,
Synthesis of 4b. TlOTf (116 mg, 0.328 mmol) was added to a
suspension of palladacycle 1b (120 mg, 0.164 mmol) in acetone (20
mL), and the resulting solution was stirred for 15 min. The mixture
was filtered through a plug of Celite, the solvent was removed from the
filtrate, and XyNC (86 mg, 0.656 mmol) and toluene (10 mL) were
added. The solution was heated at 105 °C for 5 h. Decomposition to
metallic palladium was observed. The mixture was filtered through a
40%. Mp: 216 °C. HRESIMS: calculated for C17H18NO 252.1388 [(M
+
−1
+ H) ]; found 252.1375. IR (cm ): ν(NH) 3261 m, 3169 m; ν(CO)
1
1632 vs. H NMR (400.91 MHz): δ 1.31 (s, 3 H, Me, CMe ), 1.34 (s,
3 H, Me, CMe
2
2
), 2.53 (d, 1 H, CH
Ar, JHH = 14.0 Hz), 2.75 (d, 1 H,
2
2
2
plug of Celite, the solvent was removed from the filtrate, and Et O (30
CH
2
Ar, JHH = 14.0 Hz), 5.62 (br s, 1 H, NH), 7.19−7.21 (m, 2 H,
2
mL) was added. The suspension was filtered, and the solid was washed
H10 + H7′), 7.32−7.38 (m, 3 H, H7 + H8 + H9), 7.47 (m, 2 H, H9′ +
3
4
13
1
with Et O (2 × 5 mL) and air-dried to afford a first crop of compound
H8′), 7.58 (dd, 1 H, H10′, JHH = 7.6, JHH = 1.6 Hz). C{ H} NMR
(100.81 MHz): δ 29.9 (s, Me, CMe ), 31.5 (s, Me, CMe ), 44.5 (s,
CH Ar), 54.3 (s, CMe ), 127.1 (s, CH, C8), 127.8 (s, CH, C7 or C9),
2
4
b as a colorless solid (113 mg). The filtrate was concentrated to ca. 2
2
2
mL, and n-pentane (20 mL) was added. The suspension was filtered,
and the solid was washed with n-pentane (2 × 5 mL) and air-dried to
afford a second crop of compound 4b as a colorless solid (36 mg).
2
2
127.9 (s, CH, C9′), 128.0 (s, CH, C10′), 128.8 (s, CH, C10), 128.9 (s,
CH, C9 or C7), 129.0 (s, CH, C7′), 130.0 (s, CH, C8′), 136.0 (s,
C10a), 136.9 (s, C5), 138.3 (s, C6), 141.2 (s, C6a), 172.4 (s, CO).
Synthesis of 7a. Ethyl acrylate (15 μL, 0.135 mmol) was added to
−
1
2
−1
Yield: 149 mg, 0.296 mmol, 90%. Λ (Ω cm mol ): 130 (6.35 ×
M
−
4
1
3
0
M). Mp: 168 °C. HRESIMS: exact mass calcd for C H N
25 27 2
+
−1
55.2174 [(M − OTf) ]; found 355.2179. IR (cm ): ν(NH) 3186 br
a solution of palladacycle 1a (100 mg, 0.113 mmol) in CHCl (20
3
1
m; ν(CN) 1620 s. H NMR (400.91 MHz, DMSO-d ): δ 1.27 (s, 3
mL), and the resulting solution was heated at 65 °C for 16 h. The
mixture was filtered through a plug of Celite, the filtrate was
concentrated to ca. 2 mL, and n-pentane (30 mL) was added. The
suspension was filtered, and the solid was washed with n-pentane (2 ×
5 mL) and air-dried to afford complex 7a as a yellow solid. Yield: 68
6
H, Me, CMe ), 1.29 (s, 3 H, Me, Xy), 1.34 (s, 3 H, Me, CMe ), 2.29
2
2
2
(
s, 3 H, Me, Xy), 2.46 (d, 1 H, CH Ar, J = 14.4 Hz), 2.76 (d, 1 H,
2 HH
2
CH Ar, J = 14.4 Hz), 7.02−7.04 (m, 1 H, p-H, Xy), 7.19−7.21 (m,
2
HH
2
H, m-H, Xy), 7.35−7.40 (m, 1 H, H7′), 7.46−7.53 (m, 4 H, H7 +
H8 + H9 + H10), 7.74−7.78 (m, 4 H, H8′ + H9′ + H10′ +
mg, 0.069 mmol, 62%. Mp: 100 °C. Anal. Calcd for C42
H50Br N O Pd
2 2 8
13
CMe NH), 10.90 (s, 1 H, XyNH). C NMR (100.81 MHz, DMSO-
(977.096): C, 51.63; H, 5.16; N, 2.87. Found: C, 51.28; H, 4.89; N,
2
−1
d ): δ 15.8 (s, Me, Xy), 17.8 (s, Me, Xy), 28.4 (s, Me, CMe ), 29.9 (s,
3.07. IR (cm ): ν(NH) 3295 br m, 3244 br m; ν(CO) 1712 s. The
6
2
1
Me, CMe ), 44.4 (s, CH Ar), 58.4 (s, CMe ), 127.7 (s, CH, C7), 128.1
H NMR spectrum corresponds to a 5:1 mixture of two
2
2
2
α
(
s, CH, C8), 128.4 (s, CH, C9′), 128.4 (s, CH, C8′), 129.0 (s, p-CH,
diastereoisomers that have coincident resonances except for the C H
1
3
Xy), 129.1 (s, C9 + m-CH, Xy), 128.3 (s, CH, H10), 129.7 (s, C10a),
group. H NMR (400.91 MHz): δ 0.88 (t, 3 H, Me, J = 7.2 Hz),
HH
1
29.9 (s, CH, C10′), 130.5 (s, C6a), 132.8 (s, CH, C7′), 134.5 (s, i-C,
2.22 (br s, 1 H, NH ), 2.30−2.63 (m, 2 H, CH Ar), 2.69−3.02 (m, 2
2
2
Xy), 135.5 (s, o-C, Xy), 135.7 (s, o-C, Xy), 139.9 (s, C5), 139.7 (s,
C6), 162.9 (s, CN). 2
H, CH N), 3.42−3.46 (m, 1 H, CH N), 3.81−3.88 (m, partially
2
2
obscured by the MeO signal, 1 H, NH ), 3.83 (s, 3 H, MeO), 3.97 (s,
2
2
3
Synthesis of 5a. Na CO (120 mg, 1.130 mmol) was added to a
3 H, MeO), 4.18 (q, 2 H, CH O, J = 14.1, J = 6.9 Hz), 6.34 (d,
2 HH HH
α
3
3
suspension of palladacycle 1a (100 mg, 0.113 mmol) in CHCl (25
1 H, C H, J = 15.9 Hz), 6.63 (s, 1 H, H3), 6.80 (s, 1 H, H6), 7.21−
β 3
3
HH
mL) in a Carius tube, and CO was bubbled through the solution. The
pressure of CO was increased to 1 atm, the tube was sealed, and
mixture was heated at 65 °C for 16 h. Decomposition to metallic
palladium was observed. The resulting suspension was filtered through
7.43 (m, 4 H, C H + H4′ + H5′ + H6′), 7.70 (d, 1 H, H3′, J = 6.9
HH
Hz). 13C{ H} NMR (100.81 MHz): δ 14.3 (s, Me), 34.3 (s, CH Ar),
1
2
45.7 (s, CH N), 56.0 (s, MeO), 56.2 (s, MeO), 60.5 (s, CH O), 111.5
2
2
α
(s, CH, C6), 113.6 (s, CH, C3), 119.5 (s, CH, C H), 126.8 (s, C1),
a plug of Celite, the filtrate was concentrated to ca. 2 mL, and Et O
128.0 (s, CH, C4′), 130.1 (s, CH, C5′), 131.0 (s, CH, C6′), 132.0 (s,
2
β
(
30 mL) was added. The suspension was filtered, and the solid was
C2), 133.0 (s, C2′), 141.5 (s, C1′), 142.6 (s, CH, C H), 147.6 (s, C4),
washed with Et O (2 × 5 mL) and air-dried to afford a first crop of
148.9 (s, C5), 166.7 (s, CO).
2
compound 5a as a colorless solid (35 mg). The filtrate was
concentrated to ca. 2 mL, and n-pentane (20 mL) was added. The
suspension was filtered, and the solid was washed with n-pentane (2 ×
Synthesis of 7b·H O. Ethyl acrylate (40 μL, 0.368 mmol) was
2
added to a suspension of palladacycle 1b (130 mg, 0.177 mmol) in
CH Cl2 (15 mL), and the yellow solution was stirred for 12 h.
2
5
mL) and air-dried to afford a second crop of compound 5a as a
Decomposition to metallic palladium was observed. The solvent was
1
colorless solid (10 mg). Yield: 45 mg, 0.159 mmol, 70%. The H NMR
of both crops display a variable amount of solvents, which cannot be
completely removed, even when the compound was dried in a vacuum
oven at 70 °C for 16 h. Mp: 196 °C. HRESIMS: exact mass calcd for
removed until ca. 3 mL, and Et O (20 mL) was added. The resulting
2
suspension was filtered through a plug of Celite. The filtrate was
concentrated to ca. 2 mL, and n-pentane (25 mL) was added. A waxy
residue appeared in the flask, the mother liquors were separated, n-
pentane (15 mL) was added to the residue, and the mixture was
vigorously stirred. The suspension was filtered, and the solid was
+
−1
C H NO 284.1287 [(M + H) ]; found 284.1295. IR (cm ):
17
18
3
1
ν(NH) 3260 br s; ν(CO) 1663 s. H NMR (400.91 MHz): δ 2.83 (m,
H
dx.doi.org/10.1021/om500772p | Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
washed with n-pentane (2 × 5 mL) and vacuum-dried to give the
C9 + C6′), 134.3 (s, C5), 137.7 (s, C9a), 139.9 (s, C5a), 144.1 (s,
C4).
complex 7b·H O as a hygroscopic yellow solid. Yield: 142 mg, 0.169
2
mmol, 95%. Mp: 145 °C. Anal. Calcd for C H Cl N O Pd·H O
Single-Crystal X-ray Structure Determinations. Relevant
crystallographic data, details of the refinements, complete set of
Cartesian coordinates and details (including symmetry operators) of
42
50
2
2
4
2
(
3
842.211): C, 59.90; H, 6.22; N, 3.33. Found: C, 60.10; H, 5.96; N,
.52. IR (cm ): ν(NH) 3290 w, 3206 w; ν(CO) 1711 vs. H NMR
−1
1
(
1
300.1 MHz): δ 1.11 (br s, 3 H, Me, CMe ), 1.19 (s, 3 H, Me, CMe ),
hydrogen bonds, and CIF files for compounds 2a·CH
2 2 2
Cl ·1/2H O,
2
2
3
.24 (t, 3 H, MeCH O, J = 7.2 Hz), 1.62 (br s, 2 H, H O), 2.33 (br
2b·0.72Et O·0.28CHCl , and 5a are given in the Supporting
2
3
2
HH
2
2
d, 1 H, NH , J = 10.0 Hz), 2.45 (br m, 1 H, NH ), 2.62 (d, 1 H,
CH Ar, J = 14.0 Hz), 2.78 (dd, 1 H, CH Ar, J = 14.0, J = 1.6
Hz), 4.15 (qd, 2 H, CH O, J = 7.2, J = 1.2 Hz), 6.34 (d, 1 H,
Information. Data Collection: Crystals suitable for X-ray diffraction
were mounted in inert oil on a glass fiber and transferred to a Bruker
2
HH
2
2
2
4
2
HH
2
HH
HH
3
2
SMART diffractometer. Data were recorded at 100(2) (2a·CH Cl ·1/
2
2
2
HH
HH
3
2
H O, 2b·0.72Et O·0.28CHCl ) or 223(2) K (5a), using graphite-
CH(CO), J = 16.0 Hz), 7.16 (m, 1 H, H3), 7.24−7.29 (m, 2 H,
2 2 3
HH
monochromated Mo Kα radiation (λ = 0.710 73 Å) and ω-scan mode.
Multiscan absorption corrections were applied for all complexes.
Structure Solution and Refinements: Crystal structures were solved by
H4′ + H6), 7.31−7.38 (m, 3 H, H4 + H5 + CH(Ar)C), 7.41 (dd, 1
3
4
H, H6′, J = 7.6, J = 0.8 Hz), 7.45 (br m, 1 H, H5′), 7.70 (br d, 1
HH
HH
3
13
H, H3′, J = 7.6 Hz). The C NMR spectrum corresponds to a 1:1
HH
Patterson (2a·CH Cl ·1/2H O) or direct methods (2b·0.72Et O·
mixture of two diastereoisomers that have coincident resonances
2
2
2
2
13
1
0.28CHCl , 5a), and all non-hydrogen atoms refined anisotropically
3
52
except for the CMe group. C{ H} NMR (100.81 MHz): δ 14.2 (s,
2
2
on F using the program SHELXL-97. Hydrogen atoms were refined
as follows: Compound 2b·0.72Et O·0.28CHCl : NH , free with SADI;
MeCH O), 29.41 (s, Me, CMe ), 29.44 (s, Me, CMe ), 29.66 (s, Me,
2
2
2
CMe ), 29.71 (s, Me, CMe ), 45.8 (s, CH Ar), 57.1 (s, CMe ), 60.4 (s,
2
3
2
2
2
2
2
ordered methyls, rigid group; all others, riding. Compounds 2a·
CH Cl ·1/2H O and 5a: NH or NH free; methyl, rigid group; all
CH O), 119.6 (s, CH(CO)), 126.4 (s, CH, C3′), 127.3 (s, CH,
2
2
2
2
2
C4), 128.0 (br s, CH, C5 + C6′), 130.0 (s, CH, C5′), 131.2 (s, CH,
C3), 131.4 (s, CH, C4′), 131.5 (s, CH, C6), 132.7 (s, C2′), 134.4 (s,
C1), 140.2 (s, C2), 142.0 (s, C1′), 142.2 (s, CH(Ar)C), 166.6 (s,
CO).
others, riding. Special features: For 2a·CH Cl ·1/2H O: One solitary
2
2
2
peak was assigned as the oxygen of a water molecule. Its hydrogens
were not included in the refinement. For 2b·0.72Et O·0.28CHCl :
2
3
The solvent sites were refined as a superposition of chloroform and
diethyl ether with a ca. 28:72 occupancy distribution. For 5a: The
crystal was stable neither at 100 K nor room temperature. We
therefore tried various temperatures; the final measurement temper-
ature was 223 K. 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
Synthesis of 8b. Styrene (25 μL, 0.218 mmol) was added to a
solution of palladacycle 1b (80 mg, 0.109 mmol) in CHCl (10 mL),
3
and the resulting solution was heated at 65 °C for 16 h. The mixture
was filtered through a plug of Celite, the filtrate was concentrated to
ca. 1 mL, and n-pentane (20 mL) was added. The suspension was
filtered, and the solid was washed with n-pentane (2 × 5 mL) and
dried in a vacuum oven at 60 °C for 16 h to afford complex 8b as
yellow solid. Yield: 55 mg, 0.066 mmol, 60%. Mp: 100 °C. Anal. Calcd
for C H Cl N Pd (838.264): C, 69.27; H, 6.06; N, 3.37. Found: C,
53
part of the PLATON system, was employed to remove mathemati-
cally the effects of the solvent. Standard deviations of refined
4
8
50
2
2
parameters should be interpreted with caution. The void volume per
−1
6
3
9.05; H, 6.05; N, 3.56. IR (cm ): ν(NH) 3475 w, 3362 w, 3291 w,
3
cell was 516.7 Å with a void electron count per cell of 205. This
243 w, 3187 w. The 13H NMR spectra of 8b corresponded to a 1:1
additional solvent was not taken into account when calculating derived
parameters such as the formula weight, because the nature of the
solvent was uncertain.
mixture of two diastereoisomers, which have coincident resonances
1
except for the CMe and CH Ar groups. H NMR (300.1 MHz): δ
2
2
1
.15 (s, 3 H, CMe ), 1.16 (s, 3 H, CMe ), 1.17 (s, 3 H, CMe ), 2.22
2 2 2
2
(
br d, 1 H, NH , J = 10.5 Hz), 2.34 (m, 1 H, NH ), 2.66 (d, 1 H,
2 HH 2
ASSOCIATED CONTENT
2
2
CH Ar, J = 13.8 Hz), 2.67 (d, 1 H, CH Ar, J = 13.5 Hz), 2.75
■
2
HH
2
HH
2
α
3
*
S
Supporting Information
(
d, 1 H, CH Ar, J = 13.8 Hz), 6.72 (d, 1 H, C H, J = 16.2 Hz),
2
HH
HH
β
3
1
13
7
7
.02 (d, 1 H, C H, J = 16.2 Hz), 7.17−7.26 (m, 5 H, Ph + Ar),
Copies of H and C-APT NMR spectra of compounds 4a, 4b,
5a, 5b, and 9b, crystallographic data, details of hydrogen bonds
(including symmetry operators), and CIF files for compounds
2a·CH Cl ·1/2H O, 2b·0.72Et O·0.28CHCl , and 5a. This
HH
13
1
.27−7.38 (m, 7 H, Ph + Ar), 7.75 (m, 1 H, H3′). C{ H} NMR
(
100.81 MHz): δ 29.5 (s, Me, CMe ), 29.9 (s, Me, CMe ), 45.9 (s,
2 2
α
CH Ar), 57.1 (s, CMe ), 125.4 (s, CH), 126.4 (s, CH, C H), 128.0 (s,
2
2
2
2
2
2
3
CH), 127.0 (s, CH), 127.6 (s, CH), 127.7 (s, CH), 127.9 (s, CH),
material is available free of charge via the Internet at http://
pubs.acs.org.
β
1
1
1
28.6 (s, CH), 130.2 (s, CH, C H), 131.1 (s, CH), 131.4 (s, CH),
34.4 (s, C), 134.5 (s, C), 135.5 (s, C), 137.3 (s, C), 140.1 (s, C),
41.2 (s, C).
t
AUTHOR INFORMATION
Corresponding Authors
*E-mail: ims@um.es (I. Saura-Llamas)
E-mail: jvs1@um.es (J. Vicente)
Synthesis of 9b. BuOK (100 mg, 0.890 mmol) was added to a
■
suspension of palladacycle 1b (120 mg, 0.164 mmol) in dry toluene
10 mL) under a N atmosphere in a Carius tube. The tube was sealed,
(
2
and the mixture was heated at 95 °C for 12 h. Decomposition to
metallic palladium was observed. The resulting suspension was filtered
through a plug of Celite, and the solvent was removed from the filtrate.
The residue was taken in n-pentane (15 mL), and the suspension
filtered through a plug of Celite. The solvent was removed from the
filtrate, and the residue was dried in a vacuum oven at 60 °C for 16 h
to give dibenzazepine 9b as an orange, waxy residue. Yield: 52 mg,
*
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the Ministerio de Ciencia e Innovacion
FEDER (Project CTQ2011-24016), and Fundacion
04539/GERM/06) for financial support. J.-A.G.-L. and M.-
■
́
(Spain),
Seneca
0
.233 mmol, 71%. HRESIMS: calculated for C H N 224.1434 [(M +
16 18
́
́
+
−1
1
H) ]; found 224.1437. IR (cm ): ν(NH) 3336 w. H NMR (400.91
MHz): δ 1.29 (s, 6 H, CMe ), 2.54 (s, 2 H, CH Ar), 6.84 (dd, 1 H,
(
2
2
J.O.-M. are grateful to the Fundacion
and Ministerio de Ciencia e Innovacion
for their research grants.
́
Sen
́
eca (CARM, Spain)
3
4
3
4
H9′, J = 7.2, J = 1.2 Hz), 7.12 (td, 1 H, H7′, J = 7.6, J
=
HH
HH
HH
HH
3
́
(Spain), respectively,
1
.6 Hz), 7.20−7.24 (m, 2 H, H8′ + H9), 7.28 (td, 1 H, H8, J = 7.2,
HH
4
3 4
J
= 1.2 Hz), 7.35 (td, 1 H, H7, J = 7.2, J = 1.2 Hz), 7.43 (dd,
HH HH
HH
3
2
H, H6 + H6′, JHH = 7.6, 4JHH = 1.6 Hz). The resonance
13 1
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■
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I
dx.doi.org/10.1021/om500772p | Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
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