Ortho palladation of the phenethylamines of biological relevance l -tyrosine methyl ester and homoveratrylamine. Reactivity of the palladacycles toward CO and isocyanides. Synthesis of the natural alkaloid corydaldine

Article abstract of DOI:10.1021/om300141b

Palladacycles derived from l-tyrosine methyl ester, (S)-[Pd ₂{C,N-C₆H₃CH₂CH(CO ₂Me)NH₂-2,(OH)-4}₂(μ-Br)₂] (1a-Br), and homoveratrylamine, [Pd₂{C,N-C₆H ₂CH₂CH₂NH₂-6,(OMe) ₂-3,4}₂(μ-Br)₂] (1b-Br), can be easily prepared in good yield by reacting Pd(OAc)₂, the corresponding ammonium triflate, and NaBr. Under the same conditions, the reaction of Pd(OAc)₂ with the free amine affords a low yield of the corresponding acetato complex 1a-OAc or 1b-OAc (the latter only detected in solution). In our hands, the previously reported palladation at the C2 position of homoveratrylamine with Pd(OAc)₂ is not observed. Instead, a complex mixture is obtained, mainly containing [Pd(OAc)₂{NH ₂CH₂CH₂C₆H₃(OMe) ₂-3,4}₂] and minor amounts of 1b-OAc, which reacts with NaBr to afford a new mixture from which [PdBr₂{NH₂CH ₂CH₂C₆H₃(OMe)₂-3,4} ₂] can be isolated and characterized. These and other adducts can be isolated from Pd(OAc)₂, homoveratrylamine, and various ligands (PPh₃ and Br^-). 6-Bromohomoveratrylamine reacts with Pd(dba)₂ in the presence of tmeda to give the complex [Pd{C,N-C ₆H₂CH₂CH₂NH₂-6,(OMe) ₂-3,4}(tmeda)]Br. Reactions of complexes 1 with acetylacetonato or neutral (PR₃) ligands give products resulting from substitution or bridge-splitting reactions. While 1a-Br reacts with XyNC (1:2 molar ratio) to give (S)-[Pd{C,N-C₆H₃CH₂CH(CO ₂Me)NH₂-2,(OH)-4}Br(CNXy)], 1b-Br gives [Pd{C,N-C(=NXy)-C₆H₂CH₂CH₂NH ₂-6,(OMe)₂-3,4}Br(CNXy)]. (S)-7-Hydroxy-3- (methoxycarbonyl)-3,4-dihydroisoquinolin-1(2H)-one and 6,7-dimethoxy-3,4- dihydroisoquinolin-1(2H)-one (corydaldine) have been synthesized through the stoichiometric carbonylation of palladacycles 1a-Br and 1b-Br. The crystal structures of a solvento intermediate in the ortho-metalation reaction of the triflate derivative of l-tyrosine methyl ester and four other complexes have been determined by X-ray diffraction studies.

Full text of DOI:10.1021/om300141b

Article
pubs.acs.org/Organometallics
Ortho Palladation of the Phenethylamines of Biological Relevance L-
Tyrosine Methyl Ester and Homoveratrylamine. Reactivity of the
Palladacycles toward CO and Isocyanides. Synthesis of the Natural
Alkaloid Corydaldine
†
†
,†
‡
́
María-Jose Oliva-Madrid, Jose-Antonio Garcıa-Lopez, Isabel Saura-Llamas,* Delia Bautista,
́
́
́
and Jose Vicente*,†
́
†Grupo de Química Organometal
Apartado 4021, E-30071 Murcia, Spain
́
ica, Departamento de Química Inorgan
́
ica, Facultad de Química, and ‡SAI, Universidad de Murcia,
S
* Supporting Information
ABSTRACT: Palladacycles derived from L-tyrosine methyl ester, (S)-
[Pd2{C,N-C6H3CH2CH(CO2Me)NH2-2,(OH)-4}2(μ-Br)2] (1a-Br), and
homoveratrylamine, [Pd2{C,N-C6H2CH2CH2NH2-6,(OMe)2-3,4}2(μ-Br)2]
(1b-Br), can be easily prepared in good yield by reacting Pd(OAc)2, the
corresponding ammonium triflate, and NaBr. Under the same conditions, the
reaction of Pd(OAc)2 with the free amine affords a low yield of the
corresponding acetato complex 1a-OAc or 1b-OAc (the latter only detected
in solution). In our hands, the previously reported palladation at the C2 position of homoveratrylamine with Pd(OAc)2 is not
observed. Instead, a complex mixture is obtained, mainly containing [Pd(OAc)2{NH2CH2CH2C6H3(OMe)2-3,4}2] and minor
amounts of 1b-OAc, which reacts with NaBr to afford a new mixture from which [PdBr2{NH2CH2CH2C6H3(OMe)2-3,4}2] can
be isolated and characterized. These and other adducts can be isolated from Pd(OAc)2, homoveratrylamine, and various ligands
(PPh3 and Br−). 6-Bromohomoveratrylamine reacts with Pd(dba)2 in the presence of tmeda to give the complex [Pd{C,N-
C6H2CH2CH2NH2-6,(OMe)2-3,4}(tmeda)]Br. Reactions of complexes 1 with acetylacetonato or neutral (PR3) ligands give
products resulting from substitution or bridge-splitting reactions. While 1a-Br reacts with XyNC (1:2 molar ratio) to give (S)-
[Pd{C,N-C6H3CH2CH(CO2Me)NH2-2,(OH)-4}Br(CNXy)], 1b-Br gives [Pd{C,N-C(NXy)-C6H2CH2CH2NH2-6,(OMe)2-
3,4}Br(CNXy)]. (S)-7-Hydroxy-3-(methoxycarbonyl)-3,4-dihydroisoquinolin-1(2H)-one and 6,7-dimethoxy-3,4-dihydroisoqui-
nolin-1(2H)-one (corydaldine) have been synthesized through the stoichiometric carbonylation of palladacycles 1a-Br and 1b-
Br. The crystal structures of a solvento intermediate in the ortho-metalation reaction of the triflate derivative of L-tyrosine methyl
ester and four other complexes have been determined by X-ray diffraction studies.
using the corresponding ammonium triflates as starting
materials, instead of the free amines or their hydrochlorides.19
For instance, the dimeric bromo-bridged palladacycle derived
from L-phenylalanine methyl ester can be obtained from
Pd(OAc)2, NaBr, and (1) L-phenylalanine methyl ester
hydrochloride, in 49% yield,8 or (2) the triflate derivative of
L-phenylalanine methyl ester, in 89% yield (Scheme 1).19
We report in this work the application of this improved
method to (1) synthesize a new palladacycle derived from L-
tyrosine methyl ester, a derivative of a natural amino acid, and
(2) improve the yield of the previously reported product of the
ortho palladation of homoveratrylamine,20 a hallucinogenic
compound closely related to the amphetamine family.12 This
second objective was not achieved because, in our hands, the
ortho palladation of homoveratrylamine takes place in a
position of the aryl ring different from that reported.20 We
also (1) analyze the differences and advantages of using the
triflate salts instead of the free amines as starting materials in
INTRODUCTION
■
Ortho-palladated complexes have been widely used as
precatalysts in organic synthesis1,2 or as reagents toward
unsaturated compounds to afford organic derivatives of the
corresponding arenes.2−4 We have contributed to this last
topic,5 preparing organic derivatives of benzyl-6 and phenethyl-
amines7−10 by reaction of the corresponding cyclopalladated
complexes with CO, RNC, RNCS, halogens, or olefins. A
parallel study is being carried out with ortho-palladated
benzylamines.11 We are particularly interested in using this
method to prepare derivatives of phenethylamines, because
some pharmaceuticals (i.e., amphetamines) and biologically
active amino acids belong to this family of compounds.12
For a long time, primary arylalkylamines were believed to be
inert toward direct activation of C−H bonds by Pd(II),13 but
their cyclometalation was proved to be possible when the
adequate reaction conditions were used.14,15 Nevertheless, most
derived halogen-bridged ortho-metalated complexes were
obtained in low to moderate yields (17−63%).8,16−18 Very
recently, we have found that those yields can be significantly
improved if the ortho-palladation reactions are carried out
Received: February 20, 2012
Published: April 12, 2012
© 2012 American Chemical Society
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Scheme 1. Reported Syntheses of the Bromo-Bridged Ortho-
Palladated Derivative of L-Phenylalanine Methyl Ester
Scheme 2. Synthesis of Palladacycles Containing L-Tyrosine
Methyl Ester and Homoveratrylamine
these ortho-metalation reactions, (2) prepare some derivatives
of the cyclopalladated complexes by reacting them with anionic
and neutral ligands, and (3) prepare the lactams derived from
both phenethylamines via carbonylation of their corresponding
palladacycles.
RESULTS AND DISCUSSION
■
Synthesis of Ortho-Palladated Complexes. Consistent
with our recently described method for ortho palladation of
primary arylalkylamines,19 the ammonium triflate derived from
L-tyrosine methyl ester, (S)-[4-OH-C6H4CH2CH(CO2Me)-
NH 3 ]OT f ( A), or homoveratrylamine, [3, 4-
(MeO)2C6H3CH2CH2NH3]OTf (B), reacted with Pd(OAc)2
in a 1:1 molar ratio, in acetonitrile at 78 °C, to give HAcO and,
likely, an ortho-metalated solvento intermediate (Ia·2S, Ib·2S;
Scheme 2), which in turn reacted with NaBr to afford the
bromo-bridged cyclopalladated complex 1a-Br or 1b-Br. The
addition of NaAcO to solutions of the intermediate Ib in
acetone afforded the acetato-bridged complex 1b-OAc, which
could not be isolated in pure form from the reaction mixture.
The metathesis reaction between 1b-Br and NaAcO afforded
the complex 1b-OAc contaminated with unreacted 1b-Br, even
when long reaction times and a large excess of NaOAc were
used. However, the reaction of complex 1b-Br with AgClO4 in
a 1:2 molar ratio, and the subsequent addition of NaAcO,
allowed the synthesis of pure 1b-OAc (Scheme 2).
Scheme 3. Reactions of Ortho-Palladated Complexes with
XyNC
When 1b-Br was treated with [Tl(acac)] (Hacac =
acetylacetone), precipitation of TlBr took place and the
complex [Pd{C,N-C6H2CH2CH2NH2-6,(OMe)2-3,4}(O,O′-
acac)] (2b) was obtained (Scheme 2). 1a-Br, 1b-Br, or 1b-
OAc reacted with 2 equiv of PR3 (R = Ph, p-To) to give the
mononuclear phosphino adduct [Pd{C,N-C6H3CH2CH-
(CO2Me)NH2-2,(OH)-4}Br(PPh3)] (3a-Br) or [Pd{C,N-
C6H2CH2CH2NH2-6,(OMe)2-3,4}X(PR3)] (X = Br, R = Ph
(3b-Br), To (3b′-Br); X = OAc, R = Ph (3b-OAc); Scheme 2).
1a-Br reacted with 2 equiv of XyNC to give [Pd{C,N-
C6H3CH2CH(CO2Me)NH2-6,(OH)-4}Br(CNXy)] (4a)
(Scheme 3). When an analogous reaction was tried using 1b-
Br as starting material, a mixture of the unreacted bromo-
bridged cyclometalated compound and the complex [Pd{C,N-
C(NXy)-C6H2CH2CH2NH2-6,(OMe)2-3,4}Br(CNXy)]
(5b) was isolated. Complex 5b could be prepared in good yield
by reaction of complex 1b-Br with 4 equiv of XyNC. The same
reaction with 1a-Br gave a solid insoluble in all common
organic solvents.
isocyanide.6,21−24 According to this mechanism, the different
behavior between palladacycles 1a-Br and 1b-Br toward
isocyanide insertion can be attributed to the increased
nucleophilicity of the carbon atom bonded to palladium(II)
in the homoveratrylamine derivative, which favors the insertion
of the isocyanide into the Pd−C bond.24,25 The easy insertion
of the isocyanide into the Pd−C bond of 1b-Br resembles the
behavior of the palladacycle derived from benzyl methyl sulfide,
which undergoes rapid isocyanide insertion at room temper-
ature,22 and contrasts with that exhibited by complexes derived
from classical N,N-benzylamines, for which high temperature or
The mechanism of the insertion of isocyanides into the Pd−
C bond, which has been thoroughly studied, involves (1)
coordination of the ligand to the metal center and (2)
migratory insertion of the aryl group to the coordinated
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an excess of isocyanide is required to obtain the iminoacyl
complexes.6,21
Scheme 4. Reported Synthesis of Palladacycles Containing
Homoveratrylamine20
The NMR data support the structures of compounds 1−5
shown in Schemes 2 and 3. The 1H NMR spectra of
homoveratrylamine derivatives show that only the isomer
palladated at C6 was obtained. Thus, for non-phosphino
complexes (1b-Br, 1b-OAc, 2b, and 5b) the H2 and H5
protons give singlets (δ 6.43−6.68 (H2), 6.69−7.60 (H5)).
Coordination of PR3 to the metal produces, with respect to its
precursor, a large shielding of the aromatic proton next to the
metalated carbon (e.g., δ(H5) 6.69 (1b-OAc), 6.01 (3b-OAc))
and of the adjacent methoxy protons of the homoveratrylamine
derivatives (e.g., δ(MeO) 3.80, 3.81 (1b-OAc), 3.02 (3b-
OAc)), as observed in other cases.26 Additionally, coupling of
H5 with the 31P nucleus was observed in all complexes (4JHP
=
4.8−5.2 Hz). These features are consistent with coordination of
the PR3 in a position trans to the amino group,27 which is the
expected geometry on taking into account the great trans-
phobia28 between PR3 and aryl ligands.29,30 1H and 13C NMR
spectra of complex 5b show the restricted rotation of the Xy
group of the inserted isocyanide, probably caused by steric
hindrance. We propose that, in both complexes, the
coordinated isocyanide is located in a position trans to the
amino group, because this is the normal behavior for
palladacycles containing arylalkylamines,6,9,10,21,23,31,32 and this
is in agreement with the well-established transphobia between
C-donor ligands.29,33
Ortho Palladation of Homoveratrylamine. Our results
on the ortho metalation of homoveratrylamine agree with those
obtained by other authors for similar N ligands. For instance,
Vila et al. have studied the influence on the metalation position
of different substituents at the aromatic ring in some Schiff
bases34 and conclude that a methoxy group at C3 hinders
palladation at C2. Pfeffer et al. have observed similar steric
hindrance in the synthesis of cyclometalated ruthenium(II)
complexes containing substituted N,N-dimethylbenzylamines.35
Direct palladation of N,N-diethyl-3-methoxy-4-benzyloxy-ben-
zylamine,26 N,N-dimethyl-3,4-dimethoxybenzylamine,36 N-
methyl-N-butyl-3,4-dimethoxybenzylamine,37 N-butyl-3,4-di-
methoxybenzylamine,38 N-(3,4-dimethoxybenzylidene)-
benzeneamine,39 N-(3,4-dimethoxybenzylidene)-2,4,6-trime-
thylbenzeneamine,40 N-(2-hydroxoethyl)-3,4-dimethoxybenzy-
lideneamine,41 N-(2,6-dichlorobenzylidene)-2-(3,4-
dimethoxyphenyl)ethylamine,42 and 4-(3,4-dimethoxybenzyli-
dene)-2-(3,4-dimethoxyphenyl)oxazol-5(4H)-one43 (among
others) have also been reported to occur regiospecifically at
the C6 position. Surprisingly, Hajipour et al.20 described the
reaction between homoveratrylamine and Pd(OAc)2 in
acetonitrile at 80 °C to give the ortho-palladated complex at
the C2 position. The acetato-bridged complex could not be
isolated pure, but a metathesis reaction with NaBr afforded the
corresponding bromo-bridged derivative (Scheme 4) in 39%
overall yield (based on Pd(OAc)2).
1
Figure 1. H NMR (6.4−7.0 ppm) spectra of (a) complex 6b-OAc
and (b−e) mixture X obtained from the reaction of Pd(OAc)2 and free
homoveratrylamine in acetonitrile at different reaction times and
temperatures: (b) 4 h at 80 °C; (c) 7 h at 78 °C; (d) 7 days at room
temperature; (e) 2 h at 70 °C and then 48 h at room temperature.
Signals corresponding to complex 6b-OAc are marked with red circles
and signals of complex 1b-OAc with green stars. At least two other
species are present in mixture X: a complex ortho-metalated at the C6
position (signals marked with black stars) and a non-ortho-metalated
compound (signals marked with yellow squares).
component, and the ortho-palladated complex 1b-OAc (signals
marked with green stars in Figure 1) is also present. Using
other reaction times (4−48 h) and temperatures (25−80 °C),
mixtures very similar to X were obtained. We could not
discount that a small amount of the ortho-metalated complex at
With the aim of elucidating if the use of the triflate salt
instead of the free amine as starting material could modify the
result of the metalation reaction, we repeated it under the same
conditions used by Hajipour et al.20 However, in our hands,
when a 1:1 mixture of homoveratrylamine and Pd(OAc)2 was
refluxed in acetonitrile for 4 h, the dark orange solid X could be
isolated, along with metallic palladium. The 1H NMR spectrum
of X (Figure 1, spectrum b) corresponds to a mixture in which
[Pd(OAc)2{NH2CH2CH2C6H3(OMe)2-3,4}2] (6b-OAc; sig-
nals marked with red circles in Figure 1) is the major
1
the C2 position was present in this mixture, since its H NMR
signals could be obscured by those corresponding to other
components (Figure 1, spectra b−e). When X was treated with
an excess of NaBr, a new mixture was obtained from which
[PdBr2{NH2CH2CH2C6H3(OMe)2-3,4}2] (6b-Br) could be
isolated in 48% yield. 6b-OAc and 6b-Br were independently
prepared by the reaction of Pd(OAc)2 and the free amine at
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room temperature in a 1:2 molar ratio (Scheme 5). To
characterize the components of X, the reaction of 6b-OAc or
Scheme 5. Synthesis of Non-Ortho-Palladated Complexes
Containing Homoveratrylamine
1
Figure 2. H NMR (6.4−7.0 ppm) spectra of (a) complex 8b, (b)
mixture Y, obtained when a solution of complex 8b in CH2Cl2 is
maintained at room temperature for 40 h, (c) mixture Y, obtained by
heating solid 8b at 65 °C for 5 h, (d) mixture X, and (e) complex 6b-
OAc. Signals corresponding to complex 6b-OAc are marked with red
circles, signals of complex 8b with blue circles, and signals of complex
1b-OAc with green stars. Two other species are present in both
mixtures: a complex ortho-palladated at the C6 position (signals
marked with black stars) and a non-ortho-palladated compound
(signals marked with yellow squares).
6b-Br with 1 equiv of PPh3 was carried out and
[PdX2{NH2CH2CH2C6H3(OMe)2-3,4}(PPh3)] (X = OAc
(7b-OAc), Br (7b-Br); Scheme 5) was isolated. Surprisingly,
the phosphino ligand only displaced one of the two amines
coordinated to palladium(II), even when an excess of PPh3 was
used.
We have proved15,17,18 that the reaction of Pd(OAc)2 with 1
equiv of arylalkylamines in acetonitrile gives initially the
complex [Pd(OAc)2(amine)2], which further reacts with the
remaining Pd(OAc)2 to give the dinuclear complex [Pd2(μ-
OAc)2(OAc)2(amine)2] (Scheme 5), which, in turn, can
undergo the ortho-palladation reaction upon heating in
acetonitrile. When Pd(OAc)2 and 1 equiv of homoveratryl-
amine in CH2Cl2 were reacted at room temperature, a mixture
was obtained after 1 h, from which complexes 6b-OAc (40%)
and [Pd2(μ-OAc)2(OAc)2{NH2CH2CH2C6H3(OMe)2-3,4}2]
(8b; 35%) were isolated. When longer reaction times were
used, complex 8b evolved to the mixture Y, which contained
some of the species present in the mixture X. Moreover, when
it was heated in the solid state, complex 8b also evolved to the
mixture Y (Figure 2). The complex 7b-OAc (Scheme 5) could
also be prepared by reaction of 8b with 2 equiv of PPh3.
In addition to signals for 6b-OAc (present in mixture X), 8b
(present in mixture Y), and 1b-OAc (present in X and Y), two
other sets of signals were observed in the 1H NMR spectra (in
CDCl3) of both mixtures: one pair of singlets at 6.50 and 6.65
ppm (relative intensities 1:1), probably corresponding to a
compound ortho-palladated at the C6 position (C), and a
doublet of doublets (δ 6.57, 3JHH = 8.0, 4JH3H = 2.0 Hz) plus two
observed by 31P NMR: 3b-OAc (Scheme 2), formed from 1b-
OAc (Scheme 2) and C, and 7b-OAc, formed from 6b-OAc,
8b (Scheme 5) and D. Consistent with these data, C could be
an isomer of 1b-OAc (Scheme 2) and D an isomer of 8b or 6b-
OAc, because they would give the same complexes with PPh3 as
1b-OAc and 8b or 6b-OAc, respectively.
The crystal structures of 6b-Br (Figure 3), 6b-OAc·H2O
(Figure 4), and 7b-OAc (Figure 5) have been determined by X-
ray diffraction. The molecules of 6b-Br and 6b-OAc·H2O are
centrosymmetric, with the palladium atoms coordinated to two
bromo (6b-Br) or two terminal acetato (6b-OAc·H2O) ligands
and the nitrogen atoms of two amines, in an almost perfect
square-planar geometry. For 6b-Br there are two independent
molecules in the asymmetric unit. The amino ligands adopt a
mutually trans disposition, which is the normal geometry for
this type of complex.7,44 In 7b-OAc, the palladium(II) center is
bound to the NH2 group of the homoveratrylamine, one
triphenylphosphine, and two trans acetato ligands. To our
knowledge, this is the first structurally characterized bis-acetato
complex of Pd(II) containing a primary arylalkylamine and a
phosphino ligand, although crystal structures of complexes of
the type trans-[PdCl2(arylalkylamine)(PR3)] have been re-
ported.45
4
doublets (δ 6.67, JHH = 2.0 Hz; δ 6.75, JHH = 8.0 Hz) with
relative intensities 1:1:1, which could be assigned to a non-
ortho-palladated complex (D). In order to characterize C and
D, we reacted mixtures X and Y with 1−2 equiv of PPh3/Pd,
which afforded a mixture of two complexes in both cases, as
The molecules of 6b-Br and 6b-OAc·H2O are associated
through N−H···Br and N−H···OOAc hydrogen bonds to give
chains and double chains, respectively. In 6b-Br, the chains are
connected through a weak COMe−H···OOMe interaction to
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Figure 3. X-ray thermal ellipsoid plot of one (A) of the two
independent molecules of 6b-Br (50% probability) showing the
labeling scheme. Selected bond lengths (Å) and angles (deg) are given
for both independent molecules. For A: Pd(1)−N(1) = 2.029(2),
Pd(1)−Br(1) = 2.4213(3); N(1)−Pd(1)−Br(1) = 89.33(7), N(1)−
Pd(1)−Br(1A) = 90.67(7). For B: Pd(2)−N(2) = 2.030(2), Pd(2)−
Br(2) = 2.4276(3); N(2)−Pd(2)−Br(2) = 88.73(7), N(2)−Pd(2)−
Br(2A) = 91.27(7).
Figure 4. X-ray thermal ellipsoid plot of 6b-OAc·H2O (50%
probability) showing the labeling scheme (the solvent molecule has
been omitted for clarity). Selected bond lengths (Å) and angles (deg):
Pd(1)−N(1) = 2.0451(17), Pd(1)−O(1) = 2.0161(14); N(1)−
Pd(1)−O(1) = 86.83(7), N(1)−Pd(1)−O(1A) = 93.17(7).
The oxidative addition of 2-bromo-3,4-dimethoxyphenethyl-
amine to “Pd(dba)2” was tried under a nitrogen atmosphere
using other solvents and temperatures and in the presence or
absence of auxiliary ligands, but no satisfactory results were
obtained. For instance, when the reaction was carried out (1) in
the absence of any auxiliary ligand, in toluene, at 25−60 °C,
unreacted starting material was obtained, along with other
unidentified compounds, and (2) in presence of ethylenedi-
amine and NaBr, in THF, at room temperature, abundant
decomposition to metallic palladium was observed.
generate layers, while in 6b-OAc·H2O the chains are connected
through O−H···OOAc hydrogen bonds involving the crystal-
lization water, to form a three-dimensional net. In 7b-OAc, two
adjacent molecules are connected through four N−H···OOAc
hydrogen bonds to give dimers which, in turn, are connected
through nonclassical C−H···OOAc hydrogen bonds to give
double chains along the a axis (see the Supporting
Information).
Synthesis of Ortho-Palladated Derivatives of Homo-
veratrylamine by Oxidative Addition. As we were not able
to obtain the ortho-palladated derivative of homoveratrylamine
at the C2 position by C−H activation, we tried to prepare it by
oxidative addition of 2-bromo-3,4-dimethoxyphenethylamine
(see the Experimental Section and Supporting Information) to
“Pd(dba)2” ([Pd2(dba)3]·dba; dba = dibenzylideneacetone) in
the presence of tmeda (tmeda = N,N,N′,N′-tetramethylethyle-
nediamine). When these three reagents (molar ratio 1:1:1)
were stirred in dry toluene at room temperature for 24 h, a
mixture was obtained from which no pure complex could be
isolated. Addition of PPh3 to this mixture afforded a new
mixture of at least five P-containing compounds, as observed by
31P NMR, that could not be separated (Scheme 6). When an
analogous reaction was carried out from 6-bromo-3,4-
dimethoxyphenethylamine, the complex [Pd{C,N-
C6H2CH2CH2NH2-6,(OMe)2-3,4}(tmeda)]Br (9b) precipi-
tated in the reaction mixture and could be isolated in 72%
yield (Scheme 6). Reaction of 9b with PPh3 (molar ratio 1:1)
gave 3b-Br.
Ortho Palladation of L-Tyrosine Methyl Ester. To check
the advantages of using the triflate salt instead of the free amino
acid derivative, we tried the reaction of L-tyrosine methyl ester
with 1 equiv of Pd(OAc)2 in acetonitrile at 78 °C for 8 h.
Under these conditions, a dark brown solid (Z) precipitated in
the reaction medium. From the filtrate, the complex [Pd2{C,N-
C6H3CH2CH(CO2Me)NH2-2,(OH)-4}2(μ-OAc)2] (1a-OAc)
was isolated in 15% yield (Scheme 7).
Z is very insoluble in all common organic solvents, including
acetonitrile and DMSO, which prevented the removal of the
metallic palladium that contaminated it. Its elemental analysis
detected C, H, and N, and its IR spectrum showed a strong
peak corresponding to νsym(CO2) at 1724 cm−1. Z did not react
with PPh3 or pyridine, even when it was heated to 80 °C in
t
acetonitrile. On treatment with XyNC or BuNC very complex
mixtures were obtained, which showed in their 1H NMR signals
attributable to several types of isocyanide molecules. When Z
was reacted with triflic acid, a deep red solution formed, from
1
which an oily residue was obtained, the H NMR of which
showed, in the aromatic region, the signals corresponding to an
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Scheme 7. Ortho Palladation of L-Tyrosine Methyl Ester
Figure 5. X-ray thermal ellipsoid plot of complex 7b-OAc (50%
probability) showing the labeling scheme (hydrogen atoms bonded to
carbon have been omitted for clarity). Selected bond lengths (Å) and
angles (deg): Pd(1)−N(1) = 2.1000(14), Pd(1)−O(3) = 2.0234(11),
Pd(1)−P(1) = 2.2539(4), Pd(1)−O(5) = 2.0042(11); N(1)−Pd(1)−
O(3) = 92.77(5), O(3)−Pd(1)−P(1) = 86.20(3), P(1)−Pd(1)−O(5)
= 93.24(3), O(5)−Pd(1)−N(1) = 87.89(5).
Scheme 6. Oxidative Addition of 2- and 6-Bromo-3,4-
dimethoxyphenethylamines to Pd(dba)2
Figure 6. X-ray thermal ellipsoid plot of the cation of intermediate
Ia·2MeCN (50% probability) showing the labeling scheme. Selected
bond lengths (Å) and angles (deg): Pd(1)−C(1) = 1.979(4), Pd(1)−
N(1) = 2.044(4), Pd(1)−N(2) = 2.008(4), Pd(1)−N(3) = 2.143(4);
C(1)−Pd(1)−N(1) = 87.77(16), N(1)−Pd(1)−N(3) = 92.39(15),
N(3)−Pd(1)−N(2) = 88.35(15), N(2)−Pd(1)−C(1) = 91.64(16),
Pd(1)−N(2)−C(13) = 171.6(4), Pd(1)−N(3)−C(11) = 170.3(4).
ortho-palladation reaction when the triflate salt was used as
starting material (Scheme 2; S = MeCN). Finally, when
complex 1a-OAc was stirred in acetonitrile for 18−36 h, the
solid Z formed and acetic acid could be detected in the reaction
mixture. On the basis of all these data, we conclude that Z is
mainly a polymeric complex (Scheme 7), derived from 1a-OAc.
The formation of polymer Z can be partially eluded by
changing the reaction conditions. The lowest yield (29%) of Z
was reached when a 1:1 mixture of L-tyrosine methyl ester and
Pd(OAc)2 was stirred in CH2Cl2 at room temperature for 4 h,
the solvent was removed, acetonitrile was added, and the
solution was heated at 70 °C for 2.5 h. Under these conditions,
ortho-palladated ring, along with other unidentified product. All
our efforts to obtain a solid from this residue were fruitless. In
one of these attempts the residue was repeatedly washed with
Et2O. An X-ray diffraction study of a single crystal obtained
from the combined extracts showed it to be Ia·2MeCN (Figure
6), the solvento complex proposed as an intermediate in the
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complex 1a-OAc was obtained in 63% yield. When longer
heating times or higher temperatures were used, the yield of Z
increased. In contrast, if the ortho-palladation reaction was
carried out in the presence of 2 equiv of HOAc, the amount of
polymer Z decreased to 10%, and when 3 equiv of HOAc was
used, formation of Z was not observed. In a similar way, when
the triflate A was used as the starting material, 2 equiv of HOAc
was generated during the ortho-palladation reaction (Scheme
2), preventing the deprotonation of the OH group and the
formation of Z. 1a-OAc reacted with PPh3 in a 1:2 molar ratio
to give the mononuclear phosphino adduct [Pd{C,N-
C6H3CH2CH(CO2Me)NH2-2,(OH)-4}(OAc)PPh3] (3a-OAc;
Scheme 7).
crystals suitable for X-ray diffraction studies were obtained in
very low yield.
For Ia·2MeCN, the cationic units are connected to the
triflate groups through classical and nonclassical hydrogen
bonds, generating double chains along the a axis. For 3a-OAc,
two adjacent molecules are associated through two hydrogen
bonds, both of them involving the OH group, giving rise to
dimers, which in turn are associated through nonclassical
hydrogen interactions (involving also the OH group),
generating double chains along the b axis (see the Supporting
Information).
Synthesis of Lactams by Insertion of Carbon
Monoxide into the Pd−C Bond of Cyclopalladated
Complexes. The insertion of CO into the Pd−C bond of
ortho-palladated benzyl- or phenethylamines is a well-known
process,2,3,31,47 which constitutes the key step in the Pd(II)-
catalyzed carbonylation of N-protected arylalkylamines via C−
H aryl activation, to give lactams or esters.48,49
The crystal structures of the intermediate Ia·2MeCN (Figure
6) and the complex 3a-OAc (Figure 7) have been determined
However, with the notable exception of a few α-alkyl-
substituted phenethylamines,50 the catalytic cycle seems to fail
for primary arylalkylamines.49 This result is not surprising, since
ortho palladation of primary benzyl or phenethylamines does
not occur (or is extremely slow) when an excess of the amine is
present.14,15,17 Although catalytic conversion is not generally
achieved, primary arylalkylamines could be converted to
benzolactams through a stoichiometric process.8,9,11,51
The reaction of 1a-Br or 1b-Br with CO in CH2Cl2 at room
temperature gave palladium(0) and the lactam 10a or 10b
(Scheme 8). Previous reports on the synthesis of compound
Scheme 8. Synthesis of Lactams 10a,b
Figure 7. X-ray thermal ellipsoid plot of complex 3a-OAc (50%
probability) showing the labeling scheme. Selected bond lengths (Å)
and angles (deg): Pd(1)−C(1) = 2.001(3), Pd(1)−N(1) = 2.120(2),
Pd(1)−O(4) = 2.119(2), Pd(1)−P(1) = 2.2500(10); C(1)−Pd(1)−
N(1) = 86.83(10), N(1)−Pd(1)−O(4) = 82.66(9), O(4)−Pd(1)−
P(1) = 96.72(6), P(1)−Pd(1)−C(1) = 93.73(8).
10b, a natural alkaloid known as corydaldine,52,53 involved
by X-ray diffraction studies, and they show the palladium atom
in a slightly distorted square-planar environment (mean
deviation 0.0552 Å (Ia·2MeCN), 0.0332 Å (3a-OAc)) with
dihedral angles of 5.7° (Ia·2MeCN) and 4.2° (3a-OAc)
between the N(1)−Pd(1)−C(1) and N(2)−Pd(1)−N(3)
planes (Ia·2MeCN) and the N(1)−Pd(1)−C(1) and P(1)−
Pd(1)−O(4) planes (3a-OAc). In both complexes, the
chelating amino ligand forms a six-membered metallacycle
with a boat conformation. These structural features are similar
to those of analogous complexes containing primary ortho-
palladated phenethylamines.8,17−19,46 In 3a-OAc, the phosphine
and the amino group are mutually trans, according to the
previously mentioned transphobia between the P/Ar pair of
ligands.
drastic reaction conditions or moisture-sensitive reagents.54
CONCLUSION
■
Ortho-palladated complexes derived from homoveratrylamine
and L-tyrosine methyl ester, both biologically relevant arylalkyl-
amines, can be easily prepared by reacting their corresponding
triflates and Pd(OAc)2, in a 1:1 molar ratio, in acetonitrile at 78
°C. Under these conditions, ortho palladation of the
homoveratrylamine occurs regiospecifically at the C6 position.
The use of the triflate salts instead of the free arylalkylamines as
starting materials in the ortho-palladation reactions offers
evident advantages: (1) it avoids the formation of undesirable
byproducts, which in the case of L-tyrosine methyl ester derive
from its acidic OH group, and (2) the ortho-palladated
complexes are obtained in better yields. These cyclopalladated
complexes can be used as intermediates in organic synthesis, as
proved by the fact that their reactions with CO render the
corresponding tetrahydroisoquinolones. We have investigated
Surprisingly, the X-ray crystallographic study of complexes
Ia·2MeCN and 3a-OAc shows that the single cystals contain a
racemic mixture, which must arise from the cocrystallization of
the S and R enantiomers; the latter must come from the 2%
present in the commercial L-tyrosine methyl ester. In fact,
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H, CH2, 3JHH = 5.7 Hz), 3.66 (s, 3 H, OMe), 4.08 (“t”, 1 H, CH, 3JHH
= 6.0 Hz), 6.70 (d, 2 H, m-H, C6H4, 3JHH = 7.8 Hz), 6.98 (d, 2 H, o-H,
the published ortho palladation of homoveratrylamine and
found that, in our hands, instead of palladation at C2 a mixture
containing coordination and cyclopalladated complexes at C6
were obtained.
3
C6H4, JHH = 7.8 Hz). The OH and NH3 resonances were not
observed. 13C NMR (75.45 MHz, DMSO-d6): δ 36.4 (s, CH2), 52.4 (s,
1
OMe), 54.0 (s, CH), 115.4 (s, m-CH, C6H4), 120.7 (q, CF3, JCF
=
324.4 Hz), 125.1 (s, i-C), 130.4 (s, o-CH, C6H4), 156.6 (s, C−OH),
170.9 (s, CO). (+)ESI-MS m/z 91.1, 136.1, 179.1 [(M − OH −
CF3SO3)+], 196.1 [(M − CF3SO3)+], 218.1 [(M − H − CF3SO3 +
EXPERIMENTAL SECTION
■
Caution! Special precautions should be taken in handling thallium(I)
compounds, which are toxic. Also, perchlorate salts of organic cations
may be explosive. Preparations on a larger scale than that reported
herein should be avoided.
−
Na)+]. (−)ESI-MS m/z 149.0 (CF3SO3 ). (+)ESI-HRMS: exact mass
calcd for C10H14NO3 196.0974 [(M − CF3SO3)+]; found 196.0971.
20
[α]D = +13.69° (c = 0.20, MeOH).
General Procedures. Infrared spectra were recorded in the range
4000−200 cm−1 on a Perkin-Elmer 16F-PC-FT spectrometer, using
Nujol mulls between polyethylene sheets. Conductivities in acetone
were measured with a Crison Micro CM2200 conductimeter. Melting
points were determined on a Reichert apparatus and are uncorrected.
C, H, N, and S analyses were carried out with a Carlo Erba 1106
microanalyzer. Specific optical rotations were measured in a 1 dm
thermostated quartz cell on a Jasco-P1020 polarimeter. Unless
otherwise stated, NMR spectra were recorded in CDCl3 in Bruker
Avance 200, 300, and 400 spectrometers. Chemical shifts are
referenced to TMS (1H and 13C{1H}) or H3PO4 (31P{1H}). Signals
Synthesis of [3,4-(MeO)2C6H3CH2CH2NH3]OTf (B). Triflic acid
(0.8 mL of a solution containing 11.3 mmol/mL, 9.04 mmol) was
slowly added to a solution of homoveratrylamine (1 mL, 6.02 mmol)
in Et2O (50 mL), and the resulting white suspension was vigorously
stirred for 20 min. The mixture was filtered, and the solid was washed
with Et2O (3 × 5 mL) and air-dried to give compound B as a white
solid. Yield: 1.61 g, 4.87 mmol, 81%. Mp: 99 °C. ΛM (Ω−1 cm2 mol−1)
= 95 (5.22 × 10−4 M). Anal. Calcd for C11H16F3NO5S (331.309): C,
39.88; H, 4.87; N, 4.23; S, 9.68. Found: C, 40.02; H, 4.50; N, 4.27; S,
1
9.50. IR (cm−1): ν(NH) 3243 br m, 3158 br m, 3078 br m. H NMR
3
(400.91 MHz, DMSO-d6): δ 2.77 (“t”, 2 H, CH2Ar, JHH = 8.0 Hz),
1
in the H and 13C NMR spectra of all complexes were assigned with
3
3.02 (“t”, 2 H, CH2N, JHH = 8.0 Hz), 3.71 (s, 3 H, OMe), 3.74 (s, 3
H, OMe), 6.75 (dd, 1 H, H6, 3JHH = 8.0, 4JHH = 2.0 Hz), 6.84 (d, 1 H,
H2, 4JHH = 2.0 Hz), 6.89 (d, 1 H, H5, 3JHH = 8.4 Hz), 7.61 (br s, 3 H,
NH3). 13C NMR (100.81 MHz, DMSO-d6): δ 32.7 (s, CH2Ar), 40.2
(s, CH2N), 55.4 (s, OMe), 55.5 (s, OMe), 112.1 (s, CH, C5), 112.6 (s,
CH, C2), 120.6 (s, CH, C6), 129.5 (s, C1), 147.7 (s, C4, COMe),
148.8 (s, C3, COMe). The 13C signal corresponding to the OTf group
was not observed. (+)ESI-MS m/z 165.1, 182.1 [(M − CF3SO3)+],
204.1 [(M − H − CF3SO3 + Na)+]. (−)ESI-MS m/z 149.0
the help of APT, HMQC, and HMBC techniques. Reactions were
carried out at room temperature without special precautions against
moisture, unless otherwise indicated.
L-Tyrosine methyl ester, 3,4-dimethoxyphenethylamine (homover-
atrylamine), trifluoromethanesulfonic acid (triflic acid), AgClO4
(Aldrich), XyNC, PPh3, P(p-To)3, N,N,N′,N′-tetramethylethylenedi-
amine (tmeda; Fluka), CO (Air Products), NaBr (Scharlau), NaOAc
(Sigma), and Pd(OAc)2 (Johnson Matthey) were used as received.
[Tl(acac)]55 (Hacac = acetylacetone) and [Pd2(dba)3]·dba56 were
prepared according to published procedures. 2-(2-Bromo-3,4-
dimethoxyphenyl)ethanamine has been prepared according to the
method reported by Weinstock et al.,57 but using a 1 M solution of
BH3 in THF instead of B2H6 in the last step. Chart 1 gives the
numbering scheme for the free ligands, the palladacycles, and the
tetrahydroisoquinolones.
−
(CF3SO3 ), 480.0 [(M + CF3SO3)−]. (+)ESI-HRMS: exact mass
calcd for C10H16NO2 182.1181 [(M − CF3SO3)+]; found 182.1183.
Synthesis of (S,S)-[Pd2{C,N-C6H3CH2CH(CO2Me)NH2-2,(OH)-
4}2(μ-Br)2] (1a-Br). The ammonium triflate A (800 mg, 2.32 mmol)
was added to a suspension of Pd(OAc)2 (520 mg, 2.32 mmol) in
acetonitrile (50 mL), and the resulting solution was heated to 60 °C
for 1 h and then to 78 °C for 4 h. The mixture was filtered through a
plug of Celite, the solution was concentrated to dryness, acetone (40
mL) and NaBr (1 g, 9.72 mmol) were added, and the suspension was
stirred for 12 h. The solvent was removed, and CH2Cl2 (40 mL) was
added. The suspension was filtered, and the solid was washed with
H2O (2 × 5 mL) and Et2O (2 × 5 mL) and air-dried to give the first
crop of 1a-Br (570 mg). The Et2O washing 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) to give a second
crop of complex 1a-Br as an orange solid (71 mg). Yield: 641 mg, 0.84
mmol, 73%. Mp: 202 °C. Anal. Calcd for C20H24Br2N2O6Pd2
(761.062): C, 31.56; H, 3.18; N, 3.68. Found: C, 31.14; H, 3.38; N,
4.22. IR (cm−1): ν(OH) 3423 br s; ν(NH) 3295 s, 3233 s; ν(CO)
Chart 1. Numbering Schemes for the Free Ligands, the
Ortho-Palladated Palladacycles, and the
a
Tetrahydroisoquinolones.
a
For the convenience of the reader, the notation of the free
homoveratrylamine ligand is maintained in the ortho-palladated
complexes.
1
1727 m. H NMR (400.91 MHz, DMSO-d6): δ 3.00 (dd, 1 H, CH2,
3
2
3
2JHH = 13.6, JHH = 9.2 Hz), 3.12 (dd, 1 H, CH2, JHH = 13.6, JHH
=
Most complexes containing ortho-palladated homoveratrylamine
are obtained as hydrates. Only for 6b-OAc·H2O can the crystallization
water be removed by heating the sample at 60 °C for 2 h in a vacuum
oven. It is likely that the water molecules are connected through
hydrogen interactions with the OMe or the OAc groups of the
complexes, in a way stronger than that observed in the crystal structure
of 6b-OAc·H2O (see the Supporting Information).
Synthesis of (S)-[4-(OH)-C6H4CH2CH(CO2Me)NH3]OTf (A).
Triflic acid (0.8 mL of a solution containing 11.3 mmol/mL, 9.04
mmol) was slowly added to a solution of L-tyrosine methyl ester (500
mg, 2.56 mmol) in Et2O (50 mL), and the resulting white suspension
was vigorously stirred for 20 min. The mixture was filtered, and the
solid was washed with Et2O (3 × 5 mL) and air-dried to give
compound A as a white solid. Yield: 731 mg, 2.12 mmol, 83%. Mp: 85
°C. ΛM (Ω−1 cm2 mol−1) = 70 (4.98 × 10−4 M). Anal. Calcd for
C11H14F3NO6S (345.292): C, 38.26; H, 4.09; N, 4.06; S, 9.29. Found:
C, 38.50; H, 4.60; N, 4.13; S, 8.98. IR (cm−1): ν(OH) 3592 s; ν(NH)
3353 s; ν(CO) 1737 s. 1H NMR (300.1 MHz, DMSO-d6): δ 2.91 (d, 2
3.6 Hz), 3.28 (m, 1 H, CH), 3.69 (s, 3 H, OMe), 4.46 (br s, 1 H,
NH2), 5.40 (br s, 1 H, NH2), 6.37 (br d, 1 H, H3, 3JHH = 6.8 Hz), 6.74
(br d, 1 H, H2, 3JHH = 6.8 Hz), 6.91 (d, 1 H, H5, 4JHH = 2.4 Hz), 9.03
(br s, 1 H, OH). 13C NMR (100.81 MHz, DMSO-d6): δ 44.6 (s, CH2),
50.7 (s, CH), 52.8 (s, OMe), 111.7 (s, CH, C3), 119.8 (s, CH, C5),
126.7 (s, CH, C2), 127.3 (s, C1), 150.2 (s, C6, C−Pd), 154.1 (s, C4,
C−OH), 172.3 (s, CO). The insolubility of 1a-Br in all common
solvents prevented us from recrystallizing it to obtain completely
satisfactory elemental analyses (it showed a poor value for N), and to
measure its specific optical rotation.
Synthesis of (S,S)-[Pd2{C,N-C6H3CH2CH(CO2Me)NH2-2,(OH)-
4}2(μ-OAc)2] (1a-OAc). L-Tyrosine methyl ester (500 mg, 2.56
mmol) was added to a suspension of Pd(OAc)2 (575 mg, 2.56 mmol)
in CH2Cl2 (25 mL), and the resulting mixture was stirred at room
temperature for 4 h. The solvent was removed, and acetonitrile (35
mL) was added. The resulting solution was heated at 70 °C for 2.5 h.
A dark brown solid formed. The mixture was filtered, the solution was
concentrated to dryness, and CH2Cl2 (20 mL) was added. The
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suspension was filtered, and the solid was washed with Et2O (2 × 5
mL) and air-dried to give 1a-OAc as a dark yellow solid. Yield: 585.2
mg, 0.81 mmol, 63%. Mp: 201 °C. Anal. Calcd for C24H30N2O10Pd2
(719.342): C, 40.07; H, 4.20; N, 3.89. Found: C, 40.30; H, 3.76; N,
3.92. IR (cm−1): ν(NH) 3240 br vs; ν(CO) 1735 s; ν(CO)OAc 1567 br
vs. 1H NMR (400.91 MHz, DMSO-d6): δ 1.80 (s, 3 H, Me, OAc), 3.01
(385.736): C, 46.71; H, 5.49; N, 3.63. Found: C, 46.36; H, 5.52; N,
3.83. IR (cm−1): ν(NH) 3273 m, 3220 m, 3148 m; ν(CO) 1588 s,
1508 s. 1H NMR (300.1 MHz): δ 1.91 (s, 3 H, Me), 2.02 (s, 3 H, Me),
2.68 (quint, 2 H, CH2N, 3JHH = 5.6 Hz), 2.88 (“t”, 2 H, CH2Ar, 3JHH
=
5.7 Hz), 3.24 (br s, 2 H, NH2), 3.82 (s, 3 H, OMe), 3.90 (s, 3 H,
OMe), 5.32 (s, 1 H, CH), 6.49 (s, 1 H, H2), 7.14 (s, 1 H, H5). 13C
NMR (75.45 MHz): δ 27.7 (s, MeCO), 27.8 (s, MeCO), 39.8 (s,
CH2Ar), 40.9 (s, CH2N), 55.7 (s, OMe), 56.1 (s, OMe), 100.1 (s,
CH), 110.6 (s, CH, C2), 115.4 (s, CH, C5), 128.2 (s, C6), 130.1 (s,
C1), 145.0 (s, C4, C-OMe), 146.2 (s, C3, C-OMe), 186.9 (s, CO),
187.2 (s, CO).
(dd, 1 H, CH2, 2JHH = 13.6, 3JHH = 7.6 Hz), 3.14 (dd, 1 H, CH2, 2JHH
=
13.6, 3JHH = 3.6 Hz), 3.24−3.30 (br m, partially obscured by the signal
of H2O of the solvent, 1 H, CH), 3.63 (s, 3 H, OMe), 5.36 (br s, 1 H,
NH2), 6.01 (br s, 1 H, NH2), 6.32 (dd, 1 H, H3, 3JHH = 7.8, 4JHH = 2.1
3
4
Hz), 6.68 (d, 1 H, H2, JHH = 8.1 Hz), 6.87 (d, 1 H, H5, JHH = 2.1
Hz), 8.93 (br s, 1 H, OH). 13C NMR (100.81 MHz, DMSO-d6): δ
44.6 (s, CH2), 50.3 (s, CH), 52.5 (s, OMe), 111.3 (s, CH, C3), 120.7
(s, CH, C5), 126.6 (s, CH, C2), 127.6 (s, C1), 144.8 (s, C6, C−Pd),
153.5 (s, C4, C−OH), 172.2 (s, CO). The 13C signals corresponding
Synthesis of (S)-[Pd{C,N-C6H3CH2CH(CO2Me)NH2-2,(OH)-4}-
Br(PPh3)] (3a-Br). PPh3 (55.1 mg, 0.21 mmol) was added to a
suspension of 1a-Br (80 mg, 0.11 mmol) in CH2Cl2 (20 mL), and the
resulting solution was stirred for 30 min. The mixture was filtered
through a plug of MgSO4, the filtrate was concentrated to ca. 2 mL,
and n-pentane (15 mL) was added. The suspension was filtered, and
the solid was washed with n-pentane (2 × 5 mL) and air-dried to give
3a-Br as a yellow solid. Yield: 73.7 mg, 0.12 mmol, 55%. Mp: 135 °C.
Anal. Calcd for C28H27BrNO3PPd (642.817): C, 52.32; H, 4.23; N,
2.18. Found: C, 52.03; H, 4.23; N, 2.23. IR (cm−1): ν(NH) 3320 m
20
to the acetate group were not observed. [α]D = +3.44° (c = 0.20,
MeOH).
Synthesis of [Pd2{C,N-C6H2CH2CH2NH2-6,(OMe)2-3,4}2(μ-
Br)2]·H2O (1b-Br·H2O). The ammonium triflate B (1 g, 3.02 mmol)
was added to a suspension of Pd(OAc)2 (678 mg, 3.02 mmol) in
acetonitrile (50 mL), and the resulting solution was heated to 60 °C
for 2 h and then to 78 °C for 6 h. The mixture was filtered through a
plug of Celite, the solvent was removed from the filtrate, acetone (40
mL) and NaBr (1 g, 9.72 mmol) were added, and the suspension was
stirred for 12 h. The solvent was removed, and CH2Cl2 (40 mL) was
added. The suspension was filtered, and the solid was washed with
H2O (2 × 5 mL) and Et2O (2 × 5 mL) and air-dried to give 1b-
Br·H2O as a yellow solid. Yield: 1062 mg, 1.41 mmol, 94%. Dec pt:
163 °C. Anal. Calcd for C20H28Br2N2O4Pd2·H2O (751.117): C, 31.98;
H, 4.02; N, 3.73. Found: C, 31.90; H, 3.70; N, 3.79. IR (cm−1): ν(NH)
1
3252 w; ν(CO) 1737 m. H NMR (400.91 MHz): δ 3.23 (dd, 1 H,
2
3
CH2, JHH = 13.6, JHH = 3.2 Hz), 3.66 (dd, partially obscured by the
2
3
signal of OMe, 1 H, CH2, JHH = 13.2, JHH = 5.6 Hz), 3.70 (s, 3 H,
OMe), 3.88 (br s, 1 H, CH), 3.93 (br s, 1 H, NH2), 4.05 (br s, 1 H,
4
4
NH2), 5.84 (dd, 1 H, H5, JHP = 5.2, JHH = 2.4 Hz), 6.23 (dd, 1 H,
3
4
3
H3, JHH = 8.0, JHH = 2.4 Hz), 6.62 (d, 1 H, H2, JHH = 8.0 Hz),
7.29−7.34 (m, 6 H, m-H, PPh3), 7.38−7.42 (m, 4 H, OH + p-H of
PPh3), 7.53−7.58 (m, 6 H, o-H, PPh3). 13C NMR (75.45 MHz): δ
45.5 (s, CH2), 50.4 (s, CH), 52.9 (s, OMe), 110.8 (s, CH, C3), 123.3
(d, CH, C5, 3JCP = 9.9 Hz), 126.8 (s, CH, C2), 127.6 (s, C1), 128.0 (d,
1
3340 w, 3218 m, 3265 s. H NMR (400.91 MHz, DMSO-d6): δ 2.31
3
m-CH, PPh3, JCP = 10.8 Hz), 130.7 (s, p-CH, PPh3), 131.0 (d, i-C,
(br s, 2 H, CH2N), 2.76 (br s, 2 H, CH2Ar), 3.31 (s, H2O), 3.67 (s, 3
H, OMe), 3.68 (s, 3 H, OMe), 4.72 (br s, 2 H, NH2), 6.63 (s, 1 H,
H2), 7.08 (s, 1 H, H5). 13C NMR (100.81 MHz, DMSO-d6): δ 37.6
(s, CH2N), 41.7 (s, CH2Ar), 55.7 (s, OMe), 55.8 (s, OMe), 110.9 (s,
CH, C2), 117.3 (br s, CH, C5), 131.2 (s, C1), 138.3 (br s, C6), 144.8
(s, C4), 146.5 (s, C3).
PPh3, 1JCP = 51.0 Hz), 134.8 (d, o-CH, PPh3, 2JCP = 11.5 Hz), 152.6 (s,
C4, C−OH), 155.1 (s, C6, C−Pd), 172.6 (s, CO). 31P NMR (162.29
20
MHz): δ 35.9 (s, PPh3). [α]D = +49.54° (c = 0.20, CH2Cl2).
Synthesis of (S)-[Pd{C,N-C6H3CH2CH(CO2Me)NH2-2,(OH)-4}-
(OAc)PPh3]·H2O (3a-OAc·H2O). PPh3 (73 mg, 0.28 mmol) was
added to a suspension of 1a-OAc (150 mg, 0.21 mmol) in CH2Cl2 (20
mL), and the resulting solution was stirred for 2 h. The mixture was
filtered through a plug of MgSO4, the filtrate was concentrated to ca. 2
mL, and Et2O (15 mL) was added. The suspension was filtered, and
the solid was washed with Et2O (2 × 5 mL) and air-dried to give 3a-
OAc·H2O as a yellow solid. Yield: 153 mg, 0.24 mmol, 57%. Mp: 181
°C. Anal. Calcd for C30H30NO5PPd·H2O (639.972): C, 56.30; H, 5.04;
N, 2.19. Found: C, 56.16; H, 4.86; N, 2.28. IR (cm−1): ν(NH) 3319
Synthesis of [Pd2{C,N-C6H2CH2CH2NH2-6,(OMe)2-3,4}2(μ-
OAc)2]·H2O (1b-OAc·H2O). AgClO4 (68 mg, 0.33 mmol) was
added to a suspension of 1b-Br·H2O (120 mg, 0.16 mmol) in
acetone (30 mL), and the resulting suspension was stirred for 1 h. The
mixture was filtered through a plug of Celite to remove the AgBr
formed. NaOAc (1 g, 12.20 mmol) was added, and the suspension was
stirred for 12 h. The solvent was removed, and CH2Cl2 (30 mL) was
added. 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 give 1b-OAc·H2O as a yellow solid. Yield: 83
mg, 0.12 mmol, 73%. Mp: 139 °C. Anal. Calcd for
C24H34N2O8Pd2·H2O (709.398): C, 40.63; H, 5.11; N, 3.95. Found:
C, 40.54; H, 5.36; N, 3.89. IR (cm−1): ν(OH) 3413 br, ν(NH) 3272
m, 3215 m; ν(CO)OAc 1563 br s. 1H NMR (400.91 MHz): δ 1.80 (s, 2
H, H2O), 2.02 (s, 3 H, Me, AcO), 2.21−2.32 (br s, 1 H, CH2Ar),
2.33−2.38 (br s, 1 H, CH2Ar), 2.48 (m, 1 H, CH2N), 2.69 (br dd, 1 H,
CH2N, 2JHH = 14.8 Hz, 3JHH = 6.4 Hz), 2.88 (br s, 1 H, NH2), 3.40 (br
s, 1 H, NH2), 3.80 (s, 3 H, OMe), 3.81 (s, 3 H, OMe), 6.43 (s, 1 H,
H2), 6.69 (s, 1 H, H5). 13C NMR (75.45 MHz): δ 24.3 (s, Me), 39.2
(s, CH2Ar), 40.6 (s, CH2N), 55.8 (s, OMe), 55.9 (s, OMe), 110.9 (s,
CH, C2), 115.4 (s, CH, C5), 124.6 (s, C, C6), 129.6 (s, C1), 144.8 (s,
C4), 146.1 (s, C3), 181.2 (s, CO).
1
m, 3262 m; ν(CO) 1736 s; ν(CO)OAc 1572 br s. H NMR (300.1
MHz): δ 1.45 (s, 3 H, Me, OAc), 1.86 (br s, 2 H, H2O), 3.25 (dd, 1 H,
2
3
CH2, JHH = 13.5, JHH = 3.6 Hz), 3.62 (dd, partially obscured by the
signal of OMe, 1 H, CH2, 3JHH = 4.8 Hz), 3.65 (s, 3 H, OMe), 3.72 (br
s, 1 H, CH), 3.86 (br s, 1 H, NH2), 5.21 (br s, 1 H, NH2), 5.72 (dd, 1
H, H5, 4JHP = 5.1, 4JHH = 2.1 Hz), 6.37 (dd, 1 H, H3, 3JHH = 7.8, 4JHH
=
1.8 Hz), 6.63 (br s, 1 H, OH), 6.69 (d, 1 H, H2, 3JHH = 7.8 Hz), 7.24−
7.31 (m, 6 H, m-H, PPh3), 7.34−7.46 (m, 9 H, o-H + p-H, PPh3). 13
C
NMR (75.45 MHz): δ 24.2 (s, Me, OAc), 46.1 (s, CH2), 50.5 (s, CH),
52.7 (s, OMe), 111.2 (s, CH, C3), 124.3 (d, CH, C5, 3JCP = 10.9 Hz),
3
126.7 (s, CH, C2), 127.9 (s, C1), 128.2 (d, m-CH, PPh3, JCP = 10.6
Hz), 130.2 (d, i-C, PPh3, 1JCP = 49.1 Hz), 130.3 (s, p-CH, PPh3), 134.5
2
(d, o-CH, PPh3, JCP = 11.8 Hz), 146.9 (s, C6, C−Pd), 152.9 (d, C5,
4JCP = 4.6 Hz), 172.9 (s, CO2Me), 179.3 (s, CO, OAc). 31P NMR
20
(121.5 MHz): δ 33.6 (s, PPh3). [α]D = +3.38° (c = 0.20, MeOH).
Synthesis of [Pd{C,N-C6H2CH2CH2NH2-6,(OMe)2-3,4}(O,O′-
acac)] (2b). Tl(acac) (125 mg, 0.41 mmol) was added to a
suspension of 1b-Br·H2O (150 mg, 0.20 mmol) in acetone (25
mL), and the mixture was stirred for 1 h. The solvent was removed
under vacuum, and CH2Cl2 (30 mL) was added. The resulting
suspension was filtered through a plug of MgSO4, the filtrate was
concentrated to ca. 2 mL, and Et2O (30 mL) was added. The
suspension was filtered, and the solid was washed with Et2O (2 × 5
mL) and air-dried to give complex 2b as a yellow solid. Yield: 120.4
mg, 0.31 mmol, 78%. Mp: 195 °C. Anal. Calcd for C15H21NO4Pd
Single crystals of 3a-OAc, suitable for X-ray diffraction study, were
obtained by slow diffusion of n-pentane into a solution of 3a-
OAc·H2O in CHCl3.
Synthesis of [Pd{C,N-C6H2CH2CH2NH2-6,(OMe)2-3,4}Br(PPh3)]
(3b-Br). Method A. PPh3 (107 mg, 0.41 mmol) was added to a
suspension of 1b-Br·H2O (150 mg, 0.20 mmol) in CH2Cl2 (30
mL), 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 Et2O (30 mL) was added. The
suspension was filtered, and the solid was washed with Et2O (2
3655
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4
4
× 5 mL) and air-dried to give the first crop of complex 3b-Br
(63 mg). 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 give a second crop of 3b-Br as a yellow solid (73 mg). Yield:
136 mg, 0.22 mmol, 54%.
To)3, JCP = 2.4 Hz), 142.1 (br s, C6), 145.4 (d, C4, C−OMe, JCP
=
4.9 Hz), 146.0 (s, C3, C−OMe). 31P NMR (121.50 MHz): δ 33.6 (s,
P(p-To)3).
Synthesis of (S)-[Pd{C,N-C6H3CH2CH(CO2Me)NH2-2,(OH)-4}-
Br(CNXy)] (4a). XyNC (34.5 mg, 0.26 mmol) was added to a
suspension of 1a-Br (100 mg, 0.13 mmol) in CH2Cl2 (25 mL), and
the resulting solution was stirred for 2 h. The mixture was filtered
through a plug of MgSO4, the filtrate was concentrated to ca. 2 mL,
and Et2O (15 mL) was added. The suspension was filtered, and the
solid was washed with Et2O (2 × 5 mL) and air-dried to give the first
crop of complex 4a as a yellow solid (30 mg). The filtrate was
concentrated to ca. 2 mL, and n-pentane (15 mL) was added. The
suspension was filtered, and the solid was washed with n-pentane (2 ×
5 mL) and air-dried to give a second crop of complex 4a as a pale
yellow solid (72 mg). Yield: 102 mg, 0.20 mmol, 76%. Mp: 115 °C.
Anal. Calcd for C19H21BrN2O3Pd (511.712): C, 44.60; H, 4.14; N,
5.47. Found: C, 44.97; H, 3.89; N, 5.49. IR (cm−1): ν(NH) 3304 v br;
Method B. PPh3 (54.3 mg, 0.21 mmol) was added to a suspension
of complex 9b (100 mg, 0.21 mmol) in CH2Cl2 (25 mL), and the
resulting solution was stirred for 3 h. The mixture was filtered through
a plug of MgSO4, the filtrate was concentrated to ca. 1 mL, and Et2O
(15 mL) was added. The suspension was filtered, and the solid was
washed with Et2O (2 × 5 mL) and air-dried to give 3b-Br as a pale
yellow solid. Yield: 75.3 mg, 0.12 mmol, 58%. Mp: 147 °C. Anal. Calcd
for C28H29BrNO2PPd (628.833): C, 53.48; H, 4.65; N, 2.23. Found:
1
C, 53.42; H, 4.69; N, 2.39. IR (cm−1): ν(NH) 3259 m, 3210 m. H
NMR (400.91 MHz): δ 2.77 (br s, 2 H, CH2N), 3.12 (s, 3 H, OMe),
3.13 (m, partially obscured by the signal of OMe, 2 H, CH2Ar), 3.39
4
1
(br s, 2 H, NH2), 3.77 (s, 3 H, OMe), 5.99 (d, 1 H, H5, JHP = 4.8
ν(CN) 2189 s; ν(CO) 1735 s. H NMR (400.91 MHz): δ 2.40 (s, 6
Hz), 6.54 (s, 1 H, H2), 7.28−7.33 (m, 6 H, m-H, PPh3), 7.36−7.41
(m, 3 H, p-H, PPh3), 7.49−7.55 (m, 6 H, o-H, PPh3). 13C NMR
(100.81 MHz): δ 37.7 (s, CH2N), 42.5 (s, CH2Ar), 55.0 (s, OMe),
56.0 (s, OMe), 110.4 (s, CH, C2), 118.7 (d, CH, C5, 3JCP = 11.9 Hz),
H, Me, Xy), 3.15 (dd, 1 H, CH2, 2JHH = 14.0, 3JHH = 4.8 Hz), 3.37 (dd,
1 H, CH2, 2JHH = 14.0, 3JHH = 4.0 Hz), 3.63 (br m, 1 H, CH), 3.71 (s,
3 H, OMe), 3.88 (br m, 1 H, NH2), 4.20 (br m, 1 H, NH2), 5.20 (br s,
1 H, OH), 6.51 (dd, 1 H, H3, 3JHH = 8.0, 4JHH = 2.8 Hz), 6.84 (d, 1 H,
H2, 3JHH = 8.0 Hz), 7.07 (d, 2 H, m-H, Xy, 3JHH = 7.6 Hz), 7.09 (d, 1
3
4
128.1 (d, m-CH, PPh3, JCP = 10.6 Hz), 130.4 (d, p-CH, PPh3, JCP
=
1
H, H5, JHH = 2.4 Hz), 7.21 (t, 1 H, p-H, Xy, JHH = 7.6 Hz). 13C
NMR (75.45 MHz): δ 18.9 (s, Me, Xy), 44.3 (s, CH2), 50.2 (s, CH),
53.1 (s, OMe), 112.1 (s, CH, C3), 125.0 (s, CH, C5), 127.9 (s, C1),
128.0 (s, m-CH, Xy), 128.5 (s, CH, C2), 129.7 (s, p-CH, Xy), 136.0 (s,
4
3
2.2 Hz), 131.4 (d, i-C, PPh3, JCP = 49.8 Hz), 134.8 (d, o-CH, PPh3,
2JCP = 11.5 Hz), 142.2 (s, C6), 145.5 (d, C4, 4JCP = 4.8 Hz), 146.1 (s,
C3). The C1 resonance was not observed. 31P NMR (81.01 MHz): δ
35.5 (s, PPh3).
o-C, Xy), 146.5 (s, C6, C−Pd), 152.6 (s, C4, C−OH), 172.0 (s, CO).
Synthesis of [Pd{C,N-C6H2CH2CH2NH2-6,(OMe)2-3,4}(OAc)-
PPh3]·0.25H2O (3b-OAc·0.25H2O). PPh3 (61 mg, 0.23 mmol) was
added to a solution of 1b-OAc·H2O (80 mg, 0.11 mmol) in CH2Cl2
(30 mL), and the resulting mixture was stirred for 30 min and then
filtered through a plug of Celite. The filtrate was concentrated to ca. 2
mL, and n-pentane (15 mL) was added. The suspension was filtered,
and the solid was washed with n-pentane (2 × 5 mL) and air-dried to
give 3b-OAc·0.25H2O as a pale yellow solid. Yield: 110 mg, 0.18
mmol, 79%. Mp: 170 °C. Anal. Calcd for C30H32NO4PPd·1/4H2O
(612.467): C, 58.83; H, 5.35; N, 2.29. Found: C, 58.44; H, 5.70; N,
2.67. IR (cm−1): ν(NH) 3278 w; ν(CO)OAc 1572 br s. 1H NMR
(300.1 MHz): δ 1.46 (s, 3 H, Me), 1.84 (s, 0.5 H, H2O), 2.73 (br s, 2
20
The resonances of the i-C of Xy and CN were not observed. [α]D
+5.36° (c = 0.20, CH2Cl2).
=
Synthesis of [Pd{C,N-C(NXy)-C6H2CH2CH2NH2-6,(OMe)2-
3,4}Br(CNXy)] (5b). XyNC (71.6 mg, 0.55 mmol) was added to a
suspension of 1b-Br·H2O (100 mg, 0.13 mmol) in CH2Cl2 (25 mL),
and the resulting solution was stirred for 4 h. The mixture was filtered
through a plug of MgSO4, the filtrate was concentrated to ca. 2 mL,
and Et2O (15 mL) was added. The suspension was filtered, and the
solid was washed with Et2O (2 × 5 mL) and air-dried to give the first
crop of complex 5b (83 mg). The filtrate was concentrated to ca. 2
mL, and n-pentane (15 mL) was added. The suspension was filtered,
and the solid was washed with n-pentane (2 × 5 mL) and air-dried to
give a second crop of complex 5b (27 mg). Yield: 110 mg, 0.18 mmol,
66%. Mp: 165 °C. Anal. Calcd for C28H32BrN3O2Pd (628.905): C,
53.47; H, 5.13; N, 6.68. Found: C, 53.37; H, 5.03; N, 6.93. IR (cm−1):
ν(NH) 3263 m, 3228 m, 3153 w; ν(CN) 2177 s; ν(CN) 1629 s. 1H
NMR (400.91 MHz): δ 2.16 (s, 6 H, Me, Xy), 2.18 (s, 6 H, Me, Xy),
3
H, CH2N), 3.02 (s, 3 H, OMe), 3.14 (“t”, 2 H, CH2Ar, JHH = 5.4 0
Hz), 3.78 (s, 3 H, OMe), 4.12 (br s, 2 H, NH2), 6.01 (d, 1 H, H5, 4JHP
= 4.5 Hz), 6.60 (s, 1 H, H2), 7.30−7.36 (m, 6 H, m-H, PPh3), 7.39−
7.51 (m, 9 H, p-H + o-H, PPh3). 13C NMR (75.45 MHz): δ 24.1 (s,
Me), 37.5 (s, CH2N), 43.2 (s, CH2Ar), 54.8 (s, OMe), 55.9 (s, OMe),
3
110.7 (s, CH, C2), 118.9 (d, CH, C5, JCP = 11.7 Hz), 128.3 (d, m-
3
3
CH, PPh3, JCP = 10.6 Hz), 130.4 (s, p-CH, PPh3), 130.5 (d, i-C, PPh3,
2.93 (br s, 2 H, NH2), 3.24 (quint, 1 H, CH2N, JHH = 6.0 Hz), 3.80
1JCP = 48.4 Hz), 131.7 (s, C1), 133.4 (s, C6), 134.6 (d, o-CH, PPh3,
2JCP = 12.2 Hz), 144.9 (s, C4), 146.0 (s, C3). The CO resonance was
3
(“t”, 2 H, CH2Ar, JHH = 5.6 Hz), 3.91 (s, 3 H, OMe), 3.94 (s, 3 H,
3
OMe), 6.68 (s, 1 H, H2), 6.79 (dd, 1 H, p-H, coordinated Xy, JHH
=
8.0, 3JHH = 6.4 Hz), 6.87 (d, 2 H, m-H, coordinated Xy, 3JHH = 7.6 Hz),
not observed. 31P NMR (121.5 MHz): δ 34.2 (s, PPh3).
3
7.02 (d, 2 H, m-H, inserted Xy, JHH = 7.6 Hz), 7.17 (t, 1 H, p-H,
Synthesis of [Pd{C,N-C6H2CH2CH2NH2-6,(OMe)2-3,4}Br{P(p-
To)3}] (3b′-Br). P(p-To)3 (83 mg, 0.27 mmol) was added to a
suspension of 1b-Br·H2O (100 mg, 0.13 mmol) in CH2Cl2 (30 mL),
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
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 give 3b′-
Br as an off-white solid. Yield: 132 mg, 0.197 mmol, 74%. Mp: 147 °C.
Anal. Calcd for C31H35BrNO2PPd (670.924): C, 55.50; H, 5.26; N,
2.09. Found: C, 55.35; H, 5.32; N, 2.10. IR (cm−1): ν(NH) 3550 m,
3470 m, 3411 m, 3254 w. 1H NMR (300.1 MHz): δ 2.33 (s, 9 H, Me),
2.76 (br s, 2 H, CH2N), 3.12 (s, 3 H, OMe), 3.14 (m, partially
obscured by the signal of OMe, 2 H, CH2Ar), 3.36 (br s, 2 H, NH2),
inserted Xy, JHH = 7.6 Hz), 7.60 (s, 1 H, H5), 13C NMR (100.81
3
MHz): δ 18.7 (s, Me, Xy), 19.4 (s, Me, Xy), 37.2 (s, CH2Ar), 43.3 (s,
CH2N), 56.0 (s, OMe), 56.1 (s, OMe), 110.7 (s, CH, C5), 113.0 (s,
CH, C2), 123.1 (s, p-CH, coordinated Xy), 126.5 (s, o-C, coordinated
Xy), 127.5 (s, m-CH, inserted Xy), 128.0 (s, m-CH, coordinated Xy),
129.3 (s, p-CH, inserted Xy), 129.4 (s, C1), 132.0 (s, C6), 135.1 (s, o-
C, inserted Xy), 148.0 (s, C4), 150.5 (s, C3), 151.4 (s, i-C,
coordinated Xy), 174.9 (s, CN, inserted Xy). The 13C resonances
corresponding to i-C of the inserted Xy and CN of the coordinated Xy
were not observed.
Synthesis of [Pd(OAc)2{NH2CH2CH2C6H3(OMe)2-3,4}2] (6b-
OAc). Homoveratrylamine (1 mL, 6.02 mmol) was added to a
suspension of Pd(OAc)2 (675.6 mg, 3.01 mmol) in acetone (50 mL),
and the resulting mixture was stirred for 16 h. The suspension was
filtered, and the solid was washed with Et2O (2 × 5 mL) and air-dried
to give 6b-OAc·H2O as a yellow solid (1415 mg). Yield: 1415.1 mg,
2.34 mmol, 78%. The crystallization water can be removed by heating
the sample to 60 °C for 2 h in a vacuum oven. Mp: 145 °C. Anal.
Calcd for C24H36N2O8Pd (586.971): C, 49.11; H, 6.18; N, 4.77.
Found: C, 48.92; H, 6.22; N, 4.92. IR (cm−1): ν(NH) 3244 m, 3200
4
3.77 (s, 3 H, OMe), 5.98 (d, 1 H, H5, JHP = 4.8 Hz), 6.54 (s, 1 H,
H2), 7.10 (br d, 6 H, m-H, P(p-To)3, 3JHH = 6.6 Hz), 7.38 (dd, 6 H, o-
3
3
H, P(p-To)3, JHP = 11.4, JHH = 8.1 Hz). 13C NMR (75.45 MHz): δ
21.4 (s, Me), 37.6 (d, CH2N, 3JCP = 2.3 Hz), 42.5 (s, CH2Ar), 54.9 (s,
OMe), 56.0 (s, OMe), 110.3 (s, CH, C2), 118.8 (d, CH, C5, JCP
3
=
11.8 Hz), 128.0 (d, half of the doublet was obscured by the m-CH
signal, i-C), 128.8 (d, m-CH, P(p-To)3, 3JCP = 11.0 Hz), 130.5 (s, C1),
2
134.7 (d, o-CH, P(p-To)3, JCP = 11.8 Hz), 140.4 (d, C−Me, P(p-
3656
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m, 3119 m; ν(CO)OAc 1566 s. 1H NMR (200.13 MHz): δ 1.86 (s, 3 H,
OAc, suitable for an X-ray diffraction study, were obtained by slow
diffusion of Et2O into a solution of 7b-OAc·H2O in CHCl3.
3
Me, OAc), 2.79 (quint, 2 H, CH2N, JHH = 6.8 Hz), 2.92 (“t”, 2 H,
NH2Ar, 3JHH = 6.8 Hz), 3.67 (m, 2 H, NH2), 3.86 (s, 3 H, OMe), 3.88
Synthesis of [PdBr2{NH2CH2CH2C6H3(OMe)2-3,4}PPh3] (7b-
Br). PPh3 (42 mg, 0.16 mmol) was added to a suspension of 6b-Br
(100 mg, 0.16 mmol) in CH2Cl2 (30 mL), 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 Et2O (30 mL) was
added. The suspension was filtered, and the solid was washed with
Et2O (2 × 5 mL) and air-dried to give the first crop of 7b-Br as an
orange solid (48 mg). 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 give a
second crop of complex 7b-Br as an orange solid (53 mg). Yield: 101
mg, 0.14 mmol, 89%. Mp: 163 °C. Anal. Calcd for C28H30Br2NO2PPd
(709.755): C, 47.38; H, 4.26; N, 1.97. Found: C, 47.30; H, 4.13; N,
4
(s, 3 H, OMe), 6.72 (A part of an ABC system, 1 H, H2, JAB = 2.0
3
4
Hz), 6.75 (B part of an ABC system, 1 H, H6, JBC = 8.0, JAB = 2.0
Hz), 6.80 (C part of an ABC system, 1 H, H5, JBC = 8.0 Hz). 13C
3
NMR (50.3 MHz): δ 23.4 (s, Me, OAc), 36.5 (s, CH2Ar), 44.7 (s,
CH2N), 55.8 (s, OMe), 55.9 (s, OMe), 111.4 (s, CH, C5), 111.8 (s,
CH, C2), 120.7 (s, CH, C6), 130.0 (s, C1), 147.8 (s, C4, C-OMe),
149.1 (s, C3, C-OMe), 179.9 (s, CO). Single crystals suitable for an X-
ray diffraction study were obtained by slow diffusion of n-pentane into
a solution of 6b-OAc·H2O in CH2Cl2.
Synthesis of [PdBr2{NH2CH2CH2C6H3(OMe)2-3,4}2] (6b-Br).
NaBr (500 mg, 4.859 mmol) was added to a suspension of 6b-
OAc·H2O (500 mg, 0.826 mmol) in acetone (50 mL), and the
resulting suspension was stirred for 16 h. The solvent was removed,
CH2Cl2 (40 mL) was added, and the mixture was filtered through a
plug of Celite. The filtrate was concentrated to ca. 2 mL, and Et2O (30
mL) was added. The suspension was filtered, and the solid was washed
with Et2O (2 × 5 mL) and air-dried to give 6b-Br as a yellow solid.
Yield: 479 mg, 0.76 mmol, 92%. Mp: 148 °C. Anal. Calcd for
C20H30Br2N2O4Pd (628.698): C, 38.21; H, 4.81; N, 4.46. Found: C,
38.18; H, 5.00; N, 4.34. IR (cm−1): ν(NH) 3275 s, 3213 s, 3213 m. 1H
NMR (400.91 MHz): δ 2.63 (br t, 2 H, NH2, 3JHH = 6.8 Hz), 2.83 (t, 2
1
2.01. IR (cm−1): ν(NH) 3283 s, 3240 s, 3146 m. H NMR (400.91
3
MHz): δ 2.76 (m, 2 H, NH2), 2.88 (“t”, 2 H, CH2Ar, JHP = 6.8 Hz),
3.33 (m, 2 H, CH2N), 3.85 (s, 3 H, OMe), 3.87 (s, 3 H, OMe), 6.76
(B part of an ABC system, 1 H, H6, 3JAB = 8.0, 4JBC = 1.8 Hz), 6.76 (A
4
part of an ABC system, 1 H, H2, JAB = 1.8 Hz), 6.80 (C part of an
ABC system, 1 H, H5, 3JBC = 8.0 Hz), 7.38−7.48 (m, 9 H, m-H + p-H,
PPh3), 7.69−7.74 (m, 6 H, o-H, PPh3). 13C NMR (75.45 MHz): δ
37.8 (d, CH2Ar, 3JCP = 3.2 Hz), 44.8 (d, CH2N, 3JCP = 2.6 Hz), 55.9 (s,
OMe), 56.0 (s, OMe), 111.4 (s, CH, C5), 111.7 (s, CH, C2), 121.0 (s,
CH, C6), 128.0 (d, m-CH, PPh3, 3JCP = 11.2 Hz), 129.7 (s, C1), 130.7
(d, half of the doublet was obscured by the p-CH signal), 130.9 (d, p-
3
3
H, CH2Ar, JHH = 6.8 Hz), 3.08 (quint, 2 H, CH2N, JHH = 6.8 Hz),
3.86 (s, 3 H, OMe), 3.90 (s, 3 H, OMe), 6.73 (A part of an ABC
system, 1 H, H2, 4JAB = 2.0 Hz), 6.73 (B part of an ABC system, 1 H,
4
2
CH, PPh3, JCP = 2.5 Hz), 134.8 (d, o-CH, PPh3, JCP = 10.5 Hz),
147.9 (s, C−OMe), 149.2 (s, C−OMe). 31P NMR (162.29 MHz): δ
28.0 (s, PPh3).
3
4
H6, JBC = 8.0, JAB = 2.0 Hz), 6.81 (C part of an ABC system, 1 H,
H5, 3JBC = 8.0 Hz). 13C NMR (100.81 MHz): δ 37.1 (s, CH2Ar), 44.7
(s, CH2N), 55.9 (s, OMe), 55.9 (s, OMe), 111.5 (s, CH, C6H3), 111.6
(s, CH, C6H3), 120.9 (s, CH, C6H3), 129.1 (s, C1), 148.0 (s, C-OMe),
149.2 (s, C-OMe). Single crystals suitable for an X-ray diffraction study
were obtained by slow diffusion of Et2O into a solution of 6b-Br in
CH2Cl2.
Synthesis of [Pd2(μ-OAc)2(OAc)2{NH2CH2CH2C6H3(OMe)2-
3,4}2] (8b). Homoveratrylamine (273 mg, 1.51 mmol) was added to
a suspension of Pd(OAc)2 (338 mg, 1.51 mmol) in CH2Cl2 (30 mL),
and the mixture was stirred for 1 h. The resulting solution was
concentrated to ca. 2 mL, and Et2O (30 mL) was added. The
suspension was filtered, and the solid was washed with Et2O (2 × 5
mL) and air-dried to give 6b-OAc as a yellow solid (179 mg, 0.31
mmol, 40%). The filtrate was concentrated to ca. 4 mL, and n-hexane
(20 mL) was added. The suspension was filtered, and the solid was
washed with n-hexane (2 × 5 mL) and air-dried to give 8b (214 mg,
0.26 mmol) as an orange solid (214 mg). Yield: 214 mg, 0.26 mmol,
35%. Mp: 50 °C. Anal. Calcd for C28H42N2O12Pd2 (881.486): C,
41.44; H, 5.22; N, 3.45. Found: C, 41.44; H, 5.41; N, 3.49. IR (cm−1):
Synthesis of [Pd(OAc)2{NH2CH2CH2C6H3(OMe)2-3,4}-
PPh3]·H2O (7b-OAc·H2O). Method A. PPh3 (89 mg, 0.34
mmol) was added to a suspension of 6b-OAc·H2O (200 mg,
0.33 mmol) in CH2Cl2 (30 mL), 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 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 give
7b-OAc·H2O as a yellow solid. Yield: 121 mg, 0.18 mmol, 53%.
Method B. PPh3 (129 mg, 0.49 mmol) was added to a solution of
8b (100 mg, 0.25 mmol) in CH2Cl2 (30 mL), 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 Et2O (15 mL)
was added. The suspension was filtered, and the solid was washed with
Et2O (2 × 5 mL) and air-dried to give the first crop of 7b-OAc·H2O
(153 mg). 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 give a second crop
of 7b-OAc·H2O (48 mg). Yield: 201 mg, 0.29 mmol, 60%. Mp: 126
°C. Anal. Calcd for C32H36NO6PPd·H2O (686.03): C, 56.02; H, 5.58;
N, 2.04. Found: C, 56.12; H, 5.54; N, 2.14. IR (cm−1): ν(NH) 3229
1
ν(CO)OAc 1631 br, 1567 br. H NMR (400.91 MHz): δ 1.88 (s, 3 H,
Me, OAc), 1.89 (s, 3 H, Me, OAc), 2.57 (quint, 1 H, CH2N, 3JHH = 6.4
3
Hz), 2.71 (quint, 1 H, CH2N, JHH = 6.4 Hz), 3.19 (“t”, 2 H, CH2Ar,
3JHH = 6.8 Hz), 3.86 (br m, 1 H, NH2), 3.86 (s, 3 H, OMe), 3.91 (s, 3
H, OMe), 5.09 (br m, 1 H, NH2), 6.84 (C part of an ABC system, 1 H,
3
3
H5, JBC = 8.0 Hz), 6.89 (B part of an ABC system, 1 H, H6, JAB
=
8.0, 4JBC = 1.6 Hz), 6.91 (A part of an ABC system, 1 H, H2, 4JAB = 1.6
Hz). 13C NMR (100.81 MHz): δ 22.6 (s, Me, OAc), 22.8 (s, Me,
OAc), 35.5 (s, CH2Ar), 44.4 (s, CH2N), 55.5 (s, OMe), 55.6 (s,
OMe), 111.2 (s, CH, C5), 111.9 (s, CH, C2), 120.6 (s, CH, C6),
129.8 (s, C1), 147.6 (s, C4, C−OMe), 148.8 (s, C3, C−OMe), 179.3
(s, CO), 185.2 (s, CO).
Synthesis of [Pd{C,N-C6H2CH2CH2NH2-6,(OMe)2-3,4}(tmeda)]
Br (9b). To a suspension of Pd(dba)2 (552.6 mg, 0.96 mmol) in dry
toluene (20 mL) was added tmeda (111.7 mg, 0.96 mmol), and the
mixture was stirred for 10 min under a N2 atmosphere. 6-Bromo-3,4-
dimethoxyphenethylamine (250 mg, 0.96 mmol) was then added, and
the stirring was continued for 24 h. The resulting suspension was
filtered, and the solid was washed with Et2O (3 × 5 mL) and air-dried
to give complex 9b as an ocher solid, which was contaminated with
traces of metallic palladium. Complex 9b could not be recrystallized to
obtain a satisfactory elemental analysis, because it is very insoluble in
most common solvents. Yield: 333.1 mg, 0.69 mmol, 72%. Mp: 173−
176 °C. Anal. Calcd for C16H30BrN3O2Pd (482.752): C, 39.81; H,
6.26; N, 8.70. Found: C, 39.34; H, 5.99; N, 7.68. IR (cm−1): ν(NH)
1
m, 3139 m; ν(CO)OAc 1633 vs. H NMR (400.91 MHz): δ 1.42 (s, 6
H, Me, OAc), 1.86 (br s, 2 H, H2O), 2.90 (“t”, 2 H, CH2Ar, 3JHP = 6.4
Hz), 2.97 (m, 2 H, CH2N), 3.79 (m, 2 H, NH2), 3.84 (s, 3 H, OMe),
4
3.85 (s, 3 H, OMe), 6.72 (C part of an ABC system, 1 H, H2, JBC
=
1.8 Hz), 6.74 (B part of an ABC system, 1 H, H6, 3JAB = 7.9, 4JBC = 1.8
Hz), 6.78 (A part of an ABC system, 1 H, H5, JAB = 7.9 Hz), 7.39−
3
7.44 (m, 6 H, m-H, PPh3), 7.48−7.52 (m, 3 H, p-H, PPh3), 7.69−7.75
(m, 6 H, o-H, PPh3). 13C NMR (75.45 MHz): δ 22.8 (s, Me, OAc),
37.4 (s, CH2Ar), 44.3 (s, CH2N), 55.7 (s, OMe), 55.8 (s, OMe), 111.2
(s, CH, C5), 111.8 (s, CH, C2), 120.7 (s, CH, C6), 127.7 (d, i-C,
1
3
PPh3, JCP = 52.1 Hz), 128.4 (d, m-CH, PPh3, JCP = 11.0 Hz), 130.9
4
1
(d, p-CH, PPh3, JCP = 2.7 Hz), 130.5 (s, C1), 134.3 (d, o-CH, PPh3,
3185 m, 3086 s. H NMR (400.91 MHz, DMSO-d6): δ 2.53 (s, 6 H,
2JCP = 11.0 Hz), 147.6 (s, C−OMe), 148.9 (s, C−OMe), 178.1 (s,
CO). 31P NMR (121.5 MHz): δ 21.3 (s, PPh3). Single crystals of 7b-
MeN), 2.59 (s, 6 H, MeN), 2.63 (m, 2 H, CH2, tmeda), 2.81 (m, 2 H,
CH2, tmeda), 3.06 (m, 2 H, CH2Ar), 3.65 (s, 3 H, OMe), 3.66 (m,
3657
dx.doi.org/10.1021/om300141b | Organometallics 2012, 31, 3647−3660

Organometallics
Article
partially obscured by the signal of OMe, 2 H, CH2N), 3.74 (s, 3 H,
solvent. Standard deviations of refined parameters should be
interpreted with caution. The void volume per cell was 250 Å3, with
a void electron count per cell of 83. This solvent was not taken into
account when calculating derived parameters such as the formula
weight, because the nature of the solvent was uncertain. The CO2Me
group is disordered over two positions with a ca. 52:48% occupancy
distribution. 7b-OAc: 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, 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 184
Å3, with a void electron count per cell of 46. This solvent was not
taken into account when calculating derived parameters such as the
formula weight, because the nature of the solvent was uncertain. One
OMe goup is disordered over two positions with a ca. 55:45%
occupancy distribution.
OMe), 4.30 (m, 2 H, NH2), 6.62 (s, 1 H, H2), 6.77 (s, 1 H, H5). 13
C
NMR (50.30 MHz, DMSO-d6): δ 38.4 (s, CH2Ar), 41.2 (s, CH2N),
47.4 (s, MeN), 50.2 (s, MeN), 55.7 (s, OMe), 55.9 (s, OMe), 58.1 (s,
CH2, tmeda), 62.2 (s, CH2, tmeda), 110.9 (s, CH, C2), 115.9 (s, CH,
C5), 132.2 (s, C1), 139.8 (s, C6), 145.2 (s, C4), 146.3 (s, C3).
Synthesis of (S)-7-Hydroxy-3-(methoxycarbonyl)-3,4-dihy-
droisoquinolin-1(2H)-one (10a). CO was bubbled through a
suspension of 1a-Br (150 mg, 0.20 mmol) in CH2Cl2 (20 mL), and
the resulting mixture was stirred under a CO atmosphere for 16 h.
Decomposition to metallic palladium was observed. The mixture was
filtered through a plug of MgSO4, the filtrate was concentrated to ca. 2
mL, and Et2O (30 mL) was added. The suspension was filtered, and
the solid was washed with Et2O (2 × 5 mL) and air-dried to give crude
compound 10a as a pale yellow solid. Yield: 37 mg, 0.17 mmol, 43%. A
spectroscopically pure sample of 10a was obtained by recrystallization
from CH2Cl2/Et2O. Mp: 143 °C dec. IR (cm−1): ν(NH) 3302 w;
1
ν(CO) 1722 m; ν(CO)CON 1667 m. H NMR (300.1 MHz, acetone-
2
d6): δ 3.13, 3.29 (part AB of an ABX system, 2 H, CH2, JAB = 15.8,
ASSOCIATED CONTENT
* Supporting Information
■
3JAX = 6.1, 3JBX = 5.3 Hz), 3.64 (s, 3 H, OMe), 4.42 (part X of an ABX
system, 1 H, CH), 6.94 (dd, 1 H, H6, 3JHH = 8.1, 4JHH = 2.7 Hz), 7.07
S
3
Text, tables, figures, and CIF files giving experimental details
for the synthesis of 2-bromo-3,4-dimethoxyphenethylamine,
details (including symmetry operators) of hydrogen bonding,
and all refined and calculated atomic coordinates, anisotropic
thermal parameters, bond lengths and angles, and crystallo-
graphic data for Ia·2MeCN, 3a-OAc, 6b-Br, 6b-OAc·H2O, and
7b-OAc. This material is available free of charge via the
Internet at http://pubs.acs.org.
(br s, 1 H, NH), 7.12 (d, 1 H, H5, JHH = 8.1 Hz), 7.45 (d, 1 H, H8,
4JHH = 2.7 Hz), 8.50 (s, 1 H, OH). 13C NMR (75.45 MHz, acetone-
d6): δ 30.8 (s, CH2), 52.6 (s, OMe), 53.9 (s, CH), 114.5 (s, CH, C8),
120.1 (s, CH, C6), 128.0 (s, C4a), 129.6 (s, CH, C5), 130.9 (s, C8a),
157.4 (s, C7), 165.3 (s, CO), 172.7 (s, CO2Me). ESI-HRMS: exact
20
mass calcd for C11H11NO4 221.0685; found 221.0688. [α]D
=
+26.86° (c = 0.20, MeOH).
Synthesis of 6,7-Dimethoxy-3,4-dihydroisoquinolin-1(2H)-
one (10b). CO was bubbled through a suspension of 1b-Br·H2O
(145 mg, 0.19 mmol) in CH2Cl2 (20 mL), and the resulting mixture
was stirred under a CO atmosphere for 16 h. Decomposition to
metallic palladium was observed. The mixture was filtered through a
plug of MgSO4, the filtrate was concentrated to ca. 2 mL, and Et2O
(30 mL) was added. The suspension was filtered, and the solid was
washed with Et2O (2 × 5 mL) and air-dried to give 10b as a pale
yellow solid. Yield: 47 mg, 0.23 mmol, 59%. IR (cm−1): ν(NH) 3176
m; ν(CO) 1655 s. 1H NMR (200.13 MHz): δ 2.94 (“t”, 2 H, CH2Ar,
3JHH = 6.6 Hz), 3.56 (“td”, 2 H, CH2N, 3JHH = 6.6, 3JHH = 2.4 Hz), 3.93
AUTHOR INFORMATION
Corresponding Author
*E-mail: ims@um.es (I.S.-L.); jvs1@um.es (J.V.).
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the Ministerio de Educacion
FEDER (Project CTQ2007-60808/BQU) and Fundacio
■
(s, 6 H, Me, OMe), 5.97 (br s, 1 H, NH), 6.68 (s, 1 H, H5), 7.57 (s, 1
H, H8). 13C{1H} NMR (75.45 MHz): δ 28.0 (s, CH2Ar), 40.5 (s,
CH2N), 56.0 (s, OMe), 56.1 (s, OMe), 109.5 (s, CH, C5), 110.1 (s,
CH, C8), 121.3 (s, C8a), 132.6 (s, C4a), 148.0 (s, C7), 152.1 (s, C6),
166.3 (s, CO). Spectroscopic data are in agreement with those in the
literature (1H and 13C NMR).53
Single-Crystal X-ray Structure Determinations. Relevant
crystallographic data and details of the refinement for the structures
of Ia·2MeCN, 3a-OAc, 6b-Br, 6b-OAc·H2O, and 7b-OAc are
summarized 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
SMART APEX diffractometer. Data were recorded at 100(2) K using
graphite-monochromated Mo Kα radiation (λ = 0.710 73 Å) and ω-
scan mode. Multiscan absorption corrections were applied.
Solution and Refinement. Crystal structures were solved by
Patterson (6b-OAc·H2O) or direct methods (Ia·2MeCN, 3a-OAc, 6b-
Br, and 7b-OAc) and all non-hydrogen atoms refined anisotropically
on F2 using the program SHELXL-97.58 Hydrogen atoms were refined
as follows. Ia·2MeCN: NH2 and OH, free with DFIX; ordered methyl,
rigid group; all others, riding. 3a-OAc: NH2 and OH, free with DFIX;
methyl, rigid group; all others, riding. 6b-Br: NH2, free with SADI;
methyl, rigid group; all others, riding. 6b-OAc·H2O: H2O, free with
SADI; NH2, free; methyl, rigid group; all others, riding. 7b-OAc: NH2,
free with SADI; ordered methyl, rigid group; all others, riding. Special
features are as follows. Ia·2MeCN: C10 is disordered over two
positions, with a ca. 53:47% occupancy distribution. 3a-OAc: 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,59 was employed to remove mathematically the effects of the
́
y Ciencia (Spain),
n
Sen
and M.-J.O.-M. are grateful to the Fundacion
Spain) and Ministerio de Educacion y Ciencia (Spain),
́
eca (04539/GERM/06) for financial support. J.-A.G.-L.
́
́
Seneca (CARM,
́
respectively, for their research grants. We thank the
́
Departamento de Quimica Organ
́
ica of the University of
Murcia for the facilities offered to use the polarimeter and Dr.
Jose
́
Berna
́
for his valuable help.
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