NH2 as a directing group: From the cyclopalladation of amino esters to the preparation of benzolactams by palladium(II)-catalyzed carbonylation of N-unprotected arylethylamines

Article abstract of DOI:10.1021/om301140t

An unusual NH₂-directed Pd(II)-catalyzed carbonylation of quaternary aromatic α-amino esters to yield benzolactams has been developed. The steric hindrance around the amino group is pivotal for the success of the process. The stoichiometric cyclometalation of a variety amino esters has been studied in order to evaluate the influence of the different variables (size of the metallacycle, aromatic ring substituents, and steric bulk) in the process, and a complete kinetico-mechanistic study of the cyclopalladation process has been carried out. The experimental results indicate that the full substitution of the carbon in the α position of the amino esters plays an important role in their cyclopalladation reaction. The reaction shows a strong bias toward six-membered lactams over the five-membered analogues, which can be explained by a greater reactivity of the six-membered palladacycles.

Full text of DOI:10.1021/om301140t

Article
pubs.acs.org/Organometallics
NH2 As a Directing Group: From the Cyclopalladation of Amino
Esters to the Preparation of Benzolactams by Palladium(II)-Catalyzed
Carbonylation of N‑Unprotected Arylethylamines
Joan Albert,† Xavier Ariza,‡ Teresa Calvet,§,⊥ Merce Font-Bardia,§,⊥ Jordi Garcia,*,‡ Jaume Granell,*,†
́
Andrea Lamela,‡ Blanca Lopez,‡ Manuel Martinez,† Laura Ortega,† Aleix Rodriguez,‡ and David Santos‡
́
†Departament de Quimica Inorgan
̀
ica i Institut de Biomedicina (IBUB), Facultat de Quimica, Universitat de Barcelona,
1-11, E-08028-Barcelona, Spain
‡Departament de Quimica Organ
ica i Institut de Biomedicina (IBUB), Facultat de Quimica, Universitat de Barcelona,
Martí i Franques 1-11, E-08028-Barcelona, Spain
§Unitat de Difraccio
de Raigs-X, Centre Científic i Tecnolog
Sole i Sabaris 1-3, 08028-Barcelona, Spain
⊥Departament de Crystal·lografia, Mineralogia i Dipos
Martí i Franques s/n, 08028-Barcelona, Spain
Martí i Franques
̀
̀
̀
́
̀
ic de la Universitat de Barcelona, Universitat de Barcelona,
́
̀
its Minerals, Facultat de Geologia, Universitat de Barcelona,
̀
S
* Supporting Information
ABSTRACT: An unusual NH2-directed Pd(II)-catalyzed
carbonylation of quaternary aromatic α-amino esters to yield
benzolactams has been developed. The steric hindrance
around the amino group is pivotal for the success of the
process. The stoichiometric cyclometalation of a variety amino
esters has been studied in order to evaluate the influence of the different variables (size of the metallacycle, aromatic ring
substituents, and steric bulk) in the process, and a complete kinetico-mechanistic study of the cyclopalladation process has been
carried out. The experimental results indicate that the full substitution of the carbon in the α position of the amino esters plays an
important role in their cyclopalladation reaction. The reaction shows a strong bias toward six-membered lactams over the five-
membered analogues, which can be explained by a greater reactivity of the six-membered palladacycles.
Furthermore, palladium can activate C−H bonds both at sp2 and
INTRODUCTION
■
sp3 sites, and a wide range of catalytic processes have been
described with different nitrogen-based directing groups. These
include imines, oxime ethers, azobenzenes, amides, N-alkylani-
lines, benzodiazepines, pyridines, pyrazoles, and isoxazolines.
Oxygen-based ligands, such as carboxylic acids and aldehydes,
have also been used as directing groups in some cases.1,5 In
contrast, to the best of our knowledge, the use of primary amines
as directing groups has not been described so far.
The development of selective methods for the direct conversion
of carbon−hydrogen bonds into carbon−heteroatom and
carbon−carbon bonds remains a critical challenge in organic
chemistry. An interesting approach to address this issue involves
the use of substrates that contain coordinating atoms (or
directing groups)1 that bind to the metal center in a first step; a
further rearrangement of some atoms allows the C−H bond
activation. The latter process, at stoichiometric scale, is the well-
known cyclometalation reaction.2 The first cyclometalated
compounds were reported in the mid 1960s.3 Since then, this
reaction has been extensively studied and has acquired a great
interest given the application of metallacycles in many areas,
which include organic synthesis, catalysis, design of metalo-
mesogens and antitumoral drugs, asymmetric synthesis,
resolution of racemic ligands, intermolecular aromatic C−H
bond activation, and the synthesis and reactivity of organo-
metallic complexes with biologically relevant ligands.4 In this
respect, the development of ligand-directed reactions has led to a
renewed interest in the cyclometalation reactions. Palladium
complexes are particularly attractive catalysts for such trans-
formations because ligand-directed C−H functionalization at
palladium centers can be used to obtain different types of C−Y
bonds (Y being carbon, oxygen, nitrogen, sulfur, or halogen).
The transition-metal-catalyzed carbonylation of arenes with
gaseous CO is a significant chemical transformation, since
it extends the carbon chain length and also introduces a
synthetically versatile carbonyl group. Arenes were first
carbonylated to obtain carboxylic acids by Fujiwara et al. in
1980 using Pd(AcO)2 under 15 atm of CO and the arene
substrates as solvent.6 However, no control over regioselectivity
was observed for substituted arenes. This problem has been
overcome by different research groups using the directing group
approach.1,7 Thus, Yu et al. has very recently described the
palladium acetate-catalyzed carbonylation of anilides to obtain
N-acyl anthranilic acids.7d Similarly, Orito et al. have reported the
Received: November 28, 2012
Published: January 10, 2013
© 2013 American Chemical Society
649
dx.doi.org/10.1021/om301140t | Organometallics 2013, 32, 649−659

Organometallics
Article
Scheme 1. Synthesis of Imines 2 and Aminoesters 3
direct carbonylation of aromatic C−H bonds with CO in N-alkyl-
ω- arylalkylamines to obtain benzolactams using a Pd(AcO)2/
Cu(AcO)2/air system in toluene solution at 120 °C.7b,8
However, the authors stated, “carbonylation of primary amines,
including benzylic amines or phenylethylamines, under the same
conditions, produced no benzolactams but produced ureas in
good yields.” It should be noted that Pd(II) catalysts are readily
reduced by CO, in a reaction that also produces Ac2O, which
could cause secondary reactions with primary amines.9 Thus, a
method for catalyzed C−H activation/carbonylation of primary
amines under a CO environment has not been established.
Here we describe the preparation of benzolactams via
palladium acetate-catalyzed aromatic carbonylation of quater-
nary α-amino α-alkyl esters, by an unusual process that uses NH2
as a directing group.10
formed, substituents in the aromatic ring, and steric bulk) in the
process. Thus, ligand 3f seems especially interesting due to the
fact that it can afford two different metallacycles: one by
activation of an unsubstituted benzene ring and the other by
metalation of a MeO-substituted aromatic ring. Ligand 3b is
also remarkable, as it can afford either a five- or a six-membered
metallacycle, depending on which aromatic ring undergoes the
metalation reaction.
The reaction between amino esters 3a−f and palladium
acetate in toluene at 80 °C afforded, as expected, the dinuclear
acetato-bridged compounds 4a−f (X = AcO). Dinuclear halide-
bridged compounds 4a−f (X = Cl or Br) can also be obtained by
reaction of the dinuclear acetato-bridged compounds with
lithium halide in acetone at room temperature (30 min).
Unfortunately, all attempts to purify the dinuclear six-membered
metallacycles, either by column chromatography or by recrystalli-
zation, were unsuccessful, the complexes partially decomposing
during the purification processes. In contrast 4b (X = Br) can
be purified by flash chromatography (hexane/EtAcO, 8:2) to
afford the five-membered palladacycle 4b(5) in 72% yield (see
Experimental Section). Consequently, the preparation of the
more stable mononuclear compounds 5 was attempted (see
Scheme 2). The reaction was carried out from the acetato
derivatives 4 (X = AcO) by reaction with PPh3 and the
corresponding lithium halide. Compounds 5 could be purified by
column chromatography and isolated in good yields, as expected.
The yields of the metalation reactions of amino esters 3a, 3d,
and 3e to afford the corresponding six-membered metallacycles
do not vary significantly, showing that the substituents on the
aromatic ring that experience metalation do not play a significant
role in the process. This fact has already been observed in the
kinetico-mechanistic studies carried out on a family of carefully
tuned imine derivatives.14 Furthermore, metalation of both
aromatic rings, in a equimolar ratio, is observed with ligand 3f,
which agrees with the nonelectrophilic substitution behavior of
the observed process. The sequence is better explained through a
mechanism involving a concerted proton abstraction from the
metalating C−H unit by an ancillary ligand. The trends observed
in the thermal and pressure activation parameters obtained in the
above-mentioned studies suggest that once the C−H bond being
activated reaches its correct positioning, the process is fairly
independent of its electronic nature.14 Recent computational
studies of C−H bond activation at late transition metal systems
indicate that assistance via coligands (especially carboxylates) is a
good way of cleaving these bonds; the term “ambiphilic metal
ligand activation” has been proposed to describe such reac-
tions.15 In contrast, the size of the metallacycle seems to play an
important role in the cyclometalation reaction; metalation of
ligand 3b affords the five-membered metallacycle as the major
isomer with respect to the six-membered analogue (6:1 ratio, by
proton NMR).
RESULTS AND DISCUSSION
■
As part of an ongoing research project on bioorganometallic
chemistry,11 we attempted the cyclometalation of imines RCH
NC(Me)(CH2Ph)(COOMe) (2a: R = 4-ClC6H4; 2a′: R = 2,6-
Cl2C6H3), derived from a quaternary α-amino ester, with
Pd(AcO)2 in toluene or acetic acid solution. Ligand 2a was
obtained by alkylation of imine 1a with a mixture of KOH,
K2CO3, and benzyl bromide. Ligand 2a′ was prepared from
amino ester 3a (obtained by hydrolysis of the imine 2a) via a
condensation reaction with 2,6-dichlorobenzaldehyde. The
direct alkylation of the imine 1a′, 2,6-Cl2C6H3CHNCH(Me)-
(COOMe), gave a low yield of 2a′; probably the steric hindrance
of the di-ortho-chloro-substituted fragment (Scheme 1) hampers
the process.
Treatment of imines 2a and 2a′ with Pd(AcO)2 in toluene or
acetic acid solution at 80 °C did not produce the expected imine
palladacycles. Only compound 5a, [PdCl(CN)(PPh3)] (CN
being the metalated amino ester), was isolated, in low yield, after
subsequent reaction with LiCl and PPh3. Reaction of the free
amino ester 3a under the same conditions produced palladacycle
5a in a much better yield, 50% (Scheme 2). Nevertheless, proton
NMR batch monitoring of the reaction between 2a and
palladium acetate, under milder conditions, allowed the
detection of the metalated imine (see below).
The preferential metalation of the aminoesters with respect to
the corresponding imine derivatives is an unexpected result
because closely related imines, derived from methyl glycinate,
alaninate, valinate, and tyrosinate, have been reported to metalate
in good yields;11c furthermore, the cyclometalation of primary
amines has always been considered problematic.12
Bearing these facts in mind, we tried to extend the above
cyclopalladation process to amino esters 3b−f (Scheme 2),
readily obtained by alkylation of the imines arising from
commercial α-amino acid or α-amino ester hydrochlorides by
standard procedures.13 These were selected in order to study the
influence of the different variables (size of the metallacycle
650
dx.doi.org/10.1021/om301140t | Organometallics 2013, 32, 649−659

Organometallics
Article
c
Scheme 2. Synthesis of Cyclometalated Compounds and 5
a
b
c
Detected by proton NMR. 1:1 mixture of regioisomers. Compounds 4a, 4b(6), 4c, 4d, 4e, and 4f could not be purified.
Good XRD-quality crystals of compounds 5a and 5c and the
bonds. In contrast the crystal structure of 5a reveals only
nonconventional C−H···O hydrogen bonds.
six-membered-ring isomer of 5b, 5b(6), were obtained by vapor
diffusion at 298 K of mixtures CH2Cl2/MeOH, CH2Cl2/C6H14,
and MeC6H5/C6H14, respectively (Figures 1−3). It should be
noted that the six-membered metallacycle 5b(6) crystallizes from
the mixture of five- and six-membered 5b compounds, despite
5b(6) being the minor component of the mixture. The strong
intermolecular interactions present in the structure of this
compound (see below) easily explain this fact.
For all compounds the distances between palladium and the
coordinated atoms are similar to those reported, and the
smallest angle in the coordination sphere of palladium corre-
sponds to the C−Pd−N bite angle (Table 1).16 The phos-
phorus and nitrogen atoms adopt a trans arrangement, the six-
membered metallacycle has a boat conformation in all cases,
and the coordination plane shows a slight tetrahedral distor-
tion in both 5a and 5c.
The unexpected results found in the cyclopalladation of some
of these ligands prompted us to carry out a complete kinetico-
mechanistic study on the reaction between palladium acetate,
amino esters 3a, 3b, and 3f, and imine 2a in toluene solution. The
experiments were performed at [Pd]:[N-donor ligand] ratios
within the 0.9−1.1 margin to avoid the formation of the dead-
end trans-[Pd(AcO)2(N-donor)2] species, while having
practically all the reactants as {Pd(AcO)(N-donor)} metal-
ating units.17 The reactions were monitored by UV−vis
spectroscopy in the full 300−800 nm range, with absorbance
versus time traces derived where larger differences were
detected. The kinetic and thermal and pressure activation
parameters thus obtained are collected in Table 2 (Figure 4).
The parameters corresponding to the cyclopalladation of the
N-benzylideneamine and benzylamine, previously reported,12b,17b
have also been included in the same table for comparative purposes.
The values obtained fall within the range of the values determined
for similar systems, involving a large organization on going to the
The structures of compounds 5c and 5b(6) reveal diverse
intermolecular interactions: conventional NH···O hydrogen
bonds and nonconventional CH···O and CH···X hydrogen
651
dx.doi.org/10.1021/om301140t | Organometallics 2013, 32, 649−659

Organometallics
Article
Table 1. Selected Bond Lengths (in Å) and Bond Angles
(in deg) of 5a, 5c, and 5b(6)
5a
5c
5b(6)
Bond Lengths
Pd(1)−C(1)
Pd(1)−N(1)
Pd(1)−P(1)
Pd(1)−X(1)
N(1)−C(8)
O(2)−C(9)
O(2)−C(10)
O(1)−C(9)
1.986(3)
2.136(3)
2.2488(15)
2.4198(13)
1.480(4)
1.320(4)
1.459(5)
1.203(4)
2.037(5)
2.134(4)
2.255(2)
2.4874(14)
1.480(6)
1.349(6)
1.445(6)
1.180(6)
2.003(2)
2.131(2)
2.2507(11)
2.4056(9)
1.502(3)
1.333(3)
1.453(3)
1.210(3)
a
Bond Angles
C(1)−Pd(1)−N(1)
C(1)−Pd(1)−P(1)
84.61(11)
93.52(9)
86.08(9)
96.12(5)
109.6(3)
124.6(3)
111.4(3)
89.14(17)
92.76(14)
85.96(12)
92.78(6)
109.1(4)
123.9(4)
111.0(4)
88.29(9)
93.75(7)
85.41(6)
92.58(3
Figure 1. ORTEP plot of 5a. Hydrogen atoms have been omitted for
clarity.
a
N(1)−Pd(1)−X(1)
a
P(1)−Pd(1)−X(1)
C(7)−C(8)−N(1)
C(8)−C(9)−O(1)
C(8)−C(9)−O(2)
109.28(18)
123.8(2
112.0(2)
a
X = Cl for 5a and 5c(6), and X = Br for 5c.
decrease in ΔS⧧ requirements, while for amino ester 3f the
difference in ΔH⧧ is responsible for this fact. In this respect, the
feasibility of the separation of the five- and six-membered con-
tributions to the metalation of amino ester 3b, by NMR
measurements on the final reaction mixture, allows a deeper view
of the differences. While the differences in ΔH⧧ favor the for-
mation of the five-membered metallacycles, the entropic terms
indicate a less demanding process for the formation of the
six-membered derivative, probably due to the greater flexibility of
the starting material arrangement.
Figure 2. ORTEP plot of 5b(6). Hydrogen atoms have been omitted for
A further comparison is also possible between the cyclo-
metalation of amino ester 3a and its corresponding imino
derivative, 2a; for this system the cyclometalation of the imine
derivative is ca. 30-fold slower than that of the amino ester. The
effect is, nevertheless, not originated in the separate values of
ΔH⧧ or ΔS⧧, and the acceleration decreases to 10-fold at 300 K
due to the much larger temperature dependence of the reaction
rate of the amino ester.18 Probably the higher rigidity of the
starting imine material induces the need for a more demanding
organization on going to the transition state providing lesser
enthalpic requirements. This is especially relevant as far as the
initial preparative observation (see before) of compound 4a as
the sole metalated compound on reaction of 2a with Pd(AcO)2
at 80 °C. It is evident that the metalated Pd(II) center promotes
the hydrolysis of the cyclometalated imine derivative under the
preparative conditions, and the consequent faster metalation of
the amino ester occurs within the reaction mixture. Some
preliminary kinetic runs indicate that the cyclometalated 2a
derivative undergoes the CN bond hydrolysis process at a rate
of 3.5 × 10−5 s−1 at 350 K in toluene solution, producing
compound 4a.
clarity.
Given the fact that an acceleration of the cyclopalladation
reactions is observed in protic media, due to the formation of a
highly ordered ambiphilic transition state very sensitive to the
presence of any protons, the use of acetic acid as solvent was also
tried in the present study.14,19 Surprisingly, the monitoring of the
cyclopalladation reaction in acetic acid of amino ester 3a does not
produce the expected rate enhancement. In fact, the values
measured for ΔH⧧, ΔS⧧, and ΔV⧧ follow the opposite trend from
what has been observed previously, i.e., increase in the enthalpic
Figure 3. ORTEP plot of 5c. Hydrogen atoms have been omitted for
clarity.
transition state, which is accompanied by an important contraction
in volume.
At a first glance it is evident that the cyclometalation of amino
esters 3a, 3b, and 3f in toluene is definitively faster than for other
N-donor ligands previously studied.14,17 For amino esters 3a and
3b it is also clear that this effect is related with a noticeable
652
dx.doi.org/10.1021/om301140t | Organometallics 2013, 32, 649−659

Organometallics
Article
Table 2. Kinetic and Activation Parameters for the Cyclometalation Reactions Studied
metalating ligand
N-benzylamine12b
solvent
104 × 350k /s−1
ΔH‡/kJ mol−1
ΔS⧧/J K−1 mol−1
ΔV⧧/cm3 mol−1
toluene
22
100
170
53
73
−91
3
−16
−11
−13
acetic acid
toluene
100
3a
81
49
71
70
76
50
52
62
2
2
4
1
2
2
3
3
−50
−152
6
7
1
2
acetic acid
toluene
−16
a
3b
460
580
350
520
24
−71 14
not measured
b
five-membered metalation contribution
−72
−59
−130
1
7
5
b
six-membered metalation contribution
a
3f
toluene
toluene
toluene
not measured
N-benzylidenbenzylamine17b
−150 10
−135 10
−15
−14
2
2
2a
4.8
a
Not measured given the impossibility of separation of the five- and six-membered cyclometalation contribution under the conditions needed.
Proton NMR monitoring at different temperatures of the final five- to six-membered cyclometalated compound ratio allows the estimation of the
b
k5‑membered/k6‑membered value and thus the contribution of each reaction to the overall process.
Figure 4. (a) UV−vis spectral changes observed for the reaction of an equimolar mixture of palladium acetate and amino ester 3b in toluene at 30 °C,
total time 150 min. (b) Eyring (top) and ln k versus P (bottom) plots for the reaction of amino ester 3a.
Table 3. Optimization of Carbonylation of 3a
entry
t/h
T/°C
benzoquinone (% molar)
overall yield (%)
6a/7a/8a ratio
a
1
6
6
6
6
6
reflux
65
100
100
200
100
135
200
98
95
91
92
98
94
80::20
58::42
90::10
70::30
86::14
84::16
2
3
reflux
reflux
reflux
reflux
b
4
5
6
3
b
a
2% molar of Pd(OAc)2. Two-fold 3a and benzoquinone concentration.
demands and less negative entropy, accompanied by practically
the same compression. Obviously, the existence of some
interactions between the polar groups of the amino ester and
the acetic acid used as a solvent has to be considered responsible
for this observed difference. In this respect, the X-ray determined
structure of 5a, 5c, and 5b(6) (see above) clearly shows the
tendency of these amino esters to form hydrogen bond
interactions. This lack of enhancement of the metalation process
in acetic acid solution is rather relevant for the catalytic results
indicated below. It is clear from the results obtained from the
kinetic experiments that the effect of the acetic acid solvent in the
catalysis cannot be related to the formation of the cyclometalated
derivative.
Summarizing, the results indicate that the full substitution of
the carbon in the α position of the amino esters plays a pivotal
role in their cyclopalladation reaction behavior. The differ-
ence between the ΔS⧧ values of metalation of amino ester 3a
(−50 J K−1 mol−1) and benzylamine (−91 J K−1 mol−1) suggests
that this effect is related with a noticeable decrease in ΔS⧧
requirements. This specificity can also be related with the
653
dx.doi.org/10.1021/om301140t | Organometallics 2013, 32, 649−659

Organometallics
Article
Thorpe−Ingold effect2b,20 (or gem-dimethyl effect), which
improves the outcome of organic cyclization reactions when
alkyl substituents are present on the acyclic carbon backbone.
Nevertheless the role played by other factors such as ΔH⧧ or the
hydrogen bond interactions, when acetic acid is used as a solvent,
can not be discarded.
of 1:2. Under these conditions the yield was 91% and the
benzolactam/acetamide ratio was 90:10 (entry 3).
The catalytic process was successfully expanded to other
racemic phenylethylamines and to some lactams substituted at
the aromatic ring. The results are shown in Table 4 and Scheme 3,
respectively. From the data it is clear that the steric hindrance of
the R and R′ groups plays a crucial role in the process. Thus, the
carbonylation of methylphenylalaninate produced a rather low
benzolactam/acetamide ratio, 46:54 (R′ = H, entry 4), which
improved for compound 3a (Table 3). Even no acetamides were
found in the preparation of 6g, 6f, and 6h bearing larger R′
groups (entries 1−3, R′ = propyl, benzyl, and para-
methoxybenzyl, respectively). An increase in the steric hindrance
around the amino group prevents competitive acetylation.
Interestingly, the presence of the ester group is not essential
for the success of the catalytic carbonylation (entry 6). However,
the presence of a neighboring coordinating hydroxymethyl or
allyl group erodes or inhibits completely the formation of
benzalactam (entries 7 and 5, respectively). It should be also
noted that the presence of MeO, CN, or F groups on the
aromatic ring (6f(MeO) and 6m−o in Scheme 3) is compatible
with the formation of a lactam.
Catalytic Results. The great tendency shown by the free
amino esters studied to undergo cyclopalladation prompted us to
study their palladium-catalyzed NH2-directed carbonylation at
low pressure. Initially palladacycle 4a was carbonylated to
benzolactam 6a with CO (1 atm) in different solvents at room
temperature, thus indicating the feasibility of the process. Then
the palladium acetate-catalyzed carbonylation of racemic amino
acid 3a, using Cu(AcO)2/O2 as the oxidant in toluene, was
studied. Unfortunately, only urea 7a (Table 3) was obtained
under different experimental conditions, not the expected
benzolactam 6a. Given the strong accelerating effect of acetic
acid in Pd(AcO)2-catalyzed reactions,21 we swapped to this solvent.
Under these conditions, the desired 6a lactam was obtained
although contaminated with acetamide 8a. The best ratio was
6a/8a = 64:36 in a 91% yield. Since the formation of acetamide may
also be favored by the Cu(II) salts, which can enhance the amide
bond formation,22 an alternative oxidant was tried; benzoquinone
proved to be the better choice (Table 3). The best results were
obtained with a 1.5 × 10−2 M solution of 3a in refluxing AcOH using
5% molar Pd(AcO)2 and an amino ester/benzoquinone molar ratio
The reaction is also found highly sensitive to the size of the
benzolactam formed; no five-membered lactams were detected
when the reaction was performed with ligands 3s, 3t, and 3u
(Scheme 4). Nevertheless a 57% yield of the five-membered
Scheme 4. Benzolactam 6r and Methyl Phenylgycinates 3s−u
Table 4. Carbonylation of Phenylethylamines
overall yield lactam/acetamide
entry
R
R′
lactam
(%)
ratio
1
2
3
4
5
6
7
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
Me
propyl
Bn
6g
6h
6f
6i
98
93
100:0
100:0
100:0
a
p-MeO-Bn
H
80
91
46:54
b
allyl
6j
lactam 6r was obtained from triphenylmethylamine with a total
selectivity. It should be noted that, in this last case, the corre-
sponding amino ester presents a larger steric hindrance around
the amino group. These results are in sharp contrast with those
reported by Orito et al.8 for the related carbonylation of
Me
6k
6l
89
85
82:18
50:50
c
CH2OH
Bn
a
b
Mixture of regioisomers (6f(H)/6f(MeO) = 6:4). Complex mixture
of compounds. Lactam 6l is not acetylated on the hydroxyl group.
c
Scheme 3. Benzolactams Substituted on the Aromatic Ring
a
Mixture of regioisomers (see Table 4).
654
dx.doi.org/10.1021/om301140t | Organometallics 2013, 32, 649−659

Organometallics
Article
secondary amines using Cu(II) as co-oxidant, in which the five-
membered benzolactams were favored over the six-membered
analogues.
A greater reactivity of the six-membered palladacycles involved
could explain this result. To assess this assumption, the reactivity
of the six- and five-membered cyclopalladated derivatives 4g and
4u (Scheme 5) with CO was studied. Thus, after 1 h of reaction at
solvent in the catalytic process can not be related to the
formation of the cyclometalated derivative. The good catalytic
results obtained with the palladium acetate/acetic acid system
can be explained by the fact that some key steps are assisted by
strong hydrogen bonding with AcOH molecules. Finally, the
unexpected strong bias toward the six-membered lactams over
five-membered analogues can also be explained by the greater
reactivity of the six-membered palladacycles formed. Studies
designed to expand the process to other organic derivatives of
interest are currently under way.
Scheme 5. Carbonylation of 4g and 4u
EXPERIMENTAL SECTION
■
Materials and Methods. Amino esters, aldehydes, benzyl bromide,
K2CO3, KOH, benzoquinone, PdCl2, Pd(AcO)2, LiCl, LiBr, and PPh3
were obtained from commercial sources and used as received. Solvents
were distilled and dried before use.23
Elemental analyses were carried out at the Serveis de Cientifico-
Tecnics (Universitat Barcelona). Mass spectra were obtained at the
̀
Servei d’Espectrometria de Masses (Universitat de Barcelona). Infrared
spectra were obtained with a Nicolet 400FTIR instrument using KBr
pellets, and only the most relevant absorptions of the new products are
50 °C, the six-membered benzolactam 6g was obtained in
a 80% yield from 4g, whereas 4u afforded only a 10% yield of
compound 6u, in full agreement with the catalytic results
(Scheme 5). In contrast, the catalytic carbonylation of 3b
produced only lactam 6b(6), which originates from the six-
membered metallacycle, despite the fact that the stoichiometric
cyclometalation of 3b favors the five-membered palladacycle
4b(5) as a major product in the 4b product mixture (Scheme 2).
Nevertheless, carbonylation of a pure sample of 4b(5) in
refluxing AcOH afforded the corresponding five-membered
lactam 6b(5) in 86% yield, thus indicating that both benzo-
lactams sizes (six or five) are attainable depending on the
carbonylation method (catalytic or stepwise) (Scheme 6).
1
presented in the following sections. High-resolution H NMR spectra
and the two-dimensional {1H−1H}-NOESY and COSY experiments
were registered with a Varian VRX-500 or a Bruker Avance DMX-500
MHz instrument. The solvent used for NMR experiments was CDCl3
(99.9%), and the references were SiMe4 [for 1H NMR] and P(OMe)3
[δ(31P) = 140.17 ppm, for 31P NMR]. The chemical shifts (δ) are given
in ppm, and the coupling constants (J) in Hz. In the characterization
1
section of each product the assignment of signals detected in the H
NMR spectra refers to the labeling patterns presented in Schemes 1 and 2.
Procedures for synthesis and characterization of organic compounds
3 are giving in the Supporting Information.
Preparation of the Palladium(II) Complexes. Compounds 4,
Typical Procedure. 4b(5). A mixture of 3b (500 mg, 1.96 mmol) and
palladium acetate (439 mg, 1.96 mmol) in 40 mL of toluene was stirred
at 80 °C for 22 h. The solvent was removed under vacuum, and the
residue was treated with lithium bromide (213 mg, 2.45 mmol) in
acetone (40 mL) for 1 h at rt. The suspension was filtered to obtain
783 mg (91%) of a 6:1 mixture of five-membered and six-membered
palladacycles (1H NMR of the crude). The crude was purified by flash
chromatography (hexane/EtAcO, 8:2) to afford five-membered pallada-
cycle 4b(5) (625 mg, 72%). Compound 4b(5): brownish solid; mp
Scheme 6. Catalytic and Stepwise Carbonylation of 3b
1
212−214 °C; Rf (hexane/EtAcO, 8:2) 0.32; H NMR (400 MHz;
CDCl3) δ 7.44 (3H, m, ArH), 7.33 (3H, m, ArH), 7.18 (1H, dd, J = 7.7,
1.2 Hz, ArH), 7.04 (1H, m, ArH), 6.94 (1H, m, ArH), 4.75 (1H, br d, J =
10.3, NHH), 3.86 (3H, s, OCH3), 3.72 (1H, d, J = 14.1 Hz, CHH), 3.61
(1H, d, J = 14.1 Hz, CHH), 3.67 (1H, br d, J = 10.3, NHH); 13C NMR
(CDCl3, 101 MHz) δ 171.1, 136.2, 133,9, 130.2, 130.0, 129.5, 129.4,
128.3, 127.2, 125.0, 123.0, 74.9 (q), 53.3 (OCH3), 47.4 (CH2); IR (KBr)
νmax 3296, 3256, 1730; HRMS (MALDI-TOF) calcd for
C32H32BrN2O4Pd2 (M − Br)+ 798.9609, found 798.9626. Anal. Calcd
for C32H32Br2N2O4Pd2: C, 43.61; H, 3.66; N, 3.18. Found: C, 43.7; H,
3.5; N, 3.3.
4g. 4g was obtained using the same procedure as that described above
from 191 mg (0.87 mmol) of amine 3g as a brownish solid: yield 305 mg
(87%); mp 110−112 °C; 1H NMR (300 MHz; CDCl3) δ 7.38 (1H, d,
J = 7.8 Hz), 6.90 (1H, m), 6.83 (1H, m), 6.75 (1H, dd, J = 7.3, 1.8 Hz),
4.46 (1H, br d, J = 11.3 Hz, NHH), 3.68 (3H, s, OCH3), 3.59 (1H, d, J =
13.8 Hz, CHH), 3.25 (1H, d, J = 13.8 Hz, CHH), 3.14 (1H, br d, J =
11.3 Hz, NHH), 1.98 (1H, m), 1.84 (1H, m), 1.43 (1H, m), 1.24 (1H,
m), 0.95 (3H, t, J = 7.2 Hz, CH3); 13C NMR (CDCl3, 101 MHz) δ 173.9
(COO), 136.8, 135.0, 127.5, 127.4, 125.6, 124.6, 59.7 (q), 53.2 (OCH3),
51.5 (CH2), 40.0 (CH2), 17.7 (CH2), 14.0 (CH3); IR (KBr) νmax 3302,
3237, 1726, 1571, 1558, 1435, 1230; HRMS (MALDI-TOF) calcd for
C26H36BrN2O4Pd2 (M − Br)+ 730.9928, found 730.9899. Anal. Calcd
for C26H36Br2N2O4Pd2: C, 38.40; H, 4.46; N, 3.44. Found: C, 38.67; H,
4.33; N, 3.60.
The results indicate that, even though both five-membered and
six-membered palladacycles are capable of carbonylation to
produce the corresponding lactams, the latter reacts more
quickly with CO, affording 6b(6) as the only isomer.
Conclusions. An adequate selection of the R groups
positioned on the acyclic carbon backbone of phenylethylamines
and benzylamines allows an unprecedented NH2-directed
catalytic carbonylation with high selectivity and yield. Kinetic
results of the cyclometalation process indicate that the formation
of the metalated palladium intermediate is much faster than
for other systems, even though the presence of protic medium
does not favor such a process as for other N-donor ligands. Thus,
the studies show that the favorable effect of acetic acid as the
655
dx.doi.org/10.1021/om301140t | Organometallics 2013, 32, 649−659

Organometallics
Article
4u. 4u was obtained using the same procedure as that described above
from 100 mg (0.48 mmol) of amine 3u as a brownish solid: yield 305 mg
(87%); mp 122−124 °C; 1H NMR (300 MHz; CDCl3) δ 7.38 (1H, d,
J = 7.8 Hz), 6.98 (2H, m), 6.88 (1H, m), 5.10 (1H, br d, J = 10.3 Hz,
NHH), 3.83 (3H, s, OCH3), 3.63 (1H, br d, J = 10.3 Hz, NHH), 2.18
(2H, m), 1.45 (1H, m, CHH), 1.34 (1H, m, CHH), 0.99 (3H, t, J = 7.2
Hz, CH3); 13C NMR (CDCl3, 101 MHz) δ 172.4 (COO), 150.6, 144.9,
135.6, 127.1, 124.8, 123.9, 74.7 (q), 53.5 (OCH3), 42.7 (CH2), 17.3
(CH3), 14.0; IR (KBr) νmax 3296, 3252, 1729, 1571, 1433, 1210; HRMS
(MALDI-TOF) calcd for C24H32BrN2O4Pd2 (M − Br)+ 702.9615,
found 702.9609. Anal. Calcd for C24H32Br2N2O4Pd2: C, 36.71; H, 4.11;
N, 3.57. Found: C, 36.65; H, 4.05; N, 3.75.
(s, CH3O), 25.51 (s, CH3C); ESI-MS (+) {H2O:CH3CN}, m/z [M −
Br]+ = 578.09. Anal. Calcd for C29H28BrFNO2PPd: C, 52.87; H, 4.28; N,
2.13. Found: C, 52.9; H, 4.2; N, 1.9.
5e. 5e was obtained using the same procedure as that described above
from 189 mg (0.79 mmol) of amino ester 3e. Yield: 160 mg (35%); 1H
NMR (400 MHz, CDCl3): δ 7.62−7.55 (6H, m, PPh3), 7.41−7.36 (3H,
m, PPh3), 7.34−7.29 (6H, m, PPh3), 7.53 (1H, dd, J = 2.3, 8.2 Hz, H3),
7.24 (1H, dd, J = 2.3, 4.2 Hz, H1), 6.80 (1H, d, J = 8.2 Hz, H4), 3.66 (3H,
s, CH3O), 3.63 (1H, d, J = 13.3 Hz, HCH), 3.37 (1H, d, J = 13.2 Hz,
HCH), 1.76 (3H, s, CH3C); 31P{1H} NMR (250 MHz, CDCl3) δ 34.37;
13C{1H} NMR (101 MHz, CDCl3) δ 155.53, 144.85, 134.80 (d, J =
11.5 Hz, PPh3), 131.75, 130.88 (PPh3), 130.09 (PPh3), 128.43 (d, J =
10.9 Hz, PPh3), 126.25, 118.89, 56.72 (CH3C), 53.87 (CH2), 53.47
(CH3O), 25.88 (CH3C); ESI-MS (+) {H2O:CH3CN}, m/z [M −
Cl]+ = 605.07. Anal. Calcd for C29H28ClN2O4PPd: C, 54.31; H, 4.40; N,
4.37. Found: C, 54.4; H, 4.5; N, 3.9.
5f. 5f was obtained, as a 1:1 mixture of compounds, using the same
procedure as that described above from 257 mg (0.86 mmol) of amino
ester 3f. Yield: 477 mg (75%). 5f(MeO): 1H NMR (400 MHz, CDCl3)
δ 7.59−7.53 (6H, m, PPh3), 7.41−7.36 (3H, m, PPh3), 7.33−7.28 (6H,
m, PPh3), 6.66 (1H, d, J = 8.1 Hz, H4), 6.27 (1H, dd, J = 2.5, 8.1 Hz, H3),
5.98 (1H, dd, J = 2.5, 5.3 Hz, H1), 3.77 (3H, s, CH3O), 3.65 (3H, s,
CH3OCO); 31P{1H} NMR (162 MHz, CDCl3) δ 34.47; 13C{1H} NMR
(101 MHz, CDCl3) δ 134.90 (d, J = 11.5 Hz, PPh3), 130.35 (PPh3),
128.06 (d, J = 10.6 Hz, PPh3), 126.60, 120.78, 110.43, 55.21 (CH3O),
52.81 (CH3OCO). 5f(H): 1H NMR (400 MHz, CDCl3) δ 7.59−7.53
(6H, m, PPh3), 7.36−7.41 (3H, m, PPh3), 7.28−7.33 (6H, m, PPh3),
6.72−6.33 (4H, m, H1−H4), 3.65 (3H, s, CH3OCO), 3.18 (s, 3H,
CH3O); 31P{1H} NMR (162 MHz, CDCl3) δ 34.13; 13C{1H} NMR
(101 MHz, CDCl3) δ 139.39, 134.90 (d, J = 11.5 Hz, PPh3), 130.35
(PPh3), 128.06 (d, J = 10.6 Hz, PPh3), 126.33, 114.39, 54.53 (CH3O),
52.81 (CH3OCO); ESI-MS (+) {H2O:CH3CN}, m/z [M − Br]+ =
666.14; [M − Br + CH3CN]+ = 707.17. Anal. Calcd for C36H35-
BrNO3PPd: C, 57.89; H, 4.72; N, 1.88. Found: C, 57.8; H, 4.9; N, 1.7.
Synthesis of 6a by Stoichiometric Carbonylation of 4a. A
suspension of 4a(X= Br) (120 mg, 0.16 mmol) in methanol (25 mL)
was stirred at room temperature in an atmosphere of nitrogen con-
taining carbon monoxide delivered from a toy balloon (∼200 mL) for
24 h. The reaction mixture was filtered, washed with 10% aqueous
NaHCO3 solution, and dried over MgSO4. The solvent was removed in
a rotatory evaporator to obtain 6a in 93% yield (65 mg).
Compounds 5, Typical Procedure. 5a. A suspension of 3a (318 mg,
1.64 mmol) and palladium acetate (358 mg, 1.59 mmol) in toluene
(25 mL) was stirred at 80 °C for 22 h. The reaction mixture was cooled,
and volatiles were removed under vacuum to obtain a solid. This solid
was dissolved in acetone, LiCl (180 mg, 4.24 mmol) and PPh3 (442 mg,
1.69 mmol) were added to the solution, and the resulting mixture was
stirred at room temperature for 1 h. The solution was filtered and
concentrated to afford, after addition of ethyl ether, a solid, which was
purified by chromatography, using CHCl3/MeOH (98:2) as eluent, to
1
afford 5a (532 mg, 50%): H NMR (250 MHz, CDCl3) δ 7.59−7.50
(6H, m, PPh3), 7.41−7.29 (9H, m, PPh3), 6.70 (2H, d, J = 4.2 Hz, H3,
H4), 6.46 (1H, dd, J = 7.5, 4.9 Hz, H1), 6.34 (1H, m, H2), 4.21 (2H, m,
NH2), 3.67 (3H, s, OCH3), 3.59 (1H, d, J = 13.3 Hz, CHH), 3.30 (1H, d,
J = 13.2 Hz, CHH), 1.76 (3H, s, CH3); 31P{1H}NMR (250 MHz,
CDCl3) δ 34.16; 13C{1H} NMR (101 MHz, CDCl3) δ 136.93, 134.78
(d, J = 11.7 Hz, PPh3), 130.34 (s, PPh3), 128.07 (d, J = 10.8 Hz, PPh3),
126.53, 125.63, 123.58, 54.15 (CH2), 53.07 (CH3O), 25.68 (CH3);
ESI-MS (+) {H2O:CH3CN}, m/z [M − Cl]+ = 560.10, [2M − Cl]+ =
1157.17. Anal. Calcd for C29H29ClNO2PPd: C, 58.40; H, 4.90; N, 2.35.
Found: C, 58.6; H, 5.1; N, 2.5.
5b(5). 5b(5) was obtained using the same procedure as that described
above from 311 mg (1.22 mmol) of amino ester 3b. Yield: 833 mg
(75%); 1H NMR (400 MHz, CDCl3) δ 7.75−7.70 (6H, m, PPh3), 7.50−
7.27 (17H, m), 6.89 (1H, m), 6.45 (2H, m), 4.76 (1H, dd, J = 3.9,
10.5 Hz, HNH), 4.16 (1H, dd, J = 3.1, 3.8 Hz, HNH), 3.82 (3H, s,
CH3O), 3.62 (1H, d, J = 13.9 Hz, HCH), 3.79 (1H, d, J = 14.3 Hz,
HCH); 31P{1H} NMR (250 MHz, CDCl3): δ 41.24; 13C{1H} NMR
(101 MHz, CDCl3) δ 139.00, 135.27 (d, J = 12.0 Hz, PPh3), 130.68
(PPh3), 128.13 (d, J = 10.8 Hz, PPh3), 126.38, 124.20, 123.00, 53.06
(CH3O), 48.03 (CH2); ESI-MS (+) {H2O:CH3CN}, m/z [M − Cl]+ =
622.12. Anal. Calcd for C34H31ClNO2PPd: C, 62.02; H, 4.75; N, 2.13.
Found: C, 62.3; H, 5.0; N, 1.9.
5c. 5c was obtained using the same procedure as that described above
from 255 mg (1.15 mmol) of amino ester 3c. Yield: 344 mg (45%); 1H
NMR (400 MHz, CDCl3) δ 7.56−7.51 (6H, m, PPh3), 7.40−7.34 (3H,
m, PPh3), 7.31−7.27 (6H, m, PPh3), 6.70−6.65 (2H, m, H3, H4), 6.46
(1H, dd, J = 7.6, 5.0 Hz, H1), 6.35−6.25 (1H, m, H2), 3.75 (1H, d, J =
12.7 Hz, HCH), 3.60 (3H, s, CH3O), 3.13 (1H, d, J = 12.8 Hz, HCH),
2.44 (1H, m, CHCH3), 1.34 (3H, d, J = 6.9 Hz, CH3CH), 1.03 (3H, d,
J = 6.9 Hz, CH3CH); 31P{1H} NMR (162 MHz, CDCl3) δ 33.85;
13C{1H} NMR (101 MHz, CDCl3) δ 137.03, 134.75 (d, J = 11.6 Hz,
PPh3), 130.28 (s, PPh3), 127.96 (d, J = 10.7 Hz, PPh3), 126.31, 125.45,
123.45, 52.79 (CH3O), 51.36 (CH2), 34.678 (CHCH3), 18.26
(CH3CH), 17.18 (CH3CH); ESI-MS (+) {H2O:CH3CN}, m/z
[M − Br]+ = 588.13; [M − Br + CH3CN]+ = 629.15. Anal. Calcd
for C31H33BrNO2PPd: C, 55.66; H, 4.97; N, 2.09. Found: C, 55.7; H,
4.8; N, 1.9.
6a: mp 180−182 °C (lit.24 181−183 °C); Rf (CH2Cl2/MeOH, 98:2)
0.31; 1H NMR (400 MHz; CDCl3) δ 8.07 (1H, d, J = 7.7 Hz, ArH), 7.46
(1H, m, ArH), 7.36 (1H, m, ArH), 7.22 (1H, d, J = 7.5 Hz, ArH), 6.58
(1H, br s, NH), 3.69 (3H, s, OCH3), 3.40 (1H, d, J = 15.7 Hz, CHH),
3.11 (1H, d, J = 15.7 Hz, CHH), 1.56 (3H, s, CCH3); 13C NMR (CDCl3,
101 MHz) δ 174.6 (COO), 165.5 (CONH), 136.1 (q), 132.8, 128.3,
127.9, 127.8, 127.6, 59.0 (q), 53.1 (OCH3), 37.9 (CH2), 25.9 (CH3); IR
(ATR) νmax 3195, 1737, 1665; HRMS (ESI+) calcd for C12H14NO3
(M + H)+ 220.0968, found 220.0968.
Stepwise Preparation of Lactam 6b(5). A stirred solution of
palladacycle 4b(5) (110 mg, 0.125 mmol) in AcOH (25 mL) was gently
refluxed in an oil bath at 120 °C in an atmosphere of nitrogen containing
carbon monoxide delivered from a toy balloon (∼200 mL) for 3 h. The
reaction mixture was cooled and filtered through a thin pad of Celite.
The volatiles were removed under vacuum, and the solid obtained was
purified by flash chromatography to afford 6b(5) (61 mg, 86%).
Methyl 1-benzyl-3-oxoisoindoline-1-carboxylate, 6b(5): white
1
solid; mp 140−142 °C; Rf (hexane/EtAcO, 8:2) 0.32; H NMR (400
5d. 5d was obtained using the same procedure as that described above
from 110 mg (0.52 mmol) of amino ester 3d. Yield: 170 mg (50%); 1H
NMR (400 MHz, CDCl3) δ 7.58−7.53 (6H, m, PPh3), 7.43−7.38 (3H,
m, PPh3), 7.34−7.30 (6H, m, PPh3), 6.64 (1H, dd, J = 8.1, 5.7 Hz, H4),
6.38 (1H, td, J = 8.3, 2.3 Hz, H3), 6.08 (1H, ddd, J = 2.6, 4.8, 9.2 Hz, H1),
3.67 (3H, s, CH3O), 3.55 (1H, d, J = 13.3 Hz, HCH), 3.28 (1H, d, J =
13.3 Hz, HCH), 1.74 (3H, s, CH3C); 31P{1H} NMR (162 MHz,
CDCl3) δ 33.84 (br); 19F{1H} NMR (376 MHz, CDCl3) δ −115.4 (d,
J = 105.9 Hz); 13C{1H} NMR (101 MHz, CDCl3) δ 135.75 (d, J = 11.5
Hz, PPh3), 130.56 (PPh3), 128.14 (d, J = 10.9 Hz, PPh3), 126.75 (d,
J = 7.33 Hz, C4), 123.02, 110.16 (d, J = 21.9 Hz, C3), 53.31 (CH2), 53.15
MHz; CDCl3) δ 7.82 (1H, d, J = 7.7 Hz, ArH), 7.79 (1H, d, J = 7.5 Hz,
ArH), 7.64 (1H, m, ArH), 7.52 (1H, m, ArH), 7.27 (3H, m, ArH), 7.12
(2H, m, ArH), 6.53 (1H, br s, NH), 3.77 (1H, d, J = 13.4 Hz, CHH), 3.71
(3H, s, OCH3), 2.96 (1H, d, J = 13.4 Hz, CHH); 13C NMR (CDCl3, 101
MHz) δ 170.6 (CO), 169.5 (CO), 144.9 (q), 134.5, 132.5, 130.8, 129.8,
129.5, 128.7, 127.7, 124.0, 123.3, 68.8 (q), 53.0 (OCH3), 45.0 (CH2); IR
(ATR) νmax 3219, 1733, 1695, 1611, 1250; HRMS (ESI+) calcd for
C17H16NO3 (M + H)+ 282.1130, found 282.1128.
Catalytic Synthesis of Benzolactams. Typical Procedure. A stirred
suspension of methyl 2-amino-2-benzyl-3-phenylpropanoate (3h) (100 mg,
0.38 mmol), benzoquinone (83 mg, 0.76 mmol), and palladium acetate
656
dx.doi.org/10.1021/om301140t | Organometallics 2013, 32, 649−659

Organometallics
Article
(4.5 mg, 0.02 mmol) in AcOH (25 mL) was gently refluxed in an oil bath
at 120 °C in an atmosphere of nitrogen containing carbon monoxide
delivered from a toy balloon (∼200 mL) for 6 h. The reaction mixture
was cooled and filtered through a thin pad of Celite. The volatiles were
removed under vacuum to obtain a solid corresponding to almost pure
benzolactam 6h. The residue was purified by flash chromatography to
afford 6h (105 mg, 93%).
(1H, br s, NH), 4.41 (1H, ddd, J = 9.9, 5.4, 2.1 Hz, NHCH), 3.79 (3H, s,
OCH3), 3.33 (1H, dd, J = 15.7, 5.2 Hz, CHH), 3.22 (1H, dd, J = 15.7,
9.9 Hz, CHH); 13C NMR (CDCl3, 101 MHz) δ 170.8 (COO), 165.1
(CONH), 136.1, 132.5, 129.3, 128.1, 127.5, 127.4, 53.0 (OCH3), 52.8
(NHCH), 31.1 (CH2); IR (ATR) νmax 3271, 1737, 1656, 1546, 1536,
1215, 1176; HRMS (ESI+) calcd for C11H12NO3 (M + H)+ 206.0817,
found 206.0803.
Methyl 1-oxo-3-phenyl-1,2,3,4-tetrahydroisoquinoline-3-carbox-
ylate, 6b(6): Rf (hexane/EtAcO, 7:3) 0.43; 1H NMR (300 MHz;
CDCl3) δ 8.04 (1H, d, J = 7.7 Hz, ArH), 7.48−7.25 (7H, m, ArH), 7.20
(1H, d, J = 7.6 Hz, ArH), 6.84 (1H, br s, NH), 3.75 (3H, s, OCH3), 3.71
(1H, d, J = 15.6, CHH), 3.63 (1H, d, J = 15.6, CHH); 13C NMR (CDCl3,
101 MHz) δ 171.5 (COO), 165.5 (CONH), 139.1, 135.6, 132.9, 128.9,
128.5, 128.2, 128.0, 127.8, 127.7, 127.5, 125.3, 64.3(CNH), 53.3 (OCH3),
38.0 (CH2); IR (ATR) νmax 3174, 1733, 1661, 1602, 1446, 1377; HRMS
(ESI+) calcd for C17H16NO3 (M + H)+ 282.1130, found 282.1144.
Methyl 7-fluoro-3-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-
3-carboxylate, 6d: white solid; mp 123−127 °C; 1H NMR (400 MHz;
CDCl3) δ 7.75 (1H, dd, J = 8.8, 2.4 Hz, ArH), 7.22−7.13 (2H, m, ArH),
6.26 (1H, br s, NH), 3.71 (3H, s, OCH3), 3.37 (1H, d, J = 14.8 Hz, CHH),
3.07 (1H, d, J = 15.9 Hz, CHH), 1.54 (3H, s, CH3); 13C NMR (CDCl3,
101 MHz) δ 174.5, 173.9, 162.7 (d, JCF = 245 Hz), 131.4 (d, JCF = 8 Hz),
120.9 (d, JCF = 22 Hz), 115.3 (d, JCF = 21 Hz), 114.9 (d, JCF = 23 Hz), 59.1,
53.3, 40.2, 37.3, 25.8, 23.5; IR (ATR) νmax 3201, 1734, 1668, 1443, 1199;
HRMS (ESI+) calcd for C12H13FNO3 (M + H)+ 238.0874, found 238.0870.
Methyl 3-methyl-7-nitro-1-oxo-1,2,3,4-tetrahydroisoquinoline-3-
carboxylate, 6e: reddish solid; mp 104−108 °C; 1H NMR (400 MHz;
CDCl3) δ 8.91 (1H, d, J = 2.4 Hz, ArH), 8.31 (1H, dd, J = 8.4, 2.4 Hz,
ArH), 7.44 (1H, d, J = 8.4 Hz, ArH), 6.51 (1H, br s, NH), 3.85 (1H, d, J =
16.4 Hz, CHH), 3.71 (3H, s, OCH3), 3.11 (1H, d, J = 16.4 Hz, CHH),
1.59 (3H, s, CH3); 13C NMR (CDCl3, 101 MHz) δ 171.9, 164.5, 164.4,
145.4, 144.2, 135.4, 129.1, 127.4, 121.1, 54.7, 52.3, 41.2, 22.8; IR (ATR)
νmax 3338, 1737, 1671, 1516, 1343, 1206; HRMS (ESI+) calcd for
C12H13N2O5 (M + H)+ 265.0819, found 265.0798.
Mixture of methyl 3-(4-methoxybenzyl)-1-oxo-1,2,3,4-tetrahy-
droisoquinoline-3-carboxylate, 6f(OMe), and methyl 3-benzyl-6-
methoxy-1-oxo-1,2,3,4-tetrahydroisoquinoline-3-carboxylate,
6f(H): white solid; 1H NMR (400 MHz, CDCl3) δ 8.09 (1H, d, J = 7.5 Hz,
ArH), 7.48 (1H, td, J = 7.5, 1.5 Hz, ArH), 7.37 (1H, t, J = 7.5 Hz, ArH),
7.24 (1H, d, J = 7.5 Hz, ArH), 7.33−7.02 (4H, m, ArH), 6.25 (1H, br s,
NH), 3.79 (3H, s, OCH3), 3.64 (3H, s, OCH3), 3.43 (1H, d, J = 13.6 Hz,
CHH), 3.23 (1H, d, J = 13.6 Hz, CHH) 3.17 (1H, d, J = 13.6 Hz, CHH),
2.96 (1H, d, J = 13.6 Hz, CHH); 13C NMR (101 MHz, CDCl3) δ 172.7,
165.1, 135.6, 111.3, 62.9, 55.2, 52.7, 43.8, 36.8; IR (ATR) νmax 3189, 1734,
1666, 1610, 1513; HRMS (ESI+) calcd for C19H20NO4 (M + H)+
326.1387, found 326.1412.
3,3-Dimethyl-3,4-dihydroisoquinolin-1(2H)-one, 6k: white solid;
mp 146−147 °C (lit.26 146−147); 1H NMR (300 MHz; CDCl3) δ 8.06
(1H, d, J = 7.6 Hz, ArH), 7.45 (1H, m), 7.36−7.13 (2H, m, ArH), 6.37
(1H, br s, NH), 2.92 (2H, s, CH2), 1.32 (6H, s, CH3); 13C NMR
(CDCl3, 101 MHz) δ 165.5 (CONH), 137.5, 132.2, 130.4, 127.8, 126.9,
126.2, 52.0 (CNH), 41.6 (CH2), 28.8 (CH3); IR (KBr) νmax 3395,
1660; HRMS (ESI+) calcd for C11H14NO (M + H)+ 176.1075, found
176.1069.
3-Benzyl-3-(hydroxymethyl)-3,4-dihydroisoquinolin-1(2H)-one,
1
6l: brownish oil; Rf (hexane/EtAcO, 1:1) 0.20; H NMR (300 MHz;
CDCl3) δ 8.05 (1H, d, J = 7.6 Hz, ArH), 7.50 (1H, m, ArH), 7.36 (1H,
m, ArH), 7.32−7.15 (6H, m, ArH), 6.91 (1H, br s, NH, ArH), 3.60 (1H,
d, J = 11.2 Hz, CHH), 3.52 (1H, d, J = 11.2 Hz, CHH), 3.06 (1H, J =
13.6 Hz), 2.95−2.80 (4H, m); 13C NMR (CDCl3, 101 MHz) δ 165.8
(CONH), 136.7, 135.9, 132.8, 130.4, 128.5, 128.1, 128.0, 127.1, 126.9,
65.7 (CNH), 58.4, 33.7, 30.9; IR (ATR) νmax 3383, 2927, 1651, 1387,
1253, 1094; HRMS (ESI+) calcd for C17H18NO2 (M + H)+ 268.1338,
found 268.1345.
Methyl 7-methoxy-3-methyl-1-oxo-1,2,3,4-tetrahydroisoquino-
line-3-carboxylate, 6m: white solid; mp 171−174 °C; 1H NMR
(300 MHz; CDCl3) δ 7.58 (1H, d, J = 2.8 Hz, ArH), 7.11 (1H, d, J =
8.4 Hz, ArH), 7.01 (1H, dd, J = 8.4, 2.8 Hz, ArH), 6.27 (1H, br s, NH),
3.84 (3H, s, OCH3), 3.70 (3H, s, OCH3), 3.33 (1H, d, J = 15.6 Hz,
CHH), 3.03 (1H, d, J = 15.6 Hz, CHH), 1.53 (3H, s, CCH3); 13C NMR
(CDCl3, 101 MHz) δ 174.0 (COO), 165.4 (CONH), 158.9, 130.7,
128.8, 127.9, 120.1, 111.2, 58.9 (CNH), 55.4 (OCH3), 52.7 (OCH3),
37.0 (CH2), 25.5 (CH3); IR (KBr) νmax 3195, 3075, 2951, 1736, 1668,
1493, 1451, 1437, 1382; HRMS (ESI+) calcd for C13H16NO4 (M + H)+
250.1079, found 250.1068.
Methyl 7-cyano-3-isopropyl-1-oxo-1,2,3,4-tetrahydroisoquino-
line-3-carboxylate, 6n: white solid; mp 176−178 °C; Rf (hexane/
1
EtAcO, 1:1) 0.43; H NMR (400 MHz; CDCl3) δ 8.44 (1H, d, J =
1.6 Hz, ArH), 7.72 (1H, dd, J = 8.0, 1.6 Hz, ArH), 7.36 (1H, d, J = 8.0 Hz,
ArH), 6.29 (1H, br s, NH), 3.68 (3H, s, OCH3), 3.38 (1H, d, J = 16.4 Hz,
CHH), 3.26 (1H, d, J = 16.4 Hz, CHH), 2.18 (1H, m, CHCH3), 1.00
(3H, d, J = 6.8 Hz, CHCH3), 0.98 (3H, d, J = 6.8 Hz, CHCH3); 13C
NMR (CDCl3, 101 MHz) δ 172.7 (COO), 163.7 (CONH), 141.5,
135.4, 132.8, 128.9, 128.7, 117.9 (CN), 111.5, 65.3 (CNH), 52.8
(OCH3), 35.0, 33.5, 17.1 (CH3), 16.8 (CH3); IR (ATR) νmax 3205, 2963,
2229, 1670, 1610, 1433, 1330, 1277, 1189; HRMS (ESI+) calcd for
C15H17N2O3 (M + H)+ 273.1239, found 273.1230.
Methyl 6,8-difluoro-3-isopropyl-1-oxo-1,2,3,4-tetrahydroisoqui-
noline-3-carboxylate, 6o: white solid; mp 138−140 °C; Rf (hexane/
EtAcO, 1:1) 0.45; 1H NMR (300 MHz; CDCl3) δ 6.77 (2H, m, ArH),
6.29 (1H, br s, NH), 3.68 (3H, s, OCH3), 3.27 (1H, d, J = 15.8 Hz,
CHH), 3.17 (1H, d, J = 15.8 Hz, CHH), 2.12 (1H, hept, J = 6.9 Hz,
CHCH3), 0.99 (3H, d, J = 6.9 Hz, CHCH3), 0.96 (3H, d, J = 6.9 Hz,
CHCH3); 13C NMR (CDCl3, 101 MHz) δ 172.5 (COO), 166.0
Methyl 1-oxo-3-propyl-1,2,3,4-tetrahydroisoquinoline-3-carboxy-
late, 6g: white solid; mp 120−121 °C; Rf (hexane/EtAcO, 1:1) 0.48; 1H
NMR (400 MHz; CDCl3) δ 8.06 (1H, d, J = 7.6 Hz, ArH), 7.46 (1H, m,
ArH), 7.36 (1H, m, ArH), 7.22 (1H, d, J = 7.5 Hz, ArH), 6.43 (1H, br s,
NH), 3.71 (3H, s, OCH3), 3.37 (1H, d, J = 15.7 Hz, CHH), 3.13 (1H, d,
J = 15.7 Hz, CHH), 1.79 (2H, m), 1.40 (1H, m), 1.25 (1H, m), 0.90 (3H,
t, J = 7.3 Hz); 13C NMR (CDCl3, 101 MHz) δ 173.3 (COO), 165.1
(CONH), 135.9, 132.6, 128.1, 127.9, 127.8, 127.4, 61.9 (CNH), 52.8
(OCH3), 40.7, 36.6 (CH2), 17.0 (CH2), 13.9 (CH3); IR (ATR) νmax
3209, 1727, 1664, 1606, 1578, 1390; HRMS (ESI+) calcd for
C14H18NO3 (M + H)+ 248.1287, found 248.1294.
(CONH), 164.7, 165.0 (dd, JCF = 251.2, 13.3 Hz), 163.3 (dd, JCF
=
274.2, 8.0 Hz), 141.3 (d, JCF = 10.4 Hz), 110.9 (dd, JCF = 21.9, 4.0 Hz),
104.4 (t, JCF = 25.5 Hz), 64.9 (CNH), 52.7 (OCH3), 34.9, 29.7, 17.2
(CH3), 16.9 (CH3); IR (ATR) νmax 3226, 3090, 2960, 1724, 1667, 1615,
1307, 1228, 1122; HRMS (ESI+) calcd for C14H16F2NO3 (M + H)+
284.1098, found 284.1085.
Methyl 7-hydroxy-1-oxo-3-propyl-1,2,3,4-tetrahydroisoquinoline-
3-carboxylate, 6p: white solid; mp 169−173 °C; 1H NMR (400 MHz;
CDCl3) δ 7.73 (1H, d, J = 2.8 Hz, ArH), 7.08 (1H, d, J = 7.6 Hz, ArH),
7.00 (1H, dd, J = 8.4, 2.8 Hz, ArH), 6.32 (1H, br s, NH), 3.71 (3H, s,
OCH3), 3.28 (1H, d, J = 15.6 Hz, CHH), 3.04 (1H, d, J = 15.9 Hz,
CHH), 1.78 (2H, t, J = 9.2 Hz, CH2CH2CH3), 1.42−1.16 (2H, m,
CH2CH2CH3), 1.02 (3H, t, J = 7.2 Hz, CH2CH2CH3); 13C NMR
(CDCl3, 101 MHz) δ 173.3, 165.5, 156.0, 129.1, 127.2, 120.5, 114.8,
62.3, 52.8, 40.5, 35.8, 17.1, 13.9; IR (ATR) νmax 3124, 1723, 1658, 1383,
Methyl 3-benzyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-3-carboxy-
late, 6h: white solid; mp 128−129 °C; Rf (hexane/EtAcO, 7:3) 0.30; 1H
NMR (400 MHz; CDCl3) δ 8.09 (1H, d, J = 7.6 Hz, ArH), 7.49 (1H, m,
ArH), 7.38 (1H, m, ArH), 7.31−7.23 (4H, m, ArH), 7.06 (2H, m, ArH),
6.26 (1H, br s, NH), 3.63 (3H, s, OCH3), 3.44 (1H, d, J = 15.8 Hz, CH2),
3.24 (1H, d, J = 13.4 Hz, CH2), 3.23 (1H, d, J = 15.8 Hz, CH2), 3.03 (1H,
d, J = 13.4 Hz CH2); 13C NMR (CDCl3, 101 MHz) δ 172.6 (COO),
165.0 (CONH), 135.5 (q), 134.0 (q), 132.7, 129.7, 128.7, 128.2, 127.8,
127.6, 127.5, 62.8 (CNH), 52.7 (OCH3), 44.6, 36.8; IR (ATR) νmax
3191, 1731, 1663, 1603, 1384; HRMS (ESI+) calcd for C18H18NO3 (M +
H)+ 296.1281, found 296.1283.
Methyl 1-oxo-1,2,3,4-tetrahydroisoquinoline-3-carboxylate, 6i:
oil; lit.25 1H NMR (300 MHz; CDCl3) δ 8.04 (1H, d, J = 7.5 Hz,
ArH), 7.47 (1H, m, ArH), 7.37 (1H, m, ArH), 7.25 (1H, m, ArH), 6.48
657
dx.doi.org/10.1021/om301140t | Organometallics 2013, 32, 649−659

Organometallics
Article
1260; HRMS (ESI+) calcd for C28H35N2O8 (2M + H)+ 527.2388, found
527.2381.
all the systems studied as a function of the metalating ligand, solvent,
temperature, and pressure. All postrun fittings were carried out by the
standard available commercial programs.
Methyl 1-oxo-7-propoxy-3-propyl-1,2,3,4-tetrahydroisoquino-
1
line-3-carboxylate, 6q: white solid; mp 119−123 °C; H NMR (400
MHz; CDCl3) δ 7.56 (1H, d, J = 2.8 Hz, ArH), 7.10 (1H, d, J = 8.4 Hz,
ArH), 7.00 (1H, dd, J = 8.4, 2.8 Hz, ArH), 6.32 (1H, br s, NH),
3.95 (2H, t, J = 6.8 Hz, OCH2), 3.71 (3H, s, OCH3), 3.29 (1H, d, J =
15.6 Hz, CHH), 3.04 (1H, d, J = 15.9 Hz, CHH), 1.84−1.74 (2H, m,
OCH2CH2CH3), 1.42−1.17 (2H, m, CH2CH2CH3), 1.02 (3H, t, J = 7.6
Hz, CH2CH2CH3), 0.89 (3H, t, J = 7.6 Hz, CH2CH2CH3); 13C NMR
(CDCl3, 101 MHz) δ 171.9, 164.7, 154.7, 135.2, 130.3, 128.7, 117.2,
115.4, 71.5, 55.7, 53.1, 39.0, 29.6, 23.1, 14.8, 14.1, 10.4; IR (ATR) νmax
3195, 1738, 1663, 1451, 1378, 1066; HRMS (ESI+) calcd for
C14H18NO4 (M + H)+ 306.1700, found 306.1695.
ASSOCIATED CONTENT
■
S
* Supporting Information
This material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Notes
The authors declare no competing financial interest.
3,3-Diphenylisoindolin-1-one, 6r: white solid; mp 208−210 °C
(lit.27 210−211 °C); 1H NMR (300 MHz; CDCl3) δ 7.88 (1H, d, J =
7.5 Hz, ArH), 7.56 (1H, m, ArH), 7.31−7.51 (2H, m, ArH), 7.35−7.20
(9H, m, ArH), 7.15 (1H, m, ArH), 6.65 (1H, br s, NH); 13C NMR
(CDCl3, 101 MHz) δ 169.7 (CONH), 150.1, 142.7, 138.1, 132.4, 130.5,
128.7, 128.5, 128.0, 127.9, 127.0, 126.3, 124.5, 124.3, 71.1 (CNH); IR
(ATR) νmax 291, 1692, 1651, 1446, 1258, HRMS (ESI+) calcd for
C20H16NO (M + H)+ 286.1232, found 286.1256.
Crystallography. A prismatic crystal of 5a, 5c, or 5b(6) (Table S1)
was selected and mounted on a MAR345 diffractometer and image plate
detector. Unit-cell parameters were determined from 332 (for 5a), 1574
(for 5c), and 719 (for 5b(6)) reflections, in the range 3° < θ < 31°, and
refined by least-squares methods. Intensities were collected with
graphite-monochromatized Mo Kα radiation. The number of reflections
collected were 11 514 (for 5a), 15 530 (for 5c), and 13 074 (for 5b(6)),
in the ranges 1.65° ≤ θ ≤ 30.65°, 1.65° < θ < 32.32°, and 1.57° ≤ θ ≤
30.67° for 5a, 5c, and 5b(6), respectively, of which 6314 (for 5a), 8579
(for 5c), and 7050 (for 5b(6)) were nonequivalent by symmetry.
The number of reflections assumed as observed applying the condition
I > 2σ(I) were 5492, 6203, and 6874 (for 5a, 5c, and 5b(6), respec-
tively). Lorentz−polarization corrections were made.
The structures were solved by direct methods, using the SHELXS
computer program,28 and refined by full-matrix least-squares method
with the SHELX97 computer program29 using 11 514, 15 530, and
13 074 reflections for 5a, 5c, and 5b(6), respectively (very negative
intensities were not assumed). The function minimized was ∑w||Fo|2 −
|Fc|2|2, where w = [σ2(I) + (0.0494P)2 + 0.2769P]−1 (for 5a), w = [σ2(I) +
(0.1182P)2 + 0.5077P]−1 (for 5c), and w = [σ2(I) + (0.0607P)2 +
1.4868P]−1 (for 5b(6)) and P = (|Fo|2 + 2|Fc|2)/3; f, f′, and f′′ were taken
from the bibliography.30 The final R(on F) factor was 0.0357, 0.0660,
and 0.0313 for 5a, 5c, and 5b(6), respectively, and the goodness of fit
values were equal to 1.127 (for 5a), 1.050 (for 5c), and 1.195 (for
5b(6)). Further details concerning the resolution and refinement of
these crystal structures are given in Table S1. CCDC nos. 905213−
905215 contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/
cif.
Kinetics. The kinetic profiles for the reactions were followed by UV−
vis spectroscopy in the 700−300 nm range. Atmospheric pressure runs
were recorded on HP8452A or Cary50 instruments equipped with
thermostated multicell transports. Observed rate constants were derived
from absorbance versus time traces at the wavelengths where a
maximum increase and/or decrease of absorbance was observed. For
runs at variable pressure, a previously described pressurizing system and
pill-box cell were used;31 the system was connected to a J&M TIDAS
spectrophotometer, which was used for the absorbance measurements.
The calculation of the observed rate constants from the absorbance
versus time monitoring of reactions, studied under second- or first-order
concentration conditions, was carried out using the SPECFIT
software.32 The general kinetic technique is that previously described.32
The solutions for the kinetic runs were prepared by mixing the
calculated amounts of stock solutions of the palladium compounds and
the metalating ligands in the desired solvent. In all cases no dependence
on the concentration of palladium was detected, and it was kept in the
(2−5) × 10−4 M margin. Table S2 collects all the obtained kobs values for
ACKNOWLEDGMENTS
■
Financial support from the Ministerio de Educacion
(CTQ2009-09692, CTQ2009-11501, and CTQ2012-37821-
C02-01) is gratefully acknowledged.
́
y Ciencia
REFERENCES
■
(1) (a) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147−1169.
(b) Baudoin, O. Chem. Soc. Rev. 2011, 40, 4902−4911. (c) Hickman, A.
J; Sanford, M. S. Nature 2012, 484 (7393), 177−85. (d) Wencel-Delord,
J.; Droge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev. 2011, 40, 4740−4761.
(e) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174.
(f) Chen, X.; Engle, K. M.; Wang, D. H.; Yu, J. Q. Angew. Chem., Int. Ed.
2009, 48, 5094. (g) McGlacken, G. P.; Bateman, L. M. Chem. Soc. Rev.
2009, 38, 2447. (h) Beccalli, E. M.; Broggini, G.; Martinelli, M.;
Sottocornola, S. Chem. Rev. 2007, 107, 5318. (i) Daugulis, O.; Do, H. Q.;
Shabashov, D. Acc. Chem. Res. 2009, 42, 1074.
(2) (a) Dupont, J.; Consorti, C. S.; Spencer, J. Chem. Rev. 2005, 105,
2527−2571. (b) Albrecht, M. Chem. Rev. 2010, 110, 576−623.
(c) Palladacycles; Dupont, J., Pfeffer, M., Eds.; Wiley-VCH: Weinheim,
2008.
(3) (a) Kleiman, J. P.; Dubeck, M. J. Am. Chem. Soc. 1963, 85, 1544.
(b) Cope, A. C.; Siekman, R. W. J. Am. Chem. Soc. 1965, 87, 327.
(4) For some interesting reactions and applications of cyclopalladated
compounds see: (a) Garcia-Lopez, J. A.; Oliva-Madrid, M. J.; Saura-
Llamas, I.; Bautista, D.; Vicente, J. Chem. Commun. 2012, 6744.
(b) Oliva-Madrid, M. J.; Garcia-Lopez, J. A.; Saura-Llamas, I.; Bautista,
D.; Vicente, J. Organometallics 2012, 31, 3647. (c) Gopi, K.; Thirupathi,
N.; Nethaji, M. Organometallics 2011, 30, 572. (d) Mancilha, F. S.;
Barloy, L.; Rodembusch, F. S.; Dupont, J.; Pfeffer, M. Dalton Trans.
́
2011, 40, 10535. (e) Cautivo, T.; H. Klahn, H.; Godoy, F.; Lopez, C.;
Font-Bardía, M.; Calvet, T.; Gutierrez-Puebla, E.; Monge, A. Organo-
metallics 2011, 30, 5578. (f) Martin, R.; Crespo, M.; Font-Bardia, M.;
Calvet, T. Organometallics 2009, 28, 587. (g) Bedford, R. B.; Betham,
M.; Butts, C. P.; Coles, S. J.; Hursthouse, M. B.; Scully, P. N.; Tucker, J.
H. R.; Wilkie, J.; Willener, Y. Chem. Commun. 2008, 2429. (h) Moyano,
́
A.; Rosol, M.; Moreno, R. M.; Lopez, C.; Maestro, M. A. Angew. Chem.,
Int. Ed. 2005, 44, 1865. (i) Consorti, C. S.; Flores, F. R.; Dupont, J. J. Am.
Chem. Soc. 2005, 127, 12054. (j) Slagt, M. Q.; Rodríguez, G.; Grutters,
M. M. P.; Klein Gebbink, R. J. M.; Klopper, W.; Jenneskens, L. W.; Lutz,
M.; Spek, A. L.; van Koten, G. Chem.Eur. J. 2004, 10, 1331.
(k) Martínez, J.; Pereira, M. T.; Buceta, I.; Alberdi, G.; Amoedo, A.;
́ ́
Fernandez, J. J.; Lopez-Torres, M.; Vila, J. M. Organometallics 2003, 22,
5581. (l) Vicente, J.; Saura-Llamas, I.; Cuadrado, J.; Ramírez de Arellano,
M. C. Organometallics 2003, 22, 5513. (m) Rodríguez, G.; Lutz, M.;
Spek, A. L.; van Koten, G. Chem.Eur. J. 2002, 8, 45. (n) Aiello, I.;
Datillo, D.; Ghedini, M.; Golemme, A. J. Am. Chem. Soc. 2001, 123,
5598. (o) Kleij, A. W.; Klein Gebbink, R. J. M.; van den Nieuwenhuijzen,
P. A. J.; Kooijman, H.; Lutz, M.; Spek, A. L.; van Koten, G.
Organometallics 2001, 20, 634. (p) Navarro, R.; Urriolabeitia, E.;
Cativiela, C.; Díaz de Villegas, M. D.; Lop
Catal. 1996, 105, 111. (q) Navarro-Ranninger, C.; Lop
Perez, J. M.; Masaguer, J. R.; Alonso, C. Appl. Organomet. Chem. 1993, 7,
́
ez, M. P.; Alonso, E. J. Mol.
́
ez-Solera, I.;
́
57. (r) Espinet, P.; Esteruelas, M. A.; Oro, L. A.; Serrano, J. L.; Sola, E.
658
dx.doi.org/10.1021/om301140t | Organometallics 2013, 32, 649−659

Organometallics
Article
Coord. Chem. Rev. 1992, 117, 215. (s) Dupont, J.; Pfeffer, M.; Daran, J.
C.; Jeannin, Y. Organometallics 1987, 6, 899.
D. L.; Al-Duaij, O.; Fawcett, J.; Singh, K. J. Organomet. Chem. 2008, 693,
965. (d) Teijido, B.; Fernan
́
dez, A.; Lop
́
ez-Torres, M.; Castro-Juiz, S.;
dez, J. J. J. Organomet.
(5) For some recent reports on palladium-catalyzed ligand-directed
processes: (a) Mewald, M.; Schiffner, J. A.; Oestreich, M. Angew Chem.,
Int. Ed. 2012, 51, 1763−1765. (b) Zhong, H.; Yang, D.; Wang, S.;
Huang, J. Chem. Commun. 2012, 3236−3238. (c) Nadres, E. T.;
Daugulis, O. J. Am. Chem. Soc. 2012, 134, 7−10. (d) He, G.; Zhao, Y.;
Zhang, S.; Lu, Ch.; Chen., G. J. Am. Chem. Soc. 2012, 134, 3−6.
(e) Thirunavukkarasu, S. V.; Cheng, Ch. Chem.Eur. J. 2011, 17,
14723−14726. (f) Li, D.; Yuan, T.; Wang, G. Chem. Commun. 2011,
12789−12791. (g) Stowers, K. J.; Fortner, K. C.; Sanford, M. S. J. Am.
Chem. Soc. 2011, 133, 6541−6544. (h) Karthikeyan, J.; Cheng, Ch.
Angew. Chem., Int. Ed. 2011, 50, 9880−9883. (i) García-Rubia, A.;
Suarez, A.; Ortigueira, J. M.; Vila, J. M.; Fernan
́
́
Chem. 2000, 598, 71. (e) Bedfordmpm, R. B.; Cazin, C. S. J.; Coles, S. J.;
Gelbrich, T.; Hursthouse, M. B.; Scordia, V. J. Dalton Trans. 2003, 3350.
(17) (a) Favier, I.; Gom
M.; Solans, X. Dalton Trans. 2005, 123−132. (b) Gom
Martínez, M. Organometallics 1997, 16, 2539−2546. (c) Gom
Granell, J.; Martínez, M. Eur. J. Inorg. Chem. 2000, 217−224. (d) Aullon
G.; Chat, R.; Favier, I.; Font-Bardía, M.; Gomez, M.; Granell, J.;
Martínez, M.; Solans, X. Dalton Trans. 2009, 8292−8300. (e) Gomez,
́
ez, M.; Granell, J.; Martínez, M.; Font-Bardía,
ez, M.; Granell, J.;
ez, M.;
́
́
́
,
́
́
M.; Granell, J.; Martínez, M. Inorg. Chem. Commun. 2002, 5, 67−70.
(18) At 220 K the values calculated for the cyclometalation rate
constant of 2a and 3a are 1 × 10−10 s−1 for both compounds.
Fernan
Eur. J. 2011, 17, 3567−3570. (j) Liu, Y.; Lou, S.; Xu, D.; Xu, Z. Chem.
Eur. J. 2010, 16, 13590−13593. (k) García-Rubia, A.; Urones, B.; Gomez
Arrayas
́
dez-Iban
́
ez, M. A.; Gom
́
ez, Arrayas
́
, R.; Carretero, J. C. Chem.
̃
(19) (a) Roiban, G. D.; Serrano, E.; Soler, T.; Aullon
Cativiela, C.; Martínez, M.; Urriolabeitia, E. P. Inorg. Chem. 2011, 50,
8132−8143. (b) Estevan, F.; Gonzalez, G.; Lahuerta, P.; Martínez, M.;
Peris, E.; van Eldik, R. J. Chem. Soc., Dalton Trans. 1996, 1045−1050.
(c) Gonzalez, G.; Lahuerta, P.; Martínez, M.; Peris, E.; Sanau, M. J.
́
, G.; Grosu, I.;
́
́
́
, R.; Carretero, J. C. Chem.Eur. J. 2010, 16, 9676−9685.
(l) Deprez, N. R.; Sanford, M. S. J. Am. Chem. Soc. 2009, 131, 11234−
11241. (m) Wang, X.; Mei, T. S.; Yu, J. Q. J. Am. Chem. Soc. 2009, 131,
7520. (n) Ball, N. D.; Mei, T. S.; Wang, X.; Yu, J. Q. J. Am. Chem. Soc.
2009, 131, 10806. (o) Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2009,
́
́
Chem. Soc., Dalton Trans. 1994, 545−550.
(20) (a) Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. J. Chem. Soc. 1915,
107, 1080−1106. (b) Kostal, J.; Jorgensen, W. L. J. Am. Chem. Soc. 2010,
132, 8766−8773.
́
131, 9651. (p) García-Rubia, A.; Arrayas, R. G.; Carretero, J. C. Angew.
Chem., Int. Ed. 2009, 48, 6511. (q) Zhang, Y. H.; Shi, B. F.; Yu, J. Q.
Angew. Chem., Int. Ed. 2009, 48, 6097.
(6) Fujiwara, Y.; Kawauchi, T.; Taniguchi, H. J. Chem. Soc., Chem.
Commun. 1980, 220−221. For a recent review on the synthesis of
heterocycles via palladium-catalyzed carbonylations see: Wu, X.;
Neumann, H.; Beller, M. Chem. Rev. 2013, 113, 1−35.
(7) (a) Asaumi, T.; Matsuo, T.; Fukuyama, T.; Ie, Y.; Kakiuchi, F.;
Chatani, N. J. Org. Chem. 2004, 69, 4433−4440. (b) Orito, K.; Horibata,
A.; Nakamura, T.; Ushito, H.; Nagasaki, H.; Yuguchi, M.; Yamashita, S.;
Tokuda, M. J. Am. Chem. Soc. 2004, 126, 14342−14343. (c) Vicente, J.;
́
Saura-Llamas, I.; García-Lopez, J.; Bautista, D. Organometallics 2007, 26,
2768−2776. (d) Giri, R.; Lam, J. K.; Yu, J. Q. J. Am. Chem. Soc. 2010,
132, 686−693.
(21) Nahra, F.; Liron, F.; Prestat, G.; Mealli, C.; Messaoudi, A.; Poli, G.
Chem.−Eur. J. 2009, 15, 11078−11082.
(22) Yamada, S.; Terashima, S.; Wagatsuma, M. Tetrahedron Lett.
1970, 1501−1504.
(23) Perrin, D. D.; Armarego, W. L. F.; Perrin, D. I. Purification of
Laboratory Chemicals, 3rd ed.; Butterworth-Heinemann: Oxford (UK),
1988.
(24) Cohenm, L. J. Biol. Chem. 1970, 245, 5718.
(25) Janin, L.; Roulland, E.; Beurdeley-Thomas, A.; Deucadin, D.;
Monneret, C.; Poupon, M. J. Chem. Soc. 2002, 4, 529.
(26) Bayley, D. M.; De Grazia, C. G. J. Org. Chem. 1970, 35, 4088.
(27) Koltunov, K. Y.; Prakash, G. K. S.; Rasul, G.; Olah, G. A. Eur. J.
Org. Chem. 2006, 4861.
(8) Orito, K.; Miyazawa, M.; Nakamura, T.; Horibata, A.; Ushito, H.;
Nagasaki, H.; Yuguchi, M.; Yamashita, S.; Yamazaki, T.; Tokuda, M. J.
Org. Chem. 2006, 71, 5951−5958.
(28) Sheldrick, G. M. SHELXS, A program for automatic solution of
crystal structure; University of Goettingen: Germany, 1997.
(29) Sheldrick, G. M. SHELX97, A program for crystal structure
refinement; University of Goettingen: Germany, 1997.
(30) International Tables of X-Ray Crystallography; Kynoch Press:
Birmirgham (UK), 1974; Vol. IV, pp 99−100 and 149.
(31) van Eldik, R. Inorganic High Pressure Chemistry; Elsevier, 1986; pp
1−68.
(9) Moiseev, I. I. Pure Appl. Chem. 1989, 61, 1755−1762.
(10) A preliminary communication on the preparation of benzolac-
tams by Pd(II)-catalyzed carbonylation of N-unprotected arylethyl-
amines has been published: Lopez, B.; Rodriguez, A.; Santos, D.; Albert,
J.; Ariza, X.; Garcia, J.; Granell, J. Chem. Commun. 2011, 47, 1054−1056.
(11) (a) Albert, J.; Cadena, J. M.; Gonzal
Font-Bardia, M. Chem. Commun. 2003, 528−529. (b) Albert, J.; J. M.
Cadena, J. M.; Gonzalez, A.; Granell, J.; Solans, X.; Font-Bardia, M.
́
ez, A.; Granell, J.; Solans, X.;
(32) Binstead, R. A.; Zuberbuhler, A. D.; Jung, B. SPECFIT32 [3.0.34];
Spectrum Software Associates, 2005.
́
Chem.−Eur. J. 2006, 12, 887−894. (c) Albert, J.; Crespo, M.; Granell, J.;
Rodrıíguez, J.; Calvet, T.; Zafrilla, J.; Font-Bardia, M.; Solans, X.
Organometallics 2010, 29, 214−225.
(12) Nevertheless, some groups have shown that primary aryl-
alkylamines can be ortho-metalated using the appropriate reaction
conditions: (a) Vicente, J.; Saura-Llamas, I. Comments Inorg. Chem.
́
2007, 28, 39−72. (b) Gomez, M.; Granell, J.; Martínez, M. Eur. J. Inorg.
Chem. 2000, 217−224. (c) Nieto, S.; Arnau, P.; Serrano, E.; Navarro, R.;
Soler, T.; Cativiela, C.; Urriolabeitia, E. P. Inorg. Chem. 2009, 48,
11963−11975. (d) Nieto, S.; Sayago, F. J.; Laborda, P.; Soler, T.;
Cativiela, C.; Urriolabeitia, E. P. Tetrahedron 2011, 67, 4185−4191.
(13) O’Donnell, M. J.; Bennett, W. D.; Bruder, W. A.; Jacobsen, W. N.;
Knuth, K.; LeClef, B.; Polt, R. L.; Bordwell, F. G.; Mrozack, S. R.; Cripe,
T. A. J. Am. Chem. Soc. 1988, 110, 8520−8525.
́
(14) (a) Gomez, M.; Granell, J.; Martínez, M. J. Chem. Soc., Dalton
Trans. 1998, 37−44. (b) Granell, J.; Martínez, M. J. Chem. Soc., Dalton
Trans. 2012, 41, 11243−11258.
(15) Boutadla, Y.; Davies, D. L.; Macgregor, S. A.; Poblador-
Bahamonde, A. I. Dalton Trans. 2009, 5820−5831.
(16) (a) Naya, L.; Vazquez-García, D.; Lop
́
ez-Torres, M.; Fernan
́
dez,
A.; Vila, J. M.; Gomez-Blanco, N.; Fernan
́
́
dez, J. J. J. Organomet. Chem.
2008, 693, 685. (b) Albert, J.; D’Andrea, L.; Granell, J.; Tavera, R.; Font-
Bardia, M.; Solans, X. J. Organomet. Chem. 2007, 692, 3070. (c) Davies,
659
dx.doi.org/10.1021/om301140t | Organometallics 2013, 32, 649−659