Cyclopalladation and reactivity of amino esters through C - H bond activation: Experimental, kinetic, and density functional theory mechanistic studies

Article abstract of DOI:10.1002/chem.201302693

The orthopalladation, through C - H bond activation, of a large number of amino esters and amino phosphonates derived from phenylglycine, and having different substituents at the aryl ring and the C-α atom, as well as on the N-amine atom, has been studied. The experimental observations indicated an improvement in the yields of the orthopalladated compounds when the N-amine and/or the C-α atom are substituted, when compared with the unsubstituted methyl phenylglycinate derivatives. In contrast, substitutions at the aryl ring do not promote significant changes in the orthometalation results. Furthermore, the use of hydrochloride salts of the amino esters has also been shown to have a remarkably favorable effect on the process. All these observations have been fully quantified at different temperatures and pressures by a detailed kinetic study in solution in different solvents and in the presence and absence of added Bronsted acids and chloride anions. The data collected indicate relevant changes in the process depending on these conditions, as expected from the general background known for cyclopalladation reactions. An electronic mechanism of the orthopalladation has been proposed based on DFT calculations at the B3LYP level, and a very good agreement between the trends kinetically measured and the theoretically calculated activation barriers has been obtained. The reactivity of the new orthopalladated amino phosphonate derivatives has been tested and it was found that their halogenation, alkoxylation and carbonylation resulted in formation of the corresponding functionalized ortho- haloaminophosphonates, ortho-alkoxyaminophosphonates and oxoisoindolinylphosphonates. Remote control: The orthopalladation, through C - H bond activation, of substituted amino esters and amino phosphonates derived from phenylglycine has been studied (see scheme). Determination of the reaction rates indicated a clear acceleration of the C - H activation rate when the n-amine and/or the C-α atom are substituted. Substitutions at the aryl ring do not promote changes. The use of hydrochloride salts of the amino esters also has a strong accelerating effect on the process.

Full text of DOI:10.1002/chem.201302693

DOI: 10.1002/chem.201302693
À
Cyclopalladation and Reactivity of Amino Esters through C H Bond
Activation: Experimental, Kinetic, and Density Functional Theory
Mechanistic Studies
Eduardo Laga,[a] Angel Garcꢀa-Montero,[a] Francisco J. Sayago,[a] Tatiana Soler,[b]
Salvador Moncho,[a] Carlos Cativiela,[a] Manuel Martꢀnez,*[c] and
Esteban P. Urriolabeitia*[a]
This paper is dedicated to Professor Antonio Laguna on the occasion of his 65th birthday
Abstract:
The
orthopalladation,
salts of the amino esters has also been
shown to have a remarkably favorable
effect on the process. All these obser-
vations have been fully quantified at
different temperatures and pressures
by a detailed kinetic study in solution
in different solvents and in the pres-
ence and absence of added Brønsted
acids and chloride anions. The data col-
lected indicate relevant changes in the
process depending on these conditions,
as expected from the general back-
ground known for cyclopalladation re-
actions. An electronic mechanism of
the orthopalladation has been pro-
posed based on DFT calculations at
the B3LYP level, and a very good
agreement between the trends kineti-
cally measured and the theoretically
calculated activation barriers has been
obtained. The reactivity of the new or-
thopalladated amino phosphonate de-
rivatives has been tested and it was
found that their halogenation, alkoxy-
lation and carbonylation resulted in
formation of the corresponding func-
À
through C H bond activation, of
a large number of amino esters and
amino phosphonates derived from
phenACHTUNGTRENNUNGylglycine, and having different
substituents at the aryl ring and the C-
a atom, as well as on the N-amine
atom, has been studied. The experi-
mental observations indicated an im-
provement in the yields of the ortho-
palladated compounds when the N-
amine and/or the C-a atom are substi-
tuted, when compared with the unsub-
stituted methyl phenylglycinate deriva-
tives. In contrast, substitutions at the
aryl ring do not promote significant
changes in the orthometalation results.
Furthermore, the use of hydrochloride
tionalized
ortho-haloaminophospho-
nates, ortho-alkoxyaminophosphonates
and oxoisoindolinylphosphonates.
À
Keywords: amino acids · C H acti-
vation · density functional calcula-
tions · kinetics · palladium
À
Introduction
metal-mediated tailored breaking and formation of C C or
À
C heteroatom bonds usually takes place smoothly under
The use of transition metals to build or modify organic mol-
ecules is a well-established procedure, applied from the sim-
plest compounds to the most sophisticated scaffolds.[1–3] The
convenient reaction conditions by employing catalytic
amounts of metals, thus saving energy, time and materials.
However, to attain maximal reactivity and selectivity in the
À
starting M C bond formation, the processes often involves
the use of prefunctionalized reagents, with associated prob-
lems of tedious multistep syntheses of the starting materials,
low atom economy, and waste disposal.[1–3] Therefore, the ef-
forts of many chemists have been directed towards the de-
velopment of catalytic processes by using alternative ap-
proaches. Among the different existing possibilities, proba-
bly the most successful involves metal-mediated activation
[a] E. Laga, A. Garcꢀa-Montero, Dr. F. J. Sayago, Dr. S. Moncho,
Prof. Dr. C. Cativiela, Dr. E. P. Urriolabeitia
Instituto de Sꢀntesis Quꢀmica y Catꢁlisis Homogꢂnea (ISQCH)
CSIC-Universidad de Zaragoza, Fac. de Ciencias, Edificio D
Pedro Cerbuna 12, 50009 Zaragoza (Spain)
Fax : (+34)976761187
E-mail: esteban@unizar.es
[b] Dr. T. Soler
À
À
and breaking of C H bonds as a synthetic tool for the M C
bond formation.[4] This approach avoids the cumbersome
use of prefunctionalized substrates, saving preparation steps
and, consequently, energy, time and money. This methodolo-
gy, nevertheless, has a major drawback: the selectivity of
Servicios Tꢂcnicos de Investigaciꢃn, Universidad de Alicante
03690 San Vicente de Raspeig, Alicante (Spain)
[c] Prof. Dr. M. Martꢀnez
Departament de Quꢀmica Inorgꢄnica
Universitat de Barcelona, Facultat de Quꢀmica
Martꢀ i Franquꢅs 1-11, 08028 Barcelona (Spain)
Fax : (+34)934021265
À
metal site incorporation, because C H bonds are ubiquitous
in organic species. Both specific solutions based on the
innate reactivity of the molecules, due to inherent electronic
and/or steric biases,[5] and coordination-directed reactivity,
E-mail: manel.martinez@qi.ub.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201302693.
17398
ꢆ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 17398 – 17412

FULL PAPER
as a consequence of the presence of directing groups, have
been show to be very efficient ways to address this prob-
lem.[6a] Orthopalladated complexes are excellent examples
Results and Discussion
Synthesis and characterization of orthopalladated complexes
3a–n: The amino esters and amino phosphonates shown in
Figure 1 were prepared by using previously reported meth-
À
of the latter, promoting smooth and site-selective C H bond
activation.[4j,p,6b] Furthermore, the reactive Pd C bond can
À
À
À
be transformed into new C C or C heteroatom bonds in
a variety of ways, with oxidative coupling (involving high
oxidation states) or insertion of unsaturated molecules (usu-
ally involving low oxidation states) being two possibilities.[4j,
p,6a]
It is clear that a precise knowledge of all the individual
steps involved in the functionalization sequence is highly de-
sirable to establish the optimal catalytic conditions. This
knowledge must include the role played by the substituents
of the substrate to be functionalized, as well as those origi-
nating from the ancillary ligands on the metal. From the
body of data accumulated until now it is clear that both oxi-
dation[7a,b] and C H bond activation[7c–f] can be turnover-lim-
À
iting steps; the latter being the critical step much more
often. Interestingly, even ligands that do not seem to directly
participate in the functionalization reactions have been
shown to be relevant to assisting the process.[7g,h]
We are currently interested in the functionalization of a-
amino acids, more specifically those derived from phenylgly-
cine, by using orthopalladated complexes as intermediates.[8]
The importance of the amino acids as key molecules in bio-
logical processes is unquestionable.[9] Furthermore, the in-
creasing interest in closely related species such as a-amino-
phosphonic esters, due to their biological activity[10a] as
enzyme inhibitors,[10b] powerful antibiotics,[10c] or antitumor
compounds,[10d] among others, has prompted a large number
of synthetic methods for their tailored preparation;[11] to the
best of our knowledge, however, none are based on ortho-
palladation reactions. Stoichiometric transformations of
amino acids, based on oxidative couplings[6,8] and/or inser-
tion of small molecules,[6,12] are known, with both strategies
Figure 1. Amino esters and hydrochloride salts used in this work.
ods,[8,14–18] although in most cases we introduced slight modi-
fications (see the Supporting Information) to optimize the
reported procedures. To study the individual effect of each
À
substituent on the CACTHNUTRGNEUNG(aryl) H bond-activation step, we inves-
tigated a large set of amino ester based substrates with dif-
ferent substituents in all modifiable points of the molecule;
i.e., the N-amine atom, the C-a atom and the aryl ring.
Therefore, from the hydrochloride salt of the base scaffold
1a (1a·HCl) we studied the orthopalladation of compounds
with both electron-withdrawing (triflate) and electron-do-
nating (methyl) groups at the N-amine (1b and 1c), deriva-
tives with substituents of different electronic nature (OMe,
Br, and NO2) at different positions of the aryl ring (ortho,
meta, and para) (1d·HCl–1h·HCl), quaternary amino esters
substituted at C-a with alkyl or aryl groups (1i·HCl–
1k·HCl), including a conformationally restricted example
(1l·HCl), and less common compounds in which the ester
group was substituted by the isosteric phosphonate group
(1m·HCl and 1n·HCl). In such a way, we aimed to gather
representative examples of all possible structural situations.
À
sharing the same C H bond activation step. However, cata-
lytic reactions are still limited to a few examples,[13] and the
functionalization of a-aminophosphonic esters is still un-
known. Despite recent reports,[13a] problems in the C H
À
bond activation step have been associated with these lack of
results. Aiming to develop more efficient functionalization
À
processes based on C H bond activation, we report here
a comprehensive study of the influence of the substituents
À
on the C H bond activation step in phenylglycine-based
amino acids and amino phosphonic esters. The changes at
the N atom and the C-a atom are found to be critical for
tuning the reaction rate, whereas, surprisingly, no changes
were observed when modifica-
tions are introduced at the aryl
ring. In addition, a-aminophos-
phonic esters have been effi-
ciently functionalized for the
first time.
Scheme 1. Synthesis of the orthopalladated complexes, 3a–n, and nonmetalated bis-amino complexes, 2a–n,
derived from phenylglycines.
Chem. Eur. J. 2013, 19, 17398 – 17412
ꢆ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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17399

M. Martꢀnez, E. P. Urriolabeitia et al.
The orthopalladation of 1a·HCl was performed by follow-
ing the original procedure developed by Fuchita,[19] which
was taken as reference. Attempts to improve this procedure
(acetone, reflux, 20 h, 58% isolated yield) were conducted,
but changing from acetone to other solvents did not improve
the yield. Lower conversions were obtained in MeOH, no
reaction was observed in CH2Cl2, and even decomposition
to 2-oxo-2-phenylacetic acid was detected when acetic acid
was used as solvent. A slight increase of the reaction time
up to 24 h in acetone heated to reflux allowed orthopalla-
dated 3a to be obtained in an improved yield of 67%, to-
gether with the non-metalated bis-amino coordination com-
pound 2a (32% yield). Further increases in reaction time al-
lowed a yield of 3a of 85% to be reached.[8d] The general
process is indicated in Scheme 1, and the results obtained
are summarized in Table 1; other modifications did not
cently reported that the orthopalladation of 1b,[8a] contain-
ing an electron-withdrawing triflate group, requires at least
48 h to achieve a modest 56% yield, whereas metalation of
dimethyl-substituted compound 1c affords yields of more
than 65% in only 24 h reaction time. Furthermore, in none
of these reactions was the presence of bis-amino complexes
2 detected. Therefore, in comparison with unprotected 1a,
the results obtained here show a positive effect when the N-
amine atom has at least one substituent, with higher yields
of the orthometalated compounds being obtained under the
À
same reaction conditions. Moreover, the easy C H bond ac-
tivation observed for 1c, compared with that of 1a, is consis-
tent with the generally observed better orthopalladation of
tertiary amines when compared with secondary and, mainly,
primary amines.[20]
With respect to changes of the substituents at the aromat-
ic ring, the differences in reactivity produce some remark-
able qualitative differences that merit detailed quantifica-
tion, as indicated in previous studies.[21] We have already re-
ported that the metalation of 1d·HCl–1 f·HCl (p-OMe, p-Br
and m-Br) affords the corresponding orthopalladated com-
plexes 3d–f with very similar reaction yields (60–66% in
24 h), which are similar to the yield obtained for unsubsti-
tuted 1a·HCl in the same time (67%).[8c] This results indi-
Table 1. Product distribution for the orthopalladation of amino esters
shown in Figure 1 and Scheme 1.
Amino ester Time Complex 2
[h]
[%][a]
Complex 3
Reference
[%][a]
1a·HCl
1b
1c
20/24 not reported/32 58/67
[19]/this work
[8a]
[8a,15a,b]
[8c]
[8c]
[8c]
[8c]
this work
ACHTUNGTRNE[NUNG 13a,b]
this work
this work
48
24
24
24
24
24
48
22
3
24
22
24
24
6
not observed
not observed
41
34
38
not observed
not observed
not observed
not observed
not observed
not observed
not observed
not observed
11
56
>65
59
66
62
84
1d·HCl
1e·HCl
1 f·HCl
1g·HCl
1h·HCl
1i
1i·HCl
1j·HCl
1k
1k·HCl
1l·HCl
1m·HCl
1n·HCl
À
cates that the C H bond activation step occurs in practically
the same circumstances in these cases, and that the process
is not tuned by changing the electronic nature of the aryl
substituents, as found in other cyclopalladated systems.[21b]
An exception is 1g·HCl, which seems to give a higher yield
of the palladated dinuclear complex 3g;[8c] the fact that this
complex is not obtained in pure form, and that the yield can
only be estimated by the further reactivity of the mixture
containing 3g, could be responsible for the differences re-
ported. Interestingly, a complete lack of reactivity was ob-
served for the nitro derivative 1h·HCl, but the yields ob-
served for 1d·HCl–1 f·HCl (even considering 1g·HCl) sug-
gest that the reaction rate is not critically modulated by the
electronic nature of the substituents. This fact suggests that
not observed
not reported
85
85
72[b] (see text)
ACHTUNGTRNE[NUNG 13a,b]
81 (see text)
this work
this work
this work
this work
81
72
71
2.5
not observed
[a] Isolated yield. [b] Reaction conditions: i) toluene, 22 h, 808C. ii) LiBr,
acetone, as reported.[13a,b]
À
result in further improvements in the reaction yield. Where-
the C H bond activation step is likely based on a concerted
as the free amino ester PhCH
N
metalation-deprotonation (CMD) ambiphilic mechanism, in-
stead on an aromatic electrophilic substitution.[22] The same
mechanism has recently been studied with respect to the or-
thopalladation, in carboxylic acids, of 4-arylidene-5(4H)-ox-
azolones, a type of ligand related to amino acids.[21a]
heated to reflux for 24 h afforded a mixture of 2a and 3a
containing only 30% 3a after treatment with NaCl, the use
of its ammonium triflate salt [PhCHACTHNUTGRNEG(UN CO2Me)NH3]OTf
(1a·HOTf), also followed by treatment with NaCl, resulted
in a better yield of 3a (56%), compared with 1a, although
still lower than that of the hydrochloride 1a·HCl. The supe-
rior performance of the ammonium salts with respect to
those of the free amino esters is fully consistent with previ-
ous results.[10,19] We therefore concluded that conversion of
the N-amine into the ammonium chloride was the best
option for developing the general procedure. For these rea-
sons, and also for synthetic simplicity and convenience, all
reactions were performed by using amino esters in the form
of their hydrochloride salts, except for 1b and 1c for clear
reasons.
As indicated in Table 1, a remarkable change in reactivity
was observed for the orthopalladation of quaternary amino
esters 1i·HCl–1l·HCl, which contain a fully substituted C-
a atom. In all these cases the reaction occurs with selective
formation of the orthopalladated derivatives 3i–l, in very
good yields (typically higher than 81%), and without forma-
tion of coordination compounds 2. It is clear that the prepa-
ration of complexes 3 from 1i·HCl–1l·HCl is favored with
respect to 1a·HCl, because better yields were obtained
under the same experimental conditions, even in shorter re-
action times in some instances. Table 1 also reflects the dif-
ference between the reactivity of 1i·HCl and 1k·HCl and
that reported for their free amino esters 1i and 1k.[13a,b]
The influence exerted by substituents at the N-amine
atom is also highly dependent on their nature. We have re-
17400
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Chem. Eur. J. 2013, 19, 17398 – 17412

Cyclopalladation of Amino Esters
FULL PAPER
Once again, orthopalladated compounds 3 were obtained
with better yields starting from the hydrochloride salts. In-
terestingly, whereas the reaction of 1k·HCl with PdACTHNUTRGNEUNG(OAc)2
under the standard conditions regioselectively afforded 3k,
which contains the palladium incorporated at the ortho posi-
tion of the Ph ring, thus forming a five-membered metalla-
cycle, the reaction of 1k with PdACHTNUTRGNEUNG(OAc)2 in toluene at 808C
for 22 h produced a mixture of isomers derived from the
PdII incorporation to both Ph and Bn rings (75 and 15%, re-
spectively).[13a,b] Clearly, the method reported here gives
a better yield of the orthopalladated compound, with the re-
gioselectivity also being improved.
Changing the planar trigonal carbomethoxy group with an
isosteric tetrahedral diethyl phosphonate moiety affords
amino phosphonates 1m·HCl and 1n·HCl, the orthometala-
tion of which has not been previously reported. The reaction
Figure 2. View of complex 3j. Displacement ellipsoids are scaled to 50%
À
probability level. Selected bond lengths [ꢇ] and angles [8] for 3j: Pd1
À
À
À
À
C1 1.957(8), Pd1 N1 2.028(6), Pd1 Cl1 2.327(2), Pd1 Cl2 2.467(2), Pd2
À
À
À
À
C16 1.969(7), Pd2 N2 2.030(6), Pd2 Cl2 2.347(2), Pd2 Cl1 2.445(2), N1
À
À
À
À
C7 1.514(8), C6 C7 1.515(10), C7 C10 1.544(10), C7 C8 1.559(11), C8
À
À
À
À
O1 1.180(9), C8 O2 1.333(9), O2 C9 1.463(9), N2 C22 1.489(8), C21
C22 1.522(10), C22 C25 1.520(10), C22 C23 1.555(10), C23 O4 1.200(9),
À
À
À
À
À
C23 O3 1.317(9), O3 C24 1.459(9); C1-Pd1-N1 81.4(3), C1-Pd1-Cl1
96.0(2), N1-Pd1-Cl2 96.32(17), Cl1-Pd1-Cl2 86.32(7), C16-Pd2-N2 81.6(3),
C16-Pd2-Cl2 97.3(2), N2-Pd2-Cl1 94.96(17), Cl2-Pd2-Cl1 86.42(7), Pd2-
Cl2-Pd1 93.07(7), Pd1-Cl1-Pd2 94.14(8).
of 1m·HCl with Pd
ACHTUNGTRENNUNG
action conditions (Scheme 1) afforded
a
(ca. 70%) of complex 3m. Optimization of the reaction con-
ditions allowed 3m to be obtained in an improved reaction
time of 6 h with the same yield (Table 1). In the case of qua-
ternary derivative 1n·HCl, we observed the same reactivity
trends as those described above for quaternary salts; that is,
orthopalladation of 1n·HCl gave 3n faster (ca. 70% yield in
2.5 h) than 1m·HCl gave 3m. Once again, the change from
an amino ester unit to the diethyl phosphonate moiety does
not hinder the formation of the orthopalladated complexes,
indeed, it constitutes an improvement of the reaction condi-
tions when related substrates are compared.
In spite of the apparent similarity of 3j and 3a, the struc-
ture of the former shows notable differences compared with
that previously determined for the latter.[8d] The most inter-
esting point corresponds to the transoid arrangement of the
cyclopalladated rings in 3j, probably minimizing intramolec-
ular steric interactions. This disposition opposes the cisoid
arrangement determined for 3a, even though the metrical
parameters are the same within experimental error. Further-
more, 3j crystallizes in the monoclinic space group P21/n, in-
dicating that the two enantiomers are present in the unit
cell and that the crystal is racemic.
Although the characterization of complexes 3i–l on the
basis of the data gathered through different techniques is
unambiguous, the low solubility of the dimers did not allow
complete NMR spectra (especially 13C NMR spectra) to be
recorded, and some signals were not observed. To carry out
a full characterization of the orthopalladated ligands, we
transformed the insoluble dimers 3i–l into more soluble pyr-
idine adducts 4i–l (Scheme 2), by breakage of the corre-
sponding chloride bridge with pyridine.
Characterization of complexes 3i–n was carried out on
the basis of their spectroscopic (IR and NMR) and analyti-
cal (elemental analysis and/or high-resolution mass spectra)
data. The NMR spectra of 3i–n, measured in [D6]acetone,
display in all cases a single set of signals, wherein peaks due
to the presence of the {PdC6H4} units, as well as those due
to the other functional groups are present. The observation
of a single set of signals is remarkable, given the fact that
these dimers contain two stereogenic centers, thus two dia-
stereoisomers (RR/SS and RS/SR) are expected. In addition,
each dimer can have an arrangement of the cyclometalated
units in cisoid/transoid dispositions, therefore, if a static be-
havior is assumed at room temperature, then more than one
set of signals would be expected. The NMR spectra of these
Complexes 4i–l were obtained in good yields as air-stable,
white solids, the elemental analyses and mass spectra of
which were in good agreement with the structures indicated
in Scheme 2. The NMR spectra of 4i–l show the expected
signals associated with the presence of {PdC6H4} (4i–k) or
1
species are temperature dependent, and the H NMR spec-
tra of 3i and 3j at À738C show the splitting of all the sig-
nals, appearing as two sets of peaks, strongly suggesting the
presence of a dynamic equilibria at 258C. The rapid trans-
formation of the two dimeric diastereoisomers through
i) breakage of the chloride bridging system by a weakly co-
ordinating ligand, for instance the solvent [D6]acetone, ii)
formation of a mononuclear species, and iii) recombination
of the mononuclear species to form a new dinuclear com-
plex by solvent decoordination, can be responsible for this
simplification of the NMR spectra. The crystal structure of
3j was determined by X-ray diffraction methods; Figure 2
depicts the molecular structure, as well as selected bond dis-
tances and angles.
Scheme 2. Formation of pyridine adducts 4i–l.
Chem. Eur. J. 2013, 19, 17398 – 17412
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M. Martꢀnez, E. P. Urriolabeitia et al.
Table 2. Rate constants and activation parameters obtained for the reac-
tion of some amino esters and hydrochlorides (Figure 1) with Pd
in different media. Literature data for NH2CMe(CO2Me)Bn and
NH2CBn(CO2Me)Ph, 1k, are included for comparison.
ACHTUNGTRENNUNG(OAc)2
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
Compound Solvent 10À4
[sÀ1
ꢈ
300k DH‡
[kJ molÀ1
DS‡
DV‡
N
]
G
]
[J KÀ1 molÀ1
]
[cmÀ3 molÀ1
]
1a
1a
1a
acetone 0.67
58Æ5
61Æ7
56Æ4
À134Æ15
À128Æ21
À148Æ13
À13Æ3
À17Æ2
+11Æ2
toluene
acetic
acid
0.41
0.28
1c
1c
1c
acetone 3.3
75Æ4
39Æ4
43Æ6
À64Æ14
À180Æ12
À196Æ18
nd[d]
À13Æ3
+15Æ1
toluene
acetic
acid
5.3
0.16
Figure 3. View of complex 4k. Displacement ellipsoids are scaled to 50%
1i
1i
1i
acetone 8.6
69Æ1
96Æ4
55Æ3
À76Æ3
À6Æ14
À14Æ2
À13Æ2
2Æ2
À
probability level. Selected bond lengths [ꢇ] and angles [8] for 4k: Pd1
toluene
acetic
acid
0.78
3.7
À
À
À
À
C1 1.980(3), Pd1 N1 2.036(2), Pd1 N2 2.045(2), Pd1 Cl1 2.4381(7), N1
À149Æ8
À
À
À
À
C7 1.489(3), C6 C7 1.523(4), C7 C8 1.528(4), C7 C10 1.548(3), C10
À
À
À
C11 1.513(4), O1 C8 1.195(3), O2 C8 1.331(3), O2 C9 1.450(4); C1-
Pd1-N1 80.24(10), C1-Pd1-N2 95.95(10), N1-Pd1-Cl1 90.01(6), N2-Pd1-
Cl1 94.05(7), N1-C7-C6 104.4(2), N1-C7-C8 106.1(2), C6-C7-C8 112.3(2),
N1-C7-C10 111.2(2), C6-C7-C10 114.0(2), C8-C7-C10 108.6(2).
1a·HCl
1d·HCl
1e·HCl
1i·HCl
1m·HCl
1k[a,b]
acetone 3.7
acetone 3.7
acetone 3.7
acetone 10
acetone 18
51Æ7
51Æ7
51Æ7
73Æ2
60Æ6
70Æ1
76Æ2
À143Æ21
À143Æ21
À143Æ21
À61Æ6
À5Æ4
À5Æ4
À5Æ4
À12Æ2
À3Æ1
nd[d]
À100Æ21
À72Æ1
toluene
toluene
9.3
4.0
1k[a,c]
À59Æ7
nd[d]
{PdC6H3} (4l) units, thus allowing unambiguous characteri-
zation of the cyclopalladated ligands (see the Supporting In-
formation). In addition, the molecular structure of 4k was
determined by X-ray diffraction methods. Figure 3 shows
a drawing of the molecule and some selected bond distances
and angles. The environment of the Pd atom is square-
planar, slightly distorted, and it is surrounded by the meta-
lated carbon, the aminic and pyridinic nitrogen atoms and
the chloride ligand, with the latter being trans to the palla-
dated carbon. The molecular drawing shows the orthopalla-
dation of the Ph ring directly bonded to the C-a atom, and
not that of the benzyl group, confirming the structure pro-
posed on the basis of the NMR data. As previously dis-
cussed, this contrasts with previous reports that structurally
characterized the orthopalladation of the benzyl group in
[a] Data from ref. [13a]. [b] Metallation forming a five-membered ring.
[c] Metalation forming a six-membered ring. [d] nd=not determined.
(CO2Me)NH2)PPh3].[13a]
[PdClACHTUNGTRENNUNG(C6H4CH2C(Ph)AHCTUNGTRNENGUN
Mechanistic studies on the orthopalladation reaction: kinet-
ics: In view of the important differences and trends ob-
served in the preparative procedures of the cyclometalated
derivatives of the ligands indicated in Figure 1, a detailed ki-
netic study of the process was conducted. The cyclometala-
tion reaction of the free amino ester ligands 1a, 1c, and 1i,
and hydrochlorides 1a·HCl, 1d·HCl, 1e·HCl, 1i·HCl, and
1m·HCl with PdACHTUNGTRENNUNG(OAc)2 was studied by time-resolved UV/
Vis spectroscopy. The data obtained from the equimolecular
reactions imply the metalation of {PdII(aminoester)} units is
a one-step process as already established for reactions of
other cyclometalating ligands with PdACTHNUTRGNEUNG
(OAc)2.[13a,23] Record-
ing the reaction rates at different temperatures, pressures
and solvent conditions produced the set of kinetic, thermal,
and pressure activation parameters indicated in Table 2,
once the relevant Eyring or ln k vs. P plots were conducted
(Figure 4). Parallel NMR spectroscopic monitoring of the
À
Figure 4. a) Eyring plot for the C H bond activation process for 1a·HCl,
1e·HCl, 1d·HCl, 1m·HCl, and 1a by Pd
N
À
b) Plot of ln k vs. P for the C H bond activation of 1a by Pd
G
different solvents.
À
process indicated the C H bond-activation nature of the re-
action rate studied.
It is clear from the data collected in Table 2 that the
“usual” dramatic acceleration of the cyclometalation process
in acetic acid observed for previously studied systems in-
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Chem. Eur. J. 2013, 19, 17398 – 17412

Cyclopalladation of Amino Esters
FULL PAPER
volving N-imine directing groups does not hold in this
case.[21b,23a,24] A similar behavior has also been observed in
kinetico-mechanistic studies carried out for the cyclopallada-
tion of benzyl amines,[25] which can be attributed to the ef-
fective protonation of the more basic N-amine directing
group, thus decreasing the concentration of the active {PdII-
volved.[8c,21c] Surprisingly, the values collected in Table 2 for
the reaction of 1c in acetone are rather different from the
expected values; we can speculate that the generation of
acetic acid from the transition state indicated in Figure 5, as
free acid in acetone, can lead to a partial protonation of the
basic tertiary amine, thus disrupting its coordination to form
(amine)} cyclometalating unit by the existence of a protona-
effective cyclometalating {PdII
ACTHUNGTERNNU(G amine)} units.
tion equilibrium. In fact, the existence of protonated amines
in highly acidic media has been found to be relevant for the
cyclopalladation of some amino-imino ligands,[26] and for
other systems in which the weak nature of the PdII-directing
group bond has been found to be relevant.[27] As a conse-
quence, in the present case, the determined rate constants,
when protic medium is used, are composites of an equilibri-
um and a first-order rate constant (k=Kamine deprotonation ꢈkCH
activation), and no further comparison with the processes car-
ried out in the more innocent acetone or toluene solution is
possible at this stage. Given these implications, a study of
the free amino esters 1c and 1i was conducted.
For the fully unsubstituted amino ester ligand 1a, the data
collected are consistent with the expected highly ordered
and entropy-demanding transition state, which is accompa-
nied by an important volume contraction.[13a,21a,b] In this re-
spect, it is noticeable that no significant differences in the
activation parameters are observed for the reactions carried
out in acetone or toluene solution, which is indicative of the
innocent and nonparticipative nature of these solvents in
the process. These differences (or similarities), have already
been established as very significant for other organometallic
systems of diverse nature.[28,29] For N,N-dimethyl substituted
ligand 1c, the values obtained in toluene solution also relate
to a highly ordered and compressed transition state, this
time though, the value determined for DH‡ was much lower,
in line with the better donor character of the substituted
amine. This effect would not be expected for an electrophilic
substitution reaction on the aromatic carbon,[30] and has to
be related to the induced increase in the leaving capability
of the acetate ligand attached to the palladium center,
which actuates as the proton abstractor for the reaction in
a so called ambiphilic mechanism (Figure 5).[21a,b,22e] In this
respect, the fact that the kinetic and activation parameters
determined for the cyclometalation of hydrochlorides
For the cyclopalladation reaction with methyl C-a substi-
tuted ligand 1i, the results indicate a definite acceleration of
the process, which has already been observed in the metala-
tion of similar systems,[13a,24b] as well as in the preparative
procedures indicated above. In acetone solution the effect is
mainly attributable to a decrease in the entropic demands,
while maintaining the values for DH‡ and DV‡. Nevertheless,
in toluene solution, the activation parameters show a much
larger decrease in entropy demands, compensated for by
a large increase in DH‡ and accompanied by a similar value
for DV‡. Taking into account the differences between the
two solvents used, the data in toluene solution should be
considered the most suitable for initial discussion. Clearly,
the rather important steric demands of the ligand to form
the transition state indicated in Figure 5, has to be accompa-
nied by less negative values of the activation entropy, while
increasing the enthalpic demands for the process. In acetone
solution the inductive effect on the methyl substituent at C-
a seems to be the dominating feature. The N-amine be-
comes slightly more basic and can be easily protonated in
acetone from the acetic acid liberated from the transition
state, as indicated above for tertiary amines. Again, the
values of the rate constant are then a composite of kinetic
and thermodynamic parameters, which make them much
more difficult to interpret directly (see the comments on the
data in acetic acid solution above). In this respect it is im-
portant to note that the values obtained for the thermal acti-
vation parameters for the cyclopalladation of 1i in acetone
solution are midway between those in toluene and acetic
acid solutions. The same effect has already been described
in the cyclopalladation of the phenylalanine-derived ligand
NH2CMeACHTUNGTRNEUNG
(CO2Me)CH2Ph.[13a]
Finally, the fact that the hydrochloride salts of the amino
esters show cyclopalladation reaction rates in acetone solu-
tion that are higher than those for the free amino esters has
also to be considered (Table 2, 1a·HCl, 1d·HCl, 1e·HCl,
1i·HCl, and 1m·HCl). Under the conditions used, two fac-
tors have to be taken into account: i) the presence of
a single equivalent of chloride anion/ligand, and ii) the pres-
ence of a single equivalent of acid in a polar medium. To es-
tablish whether one or both factors are involved in such an
increased reactivity, a detailed kinetic study was carried on
the reactions with ligand 1a in acetone solution in the pres-
ence of chloride anions [provided as (NBu4)Cl] and protons
(provided as HTrifl or HBF4·Et2O); furthermore, the effect
of an ion-rich medium was also studied by the use of
(NBu4)ClO4 solutions. The use of other coordinating acids
was avoided in view of the data obtained in previous stud-
ies.[21,31] Table 3 contains a summary of the data obtained at
25 and 358C under these conditions; the results can thus be
1a·HCl, 1d·HCl, and 1e·HCl by PdACTHNUTRGENUN(G OAc)2 (Table 2,
Figure 1), are the same within experimental error is again
consistent with the nonelectrophilic nature of the process in-
Figure 5. Transition state proposed for the ambiphilic mechanism in-
volved in the cyclometalation of palladium acetate by aminoesters.
Chem. Eur. J. 2013, 19, 17398 – 17412
ꢆ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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17403

M. Martꢀnez, E. P. Urriolabeitia et al.
Table 3. Values of the rate constants for the cyclometalation of 1a by palladium ace-
tate (5.3ꢈ10À4 m equimolecular ratio) in acetone solution and in the presence of addi-
tives.
a chloride further enhances the reaction rate in
such a weak protic medium (Table 3, entry 9). An
excess of both species promotes either decoordina-
tion of the amine directing group or substitution of
the acetate by chloride ligands, thus preventing
either cyclopalladation or proton abstraction from
the system.
Amino
ester
T
[8C]
Additive
Concentration
[Pd]/[Cl]/[H+]
10À4 ꢈk
[sÀ1
N
]
1a.HCl
1a
1a
1a
1a
35
35
35
35
35
35
25
25
25
25
25
25
25
25
25
25
25
25
–
–
–
–
–
–
5.1
1.3
5.0
1.4
6.0
6.5
0.67
3.5
4.2
3.5
4.5
4.2[a]
A
0.00054
0.00025
0.00050
0.00054+0.00054
–
1:1:0
1:0:0.5
1:0:1
1:1:1
–
–
–
–
–
1:2:0
1:4:0
1:4:0
1:6:0
1:6:0
1:0:1
1:0:2
HBF4
HBF4
ACHTUNGTRENNUNG(NBu4)Cl+HBF4
–
–
C
Mechanistic information on the orthopalladation re-
action: DFT calculations: DFT calculations on the
orthopalladation reaction have been carried out
based on the concerted metalation-deprotonation
ambiphilic mechanism (CMD), which is the accept-
ed sequence for this type of reaction occurring in
nonprotic innocent solvents.[33] We have already
used this reaction mechanism to successfully ex-
1a
1a
1a·HCl
1a·HCl
1a·HCl
1a·HCl
1a·HCl
1a·HCl
1a·HCl
1a·HCl
1a·HCl
1a·HCl
1a·HCl
–
0.0018
0.0044
0.0065
0.0011
0.0020
0.0022
0.0034
0.0034
0.0005
0.001
N
R
T
[b]
G
–
G
5.0[a]
[b]
À
plain the regioselectivity found in the C H bond
T
–
4.0[a]
activation step of different iminophosphoranes.[34]
The mechanism is based on the formation of an
T
HTrifl
HTrifl
50
15
À
agostic C H interaction between the metal and the
[a] A secondary reaction was observed that becomes dominant. [b] No reaction was
observed when palladium acetate was pretreated with (NBu4)Cl.
precoordinated substrate, followed by proton ab-
straction by a carboxylate acting as an internal
base. The last step is assisted by the metal and cul-
À
compared with those obtained with hydrochloride salt
1a·HCl.
minates in the formation of the metal carbon bond. In this
study, two situations have to be considered: i) orthopallada-
tion of the free amino esters for which the starting material
It is clear that the presence of (NBu4)ClO4 does not affect
the reaction rate of cyclopalladation of 1a significantly, thus
indicating that the polarity of the medium is not directly re-
sponsible for the acceleration observed (Table 3, entries 9–
11). As for the presence of chloride anions, the addition of
one equivalent of (NBu4)Cl to 1a produced an acceleration
similar to that observed when the hydrochloride salt was
used (Table 3, entries 2 and 3), indicating that the main com-
ponent of the acceleration process corresponds to the pres-
ence of one equivalent of chloride. It is clear that the pres-
ence of a chloride ligand in the coordination sphere of the
Pd center enhances the reaction rate for electronic reasons.
Interestingly, the presence of increasing quantities of chlo-
ride ligand triggers the operation of a secondary reaction
(probably producing [PdCl4]2À) that inhibits the cyclopalla-
dation reaction (Table 3, entries 12–16).[32]
can be modeled as [PdACTHNUGRTENNUG ACHUTNGTRENNGUN
(k2-OAc)(k1-OAc)(k1-N-aminoester)],
as for similar compounds;[33,34] ii) orthopalladation of the
corresponding hydrochlorides for which the implication of
a chloride ligand has to be considered during the process.
As for the orthopalladation of free amino esters, the study
of the energetics involved in the accepted general mecha-
nism indicated above is summarized in Figure 6 for ligand
1a. The formation of the agostic species INag from the start-
(k2-OAc)(k1-OAc)(k1-N-1a)], shows
ing material RN, [PdACHTUNGTRENNGUN ACHTUNRTGENNUGN ACHTNUGTRENNGUN
a relative barrier of 16.0 kcalmolÀ1. The rate-determining
step, which represents a barrier of 25.5 kcalmolÀ1, corre-
À
sponds to subsequent breakage of the C H bond and con-
certed abstraction of the proton by the acetate ligand, with
The presence of noncoordinating acids such as triflic or
tetrafluoroboric (Table 3, entries 4, 5, 17, and 18) produced
only a slight rate enhancement in a rather small concentra-
tion range going from ca. 2 to 5 fold the Pd concentration.
This fact indicates an extremely fine tuning between the
protonation of the acetate ligand in Figure 5, which has
been shown to produce significant acceleration in the cyclo-
palladation rate constants,[21] and that of the amine group
from the ligand, which prevents its coordination and conse-
quent cyclometalation (see above). Protonation of the dan-
gling acetate oxygen in the structure shown in Figure 5 pro-
duces a clear increase in the observed rate constant due to
a change in the structure of the transition state for the pro-
cess, but protonation of the free amine prevents the forma-
tion of the metalating {PdII(aminoester)} units. It is also
clear that the substitution of one of the acetate ligands by
Figure 6. Gibbs energy profile for the orthopalladation of 1a in the gas
phase and in different solvents.
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Chem. Eur. J. 2013, 19, 17398 – 17412

Cyclopalladation of Amino Esters
FULL PAPER
À
concomitant formation of the Pd C bond. The reaction is
exothermic and affords the final species PNC, which contains
the orthopalladated amino ester and two acetate groups
connected by a hydrogen bond. The effect of the solvent
(acetone and toluene) was taken into account by using the
continuum model in a single-point calculation on the gas-
phase optimized structures. Clearly, the use of acetone (a
polar solvent) is beneficial for the reaction, due to a better
stabilization of the polar agostic intermediate and the re-
spective transition states.
Given the remarkable qualitative[8c] and quantitative inde-
pendence of the reaction rate with respect to the substitu-
ents in the aromatic ring, we have studied the effect on the
energetic profile of the reaction of the electronic structure
À
Figure 8. Calculated energy profiles for the orthopalladation of methyl
phenylglycinate 1a with different substituents at the C-a atom in the gas
phase.
of the aromatic ring on which the C H position to be acti-
vated is located. In this respect, both electron-donating
(MeO) and electron-withdrawing (Br) groups were included
in the para position of the aromatic ring for the DFT calcu-
lations. Furthermore, the effect of multiple electron-donat-
ing substituents was evaluated by including two OMe
groups in the meta and para positions. The obtained results
are summarized in Figure 7, which also shows that the or-
our calculations to include these substrates. As for the qua-
ternary amino esters, a comparison of the energetic profiles
of 1a and its methyl (1i) and tert-butyl substituted deriva-
tives is shown in Figure 8. Both substituents lead to a notable
stabilization of the transition state for the rate-determining
step, due to the Thorpe–Ingold effect,[35] especially in the
case of 1i. Interestingly, the formation of the agostic inter-
mediate for the tert-butyl system requires more energy,
probably due to the clear steric requirements. On the other
hand, with respect to the N,N-dimethyl substituted deriva-
tive 1c (see Figure S1), the inclusion of N-Me groups pro-
motes a remarkable decrease in the activation barrier of
more than 9 kcalmolÀ1, in perfect agreement with the easy
orthopalladation observed experimentally for 1c (see
Table 1 and Table 2), compared with that of 1a. The large
relative stabilizations observed for all intermediates in the
orthopalladation of 1c seem to be related to the stronger
donor character of the NMe2 group compared with that of
the unsubstituted amine, again in good agreement with the
easier orthometalation of tertiary amines, compared with
their primary counterparts.[20]
Figure 7. Gibbs energy profiles computed for the orthopalladation of
aryl-substituted derivatives of 1a in the gas phase.
We have shown that the reaction model based on a con-
certed metalation-deprotonation, or ambiphilic mechanism,
reflects the trends observed experimentally. A further step
in the theoretical analysis of the orthopalladation of amino
esters involves consideration of hydrochlorides as starting
compounds (1a·HCl, and 1d·HCl–1n·HCl). The model used
for the DFT calculations so far in nonpolar solvents,[22e,33]
thopalladation of 1e seems to occur as a single-step process;
the agostic intermediate INag and the preceding transition
state TS1 were not found. The differences between the cal-
culated activation barriers for the orthopalladation process-
es of all these ligands were less than 0.4 kcalmolÀ1, i.e, the
same within error. Clearly the process can be seen as being
effectively independent of the substituents on the aryl ring
[Pd
spond to the isolated neutral noncyclometalated dimers [Pd-
(m-OAc)(OAc)(NH2CH2Ar)]2, which have been found to be
(k2-OAc)(k1-OAc)(k1-N-aminoester)], does not corre-
ACHUTGTNRENNUG CAHTUNGTRENNUGN
À
containing the metalating C H bond, and that the mecha-
A
R
ACHTUNGTRENNUNG
nism through which the reaction occurs is concerted metala-
tion-deprotonation (ambiphilic), and not electrophilic substi-
tution.
relevant intermediates in the orthopalladation of benzyla-
mines and related species.[12b,c] If the use of such a model
produces calculated data that fully agree with the experi-
In contrast, a remarkable increase in the reaction rates
has been observed when either quaternary amino esters
(containing alkyl substituents at the C-a atom) or disubsti-
tuted amino groups are cyclometalated. Thus, we extended
mental results, then species such as [PdACTHNGUTERNNUG
(k2-OAc)(Cl)(k1-N-
NH2CH2Ar)][20a] can be considered as part of a valid model
for the formation of the isolated compounds of type 3 indi-
cated in Scheme 1. Similar compounds with mixtures of ace-
Chem. Eur. J. 2013, 19, 17398 – 17412
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17405

M. Martꢀnez, E. P. Urriolabeitia et al.
Figure 10. Calculated energy profiles for the orthopalladation of hydro-
chloride salts having different substituents at C-a atom in the gas phase.
Figure 9. Gibbs energy profile for the orthopalladation of 1a (green) and
1a·HCl (red) in the gas phase.
indicating the important acceleration expected for amino-
phosphonate 1m·HCl, due to a stabilization of the transition
state TS2 of almost 5 kcalmolÀ1 with respect to 1a·HCl, as
experimentally observed. Therefore, it is clear that both the
C-a and the N atoms are the most sensitive points in the
original structure; changes of substituents at these positions
trigger remarkable effects in the reaction rate of the ortho-
palladation. Unexpectedly, the aromatic ring (i.e., the part
tate/chloride ligands have also been found to be relevant for
related metalation reactions.[36] The computed reaction path-
way for 1a·HCl starting from [Pd
(CO2Me)Ar)] is shown in Figure 9, and it is compared with
that computed for 1a.
(k2-OAc)(Cl)(k1-NH2CH-
ACHUTGTNRENNUG CAHTUNGTRENNUGN
ACHTUNGTRENNUNG
The orthopalladation of 1a·HCl seems to occur in
a single-step process, as observed for 1e. This difference
with respect to the orthopalladation of 1a is not significant
because the agostic intermediate has been found to be
a short-life species in the cases where it is detected, being in
a very shallow energy valley. On the other hand, the rate-de-
termining steps (TS2) in the two pathways are structurally
similar. The only noticeable change is a slight shortening of
the intramolecular bond distances of the moving H to the
donor C and receptor O atoms from 1a (1.376 and 1.367 ꢇ,
respectively) to 1a·HCl (1.366 and 1.357 ꢇ). Energetically,
the results obtained show that the activation barrier found
for the orthopalladation of 1a·HCl is lower (24.6 kcalmolÀ1)
than that found for 1a (25.5 kcalmolÀ1), in good agreement
with the acceleration observed experimentally (see Table 1,
Table 2 and Table 3). In the same way, the presence of sub-
stituents at the aromatic ring or at the C-a atom has been
evaluated for the hydrochloride salts. Initially both electron-
donating (MeO, 1d·HCl) and electron-withdrawing (Br,
1e·HCl) groups in para positions (Figure S2) were consid-
ered. In a second instance, methyl-substituted quaternary
amino ester 1i·HCl and isosteric aminophosphonate deriva-
tive 1m·HCl were also studied (Figure 10).
À
of the molecule where C H bond activation occurs) is ac-
tually less sensitive, or not at all, to modification and/or
change of the substituents.
Reactivity of 3m and 3n: ortho-functionalization of amino-
phosphonate derivatives: The reactivity of cyclopalladated
complexes 3m and 3n in processes involving oxidative cou-
plings (halogenation, alkoxylation) or insertion of small un-
saturated molecules, such as CO, has also been investigated.
The studied reactions and the obtained products are sum-
marized in Scheme 3. The trends observed can be easily
compared to those reported previously for the isosteric
amino esters.[8a,c,d]
In all studied cases we observe the same trend as that of
the unsubstituted couple 1a·HCl/1a; that is, the activation
barriers for the hydrochlorides (1d·HCl, 1e·HCl, 1i·HCl)
are smaller than those for the free amines (1d, 1e, 1i; com-
pare Figure 7 and Figure S2), in good agreement with the
experimental results. In the same way, the presence of sub-
stituents at the aryl ring does not induce remarkable
changes, whereas substituents at C-a promotes notable de-
creases of the activation barriers. In this respect it is worth
Scheme 3. Reactivity of 3m and 3n to give functionalized aminophospho-
nates.
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Cyclopalladation of Amino Esters
FULL PAPER
The oxidative halogenations were carried out by using dif-
ferent reagents, depending of the halogen to be introduced.
In the case of chlorinations, PhICl2 gave the best perfor-
mance for 3m,[37] whereas a complex reaction was observed
for 3n. Although extensive decomposition was observed
when Cl2 was used in both cases, Br2 and I2 were suitable re-
agents in the case of brominations and iodinations, respec-
tively, for the two complexes. The reaction of 3m and 3n
with the corresponding reagent under stoichiometric condi-
tions takes place in two steps, as previously reported.[8d,12e]
Initially, intermediate coordination complexes of stoichiom-
etry [PdCl2L2] (L=ortho-functionalized aminophosphonate)
are formed, which were not isolated. The process presuma-
bly involves the formation of a PdIV species and subsequent
which it was possible to assign signals due to the presence of
the C6H4-bonded OMe and OEt groups.
À
Insertion of small unsaturated molecules into the Pd C
bonds (for instance CO) also represents a classical tool with
which to achieve regioselective functionalization of organic
substrates;[40] thus, reaction of 3m with CO (1 atm) in
CH2Cl2 at room temperature was studied. The reaction
occurs with formation of black palladium. Its removal, fol-
lowed by simple evaporation of the resulting solution, af-
forded a white solid that was characterized as the isoindoli-
none-type derivative 10m (Scheme 3). The reaction implies
À
CO bonding, migratory insertion into the Pd Cortho bond, re-
À
ductive elimination by C N coupling and final elimination
of HCl from the resulting ammonium salt. The reactivity
pattern is identical to that observed with the isosteric amino
ester,[8c,d] but when the reaction was carried out in methanol,
instead of CH2Cl2, the same isoindolinone 10m was ob-
tained. This is a remarkable result because it implies that
the cyclization step is faster than the formation of the ester,
in contrast to results obtained with the amino ester deriva-
tive.[8a]
À
reductive elimination during formation of the C X bond.
During the reaction, PdX2 was formed as a byproduct and
removed by filtration. The decoordination of ortho-function-
alized aminophosphonate (L) from the intermediate species
is normally conducted by treatment of [PdCl2L2] with a che-
lating ligand (1,10-phenantroline),[8d,12e] which forms a very
insoluble complex [PdCl2ACTHNUTRGNEU(GN N,N-phen)] thus promoting quan-
titative release of the functionalized species L. In our case,
1,10-phen does not appear to be a good ligand for releasing
purposes, and optimum results were instead achieved by
using PPh3 (1:2 molar ratio). In this way, PdII was removed
quantitatively as [PdCl2ACHTNUGTRNE(UGN PPh3)2], and any excess of free PPh3
could be separated by column chromatography (see Experi-
mental) from the desired halogenated derivatives
Even though 5m–10m are the first aminophosphonates to
be regioselectively modified by using a transition metal, the
results obtained here show a close similarity to those report-
ed previously with the isosteric amino esters. This suggests
that replacing the ester by a phosphonate group produces
a parallel reactivity, at least for the studied cases. The effect
of the changes seem to be limited to the tuning of the rate
at which the reactions take place.
H2NC(R)[P(O)ACHTUNGTRENNUNG(OEt)2]AHCTUNGTRNE(NUGN C6H4-2-X) [Scheme 3; R=H, X=Cl
(5m), Br (6m), I 7m; R=Me, X=Br (6n), I (7n)]. Charac-
terization of 5m–7n was carried out on the basis of their an-
alytical and spectroscopic data. Elemental analyses and
mass spectra were consistent with the stoichiometries shown
in Scheme 3. The 1H and 13C NMR spectra, which show
a single set of signals each, clearly display peaks due to the
Conclusion
Interesting trends concerning the orthopalladation of differ-
ent phenylglycine-derived amino esters and aminophospho-
nates substituted at the N atom, the aryl ring, and the C-
a atom, under optimized reaction conditions, have been ob-
served during preparative procedures. The introduction of
substituents at the N atom and the C-a atom (quaternary
amino esters), as well as replacing the amino ester by
À
presence of the {C6H4} unit, whereas the existence of a C X
bond (X=Cl, Br, I) is evident in the 13C NMR spectra from
the observation of peaks at 133.7 (5m, Cl), 124.3 (6m, Br),
and 100.9 ppm (7m, I).
The incorporation of alkoxy functional groups at the
ortho position of aminophosphonates by following a similar
methodology, has also been achieved. Given the fact that io-
donium salts promote successful oxidative couplings (see
above),[38] the reactivity of 3m with alcohols in the presence
aminoACTHUNRTGNEUNGphosphonate, facilitate the preparative procedures rel-
ative to the unsubstituted amino esters. On the other hand,
the presence of substituents at the aryl ring does not seem
to exert a critical influence on the process, indicating a mech-
À
of an I
with PhI
N
anism for the C H bond activation step that is not based on
U
electrophilic substitution. Quantification of these trends by
undertaking a detailed kinetico-mechanistic study indicates
that orthopalladation of substituted amino esters occurs at
a faster rate on substitution of either the C-a or amine N
atoms, whereas no effect was evident upon the introduction
of different substituents on the metalating aryl ring. The
data also indicate that the corresponding hydrochlorides
metalate at a faster rate. The process behaves according to
the expected ambiphilic nature of the CMD mechanism,
with important changes in entropy and volume requirements
to reach the transition state. DFT modeling of the reaction,
considering such mechanism, produces a series of trends in
at room temperature afforded the corresponding coordina-
tion complexes [PdCl2L2], described above, with the L li-
gands being the ortho-alkoxy substituted aminophospho-
nates (methoxy or ethoxy, respectively). As indicated previ-
ously, the reaction of these species with PPh3 induces the
precipitation of [PdCl
aminophosphonates
(PPh3)2] and release of the alkoxy-
H2NC(H)[P(O)(OEt)2](C6H4-2-X)
N
ACHTUNGTRENNUNG
[Scheme 3; R=OMe (8m), OEt (9m)], which were subse-
quently isolated and purified. Characterization of 8m and
9m was straightforward from their analytical and spectro-
scopic parameters, mainly from the NMR spectra from
Chem. Eur. J. 2013, 19, 17398 – 17412
ꢆ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
17407

M. Martꢀnez, E. P. Urriolabeitia et al.
124.48 (CH, C6H4), 125.31 (CH, C6H4), 126.81 (CH, C6H4), 134.42 (CH,
C6H4), 173.84 ppm (CO); the two quaternary carbon atoms of the C6H4
ring were not observed, in spite of the use of long accumulation trials;
the activation barriers that are fully consistent with the ex-
perimental kinetico-mechanistic data obtained. These trends
can be easily related to the presence of the substituents in-
troduced. Interestingly, the replacement of an acetate by
IR: n˜ =3286, 3210 (nNH2), 1724 (nC O) cmÀ1 MS (ESI+): m/z: 595.6
;
=
[MÀCO2]+; elemental analysis calcd (%) for C20H24Cl2N2O4Pd2 (640.16):
a chloride in the mechanistically relevant species, [Pd
OAc)
(k1-X)(k1-N-aminoester)], also produces a favorable
(k2-
ACHTUNGTRENNUNG
C 37.52, H 3.78, N 4.38; found: C 37.58, H 3.81, N 4.33.
ACHTUNGTRENNUNG
[Pd
tained by using a method similar to that described for 3i with slight
modifications. To solution of amino ester hydrochloride 1j·HCl
(700.0 mg, 2.52 mmol) in acetone (20 mL), Pd(OAc)2 (565.6 mg,
ACHTNUGTNREN(NUG m-Cl)CAHTUNGTREN{NGU C6H4ACHTUNGERT(NGUNN (CPh)ACTHNGUTREN(NUGN CO2Me)NH2)-2}]2 (3j): Compound 3j was ob-
difference in the activation energy, as found in the experi-
mental handling of the process: the reaction is faster starting
a
AHCTUNGTRENNUNG
from [Pd
ACHTUNGTRENNUNG ACHTUNGTRENNUNG
(k2-OAc)(k1-Cl)(k1-N-aminoester)] than from [Pd-
2.52 mmol) was added and the resulting mixture was heated to reflux for
24 h. After this time the resulting solution was allowed to reach RT, and
n-hexane (40 mL) was added. The pale-yellow solid formed was filtered,
washed with additional n-hexane (30 mL), dried in vacuum and identified
as 3j. Yield: 817.3 mg (85%); 1H NMR (300.13 MHz, [D6]acetone): d=
3.87 (s, 3H; OCH3), 5.26 (s, 1H; NH), 5.58 (s, 1H; NH), 6.76 (dd, 3J-
A
ACHTUNGTRENNUNG
orthopalladated aminophosphonate complexes in oxidative
couplings and insertion of small unsaturated molecules
allows the corresponding ortho-functionalized aminophos-
ACHTUNGTRENNUNG
A
R
ACHTUNGTREN(NGNU H,H)=7.2 Hz, 1H;
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
3H; C6H5); 13C{1H} NMR (75.47 MHz, [D6]acetone): d=53.67 (OCH3),
124.78 (CH, C6H4), 126.74 (CH, C6H4), 127.11 (CH, C6H4), 128.19 (CH,
C6H5), 129.29 (2 overlapped CH, C6H5), 134.32 (CH, C6H4), 142.03 (C,
C6H5), 144.22 (C, C6H4), 150.70 (C, C6H4), 172.31 ppm (CO); the signal
due to the C-a carbon was not detected; IR: n˜ =1727 cmÀ1; MS (ESI+):
m/z: 719.7 [MÀCO2]+; elemental analysis calcd (%) for
C30H28Cl2N2O4Pd2 (764.3): C 47.14, H 3.69, N 3.67; found: C 47.28, H
3.60, N 3.61.
Experimental Section
General methods: Solvents were dried and distilled by using standard
procedures before use. Elemental analyses (CHN) were carried out with
a Perkin–Elmer 2400-B microanalyzer. Infrared spectra (4000–380 cmÀ1
)
were recorded with a Perkin–Elmer Spectrum One IR spectrophotome-
ter. H, 13C, and 31P NMR spectra were recorded at RT (unless otherwise
1
[PdACHTUGNNRET(UGNN m-Cl)CAHUTNGTREN{NGU C6H4ACHTUNGETR(NGNUN CBnCAHTNUGTREN(GUNN CO2Me)NH2)-2}]2 (3k): Compound 3k was ob-
stated) with Bruker AV300 and AV400 spectrometers (d in ppm, J in Hz)
at a 1H operating frequency of 300.13 and 400.13 MHz, respectively. 1H
and 13C NMR spectra were referenced against solvent signal as internal
standard, whereas 31P NMR spectra were referenced to H3PO4 (85%).
ESI+ mass spectra were recorded with an Esquire 3000 ion-trap mass
spectrometer (Bruker Daltonic GmbH) equipped with a standard ESI/
APCI source. Samples were introduced by direct infusion with a syringe
pump. Nitrogen served both as the nebulizer gas and the dry gas.
MALDI+ mass spectra were recorded from CHCl3 solutions with
a MALDI-TOF Microflex (Bruker) spectrometer (DCTB as matrix).
HRMS and ESI (ESI+) mass spectra were recorded with an MicroToF
Q, API-Q-ToF ESI with a mass range from 20 to 3000 m/z and mass reso-
lution 15000 (FWHM).
tained by following an experimental procedure identical to that described
for 3j. Amino ester hydrochloride 1k·HCl (200.0 mg, 0.686 mmol) was
heated to reflux with PdACHTNUGTRNEUNG(OAc)2 (153.8 mg, 0.686 mmol) in acetone
(10 mL) for 24 h to give 3k as a pale-yellow solid. Yield: 219.6 mg
(81%); 1H NMR (300.13 MHz, [D6]acetone): d=3.47 (m, 1H; CH2),
3.76 (m, 1H; CH2), 3.80 (s, 3H; OCH3), 4.56–5.00 (m, 2H; NH2), 6.90
(m, 1H; C6H4), 7.05 (m, 1H; C6H4), 7.10–7.23 (m, 2H; C6H4), 7.27–7.38
(m, 3H; C6H5), 7.38–7.50 ppm (m, 2H; C6H5); 13C{1H} NMR
(75.47 MHz, [D6]acetone): d=46.87 (CH2), 53.20 (OCH3), 124.67 (CH,
C6H4), 125.19 (CH, C6H4), 126.93 (CH, C6H4), 129.41 (CH, C6H5), 130.76
(CH, C6H5), 131.15 (C, C6H5), 144.55 (C, C6H4), 172.19 ppm (CO); the
signal due to the C-a carbon, two signals of the C6H4 ring and another
due to the C6H5 fragment were not observed; IR: n˜ =3330, 3253 (nNH2),
Compound 1a·HCl is commercially available and was used without fur-
ther purification. The amino esters 1b[14] and 1c,[8a, 15] and the hydrochlor-
ides 1d·HCl,[8c] 1e·HCl,[8c] 1 f·HCl,[8c] and 1g·HCl[8c] have been prepared
as previously described. Hydrochlorides of the quaternary amino esters
1i·HCl, 1j·HCl, 1k·HCl, 1l·HCl,[16] as well as aminophosphonates
1m·HCl[17] and 1n·HCl,[18] were prepared through modifications or adap-
tations of previously reported methods; their syntheses are detailed in
the Supporting Information. The orthopalladated derivatives 3a–g were
already known (3a,[19] 3b,[8a] 3c,[8a,15] 3d,[8c] 3e,[8c] 3 f,[8c] and 3g[8c]); they
were synthesized by following reported procedures and identified by
comparison of their spectroscopic data with those published. Compounds
closely related to 3l and 3k have been reported recently,[13a,b] but they
differ in the nature of the halide bridge (m-Cl in 3l and 3k whereas m-Br
in the reports[13a,b]) and in the method of synthesis (solvents, temperature,
time). PhICl2 was also prepared by following published procedures.[37]
1730 cmÀ1 (nC O); MS (ESI+): m/z: 747.7 [MÀCO2]+; elemental analysis
=
calcd (%) for C32H32Cl2N2O4Pd2 (792.32): C 48.51, H 4.07, N 3.54; found:
C 48.70, H 3.92, N 3.57.
[PdCATHGNUTREN(UNNG m-Cl)ACHTUNTGRNEN{GU C6H3ACHTUNEGRT(NGNUN (CH2)3CACHTNUGTREN(NNGU CO2Me)NH2)-8}]2 (3l): Compound 3l was ob-
tained by following an experimental procedure identical to that described
for 3j. Amino ester hydrochloride 1l·HCl (200.0 mg, 0.827 mmol) was
heated to reflux with PdACHTNUGTRNEUNG(OAc)2 (185.8 mg, 0.827 mmol) in acetone
(10 mL) for 24 h to give 3l as a grey solid. Yield: 475.2 mg (81%). ele-
mental analysis calcd (%) for C24H28Cl2N2O4Pd2 (692.20): C 41.64, H
4.08, N 4.05; found: C 41.52, H 4.11, N 4.01. IR: n˜ =3279, 3228 (nNH2),
1720 cmÀ1 (nC O). Compound 3l was insoluble in the usual solvents,
=
making its characterization by NMR methods impossible.
[Pd
P(O)(OEt)2]Ph}2] (2m): To a suspension of 1m·HCl (2 g, 7.16 mmol) in
acetone (100 mL), Pd(OAc)2 (1.61 g, 7.16 mmol) was added and the re-
ACHTGNURETN(NNUG m-Cl)ACHTUNTGRNEN{GU C6H4(CH[P(O)ACHTNUGERTG(NUNN OEt)2]NH2)-2}]2 (3m) and [PdCl2ACHTUNGTRENNUNG{NH2CH[-
AHCTUNGTRENNUNG
Synthesis of orthopalladated complexes
sulting mixture was heated to reflux for 6 h. The resulting solution was
evaporated to a small volume (ca. 1 mL), and the residue was subjected
to column chromatography (2.5 cm diameter, 25 cm height) over silica
gel (ethyl acetate as eluent). The first orange band collected was that
containing orthopalladated complex 3m, which was isolated by evapora-
tion of the solvent to dryness, addition of n-hexane (20 mL) and further
stirring. The solid thus obtained was filtered, washed with additional n-
hexane (10 mL) and dried in vacuum. Yield: 2.05 g (72%). Further elu-
tion with ethyl acetate gave a second orange band, from which complex
2m (0.50 g, 11%) could be isolated after evaporation of the solvent and
addition of n-hexane (15 mL).
[Pd
ester hydrochloride 1i·HCl (1000.0 mg, 4.637 mmol) in acetone (40 mL),
Pd(OAc)2 (1040.0 mg, 4.637 mmol) was added and the resulting suspen-
ACHTUNGTRENNUNG(m-Cl)ACHTUNGTRENNUNG{C6H4ACHTUNGTRENNUNG(CMeACHTUNGTRENNUNG(CO2Me)NH2)-2}]2 (3i): To a suspension of amino
ACHTUNGTRENNUNG
sion was heated to reflux for 3 h. During this time, the color of the sus-
pension changed noticeably to orange. After this time, the suspension
was allowed to reach RT and Et2O (40 mL) was added. The precipitated
orange solid was filtered, washed with Et2O (30 mL), dried in vacuum
and identified as 3i. Yield: 1270 mg (85%); 1H NMR (300.13 MHz,
[D6]acetone): d=1.88 (s, 3H; CH3), 3.78 (s, 3H; OCH3), 5.14 (br. s, 2H;
NH2), 6.79–7.02 (m, 3H; C6H4), 7.13 ppm (m, 1H; C6H4); 13C{1H} NMR
(75.47 MHz, [D6]acetone): d=27.62 (CH3), 53.53 (OCH3), 71.75 (Ca),
17408
www.chemeurj.org
ꢆ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 17398 – 17412

Cyclopalladation of Amino Esters
FULL PAPER
1
Characterization of 3m: H NMR (400.13 MHz, [D6]acetone): d=1.28 (t,
with CH2Cl2 (2ꢈ5 mL). The clear solution was washed with an aqueous
solution of sodium sulfite (32.7 mg, 0.26 mmol in 10 mL water) to elimi-
nate any Br2 in excess, and the organic fraction was dried with anhydrous
MgSO4. Further workup of the resulting solution was similar to that de-
scribed for 5m. Thus, the solution was treated with PPh3 (68.3 mg,
3J(H,H)=7.0 Hz, 3H; CH3), 1.34 (t, 3J
ACHTUNGTRENNUNG ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
3
3
d=16.52 (d, J
ACHTUNGTRENNUNG(P,C)=5.6 Hz, CH3), 16.64 (d, JACHUTNGTRNEN(NGU P,C)=5.8 Hz, CH3), 61.20
0.26 mmol) for 2 h at RT, the precipitated [PdCl2ACHTNUGTRENUNG(PPh3)2] was removed
(d, 1J(P,C)=148 Hz, CH), 64.12 (br., OCH2), 64.30 (d, 2J
ACHTUNGTRENNUNG ACHTGNUTREN(NUNG P,C)=7.0 Hz,
and the residue was purified by chromatography (silica gel, ethyl ace-
OCH2), 123.27, 124.91, 126.14, 133.72, 144.45, 146.70 ppm (C6H4); 31P{1H}
tate), to afford 6m as a yellow oil. Yield: 32.8 mg (40%); 1H NMR
3
3
NMR (161.97 MHz, [D6]acetone): d=20.32 ppm (s); IR: n˜ =3209 (nNH),
(400.13 MHz, CDCl3): d=1.14 (t, J
(H,H)=7.1 Hz, 3H; CH3), 1.95 (br. s, 2H; NH2), 3.83 (m, 1H; OCH2),
3.96 (m, 1H; OCH2), 4.11–4.25 (m, 2H; OCH2), 4.82 (d, 2J
(P,H)=
ACHTUNGRTEN(NGNU H,H)=6.9 Hz, 3H; CH3), 1.35 (t, J-
1230 cmÀ1 (nP O); MS (ESI+): m/z (%): 732.7 (40) [MÀCl]+; elemental
AHCTUNGTRENNUNG
=
analysis calcd (%) for C22H34Cl2N2O6P2Pd2: C 34.40, H 4.46, N 3.65;
found: C 34.58, H 4.54, N 3.70.
ACHTUNGTRENNUNG
18.7 Hz, 1H; CH), 7.15 (m, 1H; C6H4), 7.35 (m, 1H; C6H4), 7.55 (m, 1H;
C6H4), 7.69 ppm (m, 1H; C6H4); 13C{1H} NMR (100.61 MHz, CDCl3):
Characterization of 2m: 1H NMR (400.13 MHz, CDCl3): d=1.22–1.32
d=16.3 (d, 3J
(d, 1J
(P,C)=7.3 Hz; OCH2), 124.3 (d, 3J
(P,C)=2.8 Hz; CH, C6H4), 129.3 (d, J
(d, J(P,C)=3.6 Hz; CH, C6H4), 132.9 (d, JACTHUNGTRENNUNG
(P,C)=5.6 Hz; CH3), 16.6 (d, 3J
ACHUTGTNRENNUG CAHTUNGTRENNUNG
(m, 6H; CH3), 4.08–4.16 (m, 2H; OCH2), 4.18–4.26 (m, 2H; OCH2), 4.67
ACHUTNGRENNUG CAHTUNGTRENNUNG
(P,C)=152.1 Hz; CH), 63.0 (d, 2J
(d, 2J
ACHTUNGTRENNUNG(P,H)=16.7 Hz, 1H; CH), 6.76 (m, 1H; C6H5), 6.83 (m, 1H; C6H5),
A
ACHTUNGTRENNUNG
7.07 (m, 1H; C6H5), 7.38 (m, 1H; C6H5), 7.56 ppm (m, 1H; C6H5);
31P{1H} NMR (161.97 MHz, CDCl3): d=22.30 ppm; IR: n˜ =3221 (nNÀH),
J
N
ACHTUNGTRENNUNG
1226 cmÀ1 (nP O); MS (ESI+): m/z (%): 628.8 (100) [MÀCl]+; elemental
U
=
138.1 ppm (s; C, C6H4); 31P{1H} NMR (161.97 MHz, CDCl3): d=
24.32 ppm; MS (ESI+): m/z (%): 321.9 (18%) [M]+; HRMS (ESI-TOF):
m/z: calcd for C11H18BrNO3P 322.0202 [M+H]+; found 322.0206; elemen-
tal analysis calcd (%) for C11H17BrNO3P: C 41.01, H 5.32, N 4.35; found:
analysis calcd (%) for C22H36Cl2N2O6P2Pd: C 39.81, H 5.47, N 4.22;
found: C 39.74, H 5.47, N 4.11.
[PdACHTUNGTRENNUNG(m-Cl)ACHTUNGTRENNUNG{C6H4ACHTUNGTRENNUNG(CMe[P(O)CAHTNUGTREN(GUNN OEt)2]NH2)-2}]2 (3n): Complex 3n was ob-
tained by following the same experimental method described for 3m,
with the exception that 3n precipitated from the reaction medium and
chromatographic purification was not necessary. A suspension of 1n·HCl
C 40.72, H 5.18, N 4.38; IR: n˜ =3374, 3296 (nNÀH), 1234 cmÀ1 (nP O).
=
AHCTUNGTRENUNG{N H2NC(H)[P(O)AHCTNURTGEG(NUNN OEt)2]ACHTNUGTERN(NUGN 2-IC6H4)} (7m): The synthesis of 7m was car-
ried out by following the same experimental procedure described for 6m.
Thus, 3m (100 mg, 0.13 mmol) was reacted with I2 (66.4 mg, 0.26 mmol)
and PPh3 (68.3 mg, 0.26 mmol) in CH2Cl2 (20 mL) to give 7m as a yellow
(100 mg, 0.34 mmol) and PdACHTUNTRGNEUNG(OAc)2 (76.4 mg, 0.34 mmol) in acetone
(20 mL) was heated to reflux for 2.5 h, giving 3n as an orange solid.
Yield: 96.3 mg (71%) 1H NMR (400.13 MHz, [D6]acetone): d=1.21 (m,
1
3
3H; CH3), 1.37 (m, 3H; CH3), 1.82 (d, 3J
ACTHNUTRGEN(UNG P,H)=15.0 Hz, 3H; a-CH3),
oil. Yield: 27.1 mg (28%); H NMR (400.13 MHz, CDCl3): d=1.13 (t, J-
(H,H)=7.0 Hz, 3H; CH3), 1.35 (t, 3J
(H,H)=7.1 Hz, 3H; CH3), 1.92
(br. s, 2H; NH2), 3.80 (m, 1H; OCH2), 3.95 (m, 1H; OCH2), 4.17–4.22
(m, 2H; OCH2), 4.76 (d, 2J
(P,H)=18.7 Hz, 1H; CH), 6.97 (m, 1H;
C6H4), 7.37 (m, 1H; C6H4), 7.66 (m, 1H; C6H4), 7.83 ppm (m, 1H; C6H4);
13C{1H} NMR (100.61 MHz, CDCl3): d=16.4 (d, 3J
(C,P)=5.7 Hz, CH3),
16.7 (d, 3J(C,P)=5.8 Hz, CH3), 57.9 (d, 1J
(C,P)=151.5 Hz, CH), 63.0 (d,
2J(C,P)=7.4 Hz, OCH2), 63.1 (d, 2J(C,P)=7.3 Hz, OCH2), 100.9 (d, 3J-
(C,P)=10.4 Hz, C-I, C6H4), 128.8 (d, J(C,P)=3.1 Hz, CH, C6H4), 129.0
(d, J(C,P)=4.4 Hz, CH, C6H4), 129.7 (d, J(C,P)=2.9 Hz, CH, C6H4),
139.7 (d, J
(C,P)=1.5 Hz, CH, C6H4), 141.5 ppm (s, C, C6H4); 31P{1H}
A
ACHTUNGTRENNUNG
3.78–4.00 (m, 2H; OCH2), 4.20–4.43 (m, 2H; OCH2), 6.83 (m, 1H;
C6H4), 6.92–7.00 (m, 2H; C6H4), 7.12 ppm (m, 1H; C6H4); 31P{1H}
(161.97 MHz, [D6]acetone): d=23.38 ppm; IR: n˜ =3204 (nNÀH),
AHCTUNGTRENNUNG
1228 cmÀ1 (nP O); MS (ESI+): m/z (%): 430.9 (19) [M/2+Cl]+, 402.9 (100)
=
[MH/2]+; elemental analysis calcd (%) for C24H38Cl2N2O6P2Pd2: C 36.20,
ACHTUNGTRENNUNG
H 4.81, N 3.52; found: C 36.48, H 4.86, N 3.48.
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
Reactivity of the orthopalladated complexes 3m and 3n
A
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG{H2NC(H)[P(O)ACHTUNGTRENNUNG(OEt)2]ACHTUNGTRENNUNG(2-ClC6H4)} (5m): To a fresh solution of
A
ACHTUNGTRENNUNG
[37]
PhICl2 (71.6 mg, 0.26 mmol) in CH2Cl2 (10 mL), complex 3m (100 mg,
0.13 mmol) was added. The resulting mixture was stirred at RT for 24 h
and then filtered over a Celite bed, washing repeatedly with 5 mL frac-
tions of CH2Cl2. The resulting solution was evaporated to 10 mL, then
PPh3 (68.3 mg, 0.26 mmol) was added. After a few seconds a voluminous
AHCTUNGTRENNUNG
NMR (161.97 MHz, CDCl3): d=24.80 ppm; MS (ESI+): m/z (%): 370.1
(32) [M+H]+; HRMS (ESI-TOF): m/z: calcd for C11H18INO3P: 370.0063
[M+H]+; found: 370.0060; elemental analysis calcd (%) for
C11H17INO3P: C 35.79, H 4.64, N 3.79; found: C 35.60, H 4.68, N 4.00;
yellow precipitate of [PdCl2ACHTNUTRGNE(NUG PPh3)2] appeared. This suspension was
IR: n˜ =3374, 3296 (nNÀH), 1234 cmÀ1 (nP O).
=
stirred at RT for 2 h, then the solid was removed by filtration and the re-
sulting solution was concentrated to 2 mL. This residue was subjected to
column chromatography over silica gel with ethyl acetate as eluent. The
first colorless fraction collected was identified as unreacted PPh3. Further
elution developed a second yellow band, from which 5m was isolated as
AHCTUNGTRENUNG{N H2NC(Me)[P(O)ACHUTNRTGEG(NUNN OEt)2]ACHTNUGRTEN(NUGN 2-BrC6H4)} (6n): The synthesis of 6n was car-
ried out by following the same experimental procedure described for 6m,
except that compound 3n was used as starting material. Thus, 3n
(100 mg, 0.125 mmol) was reacted with Br2 (13.3 mL, 0.26 mmol) and
PPh3 (68.3 mg, 0.26 mmol) in CH2Cl2 (20 mL) to give 6n as a yellow oil.
Yield: 36.8 mg (41%); 1H NMR (400.13 MHz, CDCl3): d=1.29 (t, 3J-
a
yellow oil by evaporation of the solvent. Yield: 52.2 mg (72%);
1H NMR (400.13 MHz, CDCl3): d=1.12 (t, 3J
(H,H)=7.1 Hz, 3H; CH3),
1.32 (t, 3J
(H,H)=7.0 Hz, 3H; CH3), 1.91 (br. s, 2H; NH2), 3.82 (m, 1H;
OCH2), 3.94 (m, 1H; OCH2), 4.09–4.22 (m, 2H; OCH2), 4.82 (d, 2J-
(P,H)=18.7 Hz, 1H; CH), 7.20 (m, 1H; C6H4), 7.29 (m, 1H; C6H4), 7.35
(m, 1H; C6H4), 7.66 ppm (m, 1H; C6H4); 13C{1H} NMR (100.61 MHz,
CDCl3): d=16.3 (d, 3J(C,P)=5.7 Hz; CH3), 16.6 (d, 3J
(C,P)=5.7 Hz,
CH3), 49.8 (d, 1J(C,P)=152.3 Hz; CH), 62.9 (d, 2J
(C,P)=7.4 Hz, OCH2),
63.0 (d, 2J
(C,P)=7.4 Hz, OCH2), 127.3 (d, J(C,P)=2.8 Hz; CH, C6H4),
129.0 (d, J(C,P)=2.9 Hz; CH, C6H4), 129.2 (d, J(C,P)=4.3 Hz; CH,
C6H4), 129.5 (d, J
AHCTUNGTRENNUNG
A
ACHTUNGRTEN(NGNU H,H)=7.0 Hz, 3H; CH3), 1.90 (d,
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
OCH2), 7.09 (m, 1H; C6H4), 7.29 (m, 1H; C6H4), 7.60 (m, 1H; C6H4),
ACHTUNGTRENNUNG
7.76 ppm (m, 1H; C6H4); 13C{1H} NMR (100.61 MHz, CDCl3): d=16.6
(d, 3J(C,P)=2.4 Hz; CH3), 16.7 (d, 3J(C,P)=2.3 Hz; CH3), 25.7 (d, 2J-
ACTHNUTRGENNUG CAHTUNGTRENNUGN
A
ACHTUNGTRENNUNG
A
(C,P)=152.0 Hz; C), 63.1 (d, 2J
ACHUTGTNRENNUG ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
3
A
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG(C,P)=2.0 Hz; CH, C6H4), 133.7 (d, JCAHTUNGTRNE(NUGN C,P)=8.9 Hz; C-
Cl, C6H4), 136.4 ppm (s; C, C6H4); 31P{1H} NMR (161.97 MHz, CDCl3):
JACHTUNGTRENNUNG
d=24.46 ppm; IR: n˜ =3376, 3298 (nNÀH), 1235 cmÀ1 (nP O); MS (ESI+):
(161.97 MHz, CDCl3): d=26.60 ppm; IR: n˜ =3370, 3300 (nNÀH),
=
1236 cmÀ1 (nP O); MS (ESI+): m/z (%): 335.8 (2.5) [M+H]+, 279.0 (100)
m/z (%): 278.0 (70%) [M+H]+; HRMS (ESI-TOF): m/z: calcd for
C11H18ClNO3P 278.0707 [M+H]+; found: 278.0731; elemental analysis
calcd (%) for C11H17ClNO3P: C 47.58, H 6.17, N 5.04; found: C 47.89, H
6.25, N 4.88.
=
[MÀC4H9]+, 197.9 (10) [MÀP(O)
(OEt)2]+; elemental analysis calcd (%)
ACHTUNGTRENNUNG
for C12H19BrNO3P: C 42.88, H 5.70, N 4.17; found: C 43.01, H 5.67, N
4.04.
AHCTNUGTREUN{GNN H2NC(Me)[P(O)ACHTUNRTGENN(GNU OEt)2]ACHTNGURTNE(NUGN 2-IC6H4)} (7n): The synthesis of 7n was car-
ACHTUNGTRENNUNG{H2NC(H)[P(O)ACHTUNGTRENNUNG(OEt)2]ACHTUNGTRENNUNG(2-BrC6H4)} (6m): To a solution of 3m (100 mg,
0.13 mmol) in CH2Cl2 (20 mL), Br2 was added (13.2 mL, 0.26 mmol), and
the resulting suspension was stirred at RT for 20 h. The precipitated
PdBr2 was removed by filtration through a Celite bed, which was washed
ried out by following the same experimental procedure described for 6m,
except that compound 3n was used as starting material. Thus, 3n
(100 mg, 0.125 mmol) was reacted with I2 (67.4 mg, 0.26 mmol) and PPh3
Chem. Eur. J. 2013, 19, 17398 – 17412
ꢆ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
17409

M. Martꢀnez, E. P. Urriolabeitia et al.
(68.3 mg, 0.26 mmol) in CH2Cl2 (20 mL) to give 7n as a yellow oil. Yield:
25.2 mg (26%); 1H NMR (400.13 MHz, CDCl3): d=1.27 (t, 3J
(H,H)=
5.7 Hz, 6H; CH3), 1.88 (d, 3J
(P,H)=15.6 Hz, 3H; a-CH3), 2.31 (br., 2H;
X-ray crystallography: Crystals of 3j and 4k of sufficient quality for X-
ray measurements were grown by vapor diffusion of Et2O into CH2Cl2
solutions of the crude products at 258C. A single crystal was mounted in
each case at the end of a quartz fiber in a random orientation, covered
with perfluorinated oil and placed under a cold stream of N2 gas. X-ray
data collection was performed with Bruker Smart Apex CCD or Oxford
Diffraction Xcalibur2 diffractometers using graphite-monocromated Mo-
Ka radiation (l =0.71073 ꢇ). In all cases, a hemisphere of data was col-
lected based on w-scan or f-scan runs. The diffraction frames were inte-
grated by using the programs SAINT[41] or CrysAlis RED[42] and the inte-
grated intensities were corrected for absorption with SADABS.[43] The
structures were solved and developed by Patterson and Fourier meth-
ods.[44] All non-hydrogen atoms were refined with anisotropic displace-
ment parameters. The hydrogen atoms were placed at idealized positions
and treated as riding atoms. Each H atom was assigned an isotropic dis-
placement parameter equal to 1.2 times the equivalent isotropic displace-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
NH2), 4.00–4.14 (m, 4H; OCH2), 7.07 (m, 1H; C6H4), 7.28 (m, 1H;
C6H4), 7.40–7.69 ppm (m, 2H; C6H4); 31P{1H} NMR (161.97 MHz,
CDCl3): d=26.36 ppm; IR: n˜ =3365, 3301 (nNÀH), 1240 cmÀ1 (nP O); ele-
=
mental analysis calcd (%) for C12H19INO3P: C 37.62, H 5.00, N 3.66;
found: C 37.44, H 5.02, N 3.69.
A
E
a
suspension of 3m
AHCTUNGRTEGNUN(N OAc)2 (167.7 mg,
0.52 mmol) was added. The mixture was stirred at RT for 20 h, then the
suspended solid was removed by filtration through a Celite bed, which
was washed with CH2Cl2 (2ꢈ5 mL). The solid was discarded and the
combined solutions were evaporated to dryness. The remaining residue
was redissolved in CH2Cl2 (30 mL) and the clear solution was washed
with an aqueous solution of sodium sulfite (10%, 2ꢈ15 mL). The organic
fraction was dried with anhydrous MgSO4. Further workup of the result-
ing solution was similar to that described for 5m. Thus, the solution was
treated with PPh3 (68.3 mg, 0.26 mmol) for 3 h at RT, the precipitated
2
ment parameter of its parent atom. The structures were refined to Fo
and all reflections were used in the least-squares calculations.[45] CCDC-
934779 (3j) and 934780 (4k) 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.
[PdCl
raphy (silica gel, ethyl acetate), to afford 8m as a yellow oil. Yield:
6.7 mg (10%); 1H NMR (400.13 MHz, CDCl3): d=1.07 (t, 3J
(H,H)=
7.1 Hz, 3H; CH3), 1.24 (t, 3J
(H,H)=7.1 Hz, 3H; CH3), 2.82 (br., NH2),
3.77 (s, 3H; OCH3), 3.86–3.92 (m, 2H; OCH2), 3.98–4.09 (m, 2H;
2ACHTUNGTRENNUNG(PPh3)2] was removed and the residue was purified by chromatog-
AHCTUNGTRENNUNG
Kinetic measurements: Reactions at atmospheric pressure were followed
by UV/Vis time-resolved spectroscopy in the full 750–300 nm range with
a HP8543 or Cary 50 instrument equipped with a thermostated multicell
transport (Æ0.18C). Observed rate constants were derived from the ab-
sorbance versus time traces at wavelengths for which a maximum in-
crease and/or decrease of absorbance was observed. No dependence of
the rate constant values on the selected wavelengths was found, as ex-
pected for reactions in which good retention of isosbestic points is ob-
served. For runs at elevated pressure, a previously described pressurizing
system and high-pressure cell were used.[24b,46a] In these cases, the changes
in spectra with time were recorded with a J&M TIDAS instrument in the
full wavelength range. The general kinetic technique was previously de-
scribed.[13a,24c,28,46b] The solutions for the kinetic runs were prepared by
mixing the calculated amounts of palladium acetate and ligand solutions
in the solvent of choice to produce a 1:1 final concentration ratio. The
solutions also included any additional reactants in the calculated concen-
trations for the desired final reaction conditions. In all cases, no depend-
ence on the concentration of palladium [(2–5)ꢈ10À4 m range] was detect-
ed. Rate constants were derived from exponential least-square fitting by
the standard routines.[47] Table S1 (see the Supporting Information) sum-
marizes the obtained kobs values for the complexes studied as a function
of the starting complex, temperature and pressure. Least-square errors
for the rate constants were always in the 10–15% range of the calculated
value. All post-run fittings were done by standard commercially available
fitting programs.
AHCTUNGTRENNUNG
2
OCH2), 4.72 (d, JACHTUNGTRENNUNG(P,H)=17.9 Hz, 1H; CH), 6.81 (m, 1H; C6H4), 6.92 (m,
1H; C6H4), 7.15–7.75 ppm (m, 2H; C6H4); 31P{1H} NMR (161.97 MHz,
CDCl3): d=26.01 ppm; elemental analysis calcd (%) for C12H20NO4P: C
52.74, H 7.38, N 5.13; found: C 52.50, H 7.47, N 5.06.
ACHTUNGTRENNUNG{H2NC(H)[P(O)ACHTUNGTRENNUNG(OEt)2](2-EtOC6H4)} (9m): The synthesis of 9m was
carried out by following the same experimental procedure described for
8m, except that ethanol was used as solvent. Thus, 3m (100 mg,
0.13 mmol) was reacted with PhIACTHNUTRGNE(NUG OAc)2 (167.7 mg, 0.52 mmol) in ethanol
(10 mL) and with PPh3 (68.3 mg, 0.26 mmol) in CH2Cl2 (20 mL) to give
9m as a yellow oil. Yield: 8.6 mg (12% yield); 1H NMR (400.13 MHz,
[D6]acetone): d=1.08 (t, 3J(H,H)=7.0 Hz, 3H; CH3), 1.25 (t, 3J
ACTHNUGTRENNUGN ACHTUNGTRENNNUG
7.1 Hz, 3H; CH3), 1.36 (t, 3J
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
6.91 (m, 1H; C6H4), 7.25 (m, 1H; C6H4), 7.40 ppm (m, 1H; C6H4);
31P{1H} NMR (161.97 MHz, [D6]acetone): d=26.21 ppm; elemental anal-
ysis calcd (%) for C13H22NO4P: C 54.35, H 7.72, N 4.88; found: C 53.89,
H 7.65, N 4.90.
Diethyl (3-oxoisoindolin-1-yl)phosphonate (10m): A solution of cyclopal-
ladated complex 3m (100 mg, 0.13 mmol) in CH2Cl2 (20 mL) was stirred
under a CO atmosphere (1 atm) at RT for 24 h. During this time the de-
composition of the palladacycle was evident as black palladium appeared
and its amount increases along the reaction time. After 24 h, the resulting
black suspension was filtered through a Celite bed to remove Pd(0), and
the resulting pale-yellow solution was evaporated to dryness. Treatment
of the residue with n-hexane (20 mL) and continuous stirring gave 10m
as a white solid, which was filtered, washed with additional n-hexane
(10 mL) and dried by suction. Yield: 40.2 mg (58%). 1H NMR
Computational details: Calculations were carried out with the GAUSSI-
AN03 software package.[48] The hybrid density function method known as
B3LYP was applied.[49] Relativistic effective core potentials from the
Stuttgart-Dresden group were used to represent the innermost electrons
of the palladium atom and its basis set of valence double-z quality associ-
ated known as SDD.[50] The basis set for the light elements (C, N, O, and
H) was also double-z quality split-valence and includes polarization func-
tions in all atoms (known as 6–31 g(d)).[51] The geometries for minima
were fully optimized in all isomers and transition states were located to
connect two minima; these were confirmed by a vibrational analysis. En-
ergies in solution were taken into account by PCM calculations,[52] keep-
ing the geometry optimized for the gas phase (single-point calculations).
In solvent calculations, the basis set for atoms other than Pd were ex-
panded to the 6–311g+ +(d,p) triple-z basis sets. All energies reported
here are in units of kcalmolÀ1 and if not stated otherwise the energy re-
ferred to in the text are Gibbs energies in the gas phase. Gibbs energies
3
3
(400.13 MHz, CDCl3): d=1.08 (t, J
(H,H)=7.1 Hz, 3H; CH3), 3.78 (m, 1H; OCH2), 3.98 (m, 1H; OCH2),
4.12–4.23 (m, 2H; OCH2), 4.96 (d, 2J
(P,H)=13.6 Hz, 1H; CH), 6.91 (br.,
1H; NH), 7.54 (td, 3J(H,H)=7.5, 4J
(H,H)=1.3 Hz, 1H; C6H4), 7.62 (td,
3J(H,H)=7.6, 4J(H,H)=1.1 Hz, 1H; C6H4), 7.75 (dd, 3J(H,H)=7.6, 4J-
(H,H)=0.5 Hz, 1H; C6H4), 7.92 ppm (dd, 3J(H,H)=7.5, 4J
(H,H)=
0.5 Hz, 1H; C6H4, C6H4); 13C{1H} NMR (100.61 MHz, CDCl3): d=16.2
(d, 3J(C,P)=5.5 Hz; Me), 16.4 (d, 3J(C,P)=5.6 Hz; Me), 54.0 (d, 1J-
(C,P)=155.6 Hz; C-P), 63.4 (d, 2J(C,P)=7.3 Hz; CH2), 63.8 (d, 2J
(C,P)=
7.0 Hz; CH2), 124.2 (CH, C6H4), 124.3 (CH, C6H4), 129.0 (d, J(C,P)=
2.2 Hz, CH; C6H4), 131.7 (d, J(C,P)=4.7 Hz; C, C6H4), 132.2 (d, J(C,P)=
2.5 Hz; CH, C6H4), 140.0 (d, 2J
ACHTUNGRTEN(NGNU H,H)=7.1 Hz, 3H; CH3), 1.29 (t, J-
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
BS1
in solution were computed as DGsol =DEsolvBS2 +(DGgas ÀDEgasBS1).
A
ACHTUNGTRENNUNG
BS2
AHCTUNTGREN(NGUN C,P)=6.6 Hz; C, C6H4), 170.6 ppm (s;
Where DEsolv is the solution potential energy, being the sum of the po-
CO); 31P{1H} NMR (161.97 MHz, CDCl3): d=18.07 ppm; IR: n˜ =3195
(nNÀH), 1694 (nC O), 1252 cmÀ1 (nP O); MS (ESI+): m/z (%): 269.9 (90)
tential energy of the solute and the Gibbs energy of the solvent. All DFT
calculation data for the coordinates and absolute energies are available
in tabular format (Tables S2–S3) and electronic files included in the Sup-
porting Information.
=
=
[M+H]+; HRMS (ESI-TOF) m/z: calcd for C12H16NNaO4P 292.0709
[M+Na]+; found: 292.0722.
17410
www.chemeurj.org
ꢆ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 17398 – 17412

Cyclopalladation of Amino Esters
FULL PAPER
J. E. Chaves, R. Navarro, E. P. Urriolabeitia, Inorg. Chem. 2003, 42,
1006; see also ref. [13a,b].
Acknowledgements
[9] See, for instance, the collection: Amino Acids, Peptides and Proteins
in Organic Chemistry, Vol. 1–5, (Ed.: A. B. Hughes), Wiley-VCH,
Weinheim, 2009–2012.
Funding by the Ministerio de Ciencia e Innovaciꢃn (MICINN) and the
Ministerio de Economia y Competitividad (MINECO) (Spain, Projects
CTQ2011–22589, CTQ2010–17436 and CTQ2012–37821-C02–01) and the
Gobierno de Aragꢃn (Spain, groups E40 and E97) is gratefully acknowl-
edged. E. L. thanks Gobierno de Aragꢃn (Spain) for a PhD grant. The
authors thanks the computational facilities provided by Centro de Super-
computaciꢃn de Galicia (CESGA, Spain) and also by the CSIC (Spain)
(Cluster Trueno).
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Received: July 10, 2013
Published online: November 13, 2013
17412
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ꢆ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 17398 – 17412