Ortho palladation and functionalization of L-phenylalanine methyl ester

Article abstract of DOI:10.1021/om070127y

The ortho-metalated complex (S,S)-[Pd₂{κ₂(C,N)- C₆H₄CH₂CH(CO₂Me)NH ₂-2}₂(μ-Br)₂] (1b) can be prepared by refluxing in acetonitrile equimolecular amounts of Pd(OAc)₂ and L-phenylalanine methyl ester hydrochloride, followed by addition of an excess of NaBr. Complex 1b reacts with 4-picoline to give the mononuclear derivative (S)-[Pd{κ₂(CN)-C₆H₄CH ₂CH(CO₂Me)NH₂-2}₂Br(NC ₅H₄Me-4)] (2), whose crystal structure has been determined by X-ray diffraction. The precursor of 1b, (S,S)- [Pd₂{κ₂-(C,N)-C₆H₄CH ₂CH(CO₂Me)NH₂-2}₂(μ-Cl) ₂] (1a), could not be isolated in a pure form, but it can be used as the starting material for the synthesis of functionalized derivatives of the phenylalanine methyl ester. Thus, CO and RNC (R = Xy, ^tBu) insert into the Pd-C bond of 1a to afford, after depalladation, (S)-1-oxo-3- (methoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline (3) and (S)-l-R-3- (methoxycarbonyl)-3,4-dihydroisoquinolinium triflate (R = ^tBu (4), Xy (5)), respectively. Reaction of complex 1b with bromine or iodine affords trans-(S,S)-[PdBr₂{NH₂CH(CO₂Me)CH ₂C₆H₄-X-2}₂] (X = Br (6), I (7)), which further reacts with 1, 10-phenanthroline (phen) to give [PdBr ₂(phen)] and (S)-2-X-phenylalanine methyl ester (X = Br (8). I (9)).

Full text of DOI:10.1021/om070127y

2
768
Organometallics 2007, 26, 2768-2776
Ortho Palladation and Functionalization of L-Phenylalanine
†
Methyl Ester
Jos e´ Vicente,* Isabel Saura-Llamas,* Jos e´ -Antonio Garc ´ı a-L o´ pez, and
Beatrice Calmuschi-Cula
Grupo de Qu ´ı mica Organomet a´ lica, Departamento de Qu ´ı mica Inorg a´ nica, Facultad de Qu ´ı mica,
UniVersidad de Murcia, Apartado 4021, E-30071 Murcia, Spain
Delia Bautista
SAI, UniVersidad de Murcia, Apartado 4021, E-30071 Murcia, Spain
ReceiVed February 8, 2007
2
The ortho-metalated complex (S,S)-[Pd
2
{κ (C,N)-C
6
H
4
CH
2
CH(CO
2
Me)NH
and L-phenylalanine methyl
ester hydrochloride, followed by addition of an excess of NaBr. Complex 1b reacts with 4-picoline to
2
-2}
2
2
(µ-Br) ] (1b) can be
prepared by refluxing in acetonitrile equimolecular amounts of Pd(OAc)
2
2
give the mononuclear derivative (S)-[Pd{κ (C,N)-C
whose crystal structure has been determined by X-ray diffraction. The precursor of 1b, (S,S)-[Pd
C,N)-C CH CH(CO Me)NH -2} ] (1a), could not be isolated in a pure form, but it can be
used as the starting material for the synthesis of functionalized derivatives of the phenylalanine methyl
ester. Thus, CO and RNC (R ) Xy, Bu) insert into the Pd-C bond of 1a to afford, after depalladation,
S)-1-oxo-3-(methoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline (3) and (S)-1-R-3-(methoxycarbonyl)-3,4-
dihydroisoquinolinium triflate (R ) Bu (4), Xy (5)), respectively. Reaction of complex 1b with bromine
or iodine affords trans-(S,S)-[PdBr {NH CH(CO Me)CH -X-2}
reacts with 1,10-phenanthroline (phen) to give [PdBr
Br (8), I (9)).
6 4 2 2 2 2 5 4
H CH CH(CO Me)NH -2} Br(NC H Me-4)] (2),
2
2
{κ -
(
6
H
4
2
2
2
2
(µ-Cl)
2
t
(
t
2
2
2
2
C
6
H
4
2
] (X ) Br (6), I (7)), which further
2
(phen)] and (S)-2-X-phenylalanine methyl ester (X
)
Introduction
Ortho palladation of (S)-phenylalanine (L-phenylalanine)
Ortho-palladated (S)-phenylalanine complexes are interesting
for at least three reasons. First of all, palladium complexes
1
5-17
containing amino acids as ligands
complexes
as well as cyclopalladated
raises an interesting problem. If the free amino acid is used,
N,O-chelates involving the deprotonated carboxyl group may
1
7,18
have attracted great interest because their po-
1
2
tential cytotoxic activity. Second, they can be useful precursors
to prepare functionalized derivatives of L-phenylalanine, since
be formed, as has been described for other amino acids. For
instance, 4-iodo-L-phenylalanine reacts with [PdCl2(PEt3)]2 to
2
complexes containing cyclopalladated amines have found
give the N,O-chelate complex (S)-[Pd{κ (N,O)-NH2CH(CH2-
C6H4I-4)CO2}Cl(PEt3)]. The carboxylate groups of amino acids
3
19-21
widespread application in organic synthesis.
Among the
can be prevented from coordinating to the metal by using ester
possible derivatives, the ortho-halogenated amino acids are
particularly interesting, as they are not easily prepared by other
methods, such as direct electrophilic substitution, and, in
addition, they can be used for preparing other amino acids
through palladium-catalyzed reactions. Barluenga et al. have
recently reported a regioselective method to prepare ortho-
4,5
derivatives. Still, a second problem remains: ortho metalation
of primary amines has been reported to be difficult, especially
6
if the metallacycle to be formed is a six-membered ring. This
7
second issue has been avoided by using functionalized or
N-substituted4 amino groups. However, ortho metalation of
primary amines is difficult, but it can be carried out if
appropriate experimental conditions are used.9
,8
22
iodinated phenylalanine-containing peptide sequences, but the
-14
†
Dedicated to Prof. Miguel Yus on the occasion of his 60th birthday.
(9) Vicente, J.; Saura-Llamas, I.; Jones, P. G. J. Chem. Soc., Dalton
Trans. 1993, 3619.
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A. D. Inorg. Chim. Acta 2002, 340, 192.
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de Arellano, M. C. Organometallics 1997, 16, 826.
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8, 991.
*
To whom correspondence should be addressed. E-mail: jvs1@um.es
J.V.); ims@um.es (I.S.-L.). Web: http://www.um.es/gqo/.
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(
(
(
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(
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M. C. Organometallics 2003, 22, 5513.
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(
(
(
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(
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5
1
0.1021/om070127y CCC: $37.00 © 2007 American Chemical Society
Publication on Web 04/06/2007

L-Phenylalanine Methyl Ester
Organometallics, Vol. 26, No. 10, 2007 2769
method cannot be applied to the methyl ester of the amino acid.23
Finally, optically active palladacycles are suitable auxiliary
reagents for the resolution of racemic mixtures and determina-
tion of enantiomeric purity and absolute configuration of chiral
Scheme 1
phosphines,1
2,24
amino acids, and other ligands.
25
26
Fuchita et al. reported the cyclopalladation of (R)-2-phenyl-
glycine methyl ester, an amino acid derivative with an unpro-
tected amino group which gives a five-membered palladacycle,
by reacting palladium acetate with the hydrochloride salt of the
amino acid ester in acetone.27 Nevertheless, the same reaction
conditions were reported to fail when trying to prepare the
analogous compound containing (S)-phenylalanine methyl ester,
our target complex in this article.
Insertion of CO into the Pd-C bond of ortho-palladated
tertiary amines has been widely investigated,8
,19,28-30
whereas
the same reaction with primary benzylamines has been only
superficially examined. Thus, a preliminary communication by
Parkins et al. in 1984 described the reaction of [Pd(κ (C,N)-
C6H4CH2NH2-2)I]2 with CO in methanol at room temperature
to give phthalimidine and palladium metal, although experi-
mental procedures and the yield were not stated.31 Dyke et al.
in 1986 observed a similar reaction using chloroform or benzene
as solvent, although the expected phthalimidine was not obtained
pure.32 We report here that (S)-1-oxo-3-(methoxycarbonyl)-
antiallergic agent, to prevent the physical manifestation of atopic
allergic reactions. Recently, a convenient large-scale synthesis
36
2
of the R enantiomer has been reported, using the amino acid
37
methyl ester and triphosgene as starting materials.
The reaction of five-membered cyclopalladated benzylamines
and isocyanides allows the isolation of the corresponding
31,38
isoindolinium salts.
Here we report that the six-membered
cyclopalladated (S)-phenylalanine methyl ester allows the
synthesis of tetrahydroisoquinolines.
1,2,3,4-tetrahydroisoquinoline can be obtained by carbonylation
of ortho-palladated (S)-phenylalanine methyl ester. This is a
particularly interesting compound,33 as it has been extensively
used to study the steric course and stereospecificity of R-chy-
Results and Discussion
Synthesis and Structure of Ortho-Metalated Complexes.
motrypsin-catalyzed reactions.3
4,35
It has also been used as an
When (S)-PhCH CH(CO Me)NH ‚HCl (L-phenylalanine hy-
2
2
2
drochloride) is reacted with Pd(OAc)2 in a 1:1 molar ratio in
1
(
18) Higgins, J. D.; Neely, L.; Fricker, S. J. Inorg. Biochem. 1993, 49,
acetonitrile for 6 days, the orange solid A is isolated, whose H
1
49. Navarro-Ranninger, C.; Lopez-Solera, I.; Perez, J. M.; Rodriguez, J.;
NMR shows very broad signals that cannot be easily assigned.
Nevertheless, in the aromatic region of the spectrum, there are
signals corresponding to the ortho-metalated and the non-ortho-
metalated aryl ring of the starting amino acid derivative. There
are also two signals in the region corresponding to the OMe
groups, whose relative integrals indicate an average molar ratio
of 1:0.3. On the other hand, no acetate signals are present. The
components of the mixture cannot be separated by fractional
crystallization or by chromatography, although its reactivity
Garcia-Ruano, J. L.; Raithby, P. R.; Masaguer, J. R.; Alonso, C. J. Med.
Chem. 1993, 36, 3795. Navarro-Ranninger, C.; L o´ pez-Solera, I.; Gonz a´ lez,
V. M.; P e´ rez, J. M.; Alvarez-Vald e´ s, A.; Mart ´ı n, A.; Raithby, P.; Masaguer,
J. R.; Alonso, C. Inorg. Chem. 1996, 35, 5181. Riera, X.; Caubet, A.; Lopez,
C.; Moreno, V. Polyhedron 1999, 18, 2549. Tusek-Bozic, L.; Komac, M.;
Curic, M.; Lycka, A.; D’Alpaos, M.; Scarcia, V.; Furlani, A. Polyhedron
2
000, 19, 937. Rodrigues, E. G.; Silva, L. S.; Fausto, D. M.; Hayashi, M.
S.; Dreher, S.; Santos, E. L.; Pesquero, J. B.; Travassos, L. R.; Caires, A.
C. F. Int. J. Cancer 2003, 107, 498. Quiroga, A. G.; Navarro-Ranninger,
C. Coord. Chem. ReV. 2004, 248, 119. Bincoletto, C. Bioorg. Med. Chem.
2
005, 13, 3047.
2
(19) Ryabov, A. D. Synthesis 1985, 233. Omae, I. Coord. Chem. ReV.
shows that the ortho-metalated complex (S,S)-[Pd2{κ (C,N)-
2
004, 248, 995.
C6H4CH2CH(CO2Me)NH2-2}2(µ-Cl)2] (1a) is the main com-
ponent (Scheme 1). Thus, this mixture A can be used as the
starting material to synthesize in good yields some derivatives
of 1a.
Other reaction conditions (solvent, temperature, time) were
tested to prepare 1a: (i) acetonitrile at 80 °C for 4-8 h; (ii)
toluene at 60 or 75 °C for 12 h; (iii) acetic acid at 60 °C for 24
h. In all cases, decomposition to Pd(0) took place and the
(
(
(
20) Pfeffer, M. Pure Appl. Chem. 1992, 64, 335.
21) Dupont, J.; Consorti, C. S.; Spencer, J. Chem. ReV. 2005, 105, 2527.
22) Espu n˜ a, G.; Arsequell, G.; Valencia, G.; Barluenga, J.; Alvarez-
Guti e´ rrez, J.; Ballesteros, A.; Gonz a´ lez, J. M. Angew. Chem., Int. Ed. 2004,
3, 325.
23) Barluenga, J.; Garc ´ı a-Mart ´ı n, M. A.; Gonz a´ lez, J. M.; Clap e´ s, P.;
Valencia, G. J. Chem. Soc., Chem. Commun. 1996, 1505.
24) Wild, S. B. Coord. Chem. ReV. 1997, 166, 291. Camus, J.-M.; Roy-
Garc ´ı a, P.; Andrieu, J.; Richard, P.; Poli, R. J. Organomet. Chem. 2005,
4
(
(
6
6
90, 1659. Albert, J.; Granell, J.; Muller, G. J. Organomet. Chem. 2006,
91, 2101.
(
1
mixture obtained was not as rich in 1a (tested by H NMR) as
in A. However, we succeeded in isolating the pure bromo-
bridged dinuclear ortho-metalated complex (S,S)-[Pd2{κ (C,N)-
25) B o¨ hm, A.; Hauck, T.; Beck, W. Z. Naturforsch. 1999, 54b, 1360.
B o¨ hm, A.; Seebach, D. HelV. Chim. Acta 2000, 83, 3262.
26) Kurita, J.; Usuda, F.; Yasuike, S.; Tsuchiya, T.; Tsuda, Y.; Kiuchi,
2
(
C6H4CH2CH(CO2Me)NH2-2}2(µ-Br)2] (1b), by reacting the
mixture A with NaBr and recrystallizing the crude product.
4-Picoline (pic) splits the bromide bridges in complex 1b to
F.; Hosoi, S. Chem. Commun. 2000, 191. Okajima, S.; Yasuike, S.;
Kakusawa, N.; Osada, A.; Yamaguchi, K.; Seki, H.; Kurita, J. J. Organomet.
Chem. 2002, 656, 234.
(27) Fuchita, Y.; Yoshinaga, K.; Ikeda, Y.; Kinoshita-Kawashima, J. J.
2
give the mononuclear complex (S)-[Pd{κ (C,N)-C6H4CH2CH-
Chem. Soc., Dalton Trans. 1997, 2495.
(
CO2Me)NH2-2}2Br(pic)] (2). Of the two possible isomers for
(
(
28) Thompson, J. M.; Heck, R. F. J. Org. Chem. 1975, 40, 2667.
29) Dupont, J.; Pffefer, M.; Daran, J. C.; Jeannin, Y. Organometallics
1
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984, 1165.
32) Barr, N.; Bartley, J. P.; Clark, P. W.; Dunstan, P.; Dyke, S. F. J.
Organomet. Chem. 1986, 302, 117.
33) Michel, A. G.; Walnier, A.; Durant, F. Acta Crystallogr. 1976, B32,
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G.; Bautista, D. Organometallics 2002, 21, 3587.
(
(
1
(
(
3

2770 Organometallics, Vol. 26, No. 10, 2007
Vicente et al.
Figure 1. Thermal ellipsoid plot (50% probability) of 2 along with
the labeling scheme. Selected bond lengths (Å) and angles (deg):
Pd(1)-Br(1) ) 2.5458(6), Pd(1)-N(1) ) 2.066(4), Pd(1)-C(1)
Figure 2. View of the hydrogen bond interactions along the b
axis in complex 2. Only Pd and atoms involved in the H bonding
are labeled. Details (including symmetry operators) are given in
the Supporting Information.
)
1.999(5), Pd(1)-N(2) ) 2.054(4); Br(1)-Pd(1)-N(1) )
85.39(12), N(1)-Pd(1)-C(1) ) 92.19(18), C(1)-Pd(1)-N(2) )
0.22(17), N(2)-Pd(1)-Br(1) ) 92.81(11).
9
complex 2, only the one with the two nitrogen atoms in mutually
1
13
trans positions is obtained, as proved by H and C NMR and
X-ray diffraction studies. This is the normal behavior for
2
1,39
benzylamine palladacycles,
although a notable exception has
40
recently been reported.
1
13
The H and C NMR spectra of complexes 1b and 2 are in
agreement with the proposed structures. The H NMR spectrum
1
of complex 1b shows a set of three different signals, corre-
sponding to the four remaining protons in the ortho-metalated
ring: H3 (see numbering scheme in the Experimental Section)
as a doublet at 7.38 ppm, H5 as a triplet at 6.88 ppm, and H4
and H6 as a multiplet between 6.76-6.82 ppm. A similar pattern
1
is observed in the H NMR spectrum of the mononuclear
Figure 3. View of the hydrogen bond interaction between aromatic
hydrogen and bromine atoms in complex 2. Only Pd and atoms
involved in the H bonding are labeled. Details (including symmetry
operators) are given in the Supporting Information.
complex 2, although in this case H3 is significantly shifted to
lower frequencies (∆δ ) -0.92 ppm) due to the anisotropic
shielding from the picoline ring.41 In the 13C NMR spectra of
complexes 1b and 2, the resonances due to the carbon atoms
bonded to Pd (140.8 ppm, 1b; 147.4 ppm, 2) are deshielded
with respect to that of the corresponding free ligand (129.3 ppm
in DMSO-d6), as observed in other cyclopalladated com-
Each molecule of complex 2 is connected to four other
molecules through hydrogen bonds, giving a three-dimensional
network. Along the b axis, two adjacent molecules (A and C;
Figure 2) are associated through a double interaction between
the bromine atom of molecule C and one hydrogen of the methyl
group of molecule A (Br1C‚‚‚H10A-C10A) and between one
hydrogen of the amino group of molecule C and the oxygen
atom of the carbonyl group of molecule A (N1C-H01C‚‚‚O2A).
In addition, the same bromine atom is associated with two
aromatic picoline hydrogens, each belonging to other two
different molecules (Figure 3).
plexes.13,14,42
The crystal structure of complex 2 (Figure 1) shows the pal-
ladium atom in a distorted-square-planar environment (mean
deviation of the plane 0.09 Å) with a dihedral angle of 8.3°
between the N(1)-Pd(1)-C(1) and N(2)-Pd(1)-Br(1) planes.
The chelated amino acid ligand forms a six-membered metal-
lacycle with a boat conformation. These features are similar to
those of analogous complexes containing other phenethylamine
11,13
derivatives.
The nitrogen atom of the amine and the nitrogen
Reaction with Carbon Monoxide. Synthesis of (S)-1-Oxo-
3-(methoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline (3). As
stated in the Introduction, two previous works described the
atom of 4-picoline are mutually trans, and the pyridine ring is
rotated 65.3° with respect to the phenyl ring to avoid steric
hindrance.
2
reaction of [Pd(κ (C,N)-C H CH NH -2)I] with CO to give
6
4
2
2
2
phthalimidine and palladium metal, although the experimental
procedures and the yield were not stated in the first work3 and
1
(
39) Ryabov, A. D.; Kuz’mina, L. G.; Polyakov, V. A.; Kazankov, G.
M.; Ryabova, E. S.; Pfeffer, M.; van Eldik, R. J. Chem. Soc., Dalton Trans.
32
the phthalimidine was not obtained pure in the other. The
1
995, 999. Calmuschi, B.; Englert, E. CrystEngComm 2005, 7, 171.
40) Calmuschi-Cula, B.; Kalf, I.; Wang, R.; Englert, E. Organometallics
005, 24, 5491.
41) Deeming, J. A.; Rothwell, I. A.; Hursthouse, M. B.; New, L. J.
Chem. Soc., Dalton Trans. 1978, 1490.
42) Martinez-Viviente, E.; Pregosin, P. S.; Tschoerner, M. Magn. Reson.
Chem. 2000, 38, 23.
reaction of the mixture A with CO in CHCl3 at room temperature
has allowed us to prepare (S)-1-oxo-3-(methoxycarbonyl)-
,2,3,4-tetrahydroisoquinoline (3) (Scheme 2). The good isolated
yield (64% from phenylalanine methyl ester hydrochloride) also
proves that A is mainly the ortho-metalated complex 1a.
(
2
(
1
(

L-Phenylalanine Methyl Ester
Scheme 2. Synthesis of (S)-1-Oxo-3-(methoxy-
Organometallics, Vol. 26, No. 10, 2007 2771
Scheme 3
carbonyl)-1,2,3,4-tetrahydroisoquinoline (3)
The reaction conditions used to prepared the tetrahydroiso-
quinoline derivative 3 are milder than those used in analogous
reactions to prepare 2-methylphthalimidine from ortho-palla-
dated N,N-dimethylbenzylamine (xylene, 100 °C, and 1 atm of
28
CO pressure or CH2Cl2, room temperature, and 2 atm of CO
Scheme 4. Proposed Reaction Pathway for the Synthesis of
2
9
pressure ) but similar to those used to prepare 2-methyl-3-
carboxymethyl)phthalimidine from ortho-palladated N,N-di-
4
and 5
(
8
methylphenylglycine, although in the latter, a nitrogen atmo-
sphere was used. As mentioned in the Introduction, 3 has been
used to study the steric course and stereospecificity of R-chy-
motrypsin-catalyzed reactions3 and as an antiallergic agent,
to prevent the physical manifestation of atopic allergic reac-
4,35
3
6
tions. Compound 3 has been synthesized mostly by cyclation
of N-acyl-â-arylethylamines, through procedures that involve
some drastic reaction conditions or moisture-sensitive cata-
3
4,43
lysts.
Recently, a convenient large-scale synthesis of the R
enantiomer has been reported, using the amino acid methyl ester
and triphosgene as starting materials.37
Orito et al. have reported a Pd(II)-catalyzed carbonylation
of N-alkyl-ω-arylalkylamines to afford five- or six-membered
4
4
benzolactams. Under these conditions, carbonylation of pri-
mary amines does not produce benzolactams but ureas. The key
step in these reactions seems to be the metalation of the amine.
This result is not surprising, since ortho metalation of primary
amines does not occur under the reaction conditions used when
an excess of amine is present.45 Our method, although not
catalytic, allows the synthesis of a benzolactam from a primary
amine and CO.
derivative is the coordination of the isocyanide to the ortho-
metalated fragment to give the adduct B, followed by insertion
into the Pd-C bond to give the iminoacyl complex C (Scheme
4). There are some examples of such dimeric bridging iminoacyl
29,47
palladium complexes.
The instability of this triflato deriva-
tive and the strain of the seven-membered ring can explain its
decomposition and the formation of palladium(0) and the salt
Reactions with Isocyanides. Synthesis and Structure of
(
S)-1-R-3-(methoxycarbonyl)-3,4-dihydroisoquinolinium Tri-
4
or 5.
t
flate (R ) Bu (4), 2,6-Me2C6H3 (Xy) (5)). It has been reported
that the reaction of cyclopalladated benzyl-
amines and isocyanides in refluxing toluene allows the isolation
These reactions can be performed without thallium triflate,
but the yields are lower. In addition, a mixture of the chloride
1
salts and the free bases are obtained (tested by H NMR).
of the corresponding isoindolinium salts.3
1,38
The present
Recently, Saluste et al. have reported the palladium-catalyzed
synthesis of cyclic amidines, starting from 2-bromobenzylamine
availability of cyclopalladated phenethyl amines prompted us
to extend this work to the synthesis of six-membered N-
t
48
or 2-bromophenethylamine, BuNC, and Cs2CO3. Nevertheless,
it is necessary to point out the restricted availability of
heterocycles. Thus, the mixture A was treated with isocyanide
t
(
RNC, R ) Bu, Xy) and thallium(I) triflate (1:2:2). After TlCl
2
-halobenzylamines and the limitations of the process, which
was removed, the resulting solution was refluxed in toluene for
h, upon which time formation of Pd(0) was observed. From
the mother liquors, the tetrahydroisoquinoline derivatives 4 and
seems to give only good yields for tert-alkyl isocyanides.
7
1
13
The H and C NMR spectra of compounds 4 and 5 are in
agreement with the proposed structures. Additionally, the crystal
structures of both compounds have been determined by X-ray
diffraction (Figures 4 and 5). The similar N-C bond distances
in the groups N(2)-C(9)-N(1) (N(2)-C(9) ) 1.3215(18) Å,
C(9)-N(1) ) 1.3248(18) Å) (4) and N(1)-C(17)-N(2) (N(1)-
C(17) ) 1.318(3) Å, C(17)-N(2) ) 1.312(3) Å) (5) and the
significantly longer distances of N(1) and N(2) with their other
neighbors (N(2)-C(10) ) 1.4990(17) Å, N(1)-C(8) ) 1.4625-
5
could be isolated (Scheme 3).
According to previous studies,8
,38,46
it is reasonable to assume
that the first step in the formation of the tetrahydroisoquinoline
(43) Janin, Y. L.; Roulland, E.; Beurdeley-Thomas, A.; Decaudin, D.;
Monneret, C.; Poupon, M.-F. J. Chem. Soc., Perkin Trans. 1 2002, 529.
Tsuda, Y.; Isobe, K.; Toda, J.; Taga, J. Heterocycles 1976, 5, 157.
Krogsgaard-Larsen, P.; Nielsen, E. O.; Curtis, D. R. J. Med. Chem. 1984,
2
7, 585.
44) Orito, K.; Horibata, A.; Nakamura, T.; Ushito, H.; Nagasaki, H.;
Yuguchi, M.; Yamashita, S.; Tokuda, M. J. Am. Chem. Soc. 2004, 126,
4342. Orito, K.; Miyazawa, M.; Nakamura, T.; Horibata, A.; Ushito, H.;
(
(47) Us o´ n, R.; Forni e´ s, J.; Espinet, P.; Lalinde, E.; Jones, P. G.; Sheldrick,
G. M. J. Chem. Soc., Dalton Trans. 1982, 2389. Us o´ n, R.; Forni e´ s, J.;
Espinet, P.; Lalinde, E.; Jones, P. G.; Sheldrick, G. M. J. Organomet. Chem.
1983, 253, C47. Us o´ n, R.; Forni e´ s, J.; Espinet, P.; Garcia, A.; Tomas, M.;
Foces-Foces, C.; Cano, F. H. J. Organomet. Chem. 1985, 282, C35.
Zografidis, A.; Polborn, K.; Beck, W.; Markies, B. A.; van Koten, G. Z.
Naturforsch. 1994, B49, 1494.
1
Nagasaki, H.; Yuguchi, M.; Yamashita, S.; Yamazaki, H.; Tokuda, M. J.
Org. Chem. 2006, 71, 5951.
(
45) Fuchita, Y.; Yoshinaga, K.; Hanaki, T.; Kawano, H.; Kinoshita-
Nagaoka, J. J. Organomet. Chem. 1999, 580, 273.
46) Yamamoto, Y.; Yamazaki, H. Synthesis 1976, 750. Yamamoto, Y.;
(
Yamazaki, H. Inorg. Chim. Acta 1980, 41, 229. Dupont, J.; Pfeffer, M. J.
Chem. Soc., Dalton Trans. 1990, 3193.
(48) Saluste, C. G.; Crumpler, S.; Furber, M.; Whitby, R. J. Tetrahedron
Lett. 2004, 45, 6995.

2772 Organometallics, Vol. 26, No. 10, 2007
Vicente et al.
Figure 4. Thermal ellipsoid plot (50% probability) of the cation
of 4 along with the labeling scheme. Selected bond lengths (Å)
and angles (deg): N(2)-C(10) ) 1.4990(17), N(2)-C(9) )
Figure 6. View of the hydrogen bond interaction between aromatic
hydrogen and oxygen atoms of the CdO group in complex 5. Only
atoms involved in the H bonding are labeled. Details (including
symmetry operators) are given in the Supporting Information.
1
.3215(18), N(1)-C(9) ) 1.3248(18), N(1)-C(8) ) 1.4625(16),
C(2)-C(9) ) 1.4809(18); C(9)-N(2)-C(10) ) 129.35(12), C(9)-
N(1)-C(8) ) 122.87(12), N(1)-C(9)-N(2) ) 121.78(13), N(1)-
C(9)-C(2) ) 118.46(12), N(2)-C(9)-C(2) ) 119.75(12).
compound 5, there is also a hydrogen bond between the oxygen
atom of the CdO group and one aromatic hydrogen of the
phenyl ring (O1A‚‚‚H15D-C15D). This interaction leads to
zigzag chains along the b axis (see Figure 6).
Synthesis and Structure of 2-Halo Derivatives. Stoichio-
metric aromatic halogenation of tertiary amines through cyclo-
1
9,49,50
palladated complexes is a known process.
However, the
extension to the corresponding primary amines has only very
14
recently been reported by us. The reaction of complex 1b with
Br2 or I2, in CH2Cl2 at room temperature, afforded trans-
[PdBr2{NH2CH(CO2Me)Me2CH2C6H4X-2}2] (X ) Br (6), I (7))
in good yields (Scheme 5). We have proposed that the initial
step of the reaction is the oxidative addition of iodine or bromine
1
4
to give a Pd(IV) complex (see D in Scheme 5). This complex
would then undergo a reductive elimination, to give E, followed
by a symmetrization process, leading to 6 or 7 and PdX2. A
Pd(II) complex similar to the proposed intermediate E has been
50
reported by Espinet et al. Pure palladium bromide or palladium
iodide was quantitatively isolated from the reaction mixture by
filtration, as a dark brown solid. It is interesting to note that,
when I2 is used as an oxidative agent, only PdI2 and the dibromo
complex 7 are formed. These solids were then reacted with PPh3
Figure 5. Thermal ellipsoid plot (50% probability) of the cation
of 5 along with the labeling scheme. Selected bond lengths (Å)
and angles (deg): N(1)-C(1) ) 1.443(3), N(1)-C(17) ) 1.318(3),
N(2)-C(17) ) 1.312(3), N(2)-C(18) ) 1.457(3), C(17)-C(18)
(
1:2) to give [PdBr2(PPh3)2] or [PdI2(PPh3)2], which were
)
)
)
1.479(3); C(1)-N(1)-C(17) ) 124.45(19), C(17)-N(2)-C(18)
122.54(19), N(2)-C(17)-N(1) ) 120.8(2), N(2)-C(17)-C(11)
119.22(19), N(1)-C(17)-C(11) ) 120.00(19).
31
characterized by P NMR.
S)-2-Bromophenylalanine methyl ester (8) and (S)-2-io-
(
dophenylalanine methyl ester (9) were conveniently prepared
by reacting the corresponding precursor (6 or 7) with 1,10-
phenanthroline (phen). The iodo derivatives 7 and 8 decompose
slowly at room temperature. The byproduct in these reactions,
(16) Å (4); N(1)-C(1) ) 1.443(3) Å, N(2)-C(18) ) 1.457(3)
Å (5)) suggest that a delocalization of electron density occurs
among the atoms N(2), C(9), and N(1) in 4 and N(1), C(17),
and N(2) in 5. Additionally, the angles C(9)-N(2)-C(10)
[
PdBr2(phen)], precipitates from the reaction mixtures and can
be easily separated from the final amines by filtration (Scheme
). Curiously, an analogous complex, [PdCl2(phen)], has been
(
129.35(12)°) in 4 and C(17)-N(1)-C(1) (124.45(19)°) in 5
5
3
are far from the sp hybridization for N(2) and N(1), respec-
tively, if a lone pair were assumed on these atoms. The atoms
C(8), N(1), C(9), C(2), N(2), and C(10) in 4 and C(18), N(2),
C(17), C(11), N(1), and C(1) in 5 are coplanar (mean deviations
from the plane 0.0459 and 0.0417 Å, respectively).
reacted with various amino acids in the presence of a base to
prepare palladium(II) N,O-chelated amino acidato complexes
16
with cytotoxic activity.
(49) Onishi, M.; Hiraki, K.; Iwamoto, A. J. Organomet. Chem. 1984,
262, C11. Dunina, V. V.; Gorunova, O. N.; Grishin, Y. K.; Kuz’mina, L.
G.; Churakov, A. V.; Kuchin, A. V.; Howard, J. A. K. Russ. Chem. Bull.
In both compounds, the cationic units are connected to the
triflate groups through hydrogen bonds (nine interactions with
three different triflates for compound 4 and six interactions with
three different triflates for compound 5). In the cation of
2
005, 54, 2073.
50) Bartolome, C.; Espinet, P.; Mart ´ı n- AÄ lvarez, J. M.; Villafa n˜ e, F.
Inorg. Chim. Acta 2003, 347, 49.
(

L-Phenylalanine Methyl Ester
Organometallics, Vol. 26, No. 10, 2007 2773
Scheme 5. Proposed Reaction Pathway for the Synthesis of
Chart 1. Numbering Scheme for Complex 1b and
Tetrahydroisoquinoline Derivatives
2-Halo Derivatives of Phenylalanine Methyl Esters 8 and 9
and palladium acetate (Johnson Matthey) were used as received.
TlOTf (TlSO
3
CF
3
) was prepared by reaction of Tl
2 3
CO and HSO
3
-
CF (1:2) in water and recrystallized from acetone/Et
3
2
O.
Caution! Special precautions should be taken in handling
thallium(I) compounds because of their toxicity.
2
Synthesis of (S,S)-[Pd
(µ-Br)
g, 4.64 mmol) was added to a solution of Pd(OAc)
2
{κ (C,N)-C
6
H
4
CH
2
CH(CO
2
Me)NH
2
-
2}
2
2
] (1b). L-Phenylalanine methyl ester hydrochloride (1.00
(1.04 g, 4.64
2
mmol) in acetonitrile (60 mL), and the resulting solution was stirred
at room temperature for 6 days. A small amount of metallic
palladium was formed. The mixture was filtered through a plug of
MgSO
dissolved in CH
precipitate an orange solid which was filtered, washed with Et
4
, the filtrate was concentrated to dryness, the residue was
2
Cl (5 mL), and Et O (30 mL) was added to
2
2
2
O
3
1
(2 × 2 mL), and air-dried (1.26 g). H NMR of this solid in CDCl
shows very broad peaks, difficult to assign, but the analysis of the
aromatic region indicates a 1:0.35 mixture of the ortho-metalated
Substitution of the Pd atom by bromine or iodine was
confirmed by C NMR spectroscopy. The resonance due to
the aromatic carbon atom bonded to Br or I (δ 124.7 (8), 100.8
9)) is shifted to lower frequency with respect to the corre-
2
1
3
complex [Pd {κ (C,N)-C H CH CH(CO Me)NH -2} (µ-Cl) ] and
2
6
4
2
2
2
2
2
other non-ortho-metalated species such as [Pd
2
2
(µ-Cl)Cl{NH CH-
(
CO Me)CH Ph} ] and [Pd Cl {NH CH(CO Me)CH
2
2
2
2
2
2
2
2
Ph} ]. This
2
(
mixture A could not be separated, either by fractional crystallization
or by chromatography. To a solution of mixture A (950 mg) in
acetone (50 mL) was added NaBr (1.5 g, 19.4 mmol). The reaction
mixture was stirred for 12 h, and acetone was evaporated. The
sponding signals in the cyclometalated complex 1b (δ 140.8)
and in the free ligand (δ 129.3, DMSO-d6). This is a well-known
5
1
1
effect. In addition, the H NMR spectra of the 2-halo amino
acid methyl esters 8 and 9 showed the signals corresponding to
the NH2 groups shifted to lower frequency with respect to those
of 6 and 7, as expected upon palladium decoordination.
residue was taken up in CH
through a plug of MgSO , the filtrate was concentrated to dryness,
and Et O (30 mL) was added. The orange solid obtained was
filtered, washed with Et
2 2
Cl (30 mL), the suspension was filtered
4
2
2
O (2 × 2 mL), and air-dried to afford crude
Conclusions
complex 1b. Yield: 631 mg, 0.866 mmol, 49%. An analytically
pure sample of complex 1b was obtained by recrystallization of
Using the appropriate experimental conditions, L-phenylala-
nine methyl ester can be ortho-metalated. The crystal structure
of the mononuclear complex containing 4-picoline has been
determined by X-ray diffraction. The cyclopalladated compound
is an excellent starting material to prepare, in a stereospecific
form, functionalized derivatives of this amino acid, as tetrahy-
droisoquinolines and 2-halo phenylalanine methyl esters.
CH
Pd
.54; N, 4.15. IR (cm ): ν(NH) 3280, 3234; ν(CO) 1732. H NMR
2
Cl
2 2 2 2 4
/Et O. Mp: 147 °C dec. Anal. Calcd for C20H24Br N O -
2
(729.03): C, 32.95; H, 3.32; N, 3.84. Found: C, 33.49; H,
-1
1
3
2
3
(300 MHz): δ 3.31 (dd, 1 H, CH
2
, JHH ) 13.6, JHH ) 3.7 Hz),
.51 (s, 3 H, OMe), 3.82 (br d, 1 H, CH ), 4.23 (br s, 2 H, NH ),
.30 (br s, 1 H, CH), 6.76-6.82 (m, 2 H, H4 and H6, C ), 6.88
3
4
2
2
6
H
4
H
3
3
(t, 1 H, H5, C
6
H
4
, JHH ) 7.2 Hz), 7.38 (d, 1 H, H3, C
6
4,
J
HH
)
1
7
.5). 13C{ H} NMR (75.45 MHz): δ 45.5 (s, CH
2
), 49.8 (s, CH),
Experimental Section
6 4 6 4
52.8 (s, OMe), 124.7 (s, CH, C5, C H ), 125.3 (s, CH, C4, C H ),
1
C
27.5 (s, CH, C6, C
), 140.8 (s, C, C2, C
The mixture A was used as the starting material for the synthesis
6
H
4
), 134.4 (s, C, C1, C
6 4
H ), 136.9 (s, CH, C3,
General Procedures. Infrared spectra were recorded on a Perkin-
Elmer 16F-PC-FT spectrometer. C, H, N, and S analyses and
melting point determinations were carried out as described else-
H
6 4
6 4
H ), 172.3 (s, CO).
of compounds 3-5. Crude complex 1b was used as the starting
material for the synthesis of complexes 2, 6, and 7.
9
where. Unless otherwise stated, NMR spectra were recorded in
CDCl
3
with Bruker Avance 300 and 400 spectrometers. Chemical
Chart 1 gives the numbering scheme for complex 1b and
1
13
1
31
1
shifts are referenced to TMS ( H and C{ H}) or H
3 4
PO ( P{ H}).
tetrahydroisoquinoline derivatives.
1
13
Signals in the H and C NMR spectra of all complexes were
assigned with the help of HSQC and HMBC techniques. FAB MS
measurements were carried out from liquid samples using 3-ni-
trobenzyl alcohol as a matrix in a VG Autospec E apparatus.
Chromatographic separations were carried out by TLC on silica
gel 60 ACC (70-230 mesh). Reactions were carried out at room
temperature without special precautions against moisture. L-
Phenylalanine methyl ester hydrochloride, 4-methylpyridine (4-
picoline), 2,6-dimethylphenyl isocyanide (xylyl isocyanide), tert-
2
Synthesis of (S)-[Pd{κ (C,N)-C
6
H
4
CH
2
CH(CO
2
Me)NH
2
-2}
2
Br-
(
NC
a solution of crude complex 1b (150.0 mg, 0.206 mmol) in CH
Cl (30 mL), and the resulting mixture was stirred at room
temperature for 2 h. The solution was concentrated to ca. 1 mL,
and Et O (20 mL) was added to precipitate a small amount of a
5 4
H Me-4)] (2). 4-Picoline (60 µL, 0.616 mmol) was added to
2
-
2
2
yellow solid, which was separated by filtration. The filtrate was
concentrated to dryness, and the residue was vigorously stirred in
n-hexane (30 mL). The yellow solid obtained was filtered, washed
with n-hexane (2 × 5 mL), and air-dried to afford complex 2.
Yield: 123 mg, 0.269 mmol, 65%. Mp: 156 °C dec. Anal. Calcd
3
butyl isocyanide, PPh (Fluka), 1,10-phenanthroline hydrate (Merck),
(51) Prestsch, E.; Clerc, T.; Seibl, J.; Simon, W. Tablas para la
for C16
2 2
H19BrN O Pd (457.644): C, 41.99; H, 4.18; N, 6.12.
determinaci o´ n estructural por m e´ todos espectrosc o´ picos; Springer-Verlag
Ib e´ rica: Barcelona, Spain, 1998.
-
1
Found: C, 41.88; H, 4.30; N, 6.21. IR (cm ): ν(NH) 3316, 3248;

2774 Organometallics, Vol. 26, No. 10, 2007
Vicente et al.
1
ν(CO) 1726. H NMR (300 MHz): δ 2.36 (s, 3 H, Me), 3.25 (m,
Single crystals of 4, suitable for an X-ray diffraction study, were
obtained by slow diffusion of n-hexane into a solution of 4 in
CHCl .
3
1
4
(
H, CH
2
), 3.51-3.61 (m, 2 H, CH + CH
.24 (m, 2 H, NH
2
), 3.70 (s, 3 H, OMe),
3
2
), 6.46 (d, 1 H, H3, C
6
4
H , JHH ) 7.8 Hz), 6.73
3
4
td, 1 H, H4, C
H, H5 + H6, C
d, 2 H, m-C
δ 21.1 (s, Me), 44.8 (s, CH
s, CH, C5, C ), 125.5 (s, CH, C4, C
m-C N), 126.8 (s, CH, C6, C ), 134.5 (s, CH, C3, C
s, C1, C ), 147.7 (s, C2, C ), 149.7 (s, C, p-C
s, CH, o-C N), 171.8 (s, CO).
Single crystals of 2, suitable for an X-ray diffraction study, were
obtained by slow evaporation of a solution of 2 in CHCl
6
H
H
4
, JHH ) 7.5, JHH ) 2.0 Hz), 6.88-6.96 (m, 2
Synthesis of (S)-1-((2,6-Dimethylphenyl)amino)-3-(methoxy-
carbonyl)-3,4-dihydroisoquinolinium Triflate (5). XyNC (80 mg,
0.609 mmol) was added to a solution of A (from 143 mg, 0.664
mmol of phenylalanine methyl ester hydrochloride) in acetone (20
mL), and the mixture was stirred for 10 min. TlOTf (200 mg, 0.565
mmol) was added, and the resulting suspension was further stirred
for 15 min. The mixture was filtered through a plug of Celite to
remove TlCl. The filtrate was concentrated to dryness, and the
remaining residue was suspended in toluene (20 mL) and refluxed
for 7 h, upon which time Pd(0) precipitated. The mixture was cooled
3
6
4
), 7.04 (d, 2 H, o-C
5
H
4
1
N, JHH ) 6.1 Hz), 8.51
13
(
5
H
4
N, 3JHH ) 6.4 Hz). C{ H} NMR (75.45 MHz):
2
), 50.5 (s, CH), 53.0 (s, OMe), 124.5
), 125.7 (s, CH,
), 135.8
N), 153.2
(
6
H
4
6 4
H
H
5 4
6
H
4
6 4
H
H
5 4
(
(
6
H
4
6
H
4
5
H
4
3
.
to room temperature, toluene was evaporated, CH
added, and the resulting suspension was filtered through a plug of
MgSO . The filtrate was concentrated to ca. 1 mL, and Et O (30
mL) was added to precipitate an off-white solid, which was filtered,
washed with Et
O (2 × 5 mL), and air-dried to give compound 5.
Yield: 137 mg, 0.299 mmol, 45% from phenylalanine methyl ester
hydrochloride. Mp: 190-192 °C. Anal. Calcd for C20
458.455): C, 52.40; H, 4.62; N, 6.11; S, 6.99. Found: C, 52.20;
2 2
Cl (45 mL) was
Synthesis of (S)-1-Oxo-3-(methoxycarbonyl)-1,2,3,4-tetrahy-
droisoquinoline (3). CO was bubbled through a suspension of A
from 119 mg, 0.552 mmol of phenylalanine methyl ester hydro-
4
2
(
chloride) in CHCl (40 mL) for 1 h, and the resulting mixture was
3
2
stirred for 12 h under a CO atmosphere. Decomposition to metallic
palladium was observed. The mixture was filtered through a plug
of Celite, and the filtrate was concentrated to dryness to give
compound 3 as a colorless liquid. Yield: 72.0 mg, 0.351 mmol,
4% with respect to phenylalanine methyl ester hydrochloride. Anal.
Calcd for C11 (205.213): C, 64.38; H, 5.40; N, 6.83.
Found: C, 64.49; H, 5.77; N, 6.65. IR (cm ): ν(NH) 3348, 3258;
ν(CO) 1746, 1674. H NMR (400 MHz): δ 3.15, 3.26 (AB part of
an “ABX system”, 2 H, CH
Hz), 3.73 (s, 3 H, OMe), 4.35 (X part of an “ABXM system”, 1 H,
21 3 2 5
H F N O S
(
-
1
H, 4.77; N, 6.26; S, 6.74. IR (cm ): ν(NH) 3226 (b); ν(CN) 2016,
1
6
1
942; ν(CO) 1752, 1644. H NMR (400 MHz): δ 2.22 (s, 3 H,
H11NO
3
Me, Xy), 2.32 (s, 3 H, Me, Xy), 3.30, 3.44 (AB part of an “ABX
-
1
2
3
3
system”, 2 H, CH
(
2
, JAB ) 16.3, JBX ) 6.2, JAX ) 6.0 Hz), 3.70
1
3
s, 3 H, OMe), 4.53 (X part of an “ABXM system”, 1 H, CH, JMX
2
3
3
2
, JAB ) 15.6, JBX ) 9.7, JAX ) 5.1
3
)
3.9 Hz), 7.16 (d, 1 H, CHCMe, Xy, JHH ) 7.5 Hz), 7.19 (d, 1
3
3
H, CHCMe, Xy, JHH ) 7.2 Hz), 7.26 (t, 1 H, CH, Xy, JHH ) 7.5
3
3
CH, JMX ) 2.0 Hz), 6.64 (br s, 1 H, NH), 7.17 (d, 1 H, H5, JHH
3
Hz), 7.37 (br s, 1 H, NHCH), 7.40 (d, 1 H, H5, JHH ) 7.7 Hz),
3
)
J
7.5 Hz), 7.30 (t, 1 H, H7, JHH ) 7.5 Hz), 7.40 (td, 1 H, H6,
3
3
7
.59 (t, 1 H, H7, JHH ) 7.6 Hz), 7.70 (td, 1 H, H6, JHH ) 7.6,
3
HH ) 7.5, JHH ) 1.4 Hz), 8.00 (dd, 1 H, H8, 3JHH ) 7.5, JHH
4
4
)
4
3
J
HH ) 1.0 Hz), 8.50 (d, 1 H, H8, JHH ) 7.5 Hz), 10.90 (br s, 1
1
1
.2 Hz). 13C{ H} NMR (100.81 MHz): δ 31.1 (s, CH
2
), 52.9 (s,
t
13
1
H, NH- Bu). C{ H} NMR (100.81 MHz): δ 17.4 (s, Me, Xy),
OMe), 53.0 (s, CH), 127.4 (s, CH, C5), 127.5 (s, CH, C7), 128.1
s, CH, C8), 128.3 (s, C8a), 132.5 (s, CH, C6), 136.1 (s, C4a),
65.2 (s, CO-NH), 170.8 (s, CO
1
(
(
2
7.7 (s, Me, Xy), 30.4 (s, CH ), 51.8 (s, CH), 53.7 (s, OMe), 120.3
(
1
+
, 1JCF ) 319.9 Hz), 120.6 (s, C8a), 128.2 (s, CH, C8), 128.9
q, CF
3
+
2
Me). FAB -MS: m/z 206 [(M
s, CH, C5), 129.3 (s, C-NH, Xy), 129.5 (s, CH, C7), 129.5 (s,
+
1) ].
CHCMe, Xy), 129.6 (s, CHCMe, Xy), 130.3 (s, CH, Xy), 135.0
(s, C4a), 135.8 (s, CH, C6), 135.9 (s, CMe, Xy), 136.0 (s, CMe,
Xy), 157.9 (s, C1), 169.2 (s, CO).
Synthesis of (S)-1-(tert-Butylamino)-3-(methoxycarbonyl)-3,4-
t
dihydroisoquinolinium Triflate (4). BuNC (71 µL, 0.628 mmol)
was added to a solution of A (from 159 mg, 0.738 mmol of
phenylalanine methyl ester hydrochloride) in acetone (20 mL), and
the mixture was stirred for 10 min. TlOTf (220 mg, 0.624 mmol)
was added, and the resulting suspension was further stirred for 15
min. The mixture was filtered through a plug of Celite to remove
TlCl. The filtrate was concentrated to dryness, and the remaining
residue was suspended in toluene (25 mL) and refluxed for 7 h,
upon which time Pd(0) precipitated. Toluene was evaporated,
acetone (20 mL) was added, the suspension was filtered through a
plug of Celite, and HTfO (0.1 mL, 1.13 mmol) was added. The
filtrate was concentrated to dryness, and the residue was dried in
the oven at 70 °C for 24 h and then dissolved in CH
Et O (30 mL) was added to precipitate a white solid, which was
filtered, washed with Et
compound 4. Yield: 147 mg, 0.358 mmol, 49% from phenylalanine
methyl ester hydrochloride. Mp: 151 °C. Anal. Calcd for
Single crystals of 5, suitable for an X-ray diffraction study, were
obtained by slow diffusion of n-hexane into a solution of 5 in
CHCl3.
Synthesis of trans-(S,S)-[PdBr
] (6). Br (220 mg, 1.376 mmol) was added to a solution of
complex 1b (500.0 mg, 0.686 mmol) in CH Cl (25 mL), and the
resulting mixture was stirred for 12 h. A dark brown solid was
formed, which was filtered out, air-dried, and identified as PdBr
2 2 2 2 6 4
{NH CH(CO Me)CH C H Br-
2}
2
2
2
2
2
(180 mg, 0.676 mmol, 98%). The filtrate was concentrated to
2
dryness, the residue extracted with Et O (30 mL), the resulting
solution filtered through a plug of Celite, and the filtrate concen-
trated to dryness. The residue was vigorously stirred in n-pentane
(30 mL), and the dark orange solid that formed was filtered, washed
with n-pentane (2 × 3 mL), and air-dried to give 6. Yield: 376.0
mg, 0.481 mmol, 70%. Mp: 54 °C dec. Anal. Calcd for C H -
2 2
Cl (3 mL).
2
2
O (2 × 5 mL), and air-dried to afford
2
0
24
Br N O Pd (782.438): C, 30.70; H, 3.09; N, 3.58. Found: C, 30.74;
4
2
4
-
1
1
C
16
H F
21 3
N
2
O
5
S (410.411): C, 46.82; H, 5.16; N, 6.83; S, 7.81.
H, 3.13; N, 3.45. IR (cm ): ν(NH) 3268, 3205; ν(CO) 1737. H
-
1
2
3
Found: C, 46.85; H, 5.45; N, 6.93; S, 7.67. IR (cm ): ν(NH)
304; ν(CN) 1752, 1640. H NMR (400 MHz): δ 1.63 (s, 9 H,
CMe ), 3.30, 3.39 (AB part of an “ABX system”, 2 H, CH , JAB
3 2
16.4, 3JBX ) 6.2, JAX ) 4.4 Hz), 3.68 (s, 3 H, OMe), 4.86 (X
part of an “ABXM system”, 1 H, CH, JMX ) 4.6 Hz), 7.31 (d, 1
H, H5, JHH ) 7.6 Hz), 7.48 (t, 1 H, H7, JHH ) 7.6 Hz), 7.59 (td,
H, H6, JHH ) 7.5, JHH ) 0.9 Hz), 8.01 (d, 1 H, H8, JHH ) 7.7
NMR (300 MHz): δ 2.67 (dd, 1 H, CH
Hz), 3.36 (m, 1 H, NH ), 3.58 (m, 1 H, NH
partially obscured by the OMe, JHH ) 13.8, JHH ) 6.9 Hz), 3.65
2
, JHH ) 13.8, JHH ) 8.4
1
3
2
2
), 3.64 (dd, 1 H, CH
2
,
2
2
3
3
3
)
6 4
(s, 3 H, OMe), 4.27 (m, 1 H, CH), 7.13 (td, 1 H, H4, C H , JHH
3
4
) 7.8, JHH ) 1.8 Hz), 7.24-7.34 (m, 2 H, H5 + H6, C
6
H
4
), 7.56
, JHH ) 7.8, JHH ) 1.2 Hz). C{ H} NMR
(75.45 MHz): δ 40.5 (s, CH ), 52.7 (s, OMe), 57.9 (s, CH), 125.0
(s, C2, C-Br, C ), 127.7 (s, CH, C5, C ), 129.2 (s, CH, C4,
C H ), 131.6 (s, CH, C6, C H ), 133.2 (s, CH, C3, C H ), 134.9
3
3
3
4
13
1
6 4
(dd, 1 H, H3, C H
3
4
3
1
2
t
3
Hz), 8.07 (br s, 1 H, NH- Bu), 8.33 (d, 1 H, NHCH, JMX ) 4.6
6
H
4
6 4
H
Hz). 13C{ H} NMR (100.81 MHz): δ 28.3 (s, CMe
1.8 (s, CH), 53.3 (s, OMe), 55.3 (s, CMe ), 121.9 (s, C8a), 127.4
s, CH, C8), 128.8 (s, CH, C7), 128.9 (s, CH, C5), 134.9 (s, CH,
C6), 135.0 (s, C4a), 156.5 (s, C1), 169.7 (s, CO).
1
3
), 30.1 (s, CH
2
),
6
4
6
4
6
4
(
s, C1, C-CH
Synthesis of trans-(S,S)-[PdBr
] (7). I (500 mg, 1.97 mmol) was added to a solution of complex
2
, C
6
H
4
), 171.2 (s, CO).
5
3
(
2
{NH
2 2 2 6 4
CH(CO Me)CH C H I-
2}
2
2

L-Phenylalanine Methyl Ester
Organometallics, Vol. 26, No. 10, 2007 2775
Table 1. Crystal Data and Structure Refinement for
Compounds 2, 4, and 5
to give pure compound 8 as a yellow liquid. Yield: 92.8 mg, 0.359
mmol, 40%. Anal. Calcd for C10
4.67; N, 5.43. Found: C, 46.47; H, 4.83; N, 5.28. H NMR (300
2
H12BrNO (258.12): C, 46.53; H,
1
2
4
5
2
2 2
MHz): δ 1.64 (br s, 2 H, NH ), 2.92 (dd, 1 H, CH , JHH ) 13.5,
formula
fw
cryst syst
space group
temp (K)
a (Å)
C
16
H
19BrN
2
2
O Pd
C
16
H
21
F
3
N
O
2 5
S
C
20
H
21
F
3
N
2 5
O S
3
2
3
J
HH ) 8.7 Hz), 3.26 (dd, 1 H, CH
2
, JHH ) 13.5, JHH ) 5.7 Hz),
457.64
monoclinic
P2
100(2)
8.2295(7)
9.2912(8)
11.3389(12)
90
91.663(2)
90
410.41
monoclinic
P2
100(2)
9.5247(4)
10.0175(4)
9.8917(4)
90
93.333(2)
90
942.21(7)
2
458.45
monoclinic
P2
3
3
3.70 (s, 3 H, OMe), 3.85 (dd, 1 H, CH, JHH ) 8.7, JHH ) 5.4
3
3
4
1
1
1
Hz), 7.11 (ddd, 1 H, H4, C
H
4
, JHH ) 8.1, JHH ) 6.6, JHH ) 3.0
), 7.55 (d, 1 H, H3, C
HH ) 7.5 Hz). C{ H} NMR (100.81 MHz): δ 41.3 (s, CH
51.9 (s, OMe), 54.2 (s, CH), 124.7 (s, C2, C-Br, C ), 127.3 (s,
CH, C5, C ), 128.4 (s, CH, C4, C ), 131.5 (s, CH, C6, C ),
32.9 (s, CH, C3, C ), 136.9 (s, C1, C-CH
6
100(2)
Hz), 7.20-7.26 (m, 2 H, H5 + H6, C
H
6 4
6 4
H ,
9.3942(7)
11.5392(9)
10.2024(8)
90
99.789(2)
90
1089.85(15)
2
1.397
3
13
1
J
2
),
b (Å)
c (Å)
6 4
H
R (deg)
â (deg)
γ (deg)
H
6 4
H
6 4
6 4
H
1
H
6 4
2
, C
6
H
4
81
), 175.2 (s,
+
79
+
+
3
CO). FAB -MS: m/z 258 [(M( Br) + 1) ], 260 [(M( Br) + 1) ].
V (Å )
866.63(14)
2
Synthesis of (S)-2-IC
Phenanthroline hydrate (148.8 mg, 0.751 mmol) was added to a
solution of complex 7 (650 mg, 0.742 mmol) in CH Cl (30 mL),
and the resulting mixture was stirred for 3 h. A yellow solid
precipitated, which was filtered, washed with Et O, air-dried, and
identified as [PdBr (phen)] by IR spectroscopy (322.0 mg, 0.721
mmol, 97%). The filtrate was concentrated to dryness, Et O (10
6 4 2 2 2
H CH CH(CO Me)NH (9). 1,10-
Z
F
calcd (Mg m-3) 1.754
1.447
µ(Mo KR)
3.383
0.230
0.208
2
2
-
1
(
mm )
F(000)
452
428
476
cryst size (mm) 0.24 × 0.05 × 0.05 0.50 × 0.35 × 0.17 0.24 × 0.19 × 0.09
2
θ range (deg)
no. of rflns coll 10 153
no. of indep rflns 3930
2.48-27.48
2.06-26.37
10 381
3831
2.20-26.37
12 039
4419
2
2
mL) was added, and the resulting suspension was filtered through
a plug of Celite. The filtrate was concentrated to dryness to give
R
int
0.0382
0.0145
0.0281
max, min
transmissn
0.8491, 0.4973
0.9619, 0.8935
0.9816, 0.9519
crude 9 as a dark yellow liquid. This liquid was dissolved in CH
2
-
no. of data/
restraints/
3930/10/210
1.024
3831/1/257
1.079
4419/1/291
1.033
2
Cl (1 mL) and subjected to silica gel preparative thin-layer
chromatography. Elution with Et
2
O gave a wide colorless band (R
f
params
goodness of
) 0.4-0.6), which was collected and extracted with acetone; the
solution was filtered through a plug of Celite, and the filtrate was
concentrated to dryness to give spectroscopically pure compound
fit on F2
R1 (I > 2σ(I))
wR2 (all rflns)
Flack param
0.0353
0.0796
0.0035(10)
0.0265
0.0677
0.03(5)
0.211, -0.260
0.0399
0.0972
-0.08(7)
0.393,-0.176
9
as a yellow liquid. Yield: 285.3 mg, 0.935 mmol, 63%. Anal.
largest diff peak, 1.432, -0.951
Calcd for C10 (305.111): C, 39.37; H, 3.96; N, 4.59.
H12INO
2
hole (e Å-
3
)
Found: C, 40.01; H, 4.18; N, 4.63. Compound 9 decomposes slowly
at room temperature. This could explain the slightly high C analysis
found (relative error, 1.6%). H NMR (400 MHz): δ 1.79 (br s, 2
1
b (678 mg, 0.93 mmol) in CH
mixture was stirred for 4 h. A dark brown solid was formed, which
was filtered out, air-dried, and identified as PdI (305 mg, 0.847
2
Cl
2
(25 mL), and the resulting
1
2
3
H, NH
(
2
), 2.92 (dd, 1 H, CH
2
3
, JHH ) 13.7, JHH ) 8.8 Hz), 3.24
2
2
2
dd, 1 H, CH , JHH ) 13.7, JHH ) 5.6 Hz), 3.71 (s, 3 H, OMe),
mmol, 91%). The suspension was filtered through a plug of Celite,
the filtrate was concentrated to ca. 2 mL, and n-pentane (30 mL)
was added to precipitate a dark yellow solid, which was filtered,
washed with n-pentane (2 × 3 mL), and air-dried to give compound
3
3
3
C
.85 (dd, 1 H, CH, JHH ) 8.8, JHH ) 5.6 Hz), 6.94 (td, 1 H, H4,
3
4
3
H
6 4
, JHH ) 7.7, JHH ) 1.8 Hz), 7.22 (dd, 1 H, H6, C
6
H
4
, JHH
4
3
4
)
7.6, JHH ) 1.7 Hz), 7.29 (td, 1 H, H5, C
1.2 Hz), 7.84 (dd, 1 H, H3, C
6
H
4
, JHH ) 7.5, JHH
3
4
)
H
6 4
, JHH ) 7.9, JHH ) 1.2 Hz).
7
. Yield: 715 mg, 0.816 mmol, 88%. Mp: 57 °C dec. Anal. Calcd
13
1
C{ H} NMR (100.81 MHz): δ 45.6 (s, CH
2
), 52.0 (s, OMe),
),
2 2 2 4
for C20H24Br I N O Pd (876.44): C, 27.41; H, 2.76; N, 3.20.
Found: C, 28.38; H, 2.81; N, 3.26. Compound 7 decomposes slowly
at room temperature. This could explain the slightly high C analysis
found (relative error, 3.5%). IR (cm ): ν(NH) 3273, 3218; ν(CO)
5
1
4.5 (s, CH), 100.8 (s, C2, C-I, C
28.6 (s, CH, C4, C ), 130.7 (s, CH, C6, C
), 140.2 (s, C1, C-CH , C
6
H
4
), 128.2 (s, CH, C5, C H
6 4
H
6 4
6 4
H
), 139.7 (s, CH,
+
C3, C
6
H
4
2
H
6 4
), 175.0 (s, CO). FAB -
-1
+
MS: m/z 306 [(M + 1) ].
1
2
1
738. H NMR (300 MHz): δ 3.16 (dd, 1 H, CH
2
, JHH ) 13.8,
), 3.53 (m, 1 H, NH ), 3.63 (dd,
, JHH ) 13.8, JHH ) 6.9 Hz), 3.65 (s, 3 H, OMe), 4.26
X-ray Structure Determinations. X-ray data for com-
pounds 2, 4, and 5 are summarized in Table 1. For data collec-
tion, crystals were mounted in inert oil on a glass fiber and
transferred to a Bruker SMART APEX diffractometer. Data were
recorded at low temperature using ω scans. Multiscan absorption
corrections were applied. Structures were solved by the heavy-atom
method (2) or by direct methods (4, 5) and refined anisotropically
3
J
HH ) 8.4 Hz), 3.33 (m, 1 H, NH
H, CH
2
2
2
3
1
2
3
3
(
m, 1 H, CH), 6.95 (ddd, 1 H, H4, C
J
6
H
4
, JHH ) 9.0, JHH ) 6.0,
HH ) 3.0 Hz), 7.27-7.31 (m, 2 H, H6 + H5, C ), 7.84 (d, 1
, JHH ) 8.4 Hz). C{ H} NMR (75.45 MHz): δ 44.9
), 52.8 (s, OMe), 58.1 (s, CH), 101.1 (s, C2, C-I, C ),
28.6 (s, CH, C5, C ), 129.2 (s, CH, C4, C ), 130.7 (s, CH,
C6, C ), 138.2 (s, C1, C-CH , C ), 140.0 (s, CH, C3, C ),
71.2 (s, CO).
Synthesis of (S)-2-BrC
Phenanthroline hydrate (89.0 mg, 0.450 mmol) was added to a
solution of complex 6 (350 mg, 0.447 mmol) in CH Cl (25 mL),
and the resulting mixture was stirred for 3 h. A yellow solid
precipitated, which was filtered, washed with Et O, air-dried, and
identified as [PdBr (phen)] by IR spectroscopy (172 mg, 0.385
mmol, 86%). The filtrate was concentrated to dryness, Et O (10
4
6 4
H
3
13
1
H, H3, C
(
1
6 4
H
s, CH
2
6 4
H
6
H
4
H
6 4
on F2 using the program SHELX-97. Hydrogen atoms were
52
H
6 4
2
H
6 4
6 4
H
2
refined as follows: NH and NH, free; methyl, rigid group; all
1
others, riding.
6 4 2 2 2
H CH CH(CO Me)NH (8). 1,10-
Acknowledgment. We thank the Ministerio de Educaci o´ n
y Ciencia (Spain) and FEDER (CTQ2004-05396) for financial
support. J.-A.G.-L. and B.C.-C. are grateful to the Ministerio
de Educaci o´ n y Ciencia (Spain) for their research grants.
2
2
2
2
Note Added in Proof. During the correction of the galley
proof of this article, the direct iodination of phenylalanine methyl
ester has been reported to give a 1:1 mixture of the ortho- and
2
mL) was added, and the resulting suspension was filtered through
a plug of Celite. The filtrate was concentrated to dryness to give
crude 8 as a yellow liquid. This liquid was dissolved in CH
mL) and subjected to silica gel preparative thin-layer chromatog-
raphy. Elution with Et O gave a colorless band (R ) 0.4), which
5
3
para-iodo derivatives (53% yield).
2 2
Cl (1
(
52) Sheldrick, G. M. SHELX-97; University of G o¨ ttingen, G o¨ ttingen,
Germany, 1997.
53) Barluenga, J.; Alvarez-Guti e´ rrez, J. M.; Ballesteros, A.; Gonz a´ lez,
J. M. Angew. Chem., Int. Ed. 2007, 119, 1303.
2
f
was collected and extracted with acetone; the solution was filtered
through a plug of Celite, and the filtrate was concentrated to dryness
(

2776 Organometallics, Vol. 26, No. 10, 2007
Vicente et al.
Supporting Information Available: For compounds 2, 4, and
, tables and figures giving details (including symmetry operators)
CIF files. This material is available free of charge via the Internet
at http://pubs.acs.org.
5
of hydrogen bonds and all refined and calculated atomic coordinates,
anisotropic thermal parameters, and bond lengths and angles and
OM070127Y