Efficient access to (1H)-isoindolin-1-one-3-carboxylic acid derivatives by orthopalladation and carbonylation of methyl arylglycinate substrates

Article abstract of DOI:10.1016/j.tet.2011.04.064

The orthopalladation of methyl arylglycinate derivatives has been studied. The reaction proceeds efficiently for different electron-withdrawing and electron-releasing substituents at the aryl ring. The carbonylation of the orthopalladated complexes affords, in a single step, substituted (1H)-isoindolin-1-one-3-carboxylates. These compounds constitute valuable synthetic intermediates and can be transformed diastereoselectively into octahydroisoindole-1-carboxylic acid derivatives, an important scaffold in the synthesis of many biologically active compounds.

Full text of DOI:10.1016/j.tet.2011.04.064

Tetrahedron 67 (2011) 4185e4191
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Efficient access to (1H)-isoindolin-1-one-3-carboxylic acid derivatives by
orthopalladation and carbonylation of methyl arylglycinate substrates
Sonia Nieto a, Francisco J. Sayago b, Pedro Laborda b, Tatiana Soler c, Carlos Cativiela b,
,
Esteban P. Urriolabeitia a
*
a
ꢀ
ꢀ
Departamento de Compuestos Organometalicos, Instituto de Ciencia de Materiales de Aragon (CSIC-Universidad de Zaragoza), Pedro Cerbuna 12, 50009 Zaragoza, Spain
Departamento de Química Organica, Instituto de Ciencia de Materiales de Aragon (CSIC-Universidad de Zaragoza), Pedro Cerbuna 12, 50009 Zaragoza, Spain
Servicios Tecnicos de Investigacion, Facultad de Ciencias Fase II, San Vicente de Raspeig, Alicante 03690, Spain
b
c
ꢀ
ꢀ
ꢀ
ꢀ
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 March 2011
Received in revised form 14 April 2011
Accepted 15 April 2011
Available online 21 April 2011
The orthopalladation of methyl arylglycinate derivatives has been studied. The reaction proceeds efficiently
for different electron-withdrawing and electron-releasing substituents at the aryl ring. The carbonylation
of the orthopalladated complexes affords, in a single step, substituted (1H)-isoindolin-1-one-3-carboxyl-
ates. These compounds constitute valuable synthetic intermediates and can be transformed diaster-
eoselectively into octahydroisoindole-1-carboxylic acid derivatives, an important scaffold in the synthesis
of many biologically active compounds.
Keywords:
Palladium
Ó 2011 Elsevier Ltd. All rights reserved.
Phenylglycine
Carbonylation
Isoindolones
Hydrogenation
1. Introduction
O
O
OR(H)
R1
NR2R3
R1
N
O
Isoindolinone is the core skeleton present in a great variety of
natural compounds with important biological activities.1,2 In par-
ticular, the 3-substituted isoindolinone ring system is an integral
part of naturally occurring substances, such as lennoxamine or
nuevamine3 and it is present in the structure of many pharmaco-
phores.4 In fact, some of its derivatives possess anxiolytic activity
and are of interest as sedatives, hypnotics, and muscle relaxants.
Apart from the fact that (1H)-isoindolin-1-one-3-carboxylic acid
can be considered as a fused proline, many derivatives are partic-
ularly relevant because they are valuable synthetic intermediates in
the preparation of several compounds that display interesting bi-
ological activities (Scheme 1). Thus, this compound is an essential
scaffold in the synthesis of potential drugs useful in the treatment
of pain disorders5 or arrhythmias6 (compounds type A).
Ar
N
N
O
O
O
A
B
OR
R
n
OR
N
O
C
Scheme 1. (1H)-isoindolin-1-one-3-carboxylic acidderivativesassynthetic intermediates.
In addition, (1H)-isoindolin-1-one-3-carboxylic acid derivatives
are used as intermediates in the synthesis of polycyclic systems
structurally related to biologically active alkaloids. Thus, they have
been transformed into polycyclic compounds type B, structurally
related to alkaloids possessing a benzopyranisoquinoline skeleton.7
This family of substances, in many cases, exhibit a remarkable
physiological activity8 (anti-inflammatory, dopaminergic, and anti-
depressant). (1H)-isoindolin-1-one-3-carboxylic acid derivatives
have also been used in the synthesis of novel polycyclic aza-
compounds structurally related with pyrrolizidine and indolizidine
derivatives.9 Alkaloids characterized by these skeletons often display
biological activities as glycosidases inhibitors. Therefore they can be
* Corresponding author. Tel.: þ34 976762302; fax: þ34 976761187; e-mail address:
esteban@unizar.es (E.P. Urriolabeitia).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.04.064

4186
S. Nieto et al. / Tetrahedron 67 (2011) 4185e4191
used for the treatmentof many diseases, such as diabetes, cancer, and
viral infections.10
Here we report the Pd-mediated carbonylation of a series of
arylglycine derivatives, containing both electro-withdrawing and
electron-releasing groups in different positions of the aryl ring. The
reaction affords the corresponding substituted (1H)-isoindolin-1-
one-3-carboxylic acid derivatives, expanding the scope of previous
procedures and providing a general access to this class of com-
pounds. In addition, this method starts from arylglycines, which are
easily available in a few steps via a Strecker synthesis from com-
mercial aromatic aldehydes, uses mild reaction conditions and al-
lows isolation of pure compounds without need of further
chromatographic purifications.
Due to the utility of (1H)-isoindolin-1-one-3-carboxylic acid as
the starting material in the preparation of such compounds, many
synthetic approaches have been described in literature (Scheme 2).
Thus, the pattern compound can be obtained from phthalonic acid
by treatment with hydrazine and reduction with zinc11 or by cy-
clization of alkyl a-bromohomophthalates in the presence of ami-
nes7b (paths a and b). Other preparative pathways to the synthesis
of this compound consist of the addition of ammonia and cyanide
to phthalaldehydic acid12 (path c) and in the nucleophilic attack of
13
3-metalated isoindolinones to CO2 (path d).
2. Results and discussion
CO2R
NH2
2.1. Synthesis of the orthopalladated complexes
CO
+
According to that exposed above, the first stage in this strategy
involved the synthesis of the methyl arylglycinate derivatives
2aed, which were easily prepared starting from commercially
available aldehydes 1aed via conventional Strecker reaction17 and
later esterification with methanol and thionyl chloride. The re-
action of these species with Pd(OAc)2, in order to obtain the cor-
responding orthopalladated complexes, has been carried out under
the same experimental conditions as those reported previously by
Fuchita et al.18 (Scheme 3).
R
Li
N
R
+ CO2
e
d
O
O
OR(H)
R1
O
c
+
NH3
+
CN-
N
O
O
OH
O
CO2Me
NH2.HCl
b
CO2R
Br
1. Strecker
H
a
2. SOCl2, MeOH
R
R
+ NH2R
CO2H
O
2a-2d
R = 4-OMe (1a); 2-Br (1b)
3-Br (1c); 4-Br(1d).
CO2R
+ NH2NH2
Pd(OAc)2, Me2CO
24 h. reflux
CO2H
Scheme 2. Retrosynthetic analysisfor (1H)-isoindolin-1-one-3-carboxylicacidderivatives.
CO2Me
3
CO2Me
3
2
2
4
4
NH2
NH2
Pd
1
Cl
CDCl3, Py-d5
The great interest of (1H)-isoindolin-1-one-3-carboxylic acid
derivatives makes necessary efforts to find a general procedure to
give access to differently substituted derivatives that could be used
in the synthesis and exploration of new biologically active com-
pounds and pharmacophores. The synthetic methodologies de-
scribed above occur with medium to high yields, but they are not
easily extended to the synthesis of compounds with different
substituents in the aromatic ring and, to the best of our knowledge,
a general procedure of general scope has never been reported.
The use of organometallic complexes as intermediates in or-
ganic syntheses provides preparative pathways complementary,
even sometimes alternative, to the classical organic procedures
previously detailed. Orthopalladated complexes of a wide prospect
of ligands react smoothly with carbon monoxide, incorporating this
molecule to the organic skeleton of the ligand.14 Usually, this well
known reaction occurs in three steps, namely the bonding of the
CO, its subsequent migratory insertion and the final reductive
elimination with concomitant CeC and/or CeX coupling. The syn-
thesis of many carbo- and heterocycles has been achieved in this
way, and the (1H)-isoindolin-1-ones are not an exception (path e).
In fact, several reports have appeared during the last years showing
a renewed interest on this subject.15
5R
5R
Pd
1
Cl
6
6
N
2
R = 5-OMe (3a); 3-Br (3b)
4-Br (3c); 5-Br(3d).
d5
NMR-measurements
Scheme 3. Synthesis and characterization of the orthopalladated complexes.
Complexes 3aed were obtained as yellowish-orange solids in
moderate yields. The chromatographic purification of the crude
mixtures was necessary in all cases, due to the presence of variable
amounts of the coordinated complexes [PdCl2L2] (L¼amino ester).
In spite of this, we have found that the reaction works with similar
yields in the presence of electron-releasing (3a) or electron-
withdrawing (3bed) substituents at the aryl group, and regard-
less these substituents are in ortho- (3b), meta- (3c) or para- (3d)
positions with respect to the amino ester fragment. These facts
confer a wide scope of applicability to this method.
The characterization of organometallic derivatives 3aed has
been performed through the usual methods. All complexes show
correct elemental analyses and mass spectra for the proposed
dinuclear stoichiometries. The IR spectra show strong absorptions
due to the carbonyl stretch (around 1730e1740 cmꢀ1) and the NeH
stretch (3200e3300 cmꢀ1 region). In order to simplify the NMR
spectra of 3aed, and to achieve a rigourous assignation of signals,
the spectra have been measured in presence of a small amount of
pyridine-d5. This is a very common feature when complicated
spectra are expected due to the simultaneous presence of stereo-
isomers and geometric isomers. The pyridine cleaves the halide
However, the synthesis of (1H)-isoindolin-1-ones containing
a strong electron-attracting group at the benzylic Ca atom has not
been reported until recently. A report by our group described the
stoichiometric carbonylation of methyl (R)-phenylglycinate,16
while García et al. have reported a catalytic version of the process
using quaternary derivatives of phenylglycine and phenylalanine as
starting compounds.15h

S. Nieto et al. / Tetrahedron 67 (2011) 4185e4191
4187
bridge and affords a mononuclear complex with the pyridine
bonded trans to the N atom of the orthopalladated ligand (see
Scheme 3).19 In this way, only a set of signals is expected, and all
signals can be clearly identified and assigned.
is shown in Fig.1. The comparison of the structural parameters of 4c
with analogous isoindolinones shows an identical pattern of bond
distances and angles, within experimental error, and does not merit
further discussion.16
The comparison of the 1H NMR spectra of complexes 3aed with
those of the precursors 2aed show clearly the disappearance of one
signal due to an aromatic proton, with concomitant change of the
corresponding spins systems. The 13C NMR spectra of 3aed show
peaks assigned to six chemically unequivalent aromatic C nuclei.
Both facts suggest that the CeH bond activation process and the Pd
incorporation have taken place at the aryl ring. Moreover, the
N-bonding to the Pd metal center of the NH2 moiety is clearly
inferred from the deshielding of the aminic H protons, which appear
as unequivalent due to the presence of the stereogenic Ca atom.
Therefore, the C,N-chelating mode of the orthopalladated amino
ester ligand is evident from the NMR data. In addition, one of the
signals of the cyclopalladated ring (H6) in the aromatic region ap-
pears strongly shielded, due to the anisotropic shielding promoted
by the pyridine ring.19 All these data are in good agreement with the
proposed structure in Scheme 3 for complexes 3.
2.2. Synthesis of (1H)-isoindolinones by carbonylation
Fig. 1. Molecular drawing of compound 4c. Ellipsoids of non-hydrogen atoms have
been drawn at 50% probability.
The complexes 3aed react smoothly with CO in CHCl3 at room
temperature giving the corresponding methyl (1H)-isoindolin-1-
one-3-carboxylates 4aed with excellent yields (Scheme 4). The
carbonylation process takes place under mild reaction conditions
(CO 1 atm; 25 ꢁC, 12 h). During reaction the formation of black Pd is
evident. However, the isolation of 4aed as analytically pure solids is
achieved after a very simple workup, namely the filtration to
eliminate the metallic Pd0, evaporation of the solvent and pre-
cipitation with Et2O. The yields of isolated product are in all studied
cases around or higher than 90%, in spite of the presence of sub-
stituents of different electronic nature (Br vs OMe) located at dif-
ferent positions (ortho-, meta- ,and para). Particularly interesting
are the bromo-substituted derivatives 4bed, since they could be
used as starting compounds in further Pd-catalyzed CeC and/or
C-heteroatom couplings (Suzuki, Stille, Sonogashira, or others).
Therefore, both the CeH activation and the carbonylation are pro-
duced in a wide array of substrates. The general method here
presented provides access to a wide range of starting materials,
avoids extreme reaction conditions and/or unstable reagents and
uses cheap precursors like arylic aldehydes.
2.3. Synthesis of octahydroisoindole derivatives by
hydrogenation of (1H)-isoindolinones
As exposed in the Introduction, isoindolin-1-one-3-carboxylic
acid derivatives are valuable synthetic intermediates in the prep-
aration of several compounds. Herein we report a synthetic route
that allows their transformation into octahydroisoindole-1-
carboxylic acid derivatives (Scheme 5).
CO2Me
NH
CO2Me
NH
CO2Me
NH
H
H
H2, PtO2
AcOH, 70 ûC
+
H
H
O
O
O
5
(3S*,3aR*,7aS*)-6
(3R*,3aR*,7aS*)-6
96
:
4
Boc2O, DMAP
THF, r.t.
CO2Me
H
N
Boc
Br
CO2Me
NH
CO2Me
NH
H
O
CO2Me
NH2
Pd
Cl
(3S*,3aR*,7aS*)-7
3
MeO
Br
2
1
4
CO
O
O
4a
4b
1- DIBAL, THF, -78 o
C
5R
2- Et3SiH, BF3áOEt2, CH2Cl2, -78 o
C
CO2Me
CO2Me
6
NH
O
NH
O
CO2Me
H
H
R = 5-OMe (3a); 3-Br (3b)
4-Br (3c); 5-Br(3d).
Br
N
Boc
4c
4d
Scheme 4. Synthesis of the (1H)-isoindolin-1-one derivatives 4aed by carbonylation
of the orthopalladated complexes 3aed.
(1S*,3aS*,7aR*)-8
Scheme 5. Synthesis of protected (1S*,3aS*,7aR*) octahidroisoindole-1-carboxylic
acid starting from methyl (1H)-isoindolin-1-one-3-carboxylate.
The characterization of the methyl (1H)-isoindolin-1-one-3-
carboxylates has been carried out on the basis of their spectro-
scopic and analytic data. The NMR spectra of 4aed show the same
pattern of resonances as that observed for their precursors 3aed,
and a new signal in the 13C NMR spectra due to the carbonylic
amide. The IR spectra of 4aed also show a new strong absorption
around 1690 cmꢀ1, due to the new carbonyl moiety. Moreover, the
X-ray crystal structure of compound 4c has been determined by
X-ray diffraction methods. A molecular drawing of this compound
Octahydroisoindole-1-carboxylic acid, a [c]-fused bicyclic pro-
line analogue, has proven to be an essential scaffold in the synthesis
of biologically active compounds and constitutes the core structure
of molecules that can be useful in the treatment of osteoarthritis
and rheumatoid arthritis,20 in the inhibition or prevention of leu-
kocyte adhesion and leukocyte adhesion mediated pathologies21 or
as antihypertensive agents.22

4188
S. Nieto et al. / Tetrahedron 67 (2011) 4185e4191
As shown in Scheme 5, the first step in this route involved the
4.2. X-ray diffraction
reduction of the benzene ring in 5. Compound 5 was obtained as
previously described in our research group.16 The hydrogenation of
the aromatic ring was achieved following the procedure previously
described by some of us.23 The process was completed smoothly
under atmospheric pressure of hydrogen gas using platinum(IV)
Crystals of adequate quality for X-ray measurements were
grown by diffusion of Et2O into a CH2Cl2 solution of the crude 4c at
25 ꢁC. A single crystal was mounted at the end of a quartz fiber in
a random orientation, covered with magic oil and placed under the
cold stream of nitrogen. Data collection was performed at low
temperature (150 K) on an Oxford Diffraction Xcalibur2 diffrac-
oxide as catalyst and provided the stereoisomers (3S
*
,3aR
*
,7aS )-6
*
and (3R*,3aR*,7aS*)-6 in a 96:4 ratio, which was established by
analysis of the relative intensities of the appropriate signals in 1H
NMR spectra of the crude. This stereoselectivity in the reduction
process can be explained considering that benzene ring hydroge-
nation in 5 takes place from the less hindered face, i.e., that op-
posite to where carboxylate group lies. The relative configuration in
(3S*,3aR*,7aS*)-6 was confirmed by a 2D NOESYexperiment, which
showed a NOE interaction between 3-H and 7a-H.
Compound (3S*,3aR*,7aS*)-6 was separated by column chro-
matography and transformed into the N-Boc derivative
(3S*,3aR*,7aS*)-7 by treatment with di-tert-butyl dicarbonate. The
introduction of a Boc group in nitrogen improved the lactam car-
bonyl group electrophilia and allowed its reduction to a methylene
group by reaction with DIBAL and triethylsilane to afford the
octahydroisoindole-1-carboxylic acid derivative (1S*,3aS*,7aR*)-8
with a 65% overall yield starting from 5.
tometer using graphite-monochromated Mo-K
a
radiation
¼0.71073 A). A hemisphere of data was collected based on three
-scan or -scan runs. The diffraction frames were integrated using
ꢁ
(l
u
4
the program CrysAlis RED24 and the integrated intensities were
corrected for absorption with SADABS.25 The structures were solved
and developed by Patterson and Fourier methods.26 The structures
were refined to F20, and all reflections were used in the least-squares
calculations.27 Crystallographic data (excluding structure factors)
for the structure of 4c have been deposited with the Cambridge
Crystallographic Data Center as supplementary publication number
CCDC 815111. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax:
þ44 (0)1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
4.3. General procedure for the synthesis of methyl
arylglycinate derivatives
3. Conclusion
A mixture of NaCN (343 mg, 7.0 mmol) and NH4Cl (375 mg,
7.0 mmol) in H2O (3 mL) was stirred at room temperature for 10 min.
Then, aldehyde 1 (7.0 mmol) in MeOH (3 mL) was added. The re-
actionmixturewas stirred at roomtemperaturefor 24h. Then, water
(8 mL) was added and the organic solvent was evaporated. The
remaining aqueous phase was extracted with dichloromethane and
the organic layer was dried over MgSO4, filtered, and evaporated to
dryness. The crude product was dissolved in aqueous HCl 6 N (9 mL)
and stirred under reflux for 3 days. Then, the reaction mixture was
evaporated under vacuum and the white solid obtained treated with
a mixture of isopropanol/water. The precipitated solid (NH4Cl) was
filtered off and the remaining solution evaporated.
Thionyl chloride (1.1 mL, 14.51 mmol) was added dropwise to an
ice-cooled solution of the residue obtained above in dry methanol
(18 mL). The resulting solution was stirred at room temperature for
24 h. The solvent was concentrated under vacuum and the resulting
residue was liophilized and washed with small portions of ethyl
acetate to afford the corresponding methyl arylglycinate derivative.
The orthopalladation of substituted arylglycine derivatives and
subsequent carbonylation of the respective metalated complexes
affords the corresponding (1H)-isoindolin-1-one-3-carboxylates in
good yields. This synthetic route is of general applicability and can
be considered as complementary to other preparative methods.
The hydrogenation of the methyl (1H)-isoindolin-1-one-3-carbox-
ylate takes place under mild reaction conditions and gives the
octahydroisoindole-1-carboxylic acid derivative, this step occurring
diastereoselectively.
4. Experimental
4.1. General
All reagents were used as received from commercial suppliers
without further purification. Thin-layer chromatography (TLC) was
performed on MachereyeNagel PolygramÒ SIL G/UV254 precoated
silica gel polyester plates. The products were visualized by expo-
sure to UV light (254 nm), iodine vapors or charring with cerium
molybdate stain [aqueous solution of phosphomolybdic acid (2%),
CeSO4$4H2O (1%) and H2SO4 (6%)]. Column chromatography was
4.3.1. Methyl (4-methoxyphenyl)glycinate hydrochloride (2a).
White solid (941 mg, 4.06 mmol, 58%). Mp 186e188 ꢁC, (lit.28
187e189 ꢁC). IR (KBr):
(400 MHz, DMSO-d6):
Ar), 7.00 (d, J¼8.8 Hz, 2H, Ar), 5.19 (s, 1H,
3.70 (s, 3H, OMe) ppm. 13C NMR (100 MHz, DMSO-d6):
(CO), 160.05 (Ar), 129.72 (Ar), 124.46 (Ar), 114.37 (Ar), 55.32 (OMe),
n
¼3448, 3018, 1741, 1616 cmꢀ1
.
1H NMR
ꢁ
performed using 60 A (0.04e0.063 mm) silica gel from Macher-
d
¼9.03 (br s, 3H, NH3), 7.42 (d, J¼8.8 Hz, 2H,
eyeNagel. Melting points were determined on a Gallenkamp ap-
paratus. IR spectra were registered on a Nicolet Avatar 360 FTIR or
a PerkineElmer Spectrum One IR spectrophotometer; nmax is given
for the main absorption bands. 1H, and 13C NMR spectra were
recorded on a Bruker AV-400 spectrometer at 25 ꢁC using the re-
a
-H), 3.77 (s, 3H, OMe),
d
¼169.12
54.75 (a-C), 53.08 (OMe) ppm. HRMS (ESI): calcd for C10H14NO3
[MꢀCl]þ 196.0968; found 196.0960.
sidual solvent signal as the internal standard; chemical shifts (d) are
expressed in parts per million and coupling constants (J) in hertz.
Electrospray Ionization (ESI)/Atmospheric Pressure Chemical Ioni-
zation (APCI) mass spectra were recorded using an Esquire 3000
ion-trap mass spectrometer (Bruker Daltonic GmbH, Bremen,
Germany) 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. Helium served as
a cooling gas for the ion trap and collision gas for MSn experiments.
Other mass spectra (2-DIT) were recorded from CH2Cl2 solutions on
a Bruker MicroFlex spectrometer. Elemental analyses were carried
out on a PerkineElmer 2400-B microanalyzer. High-resolution
mass spectra were obtained on a Bruker Microtof-Q spectrometer.
4.3.2. Methyl (2-bromophenyl)glycinate hydrochloride (2b). White
solid (884 mg, 3.15 mmol, 45%). Mp 166e168 ꢁC. IR (KBr):
n
¼3450,
3019, 1749, 1598 cmꢀ1. 1H NMR (400 MHz, DMSO-d6):
d
¼9.36 (br s,
3H, NH3), 7.75 (dd, J¼7.9, 1.0 Hz, 1H, Ar), 7.65 (dd, J¼7.9, 1.5 Hz, 1H,
Ar), 7.50 (td, J¼7.9,1.0 Hz,1H, Ar), 7.39 (td, J¼7.9,1.5 Hz,1H, Ar), 5.42
(s, 1H, a
-H), 3.70 (s, 3H, OMe) ppm. 13C NMR (100 MHz, DMSO-d6):
d
¼168.01 (CO), 133.43 (Ar), 132.15 (Ar), 131.68 (Ar), 129.51 (Ar),
128.62 (Ar), 124.13 (Ar), 54.82 (a-C), 53.48 (OMe) ppm. HRMS (ESI):
calcd for C9H11BrNO2 [MꢀCl]þ 243.9968; found 243.9960.
4.3.3. Methyl (3-bromophenyl)glycinate hydrochloride (2c). White
solid (982 mg, 3.50 mmol, 50%). Mp 198e200 ꢁC. IR (KBr):
n¼3434,

S. Nieto et al. / Tetrahedron 67 (2011) 4185e4191
4189
3020, 1753, 1602 cmꢀ1. 1H NMR (400 MHz, DMSO-d6):
3H, NH3), 7.80 (t, J¼1.8 Hz, 1H, Ar), 7.66 (ddd, J¼7.9, 1.8, 1.0 Hz, 1H,
Ar), 7.56e7.52 (m, 1H, Ar), 7.43 (t, J¼7.9 Hz, 1H, Ar), 5.35 (s, 1H, -H),
3.72 (s, 3H, OMe) ppm. 13C NMR (100 MHz, DMSO-d6):
¼168.40
(CO), 135.01 (Ar), 132.44 (Ar), 131.19 (Ar), 131.13 (Ar), 127.45 (Ar),
d
¼9.19 (br s,
J¼8.0, 2.6 Hz, 1H, Ar), 6.98 (d, J¼8.0 Hz, 1H, Ar), 6.13 (br s, 1H, Ar),
5.11 (br s, 1H, NH), 4.89 (pseudot, J¼8.0 Hz, 1H, CH), 4.56 (br s, 1H,
NH), 3.79 (s, 3H, OMe) ppm. 13C NMR (100 MHz, CDCl3þpy-d5):
a
d
d
¼170.36 (CO), 151.12 (Ar), 135.23 (Ar), 128.15 (Ar), 125.53 (Ar),
122.18 (Ar), 117.66 (Ar), 65.02 (s, CH), 52.39 (s, OMe) ppm. Anal.
Calcd for C18H18Br2Cl2N2O4Pd2 (769.91): C, 28.08; H, 2.36; N, 3.64.
Found: C, 28.72; H, 2.09; N, 3.23. Mass Spect. (MALDIþ-DIT) [m/z]:
385.7 [M/2]þ.
121.96 (Ar), 54.56 (a-C), 53.37 (OMe) ppm. HRMS (ESI): calcd for
C9H11BrNO2 [MꢀCl]þ 243.9968; found 243.9964.
4.3.4. Methyl (4-bromophenyl)glycinate hydrochloride (2d). White
solid (1.080 g, 3.85 mmol, 55%). Mp 184e186 ꢁC. IR (KBr):
n
¼3430,
¼9.23 (br s,
3H, NH3), 7.67 (d, J¼8.5 Hz, 2H, Ar), 7.49 (d, J¼8.5 Hz, 2H, Ar), 5.31 (s,
1H,
-H), 3.70 (s, 3H, OMe) ppm. 13C NMR (100 MHz, DMSO-d6):
¼168.50 (CO), 131.99 (Ar), 131.95 (Ar), 130.61 (Ar), 123.03 (Ar),
4.5. General carbonylation procedure
3018, 1750, 1601 cmꢀ1. 1H NMR (400 MHz, DMSO-d6):
d
A suspension of the corresponding orthopalladated complex
3aed in chloroform was stirred under CO atmosphere (1 atm)
overnight. Then, the dark suspension was filtered through a plug of
Celite and the resulting solution was evaporated to dryness. The
residue was dissolved in dichloromethane and the addition of
n-hexane caused the precipitation of the corresponding iso-
indolones 4aed as white solids.
a
d
54.66 (a-C), 53.30 (OMe) ppm. HRMS (ESI): calcd for C9H11BrNO2
[MꢀCl]þ 243.9968; found 243.9962.
4.4. General orthopalladation procedure
A mixture of the corresponding
a
-amino ester hydrochlorides
4.5.1. Methyl 6-methoxy-(1H)-isoindolin-1-one-3-carboxylate (4a).
Complex 3a (200 mg, 0.30 mmol) and chloroform (20 mL) under CO
atmosphere were employed for the synthesis of the isoindolinone
4a (118 mg, 0.53 mmol, 90%). Crystals of 4a 0.25CH2Cl2 were
obtained by diffusion of n-hexane (10 mL) into a saturated solution
2aed (1 equiv) and Pd(OAc)2 (1 equiv) in acetone were refluxed for
24 h. The resulting solution was filtered through a plug of Celite,
and purified by silica gel chromatography using ethyl acetate as
eluent. The evaporation of solvent allowed the isolation of the re-
spective orthopalladated complexes 3aed.
of this compound in CH2Cl2 (5 mL). IR (neat):
n
¼3195, 1747,
In the case of the synthesis of complex [Pd(
m-Cl){C6H3-
1695 cmꢀ1. 1H NMR (400 MHz, CDCl3):
d
¼7.58 (d, J¼8.4 Hz, 1H, Ar),
(CH(CO2Me)NH2)-2-Br-3}]2 (3b) a mixture of several species was
obtained. The main component of this mixture (around 90%), was
complex 3b. This mixture could not be purified by column chro-
matography, therefore it was employed as starting material for the
synthesis of the corresponding isoindolinone 4b.
7.33 (d, J¼2.5 Hz, 1H, Ar), 7.15 (dd, J¼8.4, 2.5 Hz, 1H, Ar), 6.51 (br s,
1H, NH), 5.20 (s, 1H, 3-H), 3.86 (s, 3H, OMe), 3.81 (s, 3H, OMe) ppm.
13C NMR (100 MHz, CDCl3):
d¼171.07 (CO), 169.19 (CO), 160.95 (Ar),
132.89 (Ar), 132.66 (Ar), 124.61 (Ar), 120.76 (Ar), 106.72 (Ar), 58.10
(3-C), 55.79 (OMe), 53.10 (OMe) ppm. Anal. Calcd for [C11H11NO4]
0.25CH2Cl2 (242.21): C, 55.73; H, 4.78; N, 5.77. Found: C, 55.72; H,
5.09; N, 5.23. Mass Spect. (ESIþ) [m/z]: 221.9 [M]þ.
4.4.1. Synthesis of [Pd(m-Cl){C6H3-(CH(CO2Me)NH2)-2-OMe-5}]2 (3a).
Compound 2a (200 mg, 0.86 mmol), Pd(OAc)2 (194 mg, 0.86 mmol)
and acetone (200 mL) were reacted as previously described giving
4.5.2. Methyl 4-bromo-(1H)-isoindolin-1-one-3-carboxylate (4b).
Compound 4b was prepared by carbonylation of the crude of the
reaction between 2b and Pd(OAc)2. This mixture of species
(112 mg), containing mainly 3b (90%), was dissolved in chloroform
(10 mL) and allowed to stir under CO atmosphere. Obtained:
[Pd(
m-Cl){C6H3-(CH(CO2Me)NH2)-2-OMe-5}]2 (3a) as a yellow sol-
id.(172 mg, 0.26 mmol, 59%). IR (neat):
n
¼3367, 3265, 1737 cmꢀ1. 1H
NMR (400 MHz, CDCl3þpy-d5): ¼6.94 (d, J¼8.4 Hz, 1H, Ar), 6.53 (dd,
d
J¼8.4,2.6Hz,1H, Ar), 5.57(d, J¼2.6Hz,1H,Ar), 4.90(pseudot,J¼8.0Hz,
1H, CH), 4.66 (br s,1H, NH), 4.54 (br s,1H, NH), 3.80 (s, 3H, OMe), 3.51
61.0 mg, 0.226 mmol (86.4% yield). IR (neat):
n
¼3162, 1742,
(s, 3H, OMe) ppm. 13C NMR (100 MHz, CDCl3þpy-d5):
d¼170.87 (CO),
1697 cmꢀ1. 1H NMR (400 MHz, CDCl3):
d
¼7.77 (d, J¼7.6 Hz, 1H, Ar),
157.27 (Ar), 149.87 (Ar), 123.80 (Ar), 118.55 (Ar), 109.94 (Ar), 105.42
(Ar), 64.70 (CH), 54.97 (OMe), 53.27 (OMe) ppm. Anal. Calcd for
C20H24Cl2N2O6Pd2 (672.17): C, 35.74; H, 3.60; N, 4.17. Found: C, 36.29;
H, 4.09; N, 4.14. Mass Spect. (MALDIþ-DIT) [m/z]: 637.2 [MꢀCl]þ.
7.66 (d, J¼7.6 Hz, 1H, Ar), 7.37 (t, J¼7.6 Hz, 1H, Ar), 7.23 (br s, 1H,
NH), 5.12 (s, 1H, 3-H), 3.71 (s, 3H, OMe) ppm. 13C NMR (100 MHz,
CDCl3):
d
¼168.96 (CO), 166.90 (CO), 140.50 (Ar), 134.87 (Ar), 132.97
(Ar), 130.08 (Ar), 122.17 (Ar), 117.35 (Ar), 58.61 (3-C), 52.15 (OMe)
ppm. Anal. Calcd for [C10H8BrNO3]CHCl3 (389.46): C, 33.92; H, 2.33;
N, 3.59. Found: C, 34.02; H, 2.21; N, 3.70. Mass Spect. (ESIþ) [m/z]:
269.9 [M]þ.
4.4.2. Synthesis of [Pd(m-Cl){C6H3-(CH(CO2Me)NH2)-2-Br-4}]2 (3c).
Compound 2c (242 mg, 0.86 mmol) and Pd(OAc)2 (194 mg,
0.86 mmol) in acetone (200 mL) were reacted as previously de-
scribed giving [Pd(
m
-Cl){C6H3-(CH(CO2Me)NH2)-2-Br-4}]2 (3c) as an
4.5.3. Methyl 5-bromo-(1H)-isoindolin-1-one-3-carboxylate (4c).
Complex 3c (150 mg, 0.20 mmol) and chloroform (15 mL) under CO
atmosphere were employed for the synthesis of 4c. (97 mg,
orange solid (207 mg, 0.27 mmol, 62%). IR (neat):
n
¼3312, 3222,
1739 cmꢀ1. 1H NMR (400 MHz, CDCl3þpy-d5):
¼7.26 (d, J¼2.6 Hz,
d
1H, Ar), 6.91 (dd, J¼8.6, 2.6 Hz,1H, Ar), 5.89 (d, J¼8.6 Hz,1H, Ar), 5.10
0.36 mmol, 92%). IR (neat):
(400 MHz, CDCl3):
n
¼3172, 1744, 1699 cmꢀ1
.
1H NMR
(br s, 1H, NH), 4.92 (m, 1H, CH), 4.57 (br s, 1H, NH), 3.82 (s, 3H, OMe)
d
¼7.88 (s, 1H, Ar), 7.87 (br s, 1H, NH), 7.69e7.71
ppm. 13C NMR (100 MHz, CDCl3þpy-d5):
d¼170.16 (CO), 151.07, (Ar),
(m, 2H, Ar), 5.28 (s, 1H, 3-H), 3.85 (s, 3H, OMe) ppm. 13C NMR
(100 MHz, acetone-d6):
134.13(Ar), 129.39 (Ar), 126.15 (Ar), 123.16 (Ar), 118.43 (Ar), 65.02 (s,
CH), 52.39 (s, OMe) ppm. Anal. Calcd for C18H18Br2Cl2N2O4Pd2
(769.91): C, 28.08; H, 2.36; N, 3.64. Found: C, 28.48; H, 2.09; N, 3.23.
Mass Spect. (MALDIþ-DIT) [m/z]: 385.3 [M/2]þ.
d¼168.87 (CO), 168.40 (CO), 143.61 (Ar),
132.42 (Ar), 131.18 (Ar), 126.91 (Ar), 125.83 (Ar), 125.03 (Ar), 57.95
(3-C), 52.44 (OMe) ppm. Anal. Calcd for [C10H8BrNO3]0.35H2O
(276.38): C, 43.47; H, 3.17; N, 5.07. Found: C, 43.47; H, 3.78; N, 4.43.
Mass Spect. (ESIþ) [m/z]: 269.9 [M]þ.
4.4.3. Synthesis of [Pd(m-Cl){C6H3-(CH(CO2Me)NH2)-2-Br-5}]2 (3d).
Compound 2d (242 mg, 0.86 mmol) and Pd(OAc)2 (194 mg,
0.86 mmol) in acetone (200 mL) were reacted as previously de-
scribed giving [Pd(m-Cl){C6H3-(CH(CO2Me)NH2)-2-Br-5}]2 (3d) as
4.5.4. Methyl 6-bromo-(1H)-isoindolin-1-one-3-carboxylate (4d).
In a similar way the synthesis of 4d was carried out starting from
complex 3d (150 mg, 0.20 mmol) in chloroform (15 mL) under CO
an orange solid (217 mg, 0.28 mmol, 66%). IR (neat):
n
¼3312,
atmosphere (98 mg, 0.36 mmol, 93%). IR (neat):
n
¼3181, 1745,
3222, 1739 cmꢀ1
.
1H NMR (400 MHz, CDCl3þpy-d5):
d
¼7.11 (dd,
1706 cmꢀ1. 1H NMR (400 MHz, CDCl3):
d
¼8.00 (s, 1H, Ar), 7.75 (d,

4190
S. Nieto et al. / Tetrahedron 67 (2011) 4185e4191
J¼7.8 Hz, 1H, Ar), 7.61 (d, J¼7.8 Hz, 1H, Ar), 7.25 (br s, 1H, NH), 5.25
residue in dry dichloromethane (7 mL) triethylsilane (0.42 mL,
2.63 mmol) and boron trifluoride etherate (0.37 mL, 3.01 mmol)
were added at ꢀ78 ꢁC. After being stirred for 3 h at ꢀ78 ꢁC, the re-
action mixture was quenched with saturated aqueous sodium bi-
carbonate (10 mL) and extracted with dichloromethane (2ꢂ10 mL).
The combined organic layers were dried over magnesium sulfate,
filtered, and concentrated. The resulting residue was purified by
column chromatography (eluent: hexanes/ethyl acetate 4:1) to af-
(s, 1H, 3-H), 3.84 (s, 3H, OMe) ppm. 13C NMR (100 MHz, CDCl3):
d
¼169.24 (CO), 168.39 (CO), 139.35 (Ar), 135.46 (Ar), 133.14 (Ar),
127.24 (Ar), 125.40 (Ar), 123.64 (Ar), 58.26 (3-C), 53.31 (OMe)
ppm. Anal. Calcd for C10H8BrNO3 (270.08): C, 44.61; H, 3.00; N,
5.21. Found: C, 45.12; H, 2.61; N, 5.53. Mass Spect. (ESIþ) [m/z]:
269.9 [M]þ.
4.6. Methyl (3S*,3aR*,7aS*)-octahydroisoindol-1-one-3-
carboxylate (6)
ford 8 as a colorless oil (319 mg, 1.12 mmol, 88%). IR (neat):
n
¼1762,
1712 cmꢀ1 1H NMR (400 MHz, CDCl3):
.
d
(duplicated signals are
observed for some protons; asterisks indicate those corresponding
A solution of methyl isoindolin-1-one-3-carboxylate (400 mg,
2.09 mmol) in acetic acid (8 mL) was hydrogenated at 70 ꢁC and
atmospheric pressure using PtO2 (40 mg) as catalyst. After 48 h the
catalyst was filtered off and washed with acetic acid and the solvent
evaporated. The resulting residue was purified by flash chroma-
tography (eluent: CH2Cl2/iPrOH 95:5) to obtain 6 as a white solid
to the minor rotamer)¼4.33* (d, J¼7.0 Hz,1H,1-H), 4.28 (d, J¼6.9 Hz,
1H,1-H), 3.72 (s, 3H, OMe), 3.71 (s, 3H, OMe), 3.56e3.48* (m, 2H, 3-
*
H), 3.46e3.36 (m, 2H, 3-H), 2.45e2.37 (m, 1H, 7a-H), 2.35e2.25 (m,
1H, 3a-H), 1.75e1.10 (m, 8H, cyclohexaneeCH2), overlapped with
1.46* (s, 9H, tBu), 1.40 (s, 9H, tBu) ppm. 13C NMR (100 MHz, CDCl3):
d
(duplicated signals are observed for most carbons; asterisks in-
(389 mg, 1.92 mmol, 92%). Mp 146e148 ꢁC. IR (KBr):
n
¼3226, 1741,
dicate those corresponding to the minor rotamer)¼171.58 (CO),
170.97* (CO), 154.90* (CO), 154.33* (CO), 79.77 (tBu-C), 79.66* (tBu-
C), 63.94 (1-C), 63.44* (1-C), 51.56* (OMe), 51.40 (OMe), 48.48* (3-
C), 47.89 (3-C), 40.79 (7a-C), 39.82* (7a-C), 37.05* (3a-C), 36.40 (3a-
C), 28.31* (tBu-CH3), 28.08 (tBu-CH3), 24.67* (cyclohexaneeCH2),
24.60 (cyclohexaneeCH2), 24.02 (cyclohexaneeCH2), 23.98*
(cyclohexaneeCH2), 23.25 (cyclohexaneeCH2), 23.24* (cyclo-
hexaneeCH2), 21.16* (cyclohexaneeCH2), 21.11 (cyclohexaneeCH2)
ppm. HRMS (ESI): calcd for C15H25NNaO4 [MþNa]þ 306.1676; found
306.1678.
1712 cmꢀ1. 1H NMR (400 MHz, CDCl3):
d
¼6.36 (br s, 1H, NH), 4.26
(d, J¼5.5 Hz, 1H, 3-H), 3.75 (s, 3H, OMe), 2.72e2.63 (m, 1H, 3a-H),
2.60e2.54 (m, 1H, 7a-H), 2.20e2.13 (m, 1H, cyclohexaneeCH2),
1.68e1.36 (m, 4H, cyclohexaneeCH2), 1.20e1.05 (m, 3H, cyclo-
hexaneeCH2) ppm. 13C NMR (100 MHz, CDCl3):
d
¼177.39 (CO),
170.58 (CO), 58.35 (3-C), 52.28 (OMe), 42.09 (7a-C), 38.52 (3a-C),
23.65 (cyclohexaneeCH2), 23.47 (cyclohexaneeCH2), 22.65 (cyclo-
hexaneeCH2), 22.57 (cyclohexaneeCH2) ppm. HRMS (ESI): calcd
for C10H15NNaO3 [MþNa]þ 220.0944; found 220.0946.
4.7. Methyl (3S*,3aR*,7aS*)-N-(tert-butoxycarbonyl)
octahydroisoindol-1-one-3-carboxylate (7)
Acknowledgements
Financial support from the Spanish Ministerio de Ciencia e
To a solution of 6 (350 mg, 1.77 mmol) in THF (10 mL) was added
di-tert-butyl dicarbonate (968 mg, 4.44 mmol) and 4-(dimethyla-
mino)pyridine (19 mg, 0.18 mmol). The reaction mixture was stir-
red at room temperature for 12 h and then the solvent was
evaporated under vacuum. The residue was purified by column
chromatography (eluent: hexanes/ethyl acetate 7:3) to obtain 7 as
a white solid (429 mg, 1.44 mmol, 80%). Mp 91e93 ꢁC. IR (KBr):
ꢀ
Innovacion (projects CTQ2008-01784 and CTQ2010-17436) and
ꢀ
Gobierno de Aragon (project PI071/09; research groups E21 and
E40) is gratefully acknowledged. S. N. thanks to the CSIC (Spain) for
a JAE-DOC contract. P. L. thanks to the Spanish Ministerio de Ciencia
ꢀ
e Innovacion for a predoctoral fellowship.
n
¼1773, 1742 cmꢀ1. 1H NMR (400 MHz, CDCl3):
¼4.50 (d, J¼6.3 Hz,
d
References and notes
1H, 3-H), 3.74 (s, 3H, OMe), 2.66e2.50 (m, 2H, 3a-H, 7a-H),
2.18e2.08 (m, 1H, cyclohexaneeCH2), 1.59e1.05 (m, 7H, cyclo-
hexaneeCH2), overlapped with 1.47 (s, 9H, tBu) ppm. 13C NMR
1. (a) Lee, J. H.; Byeon, S. R.; Kim, Y. S.; Lim, S. J.; Oh, S. J.; Moon, H. C.; Yoo, K. H.;
Chung, B. Y.; Kim, D. J. Bioorg. Med. Chem. Lett. 2008, 18, 5701; (b) Lee, S.; Shinji,
C.; Ogura, K.; Shimizu, M.; Maeda, S.; Sato, M.; Yoshida, M.; Hashimoto, Y.;
(100 MHz, CDCl3):
d
¼174.18 (CO), 169.54 (CO), 149.88 (CO), 83.45
€
Miyachi, H. Bioorg. Med. Chem. Lett. 2007, 17, 4895; (c) Lubbers, T.; Angehrn, P.;
(tBu-C), 61.66 (3-C), 52.12 (OMe), 43.39 (7a-C), 33.59 (3a-C), 27.96
(tBu-CH3), 24.11 (cyclohexaneeCH2), 23.21 (cyclohexaneeCH2),
22.90 (cyclohexaneeCH2), 22.31 (cyclohexaneeCH2) ppm. HRMS
(ESI): calcd for C15H23NNaO5 [MþNa]þ 320.1468; found 320.1471.
€
Gmunderb, H.; Herzig, S. Bioorg. Med. Chem. Lett. 2007, 17, 4708; (d) Hamprecht,
D.; Micheli, F.; Tedesco, G.; Checchia, A.; Donati, D.; Petrone, M.; Terreni, S.;
ꢀ
Wood, M. Bioorg. Med. Chem. Lett. 2007, 17, 428; (e) Guillaumel, J.; Leonce, S.;
ꢀ
Pierre, A.; Renard, P.; Pfeiffer, B.; Arimondo, P. B.; Monneret, C. Eur. J. Med. Chem.
2006, 41, 379; (f) Honma, T.; Hayashi, K.; Aoyama, T.; Hashimoto, N.; Machida,
T.; Fukasawa, K.; Iwama, T.; Ikeura, C.; Ikuta, M.; Suzuki-Takahashi, I.; Iwasawa,
Y.; Hayama, T.; Nishimura, S.; Morishima, H. J. Med. Chem. 2001, 44, 4615.
2. (a) Kim, J. K.; Kim, Y. H.; Nam, H. T.; Kim, B. T.; Heo, J.-N. Org. Lett. 2008, 10,
4.8. Methyl (1S*,3aS*,7aR*)-N-(tert-butoxycarbonyl)
octahydroisoindol-1-carboxylate (8)
ꢀ
3543; (b) Wehlan, H.; Jezek, E.; Lebrasseur, N.; Pave, G.; Roulland, E.; White, A.
J. P.; Burrows, J. N.; Barrett, A. G. M. J. Org. Chem. 2006, 71, 8151; (c) Comins, D.
L.; Schilling, S.; Zhang, Y. Org. Lett. 2005, 7, 95; (d) Yoon, U. C.; Jin, Y. X.; Oh, S.
W.; Park, C. H.; Park, J. H.; Campana, C. F.; Cai, X.; Duesler, E. N.; Mariano, P. S. J.
Am. Chem. Soc. 2003, 125, 10664; (e) Link, J. T.; Raghavan, S.; Danishefsky, S. J. J.
Am. Chem. Soc. 1995, 117, 552.
To a stirred solution of 7 (380 mg, 1.28 mmol) in dry THF (7 mL)
at ꢀ78 ꢁC under argon atmosphere was added a 1M solution of di-
iso-butylaluminum hydride in hexanes (1.92 mL, 1.92 mmol) drop-
wise. The reaction mixture was stirred at ꢀ78 ꢁC for 2 h and then
quenched with a saturated potassium acetate aqueous solution
(3 mL) and allowed to warm to room temperature. After that, a 3:1
mixture of diethyl ether and saturated aqueous ammonium chloride
(23 mL) was added and the resulting mixture was stirred at room
temperature until a suspension was formed. The solid was filtered
off under reduced pressure and washed with diethyl ether
(2ꢂ10 mL). The organic layer was separated and the aqueous phase
was extracted with diethyl ether (2ꢂ20 mL). The combined organic
extracts were washed with brine (10 mL), dried over magnesium
sulfate, filtered, and evaporated. The resulting residue was used for
the next step without further purification. To a stirred solution of the
3. Lamblin, M.; Couture, A.; Deniau, E.; Grandclaudon, P. Tetrahedron: Asymmetry
2008, 19, 111.
4. For the antihypertensive activity see: (a) Ferland, J.-M.; Demerson, C. A.;
Humber, L. G. Can. J. Chem. 1985, 63, 361 For the antipsychotic activity see: (b)
Zhuang, Z.-P.; Kung, M.-P.; Mu, M.; Kung, H. F. J. Med. Chem. 1998, 41, 157; (c)
Linden, M.; Hadler, D.; Hofmann, S. Hum. Psychopharmacol. 1997, 12, 445; (d)
Norman, M. H.; Minick, D. J.; Rigdon, G. C. J. Med. Chem. 1996, 39, 149 For the
antiinflammatory activity see: (e) Li, S.; Wang, X.; Guo, H.; Chen, L. Yiyao
Gongye 1985, 16, 543; Chem. Abstr. 1986, 105, 6378 For the anaesthesic activity
see: (f) Laboratori Baldacci, S.P.A. Japanese Patent 5,946,268, 1984; Chem. Abstr.
1984, 101, 54922 For the antiulcer activity see: (g) Lippmann, W. U.S. Patent
4,267,189, 1981; Chem. Abstr. 1981, 95, 61988 For the antiviral activity see: (h)
De Clercq, E. J. Med. Chem. 1995, 38, 2491; (i) Pendrak, I.; Barney, S.; Wittrock,
R.; Lambert, D. M.; Kingsbury, W. D. J. Org. Chem. 1994, 59, 2623 For the anti-
leukemic activity see: (j) Taylor, E. C.; Zhou, P.; Jennings, L. D.; Mao, Z.; Hu, B.;
Jun, J.-G. Tetrahedron Lett. 1997, 38, 521.

S. Nieto et al. / Tetrahedron 67 (2011) 4185e4191
4191
ꢀ
ꢀ
5. Arvidsson, P.; Besidski, Y.; Csjernyik, G.; Lange, T.; Macsari, I.; Nilsson, L. WO
(g) Cho, C. S.; Ren, W. X. Tetrahedron Lett. 2009, 50, 2097; (h) Lopez, B.;
Rodríguez, A.; Santos, D.; Albert, J.; Ariza, X.; García, J.; Granell, J. Chem. Com-
mun. 2011, 1054 Selected examples of stoichiometric processes: (i) Dupont, J.;
Pfeffer, M.; Daran, J. C.; Jeannin, Y. Organometallics 1987, 6, 899; (j) Vicente, J.;
2009/145718 A1; Chem. Abstr. 2009, 152, 12153.
€
€
€
6. Bjore, A.; Bostrom, J.; Davidsson, O.; Emtenas, H.; Gran, U.; Iliefski, T.; Kajanus,
J.; Olsson, R.; Sandberg, L.; Strandlund, G.; Sundell. J.; Kuan, Z.-Q. WO 2008/
008022 A1; Chem. Abstr. 2008, 148, 168577.
ꢀ
Saura-Llamas, I.; García-Lopez, J. A.; Calmuschi-Cula, B.; Bautista, D. Organo-
metallics 2007, 26, 2768; (k) Vicente, J.; Saura-Llamas, I.; García-Lopez, J. A.;
ꢀ
7. (a) Othman, M.; Pigeon, P.; Decroix, B. Tetrahedron 1998, 54, 8737; (b) Othman,
M.; Decroix, B. Synth. Commun. 1996, 26, 2803.
Bautista, D. Organometallics 2009, 28, 448.
8. (a) Banzatti, C.; Carfagna, N.; Commisso, R.; Heidempergher, F.; Pegrassi, L.;
Melloni, P. J. Med. Chem. 1988, 31, 1466; (b) Valencia, E.; Patra, A.; Freyer, A. J.;
Shamma, M.; Fajardo, V. Tetrahedron Lett. 1984, 25, 3163.
9. (a) Ben-Othman, R.; Othman, M.; Ciamala, K.; Knorr, M.; Strohmann, C.; De-
croix, B. Tetrahedron 2009, 65, 4846; (b) Ben-Othman, R.; Othman, M.; Coste, S.;
Decroix, B. Tetrahedron 2008, 64, 559.
16. Nieto, S.; Arnau, P.; Serrano, E.; Navarro, R.; Soler, T.; Cativiela, C.; Urriolabeitia,
E. P. Inorg. Chem. 2009, 48, 11963.
17. For a recent example see: Van der Linden, M.; Borsboom, J.; Kaspersen, F.;
Kemperman, G. Eur. J. Org. Chem. 2008, 2989.
18. Fuchita, Y.; Yoshinaga, K.; Ikeda, Y.; Kinoshita-Kawashima, J. J. Chem. Soc., Dalton
Trans. 1997, 2495.
10. (a) El Nemr, A. Tetrahedron 2000, 56, 8579; (b) Legler, G. Adv. Carbohydr. Chem.
Biochem. 1990, 48, 319; (c) Ostrander, G. K.; Scribner, N. K.; Rohrschneider, L. R.
Cancer Res. 1988, 48, 1091; (d) Elbein, A. D. Annu. Rev. Biochem. 1987, 56, 497.
11. Kametani, T.; Suguhara, H.; Kanno, K. Chem. Pharm. Bull. 1967, 15, 1916.
12. Lowe, J. A.; Ewing, F. E. J. Heterocycl. Chem. 1987, 24, 877.
19. Deeming, A. J.; Rothwell, I. P.; Hursthouse, M. B.; New, L. J. Chem. Soc., Dalton
Trans. 1978, 1490.
20. Guzzo, P. R.; Hamby, J. M.; Johnson, M. R.; Le, V.-D.; Mangette, J. E.; Shenoy, R.
A.; Stier, M. A. WO 2004/092134 A1, 2004; Chem. Abstr. 2004, 141, 380131.
21. Lin, L. S.; Doherty, G.; Shah, S. K.; Chang, L. L.; Hagmann, W. K.; Mumford, R. A.
U.S. Patent 2003/0008861, 2003; Chem. Abstr. 2003, 138, 90079.
22. Blankley, C. J.; Kaltenbronn, J. S.; DeJhon, D. E.; Werner, A.; Bennett, L. R.; Bo-
bowski, G.; Krolls, U.; Johnson, D. R.; Pearlman, W. M.; Hoefle, M. L.; Essenburg,
A. D.; Cohen, D. M.; Kaplan, H. R. J. Med. Chem. 1987, 30, 992.
13. Couture,A.; Deniau, E.;Ionescu, D.;Grandclaudon, P. Tetrahedron Lett.1998, 39, 2319.
14. (a) Thompson, J. M.; Heck, R. F. J. Org. Chem. 1975, 40, 2667; (b) Modern Car-
bonylation Methods; Kollar, L., Ed.; Wiley-VCH, Weinhein: Germany, 2006; (c)
€
Brennfuhrer, A.; Neumann, H.; Beller, M. Angew. Chem., Int. Ed. 2009, 48, 4114.
ꢀ
15. Selected examples of catalytic processes: (a) Anderson, J. C.; Flaherty, A.;
Swarbrick, M. E. J. Org. Chem. 2000, 65, 9152; (b) Grigg, R.; Zhang, L.; Collard, S.;
Keep, A. Tetrahedron Lett. 2003, 44, 6979; (c) Orito, K.; Horibata, A.; Nakamura,
T.; Ushito, H.; Nagasaki, H.; Yuguchi, M.; Yamashita, S.; Tokuda, M. J. Am. Chem.
Soc. 2004, 126, 14342; (d) Orito, K.; Miyazawa, M.; Nakamura, T.; Horibata, A.;
Ushito, H.; Nagasaki, H.; Yuguchi, M.; Yamashita, S.; Yamazaki, T.; Tokuda, M. J.
Org. Chem. 2006, 71, 5951; (e) Wada, Y.; Nagasaki, H.; Tokuda, M.; Orito, K. J.
Org. Chem. 2007, 72, 2008; (f) Ren, W.; Yamane, M. J. Org. Chem. 2009, 74, 8332;
23. Sayago, F. J.; Jimenez, A. I.; Cativiela, C. Tetrahedron: Asymmetry 2007, 18, 2358.
24. CrysAlis REDVersion 1.171.27; Oxford Diffraction Ltd.: Yarnton: England, 2005;p 8.
€
25. Sheldrick, G. M. SADABS: Empirical Absorption Correction Program; Gottingen
€
University, Gottingen: Germany, 1996.
26. Sheldrick, G. M. SHELXS-86 Acta Crystallogr. 1990, A46, 467.
27. Sheldrick, G. M. SHELXL-97 Acta Crystallogr. 2008, A64, 112.
28. Baumgarten, H. E.; Dirks, J. E.; Petersen, J. M.; Zey, R. L. J. Org. Chem. 1966, 31,
3708.