Intramolecular thiopalladation of thioanisole-substituted propargyl imines: Synthesis of benzothiophene-based palladacycles

Article abstract of DOI:10.1021/om9003658

A highly selective intramolecular thiopalladation has been achieved by the treatment of o-SMeC₆H₄C≡CC(CF₃)(=N-4- OCH₃C₆H₄), 1, with PdCl₂(PhCN) ₂ in THF at O °C to aff

Full text of DOI:10.1021/om9003658

3966 Organometallics 2009, 28, 3966–3969
DOI: 10.1021/om9003658
Intramolecular Thiopalladation of Thioanisole-Substituted Propargyl
Imines: Synthesis of Benzothiophene-Based Palladacycles
Pravin R. Likhar,*,† Subhas M. Salian,† Sarabindu Roy,† M. Lakshmi Kantam,†
B. Sridhar,‡ K. Veera Mohan,§ and B. Jagadeesh§
†I&PC Division, and ‡X-ray Crystallography Center, §NMR Center, Indian Institute of
Chemical Technology, Hyderabad, India
Received May 8, 2009
Chart 1. Palladacycles Derived from Alkynes via Nucleophilic
Palladation
Summary: A highly selective intramolecular thiopalladation
has been achieved by the treatment of o-SMeC6H4CtCC-
(CF3)(dN-4-OCH3C6H4), 1, with PdCl2(PhCN)2 in THF
at 0 °C to afford [(C8H4S-3-)C(CF3)(dN-4-OCH3C6H4)-
Pd(μ-Cl)]2, 4. The mechanistic implications of the results with
1
the aid of low-temperature H NMR and ATR-IR spectros-
copy are discussed.
Palladacycles are a class of organometallic compounds of
considerable interest due to their air- and moisture-tolerant
character and also due to their variety of applications in
catalysis, material science, and organic synthesis and in
biological and medicinal chemistry as potential anticancer
agents.1 Among the known protocols,1d the synthesis of
palladacycles derived from a CtC bond has received great
attention, as this method can also be used to derive various
useful Pd-vinyl intermediate species in organic synthesis.2
The previous reports for the synthesis of this type of pallada-
cycles have been known only via intermolecular nucleophilic
addition of the chloride anion onto the CtC bond in which
the heteroatom is incorporated in the ring system of the
cyclopalladated product (Chart 1, type A).3 On the other
hand, when the reaction proceeds via an intramolecular
pathway, the formation of a heterocyclic ring system
is realized through the generation of organopalladium
intermediate species (Chart 1, type B).2a,2b,2j The synthesis
of 2,3-disubstituted indoles and benzofurans has been
achieved via an intramolecular pathway in the presence of
catalytic amounts of palladium and the corresponding
2-alkynyl anilines or 2-alkynyl phenols. However, in the case
of 2,3-disubstituted benzothiophene, the 2-alkynyl thiophe-
nol is not accessible by Songashira coupling of 2-halo
benzenethiols with alkynes because the palladium-catalyzed
reaction does not proceed due to poisoning by the mercapto
group.4 The synthesis of 2,3-disubstituted benzothiophene
via organopalladium species is a challenging research area
since the structural framework of the substituted benzothio-
phene is often seen in biologically active compounds.5 More-
over, the isolation of the corresponding intermediary
organopalladium compounds in the presence of a potentially
coordinating group is likely to provide a new route for
the synthesis of annulated benzothiophene-based palla-
dium complexes. In this respect, we herein report the first
synthesis and characterization of air- and moisture-stable
perfluoroalkyl-substituted benzothiophene-based pallada-
cycles starting from ortho-thioanisole-substituted perfluoro-
alkyl propargyl imines and palladium chloride salts via
intramolecular thiopalladation reaction.
In a continuation of our previous result on the synthesis of
highly substituted 2-perfluoroalkyl quinolines via electro-
philic iodocyclization of various perfluoroalkyl propargyl
imines/amines, we started investigating the reaction of thioa-
nisole-substituted perfluoroalkyl propargyl imines with a
stoichiometric amount of palladium salts.6 Accordingly, we
prepared propargyl imines bearing an o-SMe unit in a single
step, by Sonogashira coupling of perfluoroalkyl imidoyl
iodides and the corresponding alkyne, in excellent yields
according to the reported procedure (Chart 2).6 We initiated
the palladation reaction of a propargyl imine bearing an
*Corresponding author. E-mail: plikhar@iict.res.in. Fax: 91
4027160921; Tel: 91 4027191667.
(1) Reviews: (a) Herrmann, W. A.; Bohm, V. P. W.; Reisinger, C. P.
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Eur. J. Inorg. Chem. 2001, 1917. (c) Beletskaya, I. P.; Cheprakov, A. V. J.
Organomet. Chem. 2004, 689, 4055. (d) Dupont, J.; Consorti, C. S.; Spencer,
J. Chem. Rev. 2005, 105, 2527. (e) Dunina, V. V.; Gorunova, O. N. Russ.
Chem. Rev. 2005, 74, 871. (f) Ghedini, M.; Aiello, I.; Crispini, A.; Golemme,
A.; La Deda, M.; Pucci, D. Coord. Chem. Rev. 2006, 250, 1373. (g) Caires,
A. C. F. Anti-Cancer Agents Med. Chem. 2007, 7, 484. (h) Garoufis, A.;
Hadjikakou, S. K.; Hadjiliadis, N. Coord. Chem. Rev. 2009, 253, 1384.
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r
pubs.acs.org/Organometallics
Published on Web 06/25/2009
2009 American Chemical Society

Communication
Organometallics, Vol. 28, No. 14, 2009 3967
ortho-thioanisole unit, 2, with a methanolic solution of
Li2PdCl4/LiCl at 0 °C (Scheme 1). Initially, we observed
the formation of a red solution, which gradually transformed
into an air- and moisture-stable orange solid in 1 h. These
observations prompted us to investigate the probable for-
mation of palladacycles produced in the reaction mixture.
The solid palladacycle 4 was isolated in good yield (62%) and
characterized as given below.
suggests the interaction of the nitrogen lone pair with the
palladium atom. The single crystal of 4 was obtained on slow
evaporation of chloroform at room temperature. The struc-
ture of 4 was ascertained by means of X-ray diffraction. The
crystallographic data of the dimeric compound 4 suggest that
the Pd(II) center is coordinated in a square-planar fashion by
the N1, an imine nitrogen atom, and the C3(sp2) vinyl carbon
atom on one side and two bridging Cl atoms on other side
(Figure 1).
The 13C NMR and IR spectra of 1 show characteristic
resonances of a CtC bond at 85.5 and 97.3 ppm and a
stretching frequency at 2189 cm-1, respectively (see the
Supporting Information), which are absent upon the cyclo-
palladation in 4. Similarly, the 1H NMR spectra of 5 clearly
show the absence of a CH3 signal from the o-SCH3C6H4
group. Further, the change in chemical shift from 133 ppm to
166 ppm in the 13C NMR of the imine carbon atom (CdN)
The stereochemistry of the palladacycle 4 was observed as
a transoid dimeric form with the asymmetric unit containing
one half-molecule and the other half generated by a crystal-
lographic 2-fold axis of symmetry. We have also successfully
isolated the pincer-type complexes 5 (yield 10%) and 7 (yield
4%) from the filtrate by column chromatography. A single
crystal of 7 was obtained on slow evaporation of chloroform
at room temperature. The structure of the palladacycle 7 was
1
confirmed by H and 13C NMR, elemental analysis, and
X-ray diffraction (Figure 2).
Figure 2. X-ray structure of SCN pincer-type chloropallada-
cycle 7. Displacement ellipsoids are drawn at the 30% prob-
ability level, and H atoms are shown as small spheres of
Figure 1. X-ray structure of dimeric thiopalladacycle 4. Dis-
placement ellipsoids are drawn at the 30% probability level,
and H atoms are shown as small spheres of arbitrary radius.
Unlabeled atoms are generated by the symmetry code (-xþ
˚
arbitrary radius. Selected bond lengths [A] and bond angles
[deg]: C7-Pd1 = 1.972(5); Cl1-Pd1 = 2.3775(14); N1-Pd1 =
2.052(4); Pd1-S2 = 2.2483(13); C8-Cl2 = 1.752(5); C4-S2 =
1.780(6); C20-S2 = 1.814(6); C7-Pd1-N1 = 81.86(18);
N1-Pd1-S2 = 169.19(12); C7-Pd1-S2 = 87.42(15); C7-
Pd1-S2 = 87.42(15); C7-Pd1-Cl1 = 177.17(14); N1-Pd1-
Cl1 = 99.83(12); S2-Pd1-Cl1 = 90.93(5).
˚
1/2, -yþ3/2, -zþ1). Selected bond lengths [A] and bond
angles [deg]: N1-Pd1 = 2.0439(19); Cl1-Pd1 = 2.3152(6);
C2-S1 = 1.747(2); C9-S1 = 1.729 (3); C14-O1 = 1.375(3);
C3-Pd1-N1 = 81.16(9); N1-C1-C2 = 115.4(2); C9-S1-
C2 = 90.03(12).
Chart 2. Various Perfluoroalkyl Propargyl Imines Investigated for the Cyclopalladation Reaction
Scheme 1. Synthesis of Dimeric Palladacycles and SCN Pincer-Type Palladacycles

3968 Organometallics, Vol. 28, No. 14, 2009
Likhar et al.
Figure 3. Possible mechanism for the formation of 4 and 5. Reaction pathway for 4 and 5 investigated by 1H NMR spectroscopy.
To the best of our knowledge, this is the first cyclopallada-
tion reaction where intramolecular thiopalladation and
intermolecular chloropalladation took place simultaneously
to form a dimeric palladacycle as a major compound and a
SCN pincer-type palladacycle as a minor compound from a
single ligand precursor.
The possible reaction pathway for the formation of a
benzothiophene-based palladacycle and a pincer-type complex
has been monitored using 1H NMR and ATR-IR spectrosco-
py. In the proposed mechanism, we speculate that the first step
involves the coordination of the N atom followed by interaction
of the triple bond to the electrophilic Pd center to give an
intermediate A and B, respectively.3d,7 The formation of B8 is
observed by the change in chemical shift for the ortho-proton of
the phenyl ring to a triple bond after coordinating to a Pd center
(Hc, 7.44 to 8.42 ppm; see Figure 3). The intermediate B can
(7) (a) Dupont, J.; Casagrande, O. L.; Aiub, A. C., Jr.; Beck, J.;
€
Horner, M.; Bortoluzzi, A. Polyhedron 1994, 13, 2583. (b) Huang, Q.;
Larock, R. C. J. Org. Chem. 2003, 68, 980.
(8) Li2PdCl4 (0.03 mmol)/LiCl solution was prepared in CD3OD (0.4
mL) and transferred to an NMR tube under N2 atmosphere. Alkyne 2
(0.03 mmol) in CD3OD (0.4 mL) was added to the NMR tube at -30 °C.
The NMR tube was shaken well and subjected to 1H NMR analysis at
-5 °C (INOVA, 400 MHz).

Communication
Organometallics, Vol. 28, No. 14, 2009 3969
Table 1. Intramolecular Thiopalladation of ortho-Thioanisole-
Substituted Perfluoroalkyl Propargyl Imines
Scheme 2. Bridge Splitting of Dimeric Palladacycle 5
reaction by screening the various palladium precursors,
solvent systems, temperature, etc. To our delight, using
PdCl2(PhCN)2 in THF with alkyne 1 at 0 °C, only the
dimeric palladacycle was obtained in high yield (85%).
The scope of the thiopalladation reaction was then
extended to the alkynes 2 and 3 under the same optimized
reaction conditions (Table 1). The dimeric palladacycles
6 and 8 were fully characterized by 1H and 13C NMR and
IR (see the SI).
Finally, the bridge-splitting reaction of dimeric pallada-
cycle 4 was examined with 8-hydroxyquinoline in ethanol at
room temperature to afford monomeric palladacycle 9 in
moderate yield (Scheme 2). The molecular geometry of 9 is
expected as N,N cis- type, as confirmed by 1H NMR.9
In conclusion, this work reports the first intramolecular
thiopalladation of ortho-thioanisole-substituted propargyl
imines to annulated benzothiophene-based palladacycles in
a single step under mild reaction conditions with good yields.
The method allows an easy access to heterocyclic-based
palladacycles that does not require a heterocyclic ligand
system. The new synthetic protocol can be extended to the
synthesis of 2,3-disubstituted benzothiophenes using cataly-
tic palladium and appropriate electrophiles (work is in
progress). The application of other heteroatoms such as
N, O, and Se for the synthesis of annulated heterocyclic-
based palladacycles is also under active investigation.
Reaction conditions: alkyne (0.25 mmol), PdCl2(PhCN)2 (0.25 mmol),
and THF (5 mL) at 0 °C, stirred for 2 h and warmed slowly to room
temperature.
undergo either intramolecular thio addition or intermolecular
chloride addition. The above experimental evidence indicates
that intramolecular addition is a thermodynamically more
favored process than the intermolecular addition. In intramo-
lecular nucleophilic addition, the electronically rich thio group
attacks the activated triple bond, followed by the removal
of methyl group via SN2 nucleophilic displacement by the
Cl anion present in the reaction medium, resulting in the
intermediate C (see the SI for ATR-IR experimentation for
gradual disappearance of the triple bond). The anionic pallada-
cycle is further stabilized into a thermodynamically favored
dimeric cyclopalladated form.
Acknowledgment. M.S.S. and S.R. thank CSIR for
providing a research fellowship.
In order to achieve high selectivity and high yield
for compound 4, we have optimized the thiopalladation
Supporting Information Available: Experimental procedures,
characterization data for all ligands and palladacycles, and
X-ray crystallography data for 4 (CCDC 718850) and 7 (CCDC
718851). This material is available free of charge via the Internet
at http://pubs.acs.org.
(9) 1H NMR of 9 showed a single isomer. (a) Ghedini, M.; Aiello, I.;
La Deda., M.; Grisolia, A. Chem. Commun. 2003, 2198. (b) Pucci, D.;
Albertini, V.; Bloise, R.; Bellusci, A.; Cataldi, A.; Catapano, C. V.;
Ghedini, M.; Crispini, A. J. Inorg. Biochem. 2006, 100, 1575.