Conjugated Thiophene-Fused Isatin Dyes through Intramolecular Direct Arylation

Article abstract of DOI:10.1021/acs.joc.6b01922

We report on the design, synthesis, and properties of innovative, planar, π-conjugated compounds in which a thiophene ring is fused with the skeleton of the naturally occurring dye isatin. The synthesis is achieved in high yields making use of an intramolecular direct arylation reaction as the key step, making the overall process potentially scalable. The synthetic sequence has been demonstrated also for an isatin bearing fluorine substituents on the aromatic ring. NMR and X-ray studies demonstrate the crosstalk occurring between the fused, coplanar, and conjugated moieties, making these novel dyes with a donor-acceptor character. Cyclic voltammetry and UV-vis studies confirm very interesting HOMO-LUMO levels and energy gaps for the new compounds.

Full text of DOI:10.1021/acs.joc.6b01922

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Article
Conjugated Thiophene-Fused Isatin Dyes
through Intramolecular Direct Arylation
Andrea Nitti, Marco Signorile, Massimo Boiocchi, Gabriele Bianchi, Riccardo Po, and Dario Pasini
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01922 • Publication Date (Web): 06 Oct 2016
Downloaded from http://pubs.acs.org on October 7, 2016
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Conjugated ThiopheneꢀFused Isatin Dyes through
Intramolecular Direct Arylation
Andrea Nitti,a Marco Signorile,a Massimo Boiocchi,b Gabriele Bianchi,c
Riccardo Poc and Dario Pasini*,a,d
a) Department of Chemistry, University of Pavia, Viale Taramelli, 12 – 27100 Pavia ꢀItaly.
b) Centro Grandi Strumenti, University of Pavia, Via Bassi 21, 27100 Pavia, Italy.
c) Research Center for Renewable Energies and Environment, Istituto Donegani, Eni Spa, Via Fauser
4, 28100 Novara, Italy.
d) INSTM Research Unit, University of Pavia, Viale Taramelli, 12 – 27100 Pavia ꢀItaly.
Email: dario.pasini@unipv.it
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ABSTRACT. We report on the design, synthesis and properties of innovative, planar, πꢀconjugated
compounds in which a thiophene ring is fused with the skeleton of the naturallyꢀoccurring dye isatin.
The synthesis is achieved in high yields making use of an intramolecular Direct Arylation reaction as
the key step, making the overall process potentially scalable. The synthetic sequence has been
demonstrated also for an isatin bearing fluorine substituents on the aromatic ring. NMR and Xꢀray
studies demonstrate the crosstalk occurring between the fused, coplanar and conjugated moieties,
making these novel dyes with a DonorꢀAcceptor character. Cyclic voltammetry and UVꢀVis studies
confirm very interesting HOMOꢀLUMO levels and energy gaps for the new compounds.
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Figure for the Table of Contents
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INTRODUCTION
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Organic dyes constitute a large and important class of industrial products. They are generally
characterized by good optical absorption and mechanical properties, and by solution processability
and stability; these properties are also desirable for solidꢀstate applications, therefore major classes of
industrial dyes and pigments (phthalocyanines, naphthalene diimides, diketopyrrolopyrroles, indigos
and isoindigos, squaraines) have already found applications in the broad world of organic
electronics.1 In fact, organic dyes such as diketopyrrolopyrrole or naturallyꢀoccurring isoindigo,
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when incorporated in a
πꢀconjugated polymer scaffold, have yielded efficient materials to be used in
the field of organic photovoltaics (OPV).2
Isatin (1Hꢀindoleꢀ2,3ꢀdione) and its derivatives are synthetically versatile natural dyes,
extensively used in organic synthesis. The advances in the use of isatins for organocatalysis, as well
as their biological and pharmacological properties, have been recently reviewed.3 Although isatin is
the synthetic precursor of isoindigo (Figure 1), its direct incorporation into functional fragments for
OPV or organic electronic applications has been far from fully explored.4 The isatin skeleton
contains formally an amide functionality, linked to the aromatic ring, combined with an electronꢀ
withdrawing C3 ketone functionality, orthoꢀlinked to the aromatic ring with respect to the amide; it
thus possesses a DonorꢀAcceptor structure giving the compound a bright red color. The C3 ketone
possesses orthogonal reactivity with respect with the C2 carbonyl amide, and its derivatization
occurs with relative ease.3 Since lowꢀbandꢀgap polymers for OPV are currently engineered by
alternating electronꢀrich and electronꢀdeficient units in order to match and optimize solar photon
harvesting,5 suitable isatin derivatives can be ideal monomers. Simple and efficient synthetic
protocols are of the foremost importance in the design of
πꢀconjugated polymers for OPV,
demanding for the removal of synthetic steps requiring organometallic chemistry.6
In this paper, we present the design, synthesis and evaluation of a series of fully
πꢀconjugated
dyes in which a thiophene ring is fused into the isatin core. The synthesis adopts an intramolecular,
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direct heteroarylation (DHA) cyclization protocol as the key step, in order to ensure potential for
industrial scalability.5,6
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9
H
O
O
N
O
4
7
H
3
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N
5
6
2
O
N
N
H
H 1
N
O
O
H
DPP
II
Figure 1. The most popular dyes used for OPV applications (diketopyrrolopyrrole DPP, right and
Isoindigo II, center, and the isatin core structure with numbering).
RESULTS AND DISCUSSION
Molecular Design and Synthesis. Our retrosynthetic analysis is presented in Scheme 1. It develops
starting from commerciallyꢀavailable 7ꢀbromoisatin, possessing a bromine atom at a suitable position
for intramolecular DHA reaction, forming a stable sixꢀmembered ring system. The introduction of
the thiophene moiety (step b in Scheme 1) takes advantage of the amide nitrogen at position 1, which
has been reported to be acylated7 or alkylated.8
Scheme 1. Retrosynthetic analysis for the synthesis of target dyes
Regarding the acylation approach, the reaction between 7ꢀbromoisatin and 3ꢀ
thiophenecarbonyl chloride was explored under several conditions, by changing the nature of the
reaction solvent and base and adapting protocols reported in the literature,7 but in all cases the
conversion of the isatin starting material was minimal (see Supporting Information).
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We thus turned our attention to the
Nꢀalkylation of 7ꢀbromoisatin 1 with 3ꢀ
bromomethylthiophene (Scheme 2).8 The reaction was successfully carried out in the presence of
7
8
NaH in dry DMF at 0°C to give compound
2
in excellent yields (98%).
N
ꢀalkyl isatin derivative
2
9
was then protected on Cꢀ3 ketoꢀcarbonyl group with ethylene glycol to give spiroꢀdioxolane
3
(86%
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yield). The key DHA ring closing reaction was carried out in the presence of Pd(OAc)2 as catalyst,
an excess of potassium acetate as base and in moderate dilution conditions (100 mM for reagent in
dry DMF). The desired compound was isolated after purification by flash chromatography in good
3
4
yields (73%). The reaction was also carried out under substantially different dilution conditions (10
mM), but yields were essentially the same. Finally, deprotection under acidic conditions, and
purification by flash chromatography afforded isatinꢀbased dye
5 as a red solid (Scheme 2).
Scheme 2. Synthesis of Thiophene-Fused Isatin Dye 5
O
O
O
O
N
Br
O
OH
O
HO
PTSA
O
S
N
NaH
NH
DMF dry, 0°C-rt
Tol, reflux
Br
Br
S
Br
S
98%
86%
1
2
3
O
O
O
O
O
N
O
Pd(OAc)2
KOAc
O
O
HCl 6M
Bu4NBr
N
N
DMF, 70°C
THF/ꢀ
Br
S
73%
(100 mM)
99%
S
S
3
4
5
The protection at the C3 carbonyl was adopted since similar substrates were identically
protected before DHA reaction using Palladium as the catalyst.9 Avoiding the
protection/deprotection steps would advantageously lower the number of synthetic steps and raise the
total yield of the final compound; however, the DHA ring closing protocol, successfully applied on
protected compound 3, did not work at all when attempted directly on compound 2. Presumably,
since all starting material was recovered, the oxophilicity of the Pd(II) catalyst, which can coordinate
to the C2 and C3 neighboring carbonyls was detrimental in this case. We also attempted recently
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reported10 organocatalytic DHA reaction protocols (
o
ꢀphenantroline,
tꢀBuOK,), for the ring closing
5
6
7
8
reaction of
detected.11
2 to afford directly 5, but in this case degradation of the isatin lactam ring could be
9
Encouraged by the successful synthetic route presented in Scheme 2, we aimed at obtaining
fused substrates presenting a bromine atom at position 4 of the isatin core. Compound (Scheme 3),
presenting a nucleophilic (the carbon linked to the bromine atom) and an electrophilic (the carbon
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9
αꢀ
on the thiophene residue) site on the same molecule, could be an interesting monomer to be
polymerized or copolymerized head to tail using a DHA protocols. The spiroꢀdioxolane protecting
group, with its quaternary carbon atom, could be advantageous in solubilizing the growing polymer
chains, preventing
Our first approach to compound
available 4ꢀbromoꢀ1 ꢀindoleꢀ2,3ꢀdione
π
ꢀstacking, aggregation and precipitation from the reaction mixture. 12
9
was elaborated by implementing the use of commercially
H
6 (Scheme 3). We envisaged it could be possible, by
utilizing high dilution reaction conditions, to activate a regioselective intramolecular DHA between
position 7 of the isatin core and the position 2 of the thiophene ring.
Scheme 3. Attempted synthesis of DHA polymerizable monomer 9, and probable structures of
the obtained polymers 10 and 14
Br
O
O
O
O
N
O
OH
S
O
HO
PTSA
Br
NaH
O
N
Br
Br
O
NH
Br
DMF dry, 0°C-rt
Tol, reflux
X
S
X
X
S
Y
Y
6 X=H
11 X=Br
96%
91%
7 X=H Y=Br
12 X=Br Y=H
86%
88%
8 X=H Y=Br
13 X=Br Y=H
O
O
N
O
O
N
O
O
N
Pd(OAc)2
KOAc
S
n
O
O
10
O
Bu4NBr
Br
Br
DMF, 70°C
(1 mM)
O
X
S
O
Y
N
S
9
8 X=H Y=Br
13 X=Br Y=H
S
n
14
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4ꢀBromoꢀ1
conditions identical to those used for
with ethylene glycol gave spiroꢀdioxolane
closing reaction, attempted in high dilution conditions, did not yield the desired compound
rather an insoluble oligomeric or polymeric baseline red material. Since intermediate presents a
thiophene ring with positions orthogonally reactive in the DHA reaction, a plausible hypothesis
H
ꢀindoleꢀ2,3ꢀdione
6
was alkylated with 2ꢀbromoꢀ3ꢀbromomethylthiophene under
, to give compound in excellent yields (96%). Protection
(86% yield), but the key intramolecular DHA ring
, but
1
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8
α
provides for a polythiopheneꢀtype structure 10 (boxed in Scheme 3) of the polymer formed. The
negligible but probably not suppressed reactivity of the isatin carbon atom in position 4, linked to the
bromine, in the carbonꢀcarbon bond formation with DHA, result in the crosslinking of the structure,
and in the resulting insolubility properties.
We pursued a further possibility to obtain 9, in which both bromine atoms (the one needed for
the intramolecular DHA ring closing step, and the one to be remaining in the final product for
subsequent polymerization), are placed on the isatin core. Derivative 11 is not commercial available
and was synthesized starting from 2,5ꢀdibromoaniline following a general reported procedure for
isatins.13
Alkylation with 3ꢀbromomethylthiophene, to afford compound 12 (91% yield), and
protection, for compound 13 (88% yield), went smoothly as before, but again the key intramolecular
DHA ring closing reaction, attempted in high dilution conditions, did not yield even trace amounts of
the desired compound
9 (Scheme 3). Also in this case an insoluble oligomeric or polymeric baseline
red material was formed; it is likely in this case that the nucleophilic character of the bromine in
position 4 is much higher than of the one in position 7 of the isatin core, so that intermolecular DHA
reaction, on either of the
α−carbons of the appended thiophene residue is competitive with the
intramolecular DHA ring closing, thus affording crosslinking and intractability of the resulting
material. An indirect proof of the higher reactivity as a nucleophile in metalꢀcatalyzed crossꢀcoupling
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reactions of the carbon atom at the 4ꢀposition with respect to the 7ꢀposition is reinforced by the
results illustrated in Scheme 4, where further attempts were made by synthesizing derivatives with
three bromine atoms, in order to develop Ulmann14 or StilleꢀKelly15 ring closing strategies. However,
when attempted on compounds 15 or 16, both methodologies failed to give the desired, cyclized dyes
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or 18. Interestingly, when the Ulmann protocol was adopted on compound 15 in the presence of
solvents such as DMF or DMA, derivative 17, in which a dimethylamino group has regioselectively
substituted the bromine atom in position 4, was obtained in high yields. Both compounds 15 and 17
have been characterized by Xꢀray crystallography, and their crystal data, plots showing thermal
ellipsoids and crystallographic details are reported in the Supporting Information.
Scheme 4. Attempted synthesis of DHA Polymerizable monomer 9 and 18 through Ulmann or
Stille/Kelly coupling
Held by the success of the DHA route presented in Scheme 1, we set out to demonstrate its
feasibility with other isatin derivatives. In particular, we considered isatin 19, bearing two fluorinated
atoms on the aromatic ring, for two reasons: a) the availability of the precursor 2ꢀbromoꢀ3,4ꢀ
difluoroaniline for its synthesis13; b) the fact that the aromatic ring has only one aromatic hydrogen,
possibly allowing a selective late stage further introduction of a bromine atom through electrophilic
aromatic substitution once dye 23 has been synthesized (Scheme 5). Indeed, alkylation, protection,
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intramolecular DHA and deprotection occurred smoothly, to generate dye 23, although in sensibly
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6
reduced yields when compared to 5. Attempts to use Pd(0) sources, namely by employing Pd2(dba)3,
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9
resulted in negligible yields of the desired compound, probably because of the increased steric
hindrance around the Pd catalytic center.
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Scheme 5. Completion of the synthesis of thiophene-fused isatin-based dye 23
O
O
O
O
N
Br
O
OH
O
HO
PTSA
O
S
N
NaH
NH
DMF dry, 0°C-rt
Tol, reflux
F
Br
F
Br
S
F
Br
S
70%
F
83%
F
F
19
20
21
O
O
O
O
O
N
O
Pd(OAc)2
KOAc
Bu4NBr
O
O
HCl 6M
N
N
DMF, 70°C
THF/ꢀ
F
F
Br
F
S
46%
(100 mM)
73%
S
F
S
F
F
21
22
23
1
NMR, UV/Vis and Cyclic Voltammetry. Characterization by H NMR spectroscopy was
able to substantiate the interaction between the thiophene and isatin moieties, placed in direct
conjugation. We report in Figure 2 a comparison between the 1H NMR spectra of compounds
on one side, and 20 and 23 on the other. In both cases, peaks related to the isatin core in
above 7.5 ppm, markedly shift to higher fields in and 23, probably also as a consequence of the
loss of the bromine atom as a substituent on the aromatic ring. Peaks of the thiophene moieties
(labelled 5 and 6 for compounds and , 3 and 4 for compounds 20 and 23) shift in opposite
directions upon ring closure. A large shift upon cyclization is also detected for the benzylic CH2
2
and
5
2
and 20
5
2
5
proton resonances (labelled 4 for compounds
2
and
5
, 3 and 2 for compounds 20 and 23
)
ꢀ
demonstrating an effective charge transfer and crossꢀtalking between the moieties within the fully
conjugated molecular structure.
π
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Figure 2. Stacked 1HꢀNMR spectra (200 MHz, CDCl3) of compounds: (a)
2, (b) 5, (c) 20 and (d) 23.
Such cross talking is also evidenced by the UV/Vis spectra of compounds
5 and 23 (Figure 3,
left). Whereas the λmax is centered around 320 nm (
ε
= 4000ꢀ9000 Mꢀ1cmꢀ1 in CHCl3), a weaker
intramolecular charge transfer band centered around 490 nm is detected in both compounds (
ε
= 600ꢀ
(the
1000 Mꢀ1cmꢀ1 in CHCl3). The latter band showed solvent dependence in the case of compound
5
maximum shifting from 490 nm in CHCl3 to 478 nm in toluene, see Figure S1). Compound
5
demonstrated to be weakly emissive (Figure 2, right) when excited at 318 nm, and nonemissive when
excited on the chargeꢀtransfer band at 480 nm.
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Figure 3. Left: UV/Vis spectra of compounds
emission spectra ( ex = 318 nm) of compound
5
and 23 (10ꢀ4 M in CHCl3). Right: absorption and
λ
5
(5·10ꢀ5 M in MeCN).
Data for the HOMOꢀLUMO gaps of the final compounds
5 and 23, could be determined both
by optical and electrochemical methods, and they are compared with isoindigo (II) and
diketopyrrolopyrrole (DPP), for which literature data are available (Table 1). The effect of the
introduction of the fluorine substituents is to lower both HOMO and LUMO levels, thus maintaining
the band gap at 2.1 eV. For both compounds
5 and 23, the reduction peak is reversible, whereas it is
not reversible in the oxidation mode, indicating that the compound does not polymerize
electrochemically, even by lowering the scan rate from 200 mV/s to 20 mV/s. A slight shift of the
cathode potential is observed upon successive reduction cycles.
Table 1. Experimental values for semiconducting properties of the new dyes synthesized, and
comparison with literature values of relevant compounds
Compo
und
HOMOꢀLUMO
gap (eV) CV
HOMOꢀLUMO gap
HOMO (eV)
LUMO (eV)
(eV) optical
DPPa
IIb
2.1
2.1
2.5
2.1
2.1
ꢀ5.4
ꢀ5.9
ꢀ5.6
ꢀ5.8
ꢀ3.3
ꢀ3.1
ꢀ3.5
ꢀ3.7
2.8
5c
2.1d
23c
2.1d
a
Data taken from ref. 16. b) Data taken from ref. 17. UV/Vis and CV spectra are shown in Figures S1 and S2,
respectively. d) HOMOꢀLUMO values obtained by the analysis of the first cycle.
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X-ray crystal structure of 5. The dye
triclinic, and the 5_2 crystal, monoclinic. In both crystals the asymmetric units contain two very
similar but crystallographicallyꢀindependent molecules of ; all of them are essentially planar. Plots
showing thermal ellipsoids are drawn in Figure S3, and relevant bond distances in each independent
molecule are reported in Table S2.
5 originates in the solid state two polymorphs: the 5_1 crystal,
9
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5
The bond distances for the thiophene moiety change slightly but significantly upon fusion with the
, the sp2
isatin core with respect to those observed in the isolated system. In all molecular structures
5
thiophene carbon atoms directly connected to the isatin groups originate thiophene CꢀC and CꢀS
bonds significantly longer (by 0.02ꢀ0.05 Å) than the symmetrically placed CꢀC and CꢀS bonds,
linked with CH groups. All bonds are significantly different than those in isolated thiophene.18
A
transfer of electron density towards the CꢀC bonds connecting the thiophene rings and the isatin
aromatic groups is also evident by their shortening (1.451 for 5_1 and 1.457 Å for 5_2) with respect
to a Csp2ꢀCAr single bond (1.470 Å) observed in related structures.18
In the solid state the two polymorphs of compound
5 differ in the dihedral angle between the
two independent molecules forming the crystal: in 5_1, the dihedral angle between the two
independent polycyclic compounds is 21°, whereas in 5_2 the dihedral angle is 89°. In the 5_1
crystal, the two independent molecules originate two faceꢀtoꢀface
πꢀstacked molecular rows
extending along the direction of the crystallographic axis. Each row is made by
a
centrosymmetrically related molecules, as shown in Figure 4. The stacked molecules are placed on
overlying planes having interplanar distances in the range 3.41ꢀ3.56 Å. Molecular rows are kept
together by weak nonꢀconventional CꢀH···O interactions involving the CH group of the thiophene
unit linked to the Sulphur atom (Hꢀdonor) and one Oxygen atom of isatin (Hꢀacceptor) of adjacent
molecules of
5. Features of these interactions are shown in Figure S4.
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Figure 4. A simplified sketch of the molecular rows made by faceꢀtoꢀface πꢀstacked molecules in the
5_1 crystal. The shortest intermolecular contacts are drawn with dashed lines (values are in Å). Hꢀ
atoms are omitted for clarity.
In the 5_2 crystal, the two independent molecules of the polycyclic compound originate two
molecular rows already characterized by faceꢀtoꢀface πꢀstacking interactions: the stacked molecules
are placed on overlying planes having interplanar distances of 3.31 and 3.32 Å. However, the stacked
units along the two independent molecular rows are the pentagonal rings of the polycyclic compound
5
, i.e. the thiophene group and the pyrrole subunit of the isatin group. In particular, as shown in
Figure 5, each molecule has the pyrrole subunit placed above the thiophene group of a symmetrically
equivalent molecule placed in the underlying plane, whereas it has the thiophene group placed below
the pyrrole subunit of a symmetrically equivalent molecule placed in the overlying plane. The
molecular offset promotes the formation of zigzag like molecular rows extending along the direction
of the a crystallographic axis. The molecular rows are interconnected by weak nonꢀconventional Cꢀ
H···O interactions having as Hꢀacceptor species the O atoms of isatin groups and as Hꢀdonor groups
three different groups: the CH group of thiophene rings bonded to the Sulphur atom; one CH group
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of the phenyl ring of the isatin moiety; the CH group of the Csp3 atom of the fused rings. Features of
these interactions are shown in Figure S5.
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Figure 5. A simplified sketch of the molecular rows made by faceꢀtoꢀface πꢀstacked molecules in the
5_2 crystal. HꢀAtoms were omitted for clarity.
CONCLUSIONS
We have successfully synthesized fully conjugated molecular hybrids, in which the core of
the naturallyꢀoccurring dye isatin has been fused with a thiophene residue. We have demonstrated
that the synthesis is feasible using the mild and scalable conditions associated with the DHA
reaction, used as the key intramolecular ring closing step. The DHA reaction has however to be
performed with the correct set up in terms of nucleophilic and electrophilic atom, that is the halogen
atom on the isatin residue, and hydrogen atoms on both the
αꢀpositions of the thiophene residue, to
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avoid intermolecular propagation and crosslinking which cannot be suppressed using high dilution
reaction conditions. We have also demonstrated that the synthetic protocol is adaptable to other
substituents, namely fluorine atoms, on the aromatic isatin residue. The synthetic flexibility has
afforded tunable energy levels of the final dyes, with the fluorinated compound 23 having identical
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bandgap with respect to
5
, but lower HOMO and LUMO levels. We are currently engaged in tuning
and 23, to afford isatinꢀbased conjugated
reaction protocols for late stage dibromination of both
5
monomers capable of polymerization for organic photovoltaic applications.
EXPERIMENTAL SECTION
General Experimental. All commercially available reagents and solvents were used as received.
THF (Na, benzophenone) and CH2Cl2 (CaH2) were dried and distilled before use. Analytical thin
layer chromatography was performed on chromophore loaded, commercially available silica gel
1
plates. Flash chromatography was carried out using silica gel (pore size 60 Å, 230ꢀ400 Mesh). H
and 13C NMR spectra were recorded from solutions in CDCl3, DMSOꢀ d6 on 200 or 300
spectrometers using the solvent residual proton signal or tetramethylsilane as the internal standard.
Samples for the mass spectrometry were analysed with GCꢀMS and ESIꢀMS conventional
instrumentation. The UV/Vis and emission spectroscopic studies were recorded using conventional
spectrophotometers, with a scanning speed of 50 nm/min at 20 °C. Photoluminescence studies were
conducted using an excitation slit of 2.0 nm, and emission slit of 3.0 nm with a scanning speed of 50
nm/min at 20 °C.
Cyclic Voltammetry was performed with the sample at a concentration of 10ꢀ3M (in the case of
5) or
0,6 10ꢀ3M (in the case of 25) in oꢀDCB/MeCN (1:10 by volume) solution in the presence of Bu4NBF4
0.1 M as the supporting electrolyte. A stationary glassy carbon (GC) disk electrode was used as the
working electrode. Silver electrode Ag/AgNO3 served as the reference electrode and the potential
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sweep rate was 200 mV sꢀ1. Measurements were carried out under thermostatic conditions (20 °C) in
a nitrogen atmosphere.
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Diffraction data for 5_1 (reddish brown color, 0.60 x 0.43 x 0.36 mm3) and for 5_2 (dark brown
color, 0.51 x 0.43 x 0.36 mm3) were collected by means of a conventional diffractometer, working at
ambient temperature with graphiteꢀmonochromatized MoꢀKα Xꢀradiation (λ = 0.71073 Å). Data
reductions were performed with the WinGX package;19 absorption effects evaluated with the ψꢀscan
method20 were negligible and absorption correction was not applied to the data. All crystal structures
were solved by direct methods (SIR 97)21 and refined by fullꢀmatrix leastꢀsquare procedures on F2
using all reflections (SHELXL 2014).22 Anisotropic displacement parameters were refined for all
nonꢀhydrogen atoms; hydrogens were placed at calculated positions with the appropriate AFIX
instructions and refined using a riding model. Crystal data are reported in Table S2. Melting points
were measured on commerciallyꢀavailable instrumentation and are uncorrected.
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3ꢀBromomethylthiophene.23 A suspension of NBS (1.78 g, 10 mmol) and benzoyl peroxide (3 mg,
0.001 mmol) in CCl4 (10 mL) was heated at 40 °C for 30 min, then 3ꢀmethylthiophene (10 mmol)
was added dropwise. The mixture was refluxed for 2h. The precipitate was filtered and washed with
hexanes. The organic solvent was removed and the crude reaction was distilled in vacuo to yield the
desired product (1.54 g, 87%); 1H NMR (200 MHz, CDCl3) δ 7.33ꢀ7.31 (m, 2H), 7.14 (d, J = 5.0 Hz,
1H), 4.54 (s, 2H).
2ꢀBromoꢀ3ꢀmethylthiophene.24 NBS (1.74 g, 9.8 mmol) was added slowly to solution of 3ꢀ
methylthiophene (10 mmol) in glacial AcOH (7 mL) at 0 °C. The mixture was maintained at room
temperature for 1 h. The reaction mixture was then quenched with water and extracted with ether.
The organic solvent was removed and the crude material was purified by flash column
chromatography using hexanes as eluent. 2ꢀBromoꢀ3ꢀmethylthiophene was obtained as a pale yellow
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oil (1.47 g, 83%); H NMR (200 MHz, CDCl3) δ 7.18 (d, J = 5.6 Hz, 1H), 6.79 (d, J = 5.5 Hz, 1H),
5
6
2.21 (s, 3H).
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2ꢀBromoꢀ3ꢀBromomethylthiophene.23 A suspension of 2ꢀbromoꢀ3ꢀmethylthiophene (1.77 g, 10
mmol), NBS (1.78 g,10 mmol) and benzoyl peroxide (3 mg, 0.001 mmol) in CCl4 (10 mL) was
heated to reflux for 8h. The mixture of reaction was filtered and precipitate washed with hexanes.
The organic solvent was removed and organic crude was distilled in vacuo to yield the desired
product as a pale colorless oil (2.93 g, 87%); 1H NMR (200 MHz, CDCl3) δ 7.27 (d, J = 5.6 Hz, 1H),
7.01 (d, J = 5.7 Hz, 1H), 4.47 (s, 1H).
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General Procedure for the Synthesis of N-benzylisatins. Example for the synthesis of
2. 7ꢀ
Bromoisatin (226 mg, 1 mmol) and dry DMF (5 mL) were introduced at 0 °C, under nitrogen, in a
flameꢀdried Schlenk flask. NaH (60 mg, 1.5 mmol) was added slowly and the reaction mixture was
stirred at 0 °C for 30 min. 3ꢀBromomethylthiophene (194 mg, 1.1 mmol) was then added via syringe
and the reaction mixture was stirred at room temperature. After full conversion of the starting
material (5h, TLC monitoring), the reaction mixture was quenched with water. The aqueous phase
was extracted with ethyl acetate, the combined organic extracts were removed of the solvent in vacuo
and the crude material was purified by flash chromatography (SiO2; nꢀhexanes:ethyl acetate 8:2) to
afford pure Nꢀbenzylisatins
2
as red solid (315 mg, 98%).
). Obtained as a red solid (315 mg, 98%); 1H
7ꢀbromoꢀ1ꢀ(thiophenꢀ3ꢀylmethyl)indolineꢀ2,3ꢀdione (
2
NMR (200 MHz, CDCl3): δ 7.69 (dd, J = 8.1 and 1.3 Hz, 1H), 7.61 (dd, J = 7.3 and 1.3 Hz, 1H),
7.35 – 7.21 (m, 2H), 7.11 (dd, J = 4.8 and 1.5 Hz, 1H), 7.06–6.94 (m, 1H), 5.43 (s, 2H); 13C NMR
(75 MHz, CDCl3): δ 182.2, 158.7, 147.4, 144.0, 136.5, 126.8, 126.4, 125.1, 124.7, 122.8, 120.8,
104.3, 40.3; MSꢀESI: m/z 322 [M + H]+, 345 [M + Na]+, 644 [2M]+; GCꢀMS (EI) rt: 16.94 min, m/z
323 [M]+; anal. calcd. for C13H8BrNO2S: C 48.5; H 2.5; found: C 48.2; H 2.2. M.p. > 300°C (dec.).
4ꢀbromoꢀ1ꢀ((2ꢀbromothiophenꢀ3ꢀyl)methyl)indolineꢀ2,3ꢀdione (7). Obtained as an orange solid (385
mg, 96%); 1H NMR (200 MHz, CDCl3): δ 7.45–7.20 (m, 3H), 6.92–6.81 (m, 2H), 4.88 (s, 2H); 13C
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NMR (75 MHz, CDCl3): δ 180.3, 157.1, 151.6, 138.4, 133.8, 128.8, 127.3, 127.3, 121.7, 111.5,
109.5, 109.3, 38.6; MSꢀESI: m/z 400 [M + H]+,422 [M + Na]+, 798 [2M]+; anal. calcd. for
C13H7Br2NO2S: C 38.9; H 1.8; found: C 38.6; H 1.9. M.p. > 300°C (dec.).
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4,7ꢀdibromoꢀ1ꢀ(thiophenꢀ3ꢀylmethyl)indolineꢀ2,3ꢀdione (12). Obtained as an orange solid (365 mg,
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91%); H NMR (200 MHz, CDCl3): δ 7.50 (d, J = 8.7 Hz, 1H), 7.30 (dt, J = 5.5 and 2.7 Hz, 1H),
7.24 (s, 1H), 7.14 (d, J = 8.7 Hz, 1H), 7.11 – 7.04 (m, 1H), 5.45 (s, 2H); 13C NMR (75 MHz, CDCl3):
δ 179.6, 157.8, 149.0, 143.7, 136.1, 129.9, 126.7, 126.5, 122.8, 121.4, 118.9, 102.9, 40.4; MSꢀESI:
m/z 400 [M + H]+,422 [M + Na]+, 798 [2M]+; anal. calcd. for C13H7Br2NO2S: C 38.9; H 1.8; found: C
38.7; H 2.0. M.p. > 250°C (dec.).
4,7ꢀdibromoꢀ1ꢀ((2ꢀbromothiophenꢀ3ꢀyl)methyl)indolineꢀ2,3ꢀdione (15). Obtained as an orange solid
1
(442 mg, 92%); H NMR (200 MHz, CDCl3): δ 7.49 (d, J = 8.7 Hz, 1H), 7.24 (d, J = 5.7 Hz, 1H),
7.17 (d, J = 8.7 Hz, 1H), 6.66 (d, J = 5.7 Hz, 1H), 5.32 (s, 9H); 13C NMR (75 MHz, CDCl3): δ 179.6,
157.8, 149.0, 143.7, 136.1, 129.9, 126.7, 126.5, 122.8, 121.4, 118.9, 102.9, 40.4; MSꢀESI: m/z 400
[M + H]+,422 [M + Na]+, 798 [2M]+; single crystals suitable for XꢀRay crystallography were
obtained by slow evaporation of a solution of compound in CH2Cl2. M.p. > 250°C (dec.).
7ꢀbromoꢀ5,6ꢀdifluoroꢀ1ꢀ(thiophenꢀ3ꢀylmethyl)indolineꢀ2,3ꢀdione (20). Obtained as a pale orange
solid, (251 mg, 70%); 1H NMR (200 MHz, CDCl3): δ 7.50 (t, J = 7.2 Hz, 1H), 7.32 (dd, J = 4.9 and
3.0 Hz, 1H), 7.24 (s, 1H), 7.07 (d, J = 4.9 Hz, 1H), 5.42 (s, 2H); 13C NMR (75 MHz, CDCl3): δ
180.3, 158.5, 156.1, 152.7, 149.1, 145.8, 136.0, 126.8, 126.5, 122.8, 113.8, 95.9, 40.5, 29.6; anal.
calcd. for C13H6BrF2NO2S: C 43.6; H 1.7; found: C 43.4; H 1.6. M.p. > 250°C (dec.).
General Procedure for the Synthesis of N-benzylisatin ethylenedioxy ketals. Example for the
synthesis of 3. A solution of compound 2 (322 mg,1 mmol), ethylene glycol (1 mL, 18 mmol), pꢀ
toleunesulfonic acid (few crystals) in toluene (5 mL) was heated at reflux for 6h with a DeanꢀStark
equipment. The solvent was then removed and the solid was treated with a sat. NaHCO3 aqueous
solution, and the aqueous phase was extracted with CH2Cl2. The organic extracts were concentrated
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in vacuo and the solid purified by flash chromatography (SiO2; CH2Cl2) to afford pure product
3 as a
5
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white solid (315 mg, 86%).
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7'ꢀbromoꢀ1'ꢀ(thiophenꢀ3ꢀylmethyl)spiro[[1,3]dioxolaneꢀ2,3'ꢀindolin]ꢀ2'ꢀone (3). Obtained as a white
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solid, (315 mg, 86%); 1H NMR (200 MHz, CDCl3): δ 7.45 (dd, J = 8.1 and 1.3 Hz, 1H), 7.34 (dd, J =
7.3 and 1.3 Hz, 1H), 7.27 (dd, J = 4.9 and 3.1 Hz, 1H), 7.15 (dd, J = 2.9 and 1.3 Hz, 1H), 7.06 (dd, J
= 5.0, 1.3 Hz, 1H), 6.95 (dd, J = 8.2, 7.3 Hz, 1H), 5.31 (s, 2H), 4.72–4.25 (m, 4H); 13C NMR (75
MHz, CDCl3): δ 173.9, 141.1, 137.3, 127.4, 126.5, 126.0, 124.5, 124.1, 121.8, 102.9, 100.9, 65.9,
40.1; GCꢀMS (EI) rt: 17.94 min, m/z 268 [M]+; anal. calcd. for C15H12BrNO3S: C 49.2; H 3.3; found:
C 49.0; H 3.5.
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4'ꢀbromoꢀ1'ꢀ((2ꢀbromothiophenꢀ3ꢀyl)methyl)spiro[[1,3]dioxolaneꢀ2,3'ꢀindolin]ꢀ2'ꢀone (8). Obtained
1
as a white solid (383 mg, 86%); H NMR (200 MHz, CDCl3): δ 7.19 (td, J = 6.7, 6.2, 4.0 Hz, 3H),
6.81 (d, J = 5.7 Hz, 1H), 6.72 (dd, J = 6.5 and 2.2 Hz, 1H), 4.75 (s, 2H), 4.72–4.37 (m, 4H); 13C
NMR (75 MHz, CDCl3): δ 180.3, 157.1, 151.6, 138.4, 133,8, 128.8, 128.6, 121.6, 116.4, 111.5,
109.6, 66.7 38.6; MSꢀESI: m/z 444 [M + H]+, 466 [M + Na]+, 886 [2M]+; anal. calcd. for
C15H11Br2NO3S: C 40.5; H 2.5; found: C 40.9; H 2.2. M.p. > 200°C (dec.).
4',7'ꢀdibromoꢀ1'ꢀ(thiophenꢀ3ꢀylmethyl)spiro[[1,3]dioxolaneꢀ2,3'ꢀindolin]ꢀ2'ꢀone (13). Obtained as a
1
white solid, (392 mg, 88%); H NMR (200 MHz, CDCl3): δ 7.35–7.23 (m, 2H), 7.18–6.97 (m, 3H),
5.31 (s, 2H), 4.74–4.36 (m, 4H); 13C NMR (75 MHz, CDCl3): δ 173.6, 142.9, 138.2, 137.0, 128.7,
126.4, 126.2, 125.4, 121.8, 119.2, 102.0, 101.6, 66.7, 40.2; MSꢀESI: m/z 444 [M + H]+, 466 [M +
Na]+, 886 [2M]+; ]+; anal. calcd. for C15H11Br2NO3S: C 40.5; H 2.5; found: C 40.1; H 2.8.
4’,7'ꢀdibromoꢀ1'ꢀ((2ꢀbromothiophenꢀ3ꢀyl)methyl)spiro[[1,3]dioxolaneꢀ2,3'ꢀindolin]ꢀ2'ꢀone
(16).
Obtained as a white solid (356 mg, 68%); 1H NMR (200 MHz, CDCl3): δ 7.29 (d, J = 8.1 Hz, 1H),
7.18 (d, J = 5.7 Hz, 1H), 7.07 (d, J = 8.1 Hz, 1H), 6.60 (d, J = 5.7 Hz, 1H), 5.18 (s, 2H), 4.62–4.46
(m, 4H); 13C NMR (75 MHz, CDCl3): δ 173.6, 142.9, 138.2, 137.0, 128.7, 126.4, 126.2, 125.4, 121.8,
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119.2, 102.0, 101.6, 66.7, 40.2; MSꢀESI: m/z 444 [M + H]+,466 [M + Na]+, 886 [2M]+; anal. calcd.
5
6
for C15H10Br3NO3S: C 34.4; H 1.9; found: C 34.8; H 2.1.
7
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7'ꢀbromoꢀ5',6'ꢀdifluoroꢀ1'ꢀ(thiophenꢀ3ꢀylmethyl)spiro[[1,3]dioxolaneꢀ2,3'ꢀindolin]ꢀ2'ꢀone
(21).
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1
Obtained as a white solid (334 mg, 83%); H NMR (200 MHz, CDCl3): δ 7.29 (dd, J = 4.9 and 2.9
Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 7.11 (s, 1H), 7.01 (d, J = 6.0 Hz, 1H), 5.28 (s, 2H), 4.68–4.25 (m,
4H); 13C NMR (75 MHz, CDCl3): δ 172.6, 149.4, 148.5, 146.1, 145.1, 130.6, 128.4, 116.6, 116.5,
111.7, 103.0, 65.9, 41.7; MSꢀESI: m/z 402 [M + H]+,425 [M + Na]+, 804 [2M]+; anal. calcd. for
C15H10BrF2NO3S: C 44.8; H 2.5; found: C 44.7; H 2.9.
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General Procedure for the intramolecular DHA reaction. Example for the synthesis of
4. A
suspension of Nꢀbenzylisatin ketal (366mg, 1 mmol), Pd(OAc)2 (5 mg, 0.02 mmol), KOAc (294
3
mg, 3 mmol), Bu4NBr (322 mg, 1 mmol) in dry DMF (5 mL) was stirred and heated to reflux. After
full conversion of the starting material (8 h, TLC monitoring), the reaction mixture was quenched
with water, and the aqueous phase was extracted with ethyl acetate. The organic extracts were
concentrated in vacuo and the solid purified by flash chromatography (SiO2; nꢀhexanes:ethyl acetate
8:2) to afford the pure product
4 as a white solid (208 mg, 73%).
Spiro[[1,3]dioxolaneꢀ2,4'ꢀpyrrolo[3,2,1ꢀij]thieno[3,2ꢀc]quinolin]ꢀ5'(7'H)ꢀone (
4
). Obtained as a
white solid (208 mg, 73%); 1H NMR (200 MHz, CDCl3): δ 7.31–7.20 (m, 2H), 7.15 (dd, J = 7.5 and
1.0 Hz, 1H), 6.97 (t, J = 7.6 Hz, 1H), 6.86 (d, J = 5.1 Hz, 1H), 4.99 (s, 2H), 4.67–4.23 (m, 4H); 13C
NMR (75 MHz, CDCl3): δ 172.9, 138.6, 130.4, 129.5, 126.2, 125.3, 123.4, 123.3, 121.9, 115.4,
103.5, 65.7, 41.5; GCꢀMS (EI) rt: 18.37 min, m/z 285 [M]+; anal. calcd. for C15H11NO3S: C 63.1; H
3.9; found: C 63.4; H 3.9.
1',2'ꢀdifluorospiro[[1,3]dioxolaneꢀ2,4'ꢀpyrrolo[3,2,1ꢀij]thieno[3,2ꢀc]quinolin]ꢀ5'(7'H)ꢀone
(22).
Obtained as a white solid (148 mg, 46%); 1H NMR (200 MHz, CDCl3): δ 7.47 (d, J = 5.2 Hz, 1H),
7.09–6.88 (m, 2H), 5.02 (s, 2H), 4.67–4.22 (m, 4H); 13C NMR (75 MHz, CDCl3): δ 172.6, 149.3,
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148.5, 146.1, 145.1, 130.6, 128.4, 125.4, 116.5, 111.8, 106.4, 102.9, 65.9, 41.7; MSꢀESI: m/z 322 [M
+ H]+, 344 [M + Na]+, 642 [2M]+; anal. calcd. for C15H9F2NO3S: C 56.1; H 2.8; found: C 56.4; H 2.9.
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General Procedure for the deprotection. Example for the synthesis of 5. A solution of compound 4
9
(285 mg, 1 mmol) in THF (2.5 mL) and aqueous HCl 6M (2.5 mL) was stirred and heated to reflux
for 6h. THF was removed in vacuo and the resulting aqueous phase was extracted with ethyl acetate.
The combined organic extracts were concentrated in vacuo and resulting crude material was purified
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by chromatography (SiO2; nꢀhexanes :ethyl acetate 9:1) to afford pure product
5
in quantitative yield.
4Hꢀpyrrolo[3,2,1ꢀij]thieno[3,2ꢀc]quinolineꢀ4,5(7H)ꢀdione (5). Obtained as a red solid (241 mg,
1
99%); H NMR (200 MHz, CDCl3): δ 7.53–7.29 (m, 3H), 7.01 (t, J = 7.7 Hz, 1H), 6.93 (d, J = 5.2
Hz, 1H), 5.13 (s, 2H); 13C NMR (75 MHz, CDCl3): δ 180.6, 167.4, 155.6, 143.6, 127.5, 126.8, 124.3,
124.2, 121.8, 121.1, 114.6, 113.4; 40.0; MSꢀESI: m/z 242 [M + H]+, 264 [M + Na]+; single crystals
suitable for XꢀRay crystallography were obtained by slow evaporation of a solution of compound in
CH2Cl2. M.p. > 300°C (dec.).
1,2ꢀdifluoroꢀ4Hꢀpyrrolo[3,2,1ꢀij]thieno[3,2ꢀc]quinolineꢀ4,5(7H)ꢀdione (23). Obtained as a red solid
1
(202 mg, 73%); H NMR (200 MHz, CDCl3): δ 7.56 (d, J = 4.0 Hz, 1H), 7.19 (t, J = 7.9 Hz, 1H),
7.01 (d, J = 4.5 Hz, 1H), 5.16 (s, 2H); 13C NMR (75 MHz, CDCl3): δ 186.6, 171.4, 157.2, 152.1,
130.9, 129.6, 125.5, 122.6,117.6 111.2, 110.9, 110.2, 42.0; MSꢀESI: m/z 278 [M + H]+; anal. calcd.
for C13H5F2NO2S: C 56.3; H 1.8; found: C 56.6; H 2.0. M.p. > 300°C (dec.).
4,7ꢀdibromoindolineꢀ2,3ꢀdione 11.25 Chloral hydrate (14.7 g, 88.8 mmol) was added to a suspension
of hydroxylamine hydrochloride (18.5 g, 0.266 mol), sodium sulfate (84 g, 0.59 mol), and 2,5ꢀ
dibromoaniline (74.0 mmol) in water (500 mL) and 2 M HCl (25 mL). The mixture was then heated
at 55 °C overnight with stirring. After cooling to room temperature, the hydroxyiminoacetanilide
intermediate was collected by filtration, washed with water and dried under vacuum. The
intermediate was added in small portions, with stirring, to concentrated H2SO4 (45 mL), which had
been heated to 55 °C. The temperature of the reaction mixture was maintained below 70 °C during
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the addition. The darkꢀcolored solution was heated at 80 °C for an additional 10 min and then cooled
to room temperature, poured onto crushed ice, and allowed to stand for 30 min. The precipitate was
collected by filtration, washed three times with water, and dried under vacuum to yield isatin 11 to
be used directly in the next step without further purification. 1H NMR (200 MHz, DMSOꢀd6) δ 7.54
(d, J = 8.6 Hz, 1H), 7.12 (d, J = 8.6 Hz, 1H).
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7ꢀbromoꢀ1ꢀ((2ꢀbromothiophenꢀ3ꢀyl)methyl)ꢀ4ꢀ(dimethylamino)indolineꢀ2,3ꢀdione (17). Cu powder
(0.10 g, 1.67 mmol) was added to a solution of compound 15 (0.10 g, 0.21 mmol) in dry DMF (10
mL) under nitrogen. The reaction mixture was heated under stirring at 130 °C for 3 days. The
reaction mixture was quenched with water and the resulting aqueous phase was extracted with ethyl
acetate. The combined organic extracts were removed of the solvent in vacuo and the crude material
was purified by flash chromatography (SiO2; nꢀhexanes:ethyl acetate 8:2) to afford pure compound
17 as a red solid (43 mg, 73%). 1H NMR (200 MHz, CDCl3): δ 7.29 (d, J = 9.2 Hz, 1H), 7.19 (d, J =
5.7 Hz, 1H), 6.68 (d, J = 5.7 Hz, 1H), 6.47 (d, J = 9.4 Hz, 1H), 5.28 (s, 2H), 3.16 (s, 6H).13C NMR
(75 MHz, CDCl3): δ 176.4, 160.7, 151.2, 146.7, 143.1, 136.4, 129.5, 126.4, 124.0, 114.1, 108.6,
90.3, 43.3, 41.0; MSꢀESI: m/z 284 [M + H]+; single crystals suitable for XꢀRay crystallography were
obtained by slow evaporation of a solution of compound in CH2Cl2. M.p. > 300°C (dec.).
General Procedure for the Stille-Kelly reaction for the attempted synthesis of compounds 9
and 18. Example for the synthesis of 18. Pd(PPh3)4 (0.013 g, 10%mol) was added to a solution of
compound 16 (0.061 g, 0.12 mmol) in dry 1,4ꢀdioxane (3 mL). The reaction mixture was purged
with nitrogen for 5 min, then hexamethylditin (0.076 g, 0.24 mmol), was added under nitrogen. The
reaction mixture was quenched with water after 1d (TLC monitoring) and solvents were removed in
vacuo. The resulting crude solid was extracted with ethyl acetate and the organic extracts were
1
concentrated in vacuo. HNMR spectrum on crude of reaction did not show the expected signals of
compound 9.
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7ꢀbromoꢀ5,6ꢀdifluoroindolineꢀ2,3ꢀdione (19). Chloral hydrate (477 mg, 5.8 mmol) was added to a a
suspension of hydroxylamine hydrochloride (584 mg, 16.8 mmol), sodium sulfate (2.05 g, 28.8
mmol), and 2ꢀbromoꢀ3,4ꢀdifluoroaniline (500 mg, 2.4 mmol) in 2M aqueous HCl (5 mL). The
mixture was refluxed overnight with vigorous stirring. After cooling to room temperature, the
hydroxyiminoacetanilide intermediate was collected by filtration as a yellow solid, which was
washed with water and dried under vacuum. The intermediate was added in small portions, with
stirring, to concentrated H2SO4. The temperature of the reaction mixture was maintained below 70
°C during the addition. The darkꢀcolored solution was heated at 80 °C for 3 h and then cooled to
room temperature, poured onto crushed ice, and allowed to stand for 30 min. The precipitate was
collected by filtration, washed with water and toluene, and purified by flash chromatography (SiO2;
nꢀhexanes:ethyl acetate 8:2) to give the analytically pure product as a pale orange solid (290 mg,
46%); 1H NMR (200 MHz, DMSOꢀ d6): δ 11.41 (s, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.17 (d, J = 8.6 Hz,
1H); 13C NMR (75 MHz, DMSOꢀd6): δ 181.8, 159.8, 154.3, 150.9, 144.4, 114.5, 113.2, 94.3. GCꢀMS
(EI) rt: 9.94 min, m/z 261 [M]+; anal. calcd. for C8H2BrF2NO2: C 36.8; H 0.8; found: C 36.6; H 0.9.
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Acknowledgements. We gratefully acknowledge funding by ENI S.p.A. through its University
contact branch ENI Corporate University (agreement with the University of Pavia No. C49/09/13).
We thank A. Pellegrino (ENI) for useful discussion.
13
Supporting Information Available. Copies of 1H, C NMR, ESIꢀMS and GCꢀMS spectra for new
compounds. Additional Figures and Tables about UV/Vis spectroscopy, cyclic voltammetry, and Xꢀ
Ray crystallography. This material is available free of charge via the Internet at http://pubs.acs.org.
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