Fused arene ring construction around pyrrole to form 4,7-disubstitued indole

Article abstract of DOI:10.1002/ejoc.201200644

A method for synthesizing 4,7-diarylindoles and 4,7-di(thien-2-yl)indole by applying a strategy where the fused benzene ring was built on an existing pyrrole in an acid-catalyzed rearrangement of 1,4-diaryl-1,4-di(pyrrol-2-yl)but- 2-yne and 1,4-di(pyrrol-2-yl)-1,4-di(thien-2-yl)but-2-yne, respectively, is presented. In the presence of TFA (30 equiv.), 4,7-diarylindoles undergo thermodynamically equilibrated dimerization at 240 K as determined by ¹H NMR spectroscopy and substantiated by DFT calculations. An alternative route for the construction of indole derivatives is described. 4,7-Diarylindoles and 4,7-di(thien-2-yl)indole were synthesized by applying a strategy where the fused benzene ring was built on the existing pyrrole.

Full text of DOI:10.1002/ejoc.201200644

Job/Unit: O20644
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Date: 25-06-12 17:04:35
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FULL PAPER
DOI: 10.1002/ejoc.201200644
Fused Arene Ring Construction Around Pyrrole To Form 4,7-Disubstitued
Indole
Elzbieta Nojman,[a] Lechosław Latos-Grazyn´ski,*[a] and Ludmiła Szterenberg[a]
˙
˙
Keywords: Heterocycles / Dimerization / Rearrangement / NMR spectroscopy
A method for synthesizing 4,7-diarylindoles and 4,7-di(thien-
2-yl)indole by applying a strategy where the fused benzene
ring was built on an existing pyrrole in an acid-catalyzed re-
arrangement of 1,4-diaryl-1,4-di(pyrrol-2-yl)but-2-yne and
1,4-di(pyrrol-2-yl)-1,4-di(thien-2-yl)but-2-yne, respectively,
is presented. In the presence of TFA (30 equiv.), 4,7-diaryl-
indoles undergo thermodynamically equilibrated dimeriza-
tion at 240 K as determined by 1H NMR spectroscopy and
substantiated by DFT calculations.
Introduction
sensor for iodide ions, falls in this category. In this case,
4,7-diarylindoles were synthesized starting from 1,4-di-
bromobenzene to afford 4,7-dibromoindole to be used as
an appropriate substrate in Suzuki coupling.[24] In the
second set, the fused benzene ring is built on an existing
pyrrole. Finally, in the third group, both rings are con-
structed simultaneously. Actually, the majority of the re-
ported syntheses start with benzene-type substrates, and
evidently, they belong to the first category.[7,16–23] The alter-
native procedure (the van Leusen strategy), which uses a
pyrrole ring as the “template”-like structure (in fact appli-
cable in this study), is definitely less common[23,25,26] and
includes the recently reported palladium-catalyzed oxidat-
ive coupling of 3-substituted pyrrole with alkynes to form
4,5,6,7-tetraphenylindole[27,28] or the Lewis acid catalyzed
[4+2] benzannulation between enynal units and enols or
enol ethers to form 4,6-disubstituted or 4,5,6-trisubstituted
indoles.[26]
The indole unit is present in a multiplicity of natural
compounds, many of which reveal significant physiological
activities. Noticeably, the indole ring system can be classi-
fied as a fundamental structural component in a large vari-
ety of therapeutic agents.[1–7] The recent progress of indole
chemistry can be also related to materials chemistry, as sev-
eral indole-containing materials have been explored. For in-
stance, materials that contain indole as the functional unit
can act as nonlinear optical (NLO) chromophores[8,9] or
can be applied as fundamental building blocks for blue[10]
or red[11] electroluminescent materials. Indole-based light-
emitting oligomers containing indole moieties with arylene-
vinylene and aryl bridges have been reported as well.[12]
Branched diphenylsilane derivatives containing electroni-
cally isolated indolyl moieties act as host materials for or-
ganic blue-light-emitting diodes.[13] Finally, copolymers
containing indole-related units with fine-modulated optical
and electrical properties are promising candidates for pho-
tovoltaic application.[14,15] The fundamental role in all areas
outlined above creates unceasing demand for the develop-
ment of general, flexible, and especially regioselective syn-
thetic methods of such a structural moiety.[7,16–23]
Herein, we report an efficient synthesis of 4,7-disubsti-
tuted indoles by fused arene ring construction around a
pyrrole by applying a catalyzed rearrangement of 1,4-di-
aryl-1,4-di(pyrrol-2-yl)but-2-yne or 1,4-di(pyrrol-2-yl)-1,4-
di(thien-2-yl)but-2-yne. Subsequently, the acid-induced re-
versible dimerization was explored by applying a combined
NMR/DFT approach.
According to recently proposed classification by Taber
and Tirunahari, it is apparent that every indole synthesis
fits one of the nine strategic approaches.[23] In fact, in the
simplified view applied here for the convenience of further
discussion, these nine well-defined strategies can be gath- Results and Discussion
ered into three major groups. Thus, in the first group, the
Syntheses of 1,4-Diaryl-1,4-di(pyrrol-2-yl)but-2-yne and
1,4-Di(pyrrol-2-yl)-1,4-di(thien-2-yl)but-2-yne
pyrrolic ring is built on an existing benzene or cyclohexane
ring. The recently reported synthesis of 4,7-diarylindoles,
obtained in search of an indole-based fluorescent chemo-
A starting step in the synthesis of 4,7-diarylindoles 1a–c
and 4,7-di(thien-2-yl)indole 1d is the formation of 1,4-di-
aryl-1,4-di(pyrrol-2-yl)but-2-ynes 2a–c and 1,4-di(pyrrol-2-
yl)-1,4-di(thien-2-yl)but-2-yne 2d. Previously, we used these
ethyne derivatives for introducing the ethyne unit into the
porphyrin-like skeleton 20-thiaethyneporphyrin.[29]
[a] Department of Chemistry, University of Wrocław,
14 F. Joliot-Curie St., 50 383 Wrocław, Poland
Fax: +48-713282348
E-mail: lechoslaw.latos-grazynski@chem.uni.wroc.pl
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200644.
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FULL PAPER
1,4-Diaryl-2-butyne-1,4-diols 3a–c and 1,4-di(thien-2-yl)- ular structure of 1c was determined by X-ray diffraction
2-butyne-1,4-diol 3d were obtained by applying the stan- studies (Figure 1). The bond lengths and bond angles re-
dard approach in the reaction of aryl aldehyde or thio- semble those reported for other indole derivatives.[41,42]
phene-2-carbaldehyde with the Grignard reagent
BrMgCϵCMgBr in THF.[30,31] Subsequently, the modified
Nicholas reaction was applied (Scheme 1).[32–38] A direct re-
action between 1,4-diaryl-2-butyne-1,4-diol 3a–c or 1,4-di-
(thien-2-yl)-2-butyne-1,4-diol 3d and pyrrole (in excess) cat-
alyzed with TFA (trifluoroacetic acid) failed to produce 2a–
c or 2d but produced trace amounts of 4,7-disubstituted
indoles 1. Subsequent reaction with pyrrole as a nucleophile
followed by decomplexation afforded substituted alkynes,
that is, 2a–d. The yields (ca. 30%) of this step resembles
that of originally reported 2a.[29]
Figure 1. Molecular structure of 1c (top: perspective view, bottom:
side view). The thermal ellipsoids represent 50% probability. The
dihedral angles between aryl groups and the indole unit are –48.1°
(C5–C4–C4ipso–C4ortho) and –42.7° (C6–C7–C7ipso–C7ortho).
Suggested Mechanism
For the mechanism of formation of 4,7-disubstituted in-
doles 1 (Scheme 3), we suggest that TFA acidolysis of 2 via
formation of 2-H+[43–45] affords transient reactive cationic
Scheme 1. Synthesis of 1,4-di(pyrrol-2-yl)-2-butynes 2a–c and 2d.
species 2-1. Subsequently, the process involves a deep reor-
ganization of propargyl cation 2-1, which may undergo nec-
essary dual hydrogen migration of the atoms originally lo-
cated at the 1,4-positions of 2. This transformation gener-
Synthesis of 4,7-Disubstituted Indoles
ates substituted 1,3-diene cation 2-2, which is suitably pre-
arranged for intramolecular electrophilic attack at the adja-
cent pyrrole to close the six-membered ring.
Initially, compounds 2 were used as the fundamental
substrate in the synthesis of 20-thiaethyneporphyrin by
using a simple modification of the “3+1” approach[39,40] by
applying BF3·OEt2 as a catalyst, whereas 2 was considered
as the ethyne analogue of tripyrrane. In the course of the
reaction, 4,7-diarylindoles were identified as a specific quite
disturbing side product.
In this study, the addition of TFA to a solution of 2 in
CDCl3 was monitored by 1H NMR spectroscopy, which
provided spectroscopic evidence that under such conditions
4,7-diarylindole was immediately formed as the sole iden-
tified product of the conversion. Consequently, we decided
to optimize this route as a suitable procedure to generate
4,7-disubstituted indoles. In fact, on the synthetic scale 1,4-
diaryl-1,4-di(pyrrol-2-yl)but-2-yne [1,4-di(pyrrol-2-yl)-1,4-
di(thien-2-yl)but-2-yne] in the presence of TFA converts
preferably into 4,7-diarylindole [4,7-di(thien-2-yl)indole]
(Scheme 2). Chromatography yielded 4,7-disubstituted in-
doles 1 readily identified by NMR spectroscopy. The molec-
Scheme 3. Mechanism of transformation.
To validate the mechanism of formation, an identical re-
action was carried out by using [D]TFA instead of TFA
and [D2]dichloromethane instead of dichloromethane. The
Scheme 2. Synthesis of 4,7-di(thien-2-yl)indole.
2
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Fused Arene Ring Construction Around Pyrrole
formation of 1,3-dideuterioderivative 1a-d2 was solely ob-
served. Thus, the 5-H and 6-H hydrogen atoms of 1a are
definitely provided by an intramolecular process as pos-
tulated above. Deuteration at the N1 and C3 positions re-
flects the typical acid–base chemistry exhibited by indoles
in general.[46] Thus, addition of [D]TFA results eventually
in replacement of hydrogen by deuterium in the specified
positions according to that shown in Scheme 4 (Supporting
Information, Figure S28).
Scheme 5. Dimerization of 4,7-diarylindole.
Scheme 4. Deuteration of 4,7-diarylindole.
The dimerization requires 30 equiv. of TFA and was ac-
complished usually at 240 K. Systematic increase in the
temperature results in recovery of 4,7-diarylindole 1. In
fact, indole 1 and protonated 2-(3-indolyl)indoline 6-H+ are
in thermodynamic equilibrium as demonstrated by the ther-
mal reversibility of the process with preservation of the
1/6-H+ molar ratio for the given acid concentration and
temperature (1:9, 240 K; 9:1, 300 K, 30 equiv. of TFA). Sig-
Dimerization
Monoprotonated indoles 1-H+ have not been directly ob-
1
served by H NMR spectroscopy (Figure 2). Lowering of
the temperature favors the formation of N-protonated 2-
(3-indolyl)indoline 6-H+ (Scheme 5). The dimerization of 1
follows the pattern reported for regular indole,[47] which
suggests increased electrophilicity at the C2 position as a
result of protonation at C3.
1
nificantly, neutralization of 6-H+, monitored by H NMR
spectroscopy, carried out by addition of 100 equiv. of [D5]-
pyridine at 240 K affords free base 6, which under such con-
ditions remain the sole species in the temperature range
240–300 K. The dimerizations of indoles already reported
follow the route shown in Scheme 5.[47–52]
The identity of 6b-H+ was confirmed by high-resolution
mass spectrometry and NMR spectroscopy. Thus, the as-
signments of the resonances of 6b-H+ (Figure 3) were made
on the basis of the relative intensities and detailed 2D NMR
studies (COSY, NOESY, ROESY, HMQC, HMBC) carried
out at 260 K in [D]chloroform, where the conversion was
practically complete. The 1H NMR spectrum of 6b-H+ con-
Figure 2. Reversible dimerization of 4,7-di(p-tolyl)indole 1b
(30 equiv. of TFA added, CDCl3). Labeling of the representative
resonances: triangles 1b, circles 6b-H+: (a) 260 K, (b) 280 K,
(c) 300 K. The intensity of the peaks in all traces is standardized
with respect to the solvent. The resonance marked with an asterisk
is assigned to residual dichloromethane.
Figure 3. 1H NMR spectrum of 6b-H+ ([D]chloroform, 260 K).
Numbering: see Scheme 5. Insets demonstrate the crowded 6.9–
7.7 ppm region. Resonances of 1b are marked with asterisks.
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E. Nojman, L. Latos-Grazyn´ski,, L. Szterenberg
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FULL PAPER
tains two subsets of resonances readily assigned to 4,7-di- ses the shortest H–H distances are given). These structural
arylindole and 2,3-dihydroindole (indoline) related moieties features have been reflected in the ROESY map by two
through relays of COSY (indole 1Ј-H ↔ 2Ј-H, 5Ј-H ↔ 6Ј- well-defined cross-peaks (Supporting Information, Fig-
H, and 2,3-dihydroindole 11-H ↔ 12-H, 11-H ↔ 2-H, 2-H ure S29). Originally, the DFT model of the second rotamer
↔ 31-H, 2-H ↔ 32-H, 31-H ↔ 32-H, 5-H ↔ 6-H).
(6b-H+)3 was also analyzed. One can readily demonstrate
The dimerization experiment carried out in the presence that the above-described fundamental connectivity pattern
of [D]TFA afforded the derivative, whereas substitution by is not consistent with the geometry of (6b-H+)3. For in-
deuterium took place at C3, N1Ј, and N1 following in fact stance, the fundamental 2-H-o-H(4Ј-Tol) dipolar corre-
the deuteration pattern of 4,7-diarylindole discussed in de- lation is not feasible in the second rotamer, as the optimized
tail above. Significantly, the complementary HSQC experi- shortest distance equals 4.97 Å.
ment allowed the unambiguous identification of the unique
C2 resonance revealing its tetrahedral geometry consistent
with the 63.1 ppm chemical shift. The straightforward as-
signment of the 2-H resonance presented above provided
the initial step for the 1H NMR spectroscopic analysis (Fig-
ure 3). Once assigned, this particular set of resonances was
used as a starting point for the NOE studies. The funda-
mental relay of NOE connectivities is shown in Figure 4.
Figure 5. Geometries of (6b-H+)1 and (6b-H+)3 in a DFT optimiza-
Figure 4. The established NOE connectivities for (6b-H+)1. The
tion at the B3LYP/6-31G** level. Side projections emphasize the
spatial proximities (in Å, from DFT optimized model) are in paren-
conformations of 6b-H+ with respect to the C2–C3Ј bond (indoline
theses.
unit in front).
Noticeably, four different sets of meso-p-tolyl ring reso-
Table 1. Selected dihedral angles for 6b-H+ rotamers.
nances were detected readily via COSY and NOESY, which
correlated with particular methyl resonances. The detected
differentiation of the ortho and meta resonances seen for 4Ј-
p-tolyl, which is linked to the indole moiety, suggests that
their rotation with respect to the Cmeso–Cipso bond is slow
at 260 K, and obviously, 6b-H+ is not planar. In contrast,
Dihedral angle / °
Conformer
(6b-H+)1 (6b-H+)2 (6b-H+)3 (6b-H+)4
C3–C2–C3Ј–C2Ј
C5–C4–C4ipso–C4ortho
C6–C7–C7ipso–C7ortho
–4.7
–52.0
–48.3
–11.4
–49.6
51.3
–57.3
44.5
–115.2
–43.3
–55.4
–95.7
47.0
–116.4
–41.5
43.2
–91.9
46.6
fast rotation was detected for the 7Ј-, 4-, and 7-p-tolyl C5Ј–C4Ј–C4Јipso–C4Јortho –67.1
C6Ј–C7Ј–C7Јipso–C7Јortho
44.7
groups, as documented by a single doublet for the ortho and
meta positions in each case.
Two principal conformers of 6b-H+ can be readily distin-
Significantly, the fast exchange between rotamers is ex-
guished by the C3–C2–C3Ј–C2Ј dihedral angles (6b-H+)1: pected to produce the population-averaged chemical shift
–4.7°; (6b-H+)3: –115.2° (Figure 5, Table 1). Considering in values and the population-averaged dipolar interactions
detail the spatial proximity of the 2-H-o-Ha(4Ј-Tol) (2.55 Å) seen by the NOE experiment. Thus, ROESY analysis re-
and 11-H-o-Hb(4Ј-Tol) (2.77 Å) as found at the DFT-opti- flects the dominating impact of (6b-H+)1 but does not ex-
mized structure of (6b-H+)1, one could expect the NOE clude the significant population of other major rotamers.
cross-peaks, reflecting the coinciding dipolar coupling be-
The significant chemical shift difference of the 11-H and
tween the 2-H and 11-H hydrogen atoms, to o-H(4Ј-Tol). 12-H resonances may reflect their location with respect to
Consistently with the considered structure, only 31-H is the shielding zone of the adjacent 4Ј-p-tolyl group. The res-
close enough to produce the detectable dipolar 31-H-2Ј-H onance located upfield corresponds to the 11-H atom that
(2.25 Å) and 32-H-2Ј-H (3.17 Å) correlations (in parenthe- is positioned close to the p-tolyl plane. Alternatively, the
4
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Fused Arene Ring Construction Around Pyrrole
1
involvement of the exposed 12-H in interactions via hydro-
The H NMR chemical shifts calculated for 1b and (6b-
gen bonding with the TFA molecules may be instrumental H+)1–4 by using the GIAO B3LYP/6-31G** method are
in the detected chemical shift differentiation.[53,54] The 11- given in the Supporting Information (Tables S7–S11). There
H hydrogen encapsulated in the dimeric cleft is expected to are satisfactory qualitative agreements between the calcu-
have limited access to such hydrogen acceptors.
lated and experimental chemical shifts of the CH and 1Ј-
NH resonances, even though the experimental chemical
shifts correspond to rotamer population-averaged values,
shown practically for all rotamers (Figure 6; Supporting In-
formation, S33–S35). The experimental chemical shifts of
the ammonium unit are well reproduced for the (6b-H+)3
and (6b-H+)4 forms, whereas the marked downfield relo-
cation of 12-NH with respect to 11-NH has been clearly
replicated.
DFT Studies
The structural formula of 6b-H+ shown in Scheme 5
demonstrated merely the projection facilitating a presenta-
tion. To account for the 1H NMR characteristics of 6b-H+,
non-planar structural scaffolds were considered (Figure 4).
Consequently, DFT studies were used to visualize the sug-
gested structures of 6b-H+ and to assess the preference of
the major rotamers with respect to the C2–C3Ј bond.
Eventually, we realized that the orientation of the aryl sub-
stituents is of importance. Geometries of four fundamental
rotamers with respect to the C2–C3Ј and C(indole)–
C(aryl)ipso bonds were optimized at the B3LYP/6-31G**
level. Two representative optimized structures are shown in
Figure 5. The optimized geometries for two other rotamers
are shown in Supporting Information (Figures S30 and
S31). The structures are identified by sets of dihedral angles
as shown in Table 1. The calculated relative energies, using
the B3LYP/6-31G**//B3LYP/6-31G** approach, are gath-
ered in Table 2.
Conclusions
An atypical procedure to construct a fused arene ring
around a pyrrole to form 4,7-disubstitued indoles has been
elaborated. The indole ring, favorably decorated at the 4,7-
positions can be considered as a suitable building block ap-
propriately preorganized to be incorporated in functional
polymeric materials containing poly(p-phenylene) (PPP),
poly(p-phenylene vinylene) (PPV), or polythiophenes (PT)
backbones.
Experimental Section
Table 2. Calculated relative energies [kcalmol–1] of the 6b-H+ con-
formers.
General Methods: Dichloromethane and triethylamine were dis-
tilled from CaH2. Solvents like ethanol, n-hexane, at least pure
grade, were used without purification. Tetrahydrofuran (THF) was
purified via pushing through an absorber column (M Braun SPS-
800 system). [D2]Dichloromethane was used as received. [D]Chloro-
form was prepared directly before using by passing through a small
basic alumina column. Inorganic salts were used without purifica-
tion. Compounds 3b–d, 4b–d, 5b–d, and 2b–d were synthesized ana-
logically to the previously reported procedure.[29] NMR spectra
were measured with Bruker Avance 500 MHz and Bruker Avance
600 MHz spectrometers. 1H and 13C shifts are referenced to the
residual resonances of deuterated solvents. 2D NMR spectra were
recorded typically with 2048 data points in the t2 domain and up
to 1024 points in the t1 domain with a 1 s recovery delay. Mass
spectra (high-resolution and accurate-mass) were recorded with a
Bruker microTOF-Q spectrometer by using the electrospray tech-
nique.
Conformer
Erel.
(6b-H+)1
(6b-H+)2
(6b-H+)3
(6b-H+)4
0.00
1.00
1.94
1.69
The exact energy ordering has no quantitative signifi-
cance, as the calculations were performed without a solvent
model and feasible interaction with TFA molecules.
1,4-Di(p-tolyl)-2-butyne-1,4-diol (3b): Yield: 4.9 g, 46%. Cream
amorphous solid. Synthesized by a previously reported procedure
by using p-tolualdehyde instead of benzaldehyde.[29] 1H NMR
3
(600 MHz, CDCl3, 300 K): δ = 7.42 (d, J = 8.1 Hz, 4 H, o-Tol),
3
3
7.18 (d, J = 7.9 Hz, 4 H, m-Tol), 5.52 (d, J = 6.0 Hz, 2 H, 1-H,
3
3
4-H), 2.4 (s, 6 H, Me), 2.12 (d, J = 6.0 Hz, 1 H, OH), 2.11 (d, J
= 6.0 Hz, 1 H, OH) ppm. 13C NMR (150.90 MHz, CDCl3, 300 K):
δ = 138.4, 137.5, 129.3, 126.6, 86.4, 64.6, 21.1 ppm. HRMS (ESI):
calcd. for [C18H18O2 + Na]+ 289.1205; found 289.1201.
1,4-Di(p-methoxyphenyl)-2-butyne-1,4-diol (3c): Yield: 8.2 g, 69%.
Cream amorphous solid. Synthesized by a previously reported pro-
cedure by using p-anisaldehyde instead of benzaldehyde.[29] 1H
Figure 6. The representative linear correlation between calculated
for (6b-H+)3 (GIAO B3LYP/6-31G**) and experimental (rotamer
population averaged) values of chemical shifts (᭡: NH; ᭺: 2-H, 2Ј-
H; ᭿: 3-H; ᮀ: 5-H, 6-H, 5Ј-H, 6Ј-H; ᭹: p-Tol).
3
NMR (500 MHz, CDCl3, 300 K): δ = 7.46 (d, J = 8.7 Hz, 4 H, o-
PhOMe), 6.90 (d, 3J = 8.7 Hz, 4 H, m-PhOMe), 5.50 (d, 3J =
3
5.6 Hz, 2 H, 1-H, 4-H), 3.80 (s, 6 H, OMe), 2.22 (d, J = 5.6 Hz,
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1 H, OH), 2.21 (d, 3J = 5.6 Hz, 1 H, OH) ppm. 13C NMR anes fraction (1:1). The third step, the synthesis and purification of
(125.76 MHz, CDCl3, 300 K): δ = 159.8, 132.6, 128.1, 114.0, 86.4, 2d, was analogous to the previously reported procedure for 2a, ex-
64.3, 55.3 ppm. HRMS (ESI): calcd. for [C18H18O4 + Na]+
321.1103; found 321.1096.
cept a silica gel suspension in dichloromethane in a glass column
was purged with nitrogen for 30 min and chromatography was car-
1
ried out under a nitrogen atmosphere. Characterization of 2d: H
1,4-Di(thien-2-yl)-2-butyne-1,4-diol (3d): Yield: 7 g, 70%. Pale
brown amorphous solid. Synthesized by a previously reported pro-
cedure by using 2-thiophenecarboxaldehyde instead of benzalde-
hyde.[29] 1H NMR (600 MHz, CDCl3, 300 K): δ = 7.31 (dd, 3J =
3
NMR (600 MHz, CDCl3, 300 K): δ = 8.17 (2 H, NH), 7.22 (d, J
3
3
= 5.0 Hz, 2 H, 5-Th), 7.00 (m, 2 H, 3-Th), 6.96 (dd, J = 5.0, J =
3.5 Hz, 2 H, 4-Th), 6.71 (m, 2 H, pyr), 6.18–6.14 (bb, 4 H, pyr),
5.43 (s, 2 H, 1-H, 4-H) ppm. 13C NMR (150.90 MHz, CDCl3,
300 K): δ = 144.0 (2-Th), 129.7 (α-pyr), 126.8 (4-Th), 125.1 (3-Th),
124.8 (5-Th), 117.6 (pyr), 108.6 (pyr), 106.4 (pyr), 82.5 (C2, C3),
32.0 (C1, C4) ppm. HRMS (ESI): calcd. for [C20H16N2S2]+
348.0755; found 348.0739.
4
5.0, J = 1.2 Hz, 2 H, 5-Th), 7.19 (m, 2 H, 3-Th), 6.98 (dd, 3J =
3
5.0, J = 3.5 Hz, 2 H, 4-Th), 5.75 (br. s, 2 H, 1-H, 4-H), 2.54 (br.
s, 2 H, OH) ppm. 13C NMR (150.9 MHz, CDCl3, 300 K): δ =
143.9, 126.8, 126.3, 125.8, 85.1, 60.3 ppm. HRMS (ESI): calcd. for
[C12H10O2S2 + Na]+ 273.0020, found 273.0025.
4,7-Diphenylindole (1a): Yield: 18 mg, 31%. Brown amorphous so-
lid. Compound 2a was synthesized by a previously reported pro-
cedure.[29] Compound 2a (59 mg, 0.22 mmol) was dissolved in
freshly distilled dichloromethane (25 mL), and the solution was
purged with nitrogen gas for 15 min. Then, tifluoroacetic acid
(17 μL, 0.22 mmol) was added, and the mixture was stirred under
1,4-Di(p-tolyl)-1,4-di(pyrrol-2-yl)but-2-yne (2b): Yield: 35 mg, 30%.
Yellow oil. The first step, the synthesis and purification of the dico-
balt complex of 1,4-di(p-tolyl)-2-butyne-1,4-diol 3b (yield: 6.6 g,
95%, red amorphous solid), was analogous to the previously re-
ported procedure for 3a. The second step, the synthesis and purifi-
cation of the dicobalt complex of 1,4-di(p-tolyl)-1,4-di(pyrrol-2-yl)-
but-2-yne 4b (yield: 1.49 g, 73%, brown-red oil), was analogous to
the previously reported procedure for 4a, except 4b (main brown-
red fraction) was eluted with dichloromethane/hexanes fraction
(1:1). The third step, the synthesis and purification of 2b, was anal-
ogous to the previously reported procedure for 2a. Characterization
a
nitrogen atmosphere for 1 h. Next, triethylamine (31 mL,
0.22 mmol) was added, and the solution was stirred for 30 min.
Then, the solvent was evaporated to dryness, and the residue was
purified by chromatography on silica gel. The first yellow fraction
eluted with dichloromethane was collected to give 1a. 1H NMR
3
(600 MHz, CDCl3, 300 K): δ = 8.52 (br. s, 1 H, 1-H), 7.75 (d, J =
1
of 2b: H NMR (600 MHz, CD2Cl2, 300 K): δ = 8.18 (br. s, 2 H,
3
3
7.65 Hz, 2 H, 4-o), 7.68 (d, J = 7.56 Hz, 2 H, 7-o), 7.53 (d, J =
3
3
NH), 7.28 (d, J = 8.0 Hz, 4 H, o-Tol), 7.16 (d, J = 8.0 Hz, 4 H,
m-Tol), 6.65 (m, 2 H, pyr), 6.08 (m, 2 H, pyr), 5.98 (m, 2 H, pyr),
5.13 (s, 2 H, 1-H, 4-H), 2.33 (s, 6 H, Me) ppm. 13C NMR
(150.90 MHz, CD2Cl2, 300 K): δ = 139.2 (p-Tol), 138.6 (i-Tol),
132.7 (α-pyr), 130.9 (m-Tol), 128.9 (o-Tol), 118.8 (pyr), 110.0 (pyr),
107.6 (pyr), 84.9 (C2, C3), 38.0 (C1, C4), 22.3 (Me) ppm. HRMS
(ESI): calcd. for [C26H24N2 + H]+ 365.2018; found 365.2011.
7.5 Hz, 2 H, 7-m), 7.5 (d, 3J = 7.5 Hz, 2 H, 4-m), 7.41 (t, 3J =
3
3
7.35 Hz, 2 H, 7-p), 7.39 (t, J = 7.35 Hz, 2 H, 4-p), 7.32 (d, J =
7.4 Hz, 1 H, 6-H), 7.3 (d, J = 7.4 Hz, 1 H, 5-H), 7.26 (dd, 3J =
3
4
3
4
3.3, J = 2.3 Hz 1 H, 2-H), 6.81 (dd, J = 3.3, J = 2.2 Hz, 1 H, 3-
H) ppm. 13C NMR (150.90 MHz, CDCl3, 300 K): δ = 141.1 (4-
ipso), 139.1 (7-ipso), 134.1 (7a), 133.8 (4), 129.2 (7-m), 128.8 (4-o),
128.5 (4-m), 128.2 (7-o), 127.5 (7-p), 127.0 (4-p), 126.4 (3a), 124.8
(7), 124.7 (2), 122.3 (6), 120.3 (5), 102.7 (3) ppm. HRMS (ESI):
calcd. for [C20H15N + H]+ 270.1283; found 270.1286.
1,4-Di(p-methoxyphenyl)-1,4-di(pyrrol-2-yl)but-2-yne (2c): Yield:
47 mg, 37%. Yellow oil. The first step, the synthesis and purifica-
tion of the dicobalt complex of 1,4-di(p-methoxyphenyl)-2-butyne-
1,4-diol 3c (yield: 6 g, 82%, red amorphous solid), was analogous
to the previously reported procedure for 3a. The second step, the
synthesis and purification of the dicobalt complex of 1,4-di(p-meth-
oxyphenyl)-1,4-di(pyrrol-2-yl)but-2-yne 4c (yield: 1.35 g, 63%,
brown-red oil), was analogous to the previously reported procedure
for 4a, except 4c (main brown-red fraction) was eluted with di-
chloromethane. The third step, the synthesis and purification of 2c,
was analogous to the previously reported procedure for 2a, except
2c (second yellow fraction) was eluted with dichloromethane. Char-
Deuteration of 1a: A solution of 1a in CDCl3 was placed in an
NMR tube (typically a sample of ca. 2 mg of 1a). Addition of [D]-
TFA and D2O to the solution of 1a gave 1a-d2. 1H NMR
(600 MHz, CDCl3, 300 K): δ = 7.75 (d, 3J = 7.65 Hz, 2 H, 4-o),
3
3
7.68 (d, J = 7.56 Hz, 2 H, 7-o), 7.53 (d, J = 7.5 Hz, 2 H, 7-m),
7.5 (d, 3J = 7.5 Hz, 2 H, 4-m), 7.41 (t, 3J = 7.35 Hz, 2 H, 7-p), 7.39
(t, J = 7.35 Hz, 2 H, 4-p), 7.32 (d, J = 7.4 Hz, 1 H, 6-H), 7.3 (d,
3J = 7.4 Hz, 1 H, 5-H), 7.26 (br. s, 1 H, 2-H) ppm.
3
3
4,7-Di(p-tolyl)indole, 4,7-di(p-methoxyphenyl)indole, and 4,7-di-
(thien-2-yl)indole were prepared analogically to the procedure re-
ported for 1a.
1
acterization of 2c: H NMR (500 MHz, CDCl3, 300 K): δ = 8.06
3
3
(br. s, 2 H, NH), 7.31 (d, J = 8.8 Hz, 4 H, o-PhOMe), 6.87 (d, J
= 8.8 Hz, 4 H, m-PhOMe), 6.66 (m, 2 H, pyr), 6.14 (m, 2 H, pyr),
6.00 (m, 2 H, pyr), 5.11 (s, 2 H, 1-H, 4-H), 3.80 (s, 6 H, OMe)
ppm. 13C NMR (125.76 MHz, CD2Cl2, 300 K): δ = 158.7 (p-
PhOMe), 132.4 (i-PhOMe), 131.2 (α-pyr), 128.7 (o-PhOMe), 117.2
(pyr), 114.0 (m-PhOMe), 108.5 (pyr), 106.2 (pyr), 83.4 (C2, C3),
55.3 (OMe), 36.0 (C1, C4) ppm. HRMS (ESI): calcd. for
[C26H24N2O2]+ 396.1837; found 396.1831.
4,7-Di(p-tolyl)indole (1b): Yield: 25 mg, 38%. Brown amorphous
1
solid. H NMR (600 MHz, CDCl3, 300 K): δ = 8.51 (br. s, 1 H, 1-
3
3
H), 7.64 (d, J = 7.98 Hz, 2 H, 4-o), 7.6 (d, J = 7.98 Hz, 2 H, 7-
3
3
o), 7.33 (d, J = 7.86 Hz, 2 H, 7-m), 7.31 (d, J = 7.92 Hz, 2 H, 4-
3
3
m), 7.28 (d, J = 7.4 Hz, 1 H, 6-H), 7.26 (d, J = 7.4 Hz, 1 H, 5-
H), 7.25 (dd, 1 H, 2-H), 6.79 (dd, 3J = 3.2, J = 2.2 Hz, 1 H, 3-H),
4
2.44 (s, 3 H, 4-Me or 7-Me), 2.44 (s, 3 H, 4-Me or 7-Me) ppm. 13
C
NMR (150.90 MHz, CDCl3, 300 K): δ = 138.2 (4-ipso), 137.2 (7-
p), 136.6 (4-p), 136.2 (7-ipso), 134.1 (7a), 133.5 (4), 129.9 (7-m),
129.2 (4-m), 128.6 (4-o), 128.1 (7-o), 126.4 (3a), 124.5 (7), 124.5 (2),
122.2 (6), 120.1 (5), 102.7 (3), 21.2 (Me) ppm. HRMS (ESI): calcd.
for [C22H19N + H]+ 298.1596; found 298.1598.
1,4-Di(pyrrol-2-yl)-1,4-di(thien-2-yl)but-2-yne (2d): Yield: 18 mg,
16%. Yellow oil. The first step, the synthesis and purification of
the dicobalt complex of 1,4-di(2-thienyl)-2-butyne-1,4-diol 3d
(yield: 6.4 g, 95%, red amorphous solid), was analogous to the pre-
viously reported procedure for 3a. The second step, the synthesis
and purification of the dicobalt complex of 1,4-di(pyrrol-2-yl)-1,4-
di(2-thienyl)but-2-yne 4d (yield: 1.35 g, 68%, brown-red oil), was
analogous to the previously reported procedure for 4a, except 4d
(main brown-red fraction) was eluted with dichloromethane/hex-
4,7-Di(p-methoxyphenyl)indole (1c): Yield: 58 mg, 80%. Brown
1
amorphous solid. H NMR (500 MHz, CD2Cl2, 300 K): δ = 8.60
(br. s, 1 H, 1-H), 7.67 (d, 3J = 8.7 Hz, 2 H, 4-o), 7.61 (d, 3J =
3
4
8.7 Hz, 2 H, 7-o), 7.29 (dd, J = 3.3, J = 2.3 Hz, 1 H, 2-H), 7.24
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20644
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Date: 25-06-12 17:04:35
Pages: 9
Fused Arene Ring Construction Around Pyrrole
3
(d, 3J = 7.4 Hz, 1 H, 6-H), 7.21 (d, 3J = 7.4 Hz, 1 H, 5-H), 7.08
(d, 3J = 8.7 Hz, 2 H, 7-m), 7.04 (d, 3J = 8.7 Hz, 2 H, 4-m), 6.77
4Ј-m), 7.03 (d, J = 7.4 Hz, 1 H, 5Ј-H), 6.27 (br. s, 1 H, 1-H), 6.18
(d, 3J = 7.4 Hz, 1 H, 4Ј-m), 5.04 (m, 1 H, 2-H), 4.04 (dd, 2J =
15.5 Hz, 3J = 12.0 Hz, 1 H, 3-H), 3.43 (dd, 2J = 15.5 Hz, 3J =
6.8 Hz, 1 H, 3-H), 2.51 (s, 3 H, 7-Me), 2.43 (s, 3 H, 7Ј-Me), 2.42
3
4
(dd, J = 3.3, J = 2.3 Hz, 1 H, 3-H), 3.88 (s, 3 H, OMe), 3.87 (s,
3 H, OMe) ppm. 13C NMR (125.76 MHz, CD2Cl2, 300 K): δ =
160.8 (7-p), 160.5 (4-p), 135.7 (7a), 135.2 (4-ipso), 134.4 (4), 133.0 (s, 3 H, 4-Me), 2.15 (s, 3 H, 4Ј-Me) ppm. 13C NMR (150.9 MHz,
(7-ipso), 131.2 (4-o), 130.8 (7-o), 127.9 (3a), 126.2 (2), 125.7 (7), CDCl3, 260 K): δ = 139.7, 138.8, 138.6, 138.1, 138.0, 137.5, 134.7,
123.6 (6), 121.4 (5), 116.2 (7-m), 115.6 (4-m), 103.9 (3), 56.9 (OMe), 134.65, 134.6, 133.0, 131.9, 131.81, 131.78, 131.6, 131.2, 130.2,
56.8 (OMe) ppm. HRMS (ESI): calcd. for [C22H19NO2 + H]+
330.1489; found 330.1492.
129.6, 129.5, 129.29, 129.26, 129.2, 128.2–127.7, 126.2, 125.9,
123.5, 122.9, 122.8, 106.6, 63.1, 33.4, 21.27, 21.24, 21.17, 21.1 ppm.
HRMS (ESI): calcd. for [C44H39N2]+ 595.3113; found 595.3120.
4,7-Di(thien-2-yl)indole (1d): Yield: 25 mg, 84%. Brown amorphous
solid. Compound 2d (37 mg, 0.11 mmol) was dissolved in freshly
distilled dichloromethane (12 mL), and the solution was purged
with nitrogen gas for 15 min. Then, trifluoroacetic acid (8 μL,
0.11 mmol) was added, and the mixture was stirred under a nitro-
gen atmosphere for 30 min. Next, triethylamine (15 mL,
0.11 mmol) was added, and the solution was stirred for 30 min.
Then, the solvent was evaporated to dryness, and the residue was
purified by chromatography on silica gel. A silica gel suspension in
dichloromethane in a glass column was purged with nitrogen for
30 min and chromatography was carried out under a nitrogen at-
mosphere. The first orange fraction eluted with dichloromethane
2-(4,7-Di-p-tolylindol-3-yl)-4,7-di-p-tolylindoline (6b): [D5]Pyridine
(30 equiv.) was added to a solution of 6b-H+ prepared in previous
1
experiment. Compound 6b-H+ was converted into 6b at once. H
NMR (600 MHz, CDCl3, 240 K): δ = 10.74 (s, 1 H, 1-H), 10.70 (s,
3
3
1 H, 1Ј-H), 7.50 (d, J = 7.7 Hz, 1 H), 7.41 (d, J = 7.7 Hz, 1 H),
7.38 (d, 3J = 7.7 Hz, 2 H), 7.28 (d, 3J = 2.2 Hz, 1 H), 7.26–6.98,
6.92 (d, 3J = 7.0 Hz, 1 H), 6.87 (d, 1 H), 6.86 (d, 3J = 7.4 Hz, 1
3
3
H), 6.64 (d, J = 7.9 Hz, 1 H), 6.62 (t, 1 H), 6.44 (d, J = 7.4 Hz,
3
3
2
1 H), 4.72 (dd, J = 11.3 Hz, J = 7.8 Hz, 1 H, 2-H), 3.01 (dd, J
= 14.8 Hz, J = 11.3 Hz, 1 H, 3-H), 2.86 (dd, J = 14.8 Hz, J =
3
2
3
7.8 Hz, 1 H, 3-H), 2.31–1.93 ppm.
1
was collected to give 1d. H NMR (600 MHz, CDCl3, 300 K): δ =
Structure Analysis: An X-ray quality crystal of 1c was prepared by
diffusion of n-hexane into a solution of dichloromethane contained
in a tube stored at room temperature. Data were collected at 100 K
with an Xcalibur PX-k geometry diffractometer with Mo-Kα radia-
tion (λ = 0.71073 Å). Data were corrected for Lorentz and polar-
ization effects. Crystal data is compiled in Table S1 (Supporting
Information). The structure was solved by direct methods with
SHELXS-97 and refined by full-matrix least-squares method by
using SHELXL-97. Scattering factors were those incorporated in
SHELXS-97.[55,56] Hydrogen atoms were fixed in idealized posi-
tions using the riding model constraints.
3
4
8.77 (br. s, 1 H, 1-H), 7.49 [dd, J = 3.5 Hz, J = 1.2 Hz, 1 H, 4-
(3-th)], 7.41 (d, 3J = 7.4 Hz, 1 H, 5-H or 6-H), 7.40 [dd, 3J = 3.5 Hz,
4J = 1.2 Hz, 1 H, 7-(3-th)], 7.38 (d, J = 7.4 Hz, 1 H, 5-H or 6-H),
3
3
4
7.38–7.36 [m, 2 H, 4,7-(5-th)], 7.33 (dd, J = 3.3 Hz, J = 2.1 Hz,
1 H, 2-H), 7.20 [dd, 3J = 5 Hz, 3J = 3.5 Hz, 1 H, 7-(4-th)], 7.18
3
3
3
[dd, J = 5 Hz, J = 3.5 Hz, 1 H, 4-(4-th)], 7.04 (dd, J = 3.3 Hz,
4J = 2.1 Hz, 1 H, 3-H) ppm. 13C NMR (150.90 MHz, CDCl3,
300 K): δ = 143.4 [4-(2-th)], 140.9 [7-(2-th)], 133.7 (4), 128.0 [7-(4-
th)], 127.6 [4-(4-th)], 126.9 (3a), 125.9 (7), 125.03 (2), 124.99 [7-(3-
th)], 124.9 [4-(3-th)], 124.8 and 124.6 [4,7-(5-th)], 122.1 (5 or 6),
119.9 (5 or 6), 117.9 (7a), 103.2 (3) ppm. HRMS (ESI): calcd. for
[C16H11NS2 + H]+ 282.0406; found 282.0400.
CCDC-879658 (for 1c) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
2-(4,7-Diphenylindol-3-yl)-4,7-diphenylindolinium (6a-H+): Evidence
of compound by NMR spectroscopy. A solution of 1a in CDCl3
was placed in an NMR tube (typically a sample of ca. 2 mg of 1a).
Titration of 1a was carried out with TFA (2.2 m in CDCl3) at
240 K. The progress of the reaction was followed by NMR spec-
DFT Calculations: DFT calculations were performed with the
Gaussian 03 program.[57] Starting geometries were obtained by
using molecular mechanics calculations. Geometry optimizations
were carried out within unconstrained C1 symmetry. Becke’s three
parameter exchange functional[58] with the gradient-corrected cor-
relation formula of Lee, Yang, and Parr (B3LYP)[59] was used with
the 6-31G** basis set. The structures were found to have converged
to a minimum on the potential energy surface; the resulting zero-
point vibrational energies were included in the calculation of rela-
tive energies. The proton chemical shifts were calculated at the
GIAO-B3LYP/6-31G** level for the optimized structures. The Car-
tesian coordinates for the calculated structures are given in the Sup-
porting Information.
1
troscopy. H NMR (600 MHz, CDCl3, 240 K): δ = 9.55 (t, 1 H, 1-
3
3
H), 9.32 (d, J = 2.6 Hz, 1 H, 1Ј-H), 7.68 (d, J = 2.6 Hz, 1 H, 2Ј-
3
H), 7.63–7.49, 7.48–7.40, 7.36 (d, J = 7.5 Hz, 1 H, 4Ј-o), 7.32 (d,
3J = 7.4 Hz, 1 H, 5Ј-H or 6Ј-H), 7.28–7.23, 7.08 (d, J = 7.4 Hz, 1
3
H, 5Ј-H or 6Ј-H), 7.03 (t, 3J = 7.5 Hz, 1 H, 4Ј-m), 6.38 (t, 3J =
7.5 Hz, 1 H, 4Ј-p), 6.07 (br. s, 1 H, 1-H), 5.08 (m, 1 H, 2-H), 4.10
(dd, 2J = 15.6 Hz, J = 12.3 Hz, 1 H, 3-H), 3.45 (dd, 2J = 15.6 Hz,
3
3J = 6.8 Hz, 1 H, 3-H) ppm. 13C NMR (150.9 MHz, CDCl3,
240 K): δ = 140.1, 138.8, 137.5, 137.4, 134.3, 133.1, 132.1, 132.0,
131.9, 131.1, 129.5, 129.4, 129.2, 128.8, 128.7, 128.4, 128.1–127.9,
126.2, 126.1, 123.4, 122.8, 122.5, 106.2, 63.0, 33.4 ppm. HRMS
(ESI): calcd. for [C40H31N2]+ 539.2482; found 539.2477.
Supporting Information (see footnote on the first page of this arti-
cle): Tables of computational results (Cartesian coordinates), fig-
ures presenting correlations between calculated and experimental
1H NMR chemical shifts, NMR spectroscopic data, crystal data
for 1c.
2-(4,7-Di-p-tolylindol-3-yl)-4,7-di-p-tolylindolinium (6b-H+): Evi-
dence of compound by NMR spectroscopy. A solution of 1b in
CDCl3 was placed in an NMR tube (typically a sample of ca. 2 mg
of 1b). Titration of 1b was carried out with TFA (2.2 m in CDCl3)
at 260 K. The progress of the reaction was followed by NMR spec-
troscopy. 1H NMR (600 MHz, CDCl3, 260 K): δ = 9.52 (br. s, 1 H,
3
3
Acknowledgments
1-H), 9.21 (d, J = 2.6 Hz, 1Ј-H), 7.62 (d, J = 2.6 Hz, 2Ј-H), 7.54
(d, 3J = 8.0 Hz, 1 H, 5-H), 7.48 (d, 3J = 8.0 Hz, 2 H, 7Ј-o), 7.37
(d, J = 8.0 Hz, 1 H, 6-H), 7.36–7.29 (8 H, 4-m, 7-m, 7Ј-m and 4- Financial support from the Ministry of Science and Higher Educa-
o), 7.28 (d, J = 7.4 Hz, 1 H, 6Ј-H), 7.24 (d, 1 H, 4Ј-o), 7.15 (d, J
= 7.8 Hz, 2 H, 7-o), 7.14 (d, 1 H, 4Ј-o), 7.07 (d, J = 7.4 Hz, 1 H,
3
3
3
tion (Grant N N204 021939) is kindly acknowledged. Quantum
chemical calculations were carried out at the Poznan´ Supercom-
3
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

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Pages: 9
E. Nojman, L. Latos-Grazyn´ski,, L. Szterenberg
˙
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Published Online: ᭿
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20644
/KAP1
Date: 25-06-12 17:04:35
Pages: 9
Fused Arene Ring Construction Around Pyrrole
Disubstituted Indoles
An alternative route for the construction of
indole derivatives is described. 4,7-Diaryl-
indoles and 4,7-di(thien-2-yl)indole were
synthesized by applying a strategy where
the fused benzene ring was built on the exi-
sting pyrrole.
E. Nojman, L. Latos-Graz˙yn´ski,*
L. Szterenberg ................................... 1–9
Fused Arene Ring Construction Around
Pyrrole To Form 4,7-Disubstitued Indole
Keywords: Heterocycles / Dimerization /
Rearrangement / NMR spectroscopy
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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