2,5-Diamide-Substituted Five-Membered Heterocycles: Challenging Molecular Synthons

Article abstract of DOI:10.1002/ejoc.201402654

We describe synthetic routes for preparing previously unknown 2,5-diamide-substituted five-membered heterocycles based on the thiophene, pyrrole, and furan ring systems by exploiting Curtius-like rearrangement reactions. Conformation analysis of the 2,5-diamidothiophene derivatives identified a "closed" conformation, in which the two carbonyl O atoms are in close contact with the thiophene S atom.

Full text of DOI:10.1002/ejoc.201402654

FULL PAPER
DOI: 10.1002/ejoc.201402654
2
,5-Diamide-Substituted Five-Membered Heterocycles: Challenging Molecular
Synthons
Chiara Fabbro,[a,b][‡] Simone Armani,
[a,c][‡]
Laure-Elie Carloni, Federica De Leo,
[a]
[a]
[
a]
[a,c]
Johan Wouters, and Davide Bonifazi*
Keywords: Heterocycles / Thiophenes / Pyrroles / Furans / Rearrangement / Amides / Conformation analysis
We describe synthetic routes for preparing previously un-
known 2,5-diamide-substituted five-membered heterocycles
based on the thiophene, pyrrole, and furan ring systems by
exploiting Curtius-like rearrangement reactions. Conforma-
tion analysis of the 2,5-diamidothiophene derivatives iden-
tified a “closed” conformation, in which the two carbonyl O
atoms are in close contact with the thiophene S atom.
Introduction
“bare” monoamino derivatives have occasionally been re-
[
20,21]
ported,
they are often equipped with electron-density
Five-membered heterocycles are key molecular compo- mesomeric relief valves, in the form of electron-withdrawing
nents in polymeric or supramolecular assemblies for appli- substituents on the heterocyclic core or on the amino
[
1–9]
[22–24]
cations in material science
and they are also ubiquitous group.
To the best of our knowledge, the only 2,5-
Gaining bisamino derivatives reported so far are 2,5-bis(bisaryl-
molecular scaffolds in medicinal chemistry.[
synthetic access to a large variety of differently substituted amino)thiophenes,
10–13]
[
25]
2,5-bis(tosylamino)pyrroles and 2,5-
[
26]
heterocycles can afford a wider set of molecular modules, bis(tosylamino)furans,
thus further expanding their use as core scaffolds for natu- aminothiophenes are still unknown.
whereas non-stabilized 2,5-di-
[
27]
ral products or pharmaceutical compounds.[
14,15]
Among
the different substituted cores, 2,5-diamido-substituted five-
membered heterocycles represent a synthetically challenging
class of compounds because, to the best of our knowledge,
they have not been reported yet (see general structure de-
picted in Figure 1). Their interest lies in the fact that they
can be used as alternative molecular modules for engineer-
ing multiple H-bonding recognition motifs, the strengths
and patterns of which can be tuned through the nature of
the central heteroatom. Some examples of the use of five-
Figure 1. General structure of 2,5-diamido-substituted five-mem-
bered heterocycles targeted by this synthetic study.
Thus, in this paper we describe our synthetic efforts in-
volving the daunting task of preparing 2,5-disubstituted
five-membered heterocycles with amide functionalities. Dif-
ferent possible routes are amidation cross-coupling reac-
membered heterocycles for multiple H-bonding recognition
have recently been reported.[
16–19]
However, their 2,5-di-
[
28–32]
[33–36]
tions,
Beckmann rearrangement of ketoximes,
amino-substituted precursors are difficult to obtain due to
their inherent instability, resulting from the high electron
density, either as free amino or as salt derivatives. Although
formation of azido intermediates convertible into amide de-
[
37]
rivatives,
or formation of isocyanate intermediates
[
38]
through Curtius rearrangement of acyl azides.
[
a] Namur Research College (NARC) and Department of
Chemistry, University of Namur (UNamur),
Rue de Bruxelles 61, 5000 Namur, Belgium
E-mail: davide.bonifazi@unamur.be
Results and Discussion
www.unamur.be
[
[
[
b] Department of Molecular Sciences and Nanosystems,
Ca’ Foscari University of Venice,
Calle Larga S. Marta, Dorsoduro 2137, 30123 Venezia, Italy
c] Department of Chemical and Pharmaceutical Sciences,
University of Trieste,
Thiophene Derivatives
Our exploration begun with thiophene aromatic ring
systems (Figure 2). As a first approach, we focused our
attention on C–N cross-coupling between aryl halides and
Piazzale Europa 1, 34127 Trieste, Italy
‡] These authors contributed equally to this work.
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402654.
[
28–32]
amines or amides,
developed as an expansion and
combination of the initial synthetic scopes of Buchwald–
Eur. J. Org. Chem. 2014, 5487–5500
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D. Bonifazi et al.
FULL PAPER
Hartwig Pd-catalyzed amination on one hand,[
39,40]
and of
Finally we turned to Curtius-type reactions involving the
Goldberg’s Cu-catalyzed amidation on the other.[ Con- nucleophilic rearrangement of acyl nitrenes, formally gener-
41]
sidering the possible limitations caused by a likely poison- ated by the thermal deazotation of acyl azides, into isocyan-
[
38,58]
ing effect of the thiophene sulfur atom on Pd metal centres, ate derivatives.
Although a few scattered reports on
we decided to commence our investigations with Cu-based double Curtius rearrangements onto α-positions of five-
[
59–62]
catalysts under the conditions reported by Buchwald and membered heterocycles exist in the literature,
use of
co-workers, who described a modified version of Goldberg’s this strategy to prepare 2,5-disubstituted bisamides has not
Cu-catalyzed amidation of aryl halides, including of 2-halo- yet been reported. Starting from the commercially available
thiophene derivatives.[ In our hands, however, when acet- 2,5-disubstituted thiophenedicarboxylic acid, by treatment
amide was treated with 2,5-dibromothiophene in the pres- with (COCl)2 in the presence of a catalytic amount of
42]
ence of a catalytic mixture consisting of CuI and N,NЈ-di- DMF, followed by addition of NaN , the 2,5-diacylazido-
3
methylethylenediamine, together with K CO in 1,4-di- substituted thiophene derivative was obtained. Because of
2
3
oxane or DMF, no reaction took place and only starting its instability, this intermediate was only characterized by
material was recovered.
mass spectrometry and stored as a solution in CH Cl (1 m)
2 2
at –20 °C. The corresponding 2,5-diisocyanate was then
prepared by thermal treatment and, in the presence of the
desired alcohol, it yielded the corresponding carbamate de-
rivative.
At this point the intriguing possibility of forming the de-
sired amide bond by treatment with organometallic rea-
gents was considered. However, repeated attempts using
MeMgBr always led to decomposition. Therefore, an alter-
Figure 2. Target thiophene derivative.
In a second approach we turned our gaze to those syn- native three-step strategy, consisting of the formation of a
thetic routes involving azido precursors, because these can carbamate intermediate, acylation of the carbamic nitrogen
easily be converted into their amide derivatives by treatment and subsequent cleavage of the carbamate, was envisaged
[
37]
with thioacids. This approach is particularly attractive to (Scheme 1). We began with the preparation of 2,5-dicarb-
[
43]
us because, as demonstrated by Williams and co-workers,
amate derivative 1. The reaction was performed by adding
amine intermediates are not formed during the reaction, a solution of diacylazidothiophene to a mesitylene solution
which instead proceeds through the formation of thiatriazo- of BnOH at 130 °C, affording derivative 1 (57% yield) as a
line species. The synthesis of aryl azides is based on a more white, crystalline solid. Acetylation of compound 1 in pyr-
limited selection of transformations than that of aliphatic idine with Ac O in the presence of 4-dimethylaminopyr-
2
[
44,45]
ones.
They are commonly prepared from the corre- idine (4-DMAP) yielded conjugated 2 (84%). A small trans-
sponding amines, either via diazonium salt intermedi- parent crystal of 2, suitable for X-ray diffraction, was ob-
ates[
46–49]
or directly by treatment with triflyl azide.[50] How- tained by slow evaporation from a CHCl solution. The
3
ever, alternative methods have been investigated, such as nu- ORTEP representation of the crystal structure (belonging
cleophilic aromatic substitutions on activated aryl hal- to the monoclinic space group Pc), shown in Figure 3, re-
ides[ and Cu -catalyzed Ullmann-type cross-coupling re- veals the quasi-orthogonal arrangement of the two carb-
51]
I
actions with NaN3.[
52,53]
The latter reaction was reported amate groups with respect to the plane of the thiophene
also to work for inactivated aryl halides at temperatures low ring. The next step was the cleavage of the two benzylcarb-
enough to allow the survival of the azide, in the presence amate (Cbz) N-protecting groups. However, our attempts
[
54]
[55]
of proline
or a bisamine
as ligands. Inspired by these using TMSI were unsuccessful, resulting either in recovery
findings, we tried the literature conditions with 2-bromo- of the starting material or in decomposition. Therefore, we
thiophene, but no reaction took place and only starting ma- turned to Pd-catalyzed hydrogenolysis, which allowed us to
terial was recovered. Thus, we turned to the protocol of obtain the desired product 3 in low yield (13%).
Zanirato and co-workers, who reported, to the best of our
In the light of these results, the Cbz protecting group was
knowledge, the only example of isolation of 2-azidothio- replaced with p-methoxybenzy1 carbamate (Moz), cleavable
[
56,57]
phene.
In this two-step procedure, 2-bromothiophene under milder acidic conditions (Scheme 1, right-hand
[
63]
is lithiated and then treated with TsN to generate the corre- side).
Curtius rearrangement of the diacylazide in the
3
sponding triazene salt, which is then treated with presence of anisyl alcohol afforded carbamate derivative 4
Na P O ·10H O to afford 2-azidothiophene. Li/halogen ex- in 63% yield after chromatographic purification. The re-
4
2
7
2
change was thus performed on 2,5-dibromothiophene with arrangement reaction was followed by the acylation step,
nBuLi, and the obtained dilithium thiolyl derivative was conducted with either acetic or valeric anhydride, in the
added to a solution of TsN . However, subsequent treat- presence of 4-DMAP, to yield protected amido derivatives
3
ment with Na P O resulted in decomposition, likely be- 5 and 6, respectively. Simultaneous removal of both Moz
4
2
7
cause, as noted by Zanirato and Spagnolo,[ the triazene groups was eventually achieved by acidic solvolysis in a 5%
56]
intermediate is unstable under the workup conditions, thus TFA/CH Cl2 mixture, in the presence of an excess of
2
making this synthetic route rather inefficient for our pur- anisole as carbocation scavenger, to afford compounds 3
poses.
and 7 in high yields (75% and 61%, respectively).
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2,5-Diamide-Substituted Five-Membered Heterocycles
Scheme 1. Synthetic approaches for preparing 2,5-diamido-substituted thiophene heterocycles.
Figure 3. ORTEP representations of compound 2 as determined by X-ray diffraction analysis (displacement ellipsoids are drawn at the
30% probability level). (a) Front and (b) side views are shown.
Eur. J. Org. Chem. 2014, 5487–5500
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D. Bonifazi et al.
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Scheme 2. Synthetic approach for preparing electron-rich 2,5-diamido-substituted thiophene heterocycles.
With the aim of establishing how far we could push the with the Curtius rearrangement of acylazide intermediates
system in terms of electron density, we decided to synthesize (Scheme 3).
thiophene 14, which is an exceptionally electron-rich deriva-
tive of 3. The core unit, bearing two methoxy groups at
the two β-positions, was obtained by a four-step procedure
(Scheme 2). Commercially available thiodiacetic acid was
methylated with TMSCl in MeOH, after which the resulting
diester 8 underwent Hinsberg condensation with dimethyl
oxalate in the presence of NaOMe to yield intermediate
Figure 4. Target pyrrole derivative.
The first step involved tert-butyl carbamate (Boc) protec-
[64]
9.
The hydroxy groups in the two β-positions were then
[
65]
tion of the pyrrole nitrogen,
followed by deprotonation
methylated with MeI, and the methyl carboxylate groups in
at the α-positions and treatment with methyl chloroformate
to afford 2,5-diester derivative 16.
the two α-positions were finally cleaved to yield the
[
66]
In view of the high
64]
2
,5-dicarboxylic acid derivative 11.[ Like in the previous
lability of the Boc protecting group under acidic condi-
case, we proceeded with the transformation of the carb-
oxylic groups into carbamates, preparing the diacyl-
azido derivative with the chlorination/azidation one-pot
procedure, followed by Curtius rearrangement in the pres-
ence of anisyl alcohol. The whole procedure afforded, after
silica gel chromatographic purification, 2,5-dicarbamate de-
rivative 12 in an overall yield of 79%. Subsequently, acetyl-
ation afforded derivative 13 in 81% yield and the final de-
protection led to compound 14 in 51% yield.
[
63]
tions, this function was removed by treatment with TFA
in order to subsequently to introduce a more resistant pro-
tecting group. Fully protected 2,5-diaminopyrrole 20 was
thus synthesized, with a N-[2-(trimethylsilyl)ethoxy]methyl
(Sem) group on the pyrrole nitrogen and with two Moz
groups masking the α-amine nitrogen atoms. The diacyl
azide intermediate was prepared by the developed protocol
under the conditions described above and underwent Curt-
ius rearrangement in the presence of anisyl alcohol to pro-
vide 2,5-dicarbamate derivative 20 in 57% yield. After-
wards, acylation was performed with valeric anhydride, af-
fording highly soluble derivative 21. Subsequent removal of
the Moz groups by acidic solvolysis in a TFA/CH Cl mix-
Pyrrole Derivatives
2
2
The strategy for the preparation of targeted 2,5-diamido- ture (with an excess of anisole) afforded 2,5-diamido-substi-
substituted pyrroles (Figure 4) follows the same synthetic tuted pyrrole derivative 22 in 49% yield after precipitation
route as successfully developed for the thiophene analogues, from pentane.
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2,5-Diamide-Substituted Five-Membered Heterocycles
Scheme 3. Synthetic approach for preparing 2,5-diamido-substituted pyrrole heterocycles.
Furan Derivatives
the residual acidity of CH Cl or CHCl could suffice for
2 2 3
its degradation. Therefore, after performing the Curtius re-
arrangement, great care should be taken in rapidly purify-
ing the crude reaction product. Afterwards, the acylation of
In the case of furan, the developed route was tested for
two classes of derivatives: bis-β-substituted and β-unsubsti-
tuted furan rings (Figure 5).
intermediate 23 was performed by use of an excess of Ac O
2
and 4-DMAP, and the desired diacylated compound 24 was
recovered in 68% yield after chromatographic purification.
The deprotection of 24 was firstly attempted by treat-
ment with TFA, with use of an excess of anisole as cationic
scavenger. On performing the reaction in CH Cl only de-
2
2
Figure 5. Target furan derivative.
composition occurred, whereas in Et O the reaction pro-
2
ceeded at slower rate, allowing the isolation of the mono-
1
For the β-unsubstituted furan ring system we started deprotected product, identified by mass analysis and by H
from furan-2,5-dicarboxylic acid, which was converted into and 13C NMR spectroscopy. However, even after increasing
the diacylazide derivative in two steps by chlorination with the reaction time and dilution it was not possible to isolate
(
(
COCl)2 in THF and subsequent treatment with NaN3 the fully deprotected derivative and we observed only de-
Scheme 4). The 2,5-diacylazide underwent Curtius re- composition. The use of hydracids also proved fruitless.
arrangement in THF, in the presence of anisyl alcohol, un- Most probably, the acid sensitivity of a furan ring bearing
der microwave irradiation conditions at 110 °C, and the de- two amide moieties in its α-positions is incompatible with
sired product 23 was isolated in 40% yield. Moreover, it the acid cleavage of any protecting groups. This result sug-
needs to be underlined that the purification procedure gests that if one wants to access the fully deprotected furan
strongly influences the reaction outcome, in terms of derivative, a protecting group cleavable under basic condi-
amount of isolated product. Furan derivative 23 proved to tion should be used for further developments or applica-
be extremely susceptible to acidic environments, and even tions.
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D. Bonifazi et al.
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Scheme 4. Synthetic approach for preparing 2,5-diamido-substituted furan heterocycles.
As pursued for the thiophene derivative, the preparation To our great surprise, the outcome of the reaction was not
of derivatives bearing methoxy groups in the two β-posi- the expected 2,5-dicarbamate derivative, but the chiral (ra-
tions was attempted, and led to unexpected results cemic) derivative 29, as shown by NMR and X-ray analyses.
(Scheme 5). The synthesis started with the esterification of Suspecting that the high temperature employed might have
diglycolic acid by treatment with TMSCl in the presence of triggered the ring-opening of the furan nucleus, we decided
MeOH, giving the desired diester 25 in 75% yield. Com- to repeat the reaction at lower temperatures, in toluene,
pound 25 was subsequently condensed with (COOMe) , in with stoichiometric quantities of BnOH. Despite the tuning
2
the presence of NaH in DMF at 50 °C.[ Methylation of of the conditions, compound 29 was again obtained as the
67]
[68]
the hydroxy groups in the β-positions with MeI, followed only product. The structure of 29 was confirmed by X-ray
by saponification with LiOH in THF,[ yielded compound diffraction. Suitable crystals belonging to the monoclinic
69]
28. Conversion of the obtained carboxylic acids into acylaz- space group Pc were obtained by vapour diffusion of hex-
ides was achieved by the general protocol involving a chlori- ane into a CH Cl solution containing derivative 29 (OR-
2
2
nation step followed by addition of NaN . Afterwards, Cur- TEP representation is depicted in Scheme 5).
3
tius rearrangement was performed with use of BnOH as
A hypothetical mechanism accounting for the formation
nucleophile to trap the transient isocyanate intermediate re- of molecule 29 is presented in Scheme 6. After the forma-
sulting from the thermal transformation of the diacylazide. tion of a first carbamate group, the protonation of the furan
Scheme 5. Toward 2,5-diamido-substituted furan heterocycles. ORTEP representation of compound 29 as determined by X-ray diffraction
analysis (displacement ellipsoids are drawn at the 50% probability level). Only one of the two molecules in the asymmetric unit is shown
for sake of clarity.
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2,5-Diamide-Substituted Five-Membered Heterocycles
Scheme 6. Proposed mechanism for the formation of 29 starting from the corresponding diisocyanate precursor. For purposes of calcula-
tion the Bn groups were replaced by Et groups. All intermediates were optimized at the B3LYP/6-311G** level of theory, and the
calculated enthalpies (ΔH) for the hypothesized steps are reported.
O atom could trigger the opening of the electron-rich ring, The distance between the carbonyl O atom and the hetero-
leading to a ketenimine intermediate, most likely stabilized cyclic C–H bond might or might not allow the existence
by the presence of the methoxy groups. After a configura- of a H-bonding interaction. This contact is probably the
tional equilibrium, nucleophilic attack of the isocyanate ni- dominating attractive feature governing the stability of the
trogen at the keteniminic group leads to ring closure, form- “open” conformation in 2,6-diacetamidopyridine (experi-
ing a peculiar pyrrole-like intermediate. Final keto–enol mentally determined values for O···H 2.17, 2.16 Å, CSD
[
70]
tautomerism results in the dearomatization of the ring and code: DOPDAN, calculated value for O···H 2.24 Å). On
the formation of 29 as a racemic mixture (the calculated the other hand, thiophene derivative 3 is probably stabilized
ΔH° value for the keto derivative is 19.50 kcalmol–1 lower in the “closed” conformation by two sulfur–oxygen non-
than the corresponding enol tautomer).
bonding interactions. The contact distance obtained from
the optimized geometry of molecule 3 (S···O 2.85 Å), per-
fectly matches that from the X-ray structures (S···O 2.82,
Conformation Analysis of 2,5-Diamidothiophene 3
2.86 Å) and is much shorter than the sum of the van der
A monocrystal suitable for X-ray diffraction was also ob- Waals radii of the two atoms (3.25 Å), consistently with an
tained for thiophene conjugate 3, by slow evaporation of a attractive nature of such an interaction. Experimentally de-
9
:1 CHCl /MeOH solution. Two different crystals were termined and calculated distances are summarized in
3
found, belonging to the monoclinic Cc (depicted in Fig- Table 1. This hypothesis prompted us to investigate the elec-
ure 6, a) and Pcca space groups. In each crystal, the solved tronic properties of molecule 3 by plotting the molecular
structure clearly shows a “closed” conformation for the two electrostatic potential on its van der Waals surface, as
α substituents, with the two carbonyl groups pointing shown in Figure 6, d. Moreover, Mulliken atomic charges
towards the S atom. With the goal of elucidating the struc- were calculated (Table 2), showing a positive partial charge
tural properties of thiophene 3, density functional theory for thiophene S (0.36 esu), bigger than those calculated for
(
DFT) calculations were performed at the B3LYP/6-311G** the unsubstituted thiophene (0.25 esu).
level of theory for the “closed” and “open” conformations,
Because of the well-known basis-set sensibility of the
[
72,73]
which proved both to be actual local minima. Indeed, the Mulliken population analysis,
the Bader charges were
[
74]
“
closed” one proved to be the most favoured, with an en- calculated too,
and confirmed the reliability of the par-
–
1
thalpy difference of 2.7 kcalmol (Figure 6, b). For pur- tial charge investigation (Table 2). These findings correlate
poses of comparison, the “closed” and “open” conforma- well with the presence of Coulombic stabilized non-bonding
tions for 2,6-diacetamidopyridine (DAP), a known six- interactions with the two O atoms, as already reported by
[
75–79]
membered heterocyclic analogue used in triple H-bonded others for similar systems.
motifs, were also investigated at the same level of theory. Crystals suitable for diffraction were also obtained for
In agreement with the experimental observations (Figure 6, thiophene 14, from a 95:5 CHCl /MeOH solution (mono-
3
c),[
70,71]
the “open” conformation is energetically favoured clinic space group P2 /c). The ORTEP representation (Fig-
1
for DAP, with a considerable difference in energy of ure 7) reveals the quasi-planar arrangement of the molecule
–
1
1
6.3 kcalmol . The main reason for the opposite behaviour in the “closed” conformation, most probably stabilized by
of the two molecules is probably related to noncovalent in- non-bonding interactions (S1···O3 and S1···O4), as already
tramolecular interactions, acting as conformational locks. observed for molecule 3.
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D. Bonifazi et al.
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Figure 6. (a) ORTEP representation of compound 3 in the “closed” conformation as determined by X-ray diffraction analysis (displace-
ment ellipsoids are drawn at the 30% probability level). (b) Calculated enthalpy (ΔH) for the “open”h“closed” equilibrium of thiophene
3
. (c) ORTEP representation of 2,6-diacetamidopyridine as determined by X-ray diffraction analysis (displacement ellipsoids are drawn
[70]
at the 30% probability level) [CSD code: DOPDAN].
(d) Molecular electrostatic potential plotted on the van der Waals surface of
compound 3 in the “closed” conformation.
Table 1. Intramolecular distances observed in the X-ray crystal
structures of compound 3 and of DAP [CSD code: DOPDAN][70]
and in the “open” and “closed” B3LYP/6-311G** optimized con-
formations.
Table 2. Atomic partial charges calculated by Mulliken and Bader
methods for the “open” and “closed” conformations of molecule
3, with bare thiophene as a reference.
Molecule
Atom
Atomic charges (ESU)
Molecule
open” conformation
Thiophene 3
DAP
Contact distance [Å]
Mulliken
Bader
“
exp. O···H
–
2.17/2.16
exp. O···X
2.82/2.86
–
calcd. O···H
2.37
2.24
calcd. O···X
2.85
“
“
open” 3
S
O
S
O
S
0.18
–0.35
0.36
0.17
–1.39/–1.46
0.50
closed” 3
“closed” conformation
–0.35
0.25
–1.87/–1.85
0.24
Thiophene 3
DAP
Thiophene
2.92
Figure 7. ORTEP representations of compound 14 as determined by X-ray diffraction analysis (displacement ellipsoids are drawn at the
30% probability level). (a) Front and (b) side views are shown.
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2,5-Diamide-Substituted Five-Membered Heterocycles
were estimated from a pre-experiment run, and full data sets were
Conclusions
collected at room temperature. Structures were solved by direct
2
In this work we have been able, by exploiting the Curtius methods with the SHELXS-97 program and then refined on F by
rearrangement, to prepare a series of previously unknown use of SHELXL-97 software.[ Non-hydrogen atoms were aniso-
80]
2
,5-diamido derivatives of five-membered heterocycles. tropically refined and the hydrogen atoms (not implicated in H-
bonds) in the riding mode with isotropic temperature factors fixed
Other synthetic attempts to obtain the same molecular
modules based on amidation cross-coupling and on forma-
tion of azido intermediates were unsuccessful in our hands.
In the case of the furan derivative bearing two methoxy
groups in its β-positions, Curtius rearrangement unexpec-
tedly gave rise to saturated pyrrole derivative 29. Further-
more, theoretically conformation analysis performed for
at 1.2 times U(eq) of the parent atoms (1.5 times for methyl
groups). Hydrogen atoms implicated in H-bonds were localized by
Fourier difference maps (ΔF). CCDC-950747 (for 29), -950748 (for
14), -950749 (for 3), -950750 (for 3) and -950751 (for 2) contain the
supplementary crystallographic 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
“
,5-diamidothiophene 3 displayed a higher stability for the
closed” conformation than for the “open” one. Such re-
Density functional theory (DFT) calculations were performed with
[81]
the Gaussian 03 package.
ducted with Becke’s three-parameter exchange functional,
Geometry optimizations were con-
sults suggest that, if one could stabilize the “open” confor-
mation, featuring two NH H-bond donors and the central
[82]
the
[83]
Lee–Yang–Parr correlation functional
(B3LYP) and the 6-
S atom capable of participating in Coulombic non-bonding 311G** basis set. In geometry optimizations every bond length,
interactions, the system might possibly be used as a new angle and dihedral angle was allowed to relax, free of constraints.
supramolecular recognition platform exploiting comple- The nature of stationary points (“closed” and “open” isomers) was
confirmed by vibrational frequency analysis. Mulliken charges were
mentary noncovalent interactions.
extracted from a single-point energy calculation performed on the
optimized geometries at the B3LYP/6-311G** level of theory.
Bader charge analysis was carried out with the program written by
Experimental Section
Henkelman et al.[
74,84]
General Information: Chemicals were purchased from Sigma–Ald-
Synthetic Procedures: The following compounds were prepared by
rich, Acros Organics, Alfa Aesar or ABCR. Pyrrole was filtered
previously reported procedures, with only slight modifications
through basic alumina before use. The other chemicals were used
as received. Solvents were purchased from Sigma–Aldrich, and
deuterated solvents from Euriso-Top. When anhydrous reaction
conditions were required, reaction flasks were dried with a heating
gun (300–500 °C), placed under high vacuum with a Schlenk line
and purged with Ar. To keep the atmosphere dry and inert, bal-
loons filled with Ar were used. Anhydrous THF was distilled from
Na/benzophenone, and the other anhydrous solvents were pur-
chased from Acros Organics. Microwave reactions were performed
with a Biotage AB Initiator microwave instrument producing con-
trolled irradiation at 2.450 GHz. Model: initiator EXP EU 355301,
[64,85]
when specified: compound 9
was protonated by addition of concentrated aq. HCl, followed by
filtration, washing with H O and azeotropic distillation with tolu-
(LiOH was used instead of NaOH), com-
(the sodium salt of the product
2
[64]
ene), compound 11
[65]
[66]
[67,69]
pound 15,
compound 16,
compound 26,
compound
[68,69]
[69]
27,
and compound 28 (LiOH was used instead of NaOH).
In the paragraphs describing general procedures, the values given
between brackets indicate the volume of a given solvent or solution
used per mmol of starting material.
General Procedure for Acyl Azide Formation: DMF (0.2 equiv.) and
1
0634–13U. TLC was carried out on Machery–Nagel pre-coated
aluminium plates with silica gel 60 F254. Column chromatography
CC) was carried out with Merck silica gel 60 (particle size 40–
3 μm), and purifications were performed either with classical col-
umn chromatography equipment or with Büchi sepacore, an auto-
(COCl) (2.2 equiv.) were added with stirring at 0 °C to a solution
2
of the 2,5-dicarboxylic acid derivative of each differently substi-
–
1
(
6
tuted heterocycle in anhydrous THF (4 mLmmol ), and the mix-
ture was stirred at room temp. for 3 h. The solvents were then re-
moved under vacuum, and the residue was redissolved in anhy-
1
13
–1
matic chromatography system. H and C NMR spectra were ob-
tained with a 400 MHz instrument (Jeol JNM EX-400) working at
drous THF (2.5 mLmmol ). The resulting solution was added
–
1
dropwise to saturated aq. NaN3 (0.4 mLmmol ), stirred for
–
1
2
5 °C, if not differently specified. Chemical shifts (δ) are reported
in ppm with use of the solvent residual signal as internal reference
CDCl : δ = 7.26 ppm, δ = 77.16 ppm, CD OD: δ = 3.31 ppm,
= 49.00, [D ]DMSO: δ = 2.50 ppm, δ = 39.52 ppm). Coupling
2
30 min, diluted with Et O (5 mLmmol ), and then washed with
–
1
saturated
aq.
NaHCO3
(5 mLmmol )
and
2
H O
–
1
(
3
H
C
3
H
(5 mLmmol ϫ2). The organic phase was dried with MgSO , and
4
δ
C
6
H
C
the solvent was partially evaporated under vacuum (final volume:
–
1
constants (J) are given in Hz, and the resonance multiplicity is
described as s (singlet), d (doublet), t (triplet), q (quartet), quint
ca. 0.5 mLmmol ). This procedure was applied for compounds 1,
4, 12, 20, 23 and 29, followed by the Curtius rearrangement step.
(
quintuplet), sex (sextuplet), m (multiplet), and/or br (broad sig-
Compound 1: The starting material was thiophene-2,5-dicarboxylic
acid (2.08 g, 12.1 mmol). The obtained solution was added to a
solution of benzyl alcohol (3.75 mL, 36.2 mmol) in mesitylene
nal). Carbon spectra were acquired with complete proton decoup-
ling. Infrared (IR) spectra were recorded with a Perkin–Elmer spec-
trum RX I FTIR System. Mass analysis was performed either with
an Agilent 6200 series TOF mass spectrometer (APCI or ESI), or
with a Waters QToF2 mass spectrometer (ESI). Mass values simu-
lation was performed with IsoPro 3.1 software.
(
6 mL) at 130 °C, stirred for 5 min and then allowed to cool to
room temp. and poured into pentane (100 mL). The precipitate was
collected by vacuum filtration and purified by silica gel chromatog-
raphy (cyclohexane/EtOAc 7:3) to afford a white solid (2.65 g,
1
Single-crystal X-ray diffraction (SCXRD) was performed with a 6.93 mmol, 57% yield). H NMR (400 MHz, CDCl
3
): δ = 7.42–
Gemini Ultra R system (four-circle kappa platform, Ruby CCD 7.31 (m, 10 H, PhH), 6.94 (br. s, 2 H, NH), 6.35 (s, 2 H, thiophene-
1
3
detector) and use of MoK\α (λ = 0.71073 Å) or CuK\α (λ =
.54178 Å) radiation. Selected crystals were mounted on the tip of
a quartz pin with cyanoacrylate (commercial glue). Cell parameters
2 3
H), 5.18 (s, 4 H, OCH Ph) ppm. C NMR (100 MHz, CDCl ): δ
1
= 153.76, 135.82, 132.97, 128.75, 128.59, 112.46, 67.82 ppm. IR
(KBr): ν˜ = 3285, 2949, 1713, 1698, 1586, 1552, 1503, 1454, 1379,
Eur. J. Org. Chem. 2014, 5487–5500
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5495

D. Bonifazi et al.
FULL PAPER
1
5
290, 1245, 1062, 1049, 972, 910, 845, 799, 784, 736, 653, 590, 577,
microwave vessel. Anisyl alcohol (335 μL, 2.70 mmol) was added,
and the vessel was sealed and heated in the microwave oven at
110 °C for 5 min. The solvent was then removed under vacuum,
and the crude product was purified by filtration through a short
silica gel plug (cyclohexane/EtOAc 7:3). Precipitation from EtOAc
–1
+
18 2 4
15, 485, 410 cm . HRMS (APCI ): calcd. for [C20H N O S +
+
H] 383.1065; found 383.1101.
Compound 4: The starting material was thiophene-2,5-dicarboxylic
acid (1.30 g, 7.60 mmol). The obtained solution was added to a
solution of anisyl alcohol (2.83 mL, 22.8 mmol) in mesitylene
solution upon pentane addition afforded 23 as a white solid
1
(
154 mg, 0.360 mmol, 40% yield). H NMR (400 MHz, [D
6
]
(5 mL) at 130 °C, stirred for 5 min and then allowed to cool to
DMSO): δ = 9.89 (br. s, 2 H, NH), 7.37–7.27 (m, 4 H, PhH), 6.96–
room temp. and poured into pentane (100 mL). The precipitate was
collected by vacuum filtration and purified by silica gel chromatog-
raphy (cyclohexane/EtOAc 7:3) to afford a white solid (2.10 g,
6
3
1
5
1
9
.90 (m, 4 H, PhH), 5.94 (s, 2 H, furan-H), 5.03 (s, 4 H, OCH
3 6
.75 (s, 6 H, OCH ) ppm. C NMR (100 MHz, [D ]DMSO): δ =
2
Ph),
1
3
59.20, 153.68, 130.30, 130.01, 128.24, 127.47, 113.71, 66.06,
5.13 ppm. IR (KBr): ν˜ = 3277, 2957, 1764, 1698, 1639, 1612, 1513,
463, 1377, 1348, 1303, 1243, 1220, 1200, 1173, 1112, 1061, 1028,
1
4.75 mmol, 63% yield). H NMR (400 MHz, CDCl
3
): δ = 7.30 (d,
J = 8.6 Hz, 4 H, PhH), 7.01 (br. s, 2 H, NH), 6.87 (d, J = 8.6 Hz,
H, PhH), 6.32 (s, 2 H, thiophene-H), 5.10 (s, 4 H, OCH Ph), 3.80
s, 6 H, OCH ): δ = 159.83,
) ppm. 13C NMR (100 MHz, CDCl
53.95, 132.92, 130.44, 127.93, 114.06, 112.42, 67.59, 55.40 ppm.
4
(
1
2
–
1
+
26, 851, 818, 770, 712, 666, 637, 565, 517 cm . HRMS (ESI ):
3
3
+ Na]+ 449.1325; found 449.1345.
22 2 7
calcd. for [C22H N O
IR (KBr): ν˜ = 3287, 2958, 2838, 1698, 1691, 1615, 1586, 1554, 1516,
Compound 29: The starting material was compound 28 (400 mg,
.85 mmol), and the last extraction in the acyl azide formation pro-
cedure was performed with CH Cl instead of Et O. The solution
obtained in the end was added dropwise to benzyl alcohol (3 mL)
at 140 °C and stirred for 5 min. The benzyl alcohol was then re-
moved by bulb-to-bulb distillation, and a final precipitation with
1
7
466, 1377, 1338, 1284, 1239, 1174, 1109, 1075, 1032, 953, 817,
1
–1
+
90, 772, 762, 645, 522, 512, 489 cm . HRMS (ESI ): calcd. for
2
2
2
[C
22
H
22
N
2
O
6
S + Na]+ 465.1096; found 465.1102.
Compound 12: The starting material was compound 11 (1.00 g,
.31 mmol). The obtained solution was added to a solution of ani-
4
pentane or cyclohexane afforded 29 (335 mg, 0.790 mmol, 43%
syl alcohol (1.61 mL, 12.9 mmol) in mesitylene (4 mL) at 130 °C,
stirred for 5 min and then allowed to cool to room temp. and
poured into pentane (80 mL). The precipitate was collected by vac-
uum filtration and purified by silica gel chromatography (cyclohex-
1
yield). H NMR (400 MHz, [D
6
]DMSO): δ = 8.13 (d, J = 9.1 Hz,
1
H, NH), 7.41–7.28 (m, 10 H, PhH), 5.96 (d, J = 9.1 Hz, 1 H,
NCHNH), 5.20 (d, J = 12.7 Hz, 1 H, OCHPh), 5.15 (d, J =
2.7 Hz, 1 H, OCHPh), 5.04 (d, J = 12.3 Hz, 1 H, OCHPh), 4.99
(d, J = 12.3 Hz, 1 H, OCHPh), 3.99 (s, 3 H, OCH ), 3.72 (s, 3 H,
]DMSO): δ = 164.04,
55.15, 153.22, 149.15, 136.64, 135.72, 128.39, 128.36, 128.04,
127.94, 127.79, 127.75, 125.42, 66.81, 65.78, 61.89, 60.30,
1
ane/EtOAc 7:3) to afford a white solid (1.71 g, 3.40 mmol, 79%
1
3
yield). H NMR (400 MHz, CDCl
3
): δ = 7.33 (d, J = 8.6 Hz, 4 H,
1
3
3 6
OCH ) ppm. C NMR (100 MHz, [D
1
PhH), 6.89 (d, J = 8.6 Hz, 4 H, PhH), 6.67 (br. s, 2 H, NH), 5.13
(
s, 4 H, OCH
2
Ph), 3.81 (s, 6 H, OCH
3
), 3.79 (s, 6 H, OCH
3
) ppm.
1
3C NMR (100 MHz, CDCl
3
): δ = 159.88, 153.78, 136.51, 130.46,
1
5
3
9.09 ppm. H NMR (400 MHz, CDCl ): δ = 7.42–7.28 (m, 10 H,
1
3
1
1
6
27.90, 115.41, 114.08, 67.66, 60.61, 55.39 ppm. IR (KBr): ν˜ =
PhH), 5.90 (br. d, 1 H, NCHNH), 5.45 (br. s, 1 H, NH), 5.24 (d,
J = 12.3 Hz, 1 H, OCHPh), 5.18 (d, J = 12.3 Hz, 1 H, OCHPh),
351, 3272, 2960, 2991, 2545, 2063, 1727, 1694, 1615, 1586, 1571,
515, 1483, 1445, 1401, 1365, 1303, 1243, 1218, 1173, 1118, 1110,
082, 1053, 1036, 1005, 960, 946, 848, 828, 815, 808, 760, 738, 722,
5
.06 (m, 2 H, OCH
2
Ph), 4.04 (s, 3 H, OCH
3
), 3.81 (s, 3 H,
1
3
–1
+
OCH
3
) ppm. C NMR (100 MHz, CDCl ): δ = 164.35, 155.00,
3
70, 570, 547, 514, 427 cm . HRMS (ESI ): calcd. for
S + K]+ 541.1047; found 541.1022. C24
26 2 8
H N O S
152.31, 149.91, 135.94, 135.24, 128.67, 128.52, 128.48, 128.43,
28.26, 126.14, 68.17, 67.47, 62.31, 60.68, 59.59 ppm. IR (KBr): ν˜
3282, 3061, 2955, 1794, 1702, 1681, 1545, 1456, 1377, 1359, 1331,
[C
24
H
26
N
2
O
8
1
=
(502.54): calcd. C 57.36, H 5.21, N 5.57, S 6.38; found C 57.19, H
5.22, N 5.55, S 6.01.
1
8
282, 1255, 1221, 1191, 1150, 1093, 1056, 1008, 976, 957, 916, 871,
Compound 20: The starting material was compound 19 (1.00 g,
.50 mmol). The obtained solution was added to a solution of ani-
–1
23, 778, 748, 735, 705, 695, 641, 599, 579, 557, 510, 494 cm .
3
+
+ Na]+ 449.1325; found
22 2 7
H N O
HRMS (APCI ): calcd. for [C22
49.1317.
syl alcohol (1.30 mL, 10.5 mmol) in mesitylene (3 mL) at 130 °C,
stirred for 5 min and then allowed to cool to room temp. The sol-
vent was removed under vacuum, and the crude residue was puri-
fied by silica gel chromatography (cyclohexane/EtOAc 8:2) to af-
4
General Procedure for Acylation: 4-DMAP (1 equiv.) and acetic or
valeric anhydride (5 equiv.) were added to a solution of the biscar-
–
1
1
bamate derivative in pyridine (3–5 mLmmol ), and the solution
was stirred at room temp. for 4 h. The mixture was then diluted
ford the product (1.10 g, 1.98 mmol, 57% yield). H NMR
(400 MHz, [D
6
]DMSO): δ = 8.94 (br. s, 2 H, NH), 7.32 (br. d, 4
–
1
with EtOAc (15 mLmmol ) and washed with aq. HCl (1 n,
H, PhH), 6.93 (d, J = 8.2 Hz, 4 H, PhH), 5.77 (s, 2 H, pyrrole-H),
–
1
–1
1
(
5 mLmmol ), saturated aq. NaHCO
3
(15 mLmmol ) and H
2
O
5
3
–
.00 (s, 4 H, OCH
.33–3.25 (m, 2 H, OCH
] ppm. 1 C NMR (100 MHz, [D
0.07 [s, 9 H, Si(CH
159.12, 155.25, 129.94, 128.54, 123.34, 113.78, 102.23, 69.95,
2
Ph), 4.96 (s, 2 H, NCH
2
O), 3.75 (s, 6 H, OCH
CH Si),
]DMSO): δ
3
),
–
1
15 mLmmol ). The organic phase was dried with MgSO , and
4
2
CH Si), 0.77–0.67 (m, 2 H, OCH
2
2
2
3
the solvent was removed under vacuum. Purification by silica gel
chromatography (cyclohexane/EtOAc 8:2) afforded the desired
product. This procedure was applied for compounds 2, 5, 6, 13, 21
and 24, with slight modifications in the case of compound 21, as
specified.
3
)
3
6
=
6
3
1
8
5.79, 64.78, 55.11, 17.30, –1.40 ppm. IR (KBr): ν˜ = 3606, 3443,
262, 3000, 2953, 2898, 2836, 1697, 1614, 1588, 1518, 1466, 1419,
368, 1304, 1293, 1248, 1219, 1135, 1082, 1065, 1038, 961, 862,
–1
+
34, 772, 759, 557, 522, 444 cm . HRMS (APCI ): calcd. for
Compound 2: The starting materials were compound 1 (357 mg,
Si + H]+ 556.2479; found 556.2407; (ESI ): calcd. for
+
[C
28
H
H
37
N
N
3
O
O
7
0
.930 mmol) and acetic anhydride, and the reaction yielded the de-
+
[C
28
37
3
7
Si + Na] 578.2299; found 578.2311. C28
H
37
N
3
O
7
Si
1
sired product as a white solid (364 mg, 0.780 mmol, 84% yield). H
NMR (400 MHz, CDCl ): δ = 7.36–7.27 (m, 6 H, PhH), 7.23–7.18
m, 4 H, PhH), 6.72 (s, 2 H, thiophene-H), 5.20 (s, 4 H, OCH Ph),
): δ =
(555.70): calcd. C 60.33, H 6.68, N 7.64; found C 60.52, H 6.71, N
3
7.56.
(
2
1
3
Compound 23: The starting material was furan-2,5-dicarboxylic
acid (140 mg, 0.900 mmol). The obtained solution was dried, and
the crude solid was dissolved in THF (2 mL) and transferred to a
3 3
2.58 (s, 6 H, COCH ) ppm. C NMR (100 MHz, CDCl
172.10, 153.32, 137.85, 134.89, 128.76, 128.49, 127.52, 125.53,
68.87, 26.26 ppm. IR (KBr): ν˜ = 3028, 2947, 1744, 1712, 1584,
5496
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 5487–5500

2,5-Diamide-Substituted Five-Membered Heterocycles
1
5
562, 1468, 1382, 1286, 1251, 1100, 967, 904, 762, 735, 626, 580,
129.73, 127.28, 127.18, 124.59, 124.38, 113.99, 106.69, 106.45,
72.14, 68.41, 66.67, 66.59, 55.31, 37.11, 36.90, 31.06, 22.37, 17.77,
14.01, –1.45 ppm. Some peaks are doubled due to the presence of
rotamers. IR (neat): ν˜ = 2958, 2874, 2838, 1784, 1734, 1614, 1586,
–1
+
22 2 6
54, 513, 464, 420 cm . HRMS (ESI ): calcd. for [C24H N O S
+
+
K] 505.0835; found 505.0841.
Compound 5: The starting materials were compound 4 (1.80 g,
.07 mmol) and acetic anhydride, and the reaction yielded the de-
1
8
515, 1465, 1405, 1377, 1248, 1176, 1082, 1035, 980, 940, 924, 860,
4
–
1
+
35, 769, 694, 668, 637, 613, 576, 522, 494 cm . HRMS (ESI ):
1
sired product as a white solid (1.77 g, 3.36 mmol, 83% yield). H
NMR (400 MHz, CDCl ): δ = 7.16 (d, J = 8.6 Hz, 4 H, PhH), 6.84
d, J = 8.6 Hz, 4 H, PhH), 6.67 (s, 2 H, thiophene-H), 5.12 (s, 4 H,
+
calcd. for [C38
for [C38H N O Si + K] 762.3187; found 762.3233.
53 3 9
H N O Si + Na] 746.3448; found 746.3491; calcd.
3
+
53 3 9
(
1
3
OCH
NMR (100 MHz, CDCl
2
Ph), 3.77 (s, 6 H, OCH
3
), 2.55 (s, 6 H, COCH
3
) ppm.
C
Compound 24: The starting materials were compound 23 and acetic
): δ = 172.09, 159.82, 153.34, 137.83, anhydride (400 mg, 0.940 mmol), and the reaction yielded the de-
29.60, 126.99, 125.37, 114.06, 68.83, 55.35, 26.19 ppm. IR (KBr):
sired product as a colourless oil (326 mg, 0.640 mmol, 68% yield).
ν˜ = 2997, 2942, 2843, 1894, 1750, 1717, 1645, 1586, 1615, 1511,
3
): δ = 7.18 (d, J = 8.6 Hz, 4 H, PhH),
3
1
1
H NMR (400 MHz, CDCl
6.83 (d, J = 8.6 Hz, 4 H, PhH), 6.23 (s, 2 H, furan-H), 5.08 (s, 4
1
8
465, 1417, 1375, 1304, 1245, 1174, 1100, 1038, 1017, 961, 896,
53, 822, 799, 764, 729, 637, 627, 556, 541, 518, 461, 429 cm .
–
1
13
H, OCH
2
Ph), 3.77 (s, 6 H, OCH
3
), 2.40 (s, 6 H, COCH
3
) ppm.
C
+
+
HRMS (ESI ): calcd. for [C26
49.1330.
H
26
N
2
O
8
S + Na] 549.1307; found
NMR (100 MHz, CDCl
3
): δ = 171.50, 159.83, 152.48, 141.00,
5
129.80, 126.87, 113.99, 108.60, 68.83, 55.32, 25.46 ppm. IR (neat):
ν˜ = 3010, 2960, 2388, 2349, 2059, 1788, 1753, 1614, 1588, 1567,
Compound 6: The starting materials were compound 4 (1.40 g,
.16 mmol) and valeric anhydride, and the reaction yielded the de-
1
9
516, 1464, 1424, 1371, 1304, 1248, 1198, 1091, 1035, 1016, 974,
3
–
1
08, 823, 726, 692, 607, 574 cm . HRMS (ESI+): calcd. for
1
sired product as a white solid (1.50 g, 2.46 mmol, 78% yield). H
NMR (400 MHz, [D ]DMSO): δ = 7.18 (d, J = 8.6 Hz, 4 H, PhH),
.87 (d, J = 8.6 Hz, 4 H, PhH), 6.82 (s, 2 H, thiophene-H), 5.11 (s,
H, OCH Ph), 3.71 (s, 6 H, OCH ), 2.82 (t, J = 7.4 Hz, 4 H,
CH ), 1.51 (quint, J = 7.4 Hz, 4 H, CH CH CH ), 1.26
sex, J = 7.4 Hz, 4 H, CH CH CH ), 0.85 (t, J = 7.4 Hz, 6 H,
) ppm. 1 C NMR (100 MHz, [D
]DMSO): δ = 174.55,
[C
26
H
26
N
2
O
9
+ Na]+ 533.1536; found 533.1575.
6
General Procedure for Moz Removal: Anisole (10 equiv.) and TFA
6
4
(
5%, v/v) were added to a solution of the Moz-protected derivative
2
3
–
1
2 2
in CH Cl (7–10 mLmmol ), with stirring at 0 °C, and the solu-
COCH
2
2
2
2
2
tion was stirred at room temp. for 2 h. The mixture was then diluted
(
2
2
3
–
1
3
with EtOAc (70 mLmmol ) and washed with saturated aq.
CH
2
CH
3
6
–
1
–1
NaHCO
3
(50 mLmmol ) and H
2
O (50 mLmmol ϫ2). The or-
and the solvent was removed
1
3
2
1
9
4
6
59.10, 152.71, 137.57, 129.20, 127.11, 125.53, 113.76, 68.03, 55.03,
6.68, 26.50, 21.62, 13.78 ppm. IR (KBr): ν˜ = 3085, 2958, 2871,
838, 2358, 1902, 1748, 1724, 1614, 1587, 1564, 1512, 1481, 1466,
454, 1375, 1375, 1303, 1283, 1269, 1240, 1206, 1181, 1076, 1030,
75, 849, 822, 803, 768, 753, 716, 683, 576, 558, 540.75, 517.31,
ganic phase was dried with MgSO
4
under vacuum. Precipitation of the residual oil with pentane af-
forded the desired product. This procedure was applied for com-
pounds 3, 7, 14 and 22.
–1
+
+
09 cm . HRMS (ESI ): calcd. for [C32
38 2 8
H N O S + Na]
Compound 3: The starting material was compound 5 (340 mg,
33.2246; found 633.2243. C32 S (610.72): calcd. C 62.93,
38 2 8
H N O
0
.650 mmol), and the reaction yielded the desired product as a
H 6.27, N 4.59, S 5.25; found C 62.09, H 6.41, N 4.60, S 5.04.
1
white solid (97 mg, 0.49 mmol, 75% yield). H NMR (400 MHz,
[
2
D
6
]DMSO): δ = 10.78 (s, 2 H, NH), 6.32 (s, 2 H, thiophene-H),
Compound 13: The starting materials were compound 12 (900 mg,
1
3
3 6
.00 (s, 6 H, COCH ) ppm. C NMR (100 MHz, [D ]DMSO): δ
1
.79 mmol) and acetic anhydride, and the reaction yielded the de-
1
= 165.73, 132.37, 107.00, 22.43 ppm. IR (KBr): ν˜ = 3248, 3098,
3
1
521 cm . HRMS (APCI ): calcd. for [C H N O S + H]
8 10 2 2
1
sired product as a white solid (850 mg, 1.45 mmol, 81% yield). H
NMR (400 MHz, CDCl ): δ = 7.18 (d, J = 8.6 Hz, 4 H, PhH), 6.84
d, J = 8.6 Hz, 4 H, PhH), 5.13 (s, 4 H, OCH Ph), 3.77 (s, 6 H,
OCH ), 3.69 (s, 6 H, OCH ), 2.53 (s, 6 H, COCH
100 MHz, CDCl ): δ = 171.92, 159.79, 153.32, 144.00, 129.55,
27.04, 118.73, 114.04, 68.82, 59.85, 55.35, 25.96 ppm. IR (KBr):
001, 1748, 1667, 1645, 1588, 1557, 1480, 1495, 1427, 1370, 1323,
306, 1288, 1032, 1015, 973, 876, 812, 777, 766, 713, 683, 619, 597,
3
(
2
–
1
+
+
) ppm. 1 C NMR
3
3
3
3
99.0541; found 199.0549.
(
3
1
Compound 7: The starting material was compound 6 (500 mg,
ν˜ = 3421, 3091, 2942, 2837, 2408, 2058, 1893, 1747, 1731, 1615, 0.820 mmol), and the reaction yielded the desired product as a
1
1
1
7
531, 1515, 1456, 1418, 1394, 1376, 1304, 1264, 1242, 1191, 1179,
white solid (141 mg, 0.500 mmol, 61% yield). H NMR (400 MHz,
128, 1092, 1060, 1035, 1024, 955, 912, 865, 828, 815, 768, 744,
[D ]DMSO): δ = 10.71 (s, 2 H, NH), 6.33 (s, 2 H, thiophene-H),
2.27 (t, J = 7.4 Hz, 4 H, COCH CH ), 1.55 (quint, J = 7.4 Hz, 4
H, CH CH CH ), 1.29 (sex, J = 7.4 Hz, 4 H, CH CH CH ), 0.88
2 2 2 2 2 3
2 3
(t, J = 7.4 Hz, 6 H, CH CH ) ppm. C NMR (100 MHz, [D6]-
6
–
1
+
13, 643, 579, 543, 515, 481, 458, 437, 413 cm . HRMS (ESI ):
2
2
+
calcd. for [C28
C
H
30
N
2
O
10S + Na] 609.1519; found 609.1539.
1
3
28
H
30
N
2
O10S (586.61): calcd. C 57.33, H 5.15, N 4.78, S 5.47;
found C 57.30, H 5.21, N 4.81, S 5.35.
DMSO): δ = 168.71, 132.30, 107.07, 34.78, 27.29, 21.81, 13.72 ppm.
IR (KBr): ν˜ = 3306, 3272, 2955, 2860, 1652, 1579, 1543, 1498, 1453,
Compound 21: The starting materials were compound 20 and va-
leric anhydride (700 mg, 1.26 mmol), and the reaction was per-
formed in the microwave oven at 60 °C for 30 min. After the general
1
9
411, 1381, 1351, 1328, 1286, 1253, 1215, 1183, 1104, 1023, 963,
–
1
+
23, 809, 748, 730, 694, 541, 573, 513 cm . HRMS (ESI ): calcd.
+
22 2 2
for [C14H N O S + H] 283.1480; found 283.1478; calcd. for
[C14
purification procedure described above, the desired product was ob-
+
1
H
H
22
N
2
O
O
2
S + Na] 305.1300; found 305.1299; calcd. for
tained as a colourless oil (619 mg, 0.860 mmol, 68% yield).
NMR (400 MHz, [D
PhH), 6.87 (d, J = 8.6 Hz, 4 H, PhH), 6.02 (s, 2 H, pyrrole-H),
H
[C
14
22
N
2
2
S + K]+ 321.1039; found 321.1039. C14
22 2 2
H N O S
6
]DMSO, 80 °C): δ = 7.19 (d, J = 8.6 Hz, 4 H,
(
282.40): calcd. C 59.54, H 7.85, N 9.92, S 11.35; found C 59.40,
H 7.96, N 10.06, S 10.83.
5
3
1
4
.08 (s, 4 H, OCH
.29–3.21 (m, 2 H, OCH
.53 (quint, J = 7.3 Hz, 4 H, CH
H, CH CH CH ), 0.85 (t, J = 7.3 Hz, 6 H, CH
CH Si), –0.09 [s, 9 H, Si(CH ] ppm. The spectrum
was recorded at 80 °C due to the presence of rotamers. C NMR
100 MHz, CDCl ): δ = 175.48, 175.09, 159.75, 153.60, 153.47,
2
Ph), 4.71 (s, 2 H, NCH
CH Si), 2.66 (br. t, 4 H, COCH
CH CH
2
O), 3.74 (s, 6 H, OCH
3
),
2
2
2
CH
2
), Compound 14: The starting material was compound 13 (400 mg,
2
2
2
), 1.28 (sex, J = 7.3 Hz, 0.680 mmol), and the reaction yielded the desired product as a
1
2
2
3
2
CH
3
), 0.69–0.61 white solid (90 mg, 0.35 mmol, 51% yield). H NMR (400 MHz,
CD OD): δ = 3.83 (s, 6 H, OCH ), 2.12 (s, 6 H, COCH ) ppm, NH
protons are not visible, due to exchange with solvent. C NMR
(100 MHz, CD OD): δ = 170.60, 137.21, 117.04, 61.03, 22.23 ppm.
(m, 2 H, OCH
2
2
3
)
3
3
3
3
1
3
13
(
3
3
Eur. J. Org. Chem. 2014, 5487–5500
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5497

D. Bonifazi et al.
FULL PAPER
HRMS (APCI ): calcd. for [C10
+
S + H]+ 259.0752; found
H
14
N
2
O
4
1195, 1170, 1097, 1076, 990, 950, 859, 836, 809, 757, 650, 492, 467,
–
1
+
+
2
59.0735.
Compound 22: The starting material was compound 21 (500 mg,
.690 mmol), and the reaction yielded the desired product as a
418 cm . HRMS (ESI ): calcd. for [C14
36.1243; found 336.1251.
5
H23NO Si + Na]
3
0
Compound 19: An aq. LiOH solution (2 n, 20 mL) was added to a
solution of compound 18 (1.40 g, 4.47 mmol) in THF (10 mL), and
the mixture was stirred at room temp. overnight. It was then cooled
1
white solid (135 mg, 0.340 mmol, 49% yield). H NMR (400 MHz,
]DMSO, 80 °C): δ = 9.04 (br. s, 2 H, NH), 5.80 (s, 2 H, pyrrole-
H), 4.98 (s, 2 H, NCH O), 3.39 (t, J = 8.0 Hz, 2 H, OCH CH
.25 (br. s, 4 H, COCH CH ), 1.64–1.49 (m, 4 H, CH CH CH
.41–1.28 (m, 4 H, CH CH CH ), 0.90 (t, J = 6.8 Hz, 6 H, to afford the desired product (1.20 g, 4.21 mmol, 94% yield). H
CH ), 0.81 (t, J = 8.0 Hz, 2 H, OCH CH Si), –0.02 [s, 9 H,
NMR (400 MHz, [D ]DMSO): δ = 12.96 (s, 2 H, COOH), 6.87 (s,
Si(CH ]DMSO): δ = 172.85, 2 H, pyrrole-H), 6.16 (s, 2 H, NCH O), 3.42 (t, J = 7.8 Hz, 2 H,
] ppm. 13C NMR (100 MHz, [D
23.96, 102.09, 70.65, 65.49, 35.52, 27.66, 22.49, 18.07, 14.39, OCH CH Si), 0.75 (t, J = 7.8 Hz, 2 H, OCH CH Si), –0.10 [s, 9
[D
6
2
2
2
Si), down to 0 °C, and conc. aq. HCl was slowly added until the forma-
),
tion of a white precipitate, which was collected by vacuum filtration
2
1
2
2
2
2
2
1
2
2
3
CH
2
3
2
2
6
3
)
3
6
2
1
–
1
7
2
2
2
2
1
3
1.09 ppm. IR (KBr): ν˜ = 3251, 2957, 2931, 2874, 1657, 1584, 1559,
526, 1467, 1416, 1370, 1291, 1264, 1250, 1189, 1061, 862, 836,
57, 700, 664, 612, 599, 570, 564, 511, 490 cm . HRMS (ESI ):
3 3 6
H, Si(CH ) ] ppm. C NMR (100 MHz, [D ]DMSO): δ = 161.63,
128.58, 116.98, 72.60, 64.75, 17.20, –1.42 ppm. IR (KBr): ν˜ = 2992,
2954, 2895, 2615, 2559, 1860, 1708, 1668, 1519, 1455, 1418, 1375,
1289, 1245, 1195, 1140, 1105, 1089, 1035, 940, 915, 862, 838, 819,
–1
+
+
calcd. for [C20
for [C20
37 3 3
H N O Si + Na] 418.2502; found 418.2520; calcd.
+
–1
H
37
N
3
O
3
Si + K] 434.2241; found 434.2252.
781, 758, 703, 695, 610, 537, 505, 413 cm . HRMS (ESI-): calcd.
–
for [C12
H
19NO
5
Si – H] 284.0954; found 284.0905. C12
H19NO
5
Si
Compound 8: Trimethylsilyl chloride (TMSCl) (20.5 mL, 161 mmol)
was added dropwise at 0 °C to a solution of 2,2Ј-thiodiacetic acid
(
4
285.37): calcd. C 50.51, H 6.71, N 4.91; found C 50.44, H 6.81, N
.86.
(
11.0 g, 73.3 mmol) in anhydrous MeOH (50 mL). The solution was
then allowed to reach room temp. and was then stirred overnight.
The reaction mixture was then diluted with Et O (40 mL) and
washed with saturated aq. NaHCO (30 mLϫ2) and H O (30 mL).
The organic phase was dried with MgSO , and the solvent was
removed under vacuum to afford the product as a colourless liquid
Compound 25: TMSCl (8.54 mL, 67.3 mmol) was added dropwise
at 0 °C to a solution of 2,2Ј-oxydiacetic acid (4.10 g, 30.6 mmol) in
anhydrous MeOH (50 mL). The solution was then allowed to reach
room temp. and stirred overnight. The reaction mixture was then
2
3
2
4
diluted with Et
2
O (40 mL) and washed with saturated aq. NaHCO
2ϫ 30 mL) and H O (30 mL). The organic phase was dried with
, and the solvent was removed under vacuum to afford the
3
(
12.2 g, 68.5 mmol, 93%). Characterization was in agreement with
(
2
[
64]
literature data.
MgSO
4
product as a white solid (3.72 g, 22.9 mmol, 75% yield). Characteri-
Compound 10: K
2
7
stirred at 30 °C overnight. It was then diluted with CH
(
(
2
CO
2.0 mmol) were added to a solution of compound 9 (1.70 g,
.32 mmol) in anhydrous DMF (25 mL), and the mixture was
Cl
100 mL) and washed with aq. HCl (1 n, 100 mLϫ2) and H
100 mLϫ2). The organic phase was dried with MgSO , and the
3
(5.06 g, 36.6 mmol) and MeI (1.37 mL,
zation was in agreement with literature data.[
87]
Supporting Information (see footnote on the first page of this arti-
1
13
2
2
cle): copies of H and C NMR spectra of all the compounds and
elemental analysis certificate.
2
O
4
solvent was removed under vacuum. Purification by silica gel
chromatography (cyclohexane/EtOAc 8:2) afforded the product as Acknowledgments
a white solid (1.12 g, 4.32 mmol, 59% yield). Characterization was
in agreement with literature data.[
64]
This work was financially supported by the Fonds de la Recherche
Scientifique – Fonds National de la Recherche Scientifique (FRS-
FNRS) (contract number 2.4.550.09), the Loterie Nationale, the
Science Policy Office of the Belgian Federal Government (BEL-
SPO-IAP 7/05 project), the Actions de Recherche Concertées
Compound 17: TFA (5 mL) was added at 0 °C with stirring to a
solution of compound 16 (1.40 g, 4.94 mmol) in CH Cl (10 mL),
2 2
and the solution was further stirred at room temp. for 2 h. The
mixture was then diluted with EtOAc (50 mL) and washed with
(
ARC) (TINTIN project, number 09/14-023), the FP7 Initial Train-
saturated aq. Na
phase was dried with MgSO
vacuum to afford the product as a white solid (878 mg, 4.79 mmol,
2
CO
3
(50 mL) and H
2
O (50 mLϫ2). The organic
ing Network (ITN) Marie-Curie Actions (FINELUMEN project,
grant number PITN-GA-2008-215399) and the University of Na-
mur. D. B. gratefully acknowledges the EU through the ERC Start-
ing Grant, COLORLANDS project. S. A. thanks the University of
Trieste for his doctoral fellowship. L. E. C. thanks the Fonds pour
la Formation à la Recherche dans l’Industrie et dans l’Agriculture –
Fonds National de la Recherche Scientifique (FRIA-FNRS) for
her doctoral fellowship. Access to the computational resources sup-
plied by CINECA, Italy, is gratefully acknowledged. D. B. and
F. D. L. thank Dr. A. Magistrato for the useful suggestions about
the theoretical section.
4
, and the solvent was removed under
9
7% yield). Characterization was in agreement with literature
[
86]
data.
Compound 18: Compound 17 (2.44 g, 13.3 mmol) was added por-
tionwise to a suspension of NaH (384 mg, 16.0 mmol) in anhydrous
DMF (30 mL), and the mixture was stirred at room temp. for
30 min. Sem-Cl (2.59 mL, 14.6 mmol) was then added, and the re-
action mixture was stirred for 1 h. Afterwards, the solution was
diluted with EtOAc (60 mL) and washed with aq. HCl (1 n,
6
0 mL), saturated aq. NaHCO
3
(60 mL) and H
2
O (60 mLϫ2). The
organic phase was dried with MgSO
under vacuum. Purification by silica gel chromatography (cyclohex-
ane/EtOAc 8:2) afforded the product as a colourless oil (3.30 g,
4
, and the solvent was removed
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 5487–5500

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