Application of Ynamides in the Synthesis of 2-(Tosylamido)- and 2,5-Bis(tosylamido)thiophenes

Article abstract of DOI:10.1021/acs.orglett.6b01101

A step-economic and metal-catalyst-free synthesis of 2-(tosylamido)- and 2,5-bis(tosylamido)-thiophenes from nonsymmetrical 1,3-butadiynamides and symmetrical 1,3-butadiyne-1,4-diamides is reported. The reaction proceeds in the presence of Na₂S·9H₂O (2-3 equiv) under mild reaction conditions (50 °C) and is facilitated by polarized carbon-carbon triple bonds in ynamides. This new approach to thiophenes based on the chemistry of ynamides was applied to the synthesis of a bis(tosylamido)-capped terthiophene having a string of N,S-heteroatoms embedded in a highly π-conjugated molecular frame.

Full text of DOI:10.1021/acs.orglett.6b01101

Letter
pubs.acs.org/OrgLett
Application of Ynamides in the Synthesis of 2‑(Tosylamido)- and 2,5-
Bis(tosylamido)thiophenes
Imen Talbi,†,‡ Carole Alayrac,*,† Jean-Francois Lohier,† Soufiane Touil,‡ and Bernhard Witulski*,†
̧
†Laboratoire de Chimie Molec
Marechal Juin, 14050 Caen, France
́
ulaire et Thioorganique, CNRS UMR 6507, Normandie Univ, ENSICAEN & UNICAEN, 6 bvd
́
‡Laboratory of Heteroatom Organic Chemistry, University of Carthage, Faculty of Sciences of Bizerte, 7021 Jarzouna, Tunisia
S
* Supporting Information
ABSTRACT: A step-economic and metal-catalyst-free synthesis of 2-(tosylamido)- and 2,5-bis(tosylamido)-thiophenes from
nonsymmetrical 1,3-butadiynamides and symmetrical 1,3-butadiyne-1,4-diamides is reported. The reaction proceeds in the
presence of Na2S·9H2O (2−3 equiv) under mild reaction conditions (50 °C) and is facilitated by polarized carbon−carbon triple
bonds in ynamides. This new approach to thiophenes based on the chemistry of ynamides was applied to the synthesis of a
bis(tosylamido)-capped terthiophene having a string of N,S-heteroatoms embedded in a highly π-conjugated molecular frame.
unctionalized thiophenes are an important class of
thiophenes exhibit high charge delocalizations of their radical
cations, which makes them attractive as a hole-transporting layer
in organic electronics.9
1
Fmolecules with applications in both medicinal and material
science.2 In particular, 2-aminothiophenes display interesting
biological activities and have been noted as structural motifs in
sensors and optoelectronic materials.3 For example, PD81,7234
is an allosteric modulator of the adenosine A1 receptor, and the
strontium salt of ranelic acid is able to reduce the risk of vertebral
fracture in women with osteoporosis (Figure 1).5
Despite their relevance, the number of syntheses of 2-amino-
and 2-amidothiophenes is quite limited, and reported methods
can be classified by (i) assembly of two to three acyclic
components by condensation reactions (e.g., Gewald reac-
tion)3,10 and (ii) C−N bond-forming reaction with appropriately
functionalized thiophenes comprising SNAr11 and transition-
metal-catalyzed aryl amination and amidation reactions.12,13
Regarding 2,5-bis-aminothiophenes, the unsubstituted derivative
is very labile and decomposes at room temperature.14 Notably,
only a few examples of N-substituted analogues such as 2,5-
bis(diarylamino)thiophenes12c,15 and 2,5-bis(acetylamido)-
thiophenes16 have been described.
Within our ongoing interest in the synthesis and use of
ynamides as versatile building blocks in natural product and
electronic materials synthesis,17,18 we reasoned that treatment of
ynamide-derived buta-1,3-diynes by a sulfur reagent would allow
a straightforward approach to unprecedented 2,5-bis-
(tosylamido)thiophenes 1 as well as 2-(tosylamido)thiophenes
2 (Scheme 1). Both envisaged precursors 3 and 4 are readily
available from terminal ynamide 519,20 via Hay or Cadiot−
Chodkiewicz cross-coupling reactions. To the best of our
knowledge, ynamide to thiophene transformations have no
precedent in the literature, whereas 2,5-bis(amido)pyrroles and
furans were obtained from buta-1,3-diyne-1,4-diamides under
Au(I) catalysis.21 For thiophene syntheses based on buta-1,3-
diynes, various sulfur sources (elemental sulfur,22 sodium
Figure 1. Examples of biologically active 2-aminothiophenes and 2-
aminothiophene-based fluorescent biomarkers.
Push−pull 2-aminothiophene derivatives such as BAP-2 and
DTM-2 serve as in vivo fluorescence imaging probes of β-
amyloid (Aβ) plaques for the detection of Alzheimer’s disease.6
Notably, 2-aminothiophene moieties have also been embedded
into push−pull systems for optoelectronic applications and solar
cells,7 and they resemble the electron donor part in π-conjugated
chromophores displaying excellent nonlinear optical (NLO)
responses.8 Bis(bis(4-alkoxyphenyl)amino) derivatives of oligo-
Received: April 15, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01101
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Letter
sponding thiophenes 1b and 1c were obtained in, respectively, 69
and 92% yield (Scheme 2). On the other hand, these conditions
Scheme 1. Synthetic Strategy for 2,5-Bis(tosylamido)- (1) and
2-(Tosylamido)thiophenes (2)
Scheme 2. Synthesis of 2,5-Bis(tosylamido)thiophenes
hydrosulfide,23 or sodium sulfide23,24) with or without additional
base or metal catalysts have been used. With respect to the
inherent polarization of the carbon−carbon triple bond in
ynamides, we chose a transition-metal-free approach for the
transformation of ynamide-derived buta-1,3-diynes to the
corresponding thiophenes as the ynamide triple bond is activated
enough to interact with a sulfur nucleophile. Notably, sodium
sulfide hydrate, a very mild and readily available reagent, was
selected for initial studies.
were not suitable for the N-phenyl-substituted diyne 3d25 and
delivered only minor amounts of the thiophene 1d (7%).
Probably the addition of ethanol to the more reactive carbon−
carbon triple bonds of 3d, whose electrophilic character is now
enhanced by conjugation with the N-phenyl group, is responsible
for these nonselective reaction paths. However, these side
reactions vanished when acetonitrile was used as the solvent, and
the yield of 1d increased to 62% (Scheme 2).
The conversion of diyne 3a25 (R1 = Bn) to the corresponding
2,5-bis(tosylamido)thiophene 1a using 3 equiv of Na2S·9H2O
served for optimization studies including different solvents,
reaction temperatures, and times (Table 1).
2-(Tosylamido)thiophenes 2 are likewise accessible by
starting from nonsymmetrical 1,3-butadiynamides (Scheme 3).
Scheme 3. Synthesis of Diynes 4 via Cadiot−Chodkiewicz
Coupling between Ynamides 5 and 1-Bromoalkynes 6
Table 1. Optimization of the Reaction Conditions
a
b
temp
(°C)
time
(min)
Na2S
yield
entry
solvent
(equiv)
(%)
1
2
3
4
5
6
7
8
DMF
20
50
66
40
65
50
50
50
40
120
120
180
120
50
3
3
3
3
3
3
2
1
45
47
0
MeCN
THF
CH2Cl2
0
MeOH
3
THF/EtOH (1:1)
THF/EtOH (1:1)
THF/EtOH (1:1)
90
89
21
70
120
a
b
Na2S·9H2O was used. Yield refers to isolated 1a.
Moderate yields of 45% and 47% were obtained when the
reaction was carried out in DMF or acetonitrile, respectively.
However, no reaction took place in THF or dichloromethane,
probably due to the poor solubility of Na2S·9H2O in these
solvents. Switching to methanol brought no improvement and
only provided trace amounts of 1a. Finally, combining ethanol
with THF (1:1) allowed the reaction to proceed efficiently and
afforded 1a in 90% isolated yield after 50 min at 50 °C. The yield
was not affected when the amount of Na2S·9H2O was reduced to
2 equiv. However, the conversion of 3a to 1a was slow when 1
equiv of sulfur reagent was used, and 1a was isolated in only 21%
yield. The optimized reaction conditions involving the use of
Na2S·9H2O (2 equiv) in a 1:1 mixture of THF/EtOH at 50 °C
were also successfully applied to diynes 3b25 and 3c18b bearing,
respectively, an allyl and n-butyl group on the nitrogen atom.
These mild reaction conditions for a thiophene synthesis based
on 1,3-diynes underline the improved reactivity of polarized
ynamide carbon−carbon triple bonds. In analogy, the corre-
The therefore needed 1,3-butadiynamides 4 are readily available
through a Cadiot−Chodkiewicz coupling between terminal
ynamides 5 and 1-bromoalkynes 6 according to our previously
described method for the synthesis of push−pull ynamides, i.e.,
diyne 4a (R2 = 4-NO2C6H4) in 93% yield.18a
Thus, the conversion of N-benzyl-, N-allyl-, and N-
arylynamides 5 into various diynes 4 was performed with various
bromoalkynes 6 at 40 °C in oxygen-free methanol in the
presence of n-butylamine (2 equiv) and hydroxylamine hydro-
chloride (30 mol %) with copper iodide (5 mol %) as the catalyst.
The diynes 4b−h were obtained in isolated yields ranging from
52 to 97% yield. With the exception of compounds 4a,e18a and
4f,26 the synthesized ynamide-derived buta-1,3-diynes 4 are
unprecedented. It is worth noting that 1,3-butadiynamides are air
stable and storable at room temperature over several months.
B
DOI: 10.1021/acs.orglett.6b01101
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With a set of various functionalized 1,3-butadiynamides 4 in
hand, we investigated their conversion into the corresponding 2-
(tosylamido)thiophenes 2 (Scheme 4).
reproduced by stirring a diluted solution (10−3 M) of 2e in
CHCl3 in the presence of one drop of 37% aq HCl at room
temperature for 1 h, and thiophene 2f was thereafter isolated in
88% yield. In analogy, acid treatment of 2h and 2j delivered
thiophenes 2i and 2k in 86 and 79% respective yields. It should
be pointed out that thiophenes 2f,i,k would have been difficult to
access from the corresponding highly conjugated isopropenyl-
substituted 1,3-butadiynamides.
a
Scheme 4. Scope of 2-(Tosylamido)thiophenes
Single-crystal molecular structures of the thiophenes 1b and
2g were obtained by slow diffusion of pentane into a CHCl3−1b
or CHCl3−2g solution, respectively, and were analyzed by X-ray
diffraction (Figure 2).27
Figure 2. Crystal structures of 1b (left) and 2g (right). 50% ellipsoids;
hydrogen atoms omitted for clarity.
Unlike the crystallographic structure of 2,5-bis(acetamido)-
thiophene,16 where close contact between the S and the two
carbonyl O atoms was noticed (S···O 2.82, 2.86 Å), no
intramolecular interaction between the tosyl O atoms and the
S atom was observed. In the case of 2g, the tosyl group is located
on the side of the S atom but the distance S···O (3.51 Å) is longer
than the sum of their van der Waals radii (3.25 Å).
To further extend the scope of this new method for the
synthesis of 2-(tosylamido)- and 2,5-bis(tosylamido)thiophenes,
we applied it for the construct of the terthiophene 9 that is end-
capped with two tosylamido groups and displays a string of mixed
N,S-heteroatoms embedded into a π-extended molecular
framework (Scheme 5).
The double Cadiot−Chodkiewicz reaction between ynamide
5a and bis(bromoalkynyl)thiophene 7 was performed at room
temperature and afforded the tetrayne 8 in 52% isolated yield.
Treatment of the latter by Na2S·9H2O (4 equiv) in THF/EtOH
(1:1) at 50 °C gave terthiophene 9 in 23% isolated yield.
Terthiophene 9 is the first example of a highly conjugated
a
b
Yields refer to isolated compounds. Yield over two steps through
treatment of 2 (R2 = CMe2OH) with cat. HCl.
The reaction of N-benzyl derivatives 4a−e with Na2S·9H2O (2
equiv) readily proceeded in 1:1 EtOH/THF at 50 °C
(conditions A) and was completed during 1 h. Because of their
enhanced electrophilic character, the 1,3-butadiynamides 4a and
4b bearing either a p-NO2 or p-CN substituent were consumed in
less than 30 min at 50 °C, and the thiophenes 2a and 2b were
isolated in 47 and 66% yield, respectively. The reaction of 4a in
acetonitrile at 50 °C gave 2a in a comparable yield of 44%
(conditions B). Worthy of note is that 2a and 2b are new
specimens of push−pull thiophenes. The best yield (91%) was
obtained with the phenyl derivative 2c, but heteroaryl
substituents and free hydroxy function were also tolerated as
illustrated by the 2-thienyl-substituted thiophene 2d and the (1-
methyl-1-hydroxy)ethyl) derivative 2e, which were obtained in
67 and 79% respective yield. The N-allyl derivative 4f successfully
underwent the reaction with Na2S·9H2O (2 equiv) to give
thiophene 2g in 75% yield. By analogy to the synthesis of 2,5-
bis(tosylamido)thiophene 3d (Scheme 2), the conversion of N-
phenyl diyne 4g was performed with Na2S·9H2O (3 equiv) in
acetonitrile at 50 °C (conditions B), and 2-(tosylamido)-
thiophene 2h was obtained in 63% yield. Diyne 4h bearing a 2-
iodoaryl substituent on the nitrogen atom delivered thiophene 2j
in 51% isolated yield when reaction conditions B were applied.
Interestingly, during NMR analysis of thiophene 2e, which
bears a heteroarylic tertiary hydroxy function, the spontaneous
conversion into thiophene 2f substituted by an isopropenyl
group was observed (Scheme 4 and see the 1H NMR spectra in
the Supporting Information). This dehydration was probably
catalyzed by trace amounts of HCl contaminating the used
CDCl3. Indeed, the acid-catalyzed dehydration could be
Scheme 5. Synthesis of Terthiophene 9
C
DOI: 10.1021/acs.orglett.6b01101
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Organic Letters
Letter
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This molecular scaffold and related molecular structures are
interesting for organic electronics.28
In conclusion, we reported a step-economic synthesis of 2-
(tosylamido)thiophenes and 2,5-bis(tosylamido)thiophenes
based on the chemistry of ynamides. Attractive features of the
disclosed protocol are readily available starting materials and
mild reaction conditions. Moreover, eagerly sought thiophenes
displaying important functional groups (free hydroxy function,
isopropenyl, iodoaryl, etc.) are obtained. A terthiophene with a
string of N,S-heteroatoms could be synthesized within a short
and efficient sequence. Applications of this methodology to the
synthesis of organic electronics are underway.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01101.
■
S
(16) Fabbro, C.; Armani, S.; Carloni, L.-E.; De Leo, F.; Wouters, J.;
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Experimental details; 1H and 13C NMR spectra for all new
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: carole.witulski-alayrac@ensicaen.fr.
*E-mail: bernhard.witulski@ensicaen.fr.
Notes
The authors declare no competing financial interest.
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̈
ACKNOWLEDGMENTS
■
Financial support from the French Agence Nationale de la
Recherche through the program “Investissements d’Avenir”
(ANR-10-LABEX-09-01) is gratefully acknowledged. I.T. is
indebted to the Ministry of Higher Education and Scientific
Research of Tunisia for supporting a research stay at the LCMT
in France.
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