Improved synthesis of a quaterthiophene-triazine-diamine derivative, a promising molecule to study pathogenic prion proteins

Article abstract of DOI:10.1016/j.tetlet.2014.11.098

The 6,6′-([2,2′:5′,2″:5″,2-quaterthiophene]-5,5-diyl)bis(1,3,5-triazine-2,4-diamine) (MR100), has been previously investigated in our research group through its biological activities toward pathogenic prion proteins (PrP^Sc). This compound presents a high affinity to protein strains and interacts selectively with at least one β-sheet rich isoform of prion protein. Herein we present the improved total synthesis of MR100, through a palladium-catalyzed direct double arylation using the concerted metalation deprotonation mechanism (CMD).

Full text of DOI:10.1016/j.tetlet.2014.11.098

Tetrahedron Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Improved synthesis of a quaterthiophene-triazine-diamine
derivative, a promising molecule to study pathogenic prion proteins
a
b
b
a,
⇑
Alysson Duarte Rodrigues , Thibaut Imberdis , Véronique Perrier , Mike Robitzer
a
Institut Charles Gerhardt Montpellier, UMR 5253 CNRS-UMII-ENSCM-UMI, Matériaux Avancés pour la Catalyse et la Santé, ENSCM, 8 rue de l’Ecole Normale, 34296
Montpellier Cedex, France
Université Montpellier 2, Montpellier, F-34095 France; Inserm, U710, Montpellier, F-34095 France; EPHE, Paris, F-75007 France
b
a r t i c l e i n f o
a b s t r a c t
0
0
0
00
00 000
000
Article history:
The 6,6 -([2,2 :5 ,2 :5 ,2 -quaterthiophene]-5,5 -diyl)bis(1,3,5-triazine-2,4-diamine) (MR100), has been
previously investigated in our research group through its biological activities toward pathogenic prion
Received 2 August 2014
Revised 20 November 2014
Accepted 21 November 2014
Available online xxxx
Sc
proteins (PrP ). This compound presents a high affinity to protein strains and interacts selectively with
at least one b-sheet rich isoform of prion protein. Herein we present the improved total synthesis of
MR100, through
a palladium-catalyzed direct double arylation using the concerted metalation
deprotonation mechanism (CMD).
Keywords:
Ó 2014 Elsevier Ltd. All rights reserved.
Prion
Diaminotriazine
Quaterthiophene
CMD
C–H arylation
Pd catalysis
Introduction
templated, or seeded polymerization of PrPSc isoforms.4 The pro-
gress in the mechanism understanding and the synthesis of new
molecules having a high selectivity with the b-sheet rich PrP iso-
forms could afford a new option in the early diagnosis of prion dis-
eases enhancing the survival chances of patients.
Sc
Prion diseases are fatal neurodegenerative conditions charac-
Sc
terized by the accumulation of PrP Scrapie isoforms (PrP ) in the
brain tissues of many mammalian including humans.1 The trans-
missible subacute spongiform encephalopathies (TSSEs) cause
death in 100% of the cases by neurological damage and have
received a remarkable development since the mad cow crisis in
However, studies of this mechanism and new molecules applied
Sc
in the diagnosis of prion diseases having PrP selectivity are lim-
ited. Prusiner’s research group have done pioneering studies
exploring therapeutic candidates using persistently prion-infected
1
986. The appearance of the new variant of Creutzfeldt-Jakob dis-
5
ease (vCJD) in humans in 1996 has reinforced the interest to
develop new routes to identify and to treat prion diseases. How-
cells. He has been awarded with the Nobel Prize in Physiology or
2
Medicine in 1997 for his discovery of prions as a new biological
principle of infection. Caughey and co-workers demonstrated that
ever, at the current time, no available treatment exists for patients
suffering from TSSEs, nor is there a selective test for earlier diagno-
Sc
congo red and sulfated polyanions could partially inhibit PrP for-
3
C
6
sis. The cellular protease resistant protein (PrP ) and the scrapie
mation in prion-infected cell cultures. Kuwata and co-workers
Sc
C
protease resistant protein (PrP ) are isoforms and present
have described the affinity of GN8 with PrP doing many studies
identical primary structures due the same amino acid sequences.
They differ only in terms of their secondary and tertiary structures
where PrP has a higher content of b-pleated sheets and PrP has a
greater number of alpha helices.
The mechanism of the propagation of the disease remains
obscure at this stage but it is consistent with an autocatalytic,
with this compound in the selective interactions with the cellular
7
prion protein.
Sc
C
0
0
0
00
00 000
000
The 6,6 -([2,2 :5 ,2 :5 ,2 -quaterthiophene]-5,5 -diyl)bis(1,3,5-
triazine-2,4-diamine) (MR100) has been investigated in our
research group through its selective activity with PrP isoforms.
Sc
8
In vitro screenings on cell cultures chronically infected with prions
were performed with MR100 using murine neuroblastoma lines
chronically infected with prion strains (scrapie strain stabilized
in mice). The infected cells were incubated with solutions of
⇑
Corresponding author. Tel.: +33 467 163 494; fax: +33 467 163 470.
E-mail address: mike.robitzer@enscm.fr (M. Robitzer).
http://dx.doi.org/10.1016/j.tetlet.2014.11.098
040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
0
Please cite this article in press as: Rodrigues, A. D.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.11.098

2
A.D. Rodrigues et al. / Tetrahedron Letters xxx (2014) xxx–xxx
MR100 has been firstly synthesized using a five step protocol
where a Stille cross-coupling reaction was used in the main step
of the synthesis (Scheme 1). The double CAC bond formation
0
0
between the 5,5 -bis(trimethylstannyl)-2,2 -bithiophene (1b) and
two equivalents of the 6-(5-bromothiophen-2-yl)-1,3,5-triazine-
2
,4-diamine (1d) precursor have been accomplished with a palla-
8
dium(0) catalyst affording the desired product MR100 (1e).
The Stille cross-coupling presents some drawbacks in terms of
biological applications mostly related with the use of toxic triorga-
9
notin precursors. The biocide activities and the possible neurolog-
ical damage associated with stannanes led us to its total
1
0
elimination from the synthesis of MR100. Besides its toxicity
the purifications associated with this process also require long
time consuming preparations and specific conditions to avoid drug
degradation.
The new pathway avoiding organometallic precursors was
developed thinking in new methodologies more adapted to biolog-
ical applications. We have investigated a direct double CAH aryla-
tion as a helpful tool in the main step of the synthesis of MR100
Sc
Figure 1. Western blot showing the oligomerization of PrP (monomer) (27–30)
Sc
kDa giving PrP ꢀ60 kDa (dimmer) after incubation with MR100 at different
concentrations. Co = control where no MR100 has been used and DMSO = cells
incubated only with 5% of DMSO in water.
1
1
12
(
1e). Since works of Ohta and co-workers, reporting in 1990
the direct 2- or 5-arylation of several heteroaromatics with aryl
halides via a CAH bond activation proceed using Pd(PPh as the
catalyst, some examples of thiophene CAH arylation have been
MR100 H
2
O/DMSO 5:95 (v/v), at different concentrations from 1 to
giving positive
2
0
l
M, for a period of 3 days at 37 °C and 5% CO
2
3 4
)
Sc
results to the oligomerization of PrP . In Figure 1, Co represents
the control cells without treatment with MR100 and DMSO the
cells only treated with 5% DMSO in water. From these results, it
appears that the effect of oligomerization is very important since
M the saturation of the signal is achieved. MR100
presents a high affinity to protein strains and interacts selectively
1
3
reported. Lemaire and co-workers have proposed another cata-
lytic version of this reaction using cyanothiophenes with Pd(OAc)
Bu NBr/K CO as the catalytic system, affording the 2-cyano-5-
phenylthiophene in good yields. Doucet et al. developed a large
scope of direct 3-, 4- or 5-arylation of C5-heteroaromatic com-
2
/
4
2
3
1
4
for doses of 1
l
1
5
with at least one b-sheet rich isoform of prion.
pounds catalyzed by Pd. Fagnou and co-workers have reported
Scheme 1. Stille cross-coupling pathway (5 steps): (a) NBS, CH
3
COOH/CHCl
3
, rt, 4 h, 98%; (b) nBuLi, THF, ꢁ40 °C, 2 h/Me
3
SnCl; THF, rt, 3 h, 98%; (c) 2-cyanoguanidine, KOH,
DMSO, 80 °C, 16 h, 89%; (d) NBS, CH COOH, rt, 48 h, 90%; (e) Pd(PPh )
3
3 3
, pyridine/DMF, 110 °C, 16 h, 62%.
Scheme 2. New synthetic approach to MR100 (3 steps): (a) NBS, CH
cyanoguanidine, KOH, DMSO, 80 °C, 16 h, 91%.
3 3 3 4 2 3
COOH/CHCl , 70 °C, 4 h, 98%; (f) Pd(PPh ) , PivOH, K CO , toluene/DMA 1:1 (v/v), 110 °C, 48 h, 72%; (g) 2-
Please cite this article in press as: Rodrigues, A. D.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.11.098

A.D. Rodrigues et al. / Tetrahedron Letters xxx (2014) xxx–xxx
3
Table 1
Catalytic tries in the synthesis of 1f under different solvent and temperature conditions
Entry
Ar–X
Br
n
Ar–H
CN
mol % Pd(PPh
6%
)
3 4
K
2
CO
3
Co-catalyst
No
Solvent (v/v)
80 °C
90 °C
110 °C
Yield %
1
2
3
4
5
6
T
2
2
T
1
1.5 equiv
DMF
DMA
1,4-Dioxane
toluene
DMA/toluene 1:1
DMA/THF 1:1
19 h
19 h
19 h
0
0
0
0
0
0
2 3
Experimental conditions: 1a (1 equiv), thiophene-2-carbonitrile (6 equiv), (1.5 equiv) K CO , no co-catalyst, DMA/Toluene 1:1 (v/v), 110 °C, C: 0.23 M based on 1a initial
amounts.
Table 2
Optimization of the catalytic conditions
Entry
mol % Pd(PPh
)
3 4
Co-catalyst
Co-catalysta (pK
a
)
2
Equiv K CO
3
Yieldb
%
7
8
9
0
6
6
6
6
6
6
6
6
6
2
8
12
16
6
8
16
24
0.3 equiv pivalic acid
0.3 equiv pivalic acid
0.6 equiv pivalic acid
1.2 equiv pivalic acid
1.8 equiv pivalic acid
0.3 equiv benzoic acid
0.3 equiv pyridine
5.03
5.03
5.03
5.03
5.03
4.21
5.22
2.0; 6.7
1.7; 6.04; 9.09
11.27
5.03
5.03
5.03
5.04
5.03
5.03
5.03
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
3
0
58
34
27
33
9
8
<1
0
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
0.3 equiv phenyl phosphonic acid
0.3 equiv histidine
0.3 equiv pyrrolidine
0.3 equiv pivalic acid
0.3 equiv pivalic acid
0.3 equiv pivalic acid
0.3 equiv pivalic acid
0.3 equiv pivalic acid
0.3 equiv pivalic acid
0.3 equiv pivalic acid
0.3 equiv pivalic acid
0
46
20
23
36
27
72
16
22
3
3
3
5.03
a
See Ref 18.
b
2 3
Yields of isolated product in mol %. Catalytic conditions: 1a (1 equiv), thiophene-2-carbonitrile (6 equiv), K CO , co-catalyst, DMA/Toluene 1:1 (v/v), 110 °C, 48 h, C:
0
.23 M. All reactants have been calculated based on 1a initial amounts.
Table 3
2 3
One pot catalytic tries using Pd(OAc) /(4 equiv)PPh catalyst
Entry
mol % Pd(OAc)
2
/(4 equiv)PPh
3
Co-catalyst (0.3 equiv)
Co-catalyst (pK
a
)
Salt (1.5 equiv)
CO
Time
22 h
Yielda
%
25
26
27
28
29
30
31
6
6
6
6
6
6
6
Pivalic acid
Pivalic acid
Pivalic acid
Propionic acid
Hexanoic acid
Octanoic acid
Pivalic acid
5.03
5.03
5.03
4.87
4.88
4.89
5.03
K
2
3
38
0
0
10
11
9
KI
b
K
K
K
K
K
2
C
2
O
2
2
2
2
3
CO
CO
CO
3
3
3
PO
4
13
a
Yields of isolated product in mol %.
b
Potassium oxalate. Catalytic conditions: 1a (1 equiv), thiophene-2-carbonitrile (6 equiv), salt (1.5 equiv), co-catalyst (0.3 equiv), DMA/Toluene 1:1 (v/v), 110 °C, 22 h, C:
0
.23 M based on 1a initial amounts.
examples of palladium-catalyzed direct arylation using a concerted
Results and discussion
1
6
metalation deprotonation (CMD) pathway with thiophenes. Piva-
lic acid was used as a proton shuttle which works as a helpful tool
increasing the reaction yields. The CMD mechanism predicts rela-
With the new procedure MR100 can be obtained in three steps
(Scheme 2) where the CMD mechanism is applied in step 2
between the dibrominated compound (1a) and 2-thiophenecarbo-
nitrile. The final step of the synthesis is achieved by cycloaddition
between (1f) and 2-cyanoguanidine.
1
7
tive reactivity and regioselectivity for a diverse set of arenes.
Aryl–aryl cross-couplings can be regioselectively favored using
electron deficient aromatics as for example aryl-nitriles and aryl-
nitro compounds. The cross-couplings are directly influenced by
the presence of the electron-withdrawing groups leaving the aro-
matic ring more reactive. In our case this methodology has been
applied to selectively couple substituted thiophenes.
Those methodologies can be easily applied at both laboratory
and industrial scale on a broad range of electron poor aryl or het-
eroaryl derivatives but in this work we focus on the synthesis of
MR100 due to its biological applications in prion protein
identification.
A first screening of the experimental conditions was performed.
The CAH arylation (step f) was monitored by TLC and UV, and was
stopped when no more reactivity was observed (around 19 h). In
the presence of Pd(PPh3)4 (tetrakis(triphenylphosphine)palla-
dium(0)) and K CO , no conversion into product (1f) was observed
2
3
when no pivalic acid was used as the co-catalyst whatever the
temperature between 80 and 110 °C (Table 1). The co-catalyst
seems to play a major role in the deprotonation of 2-thiophenecar-
bonitrile favorising the CMD mechanism.
Please cite this article in press as: Rodrigues, A. D.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.11.098

4
A.D. Rodrigues et al. / Tetrahedron Letters xxx (2014) xxx–xxx
S
CN
S
S
N
R = Br,
L = PPh3
R
S
Br
R
S
S
S
R
LnPd0
S
R
Pd
Ln
S
S
N
S
Ln
R
S
Pd
Br
O
K2CO3 KHCO3
O
S
OH
O
K
KBr
R
S
L
Pd
S
S
N
R
S
O
Ln
Pd
OH
O
O
S
L
Pd
S
O
S
N
N
R
H
O
KBr + KHCO3
S
S
O
Br
S
L
Pd
S
O
H
K2CO3
+
S
R
N
Scheme 3. Proposed mechanism using the CMD pathway.
Only partial solubility of all starting reagents has been observed
improvement in terms of isolated product 1f. When the amounts
of Pd(PPh were increased (entries 18–20) to 8, 12, and
16 mol % we observed a decrease in the isolated yield due to an
increased formation of palladium black in the catalytic system.
in pure 1,4-dioxane and toluene. The DMA/Toluene 1:1 (v/v)
solvent mixture provided a better solubility at 110 °C and has been
chosen as standard conditions for the following tries.
3 4
)
The effect of the alkalinity based on the amount of K
ent in the catalytic system was studied for different concentrations
of catalyst Pd(PPh (entries 21–24). The objective was to verify if
higher amounts of K CO could promote a faster formation of piv-
alate anions promoting in this way the CMD mechanism. Indeed
with 8 mol % (PdPPh /3 equiv CO /(0.3 equiv) pivalic acid
2 3
CO pres-
Optimization of the synthetic conditions of 1f
3 4
)
When no Pd(PPh
3
)
4
catalyst was applied (entry 7) no conversion
2
3
into product 1f was observed confirming the necessity of palla-
dium species to promote the catalytic coupling. When 0.3 equiv
of pivalic acid was added (entry 8) the diarylated compound (1f)
was isolated as the major product in 58% yield. Increasing the
amounts of pivalic acid (entries 9–11) did not improve the yields
of the diarylated compound. The catalytic CMD mechanism using
pivalic acid as the proton shuttle seems to have a saturation point
around 0.3 equiv under our conditions.
3
)
4
K
2
3
(entry 22) the diarylated product (1f) was isolated with a yield of
72%. Finally, under the same conditions, we substituted the
K
2
CO
the yield was increased. In fact, whatever the salt used, yields are
always lower than with K CO (SI: Table SI1).
We also studied a one pot synthesis involving Pd(OAc)
(4 equiv)PPh as another palladium(0) catalyst. In this system,
the best yield (entry 25, 38%) was obtained when applying
6 mol % of Pd(OAc) /(4 equiv)PPh catalyst, 1.5 equiv CO
(0.3 equiv) pivalic acid, 22 h. The lower yields could be explained
by the slower in situ formation of Pd(PPh catalyst and the pres-
3
base by potassium or caesium acetate in order to see if
2
3
2
/
When changing the co-catalyst by benzoic acid (12), pyridine
3
(13), phenyl phosphoric acid (14) lower yields were obtained com-
pared to pivalic acid results. With higher and lower co-catalyst pK
a
2
3
K
2
3
,
1
8
values (entries 15 and 16 respectively) no conversions into prod-
ucts were achieved suggesting that there is a narrow interval
where the reactivity of the co-catalyst is optimal. This interval
3 3
)
ence of the acetate anions providing an increased ionic strength in
the system and generating a competition with pivalic acid.19 When
a
seems to be around pK = 4–5 where pivalic acid gave good conver-
sions and benzoic acid, pyridine (entries 12 and 13) gave lower
yields.
There is no doubt about the improvement generated by pivalic
acid in the system although no rationalization can be done in terms
2 2 2
applying another source of potassium salts such as KI and K C O
(potassium oxalate) (entries 26 and 27, respectively) no conversion
into product 1f was observed (Table 3). These results confirmed the
necessity of basic species in the catalytic system to promote the
in situ deprotonation of pivalic acid into the pivalate anion,
favoring the CMD mechanism. The entries 28–30 using other
sources of co-catalysts such as propionic, hexanoic, and octanoic
of pK
the amount of Pd(PPh catalyst to 2 mol % (entry 17) maintaining
3
the amount of CO at 1.5 equiv we did not observe an
a
influence using exclusively this parameter. When decreasing
3
)
4
K
2
Please cite this article in press as: Rodrigues, A. D.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.11.098

A.D. Rodrigues et al. / Tetrahedron Letters xxx (2014) xxx–xxx
5
acids gave low yields and could confirm the narrow interval of pK
of the co-catalyst mentioned above (Table 2) to promote the CAC
bond formation in this synthesis.
a
6. (a) Caughey, B.; Ernest, D.; Race, R. E. J. Virol. 1993, 67, 6270–6272; (b) Caughey,
B.; Raymond, G. J. J. Virol. 1993, 67, 643–650.
7.
Kuwata, K.; Nishida, N.; Matsumoto, T.; Kamatari, Y. O.; Hosokawa-Muto, J.;
Kodama, K.; Nakamura, H. K.; Kimura, K.; Kawasaki, M.; Takakura, Y.; Shirabe,
S.; Takata, J.; Kataoka, Y.; Katamin, S. PNAS 2007, 104, 11921–11926.
8
9
.
.
Robitzer, M.; Perrier, V.; Verdier, J. M., International Patent 2009, WO
CMD Proposed mechanism
2009081372 (A1).
Hunziker, R. W.; Escher, B. I.; Schwarzenbach, R. P. Environ. Toxicol. Chem. 2002,
21, 1191–1197.
The proposed CMD mechanism has been used to predict the
reactivity and the regioselectivity between the electron deficient
1
1
0. Chang, L. W.; Tiemeyer, T. M.; Wenger, G. R.; McMillan, D. E. Environ. Res. 1983,
0, 399–411.
3
0
20
2
-thiophenecarbonitrile and 2,2 -dibromobithiophene. The plau-
1. (a)For an introduction to CAH activation see: Topics in Current Chemistry—CH
Activation; Yu, J.-Q., Shi, Z., Eds.; Springer: Berlin Heidelberg, 2010; vol. 292, (b)
Seregin, I. V.; Gevorgyan, V. Chem. Soc. Rev. 2007, 36, 1173–1193; (c) Bellina, F.;
Rossi, R. Tetrahedron 2009, 65, 10269–10310; (d) Rossi, R.; Bellina, F.; Lessi, M.;
Manzini, C. Adv. Synth. Catal. 2014, 356, 17–117; (e) Djakovitch, L.; Felpin, F.-X.
ChemCatChem 2014, 6, 2175–2187.
sible transition state (TS) involving both substrates and the pro-
posed mechanism is shown in Scheme 3.
In our case the TS is the one where the pivalate anion assists the
deprotonation of the p-rich 2-thiophenecarbonitrile in C5 position
1
2. (a) Ohta, A.; Akita, Y.; Ohkuwa, T.; Chiba, M.; Fukunaga, R.; Miyafuji, A.; Nakata,
T.; Tani, N.; Aoyagi, Y. Heterocycles 1990, 31, 1951–1958; (b) Aoyagi, Y.; Inoue,
A.; Koizumi, I.; Hashimoto, R.; Miyafuji, A.; Kunoh, J.; Honma, R.; Akita, Y.;
Ohta, A. Heterocycles 1992, 33, 257–272.
favorising its oxidative addition on palladium catalyst.
The final step in the synthesis of MR100 was achieved by cyclo-
addition of 1f with dicyandiamide. The reaction was performed in
DMSO at 80 °C with KOH. Compound 1e was recrystallized from
water at 80 °C during 15 min and filtrated over celite to eliminate
the remaining dicyandiamide. The crude was purified by thin layer
chromatography (TLC), after several unsuccessful attempts by flash
chromatography techniques, giving a pure dark-red compound
13. (a) David, E.; Pellet-Rostaing, S.; Lemaire, M. Tetrahedron 2007, 63, 8999–9006;
b) Satoh, T.; Miura, M. Chem. Lett. 2007, 36, 200–205; (c) Amaladass, P.;
(
Clement, J. A.; Mohanakrishnan, A. K. Tetrahedron 2007, 63, 10363–10371; (d)
Baghbanzadeh, M.; Pilger, C.; Kappe, C. O. J. Org. Chem. 2011, 76, 8138–8142;
(e) Popowycz, F.; Métay, E.; Lemaire, M. C. R. Chimie 2011, 14, 621–628.
4. Gozzi, C.; Lavenot, L.; Llg, K.; Penalva, V.; Lemaire, M. Tetrahedron Lett. 1997, 38,
1
1
8867–8870.
(1e) in 91% yield. The extremely polar character of MR100 is a great
5. (a) Dong, J. J.; Roger, J.; Doucet, H. Tetrahedron Lett. 2009, 50, 2778–2781; (b)
Roger, J.; Fozgan, F.; Doucet, H. Green Chem. 2009, 11, 425–432; (c) Chen, L.;
Roger, J.; Bruneau, C.; Dixneuf, P. H.; Doucet, H. Chem. Commun. 2011, 1872–
asset to its biological activity but represents an inopportune char-
acteristic for its purification.21–23
1874; (d) Bheeter, C. B.; Bera, J. K.; Doucet, H. J. Org. Chem. 2011, 76, 6407–
6413; (e) Beydoun, K.; Zaarour, M.; Williams, J. A. G.; Doucet, H.; Guerchais, V.
Conclusion
Chem. Commun. 2012, 1260–1262; (f) Bensaid, S.; Doucet, H. Tetrahedron 2012,
8, 7655–7662.
6. (a) Liégaut, B.; Lapointe, D.; Caron, L.; Vlassova, A.; Fagnou, K. J. Org. Chem.
009, 74, 1826–1834; (b) René, O.; Lapointe, D.; Fagnou, K. Org. Lett. 2009, 11,
4560–4563; (c) Liégault, B.; Petrov, I.; Gorelsky, S. I.; Fagnou, K. J. Org. Chem.
6
1
1
The double direct arylation using the CMD mechanism has been
achieved between the commercially available 2-thiophenecarbo-
nitrile and the dibrominated compound (1a) as the main step
2
2010, 75, 1047–1060; (d) Schipper, D. J.; Fagnou, K. Chem. Mater. 2011, 23,
1594–1600.
0
0
0
00
00 000
toward the synthesis of 6,6 -([2,2 :5 ,2 :5 ,2 -quaterthiophene]-
7. Chen, X.; Engle, K.; Wang, D.; Yu, J. Angew. Chem. 2009, 48, 5094–5115.
18. Smith, M. B. Organic Chemistry: An Acid-Base Approach; Taylor Francis Inc:
United States, 2010.
9. Amatore, C.; Jutand, A.; Khalilb, F. ARKIVOC 2006, 4, 38–48.
0. (a) Davies, D. L.; Donald, S. M. A.; Macgregor, S. A. J. Am. Chem. Soc. 2005, 127,
13754–13755; (b) Gorelsky, S. I.; Lapointe, D.; Fagnou, K. J. Am. Chem. Soc. 2008,
0
00
5
,5 -diyl)bis(1,3,5-triazine-2,4-diamine) (MR100). The improved
protocol involving tetrakis(triphenylphosphine)palladium(0) as
the catalyst, pivalic acid, and an excess of K CO to form the piva-
1
2
2
3
late anion in situ, led to the synthesis of MR100 (1e). An overall
yield of 64% has been obtained and the time needed for the synthe-
sis of MR100 was drastically reduced.
1
1
(
30, 10848–10849; (c) Lapointe, D.; Fagnou, K. Chem. Lett. 2010, 39, 1118–
126; (d) Gorelsky, S.; Lapointe, D.; Fagnou, K. J. Org. Chem. 2012, 77, 658–668;
e) Gorelsky, S. I. Coord. Chem. Rev. 2013, 257, 153–164.
0
0
2
1. Procedure for the synthesis of 5,5 -dibromo-2,2 -bithiophene 1a: A mixture of
0
2
,2 -bithiophene (5.40 g, 32.4 mmol) and NBS (11.57 g, 64.8 mmol, 2 equiv) in
Acknowledgments
a solvent mixture CHCl
0 °C for 4 h. The reaction media was diluted with CH
saturated aqueous solution of Na CO3 (100 mL). The organic phase was
3
/acetic acid 100% (1:1 (v/v), 300 mL) was stirred at
7
2
2
Cl (50 mL) and a
The authors would like to thank the ‘Ministère de l’Éducation
Nationale, de l’Enseignement Supérieur et de la Recherche’
2
2 2
isolated and the aqueous phase extracted with CH Cl (3 x 50 mL). The
organic phases were assembled, dried with MgSO , filtered and evaporated to
4
(
MENESR), The ‘Ecole Nationale Supérieure de Chimie de Montpel-
lier’ (ENSCM), the ‘Centre National de la Recherche Scientifique’
CNRS) and the ‘Institut national de la santé et de la recherche
give a pale yellow solid that was then washed with acetone giving the pure
product 1a (10.42 g, 98%). Recrystallization from THF afforded a highly pure
product. 1H NMR (DMSO-d
, 600 MHz) d (ppm): 7.23–7.22 (d, J = 3.9 Hz, 2H),
(
6
13
7.15–7.14 (d, J = 3.9 Hz, 2H). C NMR (DMSO-d
6
, 100 MHz) d (ppm): 136.86,
médicale’ (Inserm) for supporting this work.
1
31.60, 125.22, 110.84. MS(ESI+): m/z = 324.05. UV–visible (DMSO)
ꢁ
1
ꢁ1
kmax = 325 nm. IR(ATR): 3069 cm (Ar–H)str; 1683 cm (C@C conjugated)str
;
ꢁ
1
ꢁ1
1
416 cm
(R
1
-C@C-R
2
cis)str
;
1293 cm
(C@C)bending
.
Elemental analysis:
Supplementary data
calculated: C 29.65; H 1.24; S 19.79; found: C 30.03; H 1.40; S 18.13.
0
0
00 00 000
000
-
2-
2
2. Procedure for the synthesis of [2,2 :5 ,2 :5 ,2 -quaterthiophene]-5,5
dicarbonitrile 1f: mixture of 1a (745 mg, 2.30 mmol),
thiophenecarbonitrile (1.28 mL, 13.7 mmol, 6 equiv), CO (950 mg,
.87 mmol, 3 equiv), pivalic acid (77.7 L, 0.69 mmol, 0. 3 equiv) and
Pd(PPh (212 mg, 0 18 mmol, 0.08 equiv) in a solvent mixture of anhydrous
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.11.
A
K
2
3
6
l
0
98.
)
3 4
.
toluene/DMA (1:1 (v/v), 10 mL) was stirred under argon atmosphere at 110 °C
for 48 h. The reaction mixture was diluted with toluene (50 mL), filtered over
celite and the solvent was evaporated in vacuo. The crude was purified by
precipitation from toluene (3 times) giving 1f (629 mg, 72%) which was used
References and notes
1
2
.
.
(a) Prusiner, S. B. Nobel Lecture 1998, 95, 13363–13383; (b) http://
www.nobelprize.org/nobel_prizes/medicine/laureates/1997/prusiner-
lecture.pdf.
without any further purification to the next step. 1H NMR at 40 °C (DMSO-d
,
6
6
7
00 MHz) d (ppm): 7.95–7.94 (d, J = 3.8 Hz, 2H), 7.57–7.56 (d, J = 3.8 Hz, 2H),
3
.52–7.51 (d, J = 3.8 Hz, 2H), 7.47–7.46 (d, J = 3.8 Hz, 2H). 1 C NMR at 40 °C
, 150 MHz) d (ppm): 143.09, 140.11, 136.62, 133.42, 128.05, 126.25,
24.76, 113.93, 106.32. MS(ESI+): m/z = 379.8. UV–Visible (DMSO)
(a) Nathanson, N.; Wilesmith, J.; Griot, C. Am. J. Epidemiol. 1997, 145, 959–969;
(
DMSO-d
6
(
5
b) Wadsworth, J. D. F.; Collinge, J. Biochim. Biophys. Acta 2007, 1772,
98–609.
1
ꢁ
1
ꢁ1
kmax = 424 nm. IR(ATR): 3094 cm
(Ar–H)str 2215 cm
,
(Ar–CN)str,
3
4
.
.
(a) Kübler, E.; Oesch, B.; Raeber, A. J. Brit. Med. Bull. 2003, 66, 267–279; (b)
Jackson, G.; Mead, S.; Collinge, J. Neurodegen . Dis. Manage. 2013, 3, 53–60.
(a) Caughey, B. Brit. Med. Bull. 2003, 66, 109–120; (b) Caughey, B.; Raymond, G.
J.; Acallahan, M.; Wong, C.; Baron, G. S.; Xiong, L.-W. Adv. Prot. Chem. 2001, 57,
ꢁ
1
ꢁ1
1446 cm
(C@C)bending
,
852 cm
(R
1
CH@CR R ) . Elemental analysis:
2 3 str
calculated: C 56.82; H 2.12; N 7.36; S 33.70; found: C 56.95; H 1.97; N 6.83;
S 31.71.
0
0
0
00 00 000
000
2
3. Procedure for the synthesis of 6,6 -([2,2 :5 ,2 :5 ,2 -quaterthiophene]-5,5 -
1
39–169.
diyl)bis(1,3,5-triazine-2,4-diamine) 1e: A mixture of 1f (366 mg, 0.96 mmol),
dicyandiamide (483 mg, 5.74 mmol, 6 equiv), and KOH (113 mg, 2.02 mmol,
5
.
Safar, J. G.; Geschwind, M. D.; Deering, C.; Didorenko, S.; Sattavat, M.; Sanchez,
H.; Serban, A.; Vey, M.; Baron, H.; Giles, K.; Miller, B. L.; DeArmond, S. J.;
Prusiner, S. B. PNAS 2005, 102, 3501–3506.
2.1 equiv) in DMSO (10 mL) was stirred at 80 °C for 16 h. Distilled water
Please cite this article in press as: Rodrigues, A. D.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.11.098

6
A.D. Rodrigues et al. / Tetrahedron Letters xxx (2014) xxx–xxx
(
100 mL) was added and the crude was recrystallized at 80 °C during 15 min.
The red precipitate was hot filtrated over celite, washed with acetonitrile
50 mL) and purified by thin layer chromatography (TLC) to give 481 mg (91%)
6
d , 600 MHz) d (ppm): 7.75 (d, J = 3.81 Hz, 2H), 7.42 (d, J = 3.81 Hz, 2H), 7.39–
13
7.38 (m, J = 6.74 Hz, 4H), 6.77 (s, 8H, –NH
2 6
). C NMR (DMSO-d , 150 MHz) d
(
(ppm): 166.9, 166.1, 141.7, 139.3, 135.5, 135.4, 129.7, 126.0, 125.7, 124.9.
of 1e. TLC Purification: The crude was solubilized in the minimum amount of
DMSO and spotted on TLC plaques. The plaques were oven dried at 190 °C
during 3 min and eluted using DCM/MeOH 9:1 (v/v). The separated spots were
extracted from the TLC plaques with DMF, filtrated over celite, and evaporated.
The product was dissolved in methanol (50 mL) at room temperature, filtered,
HRMS(ESI+): m/z = 549,0527. UV–Visible (DMSO)
k
max = 439 nm. IR (ATR):
ꢁ
ꢁ
1
1
1
ꢁ1
ꢁ1
3324 cm
(–NH
(NH-C)bending
CH@CR
2
)
str
,
3153 cm
(N–H)str
,
1622 cm
(C@C conjugated)str
ꢁ1
1 2 str
(R -C@C-R )
,
,
ꢁ1
1524 cm
,
1429 cm
(C@C)str
,
1386 cm
ꢁ
848 cm (R
1
2
R
3
)str. Elemental analysis: calculated: C 48.16; H 2.94;
N 25.53; S 23.37; found: C 47.43; H 2.74; N 22.20; S 22.53.
1
and dried giving 481 mg (91%) of a dark red pure product 1e. H NMR (DMSO-
Please cite this article in press as: Rodrigues, A. D.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.11.098