Improved synthesis of N-alkyl substituted dithieno[3,2-b:2′,3′- d]pyrroles

Article abstract of DOI:10.1016/j.tet.2004.10.106

A new, convergent and improved synthetic method to prepare N-alkyl substituted dithienopyrroles is described. The procedure consists of a Pd-catalyzed amination of 3,3′-dibromo-2,2′-bithiophene. The reaction conditions were optimized, which makes this method applicable to prepare these molecules easily in high yields and on a large scale. Graphical Abstract.

Full text of DOI:10.1016/j.tet.2004.10.106

Tetrahedron 61 (2005) 687–691
Improved synthesis of N-alkyl substituted
dithieno[3,2-b:20,30-d]pyrroles
Guy Koeckelberghs,a,b Lieven De Cremer,a,b Wouter Vanormelingen,a,b Wim Dehaen,c
b
Thierry Verbiest, Andre Persoons and Celest Samyn
b
a,
*
´
aLaboratory of Macromolecular and Physical Organic Chemistry, Katholieke Universiteit Leuven, Celestijnenlaan 200 F,
B-3001 Heverlee, Belgium
bLaboratory of Chemical and Biological Dynamics, Katholieke Universiteit Leuven, Celestijnenlaan 200 D, B-3001 Heverlee, Belgium
cLaboratory of Organic Synthesis, Katholieke Universiteit Leuven, Celestijnenlaan 200 F, B-3001 Heverlee, Belgium
Received 16 September 2004; revised 27 October 2004; accepted 27 October 2004
Available online 21 November 2004
Abstract—A new, convergent and improved synthetic m0ethod to prepare N-alkyl substituted dithienopyrroles is described. The procedure
consists of a Pd-catalyzed amination of 3,30-dibromo-2,2 -bithiophene. The reaction conditions were optimized, which makes this method
applicable to prepare these molecules easily in high yields and on a large scale.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Buchwald–Hartwig reaction to prepare the tertiary amine in
decent yields. Then, ring closure is performed by a one-pot
two-step reaction, which consists of bromination with NBS,
followed by Cu-mediated coupling.3b
N-Alkyl dithieno[3,2-b:20,30-d]pyrroles (DTPs) form an
interesting class of molecules, especially since they are
precursors for conducting polymers.1 N-Alkyl DTPs can be
considered as planar, fused-ring analogues of thiophene,
which, upon polymerization, may show some advantages
compared to poly(alkylthiophene)s, such as lower band gaps
and oxidation potentials. Moreover, the electron donating
nitrogen can increase the stability of the polymer in the
oxidized state and further decrease the band gap of the
polymers.
Although the method described by Ogawa et al. represents
an improved way compared to the previous one, a few
drawbacks still remain. The starting compound, 3-bromo-
thiophene (4), is quite expensive. Secondly, the shelf-life of
the secondary and tertiary amine derivatives (5 and 6) is
very limited. Moreover, scaling up the reaction from 10 to
100 mmol was cumbersome: in our hands, the overall yield
dropped to 8%. Finally, Ogawa’s way is a linear method,
which implies that the whole reaction sequence must be
repeated every time the alkyl substituent on DTP is varied.
2. Results and discussion
Here, we represent a new, convergent and improved method
to generate N-alkyl DTPs in high yields from inexpensive
starting materials. The reaction sequence is presented in
Scheme 2 and consists of a Buchwald–Hartwig reaction of
the primary amine with 3,30-dibromo-2,20-bithiophene 7.4
This strategy has already been used for the synthesis of
N-aryl substituted DTPs, but in different reaction con-
ditions.5 Compound 7 can be prepared in a high overall
yield, starting from inexpensive 2-bromothiophene. All
intermediary compounds and 7 are very stable and demand
no purification.
Two routes have already been described to prepare N-alkyl
DTPs. A first approach (Scheme 1(a)) consists of the
synthesis of the parent DTP2a (2), followed by alkylation2b
of 2 to produce the target molecules (3). Ogawa et al.
developed a new, improved pathway, with higher overall
yields, starting from 3-bromothiophene (Scheme 2(b)).
Thus, 3-bromothiophene (4) was converted into the tertiary
amine (6) using a Buchwald–Hartwig reaction.3a Since
substantial amounts of mono-aminated product (5) are
formed, it is usually necessary to carry out a second
Keywords: N-Alkyl dithieno[3,2-b:20,30-d]pyrroles; Amination.
* Corresponding author. Fax: C32 16 32 79 90;
e-mail: celest.samyn@chem.kuleuven.ac.be
In order to optimize the reaction conditions, the influence of
different parameters, i.e. the catalyst’s nature and its
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.10.106

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G. Koeckelberghs et al. / Tetrahedron 61 (2005) 687–691
Scheme 1. Previous methods to synthesize N-alkyl DTPs.
Scheme 2. Synthesis of N-alkyl DTPs.
concentration, ligands, solvent, reaction time and upscaling
were investigated. The results of the optimization of the
reaction conditions are summarized in Table 1.
We also varied the catalyst and ligand concentration (entry
9). It was found that the catalyst concentration could be
reduced from 5 to 1 mol%, without a reduction in yield,
provided that longer reaction times were applied.
In entry 1–3 the monodentate ligand P(t-Bu)3 was used and
only bithiophene (9) was formed, regardless of the Pd-
source. This is the by-product, resulting from a b-hydride
elimination instead of a reductive elimination in the
catalytic cycle (Fig. 1). Buchwald6a and Hartwig6b,c showed
that this b-hydride elimination could be suppressed by the
use of bidentate ligands. Therefore, DPPF and BINAP were
used as ligands and Pd(DPPF)Cl2 respectively Pd2dba3 as
Pd-source (entries 4 and 5). This resulted in the exclusive
formation of the target N-octyl DTP (3a). No trace of 9 was
detected. In both cases, the reaction product could easily be
purified by simple column chromatography. When BINAP
was used, the yields were higher than in the case of DPPF.
All these reactions were carried out in toluene at 110 8C
until completion of the reaction, as judged by TLC control.
Finally, the reaction was scaled up to 15 mmol (entry 10).
As follows from Table 1, this even leads to higher yields.
Presumably, working on a larger scale reduces losses during
work-up and purification, which might explain the higher
isolated yields.
In order to obtain N-alkyl DTPs, the primary amine must
react twice with 7. At this point two unwanted side-reactions
might occur. Firstly, the catalyst and ligands have shown to
possess a rather strong tendency to mono-aminate.6a In
order to produce tertiary amines from primary amines, it is
usually necessary to perform a second, separate amination
reaction. Secondly, the secondary amine can react inter-
molecularly with another bithiophene molecule, to produce
polymeric structures. After completion of the reaction,
neither of these side reactions were observed with our
method, which indicates that the second, intramolecular
amination step proceeds very smoothly. It is also worth-
while to note the intermediate mono-aminated compound
(10†) can be observed with TLC and isolated. If the reaction
is run to completion, this compound is not detected.
Subsequently, the solvent influence on the reaction was
investigated. In entry 8, DMF was used as a polar solvent. In
this case, no reaction took place and after 7 h, only starting
material was isolated.
Furthermore, the influence of the temperature was exam-
ined. If the reaction was carried out at 90 8C, the outcome
was unchanged, except that longer reaction times were
needed to allow the reaction to reach completion and that
the product was formed in lower yields (entry 6). Increasing
the reaction temperature to 130 8C requires the use of p-
xylene as solvent. The reaction time dropped, but no
increase of the yield was observed.
† 3-Bromo-30-(N-octylamino)-2,20-bithiophene: 1H NMR (CDCl3, ppm):
dZ7.27 (d; JZ5.9 Hz; 1H), 7.25 (d; JZ5.9 Hz; 1H), 7.02 (d; JZ5.9 Hz;
1H), 6.73 (d; JZ5.9 Hz; 1H), 3.76 (s; 1H), 3.16 (t; 2H), 1.55 (qu; 2H),
1.2–1.4 (m; 10H), 0.87 (t; 3H). 13C NMR (CDCl3, ppm): dZ147.0, 131.2,
131.1, 126.4, 126.3, 118.2, 110.7, 103.3, 46.9, 31.9, 30.3, 29.5, 29.4, 27.1,
22.8, 14.2. MS: m/zZ372 (MC). C16H22BrNS2: calcd: C 51.61%, H
5.95%, N 3.76%; found: C 51.24%, H 5.86%, N 3.61%.

G. Koeckelberghs et al. / Tetrahedron 61 (2005) 687–691
Table 1. Pd-catalyzed amination of 7 with n-octylamine
689
Entry
Catalyst
Ligand
addeda
Reaction
time (h)b
Solvent
Temperature 9 (%)
(8C)
3ac (%)
Catalyst
concentration (mol%)
1d
2d
3d
4d
5d
6d
7d
8d
9d
10e
Pd(OAc)2
P(t-Bu)3
P(o-tol)3
P(t-Bu)3
DPPF
3, 5
3, 5
3, 5
3, 5
7
31
4, 75
7
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
p-Xylene
DMF
110
110
110
110
110
90
130
110
110
110
Only
Only
Only
0
0
0
0
0
0
0
0
0
0
38
67
13
66
0
5
5
5
5
5
5
5
5
1
5
Pd(OAc)2
PdCl2
Pd(DPPF)Cl2
Pd2dba3$CH2Cl2 BINAP
Pd2dba3$CH2Cl2 BINAP
Pd2dba3$CH2Cl2 BINAP
Pd2dba3$CH2Cl2 BINAP
Pd2dba3$CH2Cl2 BINAP
Pd2dba3$CH2Cl2 BINAP
13, 5
7
Toluene
Toluene
68
80
a The ratio P/PdZ4 in all cases.
b Until 7 had completely reacted (TLC control).
c Isolated yields.
d On 1.5 mmol scale.
e On 15 mmol scale.
Figure 1. Reductive elimination (a) versus b-hydride elimination (b).
To prove that the reaction is not limited to one specific
amine, i.e. n-octylamine, we also prepared a novel N-alkyl
DTP. Since we are interested in chiral derivatives of DTP in
order to prepare chiral poly(DTP)s, we prepared 3b. The
chiral amine (13) has previously been prepared7 from (S)-
citronellal in three steps in an overall yield of 46%. We
designed an alternative strategy to synthesize 13 from chiral
11,8 which is obtained quantitatively from the commercially
available and relatively inexpensive (S)-citronellol. The
synthesis of 13 is presented in Scheme 3 and consists of the
Scheme 3. Synthesis of (S)-(K)-3,7-dimethyloctylamine (13).

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G. Koeckelberghs et al. / Tetrahedron 61 (2005) 687–691
preparation of phthalimide 12 from 11 by a Mitsunobu
reaction9 and subsequent hydrazinolysis of 12. In this way, 13
was prepared in an overall yield of 77%. Finally, 3b could
easily be prepared in high yields using our new method.
Yield: 12.3 g (86%); bp 117 8C/15 mmHg; 1H NMR
(CDCl3, ppm): dZ2.70 (m; 2H), 1.50 (m; 3H), 1.35–1.05
(m; 9H), 0.87 (d; 3H), 0.86 (d; 6H). [a]2D0ZK2.6 (cZ56 in
CH2Cl2).
4.2. General procedure for the synthesis of N-
functionalized dithieno[3,2-b:20,30-d]pyrroles 3a–b
3. Conclusion
We designed and optimized a new way to prepare N-alkyl
substituted DTPs, which essentially consists of a Pd-
catalyzed amination of 3,30-dibromo-2,20-bithiophene. The
advantages of this new, convergent procedure are the very
high yields, the possibility to work on large scale, the ease of
purification and the inexpensive starting materials.
A solution of 7 (4.92 g, 15.3 mmol), NaOt-Bu (3.54 g,
36.8 mmol), Pd2dba3 (0.350 g, 0.382 mmol) and BINAP
(0.950 g, 1.53 mmol) in dry toluene (30 mL) was purged
with argon for 20 min. The appropriate amine (15.3 mmol)
was added and the mixture was stirred for 7 h at 110 8C
under an argon atmosphere. After cooling down, water
(20 mL) was added and the layers were separated. The water
phase was extracted twice with diethyl ether. The combined
organic layers were dried over MgSO4 and the solvents were
removed via rotary evaporation. Finally, the crude com-
pound was purified by column chromatography (silica gel;
eluent: hexane/dichloromethane 90/10 (v/v)).
4. Experimental
4.1. General
All reagents were purchased from Aldrich Chemical Co.,
Acros Organics, Merck, Fluka and Avocado. Toluene and
p-xylene were distilled over CaH2 onto molecular sieve and
4.2.1. N-Octyldithieno[3,2-b:20,30-d]pyrrole 3a. The pro-
duct was collected as a colorless oil, which crystallized upon
standing. Yield: 3.64 g (80%); mp 34.9–35.4 8C (lit.3b 34.6–
35.2); 1H NMR (CDCl3, ppm): dZ7.12 (d; JZ5.5 Hz; 2H),
7.00 (d; JZ5.5 Hz; 2H), 4.19 (t; 2H), 1.86 (qu; 2H), 1.2–1.4
(m; 10H), 0.86 (t; 3H).
1
diethyl ether was distilled from Na/K. H and 13C nuclear
magnetic resonance (NMR) measurements were carried out
with a Bruker Avance 300 MHz. The optical rotations were
measured with an Analis Optical Activity Polaar 20.
4.1.1. Synthesis of (S)-N-3,7-dimethyloctylphthalimide
12. A solution of triphenylphosphine (26.2 g, 100 mmol),
phthalimide (14.7 g, 100 mmol) and 11 (16.0 g, 100 mmol)
in dry diethyl ether (100 mL) was purged with argon and a
solution of DIAD (20.0 mL, 100 mmol) in dry diethyl ether
(40 mL) was slowly added. After stirring overnight, the
precipitate was filtered off and washed thoroughly with
diethyl ether. The filtrate was concentrated in vacuo,
yielding a yellow oil, which was used without further
purification.
4.2.2. (S)-(C)-N-(3,7-Dimethyloctyl)dithieno[3,2-b:20,30-d]
pyrrole 3b. The product was collected as a yellow oil,
which did not crystallize. Yield: 3.19 g (65%); H NMR
(CDCl3, ppm): dZ7.12 (d; JZ5.5 Hz; 2H), 7.00 (d; JZ
5.5 Hz; 2H), 4.20 (m; 2H), 1.88 (m; 1H), 1.67 (m; 1H), 1.49
(m; 2H), 1.0–1.4 (m; 6H), 0.96 (d; 3H), 0.84 (d; 6H). 13C
NMR (CDCl3, ppm): dZ144.8, 122.8, 114.7, 110.9, 45.5,
39.2, 37.2, 37.0, 30.4, 27.9, 25.3, 22.6, 19.6. MS: m/zZ319
(MC), 192 (MCKC9H19). C18H25NS2: calcd: C 67.66%, H
7.89%, N 4.38%; found: C 67.28%, H 7.74%, N 4.19%.
[a]2D0ZC0.56 (cZ51, CH2Cl2).
1
Yield: 25.9 g (89%); 1H NMR (CDCl3, ppm): dZ7.83 (dd;
JZ5.9 Hz, JZ2.9 Hz; 2H), 7.70 (dd; JZ5.9 Hz, JZ2.9 Hz;
2H), 3.70 (t; 2H), 1.70 (m; 1H), 1.4–1.5 (m; 3H), 1.0–1.4
(m; 6H), 0.98 (d; 3H), 0.86 (d; 6H). 13C NMR (CDCl3,
ppm): dZ168.4, 133.8, 132.3, 123.1, 39.3, 37.0, 36.4, 35.5,
30.8, 27.9, 24.6, 22.7, 19.5. MS: m/zZ287 (MC), 174
(MCKC8H17), 160 (MCKC9H19), 148 (MCKC10H19).
C18H25NO2: calcd: C 75.22%, H 8.77%, N 4.87%; found: C
74.89%, H 8.59%, N 4.67%.
Acknowledgements
We thank the Fund for Scientific Research-Flanders (FWO-
Vlaanderen; G.0297.04), the Katholieke Universiteit Leuven
(GOA/2000/03) and the Belgian Government (IUAP P5/03)
for their financial support. G.K. is a postdoctoral fellow of
the FWO-Vlaanderen.
4.1.2. Synthesis of (S)-(K)-3,7-dimethyloctylamine 13. A
solution of 12 (25.8 g, 90.0 mmol) in absolute ethanol
(50 mL) was purged with argon and hydrazine monohydrate
(4.37 mL, 90.0 mmol) was added drop wise. The mixture
was heated to reflux for 2 h. Then, excess HCl-solution
(5 M) was added and the mixture was refluxed for an
additional 10 min and cooled. The precipitate was filtered
off and washed with water. The filtrate was concentrated
in vacuo and excess NaOH-solution (2 M) was added. The
crude compound was extracted twice with diethyl ether. The
combined organic layers were dried over MgSO4 and
the solvents were removed via rotary evaporation. Amine 13
was isolated as a viscous, colorless oil by vacuum
distillation.
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