Method for the Large-Scale Synthesis of Multifunctional 1,4-Dihydro-pyrrolo[3,2- b]pyrroles

Article abstract of DOI:10.1021/acs.joc.0c01665

A thorough investigation has enabled the optimization of the synthesis of 1,4-dihydro-pyrrolo[3,2-b]pyrroles. Although salts of such metals as vanadium, niobium, cerium, and manganese were found to facilitate the formation of 1,4-dihydro-pyrrolo[3,2-b]pyr

Full text of DOI:10.1021/acs.joc.0c01665

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Article
The Method for the Large Scale Synthesis of
Multifunctional 1,4-Dihydro-pyrrolo[3,2-b]pyrroles
Mariusz Tasior, Olena Vakuliuk, Daiki Koga, Beata Koszarna, Krzysztof Górski,
Marek Grzybowski, #ukasz Kielesi#ski, Maciej Krzeszewski, and Daniel T. Gryko
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01665 • Publication Date (Web): 09 Sep 2020
Downloaded from pubs.acs.org on September 12, 2020
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The Method for the Large Scale Synthesis of Multifunctional 1,4-Dihydro-pyrrolo[3,2-
b]pyrroles
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Mariusz Tasior, Olena Vakuliuk, Daiki Koga, Beata Koszarna, Krzysztof Górski, Marek
Grzybowski, Łukasz Kielesiński, Maciej Krzeszewski and Daniel T. Gryko*
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44-52, 01-224 Warsaw,
Poland
dtgryko@icho.edu.pl
ABSTRACT: A thorough investigation has enabled the optimization of the synthesis of 1,4-
dihydro-pyrrolo[3,2-b]pyrroles. Although salts of such metals as vanadium, niobium, cerium and
manganese were found to facilitate the formation of 1,4-dihydro-pyrrolo[3,2-b]pyrroles from
amines, aldehydes and diacetyl, we confirmed that iron salts are the most efficient catalysts. The
conditions identified (first step: toluene/AcOH = 1:1, 1 h, 50 °C; second step: toluene/AcOH = 1:1,
Fe(ClO
yield. For the first time, very electron-rich (4-Me
hindered substituents (2-ClC , 2-BrC , 2-CNC
4
)
3
·H
2
O, 16 h, 50 °C) resulted in the formation of tetraarylpyrrolo[3,2-b]pyrroles in 6-69%
NC , 3-(OH)C , pyrrol-2-yl) and sterically
, 2-(CO Me)C , 2-(TMS-C≡C)C ) can
2
6
H
4
6
H
4
6
H
4
6
H
4
6
H
4
2
6
H
4
6
H
4
be appended to the pyrrolo[3,2-b]pyrrole core. It is now also possible to prepare 1,4-
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dihydropyrrolo[3,2-b]pyrroles bearing and ordered arrangement of N-substituents and C-
substituents ranging from coumarin, quinoline, phthalimide to truxene. These advances in scope
enable independent regulations of many desired photophysical properties including the Stokes shift
value and emission color ranging from violet-blue through deep blue, green, yellow to red.
Simultaneously, the optimized conditions have finally allowed the synthesis of these extremely
promising heterocycles in amounts of more than 10 grams per run without concomitant decrease
in yield or product contamination. Empowered with better functional group compatibility, novel
derivatization strategies were developed.
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INTRODUCTION
The rising interest in conjugated heterocycles comprised of two or more rings has its origin in
organic electronics. Among various systems,1-2 heteropentalenes attract particular attention, with
a special focus on thieno[3,2-b]thiophene.6-10 This chromophore, especially when embedded into
larger, π-extended scaffolds has been employed in research ranging from active high efficiency
3-5
1
1
12
organic solar cells, to mechanosensitive fluorescent probes. 1,4-Dihydro-pyrrolo[3,2-b]pyrroles
are exceptionally electron-rich heteropentalenes, the chemistry of which has been developing very
13
slowly for many years due to the lack of an efficient synthesis methodology. This situation
changed dramatically in 2013, when we serendipitously found a method that allows quick access
14
to 1,4-dihydro-tetraarylpyrroles[3,2-b]pyrroles (TAPPs). Since then, TAPPs have found multiple
1
5
applications in research related to studying symmetry breaking in the excited state, two-photon
absorption,16 solvatofluorochromism,13c,d direct solvent probing via H-bonding interactions,17
photochromic analysis of halocarbons,18 organic field-effect transistors,19 dye-sensitized solar
2
0
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cells, bulk heterojunction organic solar cells organic light-emitting diodes, resistive memory
23
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devices, aggregation-induced emission and MOFs. It has been also shown that TAPPs are an
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excellent platform for the synthesis of the π-expanded heteroanalogues of polycyclic aromatic
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hydrocarbons. Access to these aza-nanographenes hinges on the ability to prepare 1,4-dihydro-
tetrarylpyrrolo[3,2-b]pyrroles possessing a suitable substitution pattern. In spite of significant
efforts, many important functionalities have been so far incompatible with the multicomponent
reaction leading to TAPPs. Simultaneously, the consequence of a growing interest in TAPPs is the
increased demand for large quantities of these compounds. The possibility of large-scale
preparation is also appreciated if industrial applications are seriously considered. Since our initial
discovery,14a the reaction conditions for the multicomponent reaction of primary aromatic amines,
aromatic aldehydes and diacetyl, leading to TAPPs, has evolved. A few years ago, we found that
the addition of p-toluenesulfonic acid to the reaction mixture significantly increased the yields,
with some limitations regarding the starting materials.14b More recently, we developed an improved
procedure with an iron salt as the catalyst, leading to TAPPs in up to 77% yield with a reasonably
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broad substrate tolerance. Huge advantages of this protocol are its simplicity, the use of cheap
starting materials, and straightforward workup as most TAPPs precipitate directly from the reaction
mixture. Routinely, this methodology was tested on the scale of 1.0 mmol of diacetyl, with amine,
aldehyde and diacetyl used in 2:2:1 molar ratio, with 6 mol% of catalyst and carried out in an open
flask. Increasing the scale by factor of 4-5 usually leads to negligible changes in the reaction
outcome, however, attempting to scale up this process even further (to 40 mmol of diacetyl)
resulted in a significant drop in reaction yield (by factor of at least 3) and the product being
contaminated with unreacted Schiff base. Reproducibility is a common problem associated with
scaling-up of chemical processes developed on a laboratory scale. The increasing interest in
pyrrolo[3,2-b]pyrroles chemistry undoubtedly hinges upon better access to these heterocyclic
compounds, and the problem of scalability might significantly hamper the further development of
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their applications. In order to solve these two challenges we decided to re-examine all factors
affecting the efficiency of TAPPs synthesis, and herein we present the results of our study.
RESULTS AND DISCUSSION
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While reexamining large scale synthesis of TAPPs, the most important factors we took into
consideration were reproducibility (in yield, in impurity profile, in reaction setup, course, and
workup) and ease of operation (no chromatography, etc.), which determined the attractiveness of
the small-scale method. Also important, but of lower significance were cost (as necessary reagents
are simple, inexpensive aromatic aldehydes and amines, and the reaction is catalyzed by a low-cost
transition metal salt), sourcing, waste handling (our method involves acceptable solvents) and
safety (no exotherms, no bad decomposition profiles). Considering these, we analyzed the plausible
mechanism of TAPPs formation (Scheme 1).14a
Scheme 1. Simplified, plausible mechanism of multicomponent reaction leading to TAPPs.
Although some aspects of this reaction, including the role of the catalyst, are still not fully
understood, the first stage, i.e. Schiff base formation, is definitely the most flexible, as it proceeds
in a broad temperature and solvent range. The second stage, involving a Mannich reaction and
cyclocondensations, followed by oxidation with air, offers much less control possibilities and,
consequently, is probably much more sensitive to changes in reaction parameters. What we learned
from previous optimization processes is that the highest yields are obtained when reactions are
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carried out in acidic media, preferably in acetic acid, while addition of toluene as a co-solvent
enables bulky, lipophilic starting materials to participate in the reaction, due to much better
solubility in the reaction media.
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Table 1. Optimization experiments using 4-cyanobenzaldehyde (1, 8 mmol), 4-tert-butylaniline
(2, 8 mmol) and diacetyl (4 mmol).
Entry Catalyst (mol%)
Solvent (mL/mL)
Temp.
Time (h)
Oxidant
Yield
(%)
18
54
14
4
(
°C)
90
90
90
50
50
90
90
50
50
50
50
rt
1
2
3
4
5
6
7
8
9
TsOH (10)
AcOH (8)
3
3
3
16
16
3
Air
Air
Fe(ClO
Fe(ClO
-
4
)
)
3
·xH
·xH
2
2
O (6)
O (6)
AcOH/Toluene (6/6)
AcOH/Toluene (6/6)
AcOH/Toluene (6/6)
AcOH/Toluene (6/6)
AcOH/Toluene (6/6)
AcOH/Toluene (6/6)
AcOH/Toluene (6/6)
AcOH/Toluene (6/6)
AcOH/Toluene (6/6)
AcOH/Toluene (8/8)
AcOH/Toluene (6/6)
AcOH/Toluene (6/6)
AcOH/Toluene (6/6)
AcOH/Toluene (6/6)
AcOH/Toluene (6/6)
AcOH/Toluene (6/6)
AcOH/Toluene (3/3)
AcOH/Toluene (3/3)
AcOH/Toluene (3/3)
AcOH/Toluene (3/3)
AcOH/Toluene (3/3)
AcOH/Toluene (3/3)
AcOH/Toluene (3/3)
AcOH/Toluene (3/3)
AcOH/Toluene (3/3)
AcOH/Toluene (6/6)
AcOH/Toluene (6/6)
AcOH/Toluene (6/6)
AcOH/Toluene (6/6)
AcOH/Toluene (6/6)
AcOH/Toluene (6/6)
a
4
3
-
-
a
-
Air
12
56
45
69
69
24
67
46
37
67
69
50
65
65
13
21
21
64
51
22
63
47
48
15
13
48
38
43
Fe(ClO
Fe(ClO
Fe(ClO
Fe(ClO
Fe(ClO
Fe(ClO
Fe(ClO
Fe(ClO
Fe(ClO
Fe(ClO
Fe(ClO
Fe(ClO
Fe(ClO
4
)
4
)
4
)
4
)
4
)
4
)
4
)
4
)
4
)
4
)
4
)
4
)
4
)
3
3
3
3
3
3
3
3
3
3
3
3
3
·xH
·xH
·xH
·xH
·xH
·xH
·xH
·xH
·xH
·xH
·xH
·xH
·xH
2
2
2
2
2
2
2
2
2
2
2
2
2
O (6)
O (6)
O (6)
O (6)
O (6)
O (6)
O (6)
O (6)
O (6)
O (10)
O (2)
O (6)
O
2
0.5
16
16
16
16
16
16
3
16
16
64
16
16
16
16
16
16
16
16
16
16
16
16
16
3
O
2
Air
b
Air
Airc
Air
Air
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
rt
O
O
2
50
50
50
35
50
50
50
50
50
50
50
50
50
50
50
50
50
90
90
2
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
d
O (6)
d
Fe
Fe
FeCl (6)
3
Fe(OTf)
Fe(OTf)
2
Fe(OAc) (6)
2
O
3
(6)
2
(SO
4
)
3
d
·xH
2
O (6)d
d
d
3
(6)
(6)
2
d
Fe(OTs)
Fe(acac)
3
·6H
(6)
2
d
O (6)d
3
HClO
VO(acac)
CeF (6)
NbCl (6)
Mn(OTf)
Fe(ClO
4
(10)
2
(6)
4
5
2
(6)
4
)
3
·xH
2
O (3)
3
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Cu(OAc) (3)
a
b
Reaction conducted under an argon atmosphere. Reaction conducted under constant air flow
c
d
(rate: 4ml/min). Reaction conducted under constant air flow (rate: 60ml/min). Twice smaller
reaction scale – 2 mmol of diacetyl.
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We decided to conduct the optimization of TAPPs’ synthesis at a relatively large scale (4 mmol of
diacetyl), 4-times larger than for previous optimizations,14b,27 in order to find optimal conditions
more adequate for larger scales. Another factor which we decided to keep constant was the reaction
setup and all optimization steps were performed in 25 mL round-bottom flasks equipped in
magnetic stirring bars of the same size (length: 20 mm). We also decided to carry out the reactions
in open flasks, because the addition of a condenser would slow down the diffusion of air into the
reaction flask. For the optimization studies we selected the synthesis of TAPP 3 from diacetyl, 4-
cyanobenzaldehyde (1) and 4-tert-butyl-aniline (2). Compound 3 is known in the literature and had
25
14b,26
been prepared with a low 12% yield using TsOH as the catalyst.
We repeated this reaction
and obtained the product in 18% yield (Table 1, entry 1). In the second experiment we applied our
27
recently optimized conditions, namely we changed the catalyst to iron(III) perchlorate hydrate (6
mol%) and the solvent to a toluene/AcOH mixture (1:1 v/v). As expected, after stirring the reactants
at 90 °C for 3 h, we witnessed a large 3-fold increase in the reaction yield to 54% (Table 1, Entry
2). As suggested by the proposed reaction mechanism (Scheme 1), oxidation takes place in the final
stage of the formation of TAPPs. Thus, we examined an effect of the presence of oxygen on the
reaction outcome (Table 1, Entries 3-7). Indeed, the reaction performed in a sealed Schlenk flask
under an argon atmosphere with catalytic amount of iron(III) perchlorate gave product 3 in 14%
yield (Table 1, entry 3). Although, the yield is significantly lower, it is not indiscernible, which is
reasoned by the oxidative nature of perchlorate. Indeed, in the case of the reaction conducted under
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ambient atmosphere with solvents bubbled with argon prior to use, without addition of any catalyst,
yield dropped ever lower to 4% with noticeably slower reaction rate (Table 1, entry 4). Most likely,
traces amount of the product is formed, due to the presence of unreacted Schiff base, which also
can react as an oxidant. Concurrently, air atmosphere facilitated formation of 3 in 12 % yield (Table
1
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, entry 5). These results show significant role of oxygen as well as a complexity of the
multicomponent reaction mechanism. On the other hand, under pure oxygen gas the reaction yield
was comparable to that of the experiment under air as an oxygen source (Table 1, entry 6). In
addition, the reaction rate under oxygen seemed to be much faster, judged from the speed of color
changes of the reaction mixture. However, after fast formation of a bright yellow suspension of the
product we observed a quick darkening of the reaction mixture which after 3 hours of stirring
appeared almost black, whereas under air at this point the reaction mixture was still a brownish-
orange suspension. This suggested that pure oxygen is too aggressive and may have caused further
oxidation of the formed TAPP to some dark decomposition products. Hence, we shortened the
reaction time to 0.5 h but the yield was not improved (Table 1, entry 7). Therefore, it can be
concluded that for the synthesis of TAPP, air is a more optimal oxygen source than pure oxygen
gas, owing to reduced risk of overoxidation of sensitive products and ease of operation, not to
mention safety matters. Having this established, wanting to keep other parameters unchanged, we
then decided to focus mostly on reaction temperature and time. Our analysis of this problem led us
to propose that one of the key factors in the synthesis of TAPPs is the accessibility of oxygen. It
can be easily estimated that to form 4.0 mmol of the product, roughly 96 ml of pure oxygen gas or
over 450 mL of air (under normal conditions) is required. While at small-scale reactions this factor
is negligible, scaling up the process may lead to decreased and inefficient access to oxygen and a
potential drop in the reaction yields, as a consequence of the square-cube law. Hence, to ensure
good contact between the reactants and oxygen, in the next optimization steps we decided to
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perform the reactions at lower temperatures and for longer times. We reasoned that lowering the
temperature should lead to increased solubility of oxygen gas in the reaction system. Moreover,
lower temperature should also prevent a potential loss of diacetyl via evaporation (boiling point of
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8 ºC). In our previous studies it turned out that this reaction occurs even at room temperature,
although it is heterogeneous and the obtained yields are slightly lower. We expected that it could
cause some problems with less soluble substrates, therefore, we decided to set up the reaction at 50
ºC for 16 h. To our delight, under these conditions the reaction of 4-tert-butylaniline with 4-
cyanobenzaldehyde and diacetyl in a 2:2:1 molar ratio in the presence of 6 mol% iron perchlorate
hydrate as the catalyst in a mixture of toluene and acetic acid (1:1 v/v) as solvent provided the
desired TAPP 3 in 69% yield (Table 1, entry 8). It is worth mentioning, that we tested the difference
between dynamic and static air atmosphere (Table 1, entries 9-10). Product 3 was obtained in
excactly the same yield (69%) under constant air stream with flow rate 4 ml/min. Increasing flow
rate to 60 ml/min led to noticeable drop of yield to 24 %, due to evaporation of solvents. Dilution
of the reaction mixture did not improve the yield (Table 1, entry 11), and further decrease of the
temperature to ambient conditions led to a significant drop in the reaction yields (entries 12 and
1
3). A good yield of TAPP 3 (65%) could still be obtained even at 35 °C, but the reaction time had
to be elongated to 64 h (entry 17). Interestingly, at 50 °C the reaction could be shortened to 3 h
when pure oxygen was used as an oxidant without appreciable loss in efficiency (Table 1, entry
1
4). Catalyst loading of 6 mol% seems to be optimal, since the increase of this amount to 10 mol%
furnished the product in the same yield (69%, Table 1, entry 15), and the decrease to 2 mol% caused
a drop in the reaction yield to 50% (Table 1, entry 16). We also investigated whether iron(III)
perchlorate can be replaced with different iron sources (entries 19-26). The use of iron(III) oxide,
iron(III) sulfate hydrate, iron(III) chloride and iron(II) acetate provided poor yields of the product
(13-22%), which in most cases was due to low solubility of these iron compounds in the reaction
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medium. Better results were obtained using iron(II) trifluoromethanesulfonate and iron(III)
acetoacetonate, however the yields of ≈50% were still considerably lower than with iron(III)
perchlorate under the same conditions. Iron(III) trifluoromethanesulfonate and iron(III) p-
toluenesulfonate hexahydrate proved almost as efficient as the perchlorate, leading to isolated
yields of 64% and 63%, respectively. While due to much higher prices of these two reagents
iron(III) perchlorate still remains an optimal catalyst, they may be convenient replacements e.g. for
industrial scale reactions where using large amounts of perchlorates may pose considerable safety
hazards. Generally, Iron(III) salts proved more effective catalysts than Iron(II) salts. Furthermore,
an experiment with catalytic amount of perchloric acid gave 3 in 48% yield (Table 1, entry 27),
higher than reaction without any catalyst, and lower than reaction with Iron(III) perchlorate,
indicating importance of both cation and anion on the catalyst performance. Replacing the catalyst
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with VO(acac) , cerium(IV) fluoride, niobium(V) chloride, manganese(II) triflate or addition of
2
copper(II) salts did not improve the yields (Table 1, entries 28-32). The choice of catalysts was
based on the assumption that an oxidant that was also a Lewis acid may facilitate the final oxidation
step. It is worthwhile to add that in our hands NbCl
5
is not an efficient catalyst for TAPPs formation
CN.28
under originally published reaction conditions i.e. in CH
3
To probe synthetic utility of the optimized reaction setup (first step: toluene/AcOH = 1:1, 1 h,
0 °C; second step: toluene/AcOH = 1:1, Fe(ClO ·H O, 16 h, 50 °C), (Table 1, entry 8), we
5
4
)
3
2
subjected a range of sterically hindered and electronically diverse aldehydes and primary aromatic
amines to these conditions, attempting to both increase the reaction scope and investigate if larger
scale will deliver pure TAPPs in non-diminished yields (Figure 1).
Figure 1. The synthesis of TAPPs – substrate scope including challenging amines and
aldehydes.
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The above-discussed modified method gives equal or higher yields of TAPPs than those previously
reported for almost all substituted benzaldehydes and anilines trialed. Typically, pyrrolo[3,2-
b]pyrroles are obtained in good yields from electron poor aldehydes (TAPPs 3-5, 7-9, 14, 36, 42
and 46, Figure 1). Importantly, lowering the reaction temperature allowed for the first time the use
of electron rich aldehydes, however, the obtained yields were reduced (TAPPs 11-13, 16, 19, 23
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and 38, Figure 1). The most outstanding expansion of scope is TAPPs synthesized from sterically
hindered primary aromatic amines. The attempts to prepare TAPPs from 2-chloroaniline or 2-
bromoaniline under previously developed conditions14a,b gave yields below the detection limit.
Under the new conditions, anilines with halo-, carboxy-, cyano- or even (trimethylsilyl)ethynyl
substituents in the ortho position now lead to the corresponding TAPPs 6, 7, 8, 9, 31, 32, 33, 40
and 41 (Figure 1) in up to 32% yield, opening the door for their further functionalization.
Exceptionally sterically hindered amines, for example 2,4,6-trimethylaniline, do not participate in
this reaction, however, TAPP 34 bearing bulky 9-anthracenyl groups was obtained with acceptable
yield from the corresponding anthracene-9-carboxaldehyde. In addition, pyrrolo[3,2-b]pyrroles
decorated with other polycyclic aromatic hydrocarbons, fluoranthene and truxene (TAPPs 37 and
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4, respectively), could be obtained in surprisingly good yields, giving the possibility for
significant expansion of the pyrrolo[3,2-b]pyrrole π-electron system. This result may prove
particularly important since the combination of electron-rich pyrrolo[3,2-b]pyrrole core with
extended π-electron substituent’s makes the discussed systems potential hole-transporting
materials.
Another valuable result is the possibility of transforming various heterocycle-derived aldehydes,
both 5-membered heterocyclic aldehydes and 6-membered pyridine derivatives into the
corresponding products 19, 20, 24-27, 39 and 43 (Figure 1). These conditions also turned out to be
effective for the synthesis of TAPPs from substituted 2-formylpyrrole and 2-formylthiophene.
Nevertheless, not all aromatic amines can form TAPPs. For example, the reaction of 4-
cyanobenzaldehyde with 3-aminophenol or 3-aminoanisole did not lead to the desired product.
Interestingly, 4-amino-2-hydroxytoluene which contains a para-substituent gave TAPP 28 under
the same conditions.
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In addition, we enriched the library of substrates with a set of hydroxybenzaldehydes, which under
developed conditions afforded the corresponding products with moderate yields (TAPPs 11, 16,
21, 23 and 38, Figure 1). For these substrates, the best outcomes (up to 32%, TAPPs 16 and 23)
were obtained for TAPPs bearing an electron-donating substituent on the N-aryl ring, while 4-
cyanoaniline afforded corresponding dye 11 in only a 13% yield. Alternatively, hydroxyphenyl-
substituted pyrrolopyrroles are achievable via O-benzyl or O-(4-methoxybenzyl) protected
derivatives (TAPPs 17 and 22, respectively), which are available in good yields and can in principle
be deprotected using known methods. Moreover, TAPP 45 possessing a phthalimide moiety can
be also synthesized. One of the biggest breakthroughs was achieved with coumarins, bearing
formyl or amino groups in various positions. The success of this attempt was not obvious, as
various side reactions could be expected, including Lewis acid catalyzed Michael addition of
pyrrolopyrrole and coumarin scaffolds. Indeed early attempts of TAPPs preparation from formyl-
coumarins and amino-coumarins with TsOH as the catalyst failed. The first member of the
coumarin-TAPPs family, compound 35, was obtained in fairly good 39% yield, which prompted
us to test other coumarin derivatives as starting materials and we found that coumarins can be used
as both amine (as 6-aminocoumarin) and aldehyde components in the TAPP preparation. The
resulting compound 44 was obtained in 34% yield. It is noteworthy that TAPP 35 (Figure 1) is the
first pyrrolo[3,2-b]pyrrole to date prepared from an aldehyde bearing CHO attached to carbon-
carbon double bond rather than to aromatic ring.
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With these results in hand, we attempted the large scale synthesis of TAPPs. Aiming to keep the
reaction setup and work-up as simple as possible, we tested this methodology with selected amines,
aldehydes and diacetyl used in amounts of 80:80:40 mmol, with the reaction carried out in an open
3-neck flask (to facilitate an access to air, see SI for further information). To our delight, the
reaction was fully reproducible at large scale, giving products 3, 9, 15 and 24, with high purity and
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with virtually the same yield as in smaller scale experiments, with all the advantages of the latter,
namely simplicity of the reaction set-up and workup (Figure 2).
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Figure 2. Large scale (200 mmol, sum of all starting materials) preparation of TAPPs. The
yield obtained in small scale 20 mmol experiment are given in parenthesis.
To demonstrate the synthetic potential of the newly developed method, we decided to use 1,4-
dihydro-pyrrolo[3,2-b]pyrrole obtained from 2-haloanilines in the preparation of hetero-analogues
of polycyclic aromatic hydrocarbons (PAHs). Therefore, we obtained the dibromo-TAPP 49 which
was subsequently transformed into the fused derivative 50 by palladium-catalyzed direct arylation
(Scheme 2). Its structure was unambiguously confirmed by X-ray analysis (see ESI for further
details, Figure S2). We recently described the synthesis of heterocycles possessing this skeleton
either by direct arylation with TAPP obtained from ortho-bromo-substituted benzaldehydes13d or
2
9
by 1,2-aryl shift in tetraarylpyrrolo[3,2-b]pyrroles. The present approach is an alternative route
giving easy access to quite elaborated hetero-PAHs in just a two-step synthesis. Interestingly the
double intramolecular direct arylation proceeds regioselectivity at phenyl rings adjacent to
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positions 2 and 5. This underlines the strong influence of the pyrrolo[3,2-b]pyrrole core, which
markedly increases electron density on these substituents affecting their reactivity.
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Scheme 2. The preparation of π-expanded TAPP 50.
Aiming to further execute the advantages of this method, we took into consideration the annulation
leading to π-expanded TAPPs. Such a strategy requires TAPPs decorated with a carbon-carbon
triple bond located on the N-aryl ring and should afford a dye with improved conjugation between
the core and substituents originating from parent aniline. Thus, we transformed parent pyrrolo[3,2-
3
0
b]pyrrole 7a (Scheme 3) in the presence of indium(III) chloride into the fused analogue. The
reaction leads predominantly to 7-endo-dig cyclization product 51, which was only isolated in 35%
yield due to limited stability. The preference for 7-endo-dig pathway versus 6-exo-dig pathway
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seems to be related to both the nature of the catalyst and the structure of the substrate which makes
the formation of seven-membered ring possible. It is likely however that product containing new
six-membered ring forms albeit due to its reactivity it reacts further under the reaction conditions.
The plausible rationale behind the fact that second annulation did not occur is the strong altering
of electron distribution in the molecule 51 compared to TAPP 50. Thorough analysis of 1D NMR
1
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and 2D NMR spectra provides sufficient structural information about the compound 51. H NMR
spectra shows two singlets, originating from the core proton (6.22 ppm) and ethynyl proton (3.15
ppm), as well as two AA’XX’ systems (from substituents at the position 2 and 5). Such
observations indicate the desymmetrization of the structure caused by monoannulation. Moreover,
1
13
the number of correlations at H C HSQC spectra, which is equal to the number of magnetically
nonequivalent protons, can be rationalized only by the formation of the 7-endo-dig product (Figure
1
13
S1) and excludes the 6-egzo-dig regioisomer. Thorough analysis of NOESY, H C HSQC and
1
3 13
C C HMBC spectra finally uncovers the structure of 51, supporting previous considerations. The
formation of 7-membered rings was heretofore unreported for alkyne benzannulation.30
Scheme 3. The synthesis of dye 51 possessing a seven-membered ring.
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As we mentioned in our previous papers, the extremely electron-rich character of the pyrrolo[3,2-
b]pyrrole scaffold is sometimes manifested by its unexpected reactiveness.29,31 In Scheme 4, we
show another example of such a phenomenon. Looking for TAPPs with strongly polarized
structures, we attempted the reaction of TAPP 18 with tetracyanoethylene (TCNE) in boiling
toluene in the presence of pyridine,32a which in line with our expectation resulted in the formation
of compound 52, however, only in a relatively small yield. To our surprise, the main product
formed during this reaction was compound 53, apparently being a result of a tandem Diels-
Alder/reoxidation reaction. Its structure was unambiguously confirmed by NMR, MS and X-ray
analysis (see ESI for further details, Figure S3). Although the chemistry of TCNE is very rich,32b,c
to our best knowledge, this is the only example of biphenyl (or heteroaryl-phenyl derivative)
participating in such a transformation, and in general, a rare example of the Diels-Alder reaction
taking place on a non-activated benzene ring. It is worth pointing out that the presence of pyridine
is crucial for this reaction and despite the presence of an excess of TCNE, only mono substitution
was achieved. Moreover, TAPP 3 bearing electron-withdrawing substituents do not undergo this
process, which underlines again the relatively strong coupling of aryl rings at positions 2 and 5
with pyrrolo[3,2-b]pyrrole core.
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Scheme 4. Reaction of TAPP 18 with tetracyanoethylene.
Finally, an easy access to 2-pyridine substituted TAPPs prompted us to use them for the synthesis
of N,C-chelated boron compounds (Scheme 5). In the last decade, 2-phenylpyridine-derived four-
coordinate organoboron chelates have been extensively studied, mostly by the group of Wang, and
3
3
34
found to show interesting properties, including photochromic reactivity, two-photon absorption,
35
strong emission and high photostability, etc. Following the well-established protocol, we treated
compound 25 with BuLi, and the resulting lithiated intermediate was reacted with dimesitylboron
fluoride, which yielded compound 54 (Scheme 5). Bis-substitution was not achieved despite
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numerous trials, probably due to the problem with bis-lithiation, which might be hampered due to
the unfavorable electrostatic interaction within the pyrrolopyrrole core.
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Scheme 5. The synthesis of N,C-chelated boron TAPP 54.
Having synthesized a library of new dyes, we investigated their fundamental photophysical
properties. All measurements were performed in toluene as a solvent. Generally, unless, decorated
with strongly electron-withdrawing or electron-donating substituents at positions 2 and 5 of the
central core, pyrrolopyrroles exhibit a broad, featureless absorption band at 350-375 nm with molar
−1
−1
extinction coefficients () of 10000-40000 M cm and emission maxima located at 400-420 nm
with fluorescence quantum yields (fl) typically ranging from 0.30-0.70 (Table 2, Figures 3 and
4
). Absorption and emission maxima are red-shifted to 400-410 nm and 450-460 nm, respectively,
for compounds 3-9 bearing electron-withdrawing 4-cyanophenyl residues at positions 2 and 5. At
−
1
−1
the same time, these compounds exhibit higher  values of 40000-60000 M cm with larger fl
=
0.50-0.90. Placing sterically hindered substituents at positions 1 and 4 does not influence
absorption and emission maxima underlying the relatively weak electronic coupling on N-
substituents with heterocyclic core. The most bathochromically shifted absorption (504 nm) and
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emission (647 nm) maxima amongst the synthesized dyes was exhibited by TAPP 43 bearing
nitrophenyl- substituents attached to the pyrrolopyrrole core through thiophene linker (Figure 3).
The remarkable red-shift of both absorption and emission spectra is attributed to two factors i.e.:
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2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(1) extremely strong electron-withdrawing character of nitrophenyl substituents; (2) smaller
dihedral angle between aryl substituents and the pyrrolo[3,2-b]pyrrole core (effect of five-
membered ring)27 leading to more effective -conjugation. Conversely, substitution of the
pyrrolo[3,2-b]pyrrole core with strong electron-donating groups at positions 2 and 5 (dyes 11-13
and 19) leads to only a slight red-shift of absorption (349-395 nm), whereas a prominent red-shift
−
1
of emission (446-534 nm) resulting in large Stokes’ shifts of 6200-8300 cm , suggests a notable
difference in geometry of the S excited state and S ground state. Concomitant drop in fluorescence
intensities (fl = 0.04-0.08), is likely due to the occurrence of charge transfer processes.
1
0
1
3
As thoroughly discussed earlier, substituents located at positions 2 and 5 of pyrrolo[3,2-b]pyrrole
scaffold have a significantly stronger impact on the optical features compared with those located
at positions 1 and 4 (attached to nitrogen atoms). This is clearly manifested in the series of dyes 6-
9
and 14 possessing sterically congested 2-halophenyl- or 2-carboxyphenyl- and truxene subunits
attached to nitrogen atoms. Undoubtedly, steric factors impose larger dihedral angles between N-
aryl substituents and the central core, causing breakage of electronic communication between them.
Nevertheless, the effect on both absorption and emission spectra is negligible in regard to sterically
unencumbered 3 indicating a minor contribution of amine-originating substituents on overall
optical characteristics. As far as 14 is concerned, a deeper comparative analysis of absorption
spectra indicates a clear increase of the molar absorption coefficient in the high-energy part of the
spectrum, which is most likely caused by the presence of the truxene subunit. Of particular note is
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
the strong blue fluorescence (fl reaching 0.93). One of the factors responsible for the observed
excellent emissive properties could be symmetry-breaking within the truxene core.36
The new methodology allowed for the first time synthesis of coumarin-containing pyrrolopyrrole
dyes 35 and 44. Their spectral features differ markedly, depending on the substitution pattern,
giving the opportunity for fine-tuning the desired properties. In the case of TAPP 44, the
fluorescence quantum yield is low which is in agreement with general trend observed for coumarins
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
37
possessing electron-donating substituents at position 6. The bulky coumarin-4-yl substituent
present at positions 2 and 5 of TAPP 35 results in the large difference in dihedral angles between
ground- and excited-state geometries which in turn manifests in large Stokes shift. According to
expectations, -extension of fused analogue 50 leads to a significant bathochromic shift of the
absorption (442 nm) and emission (575 nm) maxima. In the absorption spectrum two main bands
with fine-vibronic features located at 370 and 420-440 nm are present, which is attributed to the
rigidity of the structure. Surprisingly, a significant decrease of the fluorescent quantum yield is
observed, most likely, due to predominant radiationless de-excitation. We observed a similar
tendency for the annulated dye 51, which shows a decreased fluorescence response when compared
to parent TAPP 7. Moreover, as for TAPP 50, the formation of a seven-membered ring strongly
shifts both absorption and emission maxima, however, for compound 51 it is in the opposite
direction (hypsochromically λabs and bathochromically λem), which results in a large Stokes’ shift
−
1
of 5500 cm .
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1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 3. Absorption (solid line) and normalized emission (dotted line) spectra of 18 (black)
(excitation at 350 nm) and 43 (red) (excitation at 460 nm) measured in toluene at concentrations of
3
.53 µM for 18 and 4.26 µM for 43. Emission intensity is given in arbitrary units.
Figure 4. Absorption (solid line) and normalized emission (dotted line) spectra of 53 (green) and
4 (blue) (excitation at 450 nm) measured in toluene at concentrations of 3.44 µM for 53 and 3.40
5
µM for 54. Emission intensity is given in arbitrary units.
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 2. Spectroscopic properties of new TAPPs measured in toluene.
−3
max
em
Comp.

absmax(nm)
•10

Stokes shift
−1

fl
−
1
−1
(
M cm )
(nm)
450
460
454
447
443
443
470
533
496
548
451
408
409
414
412
446
410
414
413
416
419
452
415
443
421
462
-
(cm )
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
0.76a
0.76b
0.15b
0.90b
0.46b
0.86b
0.14b
0.05b
0.08b
0.04b
0.93b
0.66a
0.57a
0.50a
0.52a
0.08b
0.77b
0.59a
0.88a
0.82b
0.66a
0.35b
0.27b
0.09a
0.32b
3
5
6
7
8
9
403
413
407
413
403
402
321
53
2600
2500
2600
1800
2200
2300
5400
8300
7000
7000
2700
3900
3700
4600
4500
6200
3700
4400
4000
2400
2700
2400
2600
4700
2600
5400
-
57
47
60
55
50
1
0
56
3
3
3
4
3
3
3
3
3
3
3
3
3
3
4
3
3
3
3
4
3
3
3
3
22; 370
61; 11
58; 12
50; 11
48
11
21; 368
26; 395
02
1
2
13
1
4
52
23
15
55
34
1
6
48
27
17
48
nd
1
8
00; 350
56
50
19
24
2
1
50
37
22
55
29
2
3
79
43
24
77
46
2
5
07
52
28
75
38
3
1
67
35
32
80
45
3
3
70
32
0.54b
35
02
12
-
3
8
70
30
448
416
416
417
4700
2500
2600
2300
0.80a
0.18b
0.48b
0.57b
39
77
40
4
0
76
41
41
80
37
4
2
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0.41c
4
4
3
4
504
370
44
645
419
4400
3200
38
0.08b
0.0004b
0.83b
0.19b
0.05b
4
4
4
5
5
6
9
0
376
375
379
370
51
40
42
34
27
25
37
421
431
417
575
2800
3500
2400
6300
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
4
19
42
5
5
5
5
1
2
3
4
408
526
433
-
5500
7500
-
0.34b
0.001a
-
327; 476; 605 35; 7; 3
395
27
374; 451
33; 23
534
3400
0.54d
a
Fluorescence quantum yield determined with quinine sulfate as a reference.
bFluorescence quantum yield determined with 9,10-diphenylanthracene as a reference.
cFluorescence quantum yield determined with fluorescein as a reference.
dFluorescence quantum yield determined with coumarin 153 as a reference.
CONCLUSIONS
Lowering of the reaction temperature to 50 °C enabled more control of the course of the
multicomponent reaction leading to tetraarylpyrrolo[3,2-b]pyrroles. This makes it possible to
maintain high yields when increasing the scale to 4.0 and even 40 mmols. Simultaneously the
electron-rich and sterically hindered substituents become compatible with this reaction and
numerous corresponding TAPPs were obtained. Our findings expand the spectrum of possible
tetraarylpyrrolo[3,2-b]pyrroles that can be prepared. These the new reaction conditions proved to
be extremely efficient in the synthesis of potentially useful halogen derivatives of pyrrole[3,2-
b]pyrroles, which was demonstrated by the synthesis of hetero-analogues of polycyclic aromatic
hydrocarbons. The exceptionally high-lying HOMO of TAPPs has a profound influence on their
reactivity. Indeed it influences the electron density of the neighboring aryl substituents which
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
results in: (a) preferential direct arylation occurring at positions 2 and 5 activated by pyrrolo[3,2-
b]pyrrole core as an electron-donating substituent; (b) spontaneous reaction of TAPP with TCNE
including a unique Diels-Alder reaction; (c) Unprecedented alkyne benzannulation with the
formation of a 7-membered ring. The possibility to introduce such a broad range of electronically
and sterically diverse substitutes at positions 1, 2, 4 and 5 combined with relatively strong coupling
through biaryl linkages translates to an ability to modulate emission wavelengths across the entire
visible range. The presence of electron-withdrawing moieties at positions 2 and 5 combined with
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
1
2
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
−1
electron-donating N-aryls enables to increase Stokes shift to 7000-8000 cm . We envisage that the
new reactivity reported herein will not only influence directions of the chemistry of aza-
nanographenes but it will also underpin the development of novel optoelectronic materials.
EXPERIMENTAL SECTION
General information
All chemicals were used as received unless otherwise noted. Reagent grade solvents (MeCN,
CH
2
Cl
2
, hexane, toluene) were distilled prior to use. All reported NMR spectra were recorded on a
1
13
5
00 MHz spectrometer unless otherwise noted. Chemical shifts ( ppm) for H and C NMR were
determined with TMS as the internal reference; J values are given in Hz. UV-Vis absorption and
emission spectra were recorded in toluene. For all fluorescence measurements, spectrofluorometer
slits were set at 2.5nm. Fluorescence spectra were obtained by excitation at 350 nm for compounds
3
4
, 15-18, 22, 23, 25, 32, 39 and 52; 373 nm for compounds 5-14, 19, 21, 24, 28, 31, 33, 35, 40-42,
4-46 and 49-51; 450 nm for 54 and 460 nm for 43. Chromatography was performed on silica
(Kieselgel 60, 200-400 mesh). Mass spectra were obtained with an EI ion source and the EBE
double focusing geometry mass analyzer or spectrometer equipped with electrospray ion source
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with q-TOF type mass analyzer. The analytical data for compounds 3, 4, 15, 20, 26, 27, 29 and 34,
have been described previously.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
5
6
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8
9
0
1
2
3
4
5
6
7
8
9
0
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4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Synthesis
General procedure for the synthesis of pyrrolo[3,2-b]pyrroles on a 20 mmol (sum of all
starting materials) scale. Glacial acetic acid (6 mL), toluene (6 mL), aldehyde (8 mmol) and
aniline (8 mmol) were placed in a 25 ml round-bottom flask equipped with a magnetic stir bar. The
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
mixture was stirred at 50°C for 1 h. After that time, Fe(ClO
4
)
3
·xH O (85 mg) was added, followed
2
by diacetyl (0.35 mL, 4 mmol). The resulting mixture was stirred at 50 °C (oil bath) in an open
flask under air overnight. The precipitate was filtered off, washed with cold methanol (in some
cases CH CN was used) and dried under vacuum. In the event that the product does not precipitate,
3
organic solvents are removed under reduced pressure, and then the product is obtained by
crystallization from acetonitrile. In case the product contains pyridyl or amino substituent, the
reaction mixture was quenched with saturated aqueous NaHCO
3
(60 mL). The precipitate was
filtered off, washed with H O, CH CN and dried under vacuum to afford pure product.
2
3
1,4-Bis(4-(tert-butyl)phenyl)-2,5-bis(4-cyanophenyl)-1,4-dihydropyrrolo[3,2-b]pyrrole (3).
Yellow solid. Yield: 1.58 g (69%). Spectral and optical properties concur with literature data.25
1,2,4,5-Tetrakis(4-cyanophenyl)-1,4-dihydropyrrolo[3,2-b]pyrrole (4). Yellow solid. Yield:
.63 g (31%). Spectral and optical properties concur with literature data.16
0
2
,5-Bis(4-cyanophenyl)-1,4-bis(4-(diethylamine)phenyl)-1,4-dihydropyrrolo[3,2-b]pyrrole
1
(5). Yellow solid. Yield: 0.64 g (26%). M.p. 309-310 °C. H NMR (500 MHz, CDCl
3
) δ = 7.45 (d,
J = 8.4 Hz, 4H), 7.30 (d, J = 8.4 Hz, 4H), 7.08 (d, J = 8.8 Hz, 4H), 6.66 (d, J = 8.9 Hz, 4H), 6.40
1
3
1
(s, 2H), 3.39 (q, J = 7.0 Hz, 8H,), 1.20 (t, J = 7.0 Hz, 12H) ppm; C { H} NMR (126 MHz, CDCl )
3
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δ = 146.6, 138.1, 135.0, 133.8, 131.8, 127.6, 127.5, 126.7, 119.4, 112.0, 108.4, 94.6, 44.4, 12.6
·
+
ppm. HRMS (EI): m/z calculated for C40
H
38
N : 602.3158 [M ]; found: 602.3174.
6
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
,5-Bis(4-cyanophenyl)-1,4-bis(2-(methoxycarbonyl)phenyl)-1,4-dihydropyrrolo[3,2-
1
b]pyrrole (6). Yellow solid. Yield: 0.27 g (12%). M.p. 275-276 °C. H NMR (500 MHz, CDCl ,
3
mixture of atropoisomers),  = 7.94-7.84 (m, 2H), 7.61-7.54 (m, 2H), 7.50-7.44 (m, 2H), 7.42 (d,
J = 8.4 Hz, 4H), 7.38 (d, J = 7.7 Hz, 1H), 7.32 (d, J = 7.5 Hz, 1H), 7.19 (dd, J = 8.5, 2.2 Hz, 4H),
1
3
1
6
.32 (s, 1H), 6.30 (s, 1H), 3.59 (s, 6H) ppm; C { H} NMR (126 MHz, CDCl
3
) = 166.5, 166.3,
138.8, 138.6, 137.2, 137.1, 136.20, 136.18, 133.8, 133.7, 132.9, 132.8, 132.00, 131.98, 131.3,
1
1
31.2, 129.2, 129.0, 128.8, 128.7, 128.6, 128.2, 127.7, 127.53, 127.51, 127.49, 125.3, 119.06,
19.03, 109.14, 109.05, 95.4, 95.0, 52.4 ppm. HRMS (EI): m/z calculated for C36 O :
H
24
N
4
4
·
+
576.1798 [M ]; found: 576.1784.
2
,5-Bis(4-cyanophenyl)-1,4-bis(2-trimethylsilylethylenylphenyl)-1,4-dihydropyrrolo[3,2-
1
b]pyrrole (7). Yellow solid. Yield: 0.16 g (25%). M.p. 271-272 °C. H NMR (500 MHz, CDCl
3
,
mixture of atropoisomers)  = 7.66 (dd, J = 7.7, 1.4 Hz, 1H), 7.61-7.59 (m, 1H), 7.43 (t, J = 8.5
Hz, 4H), 7.37-7.22 (m, 4H), 7.19 (dd, J = 8.5, 3.0 Hz, 4H), 7.16 (dd, J = 6.0, 3.1 Hz, 1H), 6.94 (d,
13
1
J = 7.1 Hz, 1H), 6.51 (s, 1H), 6.41 (s, 1H), -0.01 (s, 9H), -0.08 (s, 9H) ppm. C { H} NMR (126
MHz, CDCl )  = 141.6, 141.1, 138.0, 137.9, 135.7, 135.4, 134.1, 133.7, 133.6, 133.50 132.0,
31.9, 129.4, 129.2, 128.2, 128.0, 127.1, 127.4, 127.0, 127.0, 121.4, 120.2, 119.2, 108.7, 108.6,
01.4, 101.3, 101.1, 100.7, 98.69, 96.68, 77.2, 77.0, 76.7, -0.5 ppm. HRMS (EI): m/z calculated
3
1
1
·
+
for C42
H
36
N
4
Si : 652.2479 [M ]; found: 652.2471.
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6
2
,5-Bis(4-cyanophenyl)-1,4-bis(2-ethylenylphenyl)-1,4-dihydropyrrolo[3,2-b]pyrrole (7a).
Parent pyrrolo[3,2-b]pyrrole 7 (81.3 mg, 0.13 mmol) was dissolved in 2 ml of THF. Next, TBAF
1M solution in THF, 0.35 ml) was added and resulted mixture was allowed to react at room
(
0
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4
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6
7
8
9
0
1
2
3
4
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
temperature for 2h. Subsequently, solvent was evaporated and resulted residue was filtered through
the silica pad (with DCM as the eluent) and crystallized from DCM/Hexanes to afford desired
product as yellow solid 57.5 mg (90%).
1
Yellow solid. Yield: 57.5 mg (90%). M.p. 274-275 °C. H NMR (500 MHz, CDCl
3
, mixture of
atropoisomers) δ 7.69 – 7.63 (m, 2H), 7.44-7.34 (m, 9H), 7.25-7.21 (m, 4H), 7.10 (dd, J = 5.7, 3.5
13
1
Hz, 1H), 6.45 (s, 1H), 6.44 (s, 1H), 3.08 (s, 1H), 3.04 (s, 1H). ppm. C { H} NMR (126 MHz,
CDCl ) δ 141.6, 141.5, 137.9, 137.8, 136.5, 136.4, 134.5, 134.4, 134.1, 133.8, 132.0, 129.9, 129.8,
28.2, 128.1, 127.5, 127.4, 127.3, 120.1, 119.2, 119.1, 110.0, 108.9, 97.1, 96.7, 83.0, 82.8, 80.0,
3
1
·
+
79.9, 29.7 ppm. HRMS (EI): m/z calculated for C36
H
20
N : 508.1688 [M ]; found: 508.1678.
4
1
,4-Bis(2-bromophenyl)-2,5-bis(4-cyanophenyl)-1,4-dihydropyrrolo[3,2-b]pyrrole
(8).
1
Yellow solid. Yield: 0.79 g (32%). M.p. 345-346 °C. H NMR (500 MHz, CDCl
3
, mixture of
atropoisomers)  = 7.80-7.72 (m, 2H), 7.43 (d, J = 8.4 Hz, 4H), 7.39-7.29 (m, 5H), 7.19 (m, 5H),
1
3
1
6.39 (s, 1H), 6.38 (s, 1H) ppm. C { H} NMR (126 MHz, CDCl
3
)  = 138.9, 137.4, 136.6, 134.1,
1
1
34.1, 133.7, 133.5, 132.0, 130.2, 130.1, 129.6, 129.5, 128.6, 128.5, 127.2, 127.1, 121.8, 119.0,
·
+
09.1, 96.5, 96.1 ppm. HRMS (EI): m/z calculated for C32
H
18
N
4
Br : 615.9898 [M ]; found:
2
615.9890.
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The Journal of Organic Chemistry
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9
1
,4-Bis(2-chlorophenyl)-2,5-bis(4-cyanophenyl)-1,4-dihydropyrrolo[3,2-b]pyrrole
(9).
Yellow solid (poor solubility in common organic solvents). Yield: 0.68 g (32%). M.p. 340-341 °C.
1H NMR (500 MHz, DMSO-d
6
, mixture of atropoisomers)  = 7.76-7.68 (m, 2H), 7.64 (dd, J =
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
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3
3
3
3
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4
4
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4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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7
8
9
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9
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0
8
.7, 2.3 Hz, 4H), 7.57-7.47 (m, 4H), 7.46-7.40 (m, 1H), 7.37-7.35 (m, 1H), 7.31-7.23 (m, 4H), 6.61
·
+
(s, 1H), 6.59 (s, 1H) ppm. HRMS (EI): m/z calculated for C32
H
18
N
4
Cl : 528.0909 [M ]; found:
2
528.0914.
1
,4-Bis(4-cyanophenyl)-2,5-bis(4-methylphenyl)-1,4-dihydropyrrolo[3,2-b]pyrrole
(10).
)  = 7.63
1
Yellow solid. Yield: 0.74 g (38%). M.p. 330 °C (decomp). H NMR (500 MHz, CDCl
3
(d, J = 8.6 Hz, 4H), 7.34 (d, J = 8.6 Hz, 4H), 7.04-7.13 (m, 8H), 6.42 (s, 2H), 2.35 (s, 6H) ppm;
13C NMR (126 MHz, CDCl
)  = 143.6, 137.1, 136.1, 133.2, 130.8, 129.8, 129.3, 128.3, 125.0,
3
·+
1
4
18.6, 108.7, 96.6, 21.2 ppm. HRMS (EI): m/z calculated for C34
88.2005.
H
24
N
4
: 488.2001 [M ]; found:
1
,4-Bis(4-cyanophenyl)-2,5-bis(4-hydroxyphenyl)-1,4-dihydropyrrolo[3,2-b]pyrrole
(11).
Yellow solid (poor solubility in common organic solvents). Yield: 0.25 g (13%). M.p. 362-363 °C.
1H NMR (500 MHz, DMSO-d
6
) δ 9.53 (s, 2H), 7.85 (d, J = 8.5 Hz, 4H), 7.38 (d, J = 8.5 Hz, 4H),
13
1
7
.00 (d, J = 8.5 Hz, 4H), 6.70 (d, J = 8.5 Hz, 4H), 6.46 (s, 2H) ppm. C { H} NMR (126 MHz,
DMSO-d ) δ 157.0, 143.7, 135.6, 133.9, 130.3, 129.9, 125.3, 123.8, 119.0, 115.9, 110.0, 108.0,
6
·
+
96.8 ppm. HRMS (EI): m/z calculated for C32
H N
20 4
O : 492.1586 [M ]; found: 492.1574.
2
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