Advances in the synthesis of functionalised pyrrolotetrathiafulvalenes

Article abstract of DOI:10.3762/bjoc.11.125

The electron-donor and unique redox properties of the tetrathiafulvalene (TTF, 1) moiety have led to diverse applications in many areas of chemistry. Monopyrrolotetrathiafulvalenes (MPTTFs, 4) and bispyrrolotetrathiafulvalenes (BPTTFs, 5) are useful struc

Full text of DOI:10.3762/bjoc.11.125

Advances in the synthesis of functionalised
pyrrolotetrathiafulvalenes
Luke J. O’Driscoll, Sissel S. Andersen, Marta V. Solano, Dan Bendixen, Morten Jensen,
Troels Duedal, Jess Lycoops, Cornelia van der Pol, Rebecca E. Sørensen,
Karina R. Larsen, Kenneth Myntman, Christian Henriksen, Stinne W. Hansen
and Jan O. Jeppesen*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2015, 11, 1112–1122.
Department of Physics, Chemistry and Pharmacy, University of
Southern Denmark, Campusvej 55, DK-5230, Odense M, Denmark
doi:10.3762/bjoc.11.125
Received: 02 March 2015
Accepted: 13 May 2015
Published: 03 July 2015
Email:
Jan O. Jeppesen* - joj@sdu.dk
* Corresponding author
This article is part of the Thematic Series "Tetrathiafulvalene chemistry".
Guest Editor: P. J. Skabara
Keywords:
heterocycles; protecting groups; sulfur chemistry; tetrathiafulvalene;
Ullman coupling
© 2015 O’Driscoll et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
The electron-donor and unique redox properties of the tetrathiafulvalene (TTF, 1) moiety have led to diverse applications in many
areas of chemistry. Monopyrrolotetrathiafulvalenes (MPTTFs, 4) and bispyrrolotetrathiafulvalenes (BPTTFs, 5) are useful struc-
tural motifs and have found widespread use in fields such as supramolecular chemistry and molecular electronics. Protocols
enabling the synthesis of functionalised MPTTFs and BPTTFs are therefore of broad interest. Herein, we present the synthesis of a
range of functionalised MPTTF and BPTTF species. Firstly, the large-scale preparation of the precursor species N-tosyl-(1,3)-di-
thiolo[4,5-c]pyrrole-2-one (6) is described, as well as the synthesis of the analogue N-tosyl-4,6-dimethyl-(1,3)-
dithiolo[4,5-c]pyrrole-2-one (7). Thereafter, we show how 6 and 7 can be used to prepare BPTTFs using homocoupling reactions
and functionalised MPTTFs using cross-coupling reactions with a variety of 1,3-dithiole-2-thiones (19). Subsequently, the incorpor-
ation of more complex functionality is discussed. We show how the 2-cyanoethyl protecting group can be used to afford MPTTFs
functionalised with thioethers, exemplified by a series of ethylene glycol derivatives. Additionally, the merits of
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as an alternative to the most common deprotecting agent, CsOH·H2O are discussed.
Finally, we show how a copper-mediated Ullman-type reaction can be applied to the N-arylation of MPTTFs and BPTTFs using a
variety of aryl halides.
Introduction
Tetrathiafulvalene (TTF) derivatives are of considerable interest chemosensors [1,8-11], coordination chemistry [12-14], cataly-
in the fields of supramolecular chemistry and molecular sis [15] and beyond [16-21]. This owes much to the strong elec-
machines [1-5], molecular and organic electronics [5-7], tron-donor character of the TTF moiety and its derivatives,
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which have been utilized in the formation of charge-transfer [13,19,26-28] to the preparation of fused ring systems [11,27],
(CT) complexes for more than 40 years [21-23].
to the incorporation of MPTTFs and BPTTFs into more com-
plex molecular architectures such as macrocycles [8,9,14],
TTF (1) (Figure 1) is not aromatic according to the Hückel calix-pyrroles [1,10,11], calixarenes [29] and porphyrins [30].
definition as its 14 π-electrons lack cyclic conjugation. Upon Note that for MPTTFs, R1 and R2 can be either the same or
oxidation to the radical cation (2) and dication (3) states, a gain different.
in aromaticity occurs: 2 contains a single aromatic, 6 π-electron
1,3-dithiolium system, and 3 possesses two such systems
(Figure 1). These oxidations occur at low potential (E11/2 =
0.34 V and E21/2 = 0.73 V vs Ag/AgCl in MeCN [4]) and can
be performed sequentially and reversibly. Additionally, both 2
and 3 are thermodynamically stable. These properties are re-
sponsible for the strong electron-donor character of TTF and its
Figure 2: Structures and possible substitution positions of MPTTFs (4)
and BPTTFs (5).
derivatives. Furthermore, the precise oxidation potential of a
TTF derivative can be changed by the addition of electron-
donating or electron-withdrawing substituents [4]. Usually, each
of the three stable oxidation states possesses a distinct UV–vis Here, we present recent developments in the synthesis of func-
absorption spectrum [4], facilitating studies of redox behaviour. tionalised MPTTFs and BPTTFs. We report a more convenient
and larger scale (>20 g) synthesis of the key building block
N-tosyl-(1,3)-dithiolo[4,5-c]pyrrole-2-one (6), than that previ-
ously published [25], in addition to the synthesis of its
dimethylated analogue, N-tosyl-4,6-dimethyl-(1,3)-
dithiolo[4,5-c]pyrrole-2-one (7). We then provide a range of
examples where 6 and 7 are used in the preparation of function-
Figure 1: The sequential, reversible oxidation of TTF (1) to its stable
radical cation (2) and dication (3) states.
alised MPTTFs and BPTTFs. We expand on this by discussing
subsequent additional functionalisation of MPTTFs and
BPTTFs by two different methods: (i) the use of 2-cyanoethyl-
To exploit the properties of TTF in more complex systems, protected thiols as a means to further functionalise MPTTFs
various functionalised derivatives have been prepared, with thioethers and (ii) copper-mediated N-arylation of both
including both alkylated, arylated and annelated species [7]. A MPTTFs and BPTTFs.
common complication encountered with such functionalised
Results and Discussion
TTFs is the existence of cis and trans stereoisomers. The
An improved large-scale synthesis of N-tosyl-
(1,3)-dithiolo[4,5-c]pyrrole-2-one (6)
investigation of the properties of a single isomer is challenging,
not only due to difficulties in the separation of the isomers, but
also because it is possible for the isomers to interconvert in the
presence of acid or light [24]. Studies of functionalised TTFs
must therefore often use mixtures of isomers, although in some
cases only one isomer exhibits the desired behaviour [9].
Isomeric mixtures can also complicate the interpretation of
spectroscopic data.
The known compound 6 [4,25] is an important building block in
the preparation of MPTTFs and BPTTFs. We have further
developed the synthesis previously reported by our group [4,25]
and can now isolate 6 in quantities in excess of 20 g. Our
current large-scale synthetic strategy (Scheme 1) is comparable
to that described in 2000 [25] but requires fewer intermediate
purification steps. Diester 8 can be prepared from commer-
cially available ethylene trithiocarbonate (9) and dimethyl acet-
ylenedicarboxylate (10) at around 100 g scale in 74% yield
(based on previously reported large-scale syntheses [31,32]).
We have scaled up the reduction of 8 using sodium boro-
hydride and lithium bromide to 40 g scale, obtaining diol 11
with only a small reduction in yield (77% vs 85% at 15 g scale
[33]). Compound 11 is then treated with phosphorus tribromide
to afford dibromide 12. The scale up of this reaction to 36 g
scale also results in a lower, but still acceptable yield (75% vs
91% at approximately 5 g scale [25]). The conversion of 12 to 6
These drawbacks led the group of Jeppesen and Becher to
develop pyrrole-annelated TTF derivatives: monopyrrolotetrath-
iafulvalenes (MPTTFs, 4) and bispyrrolotetrathiafulvalenes
(BPTTFs, 5) (Figure 2) [4,25]. The presence of either one or
two fused pyrrole rings, respectively, eliminates cis–trans
isomerism whilst still allowing for further functionalisation.
Methodologies have been developed which facilitate the prepar-
ation of MPTTFs and BPTTFs independently substituted in
almost all of the positions indicated in Figure 2. This ranges
from the addition of simple alkyl, acyl or aryl substituents
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Beilstein J. Org. Chem. 2015, 11, 1112–1122.
is achieved in three steps with minimal intermediate purifica- developed a preparation of 7 (Scheme 2) [36]. Functionalised
tion, beginning with up to 44 g of 12. Reaction of 12 with pyrrole 16 was prepared according to the literature [35,37] then
sodium tosylamide (13) (prepared from tosylamide according to tosylated in high yield to afford 17. The reduction of the
a literature procedure [34]) affords the cyclised product 14. thiocyanate moieties with LiAlH4 afforded the air-sensitive
Crude material of sufficient purity for the following step can be intermediate 18 (not characterised), which was treated with
isolated by precipitation (see the Experimental section in the 1,1’-carbonyldiimidazole to afford 7, in 83% yield over the two
Supporting Information File 1). Transchalcogenation of crude steps.
14 affords 15 and aromatisation of crude 15 using 2,3-dichloro-
Preparation of functionalised MPTTFs and
5,6-dicyano-1,4-benzoquinone (DDQ) gives 6, which is puri-
fied by column chromatography, in 52% overall yield (22.5 g) BPTTFs
from 12. We have also consistently obtained comparable yields Coupling reactions
of around 55% using the same method at approximately half Pyrrole-annelated TTF derivatives can be prepared from 6 and 7
this scale. The ability to isolate multigram quantities of 6, which by means of coupling reactions in triethyl phosphite
can be stored for years on the shelf, makes the subsequent syn- (Scheme 3). The known homocoupling reaction of 6 affords the
thesis of various MPTTF and BPTTF derivatives much more bis-tosylated BPTTF 5a in high yield with minimal purification
convenient and accessible.
[25]. We have obtained a comparable yield (76% vs 84%)
working at twice the previously published scale [25]. The
equivalent reaction can be conducted using 7 to give BPTTF 5b
with a similar yield of 79% [36], a modest improvement on the
Synthesis of N-tosyl-4,6-dimethyl-(1,3)-di-
thiolo[4,5-c]pyrrole-2-one (7)
To the best of our knowledge, the synthesis of 7, the dimethyl- reported yield of 73% for the Boc-protected analogue [35].
ated analogue of 6, has not been previously reported by other
groups. N-Phenylated and N-Boc-protected analogues were, The synthesis of MPTTFs can be achieved using cross-coup-
however, reported in 1996 [35]. Based on that work, we have ling reactions between 6 and 1,3-dithiole-2-thiones 19 [38].
Scheme 1: Large-scale synthesis of 6. Reagents and conditions: a) PhMe, reflux, 19 h, 74%; b) LiBr, NaBH4, THF, MeOH, −10 °C → rt, 20 h, 77%;
c) PBr3, THF, 0 °C → rt, 20 h, 75%; d) (i) 13, MeCN, DMF, 80 °C, 15 min, (ii) Hg(OAc)2, CHCl3, AcOH, rt, 24 h, (iii) DDQ, PhCl, reflux, 4 h, 52% (from
12).
Scheme 2: Preparation of 7. Reagents and conditions: a) TsCl, Et3N, DMAP, MeCN, rt → reflux, 3.5 h, 82%; b) (i) LiAlH4, THF, 0 °C, 2.5 h, (ii) AcOH,
Et2O, 0 °C; c) (Im)2CO, THF, 0 °C, 1 h, 83% (from 17).
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Beilstein J. Org. Chem. 2015, 11, 1112–1122.
Scheme 3: Homo and cross-coupling reactions of 6 or 7 afford BPTTFs and MPTTFs, respectively. Reagents and conditions: a) (EtO)3P,
120–130 °C, 5–5.5 h, 76–79%; b) (EtO)3P, 120–135 °C, 1–4 h, 70–87%.
These reactions (Scheme 3 and Table 1) use an excess of 19 to Table 1 lists a selection of N-tosylated MPTTFs 4a–f prepared
minimise the formation of 5a as a byproduct, making it possible from 6 and 19a–f, respectively, with yields ranging from
to isolate tosylated MPTTFs (such as 4a–f) in high yields. This 70–87% despite the concomitant formation of homocoupled
is believed to be due to the higher reactivity of sulfur ylide byproducts. Compound 7 (and related species [27]) can also be
intermediates (formed from 1,3-dithiole-2-thiones) with used in cross-coupling reactions, exemplified by its reaction
1,3-dithiole-2-ones than with excess 1,3-dithiole-2-thiones [39]. with 19g to give 4g (Scheme 3 and Table 1) [36]. Our group has
Table 1: Cross-coupling reactions between 1,3-dithiole-2-ones and 1,3-dithiole-2-thiones affording MPTTFs.
1,3-Dithiole-2-one
1,3-Dithiole-2-thione
Product
% Yield
85 (lit. 64 [41])
6
19a
4a
83 (lit. 74 [42])
71 (lit. 60 [28])
87 (lit. 62 [43])
6
6
6
19b
19c
4b
4c
19d
19e
4d
4e
70 (lit. 64 [25])
6
6
85 [44]
19f
4f
80 [36]
19g
7
4g
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Beilstein J. Org. Chem. 2015, 11, 1112–1122.
previously shown that it is also possible to introduce substitu- TTF derivatives [46]. However, some of these bases (e.g.
ents directly onto the pyrrole ring of MPTTF 4d [40].
sodium methoxide) are incompatible with the N-tosyl protecting
group typically present during the synthesis of functionalised
MPTTFs (see Scheme 3), and therefore cannot be used with
these materials.
Further functionalisation of MPTTFs bearing a
2-cyanoethyl-protected thiol
The 2-cyanoethyl protecting group offers a convenient means of
synthesising MPTTFs where one or both of R1 and R2 are We have found that in many cases the use of 1,8-diaza-
thioethers. When only simple alkyl thioethers are targeted, it is bicyclo[5.4.0]undec-7-ene (DBU, Scheme 5), rather than
often more effective to incorporate these moieties prior to the CsOH·H2O, allows for a more convenient and consistent syn-
cross-coupling step that is used to form the TTF core, as thesis with a comparable or higher yield, which is also easier to
described in the previous section. However, many functional- conduct on a larger scale. DBU is an easily handled liquid
ities or larger molecular architectures do not tolerate the harsh which can be directly added to a deprotection reaction in a
coupling conditions and must be added subsequently. The single portion. In contrast, CsOH·H2O is a highly hygroscopic
preparation of a series of analogous compounds can also be solid which must typically be added dropwise as a solution in (a
facilitated by preparing a common, protected MPTTF inter- minimum of) methanol, in which it has low solubility. This
mediate, such as 4a, 4b or 4e, in large quantities, particularly in dropwise addition is important to minimise deprotection of the
light of the good stability of the cyanoethyl and tosyl protecting tosyl group of MPTTFs, a side reaction which can be caused by
groups.
the presence of small quantities of methoxide ions in the reac-
tion mixture. As DBU is a non-nucleophilic base, such depro-
As a simple example of this protocol, it has previously been tection cannot occur. Note that unlike in the case of CsOH·H2O
shown that caesium hydroxide monohydrate (CsOH·H2O) and it is important to heat reactions using DBU to achieve good
methyl iodide can be used to accomplish the transformation of conversion. Thus, this base is unsuitable if temperature-sens-
2-cyanoethyl thioethers to methyl thioethers in high yield for itive moieties are present elsewhere in the molecule. Represen-
both TTFs [38] and MPTTFs [25]. Thus deprotection and alkyl- tative substitutions of MPTTFs [47] with alkyl halides 20-X
ation are achieved in a single synthetic step (e.g. the prepar- [48], 21-X [49] and 22-X [50] (where X is a halogen) using
ation of 4h from 4a in Scheme 4). Furthermore, when R1 and both bases are shown in Scheme 5 and Table 2. The products
R2 are both 2-cyanoethyl thioethers (4e) these reagents can be 4i–l are used as building blocks in our work on rotaxanes and
used to selectively deprotect and alkylate only one of the two psuedorotaxanes [45,50].
thiols, affording MPTTF 4a (Scheme 4) [25]. Indeed, the direct
preparation of 4h from 4e requires two iterative additions of When the preparation of the same product using each of the two
base and alkylating agent. A wide range of other, more com- bases is compared, it can be seen that the use of DBU rather
plex alkylating agents can be successfully used in place of than CsOH·H2O usually results in at least a modest increase in
methyl iodide. For example, functionalised ethylene glycol yield. We have prepared 4i several times with each base and
oligomers have been used in the preparation of rotaxanes and achieved more consistent yields with DBU (typically 88–90%)
pseudorotaxanes [28,41,42,45].
than with CsOH·H2O (typically 80–90%, occasionally lower),
although the latter afforded the highest yield of 4i we have
Although CsOH·H2O is most commonly used, other bases are obtained to date (92%). The largest difference in yields is seen
also known to remove the cyanoethyl protecting group from for the preparations of 4k, but it should be noted that the reac-
Scheme 4: Deprotection and methylation of cyanoethyl-protected thiol moieties on MPTTFs as reported by Jeppesen et al. [25]. Reagents and condi-
tions: a) (i) 1 equiv CsOH·H2O, MeOH, THF, rt, 1 h, (ii) MeI, THF, rt, 30 min; b) (i) 1 equiv CsOH·H2O, MeOH, THF, rt, 1 h, (ii) MeI, THF, rt, 45 min,
(iii) 1 equiv CsOH·H2O, MeOH, THF, rt, 1 h, (iv) MeI, THF, rt, 30 min.
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Scheme 5: Deprotection and alkylation of cyanoethyl-protected thiol moieties on MPTTFs using CsOH·H2O or DBU. Reagents and conditions are
detailed in Table 2.
Table 2: Deprotection and alkylation of cyanoethyl-protected thiol moieties on MPTTFs using CsOH·H2O or DBU.
Base and
conditions
Substrate (R1)
RX
Product
% Yield
CsOH·H2O, THF,
MeOH, rt, 16 h
92 (lit. 88 [45])
4b (SEt)
20-I
DBU, THF, reflux,
20 h
90
87
91
53
4i
4j
CsOH·H2O, THF,
MeOH, rt, 2.5 h
4a (SMe)
20-I
DBU, THF,
reflux, 18 h
CsOH·H2O, THF,
MeOH, rt, 20 h
4a (SMe)
4a (SMe)
21-Br
21-I
DBU, THF,
reflux, 17 h
93
88
CsOH·H2O, THF,
MeOH, rt, 18 h
4a (SMe)
22-I
DBU, THF,
reflux, 3 d
92
tion with CsOH·H2O used an alkyl bromide whereas that with N-Arylation of MPTTFs and BPTTFs
DBU used the more reactive alkyl iodide analogue. Therefore, N-Alkylation of MPTTFs and BPTTFs can be easily achieved
this effect may not relate to the change of base alone. In using SN2 reactions between a deprotonated pyrrole and a suit-
summary, the use of DBU as a deprotecting reagent was found ably activated aliphatic species [19,28]. N-Arylation of
to be high-yielding, consistent and more convenient than the use MPTTFs and BPTTFs, which allows an annelated TTF to be
of CsOH·H2O.
incorporated into a larger conjugated system, is less common,
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Beilstein J. Org. Chem. 2015, 11, 1112–1122.
although interest has increased in recent years. These reactions terials with molecular electronics applications [44,56]. The
can be accomplished using a copper-mediated Ullman-type N-tosyl protecting group of precursor MPTTFs (4c, 4d, 4f and
reaction, based on conditions reported by Buchwald and 4g) must first be removed. This can be achieved in excellent
co-workers for the arylation of nitrogen-containing hetero- yield (89–95%) using sodium methoxide (Scheme 6). The
cycles and the amidation of aryl halides [51,52]. Examples of deprotection of MPTTFs derived from 6 proceeded rapidly
TTF derivatives synthesised using this protocol by other groups (15–40 min), whereas that of 4g, derived from 7, required 6 h,
include: MPTTF and BPTTF-triarylamine conjugates (as presumably because of the increased steric bulk of the substi-
possible charge-transport materials) [53], MPTTF-triarylborane tuted pyrrole ring. Copper-mediated coupling between the
conjugates (with possible applications as fluoride sensors) [54], MPTTF products (4c’, 4d’, 4f’ and 4g’) and a range of aryl
and MPTTF-functionalised calix[4]arenes (which can bind to halides is then possible. In this study we have investigated
electron-deficient aromatics and form charge-transfer several p-substituted species (23-X–28-X, Scheme 6).
complexes) [29]. Alternative routes to N-arylated MPTTFs
proceed through N-arylated (1,3)-dithiolo[4,5-c]pyrrole-2-ones As satisfactory results have been reported for similar arylations
or (1,3)-dithiolo[4,5-c]pyrrole-2-thiones (i.e. analogues of 6). In [29,53,54] when (±)-trans-1,2-diaminocyclohexane, 29
some cases these can be prepared similarly to 6 [55], but an (Scheme 6), is used as the ligand, we also followed this ap-
alternative route may be required if the desired aryl unit pos- proach, rather than using the costlier methylated analogue
sesses reactive functional groups [12]. These routes are also favoured by the Buchwald group [52]. To improve reaction
limited to intermediates that can tolerate the harsh conditions of yields, we made modifications to the published procedures
the subsequent coupling reaction used to form the TTF moiety. [29,52-54], which typically utilise catalytic CuI in a sealed reac-
Our discussions here will be limited to copper-mediated tion vessel with 1,4-dioxane as solvent. Firstly, in our hands,
C–N-bond formation, as we find this to be a flexible and con- comparable yields could be achieved using either THF or
venient method.
1,4-dioxane as solvent; THF was therefore favoured to facil-
itate workup. We also saw improvement upon increasing the
Recent work in our laboratory has involved the N-arylation of amount of CuI to 1–2.5 equiv (typically 2 equiv were used). We
MPTTFs, including both unsubstituted and thioether-substi- investigated the use of a microwave reactor (exemplified by the
tuted examples (Scheme 6 and Table 3). These materials have syntheses of 4m and 4n in Table 2, which were carried out
served as intermediates and model systems in the synthesis of, under both sealed tube and microwave conditions), which typic-
for example, donor–acceptor systems, chemosensors and ma- ally allowed for shorter reaction times and resulted in higher
Scheme 6: Deprotection and N-arylation of tosylated MPTTFs. Reagents and conditions: a) NaOMe, THF, MeOH, reflux, 15 min–6 h, 89–95%;
b) CuI, K3PO4, 29, THF, 80–115 °C (sealed tube), 3–48 h, 25–68%; c) CuI, K3PO4, 29, THF, 100–130 °C (microwave), 2–3 h, 51–93%; d) CuI,
K3PO4, 29, THF, reflux, 3 h, 67%.
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Beilstein J. Org. Chem. 2015, 11, 1112–1122.
Table 3: Copper-mediated N-arylation of MPTTFs.
MPTTF
Ar-X
Product
Conditions % Yield
STa
MWb
ST
35
81
68
23-Br
4c′
4m
23-Br
24-I
MW
93
4d′
4n
4o
Refluxc
MW
67
54
4f′
4c′
4c′
25-I
26-I
ST
ST
35
52
4p
4q
26-I
ST
ST
65
25
4d′
4r
23-Br
4g′
4d′
4d′
4d′
4d′
4s
4t
25-I
26-I
27-I
28-I
MW
MW
MW
MW
82 [56]
51
4u
4v
4w
80
64
aST = sealed tube conditions; bMW = microwave conditions; cReflux = conventional reflux.
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Beilstein J. Org. Chem. 2015, 11, 1112–1122.
yields. Small alterations to base and ligand loading and reac- conventional reflux as compared to microwave conditions
tion temperature were also made, but with no significant effects. relates to the significant increase in scale. This result indicates
A larger-scale synthesis of 4o has also been conducted under that the larger scale synthesis of related species should also be
conventional reflux conditions in good yield.
viable.
Scheme 6 and Table 3 show the results of reactions between We have begun to extend the sealed tube protocol to the
MPTTFs 4c’, 4d’, 4f’ and 4g’ and aryl halides 23-X–28-X to N,N-diarylation of BPTTFs with promising initial results
give N-arylated products 4m–w. Acceptable yields can be (Scheme 7 and Table 4). Difficulties were encountered with the
obtained with both aryl bromides and aryl iodides, suggesting isolation, purification and characterisation of the targeted
that the choice of halogen is not critical. N-Arylation of species, which appeared to relate to their extremely poor solu-
dimethylated MPTTF 4g’ gave the lowest yield amongst the bility. Nonetheless, it proved possible to synthesise 5c–f (see
reactions performed under sealed tube conditions, which may Scheme 7 and Table 4), and accomplish some characterisation.
be attributable to its more sterically hindered pyrrole-H. The The parent deprotected BPTTFs 5a’ and 5b’ were first prepared
highest yielding reactions under sealed tube conditions gave in near-quantitative yield, comparably to MPTTFs 4c’, 4d’, 4f’
comparable yields to the lowest yielding reactions under and 4g’ (similarly, bulkier 5b’ required a much longer reaction
microwave conditions. In general, the microwave conditions time than 5a’). In some cases 5a’ was observed to decompose
give high yields and can tolerate a range of functional groups on when stored for periods of more than 24 h, although the nature
the aryl halide. We believe that the higher yield of 4o under of this decomposition is unclear. Therefore, these materials
Scheme 7: Deprotection and N,N-diarylation of tosylated BPTTFs. Reagents and conditions: a) NaOMe, THF, MeOH, reflux, 30 min–8 h, 95–99%;
b) CuI, K3PO4, 29, THF or 1,4-dioxane, 98–110 °C (sealed tube), 22–65 h, 24–72%.
Table 4: N,N-Diarylation of BPTTFs.
Substrate
Ar–X
Product
% Yield
42a/73b
23-Br
5a′
5c
25-I
26-I
45a [56]
24a
5a′
5a′
5d
5e
23-Br
40a/24b
5b′
5f
aTHF as solvent; b1,4-dioxane as solvent.
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Beilstein J. Org. Chem. 2015, 11, 1112–1122.
References
were prepared and isolated directly before the subsequent coup-
ling reactions, and stored for no longer than 24 h before use.
The isolated yields of the N,N-diarylated BPTTFs compare
reasonably with the N-arylated MPTTF analogues discussed
above, given that two C–N bonds are formed in these syntheses.
For these systems we observed larger variation than for
MPTTFs when the solvent was changed from 1,4-dioxane to
THF; however, a different solvent gave the higher yield in each
of the two cases where both solvents were used (5c and 5f). We
expect that further optimisation of these reactions can be
achieved using microwave or larger scale conditions, and
investigations are currently underway in our laboratory.
1. Kim, D. S.; Sessler, J. L. Chem. Soc. Rev. 2015, 44, 532.
doi:10.1039/C4CS00157E
2. Tian, J.; Ding, Y.-D.; Zhou, T.-Y.; Zhang, K.-D.; Zhao, X.; Wang, H.;
Zhang, D.-W.; Liu, Y.; Li, Z.-T. Chem. – Eur. J. 2014, 20, 575.
doi:10.1002/chem.201302951
3. Saha, S.; Flood, A. H.; Stoddart, J. F.; Impellizzeri, S.; Silvi, S.;
Venturi, M.; Credi, A. J. Am. Chem. Soc. 2007, 129, 12159.
doi:10.1021/ja0724590
4. Jeppesen, J. O.; Becher, J. Eur. J. Org. Chem. 2003, 2003, 3245.
doi:10.1002/ejoc.200300078
5. Coskun, A.; Spruell, J. M.; Barin, G.; Dichtel, W. R.; Flood, A. H.;
Botros, Y. Y.; Stoddart, J. F. Chem. Soc. Rev. 2012, 41, 4827.
doi:10.1039/c2cs35053j
6. Liao, J.; Agustsson, J. S.; Wu, S.; Schonenberger, C.; Calame, M.;
Leroux, Y.; Mayor, M.; Jeannin, O.; Ran, Y.-F.; Liu, S.-X.; Decurtins, S.
Nano Lett. 2010, 10, 759. doi:10.1021/nl902000e
Conclusion
Pyrrole-annelated tetrathiafulvalenes (MPTTFs and BPTTFs)
are versatile functional groups in many areas of chemistry. The
large-scale synthesis of the key intermediate 6 improves the
accessibility of these species and their derivatives. The related
species 7 can be used to prepare further analogues. Compounds
6 and 7 can both be used to prepare BPTTFs and MPTTFs using
homocoupling reactions or cross-coupling reactions with
1,3-dithiole-2-thiones (19), respectively. Additional functional-
isation of MPTTFs and BPTTFs is important to allow their
incorporation into systems with materials applications. The use
of the 2-cyanoethyl protecting group allows thioether-function-
alised MPTTFs to be prepared, including the addition of large
ethylene glycol-based substituents utilised in the preparation of
rotaxanes and pseudorotaxanes. N-Arylation of MPTTFs is an
area of increasing interest and can be achieved using a copper-
mediated reaction. We have applied this methodology to a range
of aryl halides and achieved improved yields using microwave
conditions. Optimisation of this arylation reaction is ongoing in
our laboratory, including its extension to BPTTFs. We are
continuing to improve and exploit these synthetic routes in our
studies of MPTTF and BPTTF-based materials with applica-
tions in supramolecular chemistry, molecular electronics and as
sensors.
7. Jiang, H.; Yang, X.; Cui, Z.; Liu, Y.; Li, H.; Hu, W.; Kloc, C.
CrystEngComm 2014, 16, 5968. doi:10.1039/c3ce41849a
8. Larsen, K. R.; Johnsen, C.; Hammerich, O.; Jeppesen, J. O. Org. Lett.
2013, 15, 1452. doi:10.1021/ol303308e
9. Trippé, G.; Levillain, E.; Le Derf, F.; Gorgues, A.; Sallé, M.;
Jeppesen, J. O.; Nielsen, K.; Becher, J. Org. Lett. 2002, 4, 2461.
doi:10.1021/ol0260829
10.Davis, C. M.; Lim, J. M.; Larsen, K. R.; Kim, D. S.; Sung, Y. M.;
Lyons, D. M.; Lynch, V. M.; Nielsen, K. A.; Jeppesen, J. O.; Kim, D.;
Park, J. S.; Sessler, J. L. J. Am. Chem. Soc. 2014, 136, 10410.
doi:10.1021/ja504077f
11.Park, J. S.; LeDerf, F.; Bejger, C. M.; Lynch, V. M.; Sessler, J. L.;
Nielsen, K. A.; Johnsen, C.; Jeppesen, J. O. Chem. – Eur. J. 2010, 16,
848. doi:10.1002/chem.200902924
12.Balandier, J.-Y.; Chas, M.; Dron, P. I.; Goeb, S.; Canevet, D.;
Belyasmine, A.; Allain, M.; Sallé, M. J. Org. Chem. 2010, 75, 1589.
doi:10.1021/jo902529e
13.Bivaud, S.; Balandier, J.-Y.; Chas, M.; Allain, M.; Goeb, S.; Sallé, M.
J. Am. Chem. Soc. 2012, 134, 11968. doi:10.1021/ja305451v
14.Goeb, S.; Bivaud, S.; Dron, P. I.; Balandier, J.-Y.; Chas, M.; Sallé, M.
Chem. Commun. 2012, 48, 3106. doi:10.1039/c2cc00065b
15.Lorcy, D.; Bellec, N.; Fourmigué, M.; Avarvari, N. Coord. Chem. Rev.
2009, 253, 1398. doi:10.1016/j.ccr.2008.09.012
16.Canevet, D.; Sallé, M.; Zhang, G.; Zhang, D.; Zhu, D. Chem. Commun.
2009, 2245. doi:10.1039/b818607n
17.Bergkamp, J. J.; Decurtins, S.; Liu, S.-X. Chem. Soc. Rev. 2015, 44,
863. doi:10.1039/C4CS00255E
18.Romero-Nieto, C.; García, R.; Herranz, M. Á.; Ehli, C.; Ruppert, M.;
Hirsch, A.; Guldi, D. M.; Martín, N. J. Am. Chem. Soc. 2012, 134, 9183.
doi:10.1021/ja211362z
Supporting Information
19.Liu, Y.; Zheng, N.; Chen, T.; Jin, L.; Yin, B. Org. Biomol. Chem. 2014,
12, 6927. doi:10.1039/C4OB01397B
Supporting Information File 1
Experimental procedures and analytical data.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-11-125-S1.pdf]
20.Bryce, M. R. J. Mater. Chem. 2000, 10, 589. doi:10.1039/a908385e
21.Martin, N. Chem. Commun. 2013, 49, 7025. doi:10.1039/c3cc00240c
22.Ferraris, J.; Cowan, D. O.; Walatka, V.; Perlstein, J. H.
J. Am. Chem. Soc. 1973, 95, 948. doi:10.1021/ja00784a066
23.Tayi, A. S.; Shveyd, A. K.; Sue, A. C. H.; Szarko, J. M.;
Rolczynski, B. S.; Cao, D.; Kennedy, T. J.; Sarjeant, A. A.; Stern, C. L.;
Paxton, W. F.; Wu, W.; Dey, S. K.; Fahrenbach, A. C.; Guest, J. R.;
Mohseni, H.; Chen, L. X.; Wang, K. L.; Stoddart, J. F.; Stupp, S. I.
Nature 2012, 488, 485. doi:10.1038/nature11395
Acknowledgements
We would like to acknowledge funding from EC FP7 ITN
“MOLESCO” Project No. 606728, EC FP7 ITN “FUNMOLS”
Project No. 212942, and the Danish Council for Independent
Research – Natural Sciences (#11-106744).
1121

Beilstein J. Org. Chem. 2015, 11, 1112–1122.
24.Ballardini, R.; Balzani, V.; Becher, J.; Fabio, A. D.; Gandolfi, M. T.;
Mattersteig, G.; Nielsen, M. B.; Raymo, F. M.; Rowan, S. J.;
Stoddart, J. F.; White, A. J. P.; Williams, D. J. J. Org. Chem. 2000, 65,
4120. doi:10.1021/jo0001941
47.We have obtained comparable results when using DBU to deprotect
cyanoethyl protecting groups of non-annelated TTFs, but further details
are beyond the scope of this paper.
48.Marquis, D.; Desvergne, J.-P.; Bouas-Laurent, H. J. Org. Chem. 1995,
60, 7984. doi:10.1021/jo00129a045
25.Jeppesen, J. O.; Takimiya, K.; Jensen, F.; Brimert, T.; Nielsen, K.;
Thorup, N.; Becher, J. J. Org. Chem. 2000, 65, 5794.
doi:10.1021/jo000742a
49.Ikeda, T.; Higuchi, M. Tetrahedron 2011, 67, 3046.
doi:10.1016/j.tet.2011.03.009
26.Gopee, H.; Nielsen, K. A.; Jeppesen, J. O. Synthesis 2005, 2005,
1251. doi:10.1055/s-2005-861879
50.Sørensen, A.; Andersen, S. S.; Flood, A. H.; Jeppesen, J. O.
Chem. Commun. 2013, 49, 5936. doi:10.1039/c3cc42201a
51.Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L.
J. Am. Chem. Soc. 2001, 123, 7727. doi:10.1021/ja016226z
52.Antilla, J. C.; Baskin, J. M.; Barder, T. E.; Buchwald, S. L.
J. Org. Chem. 2004, 69, 5578. doi:10.1021/jo049658b
53.Li, H.; Lambert, C. Chem. – Eur. J. 2006, 12, 1144.
doi:10.1002/chem.200500928
27.Zong, K.; Cava, M. P. J. Org. Chem. 1997, 62, 1903.
doi:10.1021/jo962303a
28.Nygaard, S.; Hansen, C. N.; Jeppesen, J. O. J. Org. Chem. 2007, 72,
1617. doi:10.1021/jo061962c
29.Düker, M. H.; Schäfer, H.; Zeller, M.; Azov, V. A. J. Org. Chem. 2013,
78, 4905. doi:10.1021/jo400502t
30.Nielsen, K. A.; Levillain, E.; Lynch, V. M.; Sessler, J. L.;
Jeppesen, J. O. Chem. – Eur. J. 2009, 15, 506.
54.Li, J.; Zhang, G.; Zhang, D.; Zheng, R.; Shi, Q.; Zhu, D. J. Org. Chem.
2010, 75, 5330. doi:10.1021/jo1007306
doi:10.1002/chem.200801636
55.Nygaard, S.; Leung, K. C. F.; Aprahamian, I.; Ikeda, T.; Saha, S.;
Laursen, B. W.; Kim, S.-Y.; Hansen, S. W.; Stein, P. C.; Flood, A. H.;
Stoddart, J. F.; Jeppesen, J. O. J. Am. Chem. Soc. 2007, 129, 960.
doi:10.1021/ja0663529
31.O'Connor, B. R.; Jones, F. N. J. Org. Chem. 1970, 35, 2002.
doi:10.1021/jo00831a062
32.Melby, L. R.; Hartzler, H. D.; Sheppard, W. A. J. Org. Chem. 1974, 39,
2456. doi:10.1021/jo00930a043
56.Solano, M. V.; Della Pia, E. A.; Jevric, M.; Schubert, C.; Wang, X.;
van der Pol, C.; Kadziola, A.; Nørgaard, K.; Guldi, D. M.;
Nielsen, M. B.; Jeppesen, J. O. Chem. – Eur. J. 2014, 20, 9918.
doi:10.1002/chem.201402623
33.Jeppesen, J. O.; Takimiya, K.; Thorup, N.; Becher, J. Synthesis 1999,
1999, 803. doi:10.1055/s-1999-3473
34.Mekelburger, H.-B.; Gro, J.; Schmitz, J.; Nieger, M.; Vögtle, F.
Chem. Ber. 1993, 126, 1713. doi:10.1002/cber.19931260731
35.Zong, K.; Chen, W.; Cava, M. P.; Rogers, R. D. J. Org. Chem. 1996,
61, 8117. doi:10.1021/jo961282h
36.Solano, M. V.; Nielsen, M. B.; Jeppesen, J. O. J. Heterocycl. Chem.
2015, in press.
License and Terms
37.Söderbäck, E.; Gronowitz, S.; Hörnfeldt, A.-B. Acta Chem. Scand.
1961, 15, 227. doi:10.3891/acta.chem.scand.15-0227
38.Simonsen, K. B.; Svenstrup, N.; Lau, J.; Simonsen, O.; Mørk, P.;
Kristensen, G. J.; Becher, J. Synthesis 1996, 1996, 407.
doi:10.1055/s-1996-4216
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39.Konoike, T.; Namba, K.; Shinada, T.; Sakaguchi, K.;
Papavassiliou, G. C.; Murata, K.; Ohfune, Y. Synlett 2001, 2001, 1476.
doi:10.1055/s-2001-16806
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40.Petersen, B. M.; Jeppesen, J. O.; Becher, J. Synthesis 2004, 2004,
2555. doi:10.1055/s-2004-831199
(http://www.beilstein-journals.org/bjoc)
41.Jeppesen, J. O.; Perkins, J.; Becher, J.; Stoddart, J. F. Org. Lett. 2000,
2, 3547. doi:10.1021/ol006387s
The definitive version of this article is the electronic one
which can be found at:
42.Choi, J. W.; Flood, A. H.; Steuerman, D. W.; Nygaard, S.;
Braunschweig, A. B.; Moonen, N. N. P.; Laursen, B. W.; Luo, Y.;
DeIonno, E.; Peters, A. J.; Jeppesen, J. O.; Xu, K.; Stoddart, J. F.;
Heath, J. R. Chem. – Eur. J. 2006, 12, 261.
doi:10.3762/bjoc.11.125
doi:10.1002/chem.200500934
43.Hansen, J. A.; Becher, J.; Jeppesen, J. O.; Levillain, E.; Nielsen, M. B.;
Petersen, B. M.; Petersen, J. C.; Şahin, Y. J. Mater. Chem. 2004, 14,
179. doi:10.1039/b310733g
44.Salinas, Y.; Solano, M. V.; Sørensen, R. E.; Larsen, K. R.; Lycoops, J.;
Jeppesen, J. O.; Martínez-Máñez, R.; Sancenón, F.; Marcos, M. D.;
Amorós, P.; Guillem, C. Chem. – Eur. J. 2014, 20, 855.
doi:10.1002/chem.201302461
45.Hansen, S. W.; Stein, P. C.; Sørensen, A.; Share, A. I.; Witlicki, E. H.;
Kongsted, J.; Flood, A. H.; Jeppesen, J. O. J. Am. Chem. Soc. 2012,
134, 3857. doi:10.1021/ja210861v
46.Svenstrup, N.; Rasmussen, K. M.; Hansen, T. K.; Becher, J. Synthesis
1994, 1994, 809. doi:10.1055/s-1994-25580
1122