Activation of elemental sulfur by electrogenerated cyanomethyl anion: Synthesis of substituted 2-aminothiophenes by the Gewald reaction

Article abstract of DOI:10.1002/adsc.200800503

The activation of elemental sulfur (S₈) has been achieved by means of electrogenerated cyanomethyl anion [easily obtained by galvanostatic reduction from acetonitrile/tetraethylammonium hexafluorophosphate (MeCN-Et ₄NPF₄)]. The activated sulfur reacted with ylidenemalononitriles to give substituted 2-aminothiophenes in very high yields. This variation of the Gewald reaction has been carried out using only catalytic amounts of electricity and supporting electrolyte. A proposed mechanism for the interaction between S₈ and cyanomethyl anion is described.

Full text of DOI:10.1002/adsc.200800503

FULL PAPERS
DOI: 10.1002/adsc.200800503
Activation of Elemental Sulfur by Electrogenerated Cyanomethyl
Anion: Synthesis of Substituted 2-Aminothiophenes by the
Gewald Reaction
Marta Feroci,a,* Isabella Chiarotto,a Leucio Rossi,b and Achille Inesia,*
a
Dipartimento di Ingegneria Chimica Materiali Ambiente, University “La Sapienza”, via Castro Laurenziano, 7, 00161
Rome, Italy
Fax : (+39)-06-4976-6749; e-mail: marta.feroci@uniroma1.it or achille.inesi@uniroma1.it
Dipartimento di Chimica, Ingegneria Chimica e Materiali, Universitꢀ degli Studi, 67040 Monteluco di Roio, LꢁAquila,
b
Italy
Received: August 12, 2008; Revised: October 8, 2008; Published online: November 17, 2008
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800503.
Abstract: The activation of elemental sulfur (S8) has out using only catalytic amounts of electricity and
been achieved by means of electrogenerated cyano- supporting electrolyte. A proposed mechanism for
methyl anion [easily obtained by galvanostatic reduc- the interaction between S8 and cyanomethyl anion is
tion from acetonitrile/tetraethylammonium hexa- described.
fluorophosphate (MeCN-Et4NPF6)]. The “activated”
sulfur reacted with ylidenemalononitriles to give sub- Keywords: 2-aminothiophenes; electrogenerated cya-
stituted 2-aminothiophenes in very high yields. This nomethyl anion; elemental sulfur; Gewald reaction;
variation of the Gewald reaction has been carried ylidenemalononitriles
Introduction
compound, elemental sulfur and a cyanomethylene
containing an electron-withdrawing group condense
Substituted 2-aminothiophenes are attractive mole- in the presence of an organic base to yield a thio-
cules, largely used in the industry due to their applica- phene system (Scheme 1).
tions in pharmaceuticals, agriculture, pesticides and
In the first version of this reaction, an a-mercap-
dyes.[1] They are, in fact, potent inhibitors of JNK2 toaldehyde or an a-mercaptoketone is treated with an
and JNK3 kinases,[2] allosteric enhancers of A1-adeno- activated nitrile (bearing an electron-withdrawing
sine receptor[3] and glucagon receptor antagonists.[4] group, EWG) in the presence of a basic catalyst (usu-
They also show antimicrobial activity against various ally an amine) at 508C; this reaction uses starting ma-
Gram(+) and Gram(ꢀ) bacteria and fungi,[5] antibac- terials that are unstable and difficult to prepare.[11]
terial activity against S. aureus, B. subtilis and E.
The second version of the Gewald reaction is the
coli,[6] as well as antioxidant and anti-inflammatory most elegant and consists of a one-pot condensation
activity.[7] Moreover, these molecules are dyes[8] and of the three reactants (see Scheme 1) at room temper-
precursors of azo dispersed dyes.[9]
ature, in the presence of an amine, but in this case in
Many are the routes to this kind of product (such 0.5–1.0 molar equivalent amounts; the yields are
as, for example, the cyclization of thioamides and higher than in the first version[10] (82–99% yields with
their S-alkylates),[1] but usually they involve difficult cyclohexanone derivatives[4,12]).
preparation of the starting materials, multistep syn-
thesis and do not produce high yields. The most
facile, versatile and important reaction leading to 2-
aminothiophenes with electron-withdrawing substitu-
ents (such as cyano, ethoxycarbonyl, carboxamido,
etc.) is the Gewald reaction[10] and its variations.
The Gewald reaction is a three-component conden-
sation reaction in which an a-methylene carbonyl Scheme 1.
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Activation of Elemental Sulfur by Electrogenerated Cyanomethyl Anion
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Scheme 2.
The third version is the reaction of an a,b-unsatu-
rated nitrile (prepared by a Knoevenagel condensa-
tion) with sulfur and an amine (Scheme 2). This two-
step version gives the highest yields in short times
Scheme 4.
and allows the reaction of alkyl aryl ketones, which the synthesis of 2-aminothiophenes, high yields (61–
are unreactive under the one-pot conditions.[13]
91%) were obtained.[23]
During the last decade, many papers have been
In recent papers, we showed the ability as a base of
published concerning improvements in both version 2 electrogenerated cyanomethyl anion in the synthesis,
and version 3 of the Gewald reaction.[14]
acylation and alkylation of oxazolidin-2-ones, in the
In particular, as regards the one-pot synthesis, the synthesis of organic carbamates and b-lactams.[24] As
reaction has been carried out on a solid support,[15] in the generation of this base is very simple and this
ionic liquids,[16] with microwave-assistence;[17] while, as anion (ꢀCH2CN) is highly reactive, due to the fact
concerns the two-step synthesis, a method to obtain 4- that its counter-ion is a tetraalkylammonium cation,
alkylthiophenes (instead of the mainly obtained 5- we envisaged the possibility to use electrogenerated
alkyl ones) has been depicted,[18] and the use of an in- cyanomethyl anion as the basic species necessary to
organic base in THF/water allows the suppression of activate S8 in the Gewald reaction.
by-product formation.[19]
The mechanism of this reaction is not fully clear; in
fact the reaction of addition of elemental sulfur to the Results and Discussion
nitrile group is not known in detail. Some authors
report that the Knoevenagel product is thiolated at Cyanomethyl anion was generated by galvanostatic
the methylene group with elemental sulfur, followed reduction (I=25 mAcmꢀ2) of a solution of acetoni-
by ring closure (Scheme 3).[1,18,20] In this version, the trile/0.1M tetraethylammonium hexafluorophosphate
methylene group is deprotonated and then thiolated.
(TEAHFP, as supporting electrolyte), in a two-com-
However, it is sure that S8 has to be activated to partment cell (catholyte and anolyte separated by a
react with the Knoevenagel product. This activation glass frit filled with a gel containing DMF and
can be achieved therefore by using a base, but also by TEAHFP), on a Pt cathode at room temperature
electrochemical means. In fact, it is reported in the lit- under an inert atmosphere. At the end of the electrol-
erature (and not related to the Gewald reaction) that ysis (Q=0.5 F/mol 1a), elemental sulfur and 2-(4-phe-
elemental sulfur reacts with amines to yield polysul- nylcyclohexylidene)malononitrile 1a (taken as
fide anions (Scheme 4),[21] that can behave as nucleo- model compound) were added to the catholyte, and
philes: the solution was allowed to stand under stirring for 1
a
On the other hand, the electrochemical activation hour. Usual work-up (see experimental) gave the cor-
of sulfur has been reported by Le Guillanton and co- responding 2-aminothiophene in 85% yield (see
workers:[22] as sulfur S8 is electroactive, it has been in- Scheme 5 and Table 1, entry 2).
corporated in a carbon electrode (to have sufficient
In this reduction the electroactive species should be
electric conductivity) and used as a sacrificial cathode the tetraethylammonium cation and not MeCN,[24c]
at a potential of ꢀ0.9 V (vs. SCE) to yield S3Cꢀ, S8Cꢀ
2ꢀ
and S4 species, that can act as reducing species and
nucleophiles. When this methodology was applied to
Scheme 3.
Scheme 5.
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Table 1. Electrochemical generation of cyanomethyl anion,
followed by its reaction with S8 and 2-(4-phenylcyclohexyl-
idene)malononitrile 1a to yield 2-aminothiophene 2a (see
Scheme 5).[a]
suggests the presence of anions and/or radical anions
of sulfur.[27] Any attempt to isolate the intermediate
due to the interaction of cyanomethyl anion and ele-
ꢀ
mental sulfur failed and when the mixture CH2CN/S8
was allowed to react with BuI, only the presence of
Entry Catholyte
Q (F/mol
Recovered
1a
2a[c]
1a)[b]
ꢀ ꢀ ꢀ
ꢀ ꢀ ꢀ ꢀ
Bu S S Bu and Bu S S S Bu was evidenced; the
same result has been obtained by Jonczyk by treating
alkyl halides with S8/NaOH/DMSO.[28] This seems to
suggest a behaviour of ꢀCH2CN similar to that of
amines (Scheme 4). Moreover, when the ylidenemalo-
nonitrile 1a was added to a solution of cyanomethyl
anion in the absence of S8, no change in the colour of
the catholyte was obtained, while when S8 and 1a
were added to the catholyte simultaneously, the solu-
tion become dark red-brown, the same colour as ob-
tained after the addition of only S8. From these re-
sults, it can be evinced that cyanomethyl anion reacts
with S8 also in the presence of ylidenemalononitrile
1a, thus starting the Gewald reaction. The interaction
of cyanomethyl anion and S8 is also supported by the
voltammetric curves of sulfur in MeCN in the absence
and in the presence of cyanomethyl anion: S8 in
MeCN gives rise to two reduction peaks (Pt cathode),
the first of which reꢀlated to the direct cathodic reduc-
tion of S8;[29] when CH2CN is added to a solution of
MeCN containing S8, all the peaks disappear, showing
that no S8 (or its reduction products) is now present
in the solution and excluding an electron transfer be-
tween the two species (no oxidation peak is pres-
ent).[30] An hypothesis for the mechanism is depicted
in Scheme 6, by analogy with the behaviour of sulfur
with amines reported in Scheme 4. The “activated”
sulfur could then give nucleophilic attack to the CN
triple bond of the ylidenemalononitrile, leading to the
formation of the thiophene ring.[31]
1
MeCN/
Et4NPF6
MeCN/
Et4NPF6
MeCN/
Et4NPF6
MeCN/
Et4NPF6
MeCN/
Et4NPF6
MeCN/
Et4NPF6
MeCN
–
100%
13%
12%
–
–
2[d]
3
0.50
0.50
0.50
0.25
0.10
85%
83%
65%
98%
>99%
4[e]
5
–
6
–
7
8
0.25
0.10
0.05
0.10
0.10
–
–
>99%
98%
83%
–
MeCN
MeCN
MeCN
9
10%
100%
92%
10[f]
11 g] MeCN
–
[a]
Catholyte in a two-compartment cell (~2 mL), Pt electro-
des, room temperature, N2 bubbling, galvanostatic condi-
tions (I=25 mAcmꢀ2). At the end of the electrolysis S8
(1 mmol) was added to the catholyte followed, after
1 min, by 1a (1 mmol). The mixture was allowed to stand
at room temperature, under stirring, for 1 h and then,
after work-up, thiophene 2a was isolated.
Amount of electricity (with respect to reagent 1a) flown
through the cell.
Isolated yields.
In this case, S8 and 1a were added simultaneously to the
catholyte.
Workup of the catholyte after 12 h. In this case, a 29% of
4-phenylcyclohexanone was recovered.
A one-compartment cell was used.
In this case, starting material was not 1a, but its precur-
sors, 4-phenylcyclohexanone and malononitrile.
[b]
[c]
[d]
[e]
As can be seen from Scheme 6, cyanomethyl anion
exits (last reaction) from the first cycle of reactions
(in which all eight sulfur atoms of an S8 molecule are
used to build the thiophene ring) and can reenter in
another cycle of activation (first reaction).
[f]
[g]
and cyanomethyl anion is formed by deprotona-
tion.[25,26]
As reported in Table 1, entries 2 and 3, the reaction
to give 2a is not complete (12–13% of starting materi-
This encouraging result permits us to define the al was recovered), so the next step was to prolong the
electrogenerated cyanomethyl anion as a good cata- reaction time to let the reaction go to termination. If
lyst in the Gewald reaction; in fact, when this reaction the reaction was allowed to stand for 12 h before
was carried out in the same experimental conditions, work-up, the yield in product 2a was lowered to 65%,
but in the absence of electricity (i.e., in the absence while 4-phenylcyclohexanone was obtained in 29%
of cyanomethyl anion), no product 2a was isolated (Table 1, entry 4); it is hence clear that prolonged
(see Table 1, entry 1).
times in the presence of a base lead to the decomposi-
To better understand the reaction pathway, the ad- tion of the product into its precursors.
dition of elemental sulfur to the catholyte was done
As the chosen amount of electricity was arbitrary
before the addition of 1a (about 1 min); work-up of (the Gewald reaction is formally base-catalyzed, but
the solution gave 2a in the same yield (83%, Table 1, sometimes a stoichiometric amount of base is necessa-
entry 3). The interaction between ꢀCH2CN and S8 is ry) and starting from the results of experiment of en-
proved by the change in the colour of the catholyte tries 2 and 3, we tried to lower the amount of base
(from pale yellow at the end of the electrolysis to (thus lowering the amount of electricity flowing
dark red-brown after the addition of S8). This colour through the electrolysis cell). When 0.25 F/mol of 1a
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Activation of Elemental Sulfur by Electrogenerated Cyanomethyl Anion
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Scheme 6.
were used, the yield of 2a raised to 98%, while with (90–99%) in aminothiophenes (Table 2, entries 1–7),
0.10 F/mol the yield was quantitative (Table 1, en- irrespective of the substituents and their position on
tries 5 and 6). Having obtained such good results, our the cyclohexane ring (only in the case of compound
next step was to simplify the methodology, trying to 1g, derived from the hindered 1-oxodecaline, is the
avoid the use of the supporting electrolyte Et4NPF6 in yield slightly lower, 90%), as well as cycloheptyl-
the catholyte, but mantaining the one in the gel of
ACHTUNGTRENiNGNU denemalononitrile 1i (entry 9, 99%). In the case of
separation as only a small amount of electricity is nec- compound 1j/1j’ (Table 2, entry 10), two products are
essary (and the salt in the gel could be enough to possible,
carry out the electrolysis). The results are reported in and
2-amino-4-pentylthiophene-3-carbonitrile
2-amino-5-butyl-4-methylthiophene-3-carboni-
Table 1, entries 7–9. As can be seen, the yields of 2a trile; according to what is reported in the literature,[18]
depend on the amount of electricity, the highest (99 the major isomer was the 4,5-disubstituted one
and 98%) being with 0.25 and 0.1 F/mol, while using a (50%), while the 4-substituted was obtained in 18%
value of 0.05 F/mol 10% of starting material was re- yield.
covered, along with 83% of product. Further simplifi-
When the reagent was cyclopentylidenemalononi-
cations were to use a one-compartment cell (no sepa- trile 1h (Table 2, entry 8), the yield in the correspond-
ration gel, entry 10) and to add 4-phenylcyclohexa- ing 2-aminothiophene was 58%. This was due to the
none and malononitrile instead of the Knoevenagel concomitant formation of the dimer 3h in 41% yield.
product (attempting an one-pot synthesis, entry 11), The reaction that leads to this compound is a base-
but both led to a quantitative recovery of starting ma- catalyzed dimerization that probably starts with the
terials.
deprotonation of the methylene in the a-position to
Choosing the experimental conditions reported in the double bond, followed by the addition of a second
Table 1, entry 8 as the optimum, we extended our in- molecule of ylidenemalononitrile, as depicted in
vestigation to other alkylidenemalononitriles 1b–j, as Scheme 7.[32]
reported in Table 2. All the cyclohexylidenemalononi-
The different reactivity of cyclopentylidenemalono-
triles taken into account (1a–g) gave very high yields nitrile, with respect to the cyclohexylidene analogue,
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Marta Feroci et al.
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Table 2. Electrochemically induced Gewald reaction. Experimental conditions as in Table 1, entry 8.
Entry
1[a]
Reagent
Product
Yield [%]
98
1a
1b
1c
1d
2a
2b
2c
2d
2
3
4
>99
>99
>90
5
6
1e
1f
2e
2f
97
96
7
8
1g
1h
2g
90
2h+3h
58 and 41
9
1i
1j
2i
99
10
11[b]
2j+2j’
18 and 50
1k
1l
2k
2l
>99
12[b]
94
[a]
Same result reported in Table 1, entry 8.
[b]
These electrolyses were carried out on an MeCN-Et4NPF6 solution, Q=0.2 F/mol. After the addition of S8 and 1k or 1l,
the solution was allowed to stand al 508C for 120 min.
is probably due to the higher internal strain of the cy- been slightly changed: the electrosynthesis of
clohexylidenemalononitrile ring, that renders the sp2 ꢀCH2CN was carried out from a solution of MeCN-
ring atom more reactive towards its tetrahedraliza- Et4NPF6 (thus enhancing the current efficiency) and,
tion.[33]
after the addition of S8 and 1k or 1l, the cathodic so-
When an EWG group different from CN is present lution was allowed to stand at 508C for 3 h. This var-
in the starting molecule (i.e., CO2Et or CONH2, see iation of methodology permitted us to obtained prod-
Table 2, entries 11 and 12), the reactivity of the mole- ucts 2k and 2l in very high yields (99 and 94%, re-
cule decreases and, to obtain high yields on the corre- spectively).
sponding 2-aminothiophene, the reaction protocol has
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Activation of Elemental Sulfur by Electrogenerated Cyanomethyl Anion
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Scheme 7.
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1
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generated by galvanostatic cathodic reduction on Pt
cathode. Pt cathode, n=0.20 Vsꢀ1, reference: SCE,
room temperature, N2 atmosphere. The curve relative
to S8 shows two reduction peaks, the first at a potential
of ꢀ0.75 V and the second at a potential of ꢀ1.15 V.
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desappeared.
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AHCTUNGTREGdNNUN enemalononitrile. We have carried out the selective
electrochemical reduction of S8 in the presence of 1b,
in a MeCN/Et4NPF6 0.1 mol dmꢀ3 solution, at room
temperature, under an N2 atmosphere, on a Pt cathode,
at a potential of ꢀ0.8 V vs. SCE. After 0.4 F/mol of 1b,
the electrolysis was stopped and, after 1 hour at room
temperature, the usual work-up gave 2b in a quantita-
tive yield. This methodology, that is, the direct cathodic
reduction of elemental sulfur, is slightly more compli-
cated with respect to the one described in this paper, as
a reference electrode and the supporting electrolyte
are necessary.
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[26] Cyanomethyl anion can react with a molecule of aceto-
nitrile to give aminocrotononitrile anion (see ref.[24h]);
theoretically, both anions can act as catalysts in this ac-
tivation of sulfur, but we have not evidenced the pres-
ence of aminocrotononitrile in the cathodic solution
after the work-up. As this reaction is very fast
(<10 min of electrolysis, then addition of sulfur to the
cathodic solution), it is probable that cyanomethyl
anion has not enough time to dimerize.
2746
asc.wiley-vch.de
ꢂ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 2740 – 2746