Metal and base-free synthesis of arylselanyl anilines using glycerol as a solvent

Article abstract of DOI:10.1039/c4gc00874j

We describe here a metal and base-free straightforward method to access arylselanyl anilines using glycerol as a solvent. Starting from N,N-disubstituted anilines and arylselanyl chloride, the protocol is general and was successfully applied to a sort of anilines with different substitution patterns in both the aromatic ring and the nitrogen atom. As desirable for a green synthetic procedure, the non-toxic, low volatile, renewable glycerol was used as a solvent at room temperature. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4gc00874j

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Metal and base-free synthesis of arylselanyl
anilines using glycerol as a solvent†
Cite this: DOI: 10.1039/c4gc00874j
S. Thurow, F. Penteado, G. Perin, R. G. Jacob, D. Alves and E. J. Lenardão*
We describe here a metal and base-free straightforward method to access arylselanyl anilines using
glycerol as a solvent. Starting from N,N-disubstituted anilines and arylselanyl chloride, the protocol is
general and was successfully applied to a sort of anilines with different substitution patterns in both the
aromatic ring and the nitrogen atom. As desirable for a green synthetic procedure, the non-toxic, low
volatile, renewable glycerol was used as a solvent at room temperature.
Received 13th May 2014,
Accepted 2nd June 2014
DOI: 10.1039/c4gc00874j
www.rsc.org/greenchem
as intermediates for agrochemicals and pharmaceuticals.12
Their interesting biological activities include antimicrobial,13a
Introduction
The synthetic versatility of organochalcogen compounds is antituberculosis,13a antioxidant,13a antitumor13b and antibac-
confirmed by the great amount of papers,1 books2 and terial activities.13c N,N-Dimethylaniline and its analogues are
reviews.3 Among them, organoselenium compounds are an used as photoinitiators in photopolymerization reactions in
attractive group in organic chemistry and have been receiving polymer manufacturing,14 as a substrate for selective halo-
attention due to their biological and pharmacological activities genation reactions,15 oxidation reactions,16 demethylation17
(e.g. antidepressant, antinociceptive and antioxidant),4 use in and cross-coupling reactions.18
selective reactions,5 as catalysts,6 as ionic liquids7 and syn-
Despite the high versatility and the large number of biologi-
thetic intermediates in total synthesis.2,3,8 Diaryl selenides are cal activities of organoselenium compounds and N,N-disubsti-
an important class of molecules in organoselenium chemistry, tuted anilines, there are only a few papers describing the
having a fundamental role in organic chemistry1–3 and synthesis of N,N-disubstituted anilines functionalized with
pharmacological studies on GPx-like activities.9 As a conse- organochalcogen groups and they are limited to a few, specific
quence, the number of methods for the selective formation of examples.19–22 As a consequence, virtually nothing is known
C–Se bonds has been increased throughout the years.10 In the about their chemical and biological properties. The methods
meantime, the use of electrophilic selenium species to prepare to access selenium-containing N,N-disubstituted anilines
diaryl selenides remains underexplored, although it could be a involve the use of transition metal-catalysts, specific ligands
good strategy to access these compounds.11 The use of a tran- and volatile solvents. Besides having a low E factor,23 these are
sition-metal, in the presence of bases such as KOH,10a,e,g not so green protocols, once high temperature, non-reusable
Cs2CO3,10c K2CO3,10b bipyridyl10f and organic solvents such as catalytic systems and harmful aryl halides are used in the
DMSO,10a,b,e,g MeCN,10c DMF10f and high temperature, among
the impossibility of recovering the solvent, or reusing the cata-
lyst system are the drawbacks which may increase the cost and
limit the scope of the currently described methods. The use of
alternative, greener solvents such as ionic liquids10i,j and
glycerol10k has partially circumvented some of these problems.
On the other hand, N-substituted aryl compounds and their
derivatives are a significant class of compounds, which are
widely used in the dyes and paints industry, polymers and applied
Laboratório de Síntese Orgânica Limpa, LASOL, Universidade Federal de Pelotas,
UFPel, P.O. Box 354, 96010-900 Pelotas, RS, Brazil. E-mail: lenardao@ufpel.edu.br;
Tel: +55 (53) 3275-7533
†Electronic supplementary information (ESI) available: Detailed experimental
procedures as well as spectral data of all synthesized compounds. See DOI:
10.1039/c4gc00874j
Scheme 1 General reaction summary of literature precedent (1a) and
current work (1b).
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reaction (Scheme 1a).19–22 To the best of our knowledge, there afforded product 3a in a similar yield compared to PhSeCl, but
is no general method to prepare selectively 4-arylselanyl ani- more time was needed when using PhSeBr (Table 1, entries 2
lines starting directly from N,N-disubstituted anilines.
and 4). We observed that N-(phenylselanyl)succinimide was
Due to our interest in the synthesis and the biochemistry of less reactive under the conditions tested (Table 1, entry 5).
organochalcogen compounds exploring green methodo- Aiming to reduce the reaction time, the reaction was carried
logies,10i,k,24 we describe herein our results on the first direct out at 60 °C. However, the yield decreased to 75% after 1.5 h,
and regioselective synthesis of N,N-diorganyl-4-(arylselanyl)- with the formation of diphenyl diselenide due the decom-
anilines 3, using glycerol as a green solvent,25 in reactions at position of phenylselanyl chloride (Table 1, entry 6). This is an
room temperature and without any additives or catalysts interesting finding, once reactions using glycerol as a solvent
(Scheme 1b).
are almost exclusively carried out at temperatures equal to or
above 60 °C.24a,25 The need to use an excess of PhSeCl 2a to
achieve 3a in satisfactory yield was observed; when equimolar
amounts of 1a and 2a were used, 3a was obtained only in 65%
yield (Table 1, entry 7). The excess of PhSeCl is converted
in situ to diphenyl diselenide, which is easily recovered by fil-
tration over silica gel and reused to make more 2a.30 We also
found that 3a was obtained only in 77% yield in open atmos-
phere, showing that the use of nitrogen atmosphere is essen-
tial for the total conversion of aniline 1a (Table 1, entry 8).
With the best reaction conditions established, we explored
the efficiency and generality of our methodology to other sub-
stituted arylselanyl chlorides (Table 2, entries 1–7). The reac-
Results and discussion
At first, we chose N,N-dimethylaniline (1a, R = CH3) and
phenylselanyl chloride (2a, R′ = H) to determine the best con-
ditions for the reaction. Our initial efforts were addressed to
verify whether low volatile, recyclable, green solvents could be
used in this reaction. Thus, when 1a (0.3 mmol) reacted with
2a (0.5 mmol) at room temperature in the presence of 0.5 mL
of [bmim][BF4], glycerol or PEG-400, the desired 4-(phenyl-
selanyl)aniline 3a was obtained in almost quantitative yields
after 1 h of reaction (Table 1, entries 1–3). Though these three
solvents are considered environmentally friendly,26 the syn-
thesis tree of [bmim][BF4] has more than 30 steps27 and
PEG-400 is prepared from non-renewable feedstock,28 placing
them in a position not so green if we consider the sustainabil-
ity in their manufacturing process. Taking these aspects into
consideration, glycerol was chosen for further studies on opti-
mizing the reaction conditions since, in addition to being inex-
pensive and biodegradable, obtaining it from biomass involves
very little handling and low consumption of materials and
energy.29
tion works well with
a range of arylselanyl chlorides
containing both electron-donating (–CH3 and –OCH3) and
electron-withdrawing groups (CF3, F and Cl), showing up the
sensitivity to electronic effects. It was observed that the reac-
tion is faster when electron-withdrawing groups are present in
the aromatic ring of the arylselanyl chloride. Thus, for
example, good yields were obtained with 2d (R′ = 4-F), 2e (R′ =
4-Cl) and 2f (R′ = 3-CF3) after 1–1.5 h, with the respective sela-
nylanilines 3d–f being obtained in 84, 91 and 84% yield
respectively (Table 2, entries 4–6). Conversely, 4 h was necess-
ary to convert 2c (R′ = 2-OCH3) to 3c, indicating the adverse
effect of the electron-donating methoxyl group. Satisfactorily,
good yield was obtained even for the sterically hindered
mesitylselanyl chloride 2g, which afforded 3g in 89% yield
after 3 h (Table 2, entry 7). We also extend our approach to
other N,N-disubstituted anilines and to our gratification, good
results were obtained for a variety of anilines used, including
alicyclic ones (Table 2, entries 8–13). As can be seen in Table 2,
good yields were obtained when 1b (R = C2H5) and 1g (R =
C4H9) were used, affording 3h and 3m in 81 and 99% yield
after 2 h and 1.5 h respectively (Table 2, entries 8 and 13).
The alicyclic arylamines such as 1-phenylpyrrolidine (1d),
1-phenylpiperidine (1e) and 4-phenylmorpholine (1f) were also
successfully reacted with PhSeCl 2a, with the respective
selanylanilines 3j, 3k and 3l being isolated in 70, 43 and 99%
yields after 2.5, 3 and 4 h of reaction respectively (Table 2,
entries 10–12). In these cases, the respective ortho-selanylani-
lines were also formed and although the mixture could not be
separated by column chromatography, the two isomers were
Subsequently, we examined the effect of the electrophilic
selenium species in the reaction and observed that PhSeBr
Table 1 Optimization of reaction conditionsa
Entry
X
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
Cl
Cl
Cl
Br
[bmim][BF4]
Glycerol
PEG-400
Glycerol
1
1
1
2
1
98
99
98
95
80
Glycerol
6
7
8
Cl
Cl
Cl
Glycerol
Glycerol
Glycerol
1.5
2
1
75c
65d
77e
1
observed in the H NMR spectra and the para : ortho ratio was
easily determined from them (see Table 2, footnote). The for-
mation of ortho and para isomers is probable due the acti-
vation of the benzene ring by the nitrogen unshared electron-
pair. The lower steric hindrance in 1d–f compared to acyclic
a Reaction conditions: a mixture of 1a (0.3 mmol) and 2a (0.5 mmol) in
0.5 mL of solvent was stirred at r.t. b Isolated yields. c Reaction
performed at 60 °C. d Equivalent amounts of 1a and 2a were used.
e Reaction performed in open atmosphere.
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Table 2 Generality of the reactiona
Entry
1
Aniline
ArSeCl
Time (h)
1
Productb (Yield)
2
3
1a
1a
1.5
4
4
5
1a
1a
1.5
1
6
7
1a
1a
1
2
8
9
2a
2a
2
24
10
11
2a
2a
2.5
3
12
13
2a
2a
4.5
1.5
a Reaction conditions: a mixture of aniline 1 (0.3 mmol) and arylselanyl chloride 2 (0.5 mmol) in 0.5 mL of glycerol was stirred at r.t. under a
nitrogen atmosphere. b Isolated yields. c Obtained as a mixture of para and ortho isomers in a para : ortho ratio = 89 : 11. d para : ortho ratio =
78 : 22. e para : ortho ratio = 81 : 19.
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selanyl)anilines obtained using this protocol appear highly
promising as intermediates for the preparation of more
complex molecules, such as N-propargyl amines containing
arylselanyl moieties. This new protocol to prepare arylselanyl
anilines comprises several principles of green chemistry, once
the renewable solvent glycerol successfully promotes the reac-
tion at room temperature and in the complete absence of a
metal or a base.
Scheme 2 A plausible mechanism of the reaction.
Acknowledgements
Scheme 3 Alkynylation of 4-(phenylselanyl)aniline 3a: preparation of
the densely functionalized propargyl amine 4.
The authors are grateful to FAPERGS and CNPq (PRONEX 10/
0005-1 and PRONEM 11/2026-4), CAPES, and FINEP for the
financial support.
arylamines allows the formation of ortho isomers in measur-
able amounts. Only traces of the product 3i were observed
starting from N,N-dibenzylaniline 1c, even after 24 h of stirring Notes and references
at r.t. (Table 2, entry 9).
1 (a) T. B. Grimaldi, B. Godoi, J. A. Roehrs, A. Sperança and
On the basis of recent publications on Mannich-type reac-
tions involving aniline as a nucleophile,31 a plausible mechan-
ism to the formation of 4-(phenylselanyl)aniline 3a from
N,N-dimethylaniline 1a is depicted in Scheme 2. We believe
that, at first, N,N-dimethylaniline 1a would attack the phenyl-
selanyl chloride 2a by the para-position, to form the intermedi-
ary iminium A, which suffers a proton elimination giving the
expected product 3a. We believe that the formation of inter-
molecular H-bonds between glycerol and the iminium inter-
mediate A could favor its stabilization. A similar feature was
observed in other reactions performed in the presence of
glycerol.25d–f
In order to evaluate the synthetic applicability of N,N-
dimethyl-4-(phenylselanyl)anilines 3, we decided to explore
the alkynylation of the sp3–C–H bond adjacent to the nitrogen
atom, firstly described by Li and Li32 to afford propargyl
amines (Scheme 3). Propargyl amines have a great pharma-
ceutical interest33 besides being useful intermediates in
organic synthesis.34 By using the Li’s conditions, the highly
functionalized N-methyl-N-(3-phenylprop-2-yn-1-yl)-4-(phenyl-
selanyl)aniline 4 could be prepared in 45% yield after 3 h. New
studies are necessary to optimize this reaction; however, we
envisioned 4 as a promising building block for the synthesis of
new drug candidates or more complex nitrogen and selenium-
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methodology to synthesize 4-(arylselanyl)anilines using glycerol
as an environmentally friendly solvent. The reaction occurs at
room temperature and is suitable for a range of N,N-disubsti-
tuted anilines and arylselanyl chlorides. The products were
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