Behaviour of iprit carbonate analogues in solventless reactions

Article abstract of DOI:10.1039/c4ra03254c

Sulfur iprit carbonate analogues have been investigated in neat conditions at atmospheric pressure, in the presence and in the absence of a catalytic amount of base. Furthermore, their reaction mechanism has been discussed in detail. In these novel reaction conditions, sulfur mustard carbonate analogues, that previously showed poor or no reactivity, remarkably undergo efficient nucleophilic substitution with several substrates. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ra03254c

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Behaviour of iprit carbonate analogues in
solventless reactions†
Cite this: RSC Adv., 2014, 4, 31071
*
F. Arico',‡ S. Evaristo‡ and P. Tundo
Received 10th April 2014
Accepted 11th July 2014
Sulfur iprit carbonate analogues have been investigated in neat conditions at atmospheric pressure, in the
presence and in the absence of a catalytic amount of base. Furthermore, their reaction mechanism has been
discussed in detail. In these novel reaction conditions, sulfur mustard carbonate analogues, that previously
showed poor or no reactivity, remarkably undergo efficient nucleophilic substitution with several substrates.
DOI: 10.1039/c4ra03254c
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promoted by the sulfur or nitrogen anchimeric effect.3 The
resulting cyclic episulfonium/aziridinium ion intermediates
undergo fast nucleophilic substitution (Fig. 1).4 On the other
hand, it is also noteworthy that mustard compounds, being
genotoxic and mutagenic, stop cell cycle progression, thus, they
are able, in some cases, to prevent efficiently the proliferation of
cancer cells. As a result, both sulfur and nitrogen iprits and some
opportunely synthetically designed derivates, i.e., “mustargen”,
cause dramatic tumour regression.5
The contradictory nature of mustard molecules, i.e., highly
toxic chemical weapons and extremely useful reagents and
pharmaceuticals, has contributed to the increasing interest in
these compounds that, over the years, have been widely
exploited in both inorganic6 and organic chemistry.7
Introduction
Mustard gas, bis(2-chloroethyl) sulde is a vesicant and blistering
agent that has been used for almost 100 years in several chemical
wars, i.e., WWI and the Iran–Iraq conict.1 Its nitrogen analogue,
bis(2-chloroethyl)(ethyl)-amine, as well as their monochloro
derivatives, 2-chloroethyl methyl sulde and (2-chloroethyl)-
dimethylamine (Fig. 1), are also highly toxic and harmful to
humans and the environment. The most deleterious molecular
mechanisms in nitrogen and sulfur mustards poisoning are the
inammation and the over-activation of poly(ADP-ribose) poly-
merase resulting in DNA permanent alkylation.1 Consequently
numerous efforts have been made in order to detect, convert and/
or degrade mustard gas into less poisonous products.2
In previous works, we have extensively reported that
substituting a chlorine atom with a carbonate moiety via dialkyl
carbonate (DAC) chemistry resulted in new green synthetic
pathways with various applications, i.e., synthesis of linear and
cyclic carbamates, preparation of cyclic intermediates for the
cosmetic industry, selective mono-C-methylation of CH2-acidic
compounds such as arylacetonitriles, intermediates of anti-
inammatory drugs.8
The toxicity of sulfur and nitrogen iprits has been ascribed to
the high reactivity of these molecules that readily eliminates a
chloride ion by intramolecular nucleophilic substitution
Compared to their halogen analogues, organic carbonates
resulted green and harmless for the operators and the envi-
ronment. In particular, the toxicological tests carried out on
selected DACs didn't show any acute dermal, oral or skin
toxicity and their olfactory impact was insignicant.8a,9 It is also
noteworthy that, in many synthetic procedures, i.e., synthesis of
heterocycles, alkyl carbonates act as sacricial molecules, as
Fig.
mustards.
1
Chemical structure and reactivity of sulfur and nitrogen they are not incorporated in the nal product (Fig. 2).10d This
behaviour is comparable to the use of chlorine, halogen atoms
or their suitable derivatives, as leaving groups (i.e., tosyl chlo-
ride, mesyl chloride, etc.). However, in the case of dimethyl
carbonate (DMC) the reaction products (CO2 and methanol) are
green and can be recycled, meanwhile when halogen chemistry
is employed, waste salts, formed as by products, have to be
disposed of resulting in a negative impact on the reaction green
metrics.11 Besides, as the chemical reactivity is concerned,
halogen chemistry is more energetically intensive (i.e., deriving
Green Chemistry Group, Department of Environmental Sciences, Informatics and
Statistics, Ca' Foscari University of Venice, Dorsoduro 2137, Venezia 30123, Italy.
E-mail: tundop@unive.it; Tel: +39 041234 8669
† Electronic supplementary information (ESI) available: 1H NMR, 13C NMR
spectra, GC-MS analysis, MS analysis and Hi-Res MS analysis of the new
isolated pure products. See DOI: 10.1039/c4ra03254c
‡ The authors have contributed equally to this work.
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solvent, under pressure in an autoclave and without using any
base. In these conditions, the reaction outcome was inuenced
by several factors, i.e., temperature, nucleophile and concen-
tration. Furthermore, since the reaction involves a positively
charged intermediate (Fig. 1), it is also inuenced by the solvent
employed. In particular, acetonitrile resulted to be the best
reaction media possibly due to its polarity which might stabilize
the charged cyclic intermediate.
In this work we report on the reactivity of iprit carbonate
analogues, through a deeper insight on their reaction mecha-
nism. In particular, herein for the rst time the reactivity of
sulfur (half) mustard carbonate analogues has been investi-
gated at atmospheric pressure and in neat conditions where,
due to the enhanced viscosity of the reaction media and to the
diminished mass diffusions of the reagents, several steps of the
reaction mechanism are slowed down and thus observable. It is
noteworthy that the absence of the solvent implements the
greenness of the reaction although a small amount of base is
required for nucleophiles that do not incorporate acidic
protons. In these novel reaction conditions, the reactivity of
sulfur (half-)mustard carbonate analogues with several nucleo-
philes resulted greatly enhanced.
Fig. 2 Sacrificial molecules: a comparison between (a) chlorine and (b)
DMC chemistries.
from Cl2 production via electrolysis) and the resulting products
are more reactive, meanwhile DMC chemistry requires higher
temperatures to react.
An advantage of using DACs is that they can act as versatile
solvent and/or as green reagents. In particular DMC, depending
on the substrate and reaction conditions, can be a methox-
ycarbonylation agent (BAc2 mechanism) and/or a methylating
agent (BAl2 mechanism).10 DMC is therefore an ambiphilic
electrophile that has been shown to react in a surprisingly high
selectivity with different monodentate and bidentate
nucleophiles.12
In this prospect, we have recently reported the synthesis of
novel sulfur half-mustard carbonate analogues (Fig. 3) via DMC
chemistry. The replacement of a chlorine atom with a carbonate
moiety resulted in molecules displaying a similar reactivity and
kinetic behaviour of their chlorine homologues without
showing any evident toxicological properties.8,13,14
Results and discussion
In a typical reaction, the selected nucleophile (1.0 eq. mol.), the
mustard carbonate analogue (2.0 eq. mol.) and eventually a
catalytic amount of base (0.2 eq. mol.) are placed in a test tube
ꢀ
and heated in solventless conditions at 150 C at atmospheric
pressure.
In order to conrm the presence of the anchimeric effect also
under solventless reaction conditions, the reactivity of 2-
(methoxy)ethyl methyl carbonate 8 and of 2-(methylthio)ethyl
methyl carbonate
1 with phenol was rstly compared
(Scheme 1; entries 1–4, Table 1).
Table 1 (entry 1) shows that the reaction of phenol with 2-
(methoxy)ethyl methyl carbonate 8 in neat and in the absence of
a base resulted only in unconverted starting materials; no
methylation or alkylation of the phenol occurred. This result
demonstrates that carbonate 8 has no anchimeric effect. On the
other hand, when the reaction was carried out with K2CO3 as a
base, the nucleophilicity of phenol resulted enhanced leading
mostly to the formation of anisole and a small amount of the
The reaction mechanism involved in the selective alkylation
of a nucleophile promoted by the anchimeric effect of the iprit
carbonate analogues, includes both a BAc2 and a BAl2 mecha-
nism (Fig. 2). Thus, as in the case of chlorine chemistry, DMC
acts a sacricial molecule since it is not incorporated in the
nal product (Fig. 2).10d
Our previous investigation on the reactivity of new mustard
carbonate analogues were conducted in the presence of a
alkylated product (2-methoxyethoxy)benzene
9 (entry 2,
Table 1). In fact, the phenolate anion, formed in the presence of
K2CO3, can then attack either the methyl or the 2-(methoxy)-
ethyl moiety of the carbonate 8.
Scheme
1 Reaction of phenol with 2-(methylthio)ethyl methyl
Fig. 3 Sulfur mustard carbonate analogues.
31072 | RSC Adv., 2014, 4, 31071–31078
carbonate 1 and with 2-(methoxy)ethyl methyl carbonate 8.
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Table 1 Reaction of phenol with carbonates 8 and 1 with different
bases/catalysts in neata
Selectivity (% GC-MS)
#
Base/catalyst Carb. Conv. (%) PhO(CH2)2XCH3 PhOCH3
1
2
3
4
5
6
7
8
9
None
K2CO3
None
K2CO3
t-BuOK
NaOMe
DBUc
8
8
1
1
1
1
1
1
1
1
1
0
0
19
86
90
79
87
92
85
86
97
87
0
81
6
0
7
2
6
3
4
100
56b
100b
100b
80b
75
Al2O3
66b
64b
83
KW2000d
10 Zn(Ac)2
11 Sn(OBu)2
0
1
61b
a
Reaction conditions: phenol/carbonate/base 1.0/2.0/0.2 eq. mol., neat
at 150 ꢀC for 5 hours. b Some unidentied products were present in the
reaction mixture. 1,5-Diazabiciclo[5.4.0]undec-5-ene. Hydrotalcite
KW2000 was used in 0.2 weight%.
Fig. 4 Possible reaction mechanism for the base-promoted alkylation
reaction of 2-(methoxy)ethyl methyl carbonate 8.
c
d
Results showed that methyl (2-phenoxyethyl) sulde 11 was
the major product formed in all the experiments conducted
A similar chemoselectivity for the BAl2 mechanism between under solvent free conditions in the presence of a base (entries
methyl and primary carbons was already observed studying the 4–8, Table 1). Furthermore, the reaction proceeded with quan-
reactivity of several unsymmetrical DACs. Most probably the titative conversion of phenol. In some cases, small amount of
observed products selectivity can be ascribed to the phenoxide anisole were detected. In particular, the best performance, in
attacking preferably the less sterically hindered alkyl moiety.15 terms of conversion and selectivity (100% and 90% respec-
Thus, we can condently exclude any anchimeric effect on tively), was achieved employing K2CO3 as base (entry 4, Table
oxygen compounds 8, either in the presence and in the absence 1).19 On the other hand when Lewis acids catalysts (entries 9–11,
of a base.
Table 1) were used, the reaction outcome was similar to that
On the contrary, when 2-(methylthio)ethyl methyl carbonate without any base (entry 3, Table 1).
1 was reacted with phenol, despite the moderate conversion, the
These data conrm that the episolfonium ion is the key
alkylated product 11 formed in good selectivity already without intermediate of the reaction. In fact, when Lewis acids were
the base (entry 3, Table 1). Importantly from a mechanistic employed they did not affect positively the reaction as the acidic
point of view, the reaction mixture showed also the presence of sites do not have any inuence on the positively charged
some unidentied products that weren't detected in the exper- intermediate. Conversely, the presence of the base promotes the
iments carried out in autoclave and in the presence of a formation of the phenoxide leading to the selective formation of
solvent.13 This result might be explained according to the the alkylated product 11 (eqn (4), Fig. 4).
reaction mechanism reported in Fig. 4. The reaction interme-
In terms of reaction mechanism, the role of the base can be
diate, i.e., the episolfonium ion, is trapped in a molecular cage illustrated by the eqn (2)–(5) in the Fig. 4. In fact, most probably,
in an intimate ion pair16 (I) where diffusion phenomena limit the selected nucleophile, once deprotonated by the base
and inuence the reaction rate. The trapped cyclic intermediate (eqn (2), Fig. 4), can react with the episolfonium intermediate
I, is in equilibrium with the starting carbonate 1 according to (eqn (4), Fig. 4). However, it must be mentioned that the epi-
constant k (eqn (1)). Once the episulfonium intermediate is solfonium intermediate can also react, in the absence of the
ꢁ1
freed from the solvent cage (II according to k2 constant) it can base, with a neutral nucleophile (if the acidic compound
then either react with the nucleophile or, in the absence of dissociates in some extent according to Keq) resulting in the
CH3OCOOꢁ anion and nucleophiles, decompose into other formation of the protonated alkylated product (eqn (5), Fig. 4).
products (according to a kd; eqn (3), Fig. 4).17
This latest reaction pathway is similar to the one involved in the
The moderate conversion of the nucleophile observed (entry acid-catalysed nucleophilic substitution of epoxides (eqn (6),
3, Table 1) can be also ascribed to the scarce mass diffusivity of Fig. 4).
the neat reaction conditions and/or to the absence of an acidic
In order to validate, the role of the base in the proposed
proton in the substrate. Thus, to enhance the nucleophilicity of reaction mechanism (Fig. 4), several nucleophiles having
the phenol, its reaction with the carbonate 1 was investigated in different acidity, i.e. aromatic alcohols, aromatic diols and
the presence of several bases, i.e., alkali carbonate (entry 4), compounds incorporating acidic –CH2, were tested in this
strong bases (entries 5–6), tertiary amine (entry 7), basic reaction condition (Scheme 2, Table 2).
alumina, hydrotalcite (entries 8–9) and metallic homogenous
catalysts (entries 10–11).18
In particular, the reaction of p-bromo and p-cyanophenol
with iprit carbonate 1 resulted in the quantitative conversion
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Scheme 3 Reaction of p-cyanophenol with different sulfur mustard
carbonate analogues 2–7 in neat.
cyano moiety. In fact, when the reaction was carried out in the
absence of a base, this substrate was converted in high yield
into the alkylated derivative 13.
In this case, the reaction mechanism mirrors the one
reported in eqn (5), Fig. 4, i.e., the presence of a base is not
necessary. Reacting b-naphtol with iprit carbonate 1 resulted in
the complete conversion of the substrate and moderate yield
(entry 4, Table 2) due to some unidentied product formed,
possibly due to the decomposition of the carbonate iprit.
The reactivity of aromatic diols hydroquinone and biphenyl-
2,20-diol was also investigated. In this case, both compounds
showed a quantitative conversion and a good selectivity towards
the bis alkylated products 15 and 18 (65 and 62% respectively).
Only small amount of other alkylated derivatives were detected
(16 and 17, 19 and 20).
On the other hand, when (phenylsulfonyl)acetonitrile, that
incorporates an acidic –CH2 moiety, was reacted with half-
mustard carbonate 1 the selectivity towards bisalkylated product
21 was lower than in the other cases studied. Methyl alkyl deriv-
ative 22 was the main products (43%) and the bismethyl
compound 23 was also present in modest amount (25%).20
In order to conrm the reaction mechanism proposed in
Fig. 4 and to further explore the applications of iprit carbonates
in solventless conditions, several (half-mustard) carbonate
analogues i.e., 2–7, were also reacted in the absence of a base
with p-cyanophenol (Scheme 3, Table 3).
Scheme 2 Reaction of different nucleophiles with mustard analogue
carbonate 1; a ¼ carbonate 1 (1.0 eq. mol) K2CO3 (0.2 eq. mol), neat at
150 ꢀC for 5 hours.
Table 2 Reaction of 2-(methylthio)ethyl methyl 1 carbonate with
different nucleophiles in neata
Selectivity (% GC-MS)
#
1
2
Substrate
Conv. (%)
100b
PhO(CH2)2XCH3
PhOCH3
12 57
43
41
100
13 58
3c
4
100
13 95
5
100d
92d,f
14 55
17
17 1
5e
15 63, 16 15
Table 3 Reaction of p-cyanophenol with different sulfur mustard
6e
100b
100
18 62, 19 28
21 31, 22 43
20 8
carbonate analogues in neata
Selectivity (% GC-MS)
7e
23 25
#
Carb.
Time (h)
Conv. (%)
PhO(CH2)2XCH3
PhOCH3
1
2
2
3
4
5
6
7
24
24
21
7
21
24
93
88
24 98
24 100
25 59
26 64
27 54d
27 50d
2
0
40
31
0
a
Reaction conditions: nucleophile/carbonate/K2CO3 1.0/2.0/0.2 eq. mol.,
neat at 150 ꢀC for 5 hours. b Aer 2 hours. c Reaction without any base.
3
100
87
4b
5c
6c
d
Some unidentied product were present in the reaction mixture.
e
e
Molar ratio nucleophile/carbonate/K2CO3 1.0/4.0/0.4. f Aer 3 hours.
—
e
—
0
a
Reaction conditions: p-cyanophenol/carbonate 1.0/2.0 eq. mol., neat at
150 ꢀC. b Reaction conditions: p-cyanophenol/carbonate 1.0/1.0 eq. mol.
and discrete selectivity towards the alkylated products 12, 13
(57% and 60% respectively). Among these two nucleophiles p-
cyanophenol has an enhanced acidity due to the presence of the
c
Reaction conditions: p-cyanophenol/carbonate 2.0/1.0 eq. mol.
d
Isolated yield. e The products are not visible on GC-MS analysis.
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In the present paper, sulfur iprit carbonates were employed
in neat, at atmospheric pressure and at lower temperature
(150 ꢀC), in the presence of a base (0.2 mol. eq.) and in its
absence. Several bases and catalysts have been investigated;
K2CO3 resulted the most efficient.
The results collected demonstrated clearly that also in
solventless reaction the sulphur (half-)mustard carbonate
analogues exhibited its anchimeric effect via formation of epi-
solfonium intermediate. However, due to the scarce mass
diffusivity of the neat reaction conditions and in the absence of
an acidic proton in the nucleophile, the use of a base is
necessary. This was useful to explain the importance of the
intimate and the free ion pair in the reaction mechanism.
Furthermore, in case of nucleophiles incorporating acidic
proton such as p-cyanophenol the use of the base can be avoi-
ded without affecting the conversion or the selectivity of the
alkylation reaction. Thus, the more acidic is the nucleophile
used the less is the need of a base.
It is also noteworthy that in these novel reaction conditions,
some sulfur mustard carbonates, that previously showed little
or no reactivity with nucleophiles, undergo efficient nucleo-
philic substitution with several substrates. These results
allowed a better understanding of the reaction mechanism and
showed the versatility of these safe and green electrophiles for
possible future applications.
Scheme
4 Reaction mechanism of a generic nucleophile with
different sulfur mustard carbonate analogues.
These iprit carbonates differ from the previously studied
half-mustard carbonate analogue 1 as they include an aromatic
ring in the molecule 2, 3; incorporate a propyl (4) or butyl (5)
moiety in the backbone; or they present a symmetrical structure
6, 7. As a result the reaction intermediates vary according to the
mustard carbonate used. Thus either a 3-, 4- or 5-membered
cyclic intermediate will be rst formed and will be subsequently
attacked by the selected nucleophile (Scheme 4).
In the previously studied batch reaction conditions in auto-
clave, sulfur mustard carbonates 2–7 showed very limited or no
reactivity towards nucleophiles with the exception of 4-
(methylthio)butyl methyl carbonate 5.8
In this case study, p-cyanophenol was selected as nucleo-
phile. In fact, due to the high acidity of its hydroxyl unit, the use
of the base can be avoided (Table 3).
Experimental
Both methyl 2-(phenylthio)ethyl carbonate 2 and ethyl 2-
(phenylthio)ethyl carbonate 3 reacted readily with p-cyanophe-
nol in neat at 150 ꢀC forming the alkylated product 24 in
quantitative yield. 3-(Methylthio)propyl methyl carbonate 4 can
also be converted into the alkylated product 25 with a good
selectivity (45%). In this case the formation of the methylated
product was also detected in relevant amount (55%). This result
can be ascribed to the formation of the 1-methylthietanium, a 4-
memebered cyclic intermediate, which is known to be less
stable than the 3- or 5-memebered intermediates.21 On the other
hand, 4-(methylthio)butyl methyl carbonate 5 showed to react
readily with the nucleophile forming the alkylated product 26 in
good yield (66%).
The reaction of p-cyanophenol with double-functionalized
symmetrical mustard carbonate 6 and 7 was also investigated.
In this case, the bisalkylated product 27 wasn't detectable by
GC-MS and the reaction was followed by thin layer chroma-
tography. Therefore, the reported yields (54 and 50% respec-
tively) refer only to the isolated pure compound 27.22 It is
noteworthy that the reaction mechanism proposed in Fig. 4
(eqn (5)) perfectly ts also these latest data.
All reagents were ACS grade and were employed without further
purication. Mustard carbonate analogues
1–6
and the unsym-
metrical carbonate 8 were synthesised and puried as described
in our previous paper.13 Methyl(2-phenoxyethyl)sulfane 11 and
(2-ethoxyethoxy)benzene 9 were puried and isolated according
to our already published synthetic procedure.13 The synthesis
and characterization of compounds 17,23 20 (ref. 24) and 23
(ref. 25) have already been reported in the literature.
Synthesis of sulphur iprit carbonate analogue
Bis-(2-ethylcarbonate)ethyl sulde (7). 2,20-thiodiethanol
(5.00 g, 0.04 mol), DMC (75.0 mL, 0.80 mol) and potassium
carbonate (11.30 g, 0.08 mol) were placed in a round-bottomed
ask equipped with a reux condenser. While being stirred
magnetically, the mixture was heated at reux temperature for
17 hours. The reaction mixture was then ltered and the solvent
was evaporated under vacuum to recover the product as a yellow
oil; yield 90% (8.70 g). GC-MS: calcd for C10H18O6S 266.31;
found 265.90. HRMS (TOF-MS ESI): calcd for C10H18O6S + Na+
289.7022; found 289.7020. 1H NMR (400 MHz, CDCl3): d ¼ 1.30
(t, J ¼ 7.6 Hz, 6H), 2.82 (t, J ¼ 7.6 Hz, 4H), 4.18 (q, J ¼ 7.6 Hz,
4H), 4.27 (t, J ¼ 7.6 Hz, 4H) ppm. 13C NMR (400 MHz, CDCl3):
d ¼ 14.6, 30.9, 64.4, 66.7, 155.1 ppm.
Conclusions
Herein for the rst time the reactivity of mustard carbonates in
solventless reaction conditions with several nucleophiles are
reported. In our previous work, sulfur (half-)mustard carbonate
Reaction of 2-(methylthio)ethyl methyl carbonate 1 with
several nucleophiles20
analogues, have been investigated in batch conditions
ꢀ
employing an autoclave, high temperature (180 C), high pres- In a typical experiment, a mixture of 2-(methylthio)ethyl methyl
sure (10–15 bar) and a solvent (acetonitrile).
carbonate 1 (0.5 g, 2.0 mol. eq.), the nucleophile (1.0 mol. eq.)
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and K2CO3 (0.2 mol. eq.) was placed in an open vessel and 1H NMR (400 MHz, CDCl3): d ¼ 1.98 (s, 3H), 2.71 (t, J ¼ 6.8 Hz,
heated at 150 ꢀC while stirring. The reaction was monitored by 2H), 3.77 (s, 3H), 4.13 (t, J ¼ 6.8 Hz, 2H), 6.95–7.06 (m, 4H), 7.24–
GC-MS until consumption of the selected nucleophile.
7.36 (m, 4H) ppm. 13C NMR (400 MHz, CDCl3): d ¼ 16.3, 33.2,
In the experiments involving aromatic diols the reaction 55.9, 68.9, 110.9, 111.2, 112.8, 120.4, 121.1, 128.0, 128.7, 131.6,
mixture was composed of 2-(methylthio)ethyl methyl carbonate 156.3, 157, 2 ppm.
1 (1.50 g, 4.0 mol. eq.), the nucleophile (1.0 mol. eq.) and K2CO3
(92.0 mg, 0.4 mol. eq.).
Reaction of 4-cyanophenol with sulphur mustard carbonates
Methyl 2-(4-bromophenoxy)ethyl sulde (12). Reaction time
5 h. The pure compound was obtained as light yellow oil in 49% In a typical experiment, a mixture of p-cyanophenol (0.5 g, 1.0
(0.20 g) yield by column chromatography on silica gel using as mol. eq.) and mustard carbonate (2.0 mol. eq.) was placed in an
elution mixture dichloromethane–hexane (7 : 3).26
open vessel equipped with a reux condenser and heated at
ꢀ
4-[2-(Methylthio)ethoxy]benzonitrile (13). Reaction time 5 h. 150 C while stirring. The progress of the reaction was moni-
The pure compound was obtained in 71% (0.24 g) yield as white tored by GC-MS.
solid by column chromatography on silica gel using as elution
In the experiments involving the bis-(2-ethylcarbonate)ethyl
mixture pentane–ethyl acetate (8 : 2).27 Mp 79–80 ꢀC. GC-MS: sulde 7 the reaction mixture was composed of p-cyanophenol
calcd for C10H11NOS 193.26; found 193.10. HRMS (EI): calcd (0.5 g, 2.0 mol. eq.) and the selected mustard carbonate
1
for C10H11NOS 193.0561; found 193.0560. H NMR (400 MHz, (1.0 mol. eq.).
CDCl3): d ¼ 2.22 (s, 3H), 2.90 (t, J ¼ 6.8 Hz, 2H), 4.20 (t, J ¼ 6.8
4-[2-(Phenylthio)ethoxy]benzonitrile (24). Reaction time 24
Hz, 2H), 6.95 (d, J ¼ 8.8 Hz, 2H), 7.59 (d, J ¼ 8.8 Hz, 2H) ppm. h. The pure compound was obtained by column chromatog-
13C NMR (400 MHz, CDCl3): d ¼ 16.3, 32.8, 67.8, 104.3, 115.2, raphy on silica gel using as elution mixture dichloromethane–
119.1, 134.0, 161.8 ppm.
hexane–acetic acid (8 : 2 : 0.5) as a light yellow solid in 66%
Methyl 2-(naphthalen-2-yloxy)ethyl sulde (14). Reaction yield (0.77 g). Mp 76–77 ꢀC. GC-MS: calcd for C15H13NOS 255.33;
time 5 h. The pure compound was obtained in 38% (0.14 g) yield found 255.10. HRMS (EI): calcd for C15H13NOS 255.0717; found
as white crystals by column chromatography on silica gel using 255.0721. 1H NMR (400 MHz, CDCl3): d ¼ 3.30 (t, J ¼ 6.8 Hz, 2H),
as elution mixture hexane–ethyl acetate (7 : 3).28
1,4-Bis-[2-(methylthio)ethoxy]benzene (15). Reaction time 7.35–7.29 (m, 2H), 7.45–7.39 (m, 2H), 7.59–7.53 (m, 2H) ppm.
5 h. The pure compound was obtained by column chromatog- 13C NMR (400 MHz, CDCl3): d ¼ 32.8, 67.0, 104.5, 115.2, 119.2,
raphy on silica gel using as elution mixture dichloromethane– 126.9, 129.2, 130.2, 134.0, 134.9, 161.6 ppm.
4.17 (t, J ¼ 6.8 Hz, 2H), 6.92–6.85 (m, 2H), 7.28–7.21 (m, 1H),
hexane–acetic acid (8 : 2 : 0.2) yield as a colourless oil in 18%
4-[3-(Methylthio)propoxy]benzonitrile (25). Reaction time
(0.11 g). GC-MS: calcd for C12H18O2S2 258.40; found 258.10. 21 h. The pure compound was obtained by column chroma-
1
HRMS (EI): calcd for C12H18O2S2 258.0748; found 258.0744. H tography on silica gel using as elution mixture dichloro-
NMR (400 MHz, CDCl3): d ¼ 2.21 (s, 6H), 2.86 (t, J ¼ 6.8 Hz, 4H), methane–hexane (7 : 3) in 21% yield (0.18 g) as a light yellow oil.
4.11 (t, J ¼ 6.8 Hz, 4H), 6.85–6.83 (m, 4H) ppm. 13C NMR (400 GC-MS: calcd for C11H13NOS 207.30; found 207.10. HRMS: calcd
1
MHz, CDCl3): d ¼ 16.6, 33.5, 68.4, 116.0, 153.2 ppm.
for C11H13NOS 207.0717; found 207.0714. H NMR (400 MHz,
4-[2-(Methylthio)ethoxy]anisole (16). A sample of the pure CDCl3): d ¼ 2.20–2.02 (m, 5H), 2.68 (t, J ¼ 6.8 Hz, 2H), 4.11 (t, J ¼
compound was obtained by column chromatography on silica 7.2 Hz, 2H), 6.94 (d, J ¼ 8.4 Hz, 2H), 7.57 (d, J ¼ 8.4 Hz, 2H) ppm.
gel using as elution mixture dichloromethane–hexane–acetic 13C NMR (400 MHz, CDCl3): d ¼ 15.8, 28.6, 30.7, 66.7, 104.2,
acid (8 : 2 : 0.2) as a pale yellow oil in 8% yield (40 mg). GC-MS: 115.4, 119.4, 134.2, 162.4 ppm.
1
calcd for C10H14O2S 198.07; found 198.01. H NMR (400 MHz,
4-[4-(Methylthio)butoxy]benzonitrile (26). Reaction time 7 h.
CDCl3): d ¼ 2.20 (s, 3H), 2.85 (t, J ¼ 6.8 Hz, 2H), 3.76 (s, 3H), 4.10 The pure compound was obtained by column chromatography
(t, J ¼ 6.8 Hz, 2H), 6.81–6.84 (m, 4H) ppm. 13C NMR (400 MHz, on silica gel using as elution mixture dichloromethane–hexane
CDCl3): d ¼ 16.4, 33.3, 55.9, 68.4, 114.9, 115.9, 152.8, 154.2 ppm. (7 : 3) in 25% yield (0.23 g) as a colourless oil. GC-MS: calcd for
2,20-[2-(Methylthio)ethoxy]biphenyl (18). Reaction time 5 h.
C12H15NOS 221.32; found 221.10. HRMS: calcd for C12H15NOS
The pure compound was obtained by column chromatography 221.0874; found 221.0866. 1H NMR (400 MHz, CDCl3): d ¼ 1.84–
on silica gel using as elution mixture dichloromethane–hexane 1.72 (m, 2H), 1.99–1.85 (m, 2H), 2.11 (s, 3H), 2.57 (t, J ¼ 6.8 Hz,
(8 : 2) as a colourless oil in 40% yield (0.33 g). GC-MS: calcd for 2H), 4.03 (t, J ¼ 6.4 Hz, 2H), 6.93 (d, J ¼ 8.8 Hz, 2H), 7.57 (d, J ¼
C
18H22O2S2 334.50; found 334.20. HRMS: calcd for C18H22O2S2 8.8 Hz, 2H) ppm. 13C NMR (400 MHz, CDCl3): d ¼ 15.7, 25.7,
334.1061; found 334.1073. 1H NMR (400 MHz, CDCl3): d ¼ 1.97 28.2, 34.0, 68.0, 104.1, 115.4, 119.6, 134.2, 162.5 ppm.
(s, 6H), 2.71 (t, J ¼ 6.8 Hz, 4H), 4.12 (t, J ¼ 6.8 Hz, 4H), 6.97–6.92
Bis[2-(4-cyanophenoxy) ethyl] sulde (27). Reaction time
(m, 2H), 7.05–6.98 (m, 2H), 7.35–7.23 (m, 4H) ppm. 13C NMR 21 h. The pure compound was obtained by column chroma-
(400 MHz, CDCl3): d ¼ 16.3, 33.3, 69.0, 112.7, 121.0, 128.7, 131.8, tography on silica gel using as elution mixture dichloro-
156.4 ppm.
methane–ethyl acetate (98 : 2) in 54% yield (0.37 g) as a white
2-[2-(Methylthio)ethoxy]-20-methoxybiphenyl (19). A sample solid. Mp 110–111 ꢀC. HRMS (EI): calcd for C18H16N2O2S
of the pure compound was obtained by column chromatog- 324.0932; found 324.0940. 1H NMR (400 MHz, CDCl3): d ¼ 3.05
raphy on silica gel using as elution mixture dichloromethane– (t, J ¼ 6.8 Hz, 4H), 4.23 (t, J ¼ 6.8 Hz, 4H), 6.94 (d, J ¼ 8.0 Hz,
hexane–acetic acid (8 : 2 : 0.2) as a colourless oil in 7% yield 4H), 7.59 (d, J ¼ 8.0 Hz, 4H) ppm. 13C NMR (400 MHz, CDCl3):
(48 mg). GC-MS: calcd for C12H18O2S2 274.40; found 274.20. d ¼ 31.6, 68.3, 104.5, 115.2, 119.0, 134.1, 161.6 ppm.
31076 | RSC Adv., 2014, 4, 31071–31078
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13 (a) F. Arico, M. Chiurato, J. Peltier and P. Tundo, Eur. J. Org.
The reaction led mainly to the alkylated product (87%) with
traces of phenetole (12%), meanwhile anisole was present
only in traces (1%). This excludes the attack of the
nucleophile on the methyl of the charged cyclic
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20 Alkylated products 12–16, 18, 19 have been isolated as pure
compounds and fully characterized. Compounds 17 and 20
were present just in traces and identied only by GC-MS
(ESI†). (Phenylsulfonyl)acetonitrile derivatives 21–23 were
identied only by GC-MS analysis (ESI†) attempts to isolate
them as pure products by column chromatography were
not successful due to their similar Rf.
R. C. Bingham, D. J. Raber, R. E. Hall and P. V. R. Schleyer, 21 H. M. Benn and K. A. Vinod Singh, Can. J. Chem., 1986, 64,
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17 Experiments carried out showed that when the iprit 22 Experiments in neat conditions were also attempted for
carbonate 8 was le stirring and heating at 140 ꢀC in the
presence of 0.2 mol. eq. of a base it slowly decomposes to
the starting alcohols and other unidentied products.
nitrogen mustard carbonate analogues. However, these
compounds, being more reactive, were unstable in these
reaction conditions probably due to the formation of
tetralkylammonium derivatives or unidentied polymeric
material.
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selected so to minimize decomposition of the starting
carbonate 8. Experiments conducted reacting the half- 23 R. Huot and P. Brassard, Can. J. Chem., 1974, 52, 838.
mustard carbonate analogues and 1 eq. mol of base at 150 24 A. Zweig, A. H. Maurer and B. G. Roberts, J. Org. Chem., 1967,
ꢀC showed a rapid decomposition of the carbonate.
32, 1322.
19 In order to exclude that anisole was formed by direct 25 M. Makosza, E. Bialecka and M. Ludwikow, Tetrahedron Lett.,
methylation of the methylthio moiety of the compound 1 1972, 23, 2391.
(see gure below), 2-(methylthio)ethyl ethyl carbonate 26 Takeda Chemical Industries, Ltd., Patent US6235771B1,
(CH3SCH2CH2OCOOCH2CH3) was prepared and reacted
with phenol.
2001.
27 These data are referred to the reaction carried out without
any base.
28 N. E. Shevchenko, V. G. Nenajdenko and E. S. Balenkova,
Synthesis, 2003, 8, 1190.
31078 | RSC Adv., 2014, 4, 31071–31078
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