Sulfur and nitrogen mustard carbonate analogues

Article abstract of DOI:10.1002/ejoc.201200321

Sulfur and nitrogen half-mustard compounds lose their aggressive properties when the chlorine atom is replaced by a carbonate moiety. The anchimeric effect of the novel mustard carbonate analogues is investigated. The reaction follows first-order kinetics, does not need any base, and occurs with -OH, -NH and acidic -CH nucleophiles. Most of these molecules are unexplored and might provide a novel strategy for the preparation of compounds previously not easily accessible. Copyright

Full text of DOI:10.1002/ejoc.201200321

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201200321
Sulfur and Nitrogen Mustard Carbonate Analogues
Fabio Aricò,[a] Matteo Chiurato,[a] Josephine Peltier,[a] and Pietro Tundo*[a]
Keywords: Mustard derivatives / Dialkyl carbonate / Nucleophilic substitution / Green chemistry / Reactive intermediates
Sulfur and nitrogen half-mustard compounds lose their ag- with –OH, –NH and acidic –CH nucleophiles. Most of these
gressive properties when the chlorine atom is replaced by a
carbonate moiety. The anchimeric effect of the novel mustard
carbonate analogues is investigated. The reaction follows
first-order kinetics, does not need any base, and occurs
molecules are unexplored and might provide a novel strategy
for the preparation of compounds previously not easily ac-
cessible.
tard carbonate analogues: The replacement of a chlorine
atom by a carbonate moiety not only results in harmless
compounds, but most importantly gives open access to re-
active intermediates so far only poorly exploited.
Introduction
Bis(2-chloroethyl) sulfide and bis(2-chloroethyl)(ethyl)-
amine (Figure 1), respectively, known as sulfur and nitrogen
mustards, have been used as chemical weapons for the first
time in World War I for their acutely toxic vesicant proper-
ties.[1] The toxicity of these compounds is strictly related to
their high reactivity. In fact, sulfur and nitrogen mustard,
as well as their monofunctional analogous half-mustards,
i.e., 2-chloroethyl methyl sulfide and (2-chloroethyl)dimeth-
ylamine (Figure 1), readily eliminates a chloride ion by in-
tramolecular nucleophilic substitution due to the sulfur and
nitrogen anchimeric effect, to form a cyclic episulfonium/
aziridinium ion.[2] Furthermore, in contact with the human
skin, they release HCl and can also permanently alkylate
the guanine nucleotide in DNA strands, which is particu-
larly harmful to cellular health.[1] Nevertheless, sulfur and
nitrogen (half-)mustards are of great interest as electro-
philes; in fact, they are extensively employed in inorganic
synthesis,[3] organic synthesis[4] and in the preparation of
numerous pharmaceutical intermediates.[5]
Dialkyl carbonates (DACs) in general, and dimethyl
carbonate (DMC) in particular, are well-recognized green
reagents and solvents for new synthetic pathways,[6] i.e., for
cyclic compounds[7] and varnish formulations.[8] DMC,
nowadays synthesised by CO2 insertion into epoxides,[6b]
has shown surprising high selectivity with different mono-
dentate and bidentate nucleophiles.[9] In fact, the reactivity
of the two electrophilic centers of DMC can be explained
according to the Hard-Soft Acid-Base (HSAB) theory and
modulated by temperature, which – very often – is a key
factor. In fact, DMC acts as methoxycarbonylation agent
by a BAc2 mechanism at reflux temperature (T = 90 °C),
while it acts as methylating agent via a BAl2 mechanism at
higher temperature (T Ͼ 150 °C). Both reactions give as by-
product only methanol and eventually CO2.
We already reported some examples where substituting
chlorine chemistry with DMC and taking advantage of the
related BAc2/BAl2 reaction mechanism resulted in quite un-
expected outcomes, i.e., the selective mono-C-methylation of
CH2-acidic compounds such as arylacetonitriles, intermedi-
ates for the synthesis of anti-inflammatory drugs.[10]
In this work, we account for the first time on the synthe-
sis and chemical behaviour of nitrogen and sulfur half-mus-
Figure 1. Sulfur and nitrogen (half-) mustards.
Herein we report the synthesis and a preliminary account
on the chemical behaviour of sulfur and nitrogen half-mus-
[a] Dipartimento Scienze Ambientali, Informatica e Statistica,
Università Ca’ Foscari di Venezia,
Dorsoduro 2137, 30123 Venice, Italy
Fax: +39-041-234-8620
E-mail: tundop@unive.it
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200321.
Figure 2. Sulfur and nitrogen half-mustard carbonate analogues 2–
7 and the carbonate 1 used as reference compound for this study.
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F. Aricò, M. Chiurato, J. Peltier, P. Tundo
SHORT COMMUNICATION
tard carbonate analogues (Figure 2), which showed to same way, the reaction of phenol with DEC in the presence
maintain the chemical behaviour of the parent chlorine of base resulted in the quantitative formation of ethoxyben-
compounds, while losing their toxic properties.
zene (13) after only 2 h (Entry 1, Table 1 footnote [d]).
Table 1. Reaction of phenol with sulfur and nitrogen half-mustard
carbonate analogues.[a]
Results and Discussion
Entry Carbonate Solvent Time Conversion[b]
Product
(yield [%])
k[c]
[h]
[%]
[h–1]
Sulfur half-mustard carbonate alkyl 2-(alkylthio)ethyl
carbonates 2–5, nitrogen half-mustard carbonates alkyl 2-
(dimethylamino)ethyl carbonates 6 and 7, and ethyl 2-meth-
oxyethyl carbonate 1 (Figure 2) have all been synthesised
in quantitative yield by treating the related commercially
available alcohol with the corresponding DAC by a BAc2
mechanism and using – in some cases – potassium carbon-
ate as a catalyst.
Although very simple compounds, most of these carbon-
ates, i.e., methyl 2-(methylthio)ethyl carbonate (2), ethyl 2-
(methylthio)ethyl carbonate (3), methyl 2-(phenylthio)ethyl
carbonate (4), ethyl 2-(phenylthio)ethyl carbonate (5), and
ethyl 2-(dimethylamino)ethyl carbonate (7), resulted to be
unexpectedly novel, as evidence of a chemistry not yet ex-
plored.
It is noteworthy that the carbonate analogues of the half-
mustards 2–7, isolated as pure compounds, are stable, do
not smell, and do not show any vesicant properties or harm
for the experimentator.
In order to investigate their reactivity as electrophiles,
sulfur and nitrogen half-mustard carbonate analogues were
treated with a simple nucleophile, i.e., phenol. The reactions
were conducted in an autoclave at 180 °C by using prefera-
bly acetonitrile as solvent and without any base (Scheme 1).
1[d]
2
DEC
1
1
DEC
CH3CN
CH3CN
24
24
24
33
0
97
13 (100)
8 (0)
8 (28)
–
–
–
3[e]
13 (72)
9 (100)
9 (100)
9 (58)
4
5
2
3
3
CH3CN
CH3CN
CH3CN
24
24
24
100
81
100
–
0.082
6[e]
13 (41)
9 (100)
7
3
Cyclohex- 46
ane
70
0.015
8
9
10
11
12
3
4
5
6
7
DMF
48
24
24
5
94
36
50
100
100
9 (17)
10 (45)
10 (16)
11 (100)
11 (100)
0.098
–
CH3CN
CH3CN
CH3CN
CH3CN
–
–
5
1.385[f]
[a] Carbonate (1.0 mol-equiv.) and phenol (3.0 mol-equiv.) in aceto-
nitrile (100 mL) at 180 °C in an autoclave. [b] Calculated by GC–
MS analysis using p-xylene as internal standard. [c] First-order ki-
netics constant, calculated according to the disappearance of the
starting carbonate. [d] Reaction perfomerd in the presence of
1.0 mol-equiv. of K2CO3 resulted in 100% conversion into ethoxy-
benzene (13) after 2 h. [e] Reaction performed in the presence of
1.0 mol-equiv. of K2CO3. [f] First-order kinetics were calculated
by using carbonate (1.0 mol-equiv.) and phenol (1.0 mol-equiv.) in
acetonitrile (100 mL) at 180 °C in an autoclave.
Conversely, when phenol was treated with the sulfur half-
Table 1 accounts on different aspects of the chemical be- mustard carbonate analogues 2 and 3 under neutral condi-
havior of carbonates 1–7. The reaction of phenol with di- tions, the chemical behaviour observed was different:
ethyl carbonate (DEC) and ethyl 2-methoxyethyl carbonate methyl 2-phenoxyethyl sulfide (9) formed in quantitative
(1) was used as test reaction. Phenol and DEC, employed yield (Entries 4 and 5, Table 1). This provides evidence that
as reagent and solvent (Entry 1, Table 1), gave – as only the 2-(methylthio)ethyl moiety is crucial for the reaction to
product – ethoxybenzene (13) in low conversion (33%). On occur, most probably due to the anchimeric effect of the
the other hand, phenol did not react at all with ethyl 2- sulfur atom (Figure 3).
methoxyethyl carbonate (1) (Entry 2, Table 1), most proba-
The reaction of phenol and ethyl 2-(methylthio)ethyl
bly due to the absence of an anchimeric effect. However, carbonate (3) was also conducted in the presence of a base.
when the same reaction was carried out in the presence of In this case, the sulfide 9 still formed as the main product,
a base (i.e. K2CO3), ethoxybenzene (13) formed as the main but ethoxybenzene (13) was also present in 41% yield (En-
product together with a small amount of (2-methoxye- try 6, Table 1) showing the concurrence of the BAl2 pathway
thoxy)benzene (8) (Entry 3, Table 1). This result demon- (Entry 3, footnote [e], Table 1). This result proves the im-
strates that the bimolecular substitution (BAl2 mechanism) portance of the sulfur neighboring effect in the mustard
is predominant in base-promoted DAC reactions. In the carbonate analogues. It is also evident that the anchimeric
Scheme 1. Reaction of phenol with half-mustard carbonate analogues 2–7.
2
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Sulfur and Nitrogen Mustard Carbonate Analogues
Figure 3. Reaction mechanism of sulfur half-mustard carbonate 3 with phenol.
effect does not need the presence of base, which – on the philicity of the sulfur atom compared to the carbonates 2
contrary – resulted counterproductive. It is noteworthy that and 3.
the absence of the base represents an advantage in terms of
Table 1 reports also the reactivity of the nitrogen half-
waste minimization.
mustard analogues alkyl 2-(dimethylamino)ethyl carbonates
The reaction between the sulfur half-mustard carbonate 6 and 7. Both carbonates reacted readily with phenol to
3 and phenol was then investigated by employing different give as sole product dimethyl(2-phenoxyethyl)amine (11) in
solvents. Cyclohexane resulted as a fair solvent, compared quantitative yield (Entries 11 and 12, Table 1). It is note-
to acetonitrile, in terms of conversion and selectivity (En- worthy that the reactions involving nitrogen half-mustard
try 7, Table 1), although the reaction required 46 h to carbonates 6 and 7 were much faster than the ones of sulfur
achieve 70% conversion of the starting material. N,N-Di- mustard analogues 2–5. This is almost certainly ascribed to
methylformamide (DMF) showed a poor selectivity (En- the easier formation of the aziridinium cation as the reac-
try 8, Table 1). Besides, when dimethyl sulfoxide, tetra- tion intermediate.
hydrofuran or toluene were employed, the formation of
In order to prove the reaction mechanism, some kinetics
methyl 2-phenoxyethyl sulfide (9) was not observed, al- studies were carried out both on sulfur and nitrogen half-
though the starting carbonate slowly diminished over time mustard compounds. The reaction kinetics of ethyl 2-(meth-
(24 h). Acetonitrile resulted as the best solvent for the reac- ylthio)ethyl carbonate (3) with phenol was investigated in
tion studied (Entry 5, Table 1). The effect of the solvent on different solvents resulting always in first-order kinetics
the half-mustard reactivity well agrees with what was re- (rate constants reported in Entries 5, 7 and 8, Table 1).
cently reported in the literature for functionalized aziridin-
ium salts with acetonitrile being the best solvent and THF ylamino)ethyl carbonate (7) with phenol (1:1 molar ratio)
the worst.[11]
in acetonitrile according to the reaction conditions reported
Figure 4 depicts the reaction kinetics of ethyl 2-(dimeth-
Alkyl 2-(phenylthio)ethyl carbonates 4 and 5 were also in Entry 12, Table 1. By plotting the experimental values of
treated with phenol (Entries 9 and 10, Table 1). In this ln(C0/C) and 1/C against the first- and second-order rate
cases, a low conversions of the starting carbonates and equations, respectively, it is evident that the reaction fits
modest selectivity were observed (45% and 16%, respec- first-order kinetics (Figure 4) and corroborates the reaction
tively). These results might be ascribed to the lower nucleo- mechanism reported in Figure 3.
Figure 4. Comparison between first- (black) and second-order (grey) kinetics of the reaction of carbonate 7 with phenol (1:1 molar ratio
in an autoclave 180 °C) where C is the concentration of the carbonate 7 (mol/L); p-xylene was used as internal reference.
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F. Aricò, M. Chiurato, J. Peltier, P. Tundo
SHORT COMMUNICATION
Table 1 and Figure 2 confirm that the mustard carbonate
The results reported in Table 2 prove that the novel mus-
analogues have a behaviour similar to that of the parent tard carbonates react with a wide range of nucleophiles, i.e.,
chlorine compounds,[12] i.e., the anchimeric effect follows CH- and OH-acidic compounds, carboxylic acids, amines
the order N Ͼ S ϾϾ O; no base is necessary; the reaction and inorganic anions, and give the corresponding products
follows first-order kinetics; the solvent effect is similar to in the absence of any base. The reaction between phenol
the one recently observed for aziridinium salts; besides, the and the nitrogen half-mustard carbonate 6 was also per-
novel carbonate compounds do not smell and do not show formed on a preparative scale by starting from 5.0 g of
any toxic or vesicant effects.
phenol, and the resulting product 11 was isolated in 70%
The exploitation of this reaction was next investigated by yield (see Experimental Section).
treating several nucleophiles with ethyl 2-(dimethylamino)-
ethyl carbonate (7) at 180 °C in an autoclave in acetonitrile
and under neutral conditions. The results are reported in
Conclusions
Table 2.
Replacement of the chlorine atom by a carbonate moiety
in half-nitrogen and -sulfur mustard compounds gave new,
unexplored and safe compounds that showed good reactiv-
ity and might give open access to a variety of compounds
previously not easily accessible. The reactions involving the
half-mustard carbonate analogues and a nucleophile pro-
ceed through an intramolecular SN2 mechanism promoted
by the sulfur and nitrogen anchimeric effect, which is the
rate-determining step; the subsequent nucleophilic attack,
being faster, does not influence the reaction rate.
Table 2. Reaction of different nucleophiles with nitrogen half-mus-
tard carbonate 7 in the absence of a base.[a]
The presence of a base is not required for the reaction
to proceed, since – when used – it promotes unwanted by-
products. It is also noteworthy that the novel half-mustard
carbonate electrophiles react with several nucleophiles as
well as with acetic acid.
The toxicological properties of the mustard carbonate
analogues still need to be accurately investigated. Further-
more, a study of similar systems with the heteroatom in
different positions, i.e., alkyl 3-(alkylthio)propyl carbonates
or alkyl 4-(alkylthio)butyl carbonates (and their corre-
sponding amino derivatives) will be carried out in order to
identify the extent of the neighbouring effect.[13]
Carbonates 2–7 may be a good example of Green Chem-
istry defined as innovation at molecular level.
[a] Nucleophile/carbonate (3:1) molar ratio in acetonitrile at 180 °C
in an autoclave. The conversion of the carbonate 7, calculated by
GC–MS analysis using p-xylene as internal standard, was always
quantitative. The isolated yields for compounds 15–17 were mod-
est, because purification of these compounds by column
chromatography was sometimes difficult, possibly due to their po-
larity.
Experimental Section
Methods: Details on the synthetic protocols and characterization
for carbonates 1–7 are reported in the Supporting Information.
Synthetic Protocols for Carbonates 1–7: In a typical experiment the
starting alcohol (1 mol-equiv.), DEC (10 mol-equiv.) and potas-
sium carbonate (1.1 mol-equiv.) were placed into a two-necked
round-bottomed flask equipped with a reflux condenser. While be-
ing stirred magnetically, the mixture was heated at reflux tempera-
ture for 22 h. The reaction mixture was then filtered, and the sol-
vent was evaporated.
The nucleophiles selected included an organic CH2-acidic
compound, i.e., (phenylsulfonyl)acetonitrile (Entry 1,
Table 2); salts, i.e., potassium cyanide and potassium acet-
ate (Entries 2 and 4, Table 2); a carboxylic acid, i.e., acetic
acid (Entry 3, Table 2); and an amine, i.e., N-methylaniline
(Entry 5, Table 2). In all these cases, the reactions – moni-
tored until complete disappearance of the starting carbon-
ate 7 – showed the formation of the expected substituted
compounds 14–17 as the main products together with small
amounts of several by-products that were not isolated. In
particular, dimethyl[2-(N-methylanilino)ethyl]amine (17)
was formed in low yield (Entry 5, Table 2). Potassium
cyanide also gave a poor selectivity, probably as a result of
the low solubility in the reaction mixture. All the alkylated
products 14–17 were isolated and fully characterized (see
Supporting Information).
Ethyl 2-(Methoxyethyl) Carbonate (1):[14] Colourless liquid; yield
1
96%. H NMR (400 MHz, CDCl3): δ = 1.29 (t, J = 7.2 Hz, 3 H),
3.37 (s, 3 H), 3.60 (t, J = 4.8 Hz, 2 H), 4.19 (q, J = 7.2 Hz, 2 H),
4.26 (t, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 149.8, 64.8,
61.3, 58.6, 53.6, 8.8 ppm.
Methyl 2-(Methylthio)ethyl Carbonate (2): Colourless liquid; yield
80%. HRMS: calcd. for (C5H10O4S + Na) [M]+ 189.0192; found
1
189.0192. H NMR (400 MHz, CDCl3): δ = 2.14 (s, 3 H), 2.74 (t,
J = 7.2 Hz, 2 H), 3.77 (s, 3 H), 4.28 (t, J = 7.2 Hz, 2 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 150.2, 61.1, 49.4, 27.0, 10.4 ppm.
4
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Sulfur and Nitrogen Mustard Carbonate Analogues
Ethyl 2-(Methylthio)ethyl Carbonate (3): The pure compound was
obtained by distillation under vacuum; b.p. 102 °C (0.05 bar).
Colourless liquid; yield 57%. HRMS: calcd. for (C6H12O4S + Na)
the clear solution. The pure compound was obtained by extraction
with dichloromethane/H2O. The organic phase was separated,
dried with MgSO4 and the solvent evaporated. A sample of the
pure compound was isolated as a colorless oil. Analysis of the sam-
ple was consistent with the data reported in the literature.
1
[M]+ 203.0354; found 203.0349. H NMR (400 MHz, CDCl3): δ =
1.3 (t, J = 7.2 Hz, 3 H), 2.15 (s, 3 H), 2.75 (t, J = 7.2 Hz, 2 H),
4.19 (q, J = 7.2 Hz, 2 H), 4.28 (t, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 154.9, 66.1, 64.0, 32.3, 15.7, 14.2 ppm.
Dimethyl(2-phenoxyethyl)amine (11):[17] In a stainless steel auto-
clave was placed a solution of phenol (529 mg, 5.58 mmol), 2-(di-
methylamino)ethyl ethyl carbonate (300 mg, 1.86 mmol) [or 2-(di-
methylamino)ethyl methyl carbonate] in acetonitrile (100 mL) at
180 °C while stirring. The progress of the reaction was monitored
by GC–MS. When the kinetics of the reaction was monitored, an
internal standard (p-xylene) was added to the reaction mixture, and
samples were taken at regular intervals (every hour) and analyzed
by GC–MS. After disappearance of the starting carbonate, the re-
action was stopped, the mixture cooled to room temperature, and
the solvent evaporated. The pure compound was obtained by col-
umn chromatography on silica gel using as elution mixture dichlo-
romethane/methanol (9:1) to recover the desired product as a
brown oil in 70% yield (215 mg, 1.29 mmol). Analysis of the sam-
ple was consistent with the data reported in the literature.
Methyl 2-(Phenylthio)ethyl Carbonate (4): The pure compound was
obtained by column chromatography on silica gel using hexane/
ethyl acetate (8:2). Light yellow liquid; yield 82%. HRMS: calcd.
for (C10H12O4S + H) [M]+ 229.0535; found 229.0529. 1H NMR
(400 MHz, CDCl3): δ = 3.17 (t, J = 6.8 Hz, 2 H), 3.77 (s, 3 H),
4.27 (t, J = 6.8 Hz, 2 H), 7.21 (t, J = 5.6 Hz, 1 H), 7.30 (m, 2 H),
7.40 (d, J = 6.8 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
150.2, 129.5, 124.7, 123.8, 121.4, 60.7, 49.5, 26.8 ppm.
Ethyl 2-(Phenylthio)ethyl Carbonate (5): The pure compound was
obtained by a column chromatography on silica gel using heptane/
ethyl acetate (9:1). Colourless liquid; yield 79%. HRMS: calcd. for
(C11H14O4S + Na) [M]+ 265.0505; found 265.0505. 1H NMR
(400 MHz, CDCl3): δ = 1.30 (t, J = 7.2 Hz, 3 H), 3.18 (t, J =
6.8 Hz, 2 H), 4.18 (q, J = 6.8 Hz, 2 H), 4.26 (t, J = 7.2 Hz, 2 H),
7.23 (t, J = 5.6 Hz, 1 H), 7.30 (dd, J = 7.2, 5.6 Hz, 2 H), 7.39 (d,
J = 6.8 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 154.8,
134.8, 130.0, 129.0, 126.7, 65.8, 64.1, 32.2, 14.2 ppm.
2-(Dimethylamino)ethyl Methyl Carbonate (6):[15] The pure com-
pound was obtained by fractionated distillation under vacuum; b.p.
60–62 °C (0.05 bar). Orange liquid; yield 24%. 1H NMR
(400 MHz, CDCl3): δ = 2.96 (s, 6 H), 2.61 (t, J = 5.6 Hz, 2 H),
3.77 (s, 3 H), 4.24 (t, J = 5.6 Hz, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 155.7, 65.4, 57.5, 54.7, 45.5 ppm.
4-(Dimethylamino)-2-(phenylsulfonyl)butyronitrile (14): In a stain-
less steel autoclave was placed 2-(dimethylamino)ethyl ethyl car-
bonate (300 mg, 1.86 mmol) with 2-(phenylsulfonyl)acetonitrile
(1.10 g, 5.58 mmol) in acetonitrile (100 mL) at 180 °C while stir-
ring. The progress of the reaction was monitored by GC–MS. After
disappearance of the starting carbonate, the reaction was stopped,
the mixture cooled to room temperature, and the solvent evapo-
rated. The pure compound was obtained by column chromatog-
raphy on silica gel using as elution mixture dichloromethane/meth-
anol (95:5) to recover the desired product 14 in 81% yield (380 mg,
1.50 mmol) as a brown oil. HRMS: calcd. for (C12H16N2O2S + H)
1
[M]+ 253.1011; found 253.1005. H NMR (400 MHz, CDCl3): δ =
Ethyl 2-(Dimethylamino)ethyl Carbonate (7): The pure compound
was obtained by fractionated distillation under vacuum; b.p. 73 °C
(0.05 bar). Colourless liquid; yield 42%. HRMS: calcd. for
(C7H15O3N + H) [M]+ 162.1130; found 162.1125. 1H NMR
(400 MHz, CDCl3): δ = 1.30 (t, J = 7.2 Hz, 3 H), 2.36 (s, 6 H),
2.69 (t, J = 5.6 Hz, 2 H), 4.19 (q, J = 7.2 Hz, 2 H), 4.28 (t, J =
5.6 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 155.1, 65.2,
63.8, 57.6, 45.5, 14.1 ppm.
2.25 (s, 6 H), 2.42–2.64 (m, 4 H), 4.41–4.45 (m, 1 H), 7.64 (m, 2
H), 7.76 (t, J = 6.4 Hz, 1 H), 8.02 (d, J = 7.2 Hz, 2 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 135.9, 135.1, 129.5, 113.9, 55.0, 54.8,
44.8, 24.9 ppm.
3-(Dimethylamino)propanenitrile (15):[18] In a stainless steel auto-
clave was placed 2-(dimethylamino)ethyl ethyl carbonate (150 mg,
0.98 mmol) with potassium cyanide (192 mg, 2.95 mmol) in 100 mL
of acetonitrile at 180 °C while stirring. The progress of the reaction
was monitored by GC–MS. After disappearance of the starting
carbonate, the reaction was stopped, the mixture cooled to room
temperature, and the solvent evaporated. The pure compound was
obtained by column chromatography on silica gel using as elution
mixture dichloromethane/methanol (95:5) to recover the desired
product in 40% yield (40 mg, 0.39) as a brown oil. Analysis of the
sample was consistent with data reported in the literature.
2-(Dimethylamino)ethyl Acetate (16):[19] In a stainless steel auto-
clave was placed 2-(dimethylamino)ethyl ethyl carbonate (300 mg,
1.86 mmol) with acetic acid (335 mg, 5.58 mmol) (or potassium
acetate 547 mg, 5.58 mmol) in 100 mL of acetonitrile at 180 °C
while stirring. The progress of the reaction was monitored by GC–
MS. After disappearance of the starting carbonate, the reaction was
stopped, the mixture cooled to room temperature, and the solvent
evaporated. In both reactions, the pure compound was obtained
by column chromatography on silica gel using as elution mixture
dichloromethane/methanol (95:5) to recover the desired product in
28% yield (68 mg, 0.52 mmol) (40% also in the case of potassium
acetate) as a brown oil. Analysis of the sample was consistent with
data reported in the literature.
Reaction of Carbonates with Nucleophiles
Methyl (2-Phenoxyethyl) Sulfide (9):[4b] A mixture of ethyl 2-(meth-
ylthio)ethyl carbonate (300 mg, 1.83 mmol) and phenol (516 mg,
5.49 mmol) in acetonitrile (100 mL) was placed into an autoclave
and heated at 180 °C while stirring for 23 h. The progress of the
reaction was monitored by GC–MS. When the kinetics of the reac-
tion was monitored, p-xylene (197 mg, 1.83 mmol) was added to
the reaction mixture as internal standard and samples were taken
at regular intervals (every hour) and analyzed by GC–MS. After
disappearance of the starting carbonate, the reaction was stopped
and the mixture cooled to room temperature. Then the solvent was
evaporated from the clear solution. The pure compound was ob-
tained by column chromatography on silica gel using as elution
mixture hexane/ethyl acetate (9:1). A sample of the pure compound
was isolated as a colorless oil. Analysis of the sample was consistent
with the data reported in the literature.[4b]
(2-Phenoxyethyl) Phenyl Sulfide (10):[16] A mixture of ethyl 2-(phen-
ylthio)ethyl carbonate (500 mg, 2.35 mmol) and phenol (665 mg,
7.07 mmol) in acetonitrile (100 mL) was placed into an autoclave
and heated at 180 °C while stirring for 24 h. The progress of the
reaction was monitored by GC–MS. After disappearance of the
starting carbonate, the reaction was stopped and the mixture co-
oled to room temperature. Then the solvent was evaporated from
Dimethyl[2-(N-methylanilino)ethyl]amine (17):[20] In a stainless steel
autoclave was placed 2-(dimethylamino)ethyl ethyl carbonate
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Job/Unit: O20321
/KAP1
Date: 08-05-12 09:43:05
Pages: 7
F. Aricò, M. Chiurato, J. Peltier, P. Tundo
SHORT COMMUNICATION
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(300 mg, 1.86 mmol) with N-methylaniline (598 mg, 5.58 mmol) in
100 mL of acetonitrile at 180 °C while stirring. The progress of the
reaction was monitored by GC–MS. After disappearance of the
starting carbonate, the reaction was stopped, the mixture cooled to
room temperature, and the solvent evaporated. The pure com-
pound was obtained by column chromatography on silica gel using
as elution mixture dichloromethane/methanol (95:5) in 30% yield
(97 mg, 0.54 mmol) as a brown oil. Analysis of the sample was
consistent with data reported in the literature.
Supporting Information (see footnote on the first page of this arti-
cle): 1H and 13C NMR, HR-MS and GC–MS data of the pure
compounds and an example of kinetics constant calculation.
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Received: March 15, 2012
Published Online: ᭿
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20321
/KAP1
Date: 08-05-12 09:43:05
Pages: 7
Sulfur and Nitrogen Mustard Carbonate Analogues
Green Chemistry
F. Aricò, M. Chiurato, J. Peltier,
P. Tundo* .......................................... 1–7
Sulfur and Nitrogen Mustard Carbonate
Analogues
The synthesis and the chemical reactivity
of sulfur and nitrogen half-mustard
carbonate analogues are reported. The re-
placement of the chlorine atom by a carb-
onate moiety results in harmless com-
pounds, which – maintaining the same
chemical behaviour – give access to inter-
mediates and building blocks so far only
poorly exploited.
Keywords: Mustard derivatives / Dialkyl
carbonate
/
Nucleophilic substitution
/
Green chemistry / Reactive intermediates
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