Dimethyl carbonate as an ambident electrophile

Article abstract of DOI:10.1021/jo048532b

(Chemical Equation Presented) The features of various anions having different soft/hard character (aliphatic and aromatic amines, alcohoxydes, phenoxides, thiolates) are compared with regard to nucleophilic substitutions on dimethyl carbonate (DMC), using different reaction conditions. Results are well in agreement with the Hard-Soft Acid-Base (HSAB) theory. Accordingly, the high selectivity of monomethylation of CH₂ acidic compounds and primary aromatic amines with DMC can be explained by two different subsequent reactions, which are due to the double electrophilic character of DMC. The first step consists of a hard-hard reaction and selectively produces a soft anion, which, in the second phase, selectively transforms into the final monomethylated product, via a soft-soft nucleophilic displacement (yield >99% at complete conversion, using DMC as solvent).

Full text of DOI:10.1021/jo048532b

Dimethyl Carbonate as an Ambident Electrophile
†
Pietro Tundo,* Laura Rossi, and Alessandro Loris
Dipartimento di Scienze Ambientali, Universit a` Ca’ Foscari Venezia, Italy, and Consorzio
Interuniversitario Nazionale La Chimica per l’Ambiente, Italy, Dorsoduro 2137, 30123 Venezia, Italy
tundop@unive.it
Received August 20, 2004
The features of various anions having different soft/hard character (aliphatic and aromatic amines,
alcohoxydes, phenoxides, thiolates) are compared with regard to nucleophilic substitutions on
dimethyl carbonate (DMC), using different reaction conditions. Results are well in agreement with
the Hard-Soft Acid-Base (HSAB) theory. Accordingly, the high selectivity of monomethylation of
2
CH acidic compounds and primary aromatic amines with DMC can be explained by two different
subsequent reactions, which are due to the double electrophilic character of DMC. The first step
consists of a hard-hard reaction and selectively produces a soft anion, which, in the second phase,
selectively transforms into the final monomethylated product, via a soft-soft nucleophilic
displacement (yield >99% at complete conversion, using DMC as solvent).
-
-
-
Introduction
Y + CH OCOOCH h Y-COOCH + CH O
(1)
(2)
3
3
3
3
Dimethyl carbonate (DMC) is a well-known nontoxic
reagent showing three main green-chemistry features (I,
-
Y + CH OCOOCH F Y-CH + CH OCOO
3
3
3
3
1
a-d
II, and III)
as compared to other carboxylating or
alkylating agents (phosgene and methyl halides, re-
In fact, since the leaving group, methyl carbonate,
decomposes (eq 3), the base is restored and can be used
in truly catalytic amounts. This feature allows utilization
of continuous-flow (c-f) procedures (i.e. gas-liquid phase-
2
a-d
spectively):
I. DMC does not produce inorganic salts in either
3
4a,b
acylation (eq 1) or alkylation
(eq 2) reactions:
5a,b
transfer catalysis, GL-PTC,
and continuously stirred
*
To whom correspondence should be addressed. Fax:
6
tank reactor, CSTR ).
+
390412348620.
†
On leave from the Departamento de Qu ´ı mica Org a´ nica, 5000
Cordoba, Argentina.
1) (a) Tundo, P.; Anastas, P.; Black, D.; Breen, J.; Collins, T.;
Memoli, S.; Miyamoto, J.; Polyakoff, M.; Tumas, W. Pure Appl. Chem.
-
-
CH OCOO F CH O + CO
(3)
(
3
3
2
2
000, 72, 1207. (b) Anastas, P.; Warner, J. C. Green Chemistry: Theory
II. Since reaction 1 is an equilibrium and reaction 2 is
not, the product of the process can be controlled, tem-
perature being the key factor. In fact, because methyla-
tion reactions involve higher Gibbs energies of activation,
low temperatures allow carboxymethylation (DMC as
phosgene substitutive), whereas high temperatures give
and Practice; Oxford University Press: New York, 1998; p 30. (c)
Sheldon, R. A. Pure Appl. Chem. 2000, 72, 1233. (d) Trost, B. M. Science
1
991, 254, 1471.
(
2) (a) Rivetti, F. In Green Chemistry: Challenging Perspectives;
Tundo, P., Anastas, P., Eds.; Oxford University Press: Oxford, 2000;
p 201. (b) Delledonne, D.; Rivetti, F.; Romano, U. J. Organomet. Chem.
1
995, 448, C15-C19. (c) Romano, U.; Rivetti, F.; Di Muzio, N., U.S.
Patent 4,318,862, 1979. (d) Tundo, P. Continuous Flow Methods in
Organic Synthesis; E. Horwood: Chichester, UK, 1991; Chapter 4, p
1
90.
(5) (a) Tundo, P. J. Org. Chem. 1979, 44, 2048. (b) Tundo, P.; Selva,
M. CHEMTECH 1995, 25, 31.
(6) Bomben, A.; Selva, M.; Tundo, P.; Valli, L. Ind. Eng. Chem. Res.
1999, 38, 2075.
(
(
3) Mizia, F.; Rivetti, F.; Romano, U. EP 0570071, 1993.
4) (a) Tundo, P.; Selva, M.; Bomben, A. Org. Synth. 1999, 76, 169.
(
b) Tundo, P.; Selva, M. Acc. Chem. Res. 2002, 35, 706.
1
0.1021/jo048532b CCC: $30.25 © 2005 American Chemical Society
Published on Web 02/17/2005
J. Org. Chem. 2005, 70, 2219-2224
2219

Tundo et al.
ref
TABLE 1. Monomethylation of Several CH2-Acidic Compounds
a
entry
substrate
T (°C)
product
conversion (%)
selectivity (%)
1
2
3
4
PhCH2SO2Me
200
200
180
180
PhCH(Me)SO2Me
PhOCH(Me)COOMe
PhCH(Me)CN
98
100
98
99
8c
8b
5b
8a
PhOCH2COOH
96
PhCH2CN (GL-PTC)
PhCH2CN (batch)
99
99.5
PhCH(Me)CN
100
a
Selectivity is defined as monomethylated product/(monomethylated product + dimethylated product) × 100.
methylation derivatives (DMC as a substitute of dimethyl
sulfate, methyl chloride, etc.).7
Moreover, also operating at 200-250 °C, decomposition
and polymerization products or tars are not formed and
usually clear reaction mixtures are obtained.
III. DMC has a very selective behavior on alkylation
appreciable selectivity (unpublished results from our
laboratory).
The reactions of amines with DMC also have a great
industrial interest (e.g., synthesis of isocyanates without
utilization of phosgene).
While features I and II are easily accountable, the
reasons for the selectivity in monomethylation are not
of CH
2
acidic compounds, as it yields the sole monomethyl
8a
derivative when reacting with arylacetonitriles, aryl
acetates, aryloxyacetic esters, sulfones, sulfoxides,
immediately evident. Isolation of intermediates and a
8a
8b
8c
8c
7,8a
detailed kinetic study showed us
that the reaction
8
d
and lactones. Regardless of the high temperature and
the great excess of alkylating agent (DMC is also the
solvent of the reactions), at complete conversion of the
substrate selectivity for the monomethylated product is
often >99%. One can maintain that high pressures and
high temperatures are not suitable for green chemistry;
our opinion is that technology is not limited by green
chemistry, which, vice versa, utilizes the best available
tools.
mechanism does not imply a simple nucleophilic substi-
tution (eq 6).
-
ArCH X + CH OCOOCH F
3
3
-
1
-
ArCH(CH )X + CH OCOO (6)
3
3
4
Actually, monomethylation derives from an unusual
Table 1 reports the selectivity in the monomethylation
-
reaction pathway that involves the reactivity of anion 1
of some CH
2
acidic compounds. Reaction 4, for example,
-
and anion 2 , according to two consecutive nucleophilic
displacements: the first one follows a BAc2 mechanism,
while the second occurs through a BAl2 mechanism (eqs
refers to monoalkylation of nitriles, esters, and sulfones:
K CO , 180 °C
2
3
7
and 8, respectively):
ArCH X + CH OCOOCH
3
'
2
3
1
-
ArCH X + CH OCOOCH F
3
3
ArCH(CH )X + CO + CH OH (4)
3
2
3
-
1
4
-
ArCH(COOCH )X + CH O
(7, B 2)
Ac
3
3
X ) CN, COOCH , SO R, SO Ar
3
2
2
2
-
This reaction has an industrial relevance, since ArCH-
ArC (COOCH )X
+
CH OCOOCH F
3 3
3
(
CH
3
)COOH are well know anti-inflammatory agents.8a
-
2
We also reported about primary aromatic amines
-
ArC(CH )(COOCH )X + CH OCOO
(8, B 2)
Al
(
aniline, o-toluidine, o- and p-chloroaniline) undergoing
3
3
3
3
N-methylation in c-f conditions. N-Methyl anilines and
their urethanes were continuously collected at the end
of a plug-flow reactor (eq 5), whereas N,N-dimethylated
products were present in trace amounts only.
Accordingly, 4 is produced through a series of consecutive
pathways, all of them being very selective.
9
Scheme 1 accounts for such a behavior: the reaction
proceeds through the carboxymethylation species (step
b), which afterward reacts with the methyl of DMC (step
e; this step pushes the reaction to the end). The overall
reaction of Scheme 1 is that shown in eq 4.
GL-PTC
ArNH + CH OCOOCH K2CO3, PEG, 180 °C8
2
3
3
ArNHCH + ArN(CH )COOCH (5)
3
3
3
-
In summary, while anion ArCH X does not give
ArNH ) aniline, o-toluidine, o-chloroaniline,
2
-
ArC(CH
3
)
2
X, also anion ArC (COOCH
3
)X does not allow
p-chloroaniline; PEG ) poly(ethyleneglycols)
3 2
the formation of ArC(COOCH ) X.
In this paper we report how the different reactivity
of DMC in eqs 7 and 8 may be rationalized by the
Hard-Soft Acid and Base (HSAB) theory.
Differently, under GL-PTC conditions, aliphatic amines
give both mono- and dialkylated compounds, without
(
7) Tundo, P.; Selva, M.; Perosa, A.; Memoli, S. J. Org. Chem. 2002,
7, 1071.
8) (a) Selva, M.; Marques, C. A.; Tundo, P. J. Chem. Soc., Perkin
Trans. 1 1994, 1323. Loosen, P.; Tundo, P.; Selva, M., U.S. Patent 5,-
78,533, 1994. (b) Bomben, A.; Marques, C. A.; Selva, M.; Tundo, P.
6
Results
(
According to the HSAB theory, first introduced by
Pearson in 1963
2
10,11
12
and further developed by M e` ndez,
Tetrahedron 1995, 51, 11573. (c) Bomben, A.; Selva, M.; Tundo, P. J.
Chem. Res., Synop. 1997, 448. (d) Tundo, P.; Trotta, F.; Moraglio, G.
Italian Pat. 20159A/90C, 1990.
(10) Pearson, R. G. J. Am. Chem. Soc. 1963, 85, 3533.
(11) Pearson, R. G.; Songstad, J. J. Am. Chem. Soc. 1967, 89, 1827.
(9) Trotta, F.; Tundo, P.; Moraglio, G. J. Org. Chem. 1987, 52, 1300.
2220 J. Org. Chem., Vol. 70, No. 6, 2005

Dimethyl Carbonate as Ambident Electrophile
SCHEME 1. Reaction Pathway for the Monomethylation of CH
DMC
2 2 3
-Acidic Compounds (X ) CN, CO CH ) with
SCHEME 2. DMC as Ambident Nucleophile
cluded among the ambident electrophiles, as they react
with nucleophiles, yielding either products of substitution
reactions (soft-soft reaction) or alkenes (hard-hard
interaction).2
0a,b
At this regard, the reaction of 2-bromo-
ethylarenes with different phenoxide anions is relevant:
it yields different mixtures of ethers and alkenes, ac-
cording to the nucleophilic nature of the anion species
which can modulate the reaction outcome.21
Here the reactivity of some soft/hard nucleophiles with
DMC is compared: both nucleophiles at nitrogen, oxygen,
and sulfur are considered. According to their nature,
nucleophiles can discriminate between the carbon atoms
of DMC. Some reactions have been already observed,
while others are here reported for the first time.
Nitrogen Nucleophiles. In the absence of a base,
aliphatic amines such as benzylamine react with DMC
to give both alkylation and carboxymethylation products,
without any selectivity (entry 1, Table 2 and Scheme 3);
both B 2 and B 2 mechanisms are followed. The newly
Ac Al
formed carbamate does not undergo methylation reaction
if a base is not present.
In the presence of a base, aliphatic and aromatic
amines yield carbamate only; carboxymethylation reac-
tion on benzylamine occurs quantitatively, with 100%
selectivity, in few minutes (entries 2 and 4, Table 2).
Afterward, the already formed carbamate gives off its
N-methyl derivative (entry 3 and 5). Scheme 4 out-
lines this behavior. Double carboxymethylation (i.e.,
softer nucleophiles react with softer centers, whereas
hard nucleophiles preferably react with hard electro-
1
3
philes. Some fundamental studies about this behavior
were performed by Klopman.14,15
DMC has three reactive centers that can interact with
nucleophiles: the carbonyl, and two methyl groups
(
Scheme 2). Such centers can be classified according to
the HSBA principle: the carbonyl group is the harder
electrophile, as a result of its polarized positive charge
and sp hybridization; the two methyl groups represent
2
3
softer electrophiles, thanks to their sp orbital and their
saturated carbon atom, which has a weaker positive
charge.
Many ambident nucleophiles are known, but few
ambident electrophiles have been studied. Many inves-
tigations verified the compliance of reactivity of ambident
nucleophiles and electrophiles with the HSAB theory.
Among the ambident electrophiles we can mention
1
6a-d
esters and particularly propiolactones,
R,â-unsatur-
1
7
18
ated carbonyls, 3-chloro-1,2-benzoisothiazol, and tri-
PhCH
2 3 2
N(COOCH ) ) was never observed under such
cholocarbonates.19 Actually, also alkyl halides are in-
conditions.
Aromatic amines (aniline, entry 6, Table 2) are less
reactive, as in the absence of a base they do not react at
the reflux temperature of DMC (90 °C). As reported in
Experimental Section, aniline was transformed in the
absence of a base at 200 °C in an autoclave with DMC
as solvent; after 24 h the conversion was 61% without
selectivity: 15% monomethylation product, 37% di-
methylated product, and 9% carbamate were observed.
(
(
(
12) Gazquez, J. L.; M e` ndez, F. J. J. Phys. Chem. 1994, 98, 4049.
13) Tse-Lok, H. Chem. Rev. 1975, 75, 1.
14) Chemical Reactivity and Reaction Paths; Klopman, G., Ed.;
Wiley: New York, 1974.
(
(
15) Klopman, G. J. Am. Chem. Soc. 1968, 90, 223.
16) (a) Gresham, T. L.; Jansen, J. E.; Shaver, F. W.; Gregory, J.
T.; Beears, W. L. J. Am. Chem. Soc. 1948, 70, 1004. (b) Gresham, T.
L.; Jansen, J. E.; Shaver, F. W.; Frederick, M. R.; Fiedorek, F. T.;
Bankert, R. A.; Gregory, J. T.; Beears, W. L. J. Am. Chem. Soc. 1952,
7
4, 1323. (c) Gresham, T. L.; Jansen, J. E.; Shaver, F. W.; Gregory, J.
2 3
In contrast, with K CO as a catalyst and under
GL-PTC conditions, monomethylation was reported to
T. J. Am. Chem. Soc. 1948, 70, 999. (d) Gresham, T. L.; Jansen, J. E.;
Shaver, F. W.; Bankert, R. A. J. Am. Chem. Soc. 1949, 71, 661.
(17) Davidson, R. S.; Gunther, W. H. H.; Waddington-Feather, S.
M.; Lythgoe, B. J. Chem. Soc. 1964, 4907.
18) Carrington, D. E. L.; Clarke, K.; Scrowston, R. M. J. Chem. Soc.
C 1971, 3262.
19) Pierce, A. C.; Joulli e` , M. M. J. Org. Chem. 1962, 27, 3968.
(
(20) (a) Bordwell, F. G. Organic Chemistry; Macmillan: New York,
1963; p 218. (b) Parke, A. J. Adv. Phys. Org. Chem. 1967, 5, 173.
(21) Hudson, R. F.; Klopman, G. J. Chem. Soc. 1964, 5.
(
J. Org. Chem, Vol. 70, No. 6, 2005 2221

Tundo et al.
TABLE 2. Reaction of Amines with DMC in the Presence and Absence of Basesa
entry
amine
base
time (min)
% MNM
12
% DNM
6
% carbamate
% NMcarbamate
1
2
3
4
5
6
7
8
9
0
1
2
3
4
benzylamine
360
9
180
1
30
360
210
1
180
8
360
1
60
30
4
95
46
100
32
CH3ONa
CH3ONa
(CH3)3COK
(CH3)3COK
0.5
54
68
2
aniline
nr
CH3ONa
67
100
60
94
22
100
56
100
(CH3)3COK
(CH3)3COK
CH3ONa
40
78
44
1
1
1
1
1
1-decylamine
1,6 -hexanediamine
CH3ONa
(CH3)3COK
(CH3)3COK
CH3ONa
a
DMC reflux temperature, 90 °C; molar ratio amine/DMC/base ) 1.0/40/1.2. MNM ) mono N-methylation; DNM ) di N-methylation;
NMcarbamate ) N-methyl carbamate. See Experimental Section.
SCHEME 3. Reaction of Benzylamine with DMC in the Absence of a Base
SCHEME 4. Reactions of Benzylamine with DMC in the Presence of a Base
5
TABLE 3. Reaction of Phenols with DMC in the
Presence of K2CO3a
occur selectively. Although more slowly, aromatic amines
in the presence of a base (entries 7-9, Table 2) follow
the behavior of aliphatic ones reported in Scheme 4.
Oxygen Nucleophiles. Alcohols give only transes-
terification products with DMC (eq 9),
%
%
% carboxy-
entry
phenol
conversion methylation methylation
1
2
3
4
5
p-methoxyphenol
p-cresol
7.0
36.3
27.7
62.0
23
39
77
61
28
2
phenol
72
PEG, K CO3
2
p-chorophenol
98
100
ROH + CH OCOOCH y
z
3
3
b
p-cyanophenol
100
ROCOOCH + CH OH (9)
3
3
a
DMC reflux temperature, 90 °C; molar ratio phenol/DMC/
b
K2CO3 ) 1.0/40/1.2. Conversions after 53 h. After 30 h, conver-
sion 82% in the methylated derivative only. See Exp. Section.
either under GL-PTC at 180 °C22 or under batch
conditions. Also, operating at 200 °C the reaction occurs
at the carbonyl atom only: when 1-octanol was used in
Table 3 reports the results and clearly shows that
phenoxides undergo nucleophilic substitution on either
the methyl or the carbonyl group (eqs 10 and 11,
respectively). The substituent on the aromatic ring
clearly influences the reactivity: softer phenoxide anions
23
reactions with DMC in the presence of K
2
3
CO ,
no
methyl ether was observed, but methyl octyl carbonate
and dioctyl carbonate were the only products. Methyla-
tion of alcohols was reported to occur operating in the
presence of tertiary amines24 ((dimethylamino)pyridine,
N
give S 2 displacement only, while harder ones allow both
1
,4-diazobicyclo[2,2,2]octane). In this case, however, the
B
Ac2 and BAl2 reactions.
catalyst modifies the hard-soft character of the two
centers, thus allowing the nucleophilic displacement by
the alcoxide to occur.
p-Substituted phenols were used in reactions with
2 3
DMC at its reflux temperature in the presence of K CO .
K CO
2
3
ArOH + CH OCOOCH
'
3
3
ArOCH + CO + CH OH (10)
3
2
3
Under such conditions the softer phenoxide anions could
discriminate between the two centers of DMC and their
substituent controlled the reaction outcome.
K CO
2
3
z
ArOH + CH OCOOCH y
3
3
ArOCOOCH + CH OH (11)
3
3
(
22) Tundo, P.; Trotta, F.; Moraglio, G.; Logorati, F. Ind. Eng. Chem.
Res. 1988, 27, 1565.
Sulfur Nucleophiles. Aliphatic and aromatic thiols
were reacted with DMC under comparable conditions:
the results reported in Table 4 show that they produce
only the methylated derivatives (eq 12): both 1-octanthiol
(
23) 1-Octanol (9.3 mmol) was reacted in an autoclave with 40 mL
of DMC (solvent and reactant) in the presence of 11 mmol of K
at 200 °C.
2 3
CO ,
(
24) Greenshields, J. N. U. S. Patent 4,770,871, 1988.
2222 J. Org. Chem., Vol. 70, No. 6, 2005

Dimethyl Carbonate as Ambident Electrophile
TABLE 4. Reaction of Thiols and 1-Octanol with DMC
in the Presence and Absence of K2CO3a
Oxygen and Sulfur Nucleophiles. Alcohols and
Thiols. It is well established that sulfur and oxygen
anions behave in an opposite way with electrophilic
centers during nucleophilic substitutions.27 We studied
these reactions and found a further confirmation. The
comparison of the reactivity of 1-octanthiol and 1-octanol
with DMC (entries 3 and 4, Table 4) outlines the
time
%
% carboxy-
entry
thiol
base
(h) methylation methylation
1
2
3
4
thiophenol
thiophenol
1
4
24
7
27
100
34
K2CO3
1-octanthiol K2CO3
1-octanol
K2CO3
65
-
-
difference in chemoselectivity of RS and RO anions, due
to their diverse hardness. Under all of the investigated
conditions, alkoxides show a BAc2 reaction mechanism,
differently from thiolates, which react via a BAl2 type.
Phenols. Due to their delocalized anion, phenoxides
are softer nucleophilic species than alkoxides. Such
feature can be influenced by the substituent. Their
reactivity with DMC (Table 3) fits well with the HSAB
theory and with what is already reported about the soft/
hard character of such anions, in relation to the car-
boxymethyl/methyl competition during reactions with
a
DMC reflux temperature, 90 °C; molar ratio thiol/DMC/K2CO3
1.0/40/1.2. See Experimental Section.
)
and thiophenol (entry 2 and 3) attack the methyl group.
RSH + CH OCOOCH F RSCH + CO + CH OH
3
3
3
2
3
(12)
Since the sulfur nucleophiles are very reactive, thiophe-
nol was able to react in the absence of a base as well
entry 1), giving thioanisole. To rule completely out
RSCOOCH as a possible intermediate in the reaction,
n-C 17SCOOCH was refluxed with DMC in the absence
of potassium carbonate (eq 13): no reaction was observed
after 24 h, showing that RSCOOCH is not an intermedi-
(
21
2
-bromoethylbenzene.
3
8
H
3
Conclusions
CH Acidic Compounds and Primary Amines. By
3
2
ate in methylation reactions with thiolates (see Experi-
mental Section).
comparing the here described results for nitrogen, oxy-
gen, and sulfur nucleophiles, we can assert that anions
-
-
1
and 2 give different compounds since they have
RSCOOCH + CH OCOOCH F No reaction (13)
3
3
3
different soft/hard character. Their difference in hardness
provides a reason for the discrimination observed be-
tween the two electrophilic centers of DMC.
Discussion
-
The hard nucleophile 1 first attacks only the carbonyl
The results here reported are in good agreement with
the reactivity of ambident electrophiles with soft/hard
nucleophiles, according to the HSAB theory.
Nitrogen Nucleophiles. It is well-known that bases
significantly accelerate aminolysis and transamination
reactions. Bunnett 25 suggested that the direct participa-
tion of a base was the reason for the enhanced reactivity
of nitrogen nucleophiles with the carbonyl. In accordance
with other authors,26 naked RNH is excluded from the
mechanism; it looks like the role of the base is that of
-
of DMC (eq 7); the anion of the product 2 is a softer
nucleophile and selectively produces the methyl deriva-
tive (eq 8).
The change in hardness/softness of the anion, due to
the presence of the carboxymethyl group, is enough to
significantly alter the reactivity of the DMC molecule.
Primary amines behave similarly. In the presence of
a base, which exalts the hard nature of the nucleophile,
both aliphatic and aromatic derivatives first react ac-
cording a BAc2 mechanism, so producing a softer anion.
In its turn, the latter reacts via a soft/soft interaction.
In the absence of a base, both B 2 and B 2 mecha-
-
+
removing H from protonated nitrogen during or after
the attack, increasing in any case the negative charge
on nitrogen atom. Whatever the exact mechanism may
be, the presence of a base enhances the hardness of the
nucleophile. So, the reactivity with harder electrophiles
the carbonyl in this case) is raised and aminolysis
reactions are highly favored.
DMC represents a valid model molecule; its reactivity
can explain the competition between the harder RNH
2
more or less naked) and the softer RNH , through the
HSAB theory. The behavior of amines in the presence
and in the absence of a base reported in Table 2 confirms
that since the hardness of the nucleophile is increased
while operating in the presence of a base, the BAc2 rate
is dramatically accelerated and carboxymethyl deriva-
tives are selectively obtained. Once formed, the urethans
need the presence of a base to further react with DMC.
In these conditions, their RN COOCH
nucleophiles than RNH , undergo solely BAl2 reactions.
This was proved by the fact that no RN(COOCH
products, deriving from a BAc2 reaction mechanism, were
observed during our experiments.
Ac
Al
nisms occur simultaneously, although aliphatic amines
are of course more reactive.
(
The combination of the dual electrophilic character of
DMC with its reaction products allows two consecutive
steps to occur in a selective way for what concerns both
reaction sequence and yields: first the hard-hard reac-
tion occurs and produces a soft anion only; then a soft-
soft nucleophilic displacement leads to the final product.
Since hard-soft and soft-hard interactions are inhibited,
neither double methylation nor double carboxymethyla-
tion occur.
-
(
Experimental Section
-
3
anions, softer
All compounds used were ACS grade and were employed
without further purification.
GC analyses were performed using a 30 m, CP-sil 24 CB
capillary column. GC-MS analyses were performed on a mass
detector at 70 eV coupled to a gas chromatograph fitted with
-
3
)
2
(
25) Bunnett, J. F.; Davis, G. T. J. Am. Chem. Soc. 1960, 82, 665.
26) Jencks, W. P.; Carriuolo, J. J. Am. Chem. Soc. 1960, 82, 675.
(27) Rahmathullah, S.; Hall, J. E.; Bender, B. C.; McCurdy, D. R.;
Tidwell, R. R.; Boykin, D. W. J. Med. Chem. 1999, 42, 3994.
(
J. Org. Chem, Vol. 70, No. 6, 2005 2223

Tundo et al.
-
3
a 30 m, HP 5 capillary column. Reaction mixtures were
compared with authentic commercial samples.
All reactions were carried out in a three-necked, 100-mL
round-bottomed flask with a reflux condenser and a magnetic
bar.
phenols. Phenols (9.3 × 10 mol, p-methoxyphenol, p-cresol,
phenol, p-chlorophenol, and p-cyanophenol) were refluxed
under stirring with DMC and K
2 3
CO . Molar ratio phenol/
K
2
CO /DMC was 1.0/1.2/40, respectively.
3
Reaction of DMC with Thiols (Table 4). The same
Reaction of DMC with Amines in the Presence of
Bases (Table 2). The base (sodium methylate or potassium
tert-butoxide) and DMC were charged together in the reaction
procedure described above was followed for the reactions of
-3
thiols. Thiols (9.3 × 10 mol, thiophenol and 1-octanthiol)
2 3
were refluxed under stirring with DMC and K CO . Molar ratio
-
3
flask. The amine (9.3 × 10 mol; benzylamine, aniline,
2 3
thiol/K CO /DMC was 1.0/1.2/40, respectively. Thiophenol was
1
-decylamine, and 1,6-hexanediamine) was added at reflux
reacted with DMC in the same molar ratio and at the same
temperature also in the absence of base (entry 1). The reaction
of 1-octanol with DMC (entry 4) was carried out in the same
conditions.
temperature (90 °C). Amine, base, and DMC were used in a
1.0/1.2/40 molar ratio, respectively.
2
Nitrogen gas was flowed to remove the CO that possibly
formed as a byproduct. Samples (0.5 mL) were withdrawn
periodically and treated with 1.0 mL of water and 1.0 mL of
diethyl ether. The organic phase was analyzed by GC and
GC-MS.
Reaction of n-Octanethiomethylester with DMC (eq
1
(
3). The title compound (1.5 mmol) was refluxed in DMC
1.0/40 molar ratio, respectively) in a two-necked, 50-mL
round-bottomed flask with a reflux condenser and a magnetic
bar. No reaction was observed after 24 h.
Reaction of DMC with Benzylamine in the Absence
-
3
of Base (Table 2, Entry 1). Benzylamine (9.3 × 10 mol)
was reacted with DMC in a 1.0/40 molar ratio at reflux
temperature for 6 h.
Acknowledgment. Contributions from the Con-
sorzio Interuniversitario Nazionale “La Chimica per
l’Ambiente”, INCA (Interuniversity National Consor-
tium “Chemistry for the Environment”), and Italian
Ministry for Foreign Affairs, Ufficio V, are gratefully
acknowledged.
Reactions of DMC with Aniline in the Absence of Base
-
3
(
Table 2, Entry 6 and Text). Aniline (9.3 × 10 mol) was
reacted with DMC in a 1.0/40 molar ratio both at reflux
temperature for 6.0 h and at 200 °C (thermostated stainless
autoclave) for 24 h.
Reaction of DMC with Phenols (Table 3). The same
procedure described above was followed for the reactions of
JO048532B
2224 J. Org. Chem., Vol. 70, No. 6, 2005