Uncatalyzed Friedel-Crafts alkylation of aromatic compounds through reactive benzyl cations generated from N-sulfamoylcarbamates

Article abstract of DOI:10.1021/ol0272489

(Matrix presented) A new method for the generation of highly reactive benzyl cations by thermal decomposition of aryl-benzyl-sulfamoylcarbamates, obtained in a one-pot reaction from chlorosulfonyl isocyanate, is described. The generated cations alkylate aromatic compounds efficiently in the absence of catalysts.

Full text of DOI:10.1021/ol0272489

ORGANIC
LETTERS
2003
Vol. 5, No. 2
193-196
Uncatalyzed Friedel−Crafts Alkylation of
Aromatic Compounds through Reactive
Benzyl Cations Generated from
N-Sulfamoylcarbamates
Michael Sefkow* and Jens Buchs
UniVersita¨t Potsdam, Institut fu¨r Chemie, Karl-Liebknecht-Strasse 24-25,
D-14476 Golm, Germany
sefkow@rz.uni-potsdam.de
Received November 7, 2002
ABSTRACT
A new method for the generation of highly reactive benzyl cations by thermal decomposition of aryl-benzyl-sulfamoylcarbamates, obtained in
a one-pot reaction from chlorosulfonyl isocyanate, is described. The generated cations alkylate aromatic compounds efficiently in the absence
of catalysts.
Essentially “free” benzyl cations have been generated by
thermolysis of N-benzyl-N-nitrosoamides1 in nonsolvating
solvents. These cations were spatially separated from the
anions by an inert nitrogen molecule formed after thermal
rearrangement of the nitrosoamide.2 The poorly solvated,
highly reactive cations can alkylate aromatic compounds in
the absence of a catalyst.3 Despite the reactivity of these
cations, recombination of the ions usually predominates, due
to rapid nitrogen diffusion. As a result, the yields of
alkylation products are generally low (between 2% for
4-methylbenzyl and 26% for the more reactive 4-nitrobenzyl
derivatives).3 However, electron-rich heteroaromatic com-
pounds provide up to 80% yield of solvent-derived prod-
ucts.4,5
Chlorosulfonylcarbamates of tertiary or allylic alkyl groups
decompose at elevated temperature to alkylaminosulfonyl
chlorides and CO2.6 It was expected that benzyl sulfamoyl-
carbamates would undergo a similar CO2 extrusion reaction
to yield benzylsulfamides.7,8 Obviously, such reactions would
also generate benzyl cations as reactive intermediates.
The new benzyl sulfamoylcarbamates 1-4 (Scheme 1)
were prepared in one step by treatment of the corresponding
benzyl alcohols with chlorosulfonyl isocyanate (CSI)9 at -10
°C in THF, followed by the addition of 2 equiv of aniline or
4-chloroaniline, respectively (72-90% yield).
Sulfamoylcarbamates 1-4 are crystalline compounds,
insensitive to hydrolysis and thermally stable up to 80 °C.
(6) LONZA-COR Publication Chlorosulfonyl Isocyanate, 2nd ed.; 1980.
(7) (a) Burke, P. O.; McDermott, S. D.; Hannigan, T. W.; Spillane, W.
J. J. Chem. Soc., Perkin Trans. 1 1984, 1851-1854. (b) DuBois, G. E. J.
Org. Chem. 1980, 45, 5373-5375.
(8) Buchs, J. Ph.D. Thesis, Universita¨t Potsdam, Potsdam, Germany,
1999.
(9) For similar syntheses using CSI, see: (a) Dewynter, G.; Montero,
J.-L. C. R. Acad. Sci., Ser. II 1992, 315, 1675-1682. (b) Muller, G. W.;
DuBois, G. E. J. Org. Chem. 1989, 54, 4471-4473. Since CSI is known to
be the most reactive isocyanate, this reagent must be handled with care.
On the other hand, the sulfamoylcarbamates 1-4 exhibit low cytotoxicity
(unpublished results).
(1) Darbeau, R. W.; White, E. H.; Song, F.; Darbeau, N. R.; Chou, J. J.
Org. Chem. 1999, 64, 5966-5978.
(2) White, E. H.; Field, K. W.; Hendrickson, W. H.; Dzadzic, P.; Roswell,
D. F.; Paik, S.; Mullen, P. W. J. Am. Chem. Soc. 1992, 114, 8023-8031.
(3) (a) Darbeau, R. W.; White, E. H. J. Org. Chem. 2000, 65, 1121-
1131. (b) White, E. H.; Darbeau, R. W.; Chen, Y.; Chen, S.; Chen, D. J.
Org. Chem. 1996, 61, 7986-7987.
(4) Darbeau, R. W.; White, E. H. J. Org. Chem. 1997, 62, 8091-8092.
(5) Additionally, the employed N-benzyl-N-nitrosoamides are thermo-
labile, sensitive to hydrolysis, and highly carcinogenic, thus preventing a
general use of these compounds.
10.1021/ol0272489 CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/19/2002

Scheme 1
Table 1. Alkylation of Aromatic Compounds through Thermal
Decomposition of Sulfamoylcarbamates
T
yield
arene (equiv) carbamate (°C) product (%)a
isomeric ratio
mesitylene (7)
mesitylene (1.1)c
mesitylene (7)
mesitylene (6)
mesitylene (7)
mesitylene (7)
m-xylene (10)
toluene (11)
1
1
2
3
4
115
127
115
125
120
120
118
112
80
7
7
8
6
9
71b
15
20
51
88
20d
3
3
4
1
1
3
1
1
1
4
4
1
1
1
7
26e
10
11
14
15
15
12
13
16
62 o,p-10:o,o-10 ) 6:1
40 o-11:p-11 ) 2:1
benzene (50)
<2f
25
2
benzene (56)
115g
123
125
127
125
114
120
123
122
123
110
benzene (5)c
naphthalene (8)
naphthalene (2)c
indole (3)
57 R-12:â-12 ) 4:1
10 R-13:â-13 ) 8:1
25
pyridine (12)
benzonitrile (8)
benzaldehyde (9)
4-Br-anisole (7)
4-Br-anisole (3)h
4-Cl-phenole (6)i
Upon heating above 110 °C in mesitylene, N-sulfamoylcar-
bamate 3 began to decompose as indicated by gas evolution
and formation of a dark precipitate. After 5 h at 125 °C,
TLC analysis (silica gel, 1:15 EtOAc/hexanes) indicated the
predominance of a nonpolar compound and the disappearance
of the starting material, along with several highly polar
species, which have yet to be identified. Two products were
expected to have been formed by the thermal CO2 extrusion
of 3 in mesitylene: sulfamide 5 and benzylated mesitylene
6 (Scheme 1). Indeed, mesitylene derivative 6 was isolated
as the major product in 51% yield.
17
17
18
41
20
a Yields refer to isolated and purified products. b Dibenzyl-mesitylene
(19) was isolated in 9% yield. c Octane was used as an inert solvent. d 20
) Benzyloxycarbonyl chloride ((Z)-Cl). e Benzyl chloride was obtained as
the major product (42%). f After 72 h at 80 °C. g Reaction was performed
in a screw-capped, thick-walled flask. h Chlorobenzene was used as a
solvent. i Benzyl 4-chlorophenyl ether (21) was isolated as the major product
(25%).
Sulfamoylcarbamates 1-4 were reacted with several
varyingly activated aromatic compounds (Scheme 2, Table
1), each serving either as a solvent or as a cosolvent (in
combination with octane as an “inert” solvent). In every case
in which alkylation of the arene was achieved, monoalkylated
aromatic compounds were obtained as major products.10 The
ratio of mono- to polyalkylated products was dependent upon
the relative amount of aromatic solvent to sulfamoylcarbam-
ate: With a ratio of 6-11:1 (arene/sulfamoylcarbamate), up
to 88% monoalkylation and 0-9% dialkylation were ob-
served. A large excess (∼50:1) of the arene gave exclusively
the monoalkylation product. The reaction also occurred when
nearly equimolar amounts of carbamate and arene were
heated in octane as an inert, high-boiling solvent, but the
yields were significantly lower under these conditions (entries
1 and 2, 9 and 10, and 12 and 13 in Table 1).
Scheme 2
Weakly activated aromatic compounds (mesitylene, tolu-
ene, xylene, naphthalene) reacted with carbamates 1-4 to
alkylation products 7-12 in moderate to excellent yields
(20-88%). Benzene was not alkylated in a reasonable
quantity under normal pressure (<2% of 14), due to its low
boiling point. However, in a screw-capped, thick-walled
flask, it was possible to obtain diphenylmethane (15) in 25%
yield at 115 °C. The isomeric ratio of compounds 10-12
was in agreement with the general rules of second and third
substitutions of aromatic compounds. The ratio of o,p- and
o,o-10 was 6:1; the ratio of o- and p-11 was 2:1, and that of
R- and â-12 was 4:1. The isomeric ratio of the naphthalene
analogues R- and â-13 was 8:1 when the reaction was carried
out in octane, though 13 was obtained in comparatively low
yield (10%). Electron-rich heteroarenes such as indole reacted
(10) This is particularly interesting in cases where monoalkylated products
are difficult to obtain by standard Friedel-Crafts alkylation. See: Tsuchika-
wa, H.; Iwamoto, Y. (Nisshin Oil Mills, Ltd.) JP 11 228,459, 1999; Chem.
Abstr. 1999, 131, 171853h.
194
Org. Lett., Vol. 5, No. 2, 2003

with 1 to generate 3-benzylindole (16) in 25% yield.
Deactivated aromatic compounds (pyridine, benzonitrile,
benzaldehyde) were not alkylated under these conditions
(Table 1).11 Activated aromatic compounds (4-bromoanisole,
4-chlorophenol), on the other hand, were suitable substrates
for the reaction with sulfamoylcarbamates (Table 1). As
expected from the general reactivity of halophenols or
haloaryl ether, C-alkylation occurred ortho to the oxygen,
providing 17 and 1812 in 41 and 20% yields, respectively.
In the case of 4-chlorophenol, O-alkylation strongly com-
peted with C-alkylation. Consequently, benzyl-4-chlorophe-
nyl ether (21) was obtained as major product (25%). The
alkylation of arenes with 1-4 in octane as an inert solvent
is sluggish due to the low solubility of the sulfamoylcar-
bamate. Since haloarenes do not react ortho to the halogen,
chlorobenzene was used as an “inert” solvent, in which the
sulfamoylcarbamates exhibited better solubility. However,
alkylation of 4-bromoanisole with carbamate 1 was sup-
pressed when the reaction was performed in chlorobenzene.
It is known that benzyloxycarbonyl chloride ((Z)-Cl, 20)
decomposes slowly at ambient or elevated temperature to
benzyl chloride under CO2 elimination. Considering that an
unsolvated benzyl cation is formed in this process, mesitylene
was treated with (Z)-Cl under the same reaction conditions
as employed for the reaction of mesitylene with 1. Indeed,
benzylmesitylene 7 (26%) and benzyl chloride (42%) were
obtained as major products (Table 1). However, the yield of
alkylated product was substantially lower with (Z)-Cl than
with carbamate 1.
Although a detailed study of the reaction mechanism has
not yet been carried out, it was assumed that separation of
cation and anion by one (or more) neutral molecule(s) occurs
during decomposition of sulfamoylcarbamates, similar to the
thermolysis of benzyl-N-nitrosoamides (Scheme 3). In an
initial step, the carbamate moiety is cleaved into the benzyl
cation, CO2, and the sulfamide anion. This is indicated by
the gas evolution observed during heating and by the mass
peak for the -NSO2NHPh anion found when 1 was heated
in the ionization chamber of a mass spectrometer (measured
in the negative ion mode).
The major difference of the present method for generating
carbocations from that reported1 is the efficiency with which
the aromatic solvents are alkylated. One reason for this
increased alkylation ability might be the physicochemical
properties of the neutral molecule: (1) CO2 is less volatile
than N2, and thus has a longer lifetime between the separated
ion.13 (2) In contrast to N2, CO2 is a molecule with polar
bonds and a complete separation of the cation (and/or anion)
Scheme 3
from CO2 might not occur prior to the interaction of the
cation with the π system of the aromatic solvent (pathway
A). This assumption, howeVer, cannot explain why (Z)-Cl
(20) giVes significantly lower yields of alkylated product than
sulfamoylcarbamate 1. An alternative explanation might be
the formation of a second neutral species, sulfimide,14 during
heating (pathway B, Scheme 3).15 The increased distance
between cation and anion would create an additional
hindrance for a rapid recombination of the ions. It is also
possible that, depending on the substitution pattern of the
sulfamoylcarbamate, both mechanisms shown in Scheme 3
may account for the reaction behavior of these carbamates.
A series of alkyl sulfamoylcarbamates (tert-butyl, neo-
pentyl, cyclopentyl, cyclohexylmethyl) have been prepared
and decomposed in the presence of mesitylene. In no case
were alkylation products obtained. A fast â-elimination of a
proton or steric hindrance might be responsible for their
different reactivity.16 Additionally, carbamoyl derivatives
containing two arenes at the benzylic position, e.g., diphe-
nylmethyl sulfamoylcarbamate, were not suitable for the
alkylation of benzene or other arenes due to the lower
electrophilicity of the diphenylmethyl cation.17
(14) (a) Morgon, N. H.; Linnert, H. V.; Riveros, J. M. J. Phys. Chem.
1995, 99, 11667-11672. (b) Houk, K. N.; Strozier, R. W.; Hall, J. A.
Tetrahedron Lett. 1974, 897-900.
(15) Decomposition of 1 in a mass spectrometer by electron ionization
afforded, among others, peaks at 262, 183, and 181, corresponding to
N-benzyl-N′-phenylsulfamide (M - CO2), N-benzylaniline (M - CO2 -SO2-
NH), and N-benzylideneaniline (M - CO2 -NH3 -SO2). The latter is
probably produced by the oxidation of the benzyl cation. The molecular
compositions of these fragments were established by high-resolution mass
spectrometry. Although pathway A seems more likely, the preliminary mass
spectrometric studies indicate that pathway B cannot be ruled out.
(16) For example, cyclopenene, derived from elimination from cyclo-
pentyl sulfamoylcarbamate, was easily identified by its odor and, subse-
quently, by proton NMR. However, starting materials without â-protons
such as neopentyl sulfamoylcarbamate yield three major products
whose structures are currently unknown. These products are crystalline
compounds, and efforts are underway to obtain suitable crystals for X-ray
crystallography.
(11) Structures of products obtained by the interception of benzyl cations
with the carbonyl or nitrile group were not determined. For some recent
studies on this topic, see: Darbeau, R. W.; White, E. H.; Nunez, N.; Coit,
B.; Daigle M. J. Org. Chem. 2000, 65, 1115-1120. Song, F.; Darbeau, R.
W.; White, E. H. J. Org. Chem. 2000, 65, 1825-1829.
(12) Phenol 18 is used as a key precursor for the synthesis of a reversible
inhibitor of the cytosolic phospholipase A2: Burke, J. R.; Witmer, M. R.;
Zusi, F. C.; Gregor, K. R.; Davern, L. B.; Padmanabha, R.; Swann, R. T.;
Smith, D.; Tredup, J. A.; Micanovic, R.; Manly, S. P.; Villafranca, J. J.;
Tramposch, K. M. J. Biol. Chem. 1999, 274, 18864-18871.
(13) Similar tendencies were found in the thermal decomposition of
N-nitrosoamides and N-nitroamides where N2 and the less volatile N2O,
respectively, act as neutral molecules. See ref 1.
(17) Mayr, H.; Patz, M. Angew. Chem. 1994, 106, 990-1010.
Org. Lett., Vol. 5, No. 2, 2003
195

We have developed a new method for the generation of
benzyl cations. These cations can alkylate activated aromatic
compounds in the absence of a catalyst. Further investigations
into the scope and limitation of this reaction as well as
mechanistic studies are in progress.
der Chemischen Industrie for financial support. A gift of CSI
from LONZA AG (Switzerland) is acknowledged.
Supporting Information Available: Experimental details
and spectroscopic data of all compounds except 14. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. M.S. thanks the Deutsche For-
schungsgemeinschaft for a habilitation grant and the Fonds
OL0272489
196
Org. Lett., Vol. 5, No. 2, 2003