Electrophilic catalysis in nucleophilic substitution reactions in ionic liquids

Article abstract of DOI:10.1016/j.tetlet.2004.03.050

2-Chlorotropone was obtained from 2-tosyloxytropone in 88% yield in the recyclable ionic medium BMIMBF₄/LiCl. That Li⁺ acts as a Lewis acid was proven by the lack of reactivity of 2-tosyloxytropone, under the above conditions, on replacing LiCl with NaCl or BMIMCl, or using BMIMCl alone, or a BMIMBF₄/MeCN/KCl mixture. 2-Bromo- and 2-iodotropone were obtained along similar lines from LiBr or LiI, respectively, whereas LiF proved unreactive.

Full text of DOI:10.1016/j.tetlet.2004.03.050

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3633–3634
Electrophilic catalysis in nucleophilic substitution reactions in
ionic liquids
a,
Marino Cavazza and Francesco Pietra
b
*
a
Dipartimento di Chimica e Chimica Industriale, Universit ꢀa di Pisa, via Risorgimento 35, I-56100 Pisa, Italy
Via della Fratta 9, I-55100 Lucca, Italy
b
Received 16 February 2004; revised 5 March 2004; accepted 9 March 2004
Abstract—2-Chlorotropone was obtained from 2-tosyloxytropone in 88% yield in the recyclable ionic medium BMIMBF
þ
4
/LiCl.
That Li acts as a Lewis acid was proven by the lack of reactivity of 2-tosyloxytropone, under the above conditions, on replacing
4
LiCl with NaCl or BMIMCl, or using BMIMCl alone, or a BMIMBF /MeCN/KCl mixture. 2-Bromo- and 2-iodotropone were
obtained along similar lines from LiBr or LiI, respectively, whereas LiF proved unreactive.
Ó 2004 Elsevier Ltd. All rights reserved.
The fine chemical industry faces major obstacles to the
production of pharmaceuticals and commodities from
strict environmental regulations in developed countries.
On the other hand, circumventing the problem by
moving polluting technologies to emerging countries
cannot continue endlessly. Therefore, industry sees
peculiar conditions, for example, the presence of a Lewis
8
acid, in order to proceed, in contrast with the above
processes, which are of the standard S
4–7
N
2 type.
Our general recipe (Table 1, 2nd column) involved
ꢁ
3
ꢁ3
adding LiX (1.5 ꢀ 10 –2 ꢀ 10 mol) to 1-butyl-3-
‘
green chemistry’ with increasing interest. Ionic solvents,
methylimidazolium tetrafluoroborate (BMIMBF )
4
1
which practically do not evaporate and can be recycled,
are being intensely considered to this regard. Although
very expensive, ionic solvents may be a solution for
industrial products of very high added value, such as
(2 mL), heating the resulting solution to 80 °C and
further adding 2-tosyloxytropone (1, 0.053 g,
ꢁ
4
1.92 ꢀ 10 mol), always under N
2
and stirring. The
resulting solution was held at 80 °C for 60 min (X ¼ Cl)
2
certain perfumes and drugs. Reaction types, and spe-
3
or 30 min (X ¼ Br or I), then Et O extracted (Kutscher–
2
cifically organometallic processes, in ionic solvents have
been reviewed, with an accumulation of practical recipes
Steudel apparatus) and evaporated to get a residue that
was subjected to silica-gel TLC with THF–petroleum
ether 2:3. This led to recover, according to LiX used, 2-
2
;3
for a variety of processes. A systematization of these
processes is also being sought through mechanistic
studies, in particular for S 2 reactions with methyl p-
nitrobenzenesulfonate
propyl)naphthalene.
chlorotropone (2, R ¼ 0:53, 0.024 g, 88%), 2-bromo-
f
N
tropone (3, R
f
¼ 0:54, 0.013 g, 36%) and 2-iodotropone
4;5
or 2-(3-methanesulfonyloxy-
(4, R
f
¼ 0:57, 0.017 g, 38%). Using LiF or NaCl in
6;7
place of the other lithium halogenides, or 1-butyl-3-
methylimidazolium chloride (BMIMCl) or 1-butyl-3-
methylimidazolium bromide (BMIMBr) in place of
We report here our results for a model system, that is,
the replacement of the tosyloxy group by halogen from
the a-position of the cycloheptatrienone (tropone)
nucleus in ionic solvents. These experiments with sensi-
tive and typically bioactive substrates broaden the view
on nucleophilic substitution reactions at the unsaturated
carbon. Notably, these are of a special type, requiring
BMIMBF , 1 was recovered unchanged; in particular, in
4
9
case of LiF, no trace of 2-fluorotropone was detected.
4 2
Using a mixture BMIMBF –MeCN–H O–KCl––which
worked well in the case of 2-(3-methanesulfonyloxy-
6
propyl)naphthalene ––formation of 2-chlorotropone (2)
was detected in only trace amounts. The same result was
obtained using either DMSO or DMF in place of
BMIMBF4.
Keywords: Ionic liquid; Nucleophilic substitutions; Halotropones.
*
Corresponding author. Fax: +39-050-20237; e-mail: marcav@
dcci.unipi.it
That these processes can be recycled was shown by
heating the above BMIMBF –LiCl mixture to 80 °C
4
0
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.050

3634
M. Cavazza, F. Pietra / Tetrahedron Letters 45 (2004) 3633–3634
a
Table 1. Synthesis of 2-halotropones
b
c
2-X-tropone
BMIMBF
4
/LiX
MeOH/BF
3
ÆEt
2
O/LiX
von E. Doering conditions
von E. Doering
c
conditions, in our hands
d
X ¼ Cl (1)
X ¼ Br (2)
X ¼ I (3)
88 (79)%
36 (32)%
38 (34)%
60 (54)%
32 (29)%
30 (27)%
90%
75%
54%
65 (65)%
44 (29)%
33 (21)%
a
b
c
Percent yields on reacted material, in parentheses calculated yields starting from commercially available 2-hydroxytropone.
See Ref. 8.
Starting from 2-hydroxytropone in the X ¼ Cl case, starting from 2-chlorotropone in the X ¼ Br and X ¼ I cases, see note Ref. 10.
d
During many years of use, see Refs. 8, 9.
References and notes
+
Li
1
. Rogers, R. D.; Seddon, K. R.; Volkov, S. Green Industrial
Applications of Ionic Liquids. In NATO Science Series;
Kluwer: Dordrecht, 2003; Vol. 92.
-
O
O
O
X
OTs
BMIMBF4/LiX
X
OTs -LiOTs
2. Welton, T. Chem. Rev. 1999, 99, 2071–2083.
. Wasserscheid, P.; Keim, W. Angew. Chem., Int. Ed. 2000,
9, 3773–3789.
3
3
2
3
4
X =Cl
X =Br
X = I
4. Lancaster, N. L.; Welton, T.; Young, G. B. J. Chem. Soc.,
Perkin Trans. 2 2001, 2267–2270.
1
5
6
7
. Lancaster, N. L.; Salter, P. A.; Welton, T.; Young, G. B.
J. Org. Chem. 2002, 67, 8855–8861.
. Kim, D. W.; Song, C. E.; Chi, D. Y. J. Org. Chem. 2003,
Scheme 1.
6
8, 4281–4285.
. Kim, D. W.; Chi, D. Y. Angew. Chem., Int. Ed. 2004, 43,
83–485.
4
under vacuum for ca. 1 h, then adding, under N and
2
8
9
. Cavazza, M.; Pietra, F. Synth. Commun. 1997, 27, 3405–3413.
. Pietra, F.; Del Cima, F. J. Chem. Soc. (B) 1971, 2224–2230.
ꢁ
4
stirring, 1 (0.045 g, 1.4 ꢀ 10 mol) and maintaining the
mixture under these conditions for 1 h. On cooling and
Et O extracting as above, 2 was recovered in high yield
1
0. As described in Doering, W. von E.; Knox, L. H. J. Am.
Chem. Soc. 1952, 74, 5683–5687; Doering, W. von E.;
Hiskey, C. F. J. Am. Chem. Soc. 1952, 74, 5688–5693,
2-chlorotropone was prepared from 2-hydroxytropone
2
(
0.14 g, 60%). Practical limits to the number of cycles
that can be carried out are only posed by the accumu-
lation of moisture during work up.
and SOCl
pone were prepared from 2-chlorotropone and either
HBr–MeCOOH or KI–MeCOOH–H O, respectively, at
2 6 6
–C H at reflux, while 2-bromo and 2-iodotro-
2
That these processes are efficient and can be recycled
1
–3
reflux. In our hands such drastic conditions proved
unsuitable for elaborated cycloheptatrienones, such as
colchiceine, where a mixture of 9-chloroisocolchicide
was expected from the use of an ionic solvent. But
that no catalyst needs to be added, in contrast with
8;10
previous methodologies,
is entirely novel and very
(
8.3%) and 10-chlorocolchicide (18%) was obtained; Cav-
azza, M.; Pietra, F. J. Chem. Soc., Perkin Trans. 1 1995,
657–2661. Our method described here is faster and
significant. The catalytic role is exerted here by the
reagent itself. This may be rationalized in terms of
coordination of lithium ion with both the carbonyl
oxygen and the leaving group (Scheme 1).
2
cleaner than von E. Doering method, allowing improved
yields (Table 1) and easy recovery of the products.