Variation in the regioselectivity of levulinic acid bromination in ionic liquids

Article abstract of DOI:10.1016/j.tetlet.2009.11.097

The reaction of levulinic acid and its esters with bromine in ionic liquids results in the formation of 3-bromo derivatives as the major products and not the 5-bromo substituted isomers, which are typically formed in organic solvents. The bromination of l

Full text of DOI:10.1016/j.tetlet.2009.11.097

Tetrahedron Letters 51 (2010) 545–547
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Tetrahedron Letters
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Variation in the regioselectivity of levulinic acid bromination in ionic liquids
a
b
a
Alexander G. Zavozin a, , Natalya E. Kravchenko , Nikolay V. Ignat’ev , Sergei G. Zlotin
*
a N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences (ZIOC RAS), 47 Leninsky prosp., Moscow 119991, Russia
b Merck KGaA, Frankfurter Strasse 250, D-64293 Darmstadt, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 July 2009
Revised 11 November 2009
Accepted 20 November 2009
Available online 26 November 2009
The reaction of levulinic acid and its esters with bromine in ionic liquids results in the formation of 3-
bromo derivatives as the major products and not the 5-bromo substituted isomers, which are typically
formed in organic solvents. The bromination of levulinic acid in ionic liquids in the presence of urea leads
to the formation of 5-bromolevulinic acid.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Levulinic acid
Bromination
Regioisomers
Ionic liquids
The bromo derivatives of levulinic acid (1a) are building blocks
for the synthesis of several biologically active compounds. For
example, 5-bromolevulinic acid (2a) is the starting material for
the synthesis of 5-aminolevulinic acid,1a–d which is used in photo-
dynamic therapy of cancer,2–4 or can be applied as a herbicide,5 an
insecticide6 or an anti-bacterial.7 3-Bromolevulinic acid (3a) is a
convenient starting material for the synthesis of heterocyclic com-
pounds (aminothiazoles, pyridazines, butyrolactones, etc.), which
are utilised for the preparation of biologically active compounds.8
Compounds 2a and 3a can be synthesised via bromination of levu-
Wefoundthat, incontrastto organicsolvents, brominationoflev-
ulinic acid (1a) and its methyl ester 1c with Br2 (1.1 equiv) in various
ILs such as 1-ethyl-3-methylimidazolium (emim), 1-butyl-3-meth-
ylimidazolium (bmim), 1-n-octyl-3-methylimidazolium (omim)
and 1-butyl-1-methylpyrrolidinium (bmpl) [anions: bromide, tetra-
fluoroborate (BF4), hexafluorophosphate (PF6), hydrosulfate (HSO4)
and bis(triflyl)imide (NTf2)] resulted in the preferred formation of
3-bromo derivatives, 3a and 3c, respectively.16 The best regioselec-
tivities for product 3a were obtained (ratio of 3a:2a up to 6.2:1)17
in the ILs with HSO4À, PF6 and NTf2 anions (Table 1, entries
8–10). Bromination of methyl levulinate 1c in the ILs [bmim][Br]
and [emim][HSO4] afforded products 3c:2c in the ratios of 4.5:1
and 4.2:1, respectively (Table 1, entries 11 and 12). Following isola-
tion of the brominated products, the ionic liquids were easily recov-
ered and reused in subsequent runs; the unusual regioselectivity
was maintained in these cases (Table 1, entry 9).18 Dibromides 4
were obtained as side products which became the major products
if the reaction was performed with excess Br2 (2 equiv).
The increase in the ratio of products 3:2 during the bromination
of methyl ketones in ILs compared with the same reaction in or-
ganic solvents is apparently of rather general character. We found
that the reaction of 2-heptanone 1d with bromine in [bmim][BF4]
afforded regioisomers 2d and 3d in a 1:12 ratio whereas in MeOH
the ratio was 1:4 (Table 1, entries 13 and 14).1c,9
À
À
9
linic acid in organic solvents (CHCl3 or MeOH1c,9). Typically, a
mixture of products 2a and 3a in which regioisomer 2a is the major
product is formed in this reaction (Table 1, entries 1–3). Bromina-
tion of n-butyl levulinate 1b in MeOH1c results in the formation of
regioisomer 2b as the major product (Table 1, entry 4).
Recently, ionic liquids (ILs) possessing unique physicochemical
properties have gained importance in organic synthesis applications
as replacements for volatile and toxic organic solvents.10 The bromin-
ation of aromatic compounds,11 alkenes and alkynes12 in ILs has been
reported. Ionic liquids can also be used as reaction media for the
bromination of arylketones13 and 1,3-dicarbonyl compounds.10g
However, the bromination of unsymmetrical dialkylketones, which
in organic solvents typically leads to mixtures of regioisomeric prod-
ucts,14 has not been studied in ILs. The ionic liquids should influence
the mechanism of this reaction, as well as other reactions which
involve the formation of polar intermediates.15
This phenomena might be caused by isomerisation of the terminal
bromides 2 into the thermodynamically more favourable isomers 3 in
the IL. Indeed, after keeping a mixture of the levulinic acid bromides
2a/3a (1.5:1)9 in a solution of anhydrous HBr in [bmim][BF4] at ambi-
enttemperaturefor0.5 h(i.e.,underbrominatingreactionconditions)
the ratio of 2a/3a inverted to 1:1.6 (NMR data).20
* Corresponding author. Tel.: +7 499 135 89 90; fax: +7 499 135 53 28.
E-mail address: azavozin@ioc.ac.ru (A.G. Zavozin).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.097

546
A. G. Zavozin et al. / Tetrahedron Letters 51 (2010) 545–547
Table 1
Bromination of methyl ketones with Br2 in ionic liquids and organic solvents (a comparative study)
O
O
O
O
Br2
R
+
R
+
R
R
Solvent
Br
Br
Br Br
1
2
3
4
R = CO2H (a), CO2Bun (b), CO2Me (c), Prn (d)
Entry
Ketone
Solvent
T (°C)
Time (h)
Ratio (run)
2
3
4
1a
2a
1a
1a
1a
1b
1a
1a
1a
1a
1a
1a
1c
1c
1d
1d
1a
1a
CHCl3
50
65
65
20
20
50
20
20
20
20
20
20
65
20
20
20
1.0
1.0
3.5
21
0.33
0.25
0.16
0.42
0.16 (1), 0.02 (2)
0.75
0.33
0.05
3
0.1
2.0
2.2
3.0
3.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
3.4
5.0
2.5
6.0
1.0
0.1
nd
nd
0.6
0.4
1.2
2.0
MeOHc
3b
MeOHc
MeOH
4b
5d
[bmim][Br]
[omim][Br]
[bmim][BF4]
[emim][HSO4]
[bmim][PF6]
[bmpl][NTf2]
[bmim][Br]
[emim][HSO4]
MeOH
6e
7
8
9
1.0 (1), 1.0 (2)
1.0
1.0
1.0
1.0
1.0
6.2 (1), 4.6 (2)
6.0
4.5
4.2
4.0
12.0
1.0 (1), 1.0 (2)
1.0
3.3 (1), 2.5 (2)
2.6
0.7
1.8
nd
1.5
10
11d
12
13a,b
14
15f
16f
[bmim][BF4]
[bmim][PF6]
[bmpl][NTf2]
20 (1), 20 (2)
24
1.7 (1), 1.9 (2)
1.7
0.3 (1), 0.3 (2)
0.2
a
b
c
d
e
f
Data from Ref. 9.
Data from Ref. 1c.
Products 2–4 were isolated as methyl esters, which were formed with participation of the solvent (MeOH).
Levulinic acid (1a) (entry 5) or methyl levulinate (1c) (entry 11) was added to a solution of Br2 in the IL.
A solution of Br2 in the IL was added to a solution of levulinic acid (1a) in the same IL.
The reaction was carried out in the presence of urea (1.5 equiv).19
selective synthesis of
materials for the preparation of biologically active compounds or
a-bromoketones which are useful starting
Cat
natural materials.
OH
OH
O
Br2
3
R
R
R
References and notes
H
H
5
6
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An
1 IL
Scheme 1. Establishment of an equilibrium between enols 5 and 6 in ionic liquids.
Another feasible explanation relies on the known fact21 that the
enolization of ketones is accelerated significantly in the presence of
nitrogen-based cations. The literature data shows that both induc-
tive effects and through-space electrostatic interactions of cations
with the carbonyl group are responsible for this acceleration.21 It is
likely that ionic liquids may exert a similar effect on the enoliza-
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5 and 6 which should be shifted towards the thermodynamically
more stable internal enol 6 thereby facilitating the formation of
3-bromo derivatives 3 (Scheme 1).
The latter assumption also explains the faster bromination of 1
in ionic liquids in comparison with organic solvents (Table 1, com-
pare entries 1–4, 13 and entries 5–12, 14). In the presence of urea,
which coordinates to the oxygen sites of 1 via hydrogen bonding
and competes with or hinders electrostatic interactions with the
ionic liquid, the bromination of 1a proceeds more slowly affording
5-bromolevulinic acid 2a (Table 1, entries 15 and 16). Furthermore,
the urea can form a complex with Br2, which due to steric hin-
drance, favours reaction at position 5 of levulinic acid (1a).22
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regioselectivity in the bromination of methyl ketones such as lev-
ulinic acid and its esters. This process can be applied to the regio-
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17. The ratio of brominated products was determined by 1H NMR spectroscopy;
the chemical shifts and coupling constants of compounds 2–4 corresponded
with published data.9
18. After isolation of products 2–4 the remaining ionic liquid was charged with a
second portion of substrate 1 and the bromination was repeated as described
above.
19. Bromination of levulinic acid (1a) in the presence of urea: Bromine (0.19 cm3,
3.7 mmol) was added to a stirred mixture of 1a (0.40 g, 3.4 mmol) and urea
(0.30 g, 5.1 mmol) in an IL (3.4 mmol) at 20 °C. The mixture was stirred until it
became colourless and was then extracted with diethyl ether (3 Â 3 cm3). The
combined organic extracts were evaporated under reduced pressure (15 Torr)
at 30 °C. The yield (85–90%), was calculated based on the mono-brominated
products 2 and 3. The ionic liquid, [bmim][PF6], remaining after extraction of
products 2–4, was washed with water (3 Â 1 cm3), dried at 60 °C (2 Torr) for
2 h and was used again in the next run (entry 15).
20. Isomerisation of 5-bromolevulinic acid (2a) into 3-bromolevulinic acid (3a): A
mixture of 2a/3a (1.5:1.0) (0.47 g, 2.4 mmol)9 was added to a solution of
anhydrous HBr (0.1 g, 1.2 mmol) in [bmim][BF4] (2 ml) and the resulting
mixture was stirred at ambient temperature until a clear solution formed
(30 min). The reaction was extracted with diethyl ether (3 Â 3 cm3), and the
combined organic extracts were evaporated under reduced pressure (15 Torr)
at 30 °C to afford a mixture of 2a/3a in a 1.0:1.6 ratio (1H NMR data).
21. Tobin, J. B.; Frey, P. A. J. Am. Chem. Soc. 1996, 118, 12253–12260.
22. Zavyàlov, S. I.; Kravchenko, N. E. Izv. Akad. Nauk, Ser. Khim. 1983, 1453–1454
(Russ. Chem. Bull. 1983, 32, 1324).
15. Shevtsov, A. V.; Kuznetsov, V. V.; Lyssenko, K. A.; Belyakov, P. A.; Makhova, N.
N. Mendeleev Commun. 2006, 218–220.
16. The ionic liquids [bmim][Br]23 and [omim][Br]24 were prepared by known
procedures and dried under vacuum (2 Torr) at 70 °C for 4 h. Other ILs were
obtained from Merck KGaA and used without further purification.General
procedure for the bromination of compounds 1a,c,d in ILs: To a stirred solution
of 1a, 1c or 1d (3.4 mmol) in an IL (3.4 mmol), Br2 (0.19 cm3, 3.7 mmol) was
added at 20 °C. The mixture was stirred until it became colourless and was
then extracted with diethyl ether (3 Â 3 cm3). The combined organic extracts
were evaporated under reduced pressure (15 Torr) at 30 °C. The yields (entries
5 and 6: 50–60%; and entries 7–12: 80–90%, Table 1) were calculated based on
the mono-brominated products 2 and 3.
23. Lucas, P.; El Mehdi, N.; Ho, H.-A.; Belanger, D.; Breau, L. Synthesis 2000, 1253–
1258.
24. Chu, Y.; Deng, H.; Cheng, J.-P. J. Org. Chem. 2007, 72, 7790–7793.