Direct bromination of ethyl 5-alkylthiophene-2-carboxylates

Article abstract of DOI:10.1055/s-0030-1258160

Approaches to brominated thiophene-2-carboxylic acids by electrophilic bromination of the corresponding acids and esters were compared and investigated. A synthetic route was developed involving direct bromination of ethyl 5-alkylthiophene-2-carboxylates followed by saponification of the resulting ethyl 5-alkyl-4-bromothiophene-2-carboxylates. The key bromination step is selective in dichloromethane solution at 0-5 °C and furnishes the corresponding ethyl 5-alkyl-4-bromothiophene-2-carboxylates in excellent yields. No migration or isomerization of the alkyl substituents was observed. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258160

PAPER
2965
Direct Bromination of Ethyl 5-Alkylthiophene-2-carboxylates
D
irec
t
B
l
rominat
y
ion of
E
thyl
a
5-Alkylthiophene
V
-2-carboxylate
s
. Taydakov,*a Sergey S. Krasnoselskiyb
a
G. S. Petrov Institute of Plastics, JSC, Perovskiy proezd 35, Moscow 111024, Russian Federation
Fax +7(495)6000603; E-mail: taidakov@gmail.com
People’s Friendship University of Russia, Miklukho-Maklaya str. 9, Moscow 117198, Russian Federation
b
Received 20 April 2010; revised 27 April 2010
method for obtaining thiophene-2-carboxylic acids and
their derivatives. While catalytic quantities of iron(III)
chloride have been used in the monobromination of 5-
hexylthiophene-2-carboxylic acid1c and zinc(II) chloride
Abstract: Approaches to brominated thiophene-2-carboxylic acids
by electrophilic bromination of the corresponding acids and esters
were compared and investigated. A synthetic route was developed
involving direct bromination of ethyl 5-alkylthiophene-2-carboxy-
lates followed by saponification of the resulting ethyl 5-alkyl-4-bro- has been used to catalyze the dibromination of ethyl
thiophene-2-carboxylate,3f in all these cases an evaluation
mothiophene-2-carboxylates. The key bromination step is selective
in dichloromethane solution at 0–5 °C and furnishes the corre-
of the catalyst influence on the composition of the prod-
sponding ethyl 5-alkyl-4-bromothiophene-2-carboxylates in excel-
ucts is difficult, because under these conditions excessive
lent yields. No migration or isomerization of the alkyl substituents
bromination occurs at all the accessible positions.
was observed.
Key words: bromine, esters, thiophenes, electrophilic aromatic
substitutions, aluminum
Br
AlCl3 (3–6 equiv), Br2
R2
R2
R1
R1
S
S
O
O
Thiophene-2-carboxylic acids 1 brominated at the 4-posi-
tion (Scheme 1) are of considerable interest, as they are
key starting compounds in the synthesis of biologically
active compounds (e.g., antitumor agents),1a nonlinear op-
tics materials,1b and liquid crystals.1c Previously reported
methods for the preparation of 1 include oxidation of the
corresponding aldehydes or ketones,1a carboxylation of
lithiated substituted 2,4-dibromothiophenes,2a or, alterna-
tively, debromination of 4,5-dibromothiophene-2-carbox-
ylic acids by using zinc and acetic acid2b or n-butyllithium
(Scheme 1).2c It is worth noting that direct bromination of
acids in the presence of bromine in various solvents has
also been used for the preparation of 4-bromo or 4,5-di-
bromo derivatives.1b,c,2d,e However, many of the earlier de-
scribed approaches to 1 have significant disadvantages,
for example involving laborious, cumbersome operations,
often requiring relatively uncommon starting materials,
and tending to furnish the target acids 1 in low yields.
Moreover, further scaling-up of certain key stages would
be quite challenging.
2 R1 = H, R2 = Me
oxidation
3 R1, R2 = H
Br
Br
n-BuLi, CO2
Br
Br2
R1
COOH
separation
of isomers
R1
COOH
R1
S
1
S
S
Br2
excess
n-BuLi (2 equiv), H2O
Br
or
R1
Zn, AcOH
Br
COOH
S
Scheme 1 Possible approaches to brominated thiophene-2-carboxy-
lic acids 1
To the best of our knowledge, there is only one example
of the use of catalyst swamping conditions for the bromi-
nation of methyl 3-fluorothiophene-2-carboxylate
(Scheme 2).1b This ester did not undergo bromination
even in the presence of 600 mol% of aluminum(III) chlo-
ride, so that the addition of 10 mol% of iron(III) chloride
was required to promote the reaction. A mixture of mono-
and dibrominated compounds was obtained, but no further
investigation of this reaction was carried out.
The bromination of 2-acetylthiophene (2) and thiophene-
2-carbaldehyde (3) in the presence of a large excess of
aluminum(III) chloride was investigated by Gol’dfarb
(Scheme 1).3a Importantly, only 4-brominated products
were formed under these conditions. Subsequently, this
method, termed ‘catalyst swamping conditions’, has been
used frequently for the preparation of various substituted
4-bromothiophenecarbaldehydes and ketones.3b–e In this
context, it is rather surprising that no further attempts
were made to expand the scope and applications of this
As one of the current research projects in our group focus-
es on thiophene-based dyes with nonlinear optic proper-
Br2 (1.5 equiv)
AlCl3 (6 equiv)
FeBr3 (10 mol%)
CHCl3, 17 h, r.t.
Br
Br
F
F
F
+
Br
COOMe
COOMe
COOMe
S
S
S
79%
8%
SYNTHESIS 2010, No. 17, pp 2965–2968
x
x.
x
x
.
2
0
1
0
Advanced online publication: 07.07.2010
DOI: 10.1055/s-0030-1258160; Art ID: Z10210SS
Scheme 2 Bromination of methyl 3-fluorothiophene-2-carboxylate
© Georg Thieme Verlag Stuttgart · New York

2966
I. V. Taydakov, S. S. Krasnoselskiy
PAPER
ties, we report here on a convenient and versatile method
for the preparation of ethyl 5-alkyl-4-bromothiophene-2-
carboxylates 6 (Scheme 3). This route is also perfectly
suitable for various 5-alkylated thiophene acids. Gratify-
ingly, this new procedure, in our view, is readily applica-
ble to the preparation of multigram quantities of the target
compounds.
Table 1 Synthesis of Ethyl 5-Alkyl-4-bromothiophene-2-carboxy-
lates 6a–ga
Entry
R
6
Yieldb (%)
1
2
3
4
5
6
7
H
6a
6b
6c
6d
6e
6f
62c
89
91
77
78
69
92
Me
Et
Br
n-Pr
i-Pr
t-Bu
i-Bu
Br2 (1 equiv)
R
R
COOEt
COOEt
S
5a–g
S
AlCl3 (2.5 equiv)
CH2Cl2
6a–g 62–92%
0–5 °C
Br
Br2 (2 equiv)
6g
5a R = H
AlCl3 (2.5 equiv)
CH2Cl2
a Reaction conditions: 5 (10 mmol), AlCl3 (2.5 equiv), Br2 (1 equiv),
CH2Cl2, 0–5 °C, 1.5 h.
Br
COOEt
S
0–5 °C
7 78%
b Isolated yield.
c Reaction was carried out on a 200 mmol scale.
Scheme 3 Bromination of ethyl 5-alkylthiophene-2-carboxylates
ficient column (approximately 10 theoretical plates).
Importantly, when two equivalents of bromine were used,
ester 7 was obtained quantitatively (Scheme 3).
We found that 5-alkylthiophene-2-carboxylates 5 can be
selectively brominated to form 4-substituted derivatives
under catalyst swamping conditions. The maximum
yields of the brominated derivatives 6 were obtained when
the molar ratio of ester to aluminum(III) chloride was
1:2.5. The yields reach 90–95% if the bromination is run
in chlorinated solvents such as dichloromethane, chloro-
form, or 1,2-dichloroethane and the reaction temperature
is maintained around 0–5 °C.
A further study of the bromination of the free thiophene-
carboxylic acids in the presence of aluminum(III) chloride
showed that only complex mixtures of brominated prod-
ucts along with unidentifiable tarry material can be ob-
tained. Therefore, this one-step procedure unfortunately
cannot compete with the proposed two-step method for
the preparation of brominated acids 1, which involves the
bromination of the corresponding esters 5 and subsequent
saponification of the bromo esters 6 by using a solution of
potassium hydroxide in water–ethanol.
It is remarkable that under these conditions neither the
thiophene side chain nor the ester group is affected. The
experiments carried out with the ethyl esters of 5-substi-
tuted thiophene-2-carboxylic acids clearly show that mi-
gration and isomerization of the 5-substituent do not
occur, even in the presence of a large excess of alumi-
num(III) chloride.
In conclusion, we have shown that the bromination of eth-
yl 5-alkylthiophene-2-carboxylates 5 in the presence of
2.5 equivalents of aluminum(III) chloride selectively
leads to the substitution at the 4-position of the thiophene
fragment and is therefore an excellent preparative method
for the preparation of 5-alkyl-4-bromothiophene-2-car-
boxylic acids 1 and their esters 6.
In addition to the high selectivity and yields obtained by
this method, the reaction workup and the separation of the
products are very convenient. Firstly, smooth decomposi-
tion of the aluminum complex is induced by the addition
of ice-cold diluted hydrochloric acid. Secondly, by appro-
priate extraction of the products from the resulting mix-
ture, esters 6 can in most cases be obtained in sufficiently
pure form (at least 90% GC assay) simply after evapora-
tion of the solvent. The reaction can easily be run on a
two-mole scale without deterioration of the yield
(Table 1).
All manipulations were performed in dry air. Anhyd AlCl3 (pow-
der) and solvents (synthetic grade) were purchased from Merck
KGaA (Germany) and Acros Organics (Belgium). Esters 5a–g were
purchased from ArtChem GmbH (Campus Berlin-Buch, Germany).
1H and 13C NMR spectra of samples in CDCl3 were recorded at
25 °C on a Bruker AC-300 spectrometer operated at 300 MHz and
1
75 MHz, respectively. All H chemical shifts are reported in ppm
relative to TMS (0.00 ppm); 13C shifts are reported in ppm relative
to CDCl3. Mass spectra were recorded on a Finnigan INCOS-50 in-
strument (EI, 70 eV, direct insertion). GC-MS analysis was per-
formed on a Thermo Focus DSQ II instrument with an HP-5MS
column. GC analysis was performed on a Varian 3700 instrument
equipped with FID and a 15 m × 0.53 mm × 0.5 mm Zebron ZB-5
capillary column (Phenomenex, USA) using helium (5 mL·min–1)
in temperature-programming mode.
When unsubstituted ethyl thiophenecarboxylate (5a) was
brominated with one equivalent of bromine in the pres-
ence of aluminum(III) chloride, a mixture of products was
obtained. The GC-MS analysis of the crude reaction mix-
ture indicated the presence of four main components: (i)
the unreacted ethyl thiophenecarboxylate (5a) (6.9%), (ii)
ethyl 5-bromothiophene-2-carboxylate (3.2%), (iii) ethyl
4-bromothiophene-2-carboxylate (6a) (77.8%), and (iv)
ethyl 4,5-dibromothiophene-2-carboxylate (7) (12.1%).
Pure ethyl 4-bromothiophene-2-carboxylate (6a) was sep-
arated from this mixture by careful rectification on an ef-
Ethyl 4-Bromothiophene-2-carboxylates 6a–g; General Proce-
dure
A soln of the appropriate ester 5 (10 mmol) in CH2Cl2 (5 mL) was
added dropwise to a stirred suspension of AlCl3 (3.3 g, 25 mmol) in
Synthesis 2010, No. 17, 2965–2968 © Thieme Stuttgart · New York

PAPER
Direct Bromination of Ethyl 5-Alkylthiophene-2-carboxylates
2967
CH2Cl2 (10 mL) at 0 °C; the reaction mixture was then stirred for an
additional 30 min. A 2 M soln of Br2 in CH2Cl2 (5 mL, 10 mmol)
was added at the same temperature and the stirring was continued
for 1 h. The reaction mixture was poured onto acidic crushed ice
[ice (5 g), concd aq HCl (2 mL)] and extracted with CH2Cl2 (2 × 10
mL). The combined organic layer was washed successively with
brine (10 mL) and sat. aq NaHCO3 (10 mL) and subsequently dried
over MgSO4. The solvent was evaporated under reduced pressure
and the residue was distilled; this gave the corresponding product 6.
Ethyl 4-Bromo-5-isopropylthiophene-2-carboxylate (6e)
Colorless oil; bp 136–137 °C (7 Torr).
1H NMR (300 MHz, CDCl3): d = 7.6 (s, 1 H, H-3), 4.4 (q, J = 6.6,
7.2 Hz, 2 H, CH2), 3.35 (sept, J = 6.6 Hz, 1 H, CH), 1.4 (m, 9 H, 3
CH3).
13C NMR (75 MHz, CDCl3): d = 161.5, 155.1, 135.7, 130.5, 107.8,
61.4, 30.3, 23.6, 14.4.
MS (EI, 70 eV): m/z (%) = 65 (68), 109 (63), 197 (47), 233 [79BrM
– C3H7]+ (65), 235 [81BrM – C3H7]+ (47), 261 [79BrM – Me] (98),
263[81BrM – Me]+ (100), 276 [79BrM]+ (35), 278 [81BrM]+ (35).
Ethyl 4-Bromothiophene-2-carboxylate (6a)
Colorless oil; bp 107–108 °C (3 Torr).
1H NMR (300 MHz, CDCl3): d = 7.42 (s, 1 H, H-5), 7.68 (s, 1 H, H-
3), 4.35 (q, J = 11.1 Hz, 2 H, CH2), 1.35 (t, J = 9.9 Hz, 3 H, CH3).
Anal. Calcd for C10H13BrO2S: C, 43.33; H, 4.73; S, 11.57. Found:
C, 42.99; H, 4.84; S, 11.18.
13C NMR (75 MHz, CDCl3): d = 160.2, 134.9, 134.4, 131.2, 109.7,
Ethyl 4-Bromo-5-tert-butylthiophene-2-carboxylate (6f)
Light yellow oil; bp 147–150 °C (4 Torr).
1H NMR (300 MHz, CDCl3): d = 7.6 (s, 1 H, H-3). 4.3 (m, 2 H,
CH2), 1.5 (s, 9 H, 3 CH3), 1.38 (m, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 161.5, 156.1, 138.3, 135.3, 61.3,
35.74, 32.31, 29.61, 14.38.
MS (EI, 70 eV): m/z (%) = 123 (64), 247 (41), 249 (29), 275 [79BrM
– Me] (100), 277 [81BrM – Me]+ (98), 290 [79BrM]+ (30), 292
[81BrM]+ (30).
61.4, 14.0.
MS (EI, 70 eV): m/z (%) = 81 (55), 82 (100), 189 [79BrM – C2H5O]+
(67), 191 [81BrM – C2H5O]+ (68), 204 (75), 206 (75), 234 [79BrM]+
(21), 236 [81BrM]+ (23).
Anal. Calcd for C7H7BrO2S: C, 35.76; H, 3.00; S, 13.64. Found: C,
36.13; H, 3.21; S, 14.22.
Ethyl 4-Bromo-5-methylthiophene-2-carboxylate (6b)
Light yellow oil; bp 80–82 °C (2 Torr).
1H NMR (300 MHz, CDCl3): d = 7.58 (s, 1 H, H-3) 4.34 (q, J = 7.2
Hz, 2 H, CH2), 2.42 (s, 3 H, CH3), 1.36 (t, J = 7.2 Hz, 3 H, CH3).
Anal. Calcd for C11H15BrO2S: C, 45.37; H, 5.19; S, 11.01. Found:
C, 45.45; H, 5.03; S, 10.89.
13C NMR (75 MHz, CDCl3): d = 161.2, 142.1, 135.6, 130.61, 110.1,
61.3, 15.4, 14.3.
Ethyl 4-Bromo-5-isobutylthiophene-2-carboxylate (6g)
Colorless oil; bp 147–150 °C (6 Torr).
1H NMR (300 MHz, CDCl3): d = 7.6 (s, 1 H, H-3), 4.34 (q, J = 7.2
Hz, 2 H, CH2), 2.69 (d, J = 7.2 Hz, 2 H, CH2), 2.0 (sept, J = 6.6 Hz,
1 H, CH), 1.37 (t, J = 7.2 Hz, 3 H, CH3), 0.98 (d, J = 6.6 Hz, 6 H, 2
CH3).
13C NMR (75 MHz, CDCl3): d = 146.5, 135.6, 131.0, 110.1, 61.4,
38.6, 30.2, 22.3, 14.36.
MS (EI, 70 eV): m/z (%) = 69 (93), 96 (75), 203 [79BrM – C2H5O]+
(97), 205 [81BrM – C2H5O]+ (100), 248 [79BrM]+ (39), 250 [81BrM]+
(41).
Anal. Calcd for C8H9BrO2S: C, 38.57; H, 3.64; S, 12.87. Found: C,
38.64; H, 3.89; S, 12.71.
MS (EI, 70 eV): m/z (%) = 95 (42), 219 (88), 221(87), 247 [79BrM
– C3H7]+ (100), 249 [81BrM – C3H7]+ (100), 290 [79BrM]+ (60), 292
[81BrM]+ (62).
Ethyl 4-Bromo-5-ethylthiophene-2-carboxylate (6c)
Light yellow oil; bp 105–106 °C (1 Torr).
1H NMR (300 MHz, CDCl3): d = 7.6 (s, 1 H, H-3), 4.35 (d, J = 7.2
Hz, 2 H, CH2), 2.82 (d, 2 H, J = 7.2 Hz, CH2), 1.34 (‘t’, J = 8.5 Hz,
6 H, CH3).
Anal. Calcd for C11H15BrO2S: C, 45.37; H, 5.19; S, 11.01. Found:
C, 45.67; H, 5.38 S, 11.19.
13C NMR (75 MHz, CDCl3): d = 162.35, 155.35, 133.50, 130.93,
Ethyl 4,5-Dibromothiophene-2-carboxylate (7)
The same procedure as for 6 was applied, but 2 M Br2 soln (10 mL,
20 mmol) was added. Crude solid ester was recrystallized from hex-
ane.
Yield: 2.45 g (78%); mp 50–50.5 °C (Lit.2d 51.0–51.1 °C).
1H NMR (300 MHz, CDCl3): d = 7.6 (s, 1 H, H-3), 4.35 (q, J = 10.9
Hz, 2 H, CH2), 1.35 (t, J = 10.9 Hz, 3 H, CH3).
124.46, 60.86, 23.81, 15.64, 14.36.
MS (EI, 70 eV): m/z (%) = 69 (100), 95 (67),110 (58), 217 [79BrM
– C2H5O]+ (28), 219 [81BrM – C2H5O]+ (51),247 [79BrM – Me] (20),
249 [81BrM – Me]+ (21), 262 [79BrM]+ (19), 264 [81BrM]+ (21).
Anal. Calcd for C9H11BrO2S: C, 41.08; H, 4.21; S, 12.19. Found: C,
41.33; H, 4.29; S, 12.46.
Ethyl 4-Bromo-5-propylthiophene-2-carboxylate (6d)
Light yellow oil; bp 144–1146 °C (5 Torr).
Large-Scale Preparation of 6b
A soln of 5b (100 g, 0.59 mol) in CH2Cl2 (50 mL) was added over
30 min to an ice-cooled magnetically stirred suspension of AlCl3
(196 g, 1.47 mol) in CH2Cl2 (400 mL). The resulting dark suspen-
sion was stirred for an additional 30 min at 0 °C and Br2 (30.3 mL,
94 g, 0.59 mol) was added dropwise; this resulted in vigorous effer-
vescence. The mixture was stirred on an ice bath for 2 h, poured
onto a crushed ice (1000 g)–concd aq HCl (150 mL) mixture, and
the combined organic solns were treated as above to yield, after dis-
tillation, pure 6b as an oil.
1H NMR (300 MHz, CDCl3): d = 7.6 (s, 1 H, H-3), 4.3 (q, J = 7.2
Hz, 2 H, CH2), 2.8 (t, J = 7.9 Hz, 2 H, CH2), 1.7 (sext, J = 7.2 Hz, 2
H, CH2), 1.4 (t, J = 7.2 Hz, 3 H, CH3), 1.0 (t, J = 7.2 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 161.38, 147.64, 135.64, 130.5,
109.35, 61.38, 31.78, 23.70, 14.36, 13.65.
MS (EI, 70 eV): m/z (%) = 69 (46), 95 (81), 219 (59), 221 (59), 231
[79BrM – C2H5O]+ (22), 233 [81BrM – C2H5O]+ (23), 247 [79BrM –
C2H3] (98), 249 [81BrM – C2H3]+ (100), 276 [79BrM]+ (40), 278
[81BrM]+ (39).
Yield: 130 g (89%).
Anal. Calcd for C10H13BrO2S: C, 43.33; H, 4.73; S, 11.57. Found:
C, 43.49; H, 4.60; S, 11.69.
Synthesis 2010, No. 17, 2965–2968 © Thieme Stuttgart · New York

2968
I. V. Taydakov, S. S. Krasnoselskiy
PAPER
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Acknowledgment
We are grateful to Dr. Kirill Nikitin of University College Dublin,
Ireland for helpful discussions.
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Synthesis 2010, No. 17, 2965–2968 © Thieme Stuttgart · New York