Direction of 3-bromothiophene acylation with succinyl chloride

Article abstract of DOI:10.1007/s10593-013-1258-5

In the reaction of 3-bromothiophene with succinyl chloride in the presence of AlCl₃, a mixture of three isomeric dibromo-substituted 1,4-di(2-thienyl)butane-1,4-diones was formed. The main component was the unsymmetrical 1-(3-bromo-2-thienyl)-4-(4-bromo-2-thienyl)butane-1,4-dione rather than 1,4-di-(3-bromo-2-thienyl)butane-1,4-dione expected according to the orientation rules.

Full text of DOI:10.1007/s10593-013-1258-5

Chemistry of Heterocyclic Compounds, Vol. 49, No. 3, June, 2013 (Russian Original Vol. 49, No. 3, March, 2013)
DIRECTION OF 3-BROMOTHIOPHENE ACYLATION
WITH SUCCINYL CHLORIDE
V. I. Smirnov1, A. V. Afanas'ev1, I. S. Prostakishin1, and L. I. Belen'kii2*
In the reaction of 3-bromothiophene with succinyl chloride in the presence of AlCl3, a mixture of three
isomeric dibromo-substituted 1,4-di(2-thienyl)butane-1,4-diones was formed. The main component was
the unsymmetrical 1-(3-bromo-2-thienyl)-4-(4-bromo-2-thienyl)butane-1,4-dione rather than 1,4-di-
(3-bromo-2-thienyl)butane-1,4-dione expected according to the orientation rules.
Keywords: 3-bromothiophene, dibromo-1,4-di(2-thienyl)butane-1,4-diones, succinyl chloride, thiophene,
acylation.
In recent years, 2,5-di(2-thienyl)pyrroles have been used more frequently for the preparation of organic
polymers and semiconductors [1, 2]. It is also known that such compounds are capable of exhibiting
photochromic properties [3, 4].
In addition, coplanar polycyclic conjugated systems 1, alternative paths for the synthesis of which are
presented in the scheme below, can be obtained on the basis of dithienylpyrroles. It is clear that the
dithienylpyrrole precursor in both cases during cyclization must adopt the thermodynamically unfavorable,
nearly coplanar conformation with strong steric interactions between the substituents in the heterocycles.
X
X
a
S
N
R
S
Y
S
S
N
R
Y
2
S
S
N
R
X
X
X
X
O
1
RNH2
b
S
S
N
R
S
S
O
3
_______
*To whom correspondence should be addressed, e-mail: libel@ioc.ac.ru.
1M. V. Lomonosov Moscow Academy of Fine Chemical Technology, 86 Vernadskogo Ave., Moscow 119571,
Russia; e-mail: mitht406@mail.ru.
2N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Ave., Moscow
119991, Russia.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 416-422, March, 2013. Original
article submitted August 8, 2012; revision submitted January 25, 2013.
386
0009-3122/13/4903-0386©2013 Springer Science+Business Media New York

Our previous attempt to obtain compounds 1 by the cyclization of dithienylpyrroles 2, disubstituted at
the β-positions of pyrrole ring (R = Me, p-C8H17, X = CH2OH) (path a), was unsuccessful due to competing
intermolecular processes [5]. At the same time, we hoped that the use of precursors 3 with substituents at
positions 3 and 3' of the thiophene rings would make it possible to synthesize the targeted polycyclic
compounds 1 (path b).
Most often used for the preparation of 2,5-di(2-thienyl)pyrroles is the Paal–Knorr reaction, as a result of
which 1,4-bis(2-thienyl)butane-1,4-diones undergo cyclization upon the action of primary amines in an acidic
medium and form the targeted compounds in high yields. From the same diketones in a similar way, it is
possible to obtain structures containing a thiophene or furan ring in place of the pyrrole ring.
1,4-Dithienylbutane-1,4-diones are therefore suitable starting compounds for the synthesis of a whole series of
systems like terthienyl.
A number of syntheses of these diketones have been described in the literature. Notable among them is
the Michael–Stetter condensation, which involves the addition of aldehydes at the activated double bond of
enones in the presence of a cyanide or thiazolium salt [6, 7]. We note also the method proposed by Kulinkovich
and co-workers, which is based on the condensation of acetylthiophenes with bromoacetylthiophenes by the
action of various bases [8]. A disadvantage of these and many other methods is that they are multistage
processes (if we start from the corresponding thiophenes).
The most promising version of the synthesis of symmetrical 1,4-dithienylbutane-1,4-diones is the
single-stage acylation of the correspoding thiophenes with succinyl chloride. However, under the standard
conditions for thiophene acylation with SnCl4 as catalyst, only the monoacylation product 4-oxo-4-(2-thienyl)-
butyric acid was formed [9]. It was possible to obtain 1,4-di(2-thienyl)butane-1,4-dione [10] and its analogs by
this method in the presence of aluminum chloride. However, the yields of the targeted diketones mostly did not
exceed 50% [10-12], and only in the case of 2-bromothiophene did the yield amount to 61% [13]. The reasons
for this were discussed in the work [12].
It should be noted that nearly all the papers on the acylation of thiophenes with succinyl chloride only
concern the first member of the series and its 2-substituted derivatives. The only exception is
3-methylthiophene, the acylation of which was examined briefly in the work [11]. It therefore seemed of interest
to investigate the acylation of 3-bromothiophene (4) with succinyl dichloride under Friedel–Crafts conditions as
a possible direct method for the synthesis of 1,4-bis(3-bromothiophen-2-yl)butane-1,4-dione (5). It must be
emphasized that subsequent substitution of the bromine atoms in thiophene rings opens up wide possibilities for
the modification of compound 5. Moreover, the highest yield of the corresponding 1,4-diketone was obtained in
the reaction of succinyl chloride with 2-bromothiophene [13].
Br
O
S
S
S
O
(CH2COCl)2
5
Br
S
Br
Br
AlCl3
+
O
O
Br
CH2Cl2
4
S
S
S
O
O
Br
Br
7
6
1
However, the 3-bromothiophene (4) gave a multicomponent mixture upon acylation, the H NMR
spectrum of which indicated that besides the targeted diketone 5 it also contained two of its isomers 6 and 7.
The total yield of compounds 5-7 amounted to ~42%.
387

The spectrum of the reaction mixture also contained signals belonging, in our opinion, to the
unsaturated acids 8. In particular, the chemical shifts of the triplet at 6.16 ppm (1H, J = 7.4 Hz) and its
associated doublet at 3.33 ppm (2H, J = 7.4 Hz) practically coincided with the values for the vinyl proton and
the CH2 group of analogous compounds that we obtained earlier by the action of succinyl chloride on thiophene,
2-bromothiophene and 2-methylthiophene [12].
Br
CO2H
S
Br
S
8
After treatment with a solution of NaHCO3, the obtained mixture was separated into ketone and acid
fractions (~45 and ~35% yields, respectively). Unfortunately we were unable to isolate the individual ketones
and acids. Authentic samples were therefore prepared in order to establish the ratios of compounds 5-7 in the
ketone fraction.
The previously unknown diketones 5 and 6 were synthesized by the Kulinkovich method [8] from
3-bromothiophene (4) and 2-acetylthiophene (11).
O
O
1) 9, ZnCl2, Et3N,
t-BuOH, PhH
2) H+, H2O
AcCl
SnCl4
S
S
Br
Me
Br2, AlCl3
78%
5
4
90%
Br
Br
79%
10
9
1) 10, ZnCl2, Et3N,
t-BuOH, PhH
O
O
Br2, AlCl3
65%
S
S
6
Me
Me
2) H+, H2O
42%
Br
11
12
The previously described diketone 7 [14, 15] was obtained in 87% yield (mp 134-136°C) through
bromination of 1,4-di(2-thienyl)butane-1,4-dione in the presence of an excess of aluminum chloride by analogy
to the preparation of 2-acetyl-4-bromothiophene (12) [16].
O
S
Br2, AlCl3
7
S
CHCl3
87%
O
We note that the procedure presented in the paper [14] has only slight differences from ours, and the
1H NMR spectrum of the compound that we obtained matches that described in the paper [14], but a melting
point of 172°C was reported there for the product 7. At the same time, a melting point of 142-143°C [15], close
to our value, was given for the diketone 7 obtained by the Stetter method and purified by silica gel
chromatography. It can therefore be assumed that the melting point of the diketone 7 given in the paper [14] is a
misprint.
The structure of the diketones 5 and 6 was confirmed by the 1H and 13C NMR spectra, and by elemental
analysis, and the previously obtained diketone 7 was also characterized by 1H NMR spectroscopy (Table 1).
Unfortunately, the signals of the diketone 6 in the 1H NMR spectra, recorded in CDCl3, overlapped with
the signals of the other two isomers. However, in deuterobenzene these three diketones gave some separate
signals, and this enabled determination of their ratio in the reaction mixture.
388

TABLE 1. 1H NMR Spectra of 1,4-Bis(bromo-2-thienyl)butane-1,4-diones
R1С4H2SCOCH2CH2COC4H2SR2 5–7
Chemical shifts, , ppm (J, Hz)
Diketones
Нaliph.
Нarom.(R1С4H2S)
Нarom.(R2С4H2S)
R1
R2
R1С4H2SCOCH2 CH2COC4H2SR2 β-H (d)
α-H (d)
β-H (d)
α-H (d)
Solvent CDCl3
3-Br 3-Br 3.50 (s)
3.50 (s)
7.12
(J = 5.2)
7.53
7.12
7.53
5
6
7
(J = 5.2) (J = 5.2) (J = 5.2)
3-Br 4-Br 3.53 (t, J = 6.3)
4-Br 4-Br 3.36 (s)
3.34 (t, J = 6.3) 7.12
(J = 5.2)
7.55
7.53-7.55 7.53-7.55 7.71
(m)
(m)
(J = 1.4)
3.36 (s)
7.72
7.55
7.72
(J = 1.3)
(J = 1.3) (J = 1.3) (J = 1.3)
Solvent C6D6
3-Br 3-Br 3.16 (s)
3.16
6.52
(J = ~5)
7.10
(J = ~5) (J = ~5)
7.12 6.67
(J = ~5) (J = 1.4) (J = 1.4)
7.10 6.67 7.10
(J = 1.4) (J = ~1.5) (J = 1.4)
6.52
7.13
(J = ~5)
5
6
7
3-Br 4-Br 3.13 (t, J = 6.3)
4-Br 4-Br 2.66 (s)
2.70 (t, J = 6.3) 6.52
(J = ~5)
6.67
(J = 1.5)
7.13
2.66 (s)
To our surprise, we found that the ratio of the diketones 5:6:7 was 1.0:1.6:0.5. At the same time, in the
model reaction of 3-bromothiophene (4) with acetyl chloride in the presence of AlCl3, the isomeric ketone ratio
amounted to ~10:1 in favor of the expected 2-acetyl-3-bromothiophene (9). If succinyl chloride and the
intermediate acyl chloride complexes 13 and 14 exhibited the same regioselectivity towards 3-bromothiophene
(4) as acetyl chloride, then the complexes 13 and 14 would be formed at the first acylation stage in the same
~10:1 ratio, which would lead to ~81:18:1 mixture of the diketones 5, 6, and 7 at the second stage of the
reaction.
Br
Br
O AlCl3
Cl
O AlCl3
Cl
(CH2COCl)2
AlCl3
+
4
S
S
O AlCl3
O
AlCl3
13
14
4
4
4
4
7
5
6
Such a deviation can be explained by the steric hindrance due to the bromine atom, which hinders an
attack towards position 2 by the bulky AlCl3 complexes of succinyl chloride or by the acyl chloride complexes
13 and 14. During the formation of diketone 4, the steric hindrance should appear at both acylation stages,
whereas for the diketone 5 it should appear at one of the stages only.
Thus, the acylation of 3-bromothiophene with succinyl chloride is not a feasible method for the
synthesis of 1,4-bis(3-bromo-2-thienyl)butane-1,4-dione due to the formation of at least three isomeric
diketones. At the same time, the preferential formation of the unsymmetrical diketone in this reaction may be of
some interest, although the possibility of its isolation requires further investigation.
EXPERIMENTAL
1
The H and 13C NMR spectra were recorded on a Bruker DPX-300 spectrometer (300 and 75 MHz,
respectively) with the residual proton signals of chloroform (7.27 ppm) or benzene (7.16 ppm) as standard for
1H nuclei, and chloroform (77.0 ppm) for 13C nuclei. The reaction progress and the product purity were
389

monitored by TLC on Silufol UV-254 plates with 1:4 ethyl acetate–hexane, 1:2 methylene chloride–petroleum
ether (40-60°C), and other mobile phases, with visualization in iodine vapor or in UV light. The melting points
were determined on a Boetius microscope hot stage apparatus.
2-Acetyl-3-bromothiophene (9) [17], 3-bromo-2-(bromoacetyl)thiophene (10) [18], and 2-acetyl-4-bromo-
thiophene (12) [16], as well as succinyl chloride [19] were obtained by known methods. 2-Acetylthiophene (11)
and 3-bromothiophene (4) were purchased from Sigma-Aldrich.
Reaction of 3-Bromothiophene with Succinyl Chloride (General Method). A solution of succinyl
chloride (0.50 ml, 4.5 mmol) and 3-bromothiophene (4) (0.95 ml, 10.0 mmol) in dry CH2Cl2 (3 ml) was added
dropwise with cooling and stirring to a suspension of AlCl3 (4.10 g, 30.7 mmol) in dry CH2Cl2 (7 ml). The
mixture was then refluxed with stirring for 6 h and poured onto ice (60-70 g), conc. HCl (1 ml) was added, and
the mixture was stirred for 1 h. The organic layer was separated, and the aqueous layer was extracted with
CH2Cl2 (2×30 ml). The combined organic extracts were washed with 2 N HCl solution and twice with water,
dried over Na2SO4, filtered, and evaporated on a rotary evaporator to give the product as an oil (1.85 g) (a
mixture of the diketones 5-7 and the acids 8).
The mixture was dissolved in CH2Cl2 and washed three times with a saturated solution of sodium
bicarbonate. The organic phase was separated, dried over Na2SO4, and evaporated on a rotary evaporator. The
1
product was obtained as oil (0.77 g, 42% yield, a mixture of diketones 5-7). According to the H NMR
spectrum, the ratio of 5 : 6 : 7 was equal to 1.0:1.6:0.5.
Concentrated hydrochloric acid was added to the aqueous layer to pH 2, and the product was extracted
with CH2Cl2 (3×25 ml). The organic layer was washed with hydrochloric acid solution (1:10) and with water,
dried over Na2SO4, and evaporated. The product was obtained as an oil (0.66 g, 36%), which presumably
represented a mixture of the acids 8. The losses of 0.42 g were due to the difficulty of separating the stable
emulsions, as the acids 8 acted as surfactants. The 1H NMR spectrum in CDCl3 contained coupled triplet at 6.16
ppm (1H) and doublet at 3.33 ppm (2H), J = 7.4 Hz, characteristic of such acids, where the chemical shifts
matched the previously obtained analogs [12]. There were also poorly resolved partially overlapping proton
signals from the isomeric bromine-substituted thienyl groups.
1,4-Bis(3-bromothiophen-2-yl)butane-1,4-dione (5). ZnCl2 (2.65 g, 19.4 mmol) was calcined under
vacuum for 15 min at ~300°C. The flask was then cooled, and a solution of tert-butyl alcohol (1.4 ml,
15.0 mmol) and triethylamine (2.1 ml, 15.0 mmol) in dry benzene (10 ml) was added to it. The mixture was
stirred for 2 h until the zinc chloride had completely dissolved, after which 2-acetyl-3-bromothiophene (9)
(3.00 g, 14.6 mmol) and 3-bromo-2-(bromoacetyl)thiophene (10) (2.77 g, 9.7 mmol) were added. The reaction
mixture was stirred for seven days, after which 5% H2SO4 was added. The precipitate was filtered off and
washed with benzene. The filtrate was washed with a 5% solution of NaCl, dried over MgSO4, filtered, and
evaporated to dryness on a rotary evaporator. The residue was washed on the filter with cold methanol and
recrystallized from benzene to give the diketone 5. Yield 3.14 g (79%); mp 136-138°C. 13C NMR spectrum
(CDCl3), δ, ppm: 36.2 (СН2СО); 115.1; 132.9; 134.3; 138.7; 191.2 (СО). Found, %: С 35.37; Н 1.90.
C12H8Br2O2S2. Calculated, %: С 35.31; Н 1.98.
1-(3-Bromothiophen-2-yl)-4-(4-bromothiophen-2-yl)butane-1,4-dione (6). This product was
obtained by a similar procedure from ketone 10 (1.48 g, 5.2 mmol) and 2-acetyl-4-bromothiophene (12) (1.60 g,
7.8 mmol), t-BuOH (0.75 ml, 7.8 mmol), triethylamine (1.10 ml, 7.8 mmol) in dry benzene (5 ml), and zinc
chloride (1.42 g, 10.4 mmol). The mixture was stirred for 14 days. The obtained product 5 was recrystallized
13
from ethanol. Yield 0.88 g (42%); mp 133-137°С. C NMR spectrum (CDCl3), δ, ppm: 32.5 (СН2СО); 35.4
(СН2СО); 110.6; 114.3; 130.7; 132.3; 133.5; 133.9; 137.8; 143.8; 190.1 (СО); 190.3 (СО). Found, %: С 35.45;
Н 1.81. C12H8Br2O2S2. Calculated, %: С 35.31; Н 1.98.
1,4-Bis(4-bromothiophen-2-yl)butane-1,4-dione (7). 1,4-Di(2-thienyl)butane-1,4-dione (0.200 g, 0.8
mmol) was added to a suspension of aluminum chloride (0.375 g, 2.3 mmol) in dry chloroform (10 ml), after
which a solution of bromine (0.12 ml, 2.4 mmol) in dry chloroform (3 ml) was added dropwise with cooling.
The reaction mixture was stirred for ~16 h and poured into a 2 N HCl solution, and the mixture was stirred for
390

20-30 min. The organic layer was separated and extracted with chloroform (3×10 ml). The combined extract
was washed with a dilute solution of sodium carbonate and with water, dried over MgSO4, evaporated, and the
residue was triturated in a small amount of cold ethanol. The precipitate was filtered off and dried. Yield 0.28 g
(87%); mp 134-136°C (CHCl3). The 1H NMR spectrum agreed fully with the spectrum given in the work [14].
Reaction of 3-Bromothiophene (4) with Acetyl Chloride. A solution of 3-bromothiophene (4)
(0.64 ml, 6.8 mmol) and acetyl chloride (0.50 ml, 7.0 mmol) in dry CH2Cl2 (5 ml) was added dropwise over 20
min with stirring and cooling to a suspension of aluminum chloride (1.6 g, 12.0 mmol) in CH2Cl2 (10 ml). At
the end of the addition, the mixture was heated with stirring for 6 h to 40°C, poured onto ice (100 g), conc. HCl
(1 ml) was added, and the mixture was stirred for a further 1 h. The organic phase was separated, and the
aqueous layer was extracted with methylene chloride (3×25 ml). The combined extract was washed with
hydrochloric acid solution and with water, dried over Na2SO4 ,filtered and evaporated, after which 1.27 g (91%)
of a mixture of isomeric 2-acetyl-3-bromothiophene (9) and 2-acetyl-4-bromothiophene (12) was obtained in a
ratio of 10:1 (according to the 1H NMR spectrum).
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