Synthesis of heteroaromatic carboxylic acids by carbonylation of hetaryl halides with catalysts based on cobalt carbonyl modified with epoxides

Article abstract of DOI:10.1134/S1070427207040106

A new method for the synthesis of heteroaromatic acids and their derivatives (esters and salts) by carbonylation of the corresponding halides was developed. Hetaryl halides were activated in alcoholic-alkali medium by highly active catalytic systems based on cobalt carbonyl modified with epoxides, developed previously for carbonylation of aryl halides.

Full text of DOI:10.1134/S1070427207040106

ISSN 1070-4272, Russian Journal of Applied Chemistry, 2007, Vol. 80, No. 4, pp. 571 575.
Pleiades Publishing, Ltd., 2007.
Original Russian Text
No. 4, pp. 584 589.
V.P. Boyarskii, T.E. Zhesko, E.V. Larionov, V.A. Polukeev, 2007, published in Zhurnal Prikladnoi Khimii, 2007, Vol. 80,
CATALYSIS
Synthesis of Heteroaromatic Carboxylic Acids by Carbonylation
of Hetaryl Halides with Catalysts Based on Cobalt
Carbonyl Modified with Epoxides
V. P. Boyarskii, T. E. Zhesko, E. V. Larionov, and V. A. Polukeev
VNIIneftekhim Open Joint-Stock Company, St. Petersburg, Russia
NPF Gallar Limited Liability Company, St. Petersburg, Russia
St. Petersburg State University, St. Petersburg, Russia
Vekton Private Company, St. Petersburg, Russia
Received November 9, 2006
Abstract A new method for the synthesis of heteroaromatic acids and their derivatives (esters and salts) by
carbonylation of the corresponding halides was developed. Hetaryl halides were activated in alcoholic-alkali
medium by highly active catalytic systems based on cobalt carbonyl modified with epoxides, developed
previously for carbonylation of aryl halides.
DOI: 10.1134/S1070427207040106
Heteroaromatic acids are widely used in preparative
organic chemistry and as a raw material in the produc-
tion of a wide range of substances, mainly biological-
ly active, and first of all of drugs and plant protection
agents [1].
It was found that alkylcobalt carbonyl complexes
R Co(CO)4 formed in situ by the reaction of alkyl
halides R X, active in nucleophilic substitution
(e.g., methyl iodide or methyl monochloroacetate
ClCH2COOCH3), with cobalt carbonyl in an alco-
holic-alkaline medium can activate comparatively
inert aryl halides in carbonylation reactions [2]. In
the process, alkyl halides act as cocatalysts (activa-
tors) of cobalt carbonyl in aryl halide carbonylation.
The reaction proceeds under very mild conditions:
CO pressure of 1 3 atm and temperature of 60 65 C.
We have shown [3, 4] that benzyl chloride forming
the catalytic complex PhCH2Co(CO)4 is the best ac-
tivator (A) among alkyl halides.
The traditional methods for preparing heteroaro-
matic acids, used today in the industry and labora-
tory practice, are diverse. They are based on a set
of classical reactions of organic chemistry (alkyla-
tion, acylation, oxidation, cyanidation) and have
a number of serious disadvantages: multistep syn-
thesis, low selectivity, large consumption of raw ma-
terials, and complex process flowsheet. Some of these
methods are environmentally unfavorable. Recently,
the method of carbonylation of the corresponding
halides has come into use for selective (one-step)
introduction of the carboxy group into an aromatic
core, i.e., for the synthesis of aromatic acids. Prep-
aration of arenecarboxylic acids by carbonylation of
aryl halides using cobalt carbonyl complex modified
with alkyl halides as a catalyst has been known since
the mid-1980s [2 6]:
Miura et al. [7] found that aryl halide carbonylation
can proceed at room temperature and atmospheric
pressure of CO, with the system cobalt(II) chloride-
methyl iodide is used as a catalyst, but the reaction
is slow. To accelerate the reaction in this catalytic
system, Nindakova et al. [8] used reducing agents and,
in particular, sodium borohydride or sodium naph-
thalenide. Nindakova et al. [8] believe that elimina-
tion of the stage of cobalt carbonyl preparation is
an advantage of such an approach. However, in spite
of the fact that such systems do not differ in activity
from the systems studied in [2 6], additional reduc-
ing agents complicate the process.
Co(CO)8 + A
ArHal + CO
ArCOOR,
ROH + B
where A is an activator (alkyl halide) and B, base.
571

572
BOYARSKII et al.
In 1994, we discovered a new catalytic system for
First of all, we examined the possibility of using
carbonylation to prepare acids derived from a nitro-
gen-containing heterocycle. It is well known that
pyridine can form complexes with cobalt carbonyl,
acting as a base ligand [11]. Therefore, it was neces-
sary to check to what extent the catalytic activity
of the carbonyl-base-propylene oxide system is pre-
served in the presence of the pyridine compound. We
found that 2-chloropyridine undergoes carbonylation.
Some important conclusions follow from this fact:
(1) The system preserves the catalytic activity under
the above conditions, i.e., in the presence of the po-
tential heterocyclic ligand. (2) Hetaryl halides can
undergo carbonylation. (3) As in usual reactions of
nucleophilic substitution, halopyridine is more active
than the corresponding halobenzene, i.e., the activat-
ing effect of the pyridine ring is preserved. This
allows preparation of pyridinecarboxylic (and, appar-
ently, also quinolinecarboxylic) acids by carbonyla-
tion of the corresponding hetaryl chlorides, which are
substantially more readily available than the corre-
sponding hetaryl bromides.
carbonylation of bromobenzene and chloronaphtalene,
which consists of cobalt carbonyl, potassium carbon-
ate, and olefin oxide (e.g., ethylene oxide or propyl-
ene oxide) [9]:
Co(CO)4
ArHal + CO + CHO
ArCOOCH + Hal
R
O
CH3OH, K2CO3, 60 C, PCO = 1 atm.
We found that this catalytic system noticeably
surpasses in activity the previously used system based
on alkyl halides.
The new catalyst was used to prepare various ar-
omatic carboxylic acids: 4-butylbenzoic, 4-acetyl-
benzoic, 4,4 -diphenyl- and 4,4 -(diphenyl oxide)dicar-
boxylic, and 2,6-naphtalenedicarboxylic. It was shown
that this system can be successfully used for labora-
tory and commercial synthesis of a wide range of
aromatic carboxylic acids of various structures [10].
At the same time, the synthesis, using this catalytic
system, of aromatic carboxylic acids with a complex
structure containing heterocyclic substituents has not
been studied. At the same time, the exclusively high
selectivity of the new catalytic system can become
especially useful in the case of difficultly available
and expensive heterocyclic compounds. Taking into
account the fact that a number of various heteroaro-
matic halides can be prepared comparatively simply
(by direct introduction of halogen into the aromatic
core or by substitution with halogen of hydroxy group
often formed in synthesis of the heterocycle), the use
of cobalt carbonyl as an inexpensive and readily avail-
able catalyst of oxo synthesis, as applied to carbon-
ylation of hetaryl halides, seemed very attractive from
the practical and theoretical viewpoints. At the same
time, this question required special consideration,
because the majority of the heterocyclic compounds
can potentially react as ligands and affect the cata-
lytic properties of the cobalt complex.
The synthesis of various quinolinecarboxylic acids,
which are difficult to prepare by other methods, is of
particular practical interest. We studied carbonylation
of a series of halides containing tetrahydroquinoline
(I), quinoline (IV, V), tetrahydroqiunazoline (II), and
tetrahydroquinoxaline (III) rings:
O
N
N
Br
Br
Br
O
O
N
O
N
N
SO2CH3
III
I
II
CH3
CH3
Br
OH Cl
OH
N
N
IV
V
Table 1. Carbonylation of hetaryl halides containing fused nitrogen-containing heterocycles (T = 61 63 C, PCO = 1 atm,
reaction time 6 h)
Substrate
concentration,
M
Molar ratio
substrate : cobalt carbonyl : propylene
oxide : potassium carbonate
Substrate conversion*
Product yield**
Substrate
%
I
II
III
IV
V
0.34
0.27
0.27
0.2
100 : 1 : 100 : 310
92 : 1 : 111 : 310
15 : 1 : 41 : 74
22 : 1 : 107 : 40
65 : 1 : 91 : 196
91
87
89
23
85
86 (95)
86 (99)
49
0.34
81 (95)
*
From the volume of carbon monoxide taken up.
Preparation yield (in parenthese, taking into account isolated unchanged substrate); the same for Table 2.
**
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SYNTHESIS OF HETEROAROMATIC CARBOXYLIC ACIDS
573
Table 2. Influence of reaction conditions on carbonylation of hetaryl halide I (T = 63 C, PCO = 1 atm, reaction time 4 h)
Substrate
concentration,
M
Molar ratio
substrate : cobalt carbonyl : propylene
oxide : potassium carbonate
Substrate conversion*
Product yield
%
0.17
0.34
0.69
0.34
0.34
0.34
0.34
0.48
50 : 1 : 50 : 130
100 : 1 : 100 : 310
200 : 1 : 200 : 600
200 : 1 : 200 : 635
194 : 1 : 200 : 620
190 : 1 : 190 : 600
194 : 1 : 400 : 620
200 : 1 : 200 : 600
87
91
28
52
52
75
68
78
83 (95)
86 (95)
26 (93)
51 (98)
52 (100)
71 (95)
64 (94)
75 (96)
*
1
From H NMR data.
The results obtained are listed in Table 1. As seen,
We found that the substrate conversion in 4 h
reached 94%, and the yield of isolated acid VII
was 79%.
all the hetaryl bromides studied readily undergo car-
bonylation with the catalytic system suggested. More-
over, chlorine derivatives of quinoline can also be, as
expected, substrates in carbonylation. With the car-
bonylation of I as an example, we examined the in-
fluence of the reactant, catalyst, and activator concen-
trations on the reaction yield (Table 2).
Preparation of 4-(4-carboxyphenyl)thiazoles VIII
X
Z
O
S
The data obtained show that the method suggested
is suitable for preparing heteroaromatic carboxylic
acids.
N
Y
VIII
is of great interest. At present, such derivatives are
studied as biologically active substances, e.g., po-
tential COX-2 inhibitors [12]. Preparation of these de-
rivatives involves the use of expensive starting com-
pounds, 4-acylbenzoic acids, whereas carbonylation of
aryl halides would allow the use of the substantially
less expensive 4-bromoacylbenzenes.
To check whether the activity of the catalytic sys-
tem is preserved with sulfur-containing heterocycles
as substrates, we studied carbonylation of 2-bromo-5-
(piperidyl-1-sulfo)thiophene VI:
N
N
The synthesis of 4-(2-methylthiazol-4-yl)benzoic
acid X from 4-bromoacetophenone by carbonylation
can be performed along two pathways:
O
Br
SO2
SO2
S
S
O
VI
VII
A:
1. CO/MeOH/K2CO3/Co2(CO)8/epoxide
2. HCl
Br
COOH
COOH
COOH
Br2/AcOH
Br
O
O
O
1. MeCSNH2/AcOH
2. NaOAc
N
S
X
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 80 No. 4 2007

574
BOYARSKII et al.
B:
1. MeCSNH2/AcOH
Br
Br
Br
2. NaOAc
Br2/AcOH
Br
N
S
O
O
IX
COOH
1. CO/MeOH/K2CO3/Co2(CO)8/epoxide
2. HCl
N
S
X
Pathway A involves carbonylation of aryl halide
(4-bromoacetophenone) described in [10]. Pathway B
includes the stage of carbonylation of halide IX,
which required preliminary examination.
Carbonylation of 4-(4-bromophenyl)-2-methylthi-
azole IX catalyzed by the cobalt complex readily
occurs in methanol with potassium carbonate as
a base:
O
OMe
Co2(CO)8
PCO = 1 atm, T = 80 C
Br
O
+ KBr.
+ CO + MeOK
S
S
N
N
Analysis of the reaction mixture showed a high se-
lectivity of carbonylation of this substrate and good
preparation yield (Table 3).
formation (but not in the early stage of the synthesis)
improves the overall parameters of the process.
As can be seen from the above data, the efficient
catalytic system Co(CO)4 propylene oxide K2CO3 in
metanol, developed previously for aryl halide carbon-
ylation, can also be successfully used in the selective
synthesis of various heteroaromatic carboxylic acids
with a good yield and high selectivity under very mild
Thus, we can synthesize X by two methods
(A and B). The preparation yields are compared in
Table 4. The data obtained show that the presence of
thiazole fragment in the aryl halide molecule does not
prevent carbonylation. Carbonylation after heterocycle
Table 3. Results of carbonylation of 4-(4-bromophenyl)-
2-methylthiazole IX at various molar ratios of reactants
Table 4. Comparison of the yields in the synthesis
of 4-(2-methylthiazol-4-yl)benzoic acid X synthesis by
methods A and B
Molar ratio
IX : Co2(CO)8 :
propylene oxide :
K2CO3
Reac-
tion
time,
h
Substrate
Product
yield**
conversion*
Product yield, % of theory
Reaction step
pathway A pathway B
%
Bromination of acetyl group
Formation of heterocycle by
reaction with thioacetamide
Carbonylation*
Total product yield based
on p-bromoacetophenone
76
78
79
94
73 : 1 : 137 : 160
80 : 1 : 90 : 170
152 : 1 : 170 : 330
8.0
6.0
6.0
95
93
86
93
92
84
74
44
84
62
*
Conversion is determined by NMR analysis of the reaction
mixture.
**
*
Yield of isolated 4-(2-methylthiazol-4-yl)benzoic acid X
after carbonylation, base hydrolysis, and acidification of
the reaction mixture.
Equal conditions and reactant ratios for 4-bromoacetophe-
none and 4-(4-bromophenyl)-2-methylthiazole; without taking
the probable recycle of the substrate into consideration.
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SYNTHESIS OF HETEROAROMATIC CARBOXYLIC ACIDS
575
conditions both in laboratory practice and on the com-
mercial scale for production of raw materials required
for fine chemistry.
concentrated hydrochloric acid to pH 4 5 and kept
until the acids precipitated. The precipitate was filter-
ed off and dried.
EXPERIMENTAL
CONCLUSIONS
The carbonylation reactions were studied at CO at-
mospheric pressure in ordinary temperature-controlled
glass apparatus with vigorous stirring in a CO atmo-
sphere. The reaction products were analyzed by GLC
and 1H NMR. The identification of products was
(1) A new method was developed for synthesis of
heteroaromatic acids and their derivatives by carbon-
ylation of the corresponding hetaryl halides using
highly active catalytic systems based on cobalt car-
bonyl, modified with epoxides.
1
based on data of H and 13C NMR spectroscopy and
(2) It was demonstrated that carbonylation of het-
aryl halides proceeds under very mild conditions (CO
pressure 1 atm) in alcohols in the presence of bases.
mass spectrometry.
The mass spectra were recorded on an MKh-1321
mass spectrometer using direct sample inlet and ion-
ization by electron impact (70 eV); the temperature of
the ionization chamber was 200 C.
(3) It was shown that hetaryl halides with various
structures, containing pyridine, quinoline, tetrahydro-
quinoline, tetrahydroquinazoline, thiophene, or thiazole
fragments can be substrates in the above synthesis.
GLC analysis was performed on a Chrom-5 chro-
matograph with a flame ionization detector; the car-
(4) A series of previously unknown heteroaromatic
acids were synthesized.
1
rier gas was argon, flow rate 20 30 ml min . Glass
columns, 3 mm in diameter and 2500 mm long, were
packed with SF-30 (10%) on Chromaton N-Super
(80 100 mesh). The vaporizer and column tempera-
ture was 200 C.
REFERENCES
1. Mashkovskii, M.D., Lekarstvennye sredstva (Drugs),
Moscow: Meditsina, 1998.
2. Foa, M. and Francalanci, F., J. Mol. Catal., 1987,
vol. 41, nos. 1 2, pp. 89 107.
3. Zhesko, T.E., Boyarskii, V.P., and Beletskaya, I.P.,
The NMR spectra were recorded on a Bruker DPX
300 spectrometer [operating frequency 300.130 (1H)
and 75.03 (13C) MHz]; solvent: 2 : 1 (by volume)
mixture of CCl4 with deuterated dimethyl sulfoxide.
Metalloorg. Khim., 1998, vol. 68, no. 1, pp. 385 387.
A 2-l round-bottomed flask equipped with a pow-
er-driven stirrer, reflux condenser, thermometer, gas-
feeding tube, and dropping funnel was purged with
CO and charged with 200 g (1.4 mol) of K2CO3,
1200 ml of methanol, and 0.5 mol of a substrate.
The reaction mixture was purged with CO under stir-
ring for 0.5 h. Then, in a CO flow, 2.4 g of octacar-
bonyldicobalt (7 mmol) was added, and the tempera-
ture of the reaction mixture was elevated to 62 C.
Then, the required amount of propylene oxide and
15 20 ml of methanol were added from a dropping
funnel over a period of 10 min. After that, the tem-
perature of the reaction mixture was elevated to 64 C,
and the reaction was performed for 6 h at this tem-
perature. Then the CO flow was stopped, the reac-
tion mixture was cooled, 56 g of KOH (1 mol) was
added, and methanol was distilled off at atmospheric
pressure with stirring for several hours. After meth-
anol distillation, water and diethyl ether were added
into the reaction mixture, the organic phase was sep-
arated, and the aqueous phase was acidified with
4. Zhesko, T.E., Boyarskii, V.P., and Nikitina, A.G.,
Zh. Obshch. Khim., 1998, vol. 68, no. 1, pp. 85 89.
5. Miura, M., Itoh, K., and Nomura, M., J. Mol. Catal.,
1990, vol. 59, no. 1, pp. 11 15.
6. Shim, S.C., Lee, Y.D., Choi, H.J., et al., Bull. Korean
Chem. Soc., 1994, vol. 15, no. 9, pp. 772 774.
7. Miura, M., Itoh, K., and Nomura, M., J. Mol. Catal.,
1988, vol. 48, no. 1, pp. 11 13.
8. Nindakova, L.O., Shmidt, F.K., Reshetnikova, O.M.,
and Dmitrieva, T.V., Zh. Org. Khim., 1991, vol. 27,
no. 11, pp. 2276 2281.
9. Zhesko, T.E. and Boyarskii, V.P., Kinet. Katal., 1994,
vol. 35, no. 2, p. 320.
10. Zhesko, T.E., Boyarskii, V.P., and Lanina, S.A.,
Zh. Prikl. Khim., 2005, vol. 78, no. 11, pp. 1875 1880.
11. Vigranenko, Yu.T., Vysokinskaya, A.T., Ryba-
kov, V.A., et al., Neftepererab. Neftekhim., 1987,
no. 3, p. 21.
12. Woods, K.W., McCroskey, R.W., Michaelides, M.R.,
et al., Bioorg. Med. Chem. Lett., 2001, vol. 11, no. 10,
pp. 1325 1328.
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