Synthesis of 1-acylisoquinolines from isoquinoline, alcohols, and CCl 4 catalyzed by iron complexes

Article abstract of DOI:10.1134/S1070428010090228

Reactions of isoquinoline with normal alcohols (ethanol, 1-propanol, 1-butanol) and tetrachloromethane in the presence of iron-containing catalysts afforded 1-acylisoquinolines in 38-75% yield.

Full text of DOI:10.1134/S1070428010090228

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 9, pp. 1399−1402. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © R.I. Khusnutdinov, A.R. Baiguzina, R.R. Mukminov, 2010, published in Zhurnal Organicheskoi Khimii, 2010, Vol. 46, No. 9, pp. 1395−1398.
Synthesis of 1-Acylisoquinolines from Isoquinoline, Alcohols,
and CСl4 Catalyzed by Iron Complexes
R. I. Khusnutdinov, A. R. Baiguzina, and R. R. Mukminov
Institute of Petrochemistry and Catalysis, Russian Academy of Sciences
Ufa, 450075 Russia; e-mail: ink@anrb.ru
Received January14, 2010
Abstract—Reactions of isoquinoline with normal alcohols (ethanol, 1-propanol, 1-butanol) and tetrachloromethane
in the presence of iron-containing catalysts afforded 1-acylisoquinolines in 38–75% yield.
DOI: 10.1134/S1070428010090228
1-Acylisoquinolines, in particular, 1-acetylisoquino- and FeSO4·7 H2O in 21% yield [8].
line (I) are used for preparation of malaricidal [1] and
antiviral drugs [2, 3].
In this study we developed a new method for direct
introduction of the acyl group into the isoquinoline mole-
cule by the reaction with alcohols and tetrachloromethane
in the presence of iron-containing catalysts [Fe(acac)3,
Fe(OAc)2, FeBr2, iron trinaphthenate, ferrocene]. By an
example of the isoquinoline reaction with ethanol giving
1-acetylisoquinoline (I) we established that the most ef-
ficient catalyst of this process was ferrocene (Scheme 1).
Various syntheses of 1-acylisoquinolines were pub-
lished. For instance, the 1-acylisoquinolines were ob-
tained by the cleavage of β-ketoesters formed by Claisen
condensation of isoquinolinecarboxylic acids with ethyl
acetate. The other method of 1-acylisoquinolines prepa-
ration is based on the reaction of 1-cyanoisoquinolines
with various organomagnesium compounds by Kaufmann
method [4, 5].
The optimum conditions of the synthesis of
1-acetylisoquinoline (I) in the presence of ferrocene were
adjusted experimentally. For instance, within 5 h at 150°С
and the molar ratio ferrocene–isoquinoline–ethanol–ССl4
1 : 100 : 1500 : 500 the yield of 1-acetylisoquinoline (I)
calculated on the reacted isoquinoline was 75%, at the use
of the other iron complexes the yield was lower (~50%).
1-Acetylisoquinoline (I) was synthesized by Heck
reaction from ethyl isopropenyl ether and 1-trifluorometh-
ylsulfonyloxyisoquinoline in the presence of the catalytic
system Pd2(dba)3–PPh3 in 52% yield[6], by Kucherov
reactioin from 1-ethynylisoquinoline and concn. H2SO4
in the presence of mercury(II) sulfate in acetone medium
in 75% yield [7], by the reaction of isoquinoline with
acetaldehyde in the presence of radical initiators, like
tert-butylhydroperoxide, in the presence of 40% H2SO4
The large consumption of ethanol calls for attention:
It is due to side reactions of oxidation with successive
formation ethyl hypochlorite (found by iodometric titra-
tion), acetaldehyde, and HCl.
Scheme 1.
Fe(C5H5)2
150°C, 5 h
N
COOEt
+ EtOH + CCl4
I
Ac
N
Fe(C5H5)2
+ II
I
I
+
4 h
150°C, 8_10 h
N
1 : 4.5
1.1 : 1
Ac
II
1399

KHUSNUTDINOVA et al.
1400
As to the mechanism of the reaction in question, tak-
d (H8, J 8.2 Hz), 7.61–7.83 m (H5–7) ppm] fragments
of the molecule unambiguously proved that the acetyl
substituent was linked to atom C1.
ing into account the acetaldehyde formation the most
probable path involves the acetaldehyde through the
generation of an acetyl radical like in the Minisci reaction
giving as a result 1-acetylisoquinoline (I) [9].
The increase in the reaction time to 8–10 h resulted in
the decrease in the yield of 1-acetylisoquinoline (I) to 45%
caused by the formation of ethyl 1-acetylisoquinoline-4-
carboxylate (II). The only proton signal in the weak field
at δ 9.12 ppm (1H) connected by a cross-peak with a sig-
nal of atom С3 in the spectrum of compound II indicates
that the ethoxycarbonyl group is located at the С4 atom of
the pyridine fragment of the molecule whereas the spin
system ABCD of the protons of the benzene fragment is
conserved with the characteristic values of the chemical
shifts 8.81 d (H8, J 8.4 Hz), 7.80 m (Н6–7), 8.82 d (H5,
8.4 Hz) ppm.
An additional argument supporting the radical mecha-
nism of the reaction is the presence in the reaction mixture
of a redox system consisted of Fe(II)/Fe(III), 1:1and an
oxidant, ethyl hypochlorite. The oxidation of Fe(II) to
Fe(III) was proved by the titration of the reaction mixture
with solutions of K3[Fe(CN)6] and K4[Fe(CN)6].
The hydrogen chloride also considerably affects the
course of the reaction forming a salt of isoquinoline and
thus ensuring the high selectivity of the attack of radical
CH3CO. on the position 1 of the heterocycle molecule.As
known, the protonated form of isoquinoline reacts with
nucleophilic radicals exclusively at the position 1 [10, 11].
It is highly probable that the carboxy group forms by
the alkylation of I by CCl4 and followed by the alcoholy-
sis of the formed 1-acetyl-4-trichloromethylisoquinoline
(III) under the conditions of the reaction (Scheme 2).
The structure of compound I was established by
comparison with the published data [7] and by the use of
NMR methods 1D-(1H and 13C) and 2D-COSY, HSQC,
HMBC. Thus, the presence of two isolated spin systems
АB and ABCD for protons of the pyridine [8.53 d (H3, J
6.2 Hz), 7.75 d (H4, J 6.2 Hz) ppm] and benzene [8.92
Actually, the experiments with the use of 1-propanol
and 1-butanol instead of ethanol resulted in the corre-
sponding esters of 1-propionyl- and 1-butyroyl-isoquin-
oline-4-carboxylic acids VI, VIII (Scheme 3).
Scheme 2.
COOEt
N
CCl3
CCl4,
[Fe]
EtOH
N
_HCl
N
Ac
Ac
Ac
II
I
III
Scheme 3.
COOPr
+ CCl4 + PrOH
+
N
N
N
Conversion 50%
O
Et
Fe[C5H5]2
150°C, 5 h
O
Et
13:1
VI
V
COOBu
+ CCl4 + BuOH
+
N
N
N
Conversion 40%
O
Pr
O
Pr
VII
24:1
VIII
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 9 2010

SYNTHESIS OF 1-ACYLISOQUINOLINES
1401
It should be noted that the reaction mixture contains
a small quantity of dichloromethylisoquinoline IV (2%)
and tetrachloroethylene (3%) whose presence suggests
the possibility of generation of dichlorocarbene under
the reaction conditions and its further insertion into the
С1–H bond of isoquinoline giving compound IV.
organic layer was filtered through a bed of silica gel (2
g) (eluent chloroform). The reaction product was eluted
with the first fraction of the solvent, afterwards was eluted
the initial isoquinoline. The recovered isoquinoline after
evaporation of the solvent could be returned into the reac-
tion. From the first fraction the solvent was distilled off.
The esters of 1-acylisoquinoline-4-carboxylic acids and
1-acylisoquinoline were isolated by column chromatog-
raphy on silica gel (eluents hexane and chloroform re-
spectively). The analytically pure samples of compounds
I, II, V–IX were isolated by preparative HPLC.
When the reaction was carried out with 1-acetyl-
isoquinoline (I) and methanol (6 h at 150°С), the only
reaction product was methyl 1-acetylisoquinoline-4-
carboxylate (IX) (overall yield 50%). Thus the studied
reaction makes it possible to introduce an ester group
into the position 4 of the 1-acylisoquinoline, and this
opens a wide opportunities for a selective synthesis of
1,4-disubstituted isoquinolines.
1-Acetylisoquinoline (I). bp 135–136°С (10 mm Hg)
{148–148.5°С (11 mm Hg) [4]}. 1H NMR spectrum,
δ, ppm: 2.91 s (3H, COCH3), 7.61–7.83 m (3H, Н5–7),
7.75 d (1Н, Н4, J 6.2 Hz), 8.53 d (1Н, Н3, J 6.2 Hz), 8.92 d
(1Н, Н8, J 8.2 Hz). 13С NMR spectrum, δ, ppm: 28.53
(COCH3), 123.14 (С8а), 124.57 (С4), 126.72 (С8), 126.92
(С5), 129.06 (С6), 130.27 (С7), 136.96 (С4а), 140.97 (С3),
152.68 (С1), 202.52 (СOCH3). Mass spectrum, m/z (Irel,
%): 171 (75) [M]+, 170 (70), 143 (45), 129 (100), 128 (88),
102 (32), 101 (40), 77 (20), 75 (30), 43 (30). Found, %:
C 76.98; H 5.00; N 8.75; O 9.27. С11H9NO. Calculated,
%: C 77.19; H 5.26; N 8.19; O 9.36. M 171.20.
EXPERIMENTAL
1Н and 13С NMR spectra were registered on a spec-
trometer Bruker Avance-400 (400.13 and 100.62 MHz)
in CDCl3. Chemical shifts are reported with respect to
TMS. Mass spectra were measured on a GC-MS instru-
ment Finnigan-4021 (electron impact, 70 eV, 200°С,
direct admission). The chromatographic analysis was
carried out on a chromatograph Chrom-5 [column 1200×3
mm, stationary phase SE-30 (5%) on carrier Chromaton
N-AW-HMDS (0.125–0.160 mm)], carrier gas helium
(flow rate 47 ml/min), ramp from 50 to 250°С at a rate
8 deg/min. The structure of compounds obtained was
confirmed by the identity of their physical properties to
authentic samples.
Ethyl 1-acetylisoquinoline-4-carboxylate (II).
1
bp 130–132°С (0.2 mm Hg), mp 42–43.5°С. H NMR
spectrum, δ, ppm: 1.54 t (3H, СН3, J 7.0 Hz), 2.84 s (3H,
COCH3), 4.50 q (2H, CH2, J 7.0 Hz), 7.68–7.80 m (2H,
Н6,7), 8.81 d (1Н, Н8, J 8.4 Hz), 8.82 d (1Н, Н5, J 8.4 Hz),
9.12 s (1Н, Н3). 13С NMR spectrum, δ, ppm: 14.28
(СO2СH2CH3), 28.78 (COCH3), 61.75 (СO2СH2CH3),
123.88 (С4), 125.01 (С8), 125.20 (С8а), 126.91 (С5),
128.93 (С7), 131.81 (С6), 135.01 (С4а), 144.15 (С3),
156.30 (С1), 165.92 (СOOС2H5), 202.09 (СOCH3). Mass
spectrum, m/z (Irel, %): 243 (12) [M]+, 215 (20), 214 (100),
201 (18), 198 (12), 173 (22), 156 (12), 128 (30), 127 (28),
101 (12), 75 (8), 43 (52). Found, %: C 69.25; H 5.55;
N 6.05; O 19.15. C14H13NO3. Calculated, %: C 69.14;
H 5.35; N 5.76; O 19.75. M 243.26.
The commercial isoquinoline was used in the study.
The purification of CCl4, MeOH, EtOH, 1-PrOH,
1-BuOH was performed by known procedures [12].
The iron compounds before the reaction were dried in a
vacuum-desiccator.
The reactions were performed in glass ampules of
12 ml capacity placed into a pressure microreactor of
stainless steel (17 ml).
1-Acylisoquinoline I, II, V–IX. Into the ampule in
an argon flow was charged 0.0031 g (0.016 mmol) of
Fe(С5H5)2, 0.2 g (1.66 mmol) of isoquinoline, 1.27 g
(8.3 mmol) of CCl4, and 25 mmol of alcohol (1.15 g of
C2H5OH, 1.5 g of PrOH, 1.85 g of BuOH). The ampule
was sealed, the microreactor was tightly closed and heated
to 150°С for 4–14 h at constant stirring. On completion
of the reaction the reactor (with the ampule) was cooled
to 20°С, opened, the content of the ampule was passed
through a bed of Al2O3, neutralized with the water so-
lution of Na2CO3, and extracted with chloroform. The
1-Propionylisoquinoline (V). bp 110–115°С (1 mm
Hg). H NMR spectrum, δ, ppm: 1.23 t (3H, COCH2CH3,
1
J 7.2 Hz), 3.31 q (2H, COCH2CH3, J 7.2 Hz), 7.55–7.78 m
(3H, Н5–7), 7.80 d (1Н, H4, J 6.0 Hz), 8.81 d (1Н, Н8,
J 8.0 Hz). 13С NMR spectrum, δ, ppm: 8.12 (COCH2CH3),
33.53 (COCH2CH3), 123.08 (С8а), 124.18 (С4), 126.64
(С8), 126.89 (С5), 128.83 (С6), 130.20 (С7), 136.68
(С4а), 140.97 (С3), 153.19 (С1), 205.10 (СOСH2CH3).
Found, %: C 77.50; H 5.70; N 7.85; O 8.95. C12H11NO.
Calculated, %: C 77.84; H 5.95; N 7.56; O 8.65.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 9 2010

KHUSNUTDINOVA et al.
1402
Propyl 1-propionylisoquinoline-4-carboxylate
H 7.02; N 4.68; O 16.06.
(VI). bp 110–115°С (0.02 mm Hg), mp 30–34°С.
1H NMR spectrum, δ, ppm: 1.097 t (3H, CH2СH2CH3,
J 7.6 Hz), 1.28 t (3H, COСH2CH3, J 7.2 Hz), 1.65–1.95
m (2H, CH2СH2CH3), 3.34 q (2H, COСH2CH3, J 7.2 Hz),
4.39 t (2H, CH2СH2CH3, J 7.2 Hz), 7.68–7.97 m (2H,
Н6,7 of isoquinoline), 8.73 d (1Н, Н8, J 8.8 Hz), 8.93 d
(1Н, Н5, J 8.8 Hz), 9.14 s (1Н, Н3). 13С NMR spectrum,
δ, ppm: 7.93 (COCH2CH3), 10.57 (СO2CH2СH2CH3),
22.07 (СO2CH2СH2CH3), 34.04 (COCH2CH3), 67.23
(СO2CH2СH2CH3), 123.54 (С4), 124.62 (С8а), 125.09
(С8), 135.01 (С4а), 126.83 (С5), 128.81 (С7), 131.90 (С6),
144.26 (С3), 157.32 (С1), 165.8 (СOOС3H7), 204.87
(COCH2CH3). Found, %: C 70.60; H 6.50; N 5.00;
O 17.90. C16H17NO3. Calculated, %: C 70.85; H 6.27;
N 5.17; O 17.71.
Methyl 1-acetylisoquinoline-4-carboxylate (IX).
bp 135–137°С (1 mm Hg). Mp 48–50°С. 1H NMR spec-
trum, δ, ppm: 2.84 s (3H, COCH3), 4.04 s (3H, СO2CH3),
7.25–7.80 m (2H, Н6,7), 8.81 d (1Н, Н8, J 8 Hz), 8.87 d
(1Н, Н5, J 8 Hz), 9.10 s (1Н, Н3). 13С NMR spectrum,
δ, ppm: 28.79 (COCH3), 52.59 (СO2CH3), 121.50 (С8а),
123.42 (С4), 124.99 (С7), 126.90 (С8), 128.96 (С6),
131.88 (С5), 134.98 (С4а), 144.25 (С3), 156.46 (С1),
166.34 (СOOСH3), 202.09 (СOCH3). Found, %: C 68.20;
H 4.55; N 6.10; O 21.15. C13H11NO3. Calculated, %:
C 68.12; H 4.80; N 6.12; O 20.96.
The authors are grateful to the Head of Laboratory
of structural chemistry of the Institute of Petrochemistry
and Catalysis, Russian Academy of Sciences, Professor
L.M. Khalilov and to the Head of Laboratory of chroma-
tography of the Institute of Petrochemistry and Catalysis,
Russian Academy of Sciences, Candidate of Chemical
Sciences Z.S. Muslimov for the help in isolation and
identification of compounds obtained.
1-Butyroylisoquinoline (VII). bp 110–112°С
(0.2 mm Hg). 1H NMR spectrum, δ, ppm: 1.03 t
(3H, COCH2CH2CH3, J 7.2 Hz), 1.75–1.83 m (2H,
COCH2CH2CH3), 3.28 t (2H, COCH2CH2CH3, J 7.2 Hz),
7.57–7.98 m (3H, Н5–7 of isoquinoline), 8.53 d (1Н,
H4, J 4.8 Hz), 8.82 d (1Н, Н8, J 8.4 Hz). 13С NMR
spectrum, δ, ppm: 13.80 (COCH2CH2CH3), 17.52
(COCH2CH2CH3), 42.04 (COCH2CH2CH3), 124.05
(С4), 125.46 (С8а), 126.49 (С5), 126.80 (С8), 128.68
(С6), 130.06 (С7), 136.75 (С4а), 140.84 (С3), 153.10 (С1),
204.34 (СOСH2CH2CH3). Mass spectrum, m/z (Irel, %):
199 (11) [M]+, 198 (15), 184 (25), 170 (70), 156 (20),
143 (20), 129 (100), 128(70), 101 (30), 77 (15), 75 (16),
43 (14). Found, %: C 78.45; H 6.70; N 6.94; O 7.91.
C13H13NO. Calculated, %: C 78.39; H 6.53; N 7.04;
O 8.04. M 199.25.
The study was carried out under the financial support
of the Russian Foundation for Basic Research (grant no.
09-03-00472) and of the Ministry of Education and Sci-
ence of the Russian Federation (grant NSh 2349.2008.3).
REFERENCES
1. Klayman, D.L., Scovill, J.P., Bruce, J., and Bartose-
vich, J.F., J. Med. Chem., 1984, vol. 27, p. 84.
2. Elford, H.L. and Riet, B., US Patent 6248787, 2001.
3. Shipman, C. Jr., Smith, S.H., Drach, J.C., and Klay-
man, D.L., Antiviral Research., 1986, vol. 6, p. 197.
4. Padburg, J. and Lindwall, H.G., J. Am. Chem. Soc., 1945,
vol. 67, p. 1268.
5. Heterocyclic Compounds, Elderfield, R.C., Ed., NewYork:
Wiley, 1957
6. Legros, J.-Y., Primault, G., and Fiaud, J.-C., Tetrahedron,
2001, vol. 57, p. 2507.
7. Sakamoto, T., Kondo, Y., Shiraiwa, M., andYamanaka, H.,
Synthesis, 1984, p. 245.
8. Budyka, M.F., Kantor, M.M., and Alfimov, M.V., Khim.
Geterotsikl. Soedin., 1991, p. 1340.
9. Fontana, F., Minisci, F., Barbossa, M., and Vismarta, E.,
J. Org. Chem., 1991, vol. 56, p. 2866.
10. Comprehensive Organic Chemistry, Barton, D. and Ollis,
W.D., Eds., Oxford: Pergamon, 1979, vol. 8.
11. Joule, J.A. and Mills., K., Heterocyclic Chemistry, Wiley-
Blackwell, 4 ed. 2000.
Butyl 1-butyroylisoquinoline-4-carboxylate
(VIII). bp 130–135° (0.02 mm Hg). 1H NMR spectrum,
δ, ppm: 1.00 t (3H, СH2CH2СH2CH3, J 4 Hz), 1.03 t
(3H, COСH2CH2CH3, J 4 Hz), 1.30–1.85 m (6H,
COСH2CH2CH3, СH2CH2СH2CH3, СH2CH2СH2CH3),
3.26 t (2H, COСH2CH2CH3, J 7.2 Hz), 4.45 t (2H,
CH2СH2CH2CH3, J 6.8 Hz), 7.60–7.95 m (2H, Н6,7 of
isoquinoline), 8.70 d (1Н, Н8, J 8.8 Hz), 8.92 d (1Н, Н5,
J 8.4 Hz), 9.13 s (1Н, Н3). 13С NMR spectrum, δ, ppm:
13.73 (СO2CH2СH2СH2CH3), 13.83 (COCH2CH2CH3),
17.60 (СOCH2CH2CH3), 19.31 (CO2CH2CH2CH2CH3),
30.69 (СO2CH2СH2CH2CH3), 42.63 (COCH2CH2CH3),
65.49 (СO2CH2CH2СH2CH3), 123.47 (С4), 124.75 (С8а),
125.09 (С8), 127.05 (С5), 128.78 (С7), 131.88 (С6), 135.01
(С4а), 144.25 (С3), 157.41 (С1), 166.03 (СOOС4H9),
204.39 (COCH2СH2CH3). Found, %: C 71.90; H 7.10;
N 5.00; O 16.00. C18H21NO3. Calculated, %: C 72.24;
12. Organikum. Organisch-Chemisches Grundpraktikum,
Berlin: VEB Deutscher Verlag der Wissenschaften, 1976.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 9 2010