Isoquinoline in the synthesis of 1-dichloromethylisoquinoline and 1-formylisoquinoline

Article abstract of DOI:10.1134/S1070428010050192

By the reaction of isoquinoline with CCl₄ and methanol catalyzed by iron-containing compounds a synthesis was performed of 1- dichloromethylisoquinoline that was quantitatively converted into 1-formylisoquinoline by the treatment with dimethyl sulfoxide. Pleiades Publishing, Ltd., 2010.

Full text of DOI:10.1134/S1070428010050192

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 5, pp. 706−708. © ©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. 5, pp. 713−715.
Isoquinoline in the Synthesis of 1-Dichloromethylisoquinoline
and 1-Formylisoquinoline
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 July 4, 2009
Abstract—By the reaction of isoquinoline with CCl and methanol catalyzed by iron-containing compounds a
4
synthesis was performed of 1-dichloromethylisoquinoline that was quantitatively converted into 1-
formylisoquinoline by the treatment with dimethyl sulfoxide.
DOI: 10.1134/S1070428010050192
1
-Dichloromethylisoquinoline (I) and 1-formyliso-
+
CCl + CH OH
4 3
quinoline (II) and their derivatives are reactive building
blocks for the synthesis of versatile compounds of the
isoquinoline series exhibiting a strong biological activity
1, 2].
In the laboratory routine 1-dichloromethylisoquinoline
I) is obtained in 20% yield by free-radical chlorination of
N
Fe(C H )
5
5 2
[
1
50°C, 6 h,
conversion of
isoquinoline 60%
N
(
CHCl2
I
the 1-methylisoquinoline with N-chlorosuccinimide in the
presence of benzoyl peroxide in an argon atmosphere [3].
In the best runs the isoquinoline conversion reached
60%, and the selectivity with respect to compound I
attained 95–98%. No reaction occurred without the
catalyst.
~
Another preparation method of 1-dichloromethyliso-
quinoline (I) is based on the reaction of the dichloroketene
with isoquinoline N-oxide in triethylamine solution at
a reduced temperature (yield 42%) [4].
In the conditions employed a part of methanol was
oxidized by CCl under the catalysis of the Fe-containing
catalyst forming the formaldehyde and HCl [5].
4
The goal of this study was a development of a new
method of introduction of the dichloromethyl group into
the isoquinoline molecule and the subsequent conversion
of 1-dichloromethylisoquinoline into 1-formylisoquino-line.
[
Fe]
CH OH + CCl
[CH OCl]
CH O
2
3
4
3
_HCl
Proceeding from our previous results on the conjugate
chloromethylation of pyridine derivatives [5] we attempted
in this study a directional chloromethylation of isoquinoline
In the presence in the reaction mixture of CH O and
2
HCl and also of the Fe-containing catalyst occurred
presumably the chloromethylation of the isoquinoline with
the mentioned chloromethylating mixture providing
compound I (Scheme 1).
containing a reactive methine group with CCl and MeOH
4
effected by iron-containing catalysts.
The performed experiments showed that the reaction
proceeded at 145–155°C within 4–6 h at the molar ratio
of the catalyst and the reagents [Fe(C H ) or
In the reaction carried out with the deuterated
methanol we obtained in 10% yield 1-dichloro-deutero-
methylisoquinoline (IV) in keeping with the above
suggested reaction mechanism (Scheme 2).
5
5 2
(
Fe(acac) ] : [C H N] : [CCl ] : [MeOH] = 1–5 : 100 :
3 9 7 4
7
1
00–1000 : 800–1100, preferably 1 : 100 : 1000 : 1000,
50°C, 6 h.
According to [4] 1-dichloromethylisoquinoline (I) can
706

ISOQUINOLINE IN THE SYNTHESIS OF 1-DICHLOROMETHYLISOQUINOLINE
707
Scheme 1.
preparation of compound II by the oxidation of 1-
methylisoquinoline with the use of SeO the yield did not
2
exceed 42% [10].
In extension of these studies we wished to use the
developed method of isoquinoline chloromethylation with
the quinoline. It turned out that the quinoline difficultly
reacted with CCl and MeOH in the presence of Fe-
4
containing catalysts, and the process was quite non-
selective giving a mixture of isomeric dichloromethyl-
quinolines. The introduction into the catalyst composition
of versatile ligands (PPh , CH CN, pyridine, CH COOH,
3
3
3
HCONH ) did not increase the selectivity of the reaction,
and the conversion of quinoline was no more than 15%.
2
Scheme 2.
EXPERIMENTAL
1
13
H and C NMR spectra were registered on a spec-
trometer Bruker Avance-400 (400.13 and 100.62 ΜHz)
in CDCl , the chemical shifts are reported with respect
3
to TMS. Mass spectra were measured on a GC-MS
instrumenr Finnigan-4021 (electron impact, 70 eV, 200°C,
direct admission into the ion source). GLC was carried
out on a chromatograph Chrom-5 [column 1200×3 mm,
stationary phase silicone SE-30 (5%) on Chromaton
N-AW-HMDS (0.125–0.160 mm)], carrier gas helium
serve as initial compound for the preparation of valuable
for practice 1-formylisoquinoline (II) used in the synthesis
of some known alkaloids (trolin, crispin A, crispin E)
containing in their molecules a tetrahydroisoquinoline
fragment. Taking into account this information we tried
further to convert compound I into aldehyde II, but the
known methods of hydrolysis of the dichloromethyl group
into the aldehyde one (acid [6], alkaline hydrolysis [7],
and hydrolysis through morpholine derivatives [8]) were
inefficient with compound I.
(
47 ml/min), ramp from 50 to 250°C at the rate
8
deg/min.
The initial reagents were commercially available
isoquinoline, CCl , methanol. CCl and MeOH were
4
4
purified by known methods [11].
The conversion of compound I into 1-formyliso-
quinoline (II) we succeed to achieve using the method
applied in [9] for the transformation of dihalomethylarenes
into aromatic aldehydes. The specific feature of this
method consists in the rejection of the use of strong acids
and alkalis and the application of DMSO for oxygen
transfer. The complete conversion of compound I was
reached under more stringent conditions than in the
reactions with dihalomethylarenes (150°C, 8 h), but
nonetheless the yield of 1-formylisoquinoline (II) attained
The iron compounds [ferrocene and Fe(acac) ] were
dried in a vacuum desiccator before use.
3
The reactions were carried out in glass ampules of 10
ml capacity placed into a small stainless-steel pressure
reactor of 17 ml capacity. The process was performed
at constant stirring and controlled heating.
1-Dichloromethylisoquinoline (I). In an argon
atmosphere into the ampule was charged 0.1 mmol of
the iron-containing catalyst [Fe(acac) or Fe(C H ) ], 10
3
5
5 2
~
95%. For instance, in the known procedure for the
mmol of isoquinoline, 100 mmol of CCl , and 100 mmol
4
Scheme 3.
DMSO
I
_
o
_
S+Cl
N
1
50 C, 8 h
N
Cl
S+
_
CHO
II, 98%
Cl
Cl
O
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 5 2010

708
KHUSNUTDINOV et al.
residue was crystallized within 10 h at –5°C. Yield ~95%,
of MeOH. The sealed ampule was placed into the
pressure reactor, which was tightly closed and heated
for 5 h at 150°C. On the completion of the reaction the
reactor was cooled to 20°C, the ampule was opened, the
reaction mixture was filtered through a bed of silica gel
1
mp 55–56°C (55–55.5°C) [10]. H NMR spectrum, δ,
1
3
ppm: 7.50–8.60 m (8Hisoquin), 10.37 s (1H, CHO). C
8
a
4
NMR spectrum, δ, ppm: 121.20 (C ), 125.35 (C ), 130.83
5
7
6
8
4a
(
C ), 130.08 (C ), 131.10 (C ), 132.30 (C ), 134.60 (C ),
142.55 (C ), 151.30 (C ), 195.66 (CHO). Mass spectrum,
m/z (I , %): 157 [M] (30), 51 (10), 75 (18), 76 (10), 77
3
1
(2 g), the unreacted methanol was distilled off, the reaction
+
mixture was neutralized with 10% aqueous Na CO
rel
2
3
(
10), 102 (35), 115 (25), 128 (39), 129 (100), 130 (10).
(stirring for 0.5–1 h), the organic products were extracted
into chloroform. 1-Dichloromethylisoquinoline (I) was
purified by column chromatography on silica gel (40–100
μm), eluent chloroform. Compound I was eluted with
the first fraction of the solvent, the initial isoquinoline,
with the subsequent fragtion. The solvent was distilled
off, the separated crystals were recrystallized from ethyl
ether. Yield 59%.
The study was carried out under a financial support
of the Russian Foundation for Basic Research (grant no.
9-03-00472) and of the Ministry of Education and
Science of the Russian Federation (grant no.NSh
349.2008.3).
0
2
REFERENCES
On evaporation of the second fraction we obtained
0
.35 mmol of the initial isoquinoline (of purity ~95%) that
1
. Khimiya geterotsiklicheskikh soedinenii (Chemistry of
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Heterocycles, 2007, vol. 74, p. 199.
could be repeatedly used in the reaction.
The isolated 1-dichloromethylisoquinoline (I), mp 57.5–
2
1
5
9°C (57–59°C) [4], H NMR spectrum, δ, ppm: 7.24 s
5
,6,7
(
(
1H, CHCl ), 7.50–7.75 m (3H, H
1H, H , J 8.4 Hz), 8.4 d (1H, H , J 5.6 Hz), 8.59 d (1H,
isoquin), 7.84 d
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2
4
8
vol. 8, p. 676.
3
13
H , J 8 Hz). C NMR spectrum, δ, ppm: 71.52 (CHCl ),
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2
8
a
8
7
6
1
1
1
7
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4
3
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1
+
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rel
2
5 (17), 88 (15), 113(20), 115 (25), 128 (11), 129 (3), 140
6
(
30), 176 (100), 178 (30), 211 (27), 213 (20).
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ml of DMSO (in excess). The sealed ampule was placed
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extract was dried with Na SO . The mixture of ethyl
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1
2
4
1
acetate and DMSO was distilled off in a vacuum, the
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 5 2010