6,7-Dimethoxy-3,4-dihydroisoquinolin-1(2H)-ylidenoacetonitrile in some fusion reactions

Article abstract of DOI:10.1134/S1070428011050137

6,7-Dimethoxy-3,4-dihydroisoquinolin-1-ylacetonitrile in the enamine form readily reacts with acyl iso(thio)cyanates affording in high yields 1,2-fused oxo- and thioxodihydropyrimidoisoquinolines and thiouracyloisoquinolines. The reaction of the enamine with primary amines of diverse classes in the presence of 2 equiv of formaldehyde resulted in 1,2-fused N-substituted tetrahydropyrimidinoisoquinolines whose yields depended on the basicity and sterical accessibility of the reagent. Fused 5-hydroxyindolo-, dioxopyrrolo-, pyrroloisoquinolines formed in medium yields in the one-stage reactions of the enamine with p-benzoquinone, oxalyl chloride, and β-nitrostyrene respectively. The reaction of 1-cyanomethyl-6,7-dimethoxydihydroisoquinoline with acrylonitrile leads to the formation of 1,2-fused iminopyridinoisoquinoline easily hydrolysable to pyridine derivative and readily reacting by the amidine group with aroyl chlorides and arylsulfonyl chlorides. Pleiades Publishing, Ltd., 2011.

Full text of DOI:10.1134/S1070428011050137

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2011, Vol. 47, No. 5, pp. 731−745. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © A.A. Afon’kin, M.L. Kostrikin, A.E. Shumeiko, A.F. Popov, 2011, published in Zhurnal Organicheskoi Khimii, 2011, Vol. 47, No. 5,
pp. 726−740.
6,7-Dimethoxy-3,4-dihydroisoquinolin-1(2H)-ylidenoacetonitrile
in Some Fusion Reactions
A. A. Afon’kin, M. L. Kostrikin, A. E. Shumeiko, and A. F. Popov
Litvinenko Institute of Physical Organic and Coal Chemistry,
National Academy of Sciences of Ukraine, Donetsk, 83114 Ukraine
e-mail: AAAfonkin@newmail.ru
Received January 12, 2010
Abstract—6,7-Dimethoxy-3,4-dihydroisoquinolin-1-ylacetonitrile in the enamine form readily reacts with
acyl iso(thio)cyanates affording in high yields 1,2-fused oxo- and thioxodihydropyrimidoisoquinolines and
thiouracyloisoquinolines. The reaction of the enamine with primary amines of diverse classes in the presence
of 2 equiv of formaldehyde resulted in 1,2-fused N-substituted tetrahydropyrimidinoisoquinolines whose yields
depended on the basicity and sterical accessibility of the reagent. Fused 5-hydroxyindolo-, dioxopyrrolo-,
pyrroloisoquinolines formed in medium yields in the one-stage reactions of the enamine with p-benzoquinone,
oxalyl chloride, and β-nitrostyrene respectively. The reaction of 1-cyanomethyl-6,7-dimethoxydihydroisoquinoline
with acrylonitrile leads to the formation of 1,2-fused iminopyridinoisoquinoline easily hydrolysable to pyridine
derivative and readily reacting by the amidine group with aroyl chlorides and arylsulfonyl chlorides.
DOI: 10.1134/S1070428011050137
1-Alkyl-6,7-dimethoxy-3,4-dihydroisoquinolines
as typical cyclic Schiff bases suffer the imine-enamine
isomerization [1–4].
of this research has been summarized in a number of re-
views and books [1–5, 9–12]. For instance, examples are
known of reactions of enamines of B type with diverse
representatives of α,β-unsaturated carbonyl compounds
(nitriles, amides, esters and anhydrides of unsaturated
acids, enones and enales, acetylenedicaboxylic acid es-
ters), with β-di- and some β,β'-tricarbonyl compounds and
their enol forms, with dielectrophiles of various character
( 1,3-dihaloalkanes) [3, 4], and also with haloalkan-
ecarboxylic acids esters [13], bromoacetal [13], oxalyl
chloride [14, 15], alkyl isocyanate haloderivatives [5],
quinones [13], pyrilium salts [3], etc. Many among the
above cited compounds are prone to react also with the
imine form A forming sometimes the products of quite
different structure [16, 17]. The range of dielectrophiles
brought into the reactions of cycles formation is signifi-
cantly wider for aliphatic enamines with the open chain,
in particular, with the primary, secondary and especially
with the tertiary amino function of enamine [9–12].
Each tautomeric form possesses a considerable syn-
thetic potential in 1,2-cyclocondensation reactions lead-
ing to the formation of alkaloid- [5] and steroid-like [3,
5] compounds. Imine tautomer A being a dipole is prone
to reactions with dipolarophiles, enamine tautomer B is
a pronounced C,N-dinucleophile [3, 6, 7] ready to react
with dielectrophiles of various nature. Both isomers can
be involved into various modifications of Diels–Alder re-
action as a dienophile [3], and sometimes also as diene [8].
MeO
MeO
N
NH
MeO
MeO
R
R
B
A
Therefore disregarding the huge amount of research
performed on 1-alkyl-3,4-dihydroisoquinolines still the
extension of the reagents series remains urgent with
In the 1-alkyl-3,4-dihydroisoquinoline series the reac-
tions involving imine and/or enamine forms have been
thoroughly studied within the last 40 years; the results
731

AFON’KIN et al.
732
respect to dielectrophiles (dipolarophiles) whose reac-
tions with enamines (imines) of another structure would
provide isoquinoline compounds previously unknown or
difficultly available, with the selective involvement of
one of the tautomeric forms A, B into fusion reactions.
a tertiary amino group loose it in the stage of cyclization
giving as a result fused oxazinethiones [8, 25–27], and
in the presence of a source of ammonium group (am-
monia, ammonium acetate), substituted and/or fused
pyrimidones, pyrimidonethiones [26], pyrimidonethiols
[10] of various degree of aromatization. Yet the primary
and secondary amino groups as structural elements of
aliphatic [10, 19, 25–27], carbocyclic [25–27] and some
heterocyclic [20–27] enamines in analogous transfor-
mations remain intact in the course of the formation of
similar cyclization products, pyrimidone(thione)s of
various structures.
This target can presumably be fulfilled by the use as
substrates in the new fusion versions of such 1-alkyl-
3,4-dihydroisoquinolines where the equilibrium is es-
sentially shifted to the side of one of the isomers. The
easiest case is the materially complete shift of the equi-
librium to the side of enamine B. This is favored either
by the N-acylation of 1-alkyl-3,4-dihydroisoquinolines
with the formation of the corresponding enamides [1,
9], or by the introduction of an electron-withdrawing
substituent R [3, 4].
Unlike the acyl derivatives the alkyl isocyanates
require severe conditions in the reactions with enamines
and basic catalysis in the cyclization stage [25]. Therewith
the intermediate products of the reaction between the
aliphatic enamines and activated chloroalkyl isocyanates
[25–27] can suffer more complex transformations loosing
a number of functional groups and forming dihydropyri-
dones of various structures.
6,7-Dimethoxy-3,4-dihydroisoquinolin-1-ylacetoni-
trile (I) exists mainly in the enamine form B [20]. This
is confirmed by the presence of the absorption bands
at 3332, 3335 (N–H) and 2185 cm–1 (conjugated C≡N
bond) in the IR spectrum [18], by the presence of strong
absorption maxima at 328 nm and weak absorbance
at 280 nm (characteristic maximum for 1-methyl-3,4-
dihydroisoquinoline existing mainly in the imine form)
in the UV spectrum [18], the appearance of singlet sig-
nals at 5.65 (methylene CH) and 4.25 ppm (NH) in the
1H NMR spectrum with an appropriate integral intensity.
The assignment of the signals of the enamine fragment
was performed taking into account the results of the study
of various isomers of N-methylated structural analogs of
compound I [19].
We did not find any publications on the reactions of
acyl iso(thio)cyanates with enamines1 of type B.
We found that compound I readily reacted with
acyl iso(thio)cyanates of various structures. In an-
hydrous acetonitrile after heating for 15 min at 50°C
enamine I with 5% excess of benzoyl isothiocyanate or
benzoyl isocyanate (at room temperature) we obtained
in 88 and 85% yield two compounds whose presumable
structures were 9,10-dimethoxy-4-phenyl-2-thioxo-6,7-
dihydro-2H-pyrimido-[6,1-a]isoquinoline-1-carbonitrile
(ΙI) and its 2-oxo-analog III respectively (Scheme 1).
In the 1H NMR spectra of arising compounds II and
III the singlet signals 4.25 and 5.55 ppm of amino group
and the hydrogen at sp2-carbon atom of the initial enamine
disappear, and a new group of signals of five aromatic
protons of the phenyl group appears. The IR spectrum
contains the characteristic absorption bands of the stretch-
ing vibrations of thion and carbonyl groups respectively.
We brought compound I into reactions with versatile
dielectrophiles and obtained as a result 1,2-heterofused
6,7-dimethoxytetrahydroisoquinolines, structural analogs
of a series of natural alkaloids promising as biologically
active substances.
Iso(thio)cyanates, highly reactive biselectrophiles,
are widely applied as C,N,O(S)-containing α-synthons
in designing heterocycles [20, 21]. They readily react
with enamines of diverse structures [8, 10, 20–27]. The
reaction as a rule is started by the attack of the carbon
atom of the iso(thio)cyanate group on the C-nucleophilic
site of the enamine (when it is inaccessible, the attack
is directed on the N-nucleophilic site [25]) followed by
the cyclization of the formed intermediate [25–27]. The
cyclization character depends on the structure of the initial
enamine and the type of isocyanate.
Compound II at the treatment with methyl iodide in
DMSO formed an orange precipitate of compound IV
1
whose H NMR spectrum contains a singlet signal at
––––––––––––––
1
Similar in structure 6,7-dimethoxy-1-(cyanomethyl)tetrahydroiso-
quinoline reacted like a common secondary amine with β-chloroethyl
isocyanate at the NH group, and further under the action of a base
suffered tandem cyclizations involving the cyano group of the side
chain and formed finally an imidazo[1’,2’,3,4]pyrimido[6,1-a]
isoquinoline[15].
For instance, after the reaction with acyl iso(thio)
cyanates the aliphatic and carbocyclic enamines with
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 5 2011

6,7-DIMETHOXY-3,4-DIHYDROISOQUINOLIN-1(2H)-YLIDENOACETONITRILE
733
Scheme 1.
2.95 ppm from the protons of CH3 group and the retained
set of signals of the initial compound. This means that
a methylsulfanyl group formed indicating the presence
of a thione fragment in compound II. Also the argento-
metric titration showed the presence of a iodide anion in
the composition of compound IV. The assumed conver-
sions are also confirmed by significant changes in the IR
spectrum in going from compound II to its methylation
product IV: The absorption bands at 1203, 1155, 1107
cm–1 disappeared, and the intensity of absorption in the
MeO
O
N
X
Ph
NCX
MeO
I
N
NC
II, III
MeO
MeO
region 1560 and 1278 cm–1 essentially decreased
.
N
MeI
+
I_
X = S
The result of the reaction of enamine I with acyl
iso(thio)cyanates significantly depends on the reactivity
and the structure of the latter. In the series of the investi-
gated iso(thio)cyanates the benzoyl derivatives leading to
the formation of fused pyrimidoisoquinoline derivatives
possess moderate reactivity.
N
NC
SMe
IV
X = O (II), S (III).
formed a mixture of compounds V and VI (R = OEt),
~90:10, which in the conditions of recording the spec-
trum (DMSO, 25°C) spontaneously converted into the
monosubstituted product V. In ether the intermediate
compound (VI, R = OEt) prevailingly formed which
was successfully isolated and characterized. Its 1H NMR
spectrum contained a signal at 10.45 ppm, and also a set
of signals characteristic of the ethoxy and NH groups of
enamine; the signal at 13.05 ppm characteristic of the
final product was absent.
The most active chlorosulfonyl and also trichloro-
acetyl iso(thio)cyanates with a labile acyl moiety even
at low temperature and in solvents of low polarity af-
forded intractable mixtures containing both the products
of the reaction of the iso(thio)cyanate group with each
nucleophilic site of the enamine and a mixture of the
decomposition products of the acylating agent itself and
the intermediates of acylation.
The least reactive ethoxycarbonyl isothiocyanate
reacted with enamine I loosing the ethoxy group and
forming fused thiouracyl (V) (Scheme 2). This structure
is confirmed by the lack of the amino group protons and of
the sp2-carbon atom of the initial enamine, of the ethoxy
group of the reagent, by the appearance of a broad signal
at 13.05 ppm in the 1H NMR spectrum and of the char-
acteristic bands of the stretching vibrations of S=O and
C=O groups in the IR spectrum. In contrast to the reaction
with benzoyl iso(thio)cyanates where the 1,2-cyclization
results apparently from the intramolecular dehydration
of the formed in the equilibrium the hydroxyimine and
amine structural fragments of intermediates of VI type,
the fusion involving the ethoxycarbonyl isothiocyanate
(Scheme 2) alongside the above mentioned has another
possibility of the intramolecular attack on the amino
group of the enamine of the carbon atom of the ester group
in intermediate VI giving reaction product V.
At heating in DMSO or at treating with pyridine com-
pound (VI, R = OEt) gave cyclization product V identical
to that obtained directly from compound I in acetonitrile.
Enamines, especially those containing a primary
and a secondary amino groups, seldom are used [28]
as substrates in the Mannich reaction for they include
at least two reaction sites of aminomethylation capable
of reacting as an independent amine component and
thus compete with the target amine. The enamines of
the B type are only occasionally used as substrates of
amino(oxy)methylation [29]. For instance, at the action of
the mixture formaldehyde–amine [29] or of single form-
aldehyde [30] compound I was converted respectively
into C-monoaminomethylated derivatives of VIII kind
(Scheme 3) (in the case of a series of secondary aliphatic
amines) in low yield, or into 1,2-fusedый oxazine (at the
use at least of 2 equiv of formaldehydea in the absence
of amine) in a moderate yield. For a limited number of
primary amines the fundamental possibility was shown
[29] of the bisaminomethylation opening another path
to the preparation of 1,2-fused hydropyrimidinoiso-
For the less active ethoxycarbonyl isothiocyanate we
were able to establish the sequence of the reaction of the
nucleophilic centers of enamine I with the thiocyanate
group of the reagent reacting first of all. In acetonitrile,
in keeping with the data of 1H NMR spectra and HPLC,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 5 2011

AFON’KIN et al.
734
Scheme 2.
MeO
MeO
MeO
MeO
O
NH
H
NH OH
R
NCS
I
N
R
N
R
NC
NC
S
O
S
C
VI
MeCN
Δ
R = OEt,
_EtOH
or DMSO
(spontaneously) R = OEt
Py
_H2O R = Ph
_EtOH
MeO
II
N
S
O
MeO
NH
NC
V
Scheme 3.
MeO
MeO
MeO
MeO
CH2O
CH2O
NH
OH
N
O
NC
NC
VII
C
MeO
NH
CH2O, RNH2
MeO
I
NC
NHR
CH2O
VIII
MeO
a
b
N
MeO
2CH2O, RNH2
N
NC
IXа_IXll
R
Side products
R = PhCH2CH2 (a), 3,4-(MeO)2C6H3CH2CH2 (b), 4-EtOC6H4CH2CH2 (c), 2,4-(MeO)2C6H3CH2CH2 (d),
2,5-(MeO)2C6H3CH2CH2 (e), 4-MeSC6H4CH2CH2 (f), 2-(4-methylpiperidino)ethyl (g), 2-(cyclohex-1-en-1-yl)ethyl (h),
3-(2-oxopyrrolidin-1-yl)propyl (i), 3-[3,4-dihydro-2(1H)-isoquinolin-1-yl]propyl (j), HOCH2CH2 (k), HOCH2CH2CH2 (l),
MeOCH2CH2 (m), Ph (n), 3,4-Me2C6H3 (o), 4-BrC6H4 (p), 3-CF3C6H4 (q), 3-MeC6H4 (r), 4-EtOC6H4 (s), 4-(Et2NSO2)C6H4
(t), 4-(EtOCO)C6H4 (u), 3-pyridyl (v), Bn (w), Me(Ph)CH2 (x), 1,3-dihydro-2-benzofuran-5-ylmethyl (y), 1-(2,3-dihydro-
1,4-benzodioxan-6-yl)ethyl (z), HOCH2CHPh (aa), 4-TolCH2 (bb), 4-ClC6H4CH2 (cc), 3-ClC6H4CH2 (dd), 3-FuCH2
(ee), 3-tetrahydrofurfuryl (ff), cyclohexyl (gg), cyclopentyl (hh), HOCOCH2 (ii), HOCOCH2CH2 (jj), EtOCOCH2 (kk),
1-(ethoxycarbonyl)piperidino (ll).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 5 2011

6,7-DIMETHOXY-3,4-DIHYDROISOQUINOLIN-1(2H)-YLIDENOACETONITRILE
735
quinolines, structural analogs of some antihelmintic and
antihypertensive agents, hair growth stimulators [31, 32].
Enamine I reacts with various primary amines in the pres-
ence of 2 equiv of formaldehyde with the formation of
N-R3-substituted 6,7-dihydro-2H-pyrimidoisoquinolines
IXa–IXll (path a, Scheme 3). Thus after short boiling
in ethanol compounds formed in 12–94% yield whose
1H NMR spectrum lacked the signals of both protons
CH and NH of the initial enamine moiety, and the spectra
contained a set of singlet signals from two methylene
groups (4.20–4.90 and 3.60–4.35 ppm), and also specific
signals belonging to the variable N-R-substituent. These
compounds may sometimes be isolated as free Mannich
bases or in most cases as hydrochlorides or hydrooxalates.
Hydrochlorides of some compounds IX readily absorb
water and/or suffer tarring and require anhydrous condi-
tions of isolation (first of all, at the filtration).
the yield from 92 to 45% in going from benzylamine to
α-methylbenzylamine.
At the use of weakly basic heteroaromatic exocyclic
amines (thiazo-2-ylamines, 1-aminotriazole), aromatic
amines with ortho-substituents (2,5-dimethoxyaniline,
2-chloroaniline), some functional amines (triptamine,
a series of aminoalcohols) the Mannich bisaminometh-
ylation finishes either by the formation of side products2
(path b, Scheme 3) where alongside compound VII
products are present of the intermolecular reaction of two
molecules of initial enamine I and formaldehyde, or by
the formation of unstable target products that easily suf-
fer tarring and whose stabilization as tertiary ammonium
salts is unsuccessful.
Among the free amino acids only with glycine and
β-alanine plausible results of bisaminomethylation were
obtained at the use of these amino acids as the source of
the primary amino group. The reaction does not occur
with α-alanine, tryptophan, methionine, and also with
ortho-anilines mainly due to the steric shielding of the
amino group. Since the esters of these amino acids also
cannot be brought into the bisaminomethylation reaction,
it confirms the dominant effect of the steric factors and
lesser effect of low solubility of amino acids in ethanol,
and of compound I in water (the medium for the reaction
with amino acids is aqueous ethanol).
Under alkaline conditions in the absence of the amine
component the reaction actually results in the formation
of fused oxazine VII (yield 76%) whose characteristics
are identical to those described in [29]. Its formation is
likely to result from the successive hydroxymethylation
first of enamine I and then its C-hydroxymethyl derivative
C with the second formaldehyde molecule [29]. A like
sequence may also exist in the bisaminomethylation in-
volving primary amines where as intermediates may serve
either compound C or, more likely, its aminomethylene
analog of type VΙII, (R = H), where the free NH group
is capable of the subsequent reaction with the second
formaldehyde molecule with the closure of the dihydro-
pyrimidine ring and the formation of compound IX.
Enamine fragment of reagent I can potentially react
with many α-functional components, in particular, with
unsaturated compounds often used as synthons in cycle
formation [4]. A special interest attracts the reaction of
enamine I with p-benzoquinone under the conditions
of Nenitzescu reaction as a route to fused 5-hydroxy-
indoloisoquinolines exhibiting anticancer [13, 33],
antidepressant [34], and the other kinds of physiologic
activity. A number of approaches to the synthesis of the
like compounds was described that were developed for
the preparation of dibenzopyrrocoline alkaloids and
were based on the photocyclization of enamines [35], on
the transformations of 1-(2-bromobenzyl)isoquinolines
[36], on the cyclization by Bischler-Napieralski reac-
tion [37] etc. The Nenitzescu reaction with enamine I
was not described in the literature, but close in structure
1-ketoderivatives enamines of type B (R= COMe) in ni-
The range of the primary amines capable to act as
a donor of the N-R-function in the formation of the fused
dihydropyrimidine ring (Scheme 3) is sufficiently wide
and includes aliphatic amines, phenethylamine and its
structural analogs, aminoalcohols and their derivatives,
benzylamines of diverse structure, alicyclic amines and
their heteroanalogs, aromatic amines, some amino acids
and their esters.
As a rule the preparative yields of the fused hydro-
pyrimidinoisoquinolines IX is 1.5–2 times higher with
more basic aliphatic amines, but the yields decrease
with the diminishing spatial accessibility of the primary
amino group of the reagent and with its functionalization,
impeding the isolation of the final product. For instance,
the high sensitivity of the bisaminomethylation of en-
amine I toward the spatial accessibility of the primary
amino group is clearly demonstrated by the decrease in
––––––––––––––––––
1
2 In H NMR spectra of side products (path b, Scheme 3) appear
singlets of the methylene protons, a double set of proton signals
of methoxy groups and the aromatic ring enamine, and one proton
signal of CH or NH functions of enamine fragment is absent.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 5 2011

AFON’KIN et al.
736
tromethane medium led to the formation of indolo[2,1-a]
isoquinolines in up to 75% yields [13].
presence of Et3N and after 3 h of boiling with β-methyl-
3,4-dimethoxy-β-nitrostyrene in ethanol respectively
(Scheme 4).
Under the conditions described in [13] (stirring for
two days of the mixture of enamine I with 40% excess
of p-benzoquinone at room temperature in nitromethane)
the target compound X formed in small quantity and
was contaminated with difficultly separable impurities.
For practical purposes it proved to be more convenient
to carry out the reaction in acetic acid which had been
successfully used as solvent in a number of Nenitzescu
reactions [38].
Dioxo compound XI was obtained as bright red
crystals characteristic of isatin-like derivatives. Yield of
64% was not optimized; evidently higher yield would be
obtained at stronger cooling of the reaction mixture. Its
1H NMR spectrum characteristically lacked the singlet
signals of NH and CH of the initial enamine and pos-
sessed all groups of signals corresponding to the 3,4-di-
methoxytetrahydroisoquinoline fragment.
Nitrile XII was obtained in 86% yield along the
method described for the reaction of compound B (R =
COOEt) with some nitroalkanes [39]. It was presumed
that such Michael addition proceeded through the stage
of attack of the CH group of enamine on the α-position
of the activated double bond of the alkene followed by
the attack of the NH group of the enamine now on the
β-carbon atom with the loss of the nitro group and the
closure of the pyrrole ring [39].
MeO
O
O
N
MeO
I
AcOH, Δ
NC
OH
X
For instance, after stirring equimolar amounts of re-
agents at 40°C in acetic acid for 2 h a light-green precipi-
tate formed in 38% yield, and its spectral characteristics
and elemental analysis were consistent with the expected
The Michael addition of enamine I to acrylonitrile
widely used in fusion reactions finished by the formation
of a product of fundamentally another structure, tetrahy-
dropyridinoisoquinoline (XIII). Therewith the acrylo-
nitrile in contrast to β-nitrostyrene acted as 1,3-carbon
synthon, namely, in the formation of the hydropyridine
ring the carbon atom of the cyano group was involved,
and the nitrogen atom was converted into a part of the
amidine group. It is known that acryl derivatives in the
fusion reactions with some enamines are capable of mul-
tiple reactions, especially when they are present in excess
[40]. Yet in ethanol in the presence of 1 equiv of sodium
ethylate3 the boiling of enamine I with 10% excess of
acrylonitrile for 30 min led to the formation of mono-
product of the reaction XIII in 79% yield (Scheme 5).
1
structure X. Its H NMR spectrum contained a charac-
teristic signal of the OH group (8.85 ppm), an adequate
set of signals from both aromatic rings (7.9, 7.7, 7.45,
7.10, 6.95 ppm), triplet signals of the methylene protons
of the tetrahydroisoquinoline ring (4.4 and 3.15 ppm),
and singlets from methoxy groups (3.8 and 3.9 ppm); the
proton signals of the fragments CH and NH of the initial
enamine were absent. The IR spectrum characteristically
contained strong bands of cyano and and hydroxy groups
(2210 and 3350 cm–1).
Fused pyrroloisoquinolines XI and XII of similar
structure were obtained by the reaction of enamine I
with oxalyl chloride in anhydrous chloroform in the
Scheme 4.
OMe
OMe
MeO
Me
NO2
MeO
(COCl)2
MeO
NC
I
N
O
MeO
MeO
MeO
Me
N
NC
XI
O
XII
––––––––––––––––––
3 The reaction with acrylonitrile proceeds in the presence of bases in contrast to the reaction with β-nitrostyrene where the basic catalysis
essentially complicates the course of the process.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 5 2011

6,7-DIMETHOXY-3,4-DIHYDROISOQUINOLIN-1(2H)-YLIDENOACETONITRILE
737
Scheme 5.
MeO
H+
N
O
MeO
H2O
MeO
MeO
CN
NC
XIV
I
XIV
N
NH
MeO
MeO
NC
XIII
AcCl
N
NAcyl
NC
XVа_XVf, XVIа_XVIc
Acyl =ArCOCl (XV), ArSO2Cl (XVI); XV, Ar = Ph (a), 3-IC6H4 (b), 4-ClC6H4 (c), 2-FC6H4 (d), 4-MeOC6H4 (e), furfuryl
(f); XVI, Ar = Ph (a), 3-ClC6H4 (b), 3-NO2C6H4 (c).
After crystallization from ethanol its physicochemical
characteristics were well consistent with published data
[18]. Imine XIII is easily hydrolyzed in the presence of
acids giving hydropyridonoisoquinoline XIV in 78%
yield, and its amidine group due to sufficiently high basic-
ity is able to react with aroyl chlorides and arylsulfonyl
chlorides providing the corresponding N-acyl and
N-sulfonyl derivatives XVa–XVf, XVIa–XVIc. Chlo-
rides and anhydrides of aliphatic acids (in particular acetic
and succinic anhydrides, phenylacetyl chloride, chloride
of O-acetylmandelic acid) under similar conditions react
more complex and provide intractable products.
FTIR-8400S. The completeness of the reactions was
monitored and the chromatographic purity of the reaction
products was tested by HPLC on an instrument Shimadzu
equipped with UV detector (254 nm). Columns ProntoSIL
120-5-C18AQ 5.0 μm (150 × 4.6 mm), gradient elution,
0.1 N H3PO4–acetonitrile, and Hypersil-Silica 5.0 μm
(150 × 4.6 mm), isocratic elution, hexane–ethyl acetate–
acetonitrile, 72 : 17 : 11. Melting points were measured
on the Boёtius heating block. The solvents were puri-
fied as described in [45], the moisture was determined
by Fischer method on an instrument Metrohm 787 KF
Titrino/703 Ti Stand.
Reagent I was obtained by cyclization of cyanoacetic
acid homoveratrylamide in boiling toluene by the action
of P2O5, yield 85%, mp 170–171°C (EtOH) [18 1H NMR
spectrum (CDCl3), δ, ppm: 2.85–2.90 t (2H, CH2), 3.40–
3.45 t (2H, CH2), 3.85 s (3H, CH3O), 3.95 s (3H, CH3O),
4.25 s (1H, NH), 5.60 s (1H, CH), 6.65 s (1H, Ht), 6.95 s
(1H, Ht). The initial homoveratrylamide was synthesized
by procedure [46] reacting the homoveratrylamine with
freshly distilled ethyl cyanoacetate at 100°C over 16 h,
mp 113–115°C [46].
In some known cyclization reactions enamine I among
the other enamines, in particular, of B type (R ≠ CN)
shows significant special features of the reactivity. For
instance, attempts failed to prepare hydroxypyrrolo- and
pyridonoisoquinolines respectively from enamine I and
1 equiv of glyoxal by analogy with [41, 42], or ethyl
phenylpropiolate by procedure [43]; the reagent I was
recovered from these attempts. We also failed to involve
into reactions of 1,2-fusion with compound I the barbitu-
ric acid and its derivatives, which relatively easily reacted
with 1-methyl-6,7-dimethoxy-3,4-dihydroisoquinoline
[44] less prone to the formation of enamine isomer B.
Ethoxycarbonyl isothiocyanate and trichloroacetyl
isothiocyanate were obtained by procedure [47] from
potassium thiocyanate and ethyl chloroformate or trichlo-
roacetyl chloride respectively, their characteristics were
consistent with the published data. Benzoyl isothiocya-
nate was used as a solution obtained as described above;
the other acyl isocyanate were commercial products and
were used without purification.
EXPERIMENTAL
1H NMR spectra were registered on spectrometers
Bruker AM-200 and Bruker AM-400 (200 and 400
MHz), internal reference TMS. IR spectra were recorded
from pellets with KBr on a spectrophotometer Shimadzu
Reaction of enamine Ι with acyl iso(thio)cyanates.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 5 2011

AFON’KIN et al.
738
To a solution of 4 mmol of enamine in 10 ml of aceto-
nitrile was added 5 ml of solution of 4.2 mmol of acyl
iso(thio)cyanate4 in acetonitrile. The mixture was kept
for 20 min at room temperature and 15 min at 50°C. On
cooling the precipitate (compounds II, III, V) were fil-
tered off and recrystallized. Reactions with trichloroacetyl
iso(thio)cyanate, chlorosulfonyl isocyanate were carried
out at 0°C for 10 h.
N 13.38, 13.31; S 10.19, 10.26. C15H13N3O3S. Calculated,
%: C 57.13; H 4.16; N 13.33; S 10.17.
2-(Methylsulfanyl)-9,10-dimethoxy-4-phenyl-1-
cyano-6,7-dihydropyrimido[6,1-a]isoquinolin-5-ium
iodide (IV). To a dispersion of 1.8 mmol of compound
II in 5 ml of DMSO was added a 10% excess (0.12 ml)
of methyl iodide. On adding the methyl iodide the ini-
tial dispersion of substrate II became a homogeneous
solution, and after stirring for 15 min precipitated or-
ange substance, it was washed with ether till complete
removal of DMSO and dried in a vacuum. Yield 65%,
mp 236–237°C (decomp., from DMSO). IR spectrum,
ν, cm–1: 2222, 1585 m, 1555 m, 1487 s, 1281 s, 1055 m.
1H NMR spectrum (DMSO-d6), δ, ppm: 2.95 s (3H,
CH3S), 3.05–3.15 m (2H, CH2), 3.90 C (3H, CH3O),
4.00 C (3H, CH3O), 4.40–4.50 m (2H, CH2), 7.30 s (1H,
Ht), 7.65–7.80 m (3H, Ar), 7.90 m (2H, Ar), 8.00 s (1H,
Ht). Found, %: C 51.10, 51.15; H 3.85, 3.91; I 24.57,
24.62; N 8.15, 8.19; S 6.13, 6.25. C22H20IN3O2S. Calcu-
lated, %: C 51.07; H 3.90; I 24.53; N 8.12; S 6.20.
9,10-Dimethoxy-2-thioxo-4-phenyl-6,7-dihydro-
2H-pyrimido[6,1-a]isoquinoline-1-carbonitrile (ΙI).
Yield 88%, mp 282–283°C (from acetonitrile). IR spec-
trum, ν, cm–1: 2217, 1587 s, 1560 s, 1521, 1479 s, 1392 m,
1350 m, 1277 s, 1203 m, 1155 m, 1107 m, 1064 m.
1H NMR spectrum (DMSO-d6), δ, ppm: 2.80–2.90 m
(2H, CH2), 3.90 s (3H, CH3O), 3.95 s (3H, CH3O),
3.95–4.0 m (2H, CH2), 7.00 s (1H, Ht), 7.50–7.60 m
(3H, Ar), 7.70–7.80 m (2H, Ar), 7.90 s (1H, Ht). Found,
%: C 67.22, 67.31; H 4.58, 4.60; N 11.28, 11.23; S 8.55,
8.57. C21H17N3O2S. Calculated, %: C 67.18; H 4.56;
N 11.19; S 8.54.
9,10-Dimethoxy-2-oxo-4-phenyl-6,7-dihydro-2H-
pyrimido[6,1-a]isoquinoline-1-carbonitrile (ΙΙΙ). Yield
85%, mp 222–223°C (from acetonitrile). IR spectrum,
ν, cm–1: 2183, 1716 s, 1647 m, 1597 s, 1560 m, 1473 s,
Ethyl [2-(6,7-dimethoxy-3,4-dihydro-2H-isoquino-
lin-1-ylidene)-2-cyanothioacetyl]carbaminate (VI,
R = OEt). A solution of 4 mmol of enamine I in 5 ml of
acetonitrile was added to a solution of 4 mmol of eth-
oxycarbonyl isothiocyanate in 20 ml at 25°C. In some
time yellow precipitate formed, it was washed with ether
1
1434 m, 1274 m, 1215 s, 1120 m. H NMR spectrum
(DMSO-d6), δ, ppm: 2.80–2.9 m (2H, CH2), 3.50–3.60 m
(2H, CH2), 3.80 s (3H, CH3O), 3.90 s (3H, CH3O), 7.00 s
(1H, Ht), 7.45–7.50 m (2H, Ar), 7.55–7.60 m (1H, Ar),
7.75 s (1H, Ht), 7.85–7.90 d (2H,Ar). Found, %: C 70.20,
70.11; H 4.79, 4.71; N 11.62, 11.71. C21H17N3O3. Calcu-
lated, %: C 70.18; H 4.77; N 11.69.
1
on the filter and dried in a vacuum. H NMR spectrum
(DMSO-d6), δ, ppm: 1.20 t (3H, CH2CH3), 2.85–2.95 m
(2H, CH2), 3.50–3.60 m (2H, CH2), 3.80 s (3H, CH3O),
3.90 s (3H, CH3O), 4.00 s (1H, NH), 4.05–4.15 q (2H,
CH2CH3), 7.10 s (1H, Ht), 7.55 s (1H, Ht), 10.45 s (1H,
NH imide). Found, %: C 56.42, 56.55; H 5.31, 5.25;
N 11.65, 11.72; S 8.80, 8.92. C16H17N3O4S. Calculated,
%: C 56.50; H 5.30; N 11.63; S 8.87.
9,10-Dimethoxy-4-oxo-2-thioxo-3,4,6,7-tetrahy-
dro-2H-pyrimido[6,1-a]isoquinoline-1-carbonitrile
(V). Yield 87%, mp 297–298°C (from acetonitrile). IR
spectrum, ν, cm–1: 2220, 1717 s, 1577 m, 1545 s, 1508 s,
1294 m, 1279 m, 1265 m, 1253 m, 1223 m, 1068 s.
1H NMR spectrum (DMSO-d6), δ, ppm: 2.80–2.90 m
(2H, CH2), 3.80 s (3H, CH3O), 3.90 s (3H, CH3O),
3.95–4.05 m (2H, CH2), 7.00 s (1H, Ht), 7.90 s (1H, Ht),
13.05 s (1H, NH). Found, %: C 57.18, 57.11; H 4.09, 4.11;
A slight heating for 10 min of 0.7 g of ester VI (R =
OEt) in 5 ml of anhydrous pyridine followed by adding to
the cooled reaction mixture of ethyl ether led to precipita-
tion of the product whose physicochemical and spectral
characteristics were identical to those of compound V.
9,10-Dimethoxy-6,7-dihydro-2H-[1,3]oxazino-
[4,3-a]isoquinoline-1-carbonitrile (VII) was obtained
by treating enamine I with 2 equiv of formaldehyde by
method [29]. Yield 76%, mp 152–153°C (from MeOH)
{154°C (from anhydrous EtOH) [29]}. 1H NMR spectrum
(DMSO-d6), δ, ppm: 2.80–2.85 t (2H, CH2), 3.30–3.35 t
(2H, CH2), 3.80 s (3H, CH3O), 3.90 s (3H, CH3O), 4.45 s
(2H, CH2 oxazine), 4.75 s (2H, CH2 oxazine), 6.70 s (1H,
Ht), 7.85 s (1H, Ht) {publ. (CDCl3–DMSO-d6): 4.48 s
––––––––––––––––––
4 The solution of benzoyl isothiocyanate was prepared in situ by short
heating of a mixture of 4.3 mmol of benzoyl chloride with the 10%
molar excess of potassium thiocyanate in 7 ml of dried acetonitrile.
On completing the reaction the suspension was separated on a cen-
trifuge, the separated solution of isothiocyanate was mixed with
a solution of 4 mmol of enamine. In other events the solutions of
acyl iso(thio)cyanates were prepared by dissolving a weighed portion
in dry solvent.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 5 2011

6,7-DIMETHOXY-3,4-DIHYDROISOQUINOLIN-1(2H)-YLIDENOACETONITRILE
739
(2H, CH2), 4.75 s (2H, CH2) [29]}.
4.25 s (2H, CH2), 6.65 s (1H, Ht), 6.70–6.75 m (3H,
Ar), 7.80 s (1H, Ht). Found, %: C 69.01, 69.03; H 6.69,
6.66; N 9.70, 9.74. C25H29N3O4. Calculated, %: C 68.95;
H 6.71; N 9.65.
Reactions of enamine Ι with primary amines
in the presence of formaldehyde. Into a solution of
4.35 mmol of enamine and 5.4 mmol of primary amine5
in 20 ml of ethanol was added 0.87 ml (2.3 equiv) of
formaldehyde water solution, the mixture was boiled
for 10 min and evaporated on a rotary evaporator. The
residue as a viscous mass was either crystallized from
MeOH or was converted into hydrochloride. To this end
the residue was dissolved in 20 ml of dried acetone, and
a calculated amount of HCl solution in ether was added.
The precipitate was filtered off at exclusion of the contact
with air moisture, washed on the filter with ether, and
dried over P2O5.
9,10-Dimethoxy-3-[2-(4-ethoxyphenyl)ethyl]-
3,4,6,7-tetrahydro-2H-pyrimido[6,1-a] isoquinoline-
1-carbonitrile (IXc). Yield 77% (hydrochloride).
1H NMR spectrum (DMSO-d6), δ, ppm: 1.40 m (3H,
CH3), 2.85–2.90 m (CH2), 3.25–3.30 m (2H, CH2),
3.35–3.40 m (2H, CH2), 3.45–3.50 m (2H, CH2), 3.80 s
(6H, 2CH3O), 4.10 s (2H, CH2), 4.75 s (2H, CH2), 6.65 s
(1H, Ht), 6.80–6.90 m (2H, Ar), 6.95–7.00 m (2H, Ar),
7.80 s (1H, Ht). Found, %: C 65.81, 65.85; H 6.60, 6.69;
Cl 7.70, 7.72; N 9.22, 9.35. C25H30ClN3O3. Calculated,
%: C 65.85; H 6.63; Cl 7.78; N 9.22.
In the case of especially moisture-sensitive hydro-
chlorides the products of Mannich aminomethylation
were transformed into hydrooxalates: The residue after
evaporation of the reaction mixture was dissolved in
15–20 ml of MeOH, and 1 equiv of oxalic acid was added.
On cooling the precipitated crystals were filtered off and
recrystallized from methanol.
3-[2-(2,4-Dimethoxyphenyl)ethyl]-9,10-dime-
thoxy-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]iso-
quinoline-1-carbonitrile (IXd). Yield 45% (hydro-
1
chloride). H NMR spectrum (DMSO-d6), δ, ppm:
2.85–2.90 m (2H, CH2), 3.25–3.30 m (2H, CH2),
3.35–3.40 m (2H, CH2), 3.45–3.50 m (2H, CH2), 3.70 s
(6H, 2CH3O), 3.80 s (6H, 2CH3O), 4.10 s (2H, CH2),
4.75 s (2H, CH2), 6.35 s (1H, Ar), 6.65 s (1H, Ht), 6.75 d
(1H, Ar), 7.00 d (1H, Ar), 7.80 s (1H, Ht). Found,
%: C 63.57, 63.60; H 6.37, 6.34; Cl 7.45, 7.46;
N 8.94, 8.83. C25H30ClN3O4. Calculated, %: C 63.62;
H 6.41; Cl 7.51; N 8.90.
At the use of amino acids in Mannich reaction they
were dissolved in 5 ml of water, a calculated amount of the
formaldehyde solution in 15–20 ml of EtOH was added,
the mixture was boiled for 10 min, then a weighed portion
of enamine was added, and the mixture again was boiled
for 10 min. Several days after from the solution cooled
to 2–6°C a precipitate separated, it was filtered off and
recrystallized from methanol.
3-[2-(2,5-Dimethoxyphenyl)ethyl]-9,10-dimethoxy-
3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinoline-
1-carbonitrile (IXe). Yield 51% (hydrochloride).
1H NMR spectrum (DMSO-d6), δ, ppm: 2.85–2.90 m
(2H, CH2), 3.25–3.30 m (2H, CH2), 3.35–3.40 m (2H,
CH2), 3.45–3.50 m (2H, CH2), 3.65 s (6H, 2CH3O), 3.80 s
(6H, 2CH3O), 4.10 s (2H, CH2), 4.75 s (2H, CH2), 6.65 s
(1H, Ht), 6.95–7.00 m (3H, Ar), 7.80 s (1H, Ht). Found,
%: C 63.52, 63.65; H 6.38, 6.42; Cl 7.43, 7.54; N 8.93,
8.98. C25H30ClN3O4. Calculated, %: C 63.62; H 6.41;
Cl 7.51; N 8.90.
9,10-Dimethoxy-3-phenethyl-3,4,6,7-tetrahydro-
2H-pyrimido[6,1-a]isoquinoline-1-carbonitrile (IXa).
Yield 86% (hydrochloride). 1H NMR spectrum (DMSO-
d6), δ, ppm: 2.85–2.90 m (2H, CH2), 3.25–3.30 m (2H,
CH2), 3.35–3.40 m (2H, CH2), 3.45–3.50 m (2H, CH2),
3.80 s (6H, 2CH3O), 4.10 s (2H, CH2), 4.75 s (2H, CH2),
7.15–7.35 m (5H, Ar), 6.75 s (1H, Ht), 7.80 s (1H, Ht),
8.60 (HCl). Found, %: C 67.00, 67.09; H 6.28, 6.33; Cl
8.58, 8.70; N 10.18, 10.23. C23H26ClN3O2. Calculated,
%: C 67.06; H 6.36; Cl 8.61; N 10.20.
3-{2-[4-(Methylsulfanyl)phenyl]ethyl}-9,10-
dimethoxy-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]-
isoquinoline-1-carbonitrile (IXf) Yield 36% (hydro-
chloride). 1H NMR spectrum (DMSO-d6), δ, ppm: 2.50 s
(3H, CH3), 2.85–2.90 m (2H, CH2), 3.25–3.30 m (2H,
CH2), 3.35–3.40 m (2H, CH2), 3.45–3.50 m (2H, CH2),
3.80 s (6H, 2CH3O), 4.10 s (2H, CH2), 4.75 s (2H, CH2),
6.65 s (1H, Ht), 6.80 m (2H, Ar), 6.80–6.90 m (2H, Ar),
7.80 s (1H, Ht). Found, %: C 62.90, 62.85; H 6.10, 6.05;
Cl 7.70, 7.65; N 9.12, 9.19; S 6.95, 6.90. C24H28ClN3O2S.
3-[2-(3,4-Dimethoxyphenyl)ethyl]-9,10-dimethoxy-
3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinoline-
1-carbonitrile (IXb). Yield 77%. H NMR spectrum
(DMSO-d6), δ, ppm: 2.70–2.85 m (6H, 2CH2), 3.20 m
(2H, CH2), 3.60 s (2H, CH2), 3.75 s (3H, CH3O), 3.78 s
(3H, CH3O), 3.82 s (3H, CH3O), 3.85 s (3H, CH3O),
––––––––––––––––
5 The samples of primary amines were supplied by “Kontakt-Servis”
Co. (Dolgoprudnyi, Russian Federation).
1
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 5 2011

AFON’KIN et al.
740
Calculated, %: C 62.94; H 6.16; Cl 7.74; N 9.17; S 7.00.
1-carbonitrile (IXl). Yield 87% (hydrochloride).
1H NMR spectrum (DMSO-d6), δ, ppm: 2.00–3.70 m
(5CH2), 3.80 s (6H, 2CH3O), 3.90 s (2H, CH2), 4.60 s
(2H, CH2), 6.75 s (1H, Ht), 7.80 s (1H, Ht). Found, %:
C 59.00, 58.86; H 6.55, 6.47; Cl 9.60, 9.68; N 11.47,
11.55. C18H24ClN3O3. Calculated, %: C 59.09; H 6.61;
Cl 9.69; N 11.49.
3-[2-(4-Methylpiperazin-1-yl)ethyl]-9,10-di-
methoxy-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]-
isoquinoline-1-carbonitrile (IXg). Yield 26% (hydro-
1
oxalate). H NMR spectrum (DMSO-d6), δ, ppm:
1.25–2.00 (group of multiplets), 2.30 s (3H, CH3), 3.80 s
(6H, 2CH3O), 4.10 s (2H, CH2), 4.75 s (2H, CH2), 6.65 s
(1H, Ht), 7.80 s (1H, Ht). Found, %: C 59.10, 58.86;
H 6.78, 6.78; N 14.34, 14.28. C24H33N5O6. Calculated,
%: C 59.12; H 6.82; N 14.36.
9,10-Dimethoxy-3-(2-methoxyethyl)-3,4,6,7-
tetrahydro-2H-pyrimido[6,1-a]isoquinoline-1-
carbonitrile (IXm). Yield 25% (hydrochloride).
1H NMR spectrum (DMSO-d6), δ, ppm: 2.85–2.90 m
(2H, CH2), 3.20 s (3H, CH3), 3.30 m (2H, CH2), 3.45 m
(2H, CH2), 3.80 s (6H, 2CH3O), 3.90 m (2H, CH2),
4.10 s (2H, CH2), 4.75 s (2H, CH2), 6.65 s (1H, Ht),
7.80 s (1H, Ht). Found, %: C 59.16, 58.93; H 6.55, 6.47;
Cl 9.60, 9.53; N 11.54, 11.58. C18H24ClN3O3. Calculated,
%: C 59.09; H 6.61; Cl 9.69; N 11.49.
9,10-Dimethoxy-3-[2-(cyclohex-1-en-1-yl)-ethyl]-
3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinoline-1-
carbonitrile (IXh). Yield 26% (hydrochloride). 1H NMR
spectrum (DMSO-d6), δ, ppm: 1.25–2.50 (group of
multiplets), 3.80 s (6H, 2CH3O), 4.10 s (2H, CH2), 4.75 s
(2H, CH2), 6.65 s (1H, Ht), 7.80 s (1H, Ht). Found, %:
C 66.38, 66.35; H 7.20, 7.16; Cl 8.45, 8.42; N 10.18,
10.25. C23H30ClN3O2. Calculated, %: C 66.41; H 7.27;
Cl 8.52; N 10.10.
9,10-Dimethoxy-3-phenyl-3,4,6,7-tetrahydro-2H-
pyrimido[6,1-a]isoquinoline-1-carbonitrile (IXn).
Yield 33%, mp 135–136°C (andз MeOH) {136°C (from
9,10-Dimethoxy-3-[3-(2-oxopyrrolidin-1-yl)-
propyl]-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]
isoquinoline-1-carbonitrile (IXi).Yield 37% (hydrooxa-
late). 1H NMR spectrum (DMSO-d6), δ, ppm: 1.30–3.60
(group of multiplets), 3.80 s (6H, 2CH3O), 4.10 s (2H,
CH2), 4.75 s (2H, CH2), 6.65 s (1H, Ht), 7.80 s (1H, Ht).
Found, %: C 59.20, 59.18; H 6.12, 6.17; N 11.52, 11.61.
C24H30N4O7. Calculated, %: C 59.25; H 6.22; N 11.52.
1
EtOH) [29]}. H NMR spectrum (DMSO-d6), δ, ppm:
2.75–2.80 m (2H, CH2), 3.30–3.40 m (2H, CH2), 3.80 s
(6H, 2CH3O), 4.20 s (2H, CH2), 4.75 s (2H, CH2), 6.65 s
(1H, Ht), 6.85 t (1H,Ar), 7.0 d (2H,Ar), 7.20–7.25 t (2H,
Ar), 7.80 s (1H, Ht) {publ. in DMSO-d6–CDCl3: 4.25 s
(2H, CH2), 4.72 s (2H, CH2) [29]}.
3-(3,4-Dimethylphenyl)-9,10-dimethoxy-3,4,6,7-
tetrahydro-2H-pyrimido[6,1-a]isoquinoline-1-
carbonitrile (IXo). Yield 41%. H NMR spectrum
3-{3-[3,4-Dihydro-2(1H)-isoquinoline]propyl}-
9,10-dimethoxy-3,4,6,7-tetrahydro-2H-pyrimido-
[6,1-a]isoquinoline-1-carbonitrile (IXj). Yield 69%
(hydrooxalate). 1H NMR spectrum (DMSO-d6), δ, ppm:
1.30–2.70 (group of multiplets), 3.80 s (6H, 2CH3O),
4.10 s (2H, CH2), 4.75 s (2H, CH2), 6.65 s (1H, Ht),
7.00–7.20 m (4H,Ar), 7.80 s (1H, Ht). Found, %: C 65.11,
65.28; H 6.28, 6.34; N 10.40, 10.52. C29H34N4O6. Cal-
culated, %: C 65.15; H 6.41; N 10.48.
1
(DMSO-d6), δ, ppm: 2.15 s (3H, CH3, Ar), 2.25 s (3H,
CH3, Ar), 2.75 m (2H, CH2), 3.30 m (2H, CH2), 3.80 s
(6H, 2CH3O), 4.15 s (2H, CH2), 4.70 s (2H, CH2), 6.65
s (1H, Ht), 6.70 d (1H, Ar), 6.80 s (1H, Ar), 6.95 d
(1H, Ar), 7.80 s (1H, Ht). Found, %: C 73.45, 73.58;
H 6.68, 6.55; N 11.10, 11.23. C23H25N3O2. Calculated,
%: C 73.57; H 6.71; N 11.19.
3-(4-Bromophenyl)-9,10-dimethoxy-3,4,6,7-tetra-
3-(2-Hydroxyethyl)-9,10-dimethoxy-3,4,6,7-
tetrahydro-2H-pyrimido[6,1-a]isoquinoline-
1-carbonitrile (IXk). Yield 69% (hydrochloride).
1H NMR spectrum (DMSO-d6), δ, ppm: 2.85–2.90 m (2H,
CH2), 3.25 m (2H, CH2), 3.45 m (2H, CH2), 3.80 s (6H,
2CH3O), 3.90 m (2H, CH2), 4.10 s (2H, CH2), 4.75 s (2H,
CH2), 6.80 s (1H, Ht), 7.80 s (1H, Ht), 8.20–8.30 (HCl).
Found, %: C 57.93, 58.00; H 6.25, 6.13; Cl 10.00, 9.84;
N 11.90, 12.05. C25H34ClN6O3. Calculated, %: C 58.03;
H 6.30; Cl 10.08; N 11.94.
hydro-2H-pyrimido[6,1-a]isoquinoline-1-carbonitrile
1
(IXp). Yield 30%. H NMR spectrum (DMSO-d6), δ,
ppm: 2.70–2.80 m (2H, CH2), 3.30–3.40 m (2H, CH2),
3.75 s (3H, CH3O), 3.85 s (3H, CH3O), 4.25 s (2H, CH2),
4.90 s (2H, CH2), 6.90 s (1H, Ht), 7.10–7.15 d (2H,
Ar), 7.40–7.50 d (2H, Ar), 7.70 s (1H, Ht). Found, %:
C 59.21, 59.12; H 4.67, 4.65; Br 18.78, 18.67; N 9.88,
9.96. C21H20BrN3O2. Calculated, %: C 59.17; H 4.73;
Br 18.74; N 9.86.
9,10-Dimethoxy-3-[3-(trifluoromethyl)phenyl]-
3-(3-Hydroxypropyl)-9,10-dimethoxy-3,4,6,7-
3,4,6,7-tetrahydro-2-pyrimido[6,1-a]isoquinoline-
tetrahydro-2H-pyrimido[6,1-a]isoquinoline-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 5 2011

6,7-DIMETHOXY-3,4-DIHYDROISOQUINOLIN-1(2H)-YLIDENOACETONITRILE
741
1
1
1-carbonitrile (IXq). Yield 44%. H NMR spectrum
Yield 40%. H NMR spectrum (DMSO-d6), δ, ppm:
3.40 m (2H, CH2), 3.80 s (3H, CH3O), 3.90 s (3H,
CH3O), 3.95 m (2H, CH2), 4.35 s (2H, CH2), 4.65 s
(2H, CH2), 6.80 s (1H, Ht), 7.30 d (1H, Ar), 7.40 m (1H,
Ar), 7.80 s (1H, Ht), 8.20 d (1H, Ar), 8.50 s (1H, Ar).
Found, %: C 68.90, 68.88; H 5.75, 5.63; N 16.20, 16.12.
C20H20N4O2. Calculated, %: C 68.95; H 5.79; N 16.08.
(DMSO-d6), δ, ppm: 2.70–2.80 m (2H, CH2), 3.30–
3.40 m (2H, CH2), 3.80 s (6H, 2CH3O), 4.10 s (2H, CH2),
4.75 s (2H, CH2), 6.40–6.60 m (4H, Ar), 6.65 s (1H,
Ht), 7.80 s (1H, Ht). Found, %: C 63.57, 63.55; H 4.80,
4.68; N 10.21, 10.15. C26H25F3N3O2. Calculated, %:
C 63.61; H 4.85; N 10.12.
3-(3-Methylphenyl)-9,10-dimethoxy-3,4,6,7-
tetrahydro-2H-pyrimido[6,1-a]isoquinoline-
1-carbonitrile (IXr). Yield 35% (hydrochloride).
1H NMR spectrum (DMSO-d6), δ, ppm: 2.30 s (3H, CH3),
2.70–2.80 m (2H, CH2), 3.30–3.40 m (2H, CH2), 3.80 s
(6H, 2CH3O), 4.10 s (2H, CH2), 4.75 s (2H, CH2), 6.40 m
(2H,Ar), 6.50 s (1H,Ar), 6.65 s (1H, Ht), 6.80 m (1H,Ar),
7.80 s (1H, Ht). Found, %: C 66.38, 66.35; H 6.03, 6.00;
Cl 8.88, 8.95; N 10.65, 10.55. C22H24ClN3O2. Calculated,
%: C 66.41; H 6.08; Cl 8.91; N 10.56.
3-Benzyl-9,10-dimethoxy-3,4,6,7-tetrahydro-
2H-pyrimido[6,1-a]isoquinoline-1-carbonitrile
1
(IXw). Yield 92% (hydrochloride). H NMR spec-
trum (DMSO-d6), δ, ppm: 2.90 m (2H, CH2), 3.40 m
(2H, CH2), 3.80 s (6H, 2CH3O), 3.95 m (2H, CH2),
4.35 s (2H, CH2), 4.65 s (2H, CH2), 6.75 s (1H, Ht),
7.40–7.65 m (5H, Ar), 7.80 s (1H, Ht), 8.90 (HCl).
Found, %: C 66.38, 66.35; H 6.06, 6.04; Cl 8.88, 8.87;
N 10.58, 10.52. C22H24ClN3O2. Calculated, %: C 66.41;
H 6.08; Cl 8.91; N 10.56.
9,10-Dimethoxy-3-(4-ethoxyphenyl)-3,4,6,7-
9,10-Dimethoxy-3-(1-phenylethyl)-3,4,6,7-tetra-
tetrahydro-2H-pyrimido[6,1-a]isoquinoline-
1-carbonitrile (IXs) Yield 65%. H NMR spectrum
hydro-2H-pyrimido[6,1-a]isoquinoline-1-carbonitrile
(IXx). Yield 45% (hydrochloride). H NMR spectrum
1
1
(DMSO-d6), δ, ppm: 1.40 m (3H, CH3), 2.75 m (2H,
CH2), 3.25–3.30 m (2H, CH2), 3.80 s (6H, 2CH3O),
3.95 m (2H, CH2), 4.10 s (2H, CH2), 4.65 s (2H, CH2),
6.70 s (1H, Ht), 6.75 m (2H, Ar), 6.90 m (2H, Ar),
7.75 s (1H, Ht). Found, %: C 70.55, 70.45; H 6.47, 6.38;
N 10.77, 10.68. C23H25N3O3. Calculated, %: C 70.57;
H 6.44; N 10.73.
(DMSO-d6), δ, ppm: 2.90 m (2H, CH2), 3.40 m (2H,
CH2), 4.30 m, 4.40 m, 3.30 m, 1.75–1.85 m (3H, CH3),
3.80 s (3H, CH3O), 3.90 s (3H, CH3O), 4.60 s (2H, CH2),
6.75 s (1H, Ht), 7.35–7.45 m (3H, Ar), 7.65 m (2H, Ar),
7.80 s (1H, Ht). Found, %: C 67.01, 66.95; H 6.34, 6.23;
Cl 8.67, 8.64; N 10.25, 10.29. C23H26ClN3O2. Calculated,
%: C 67.06; H 6.36; Cl 8.61; N 10.20.
4-{9,10-Dimethoxy-1-cyano-6,7-dihydro-2H-
pyrimidino[6,1-a]isoquinolin-3(4H)-yl}-N,N-di-
ethylbenzenesulfamide (IXt). Yield 32%. H NMR
spectrum (DMSO-d6), δ, ppm: 1.10 m (6H, 2CH3), 2.75 m
(2H, CH2), 2.80–2.90 m (4H, 2CH2), 3.25–3.30 m (2H,
CH2), 3.80 s (6H, 2CH3O), 4.10 s (2H, CH2), 4.75 s (2H,
CH2), 6.65 s (1H, Ht), 6.75 m (2H, Ar), 6.90 m (2H, Ar),
7.80 s (1H, Ht). Found, %: C 62.18, 62.16; H 6.20, 6.12;
N 11.68, 11.76; S 6.60, 6.58. C25H30N4O4S. Calculated,
%: C 62.22; H 6.27; N 11.61; S 6.64.
3-(1,3-Dihydro-2-benzofuran-5-ylmethyl)-
9,10-dimethoxy-3,4,6,7-tetrahydro-2H-pyrimido-
[6,1-a]isoquinoline-1-carbonitrile (IXy). Yield 49%
1
1
(hydrochloride). H NMR spectrum (DMSO-d6), δ,
ppm: 2.70 s (2H, CH2), 2.90 m (2H, CH2), 3.40 m
(2H, CH2), 3.80 s (6H, 2CH3O), 3.90 s (4H, 2CH2),
4.10 s (2H, CH2), 4.75 s (2H, CH2), 6.65 s (1H, Ht),
6.70–6.85 m (3H, Ar), 7.80 s (1H, Ht). Found, %:
C 65.48, 65.46; H 5.91, 5.88; Cl 7.98, 8.03; N 9.65, 9.52.
C24H26ClN3O3. Calculated, %: C 65.52; H 5.96; Cl 8.06;
N 9.55.
4-{9,10-Dimethoxy-1-cyano-6,7-dihydro-2H-
pyrimidino[6,1-a]isoquinolin-3(4H)-yl}ethyl benzoate
(IXu).Yield 30%. 1H NMR spectrum (DMSO-d6), δ, ppm:
1.20 m (3H, CH3), 2.75 m (2H, CH2), 3.25–3.30 m (2H,
CH2), 3.80 s (6H, 2CH3O), 4.10 m (2H, CH2), 4.20 s (2H,
CH2), 4.75 s (2H, CH2), 6.65 s (1H, Ht), 6.75 m (2H,Ar),
6.90 m (2H, Ar), 7.80 s (1H, Ht). Found, %: C 68.68,
68.66; H 6.08, 5.99; N 10.08, 10.16. C24H25N3O4. Cal-
culated, %: C 68.72; H 6.01; N 10.02.
3-[1-(2,3-Dihydro-1,4-benzodioxin-6-yl)-
ethyl]-9,10-dimethoxy-3,4,6,7-tetrahydro-2H-
pyrimido[6,1-a]isoquinoline-1-carbonitrile (IXz).
Yield 34% (hydrochloride). 1H NMR spectrum (DMSO-
d6), δ, ppm: 2.90 m (2H, CH2), 1.75–1.85 m (3H, CH3),
4.30 m, 4.40 m, 3.30 m, 3.40 m (2H, CH2), 3.80 s (6H,
2CH3O), 4.10 s (2H, CH2), 4.75 s (2H, CH2), 6.65 s
(1H, Ht), 6.70–6.90 m (3H, Ar), 7.80 s (1H, Ht). Found,
%: C 63.85, 63.82; H 6.01, 5.95; Cl 7.57, 7.49; N 8.98,
9.04. C25H28ClN3O4. Calculated, %: C 63.89; H 6.01;
9,10-Dimethoxy-3-(3-pyridyl)-3,4,6,7-tetrahydro-
2H-pyrimido[6,1-a]isoquinoline-1-carbonitrile (IXv).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 5 2011

AFON’KIN et al.
742
Cl 7.54; N 8.94.
9.11, 9.08; N 10.84, 10.76. C20H22ClN3O3. Calculated,
%: C 61.93; H 5.72; Cl 9.14; N 10.83.
3-(2-Hydroxy-1-phenylethyl)-9,10-dimethoxy-
3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinoline-
1-carbonitrile (IXaa). Yield 12% (hydrooxalate).
1H NMR spectrum (DMSO-d6), δ, ppm: 1.50–2.70 (group
of multiplets), 3.40 m (2H, CH2), 3.80 s (6H, 2CH3O),
2.90 m (2H, CH2), 4.10 s (2H, CH2), 4.75 s (2H,
CH2), 6.65 s (1H, Ht), 7.15–7.35 m (5H, Ar), 7.80 s
(1H, Ht). Found, %: C 62.31, 62.28; H 5.60, 5.62;
N 8.77, 8.85. C32H33N5O7. Calculated, %: C 62.36;
H 5.65; N 8.73.
9,10-Dimethoxy-3-tetrahydrofurfuryl-3,4,6,7-
tetrahydro-2H-pyrimido[6,1-a]isoquinoline-1-
carbonitrile (IXff). Yield 91% (hydrochloride).
1H NMR spectrum (DMSO-d6), δ, ppm: 1.60–
2.30 m (6H, CH2), 3.10–3.30 m (2H, CH2), 3.40 m
(2H, CH2), 3.80 s (6H, 2CH3O), 4.10 s (2H, CH2),
4.65 s (2H, CH2), 6.75 s (1H, Ht), 7.80 s (1H, Ht). Found,
%: C 61.24, 61.27; H 6.60, 6.56; Cl 9.08, 9.13; N 10.79,
10.76. C20H26ClN3O3. Calculated, %: C 61.30; H 6.69;
Cl 9.05; N 10.72.
3-(4-Methylbenzyl)-9,10-dimethoxy-3,4,6,7-
3-Cyclohexyl-9,10-dimethoxy-3,4,6,7-tetrahydro-
2H-pyrimido[6,1-a]isoquinoline-1-carbonitrile (IXgg).
Yield 65%, mp 139–140°C (from MeOH) {140°C (from
MeOH) [29]}. 1H NMR spectrum (DMSO-d6), δ, ppm:
1.25–2.00 m (10H, 5CH2), 2.60 m (1H, CH), 2.80–2.85 m
(2H, CH2), 3.20–3.30 m (2H, CH2), 3.80 s (6H, 2CH3O),
3.65 s (2H, CH2), 4.20 s (2H, CH2), 6.65 s (1H, Ht),
7.80 s (1H, Ht).
tetrahydro-2H-pyrimido[6,1-a]isoquinoline-
1-carbonitrile (IXbb). Yield 55%. H NMR spectrum
1
(DMSO-d6), δ, ppm: 2.40 s (3H, CH3), 2.70 s (2H,
CH2), 2.90 m (2H, CH2), 3.40 m (2H, CH2), 3.80 s (6H,
2CH3O), 4.10 s (2H, CH2), 4.75 s (2H, CH2), 6.65 s
(1H, Ht), 6.95–7.00 m (4H, Ar), 7.80 s (1H, Ht).
Found, %: C 73.57, 73.48; H 6.67, 6.75; N 11.15, 11.22.
C23H25N3O2. Calculated, %: C 73.57; H 6.71; N 11.19.
9,10-Dimethoxy-3-cyclopentyl-3,4,6,7-tetrahy-
dro-2H-pyrimido[6,1-a]isoquinoline-1-carbonitrile
(IXhh). Yield 94% (HCl). 1H NMR spectrum (DMSO-
d6), δ, ppm: 1.60–2.25 m (9H, CH2), 2.90 m (2H, CH2),
3.45–3.60 m (4H, 2CH2), 3.80 s (6H, 2CH3O), 4.65 s
(2H, CH2), 6.75 s (1H, Ht), 7.80 s (1H, Ht), 8.40 (hy-
drochloride). Found, %: C 63.88, 63.86; H 6.94, 6.96;
Cl 9.40, 9.38; N 11.14, 11.22. C20H26ClN3O2. Calculated,
%: C 63.91; H 6.97; Cl 9.43; N 11.18.
9,10-Dimethoxy-3-(4-chlorobenzyl)-3,4,6,7-
tetrahydro-2H-pyrimido[6,1-a]isoquinoline-
1-carbonitrile (IXcc). Yield 69% (hydrochloride).
1H NMR spectrum (DMSO-d6), δ, ppm: 2.70 s (2H,
CH2), 2.90 m (2H, CH2), 3.40 m (2H, CH2), 3.80 s (6H,
2CH3O), 4.10 s (2H, CH2), 4.75 s (2H, CH2), 6.65 s
(1H, Ht), 6.95–7.00 m (2H, Ar), 7.20 m (2H, Ar), 7.80 s
(1H, Ht). Found, %: C 61.21, 61.18; H 5.22, 5.34;
Cl 16.34, 16.45; N 9.77, 9.84. C22H23Cl2N3O2. Calcu-
lated, %: C 61.12; H 5.36; Cl 16.40; N 9.72.
2-{9,10-Dimethoxy-1-cyano-6,7-dihydro-2H-
pyrimido[6,1-a]isoquinolin-3(4H)-yl}acetic acid (IXii).
Yield 73%. 1H NMR spectrum (DMSO-d6), δ, ppm: 2.85
m (2H, CH2), 3.20 m (2H, CH2), 3.40 s (2H, CH2 of gly-
cine), 3.60 s (2H, CH2), 3.80 s (6H, 2CH3O), 4.25 s (2H,
CH2), 6.90 s (1H, Ht), 7.80 s (1H, Ht), 12.50 (1H, COOH).
Found, %: C 61.96, 61.89; H 5.8, 5.86; N 12.78, 12.72.
C17H19N3O4. Calculated, %: C 62.00; H 5.81; N 12.76.
9,10-Dimethoxy-3-(3-chlorobenzyl)-3,4,6,7-
tetrahydro-2H-pyrimido[6,1-a]isoquinoline-
1-carbonitrile (IXdd). Yield 72% (hydrochloride).
1H NMR spectrum (DMSO-d6), δ, ppm: 2.70 s (2H,
CH2), 2.90 m (2H, CH2), 3.40 m (2H, CH2), 3.80 s (6H,
2CH3O), 4.10 s (2H, CH2), 4.75 s (2H, CH2), 6.65 s
(1H, Ht), 7.10–7.30 m (3H, Ar), 7.30 s (1H, Ar), 7.80 s
(1H, Ht). Found, %: C 61.16, 61.20; H 5.32, 5.37;
Cl 16.38, 16.35; N 9.70, 9.65. C22H23Cl2N3O2. Calcu-
lated, %: C 61.12; H 5.36; Cl 16.40; N 9.72.
3-{9,10-Dimethoxy-1-cyano-6,7-dihydro-2H-
pyrimido[6,1-a]isoquinolin-3(4H)-yl}propanoic
1
acid (IXjj). Yield 74%. H NMR spectrum (DMSO-
d6), δ, ppm: 2.40 m (2H, CH2 of β-alanine), 2.75–
2.95 m (4H, CH2, CH2 of β-alanine), 3.20–3.30 m
(2H, CH2), 3.60 s (2H, CH2), 3.80 s (6H, 2CH3O),
4.20 s (2H, CH2), 6.70 s (1H, Ht), 7.80 s (1H, Ht).
Found, %: C 62.92, 62.98; H 6.12, 6.01; N 12.20, 12.34.
C18H21N3O4. Calculated, %: C 62.96; H 6.16; N 12.24.
9,10-Dimethoxy-3-furfuryl-3,4,6,7-tetrahydro-2H-
pyrimido[6,1-a]isoquinoline-1-carbonitrile (IXee).
Yield 91% (hydrochloride). 1H NMR spectrum (DMSO-
d6), δ, ppm: 2.90 m (2H, CH2), 3.30–3.40 m (2H, CH2),
3.75 s (3H, CH3O), 3.80 s (3H, CH3O), 3.90 s (2H, CH2),
4.35 s (2H, CH2), 4.60 s (2H, CH2), 6.55 m (1H, Ar),
6.70 m (1H, Ar), 6.95 s (1H, Ht), 7.75 s (1H, Ar), 7.80 s
(1H, Ht). Found, %: C 61.88, 61.86; H 5.75, 5.68; Cl
Ethyl 2-{9,10-dimethoxy-1-cyano-6,7-dihydro-2H-
pyrimido[6,1-a]isoquinolin-3(4H)-yl}acetate (IXkk).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 5 2011

6,7-DIMETHOXY-3,4-DIHYDROISOQUINOLIN-1(2H)-YLIDENOACETONITRILE
743
Yield 23% (hydrochloride). 1H NMR spectrum (DMSO-
d6), δ, ppm: 1.20 m (3H, CH3), 2.75–2.85 m (2H, CH2),
3.25 m (2H, CH2), 3.40 s (2H, CH2 of glycine), 3.65 s
(2H, CH2), 3.80 s (6H, 2CH3O), 4.00 m (2H, CH2), 4.25 s
(2H, CH2), 6.65 s (1H, Ht), 7.80 s (1H, Ht). Found, %:
C 57.89, 57.98; H 6.10, 6.01; Cl 9.03, 9.09; N 10.62,
10.69. C19H24ClN3O4. Calculated, %: C 57.94; H 6.14;
Cl 9.00; N 10.67.
Ht). Found, %: C 63.36, 63.32; H 4.21, 4.12; N 9.88, 9.93.
C15H12N2O4. Calculated, %: C 63.38; H 4.25; N 9.85.
2-(3,4-Dimethoxyphenyl)-3-methyl-8,9-dimethoxy-
5,6-dihydro-2H-pyrrolo[2,1-a]isoquinoline-1-carbo-
nitrile (XII). A solution of 8.5 mmol of enamine I and
8.5 mmol of β-nitro-β-methyl-3,4-dimethoxystyrene
in 20 ml of EtOH was boiled for 3 h. The light-yellow
precipitate was filtered off, washed with 30–50 ml of
MeOH, and recrystallized. Yield 86%, mp 193–194°C
(EtOH). 1H NMR spectrum (DMSO-d6), δ, ppm: 2.25 s
(3H, CH3), 3.00–3.10 t (2H, CH2), 3.75 s (3H, CH3O),
3.78 (3H, CH3O), 3.82 s (3H, CH3O), 3.90 s (3H, CH3O),
4.00–4.10 t (2H, CH2), 6.90–6.95 d (1H, Ar), 6.98 s (1H,
Ar), 7.00 s (1H, Ht), 7.05–7.10 d (1H, Ar), 7.60 s (1H,
Ht). Found, %: C 71.28, 71.22; H 5.92, 5.94; N 6.99, 6.88.
C24H24N2O4. Calculated, %: C 71.27; H 5.98; N 6.93.
Ethyl 4-{9,10-dimethoxy-1-cyano-6,7-dihydro-
2H-pyrimido[6,1-a]isoquinolin-3(4H)-yl}-piperidine-
1
1-carboxylate (IXll). Yield 43%. H NMR spectrum
(DMSO-d6), δ, ppm: 2.40–2.90 m, 1.20 m (3H, CH3),
3.25 m (2H, CH2), 3.80 s (6H, 2CH3O), 4.00 m (2H,
CH2), 4.10 s (2H, CH2), 4.75 s (2H, CH2), 6.65 s (1H, Ht),
7.80 s (1H, Ht). Found, %: C 64.67, 64.78; H 6.95, 7.02;
N 13.21, 13.24. C23H30N4O4. Calculated, %: C 64.77;
H 7.09; N 13.14.
4-Imino-9,10-dimethoxy-3,4,6,7-tetrahydro-2H-
pyrido[2,1-a]isoquinoline-1-carbonitrile (XIII) was
obtained by procedure [18] heating the mixture of
44 mmol of enamine I and 47 mmol of acrylonitrile
(Merck) in 60 ml of anhydrous EtOH in the presence of
44 mmol of sodium ethylate for 30 min. On cooling the
separated precipitate was filtered off, washed with 10 ml
of alcohol, and recrystallized. Yield 79%, mp 158–159°C
10-Hydroxy-2,3-dimethoxy-5,6-dihydroindolo[2,1-
a]isoquinoline-12-carbonitrile (X). To a solution of
4.3 mmol of enamine I in 20 ml of glacial acetic acid
heated to 40°C was added within 1 h by small portions
at stirring 4.3 mmol of freshly sublimed p-benzoquinone,
and the mixture was stirred under the same conditions till
complete separation of the precipitate. The precipitate was
filtered off, washed with a fresh portion of acetic acid and
a large volume of methanol and dried in a deep vacuum.
Yield 38%. IR spectrum (KBr), ν, cm–1: 3350, 2210 s,
1540 m, 1490 m, 1480 s, 1430 m, 1350 m, 1300 m, 1260 s,
1
(EtOH) [18]. H NMR spectrum (DMSO-d6), δ, ppm:
2.50–2.55 m (2H, CH2), 2.65–2.70 m (2H, CH2), 2.80–
2.90 m (2H, CH2), 3.80 s (3H, CH3O), 3.85 s (3H, CH3O),
3.90–3.95 t (2H, CH2), 6.75 s (1H, Ht), 7.60–7.65 br.s
(1H, =NH), 7.65–7.70 s (1H, Ht).
1
1230 s, 1160 m, 1020 m. H NMR spectrum (DMSO-
d6), δ, ppm: 3.15–3.20 t (2H, CH2), 3.80 s (3H, CH3O),
3.90 s (3H, CH3O), 4.40–4.45 t (2H, CH2), 6.95 d (1H,
Ar), 7.10 s (1H, Ar), 7.45 d (1H, Ar), 7.70 s (1H, Ar),
7.90 s (1H, Ht), 8.85 s (1H, OH). Found, %: C 70.46;
H 5.42; N 8.80. C19H16N2O3. Calculated, %: C 71.24;
H 5.03; N 8.74.
9,10-Dimethoxy-4-oxo-3,4,6,7-tetrahydro-2H-
pyrido[2,1-a]isoquinoline-1-carbonitrile (XIV) was
obtained by boiling a solution of 2 mmol of imine XIII
in a mixture of 12 ml of water and 1.5 ml of acetic acid
over 2 h. In the course of the reaction the initial disper-
sion of amidine dissolved, and to the end of hydrolysis
precipitate formed again. The precipitate was filtered
off, washed with water, and dried. Yield 78%, mp 147°C
(from petroleum ether) [18]. 1H NMR spectrum (DMSO-
d6), δ, ppm: 2.60–2.70 m (4H, 2CH2), 2.80–2.90 m (2H,
CH2), 3.75–3.80 t (2H, CH2), 3.85 s (3H, CH3O), 3.90 s
(3H, CH3O), 6.75 s (1H, Ht), 7.65 s (1H, Ht).
8,9-Dimethoxy-2,3-dioxo-2,3,5,6-tetrahydro-
pyrrolo[2,1-a]isoquinoline-1-carbonitrile (XI). To
a solution of 12 mmol of oxalyl chloride in 50 ml of dry
chloroform cooled to 0°C was added at stirring within
30 min a mixture of 10 mmol of enamine I and 20 mmol of
Et3N in 25 ml of dry chloroform, and the obtained mixture
was left standing for 10 h at 25°C. The separated red pre-
cipitate was filtered off, washed with chloroform, water,
and ether, dried, and crystallized. Yield 64%, mp 241°C
General procedure of acylation (sulfonylation) of
amidine XIII. To a solution of 2.65 mmol of amidine
and 7.9 mmol of Et3N in 7 ml of dioxane was added at
25°C while stirring 3.0 mmol of carboxylic or arenesul-
fonic acid chloride prepared by common method and
dissolved in 3 ml of dioxane. After 2 h the solution was
slightly heated for 10 min, on cooling it was diluted with
1
(decomp., from i-PrOH–acetone). H NMR spectrum
(DMSO-d6), δ, ppm: 3.15–3.20 t (2H, CH2, overlapped
with H2O signal), 3.75–3.80 t (2H, CH2), 3.85 s (3H,
CH3O), 3.95 s (3H, CH3O), 7.15 s (1H, Ar), 7.85 s (1H,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 5 2011

AFON’KIN et al.
744
methanol and water and was kept in a refrigerator till the
formation of a precipitate. The precipitate was filtered
off, washed with water and minimal quantity of methanol
and recrystallized.
2CH3O), 4.05 m (2H, CH2), 6.85 s (1H, Ht), 6.90 d
(2H, Ar), 7.60 s (1H, Ht), 7.95 d (2H, Ar). Found, %:
C 69.08, 69.03; H 5.45, 5.51; N 10.13, 10.18. C24H23N3O4.
Calculated, %: C 69.05; H 5.55; N 10.07.
N-{(4E)-9,10-Dimethoxy-1-cyano-2,3,6,7-tet-
rahydro-4H-pyrido[2,1-a]isoquinolin-4-ylidene}-
2-furamide (XVf). Yield 82%, mp 162–163°C (from
N-{(4E)-9,10-Dimethoxy-1-cyano-2,3,6,7-tet-
rahydro-4H-pyrido[2,1-a]isoquinolin-4-ylidene}-
benzamide (XVa). Yield 48%, mp 188–190°C (EtOH).
1H NMR spectrum (CDCl3), δ, ppm: 2.60 m (2H, CH2),
2.80–2.90 m (4H, 2CH2), 3.95 s (6H, 2CH3O), 4.10 m
(2H, CH2), 6.75 s (1H, Ht), 7.40–7.60 m (3H, Ar), 7.70 s
(1H, Ht), 8.05 d (2H, Ar). Found, %: C 71.25, 71.23;
H 5.54, 5.42; N 10.80, 10.82. C23H21N3O3. Calculated,
%: C 71.30; H 5.46; N 10.85.
1
MeOH). H NMR spectrum (DMSO-d6), δ, ppm:
2.60 m (2H, CH2), 2.80–2.95 m (4H, 2CH2), 3.85 s
(3H, CH3O), 3.90 s (3H, CH3O), 4.05 m (2H, CH2),
6.55 m (1H, Ar), 6.80 s (1H, Ht), 7.10 d (1H, Ar), 7.65 s
(1H, Ht), 7.70 m (1H, Ar). Found, %: C 66.78, 66.77;
H 5.01, 4.98; N 11.16, 11.19. C21H19N3O4. Calculated, %:
C 66.83; H 5.07; N 11.13.
N-{(4E)-9,10-Dimethoxy-1-cyano-2,3,6,7-tetra-
hydro-4H-pyrido[2,1-a]isoquinolin-4-ylidene}-3-
iodobenzamide (XVb). Yield 96%, mp 134–135°C
(methanol–toluene, 2:1). 1H NMR spectrum (DMSO-d6),
δ, ppm: 2.55 m (2H, CH2), 2.80 m (2H, CH2), 2.95 m (2H,
CH2), 3.75 s (3H, CH3O), 3.85 s (3H, CH3O), 3.95 m (2H,
CH2), 7.05 s (1H, Ht), 7.30 t (1H, Ar), 7.60 s (1H, Ht),
7.95 d (1H, Ar), 8.05 d (1H, Ar), 8.30 s (1H, Ar). Found,
%: C 53.76, 53.78; H 3.89, 3.83; I 24.76, 24.68; N 8.15,
8.23. C23H20IN3O3. Calculated, %: C 53.81; H 3.93;
I 24.72; N 8.19.
N-{(4E)-9,10-Dimethoxy-1-cyano-2,3,6,7-tetra-
hydro-4H-pyrido[2,1-a]isoquinolin-4-ylidene}-
benzenesulfamide (XVIa). Yield 58%, mp 179–180°C
1
(from EtOH). H NMR spectrum (DMSO-d6), δ, ppm:
2.65 m (2H, CH2), 2.80–2.90 m (2H, CH2), 3.30 m (2H,
CH2), 3.75 m (2H, CH2), 3.80 s (3H, CH3O), 3.90 s (3H,
CH3O), 6.80 s (1H, Ht), 7.50–7.60 s+m (4H, Ar, Ar),
7.85 d (2H, Ar). Found, %: C 62.42, 62.49; H 4.94, 5.03;
N 9.95, 9.86; S 7.66, 7.59. C22H21N3O4S. Calculated, %:
C 62.40; H 5.00; N 9.92; S 7.57.
N-{(4E)-9,10-Dimethoxy-1-cyano-2,3,6,7-tetrahy-
dro-4H-pyrido[2,1-a]isoquinolin-4-ylidene}-3-chloro-
benzenesulfamide (XVIb). Yield 41%, mp 174°C (from
toluene). 1H NMR spectrum (DMSO-d6), δ, ppm: 2.65 m
(2H, CH2), 2.80 m (2H, CH2), 3.30 m (2H, CH2), 3.75 m
(2H, CH2), 3.80 s (3H, CH3O), 3.90 s (3H, CH3O), 6.80 s
(1H, Ht), 7.50–7.60 s+m (3H,Ar), 7.80–7.90 m (2H,Ar).
Found, %: C 57.75, 57.79; H 4.37, 4.41; Cl 7.72, 7.66;
N 9.26, 9.20; S 7.02, 7.08. C22H20ClN3O4S. Calculated,
%: C 57.70; H 4.40; Cl 7.74; N 9.18; S 7.00.
N-{(4E)-9,10-Dimethoxy-1-cyano-2,3,6,7-tetra-
hydro-4H-pyrido[2,1-a]isoquinolin-4-ylidene}-4-
chlorobenzamide (XVc). Yield 84%, mp 156–157°C
(MeOH–toluene, 2:1). 1H NMR spectrum (DMSO-d6), δ,
ppm: 2.55 m (2H, CH2), 2.80–2.85 m (2H, CH2), 2.95 m
(2H, CH2), 3.85. Found, %: C 65.42, 65.48; H 4.72, 4.63;
Cl 8.42, 8.35; N 10.09, 9.99. C23H20ClN3O3. Calculated,
%: C 65.48; H 4.78; Cl 8.40; N 9.96.
N-{(4E)-9,10-Dimethoxy-1-cyano-2,3,6,7-tetrahy-
dro-4H-pyrido[2,1-a]isoquinolin-4-ylidene}-2-fluo-
robenzamide (XVd). Yield 83%, mp 164–165°C (from
MeOH). 1H NMR spectrum (DMSO-d6), δ, ppm: 2.60 m
(2H, CH2), 2.80–2.95 m (4H, 2CH2), 3.85 s (3H, CH3O),
3.90 s (3H, CH3O), 4.05 m (2H, CH2), 6.80 s (1H, Ht),
7.15 m (1H,Ar), 7.20 m (1H,Ar), 7.50 m (1H,Ar), 7.60 s
(1H, Ht), 7.90 m (1H, Ar). Found, %: C 68.11, 68.08;
H 4.82, 4.85; N 10.38, 10.42. C23H20FN3O3. Calculated,
%: C 68.14; H 4.97; N 10.36.
N-{(4E)-9,10-Dimethoxy-1-cyano-2,3,6,7-tet-
rahydro-4H-pyrido[2,1-a]isoquinolin-4-ylidene}-
3-nitrobenzenesulfamide (XVIc). Yield 33%, mp 219–
220°C (EtOH–C6H6, 2:1). 1H NMR spectrum (DMSO-
d6), δ, ppm: 2.65 m (2H, CH2), 2.80 m (2H, CH2),
3.30 m (2H, CH2), 3.75 m (2H, CH2), 3.80 s (3H,
CH3O), 3.90 s (3H, CH3O), 6.80 s (1H, Ht), 7.50 s
(1H, Ht), 8.25 d (1H, Ar), 8.40 d (1H, Ar), 8.65 s (1H,
Ar). Found, %: C 56.42, 56.45; H 4.29, 4.33; N 11.90,
11.97; S 6.78, 6.82. C22H20N4O6S. Calculated, %:
C 56.40; H 4.30; N 11.96; S 6.84.
N-{(4E)-9,10-Dimethoxy-1-cyano-2,3,6,7-tetra-
hydro-4H-pyrido[2,1-a]isoquinolin-4-ylidene}-4-
methoxybenzamide (XVe). Yield 76%, mp 170–171°C
1
(MeOH–toluene, 3:1). H NMR spectrum (DMSO-d6),
REFERENCES
δ, ppm: 2.55 m (2H, CH2), 2.80–2.85 m (2H, CH2),
2.95 m (2H, CH2), 3.85 s (3H, CH3O), 3.90 s (6H,
1. Cook, A., Enamines: Synthesis, Structure, and Reactions,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 5 2011

6,7-DIMETHOXY-3,4-DIHYDROISOQUINOLIN-1(2H)-YLIDENOACETONITRILE
New York: Marcel Dekker, Ltd, 1969.
Chem., 1964, p. 2887.
745
2. Shmushkevich, D., Usp. Org. Khim., Knunyants, I.L.,
26. Wamhoff, H. and Erstas, M., Synth. Commun., 1985, p. 190.
Moscow: Mir, 1966, vol. 4, p. 5.
27. Vovk, M.V. and Sukach, V.A., Zh. Org. Khim., 2005,
3. Akhrem,A.A., Gulyakevich, O.V., and Mikhal’chuk,A.L.,
Azotistye geterotsikly i alkaloidy (Nitrogen Heterocycles
and Alkaloids), Kartsev, V.G. and Tolstikov, G.A., Mos-
cow: IBSpress, 2001, vol. 1, p. 31.
vol. 41, p. 1261.
28. Tramontini, M., Synthesis, 1973, p. 703.
29. Harsanyi, K., Kiss, P., and Korbonits, D., J. Heterocycl.
Chem., 1973, vol. 10, p. 435.
4. Akhrem, A.A., Gulyakevich, O.V., and Mikhal’chuk, A.L.,
Izbrannye metody sinteza i modifikatsii geterotsiklov (Se-
lected Methods of Synthesis and Modifications of Hetero-
cycles), Kartsev, V.G., Moscow: IBSpress, 2003, 1, p. 22.
30. Lenz, G.R. and Koszyk, F.J., J. Chem. Soc., Perkin Trans.
1, 1984, p. 1273.
31. Kleemann, A. and Engel, J., Pharmazeutische Wirkst-
offe. Synthesen-Patente-Anwendungen, Stuttgart: George
Thieme Verlag, 1982.
5. Kuehne, M.E., Synthesis, 1970, p. 510.
6. Lue, P.N. and Greenhill, J.V., Adv. Heterocycl. Chem.,
32. Kim, J.H., Lee, Y.S., Park, H.N., and Kim, C.S., Tetrahe-
dron, 1998, vol. 54, p. 7395.
1997, vol. 67, p. 207.
7. Boyd, G.V., The Chemistry of Enamines, Rappoport, Z.,
33. Anderson, W.K., Heider,A.R., Raju, N.J., and Yucht, J.A.,
J. Med. Chem., 1998, vol. 31, p. 2097.
Ed., New-York: Wiley, 1994, vol. 2, p. 1365.
8. Boger, D.L., Tetrahedron, 1983, vol. 39, p. 2869.
9. Campbell, A.L. and Lenz, G.R., Synthesis, 1987, p. 452.
10. Erian, A.W., Chem. Rev., 1993, vol. 93, p. 1991.
11. Rajappa, S., Tetrahedron, 1999, vol. 55, p. 7065.
34. Elvan, N.M., Abdelhadi, H.A., Abdallah, T.A., and Has-
saneen, H.M., Tetrahrdron, 1996, vol. 52, p. 3451.
35. Ninomiya, I., Yasui, J., and Kiguchi, T., Heterocycles, 1977,
vol. 6, p. 1855.
12. Lebed’, P.S. and Vovk, M.V., Zh. Org. Farm. Khim., 2006,
36. Hess, U., Hiller, K., and Schroeder, R., J. Pract. Chem.,
vol. 4, p. 3.
1977, vol. 319, p. 568.
13. Barum, O., Chakrabarti, S., Ila, H., and Jujappa, H., J. Org,
.Chem., 2001, vol. 66, p. 4461.
37. Yasuda, S., Hirasawa, T., Yoshida, S., and Hanaoka, M.,
Chem. Pharm. Bull., 1989, vol. 37, p. 1682.
14. Mikhailovskii, A.G., Azotistye geterotsikly i alkaloidy
(Nitrogen Heterocycles andAlkaloids), Kartsev, V.G. and
Tolstikov, G.A., Moscow: IBSpress, 2001, vol. 1, p. 423.
38. Yokoyama, M., Watanabe, S., and Hatanaka, H., Synthesis,
1987, p. 846.
39. Meyer, H., Lieb. Ann., 1981, p. 1534.
15. Fülöp, F., Wamhoff, H., and Sohár, P., Synthesis, 1995,
40. Atta-ur-Rahman., J. Chem. Soc., Perkin Trans. 1, 1972,
p. 863.
p. 731.
16. Akhrem,A.A. and Chernov, Yu.G., Synthesis, 1980, p. 996.
41. Dobeneck, H., Brunner, E., and Bunke, H., Lieb. Ann.,
17. Kobayashi, S. and Ischitani, H., Chem. Rev., 1999, vol. 99,
1981, p. 410.
p. 1069.
42. Feliciano, A., Caballero, E., Pereira, J., and Puebla, P.,
Tetrahedron, 1989, vol. 45, p. 6553.
18. Openshaw, H. and Whittaker, H., J. Chem. Soc., 1961,
p. 4939.
43. Singh, B.N., Lesher, G.Y., and Brundage, R.P., Synthesis,
19. Lenz, G.R. and Chi-Min, Woo., J. Org. Chem., 1982,
1991, p. 894.
vol. 47, p. 3049.
44. Mikhal’chuk, A.L. and Gulyakevich, O.V., Azotistye get-
erotsikly i alkaloidy (Nitrogen Heterocycles andAlkaloids),
Kartsev, V.G. and Tolstikov, G.A., Moscow: IBSpress,
2001, vol. 2, p. 426.
20. Arbuzov, B.A. and Zobova, N.N., Synthesis, 1974, p. 461.
21. Esmail, R. and Kurzer, F., Synthesis, 1975, p. 301.
22. Rassmussen, J. and Hassner,A., Chem. Rev., 1976, vol. 76,
p. 389.
45. Gordon, A.J. and Ford, R.A., The Chemist’s Companion,
New York: Wiley, 1972.
23. Dhar, D.N. and Murthy, K.S., Synthesis, 1986, p. 437.
46. Osbond, J.M., J. Chem. Soc., 1951, p. 3464.
24. Kawamura, Sh. and Sanemitsu, Yu., J. Org. Chem., 1993,
vol. 58, p. 414.
47. Fieser, L. F. and Fieser, M., Reagents for Organic Synthesis,
25. Carney, R., Wojtkunski, J., and De Stevens, G., J. Org.
New York: Wiley-Intersci., 1972.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 5 2011