Synthesis and conformational study of 1,2,3,4,5,6,7,8-octahydro-1,6- naphthiridines

Article abstract of DOI:10.1134/S1070428006050162

A new class of endocyclic enamines, 1,6-disubstituted 1,2,3,4,5,6,7,8- octahydro-1,6-naphthiridines, was synthesized from 4-piperidone imines by successive subjecting the latter to lithiation with lithium diethylamide, to alkylation with 1-bromo-3-chloropropane, and to intramolecular cyclization. All stages were carried out as a unique process without isolation of the intermediate compounds. A thorough optimization of the process conditions, workup, and product storage was carried out. The conformational study of 1,6-disubstituted 1,2,3,4,5,6,7,8-octahydro-1,6-naphthiridines was performed. Pleiades Publishing, Inc. 2006.

Full text of DOI:10.1134/S1070428006050162

ISSN 1070-4280 Russian Journal of Organic Chemistry, 2006, Vol. 42, No. 5, pp. 742-747. Ó Pleiades Publishing, Inc. 2006.
Original Russian Text Ó T.V. Esipova, A.A. Borisenko, P.B. Terent’ev, G.V. Grishina, R. Herzshuh, 2006, published in Zhurnal Organicheskoi
Khimii, 2006, Vol. 42, No. 5, pp. 758-763.
Synthesis and Conformational Study
of 1,2,3,4,5,6,7,8-Octahydro-1,6-naphthiridines
T.V. Esipovaa, A.A. Borisenkoa, P.B. Terent’eva, G.V. Grishinaa, and R. Herzshuhb
aLomonosov Moscow State University, Moscow, 119992 Russia
e-mail: grishina@org.chem.msu.su
bLeipzig University, BRD
e-mail: rher@rz.uni-leipzig.de
Received January 17, 2005
Abstract—A new class of endocyclic enamines, 1,6-disubstituted 1,2,3,4,5,6,7,8-octahydro-1,6-naphthiridines,
was synthesized from 4-piperidone imines by successive subjecting the latter to lithiation with lithium diethylamide,
to alkylation with 1-bromo-3-chloropropane, and to intramolecular cyclization. All stages were carried out as
a unique process without isolation of the intermediate compounds. A thorough optimization of the process
conditions, workup, and product storage was carried out. The conformational study of 1,6-disubstituted
1,2,3,4,5,6,7,8-octahydro-1,6-naphthiridines was performed.
DOI: 10.1134/S1070428006050162
1,2,3,4,5,6,7,8-Octahydro-1,6-naphthiridines are
interesting as synthons for preparation of new physio-
logically active compounds. We formerly developed a con-
venient synthetic procedure for previously non-studied
bicyclic endoenamines, 1,2,3,4,5,6,7,8-octahydro-1,6-
naphthiridines, whose structure includes two fused
piperidine rings [1]. The study of the reactivity of endo-
enamines and their derivatives opens a prospect of a syn-
thesis therefrom of unknown earlier decahydro-1,6-
naphthiridines that are biomimetics of matrine alkaloids,
for instance, matridine. The matridine alkaloids N-oxides
control the intensity of the respiratory process in plant
tissue: at decrease in their amount the respiration sharply
gets slower [2]. The synthesis of cyclic endo-enamines
from acyclic ketone imines was first introduced by
D. Evans [3, 4].
Endocyclic enamines, 1,6-disubstituted 1,2,3,4,5,6,7,8-
octahydro-1,6-naphthiridines, were obtained by subjecting
piperidone imines I–V in succession to lithiation with
lithium diethylamide, to alkylation of azaenolates
(intermediate A) with 1-bromo-3-chloropropane yielding
intermediate B, and to intramolecular cyclization of the
latter affording the target 1,6-disubstituted 1,2,3,4,5,6,7,8-
octahydro-1,6-naphthiridines VI–IX and XIV. All reaction
sequence was carried out without isolation of the inter-
mediate compounds [1] (Scheme 1) .
Octahydro-1,6-naphthiridines similarly to common
enamines proved to be relatively unstable and difficult to
isolate. Therefore virtually in every instance the synthesis
conditions, workup, and storage required a thorough
adjustment [1].
2
5
1
1
We communicate in this paper a detailed optimization
of the synthetic conditions, and adjustment of the isolation
and storage procedures for the target compounds. Then
in the conditions developed we carried out the synthesis
and conformational investigation of new octahydro-1,6-
naphthiridines VI–IX and XIV. We found that the
synthesis of octahydro-1,6-naphthiridines VI–IX was
successful only when at each stage of the process the
monitoring showed that the reaction completion was
attained; also the factors affecting the course of the
1
1
5ꢀ
2FWDK\GURꢁꢂꢃꢄꢁQDSKWKLULGLQH
+
0DWULGLQH
5
1
1
+
'HFDK\GURꢁꢂꢃꢄꢁQDSKWKLULGLQH
742

SYNTHESIS AND CONFORMATIONAL STUDY OF 1,2,3,4,5,6,7,8-OCTAHYDRO-1,6-NAPHTHIRIDINES
743
Scheme 1.
&O
5
1
5
1
5
1
5
1
/L
ꢇꢇ &ꢁ
7+)ꢁꢂꢈ ꢆꢂK
(W 1/Lꢁ
7+)ꢂ ꢃꢄ &
%U
&O
ꢅꢆꢀꢀꢀ ꢃꢄ &
1
1
1
1
5ꢀ
5ꢀ
5ꢀ
5ꢀ
9, ,;ꢁꢂ;,9
, 9
%
$
R = C6H5, R' = CH2C6H5 (I, VI), CH3 (II, VII); R' = CH2C6H5, R = C6H4CH3-p(III, VIII), C6H4OCH3-p(IV, IX),
C6H5CH(CH3) (V, XIV).
therefore in the reaction mixture alongside the target
naphthiridine XIV was present the practically inseparable
intermediate B. The prolonging of the process to 48 h,
replacement THF by toluene or dioxane was unsuccess-
ful. In this case the microwave irradiation of 180W power
efficiently promoted cyclization of intermediate B in the
absence of solvent: The cyclization was complete within
3-3.5 min affording the target 1-(1-phenylethyl)-6-benzyl-
1,2,3,4,5,6,7-octahydro-1,6-naphthiridine in a 58% yield.
Another possible way to perform the cyclization of
1-benzyl-3-(3-chloropropyl)-4-(1-phenylethylimino)-
piperidine was a solid-phase synthesis on an activated
aluminum oxide at 135°C within 30 min.However the yield
of 1-(1-phenylethyl)-6-benzyl-1,2,3,4,5,6,7-octahydro-1,6-
naphthiridine in this case was only 27%. The application
of the microwave irradiation to the synthesis of all
octahydro-1,6-naphthiridines at the stage of intermediate
B cyclization efficiently accelerated the process and
shortened the time of the last stage, e.g., for naphthiridine
VI actually 240-fold.
Scheme 2.
1 5ꢀ
5ꢀ1 &+
1
5
&+ &+
)
)
1 5ꢀ
1
5
1
5
reaction (variation of solvents, temperature, and the
reaction time) should be accurately controlled. The
chromatographic monitoring by sampling the reaction
mixture at all the process stages showed that in the range
–78...–50°C practically no alkylation of azaenolate A with
1-bromo-3-chloropropane occurred, and intermediate B
started to form at –18°C, and its formation totally
completed within 12 h. The 4-piperidone imines are
unstable at the chromatography on SiO2 and suffer
decomposition into the initial amine and 4-piperidone.
Therefore the completion of the alkylation and con-
sequently the completion of intermediate B formation is
indicated by total disappearance of the corresponding
initial 1-benzyl-4-piperidone (X) and by appearance of
the respective 1-benzyl-3-(3-chloropropyl)-4-piperidone
(XI). The completion of the final stage, intramolecular
cyclization of intermediate B affording the target
1,2,3,4,5,6,7,8-octahydro-1,6-naphthiridines VI–IX, also
in all cases was chromatographically monitored.
The composition of endocyclic enamines VI–IX and
XIV was established by GC-MS method from the
existence of their molecular ions corresponding to the
respective empirical formulas. In all series the fragmenta-
tion under the electron impact occurrs in a characteristic
fashion, and it can be used further for identification of
the structures of new endo-enamine. The main patterns
of octahydro-1,6-naphthiridines fragmentation involve
elimination of substituents from both nitrogen atoms and
two ways of retrodiene decomposition giving fragment
ions F1 and F2 (Scheme 2).
In the preparation of octahydro-1,6-naphthiridines with
1-aralkyl substituents, for instance, 1-(1-phenylethyl)-
octahydro-1,6-naphthiridine XIV, the alkylation of the
azaenolate of 1-benzyl-4-(1-phylethylimino)piperidine (V)
occurred completely, and the intramolecular cyclization,
according to GC-MS data proceeded only to 50%,
The most suitable storage form of the endocyclic
enamines are their iminium salts, octahydro-1,6-naphthi-
ridiniums trifluoroacetates.According to the data of mass
spectrometry (direct admission, chemical ionization) and
high resolution mass spectrometry applying electrospray
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 5 2006

ESIPOVA et al.
744
Table 1. Chemical shifts in 13C NMR spectra
of 1,6-naphthiridines VI–IX and XIV
The presence of the enamine moiety in all members
of the series of octahydro-1,6-naphthiridines VI–IX and
XIV was proved by the appearance in the IR spectra of
a strong band of the stretching vibrations of the N–C=C
&RPSGꢀꢁQRꢀꢁ
9,ꢀ
& ꢁ
& ꢁ
ꢂꢂꢃꢀꢄꢅꢁ
ꢂꢂꢃꢀꢈꢂꢁ
ꢂꢂꢈꢀꢅꢆꢁ
ꢂꢃꢉꢀꢆꢊꢁ
ꢂꢆꢆꢀꢇꢂꢁ
ꢂꢆꢆꢀꢉꢉꢁ
ꢂꢆꢄꢀꢊꢂꢁ
ꢂꢃꢄꢀꢊꢊꢁ
–1
group in the region 1690 cm . In the 13C NMR spectra
9,,,ꢀ
,;ꢀ
;,9ꢀ
of compounds VI, VIII, IX, and XIV the downfield
signals of atoms C9 and C10 correspond to the enamine
fragment (Table 1).
ꢁ
Scheme 3.
1
In the H NMR spectra of octahydro-1,6-naphthi-
ridines VI–IX six multiplets were observed belonging to
coupled protons of all methylene groups. To reveal the
conformational features of enamines VI–IX a complete
assignment was perforemed of the observed multiplets
to the definite proton groups by means of the double
resonance technique using successive irradiation of the
separate groups of signals. However we succeeded only
in estimating the coupling constants between the protons
attached to C7 and C8, therefore the conformational
fashion in general remained indeterminate (Table 2).
ꢁDꢂꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢁEꢂ
Therefore with the use of software PCMODEL v7
by HF/6-31G** method we carried out a computer
simulation of the molecule of 1-phenyl-6-methyl-
1,2,3,4,5,6,7,8-octahydro-1,6-naphthiridine (VI).
According to the results of the quantum-chemical
calculations the molecule of 1,6-naphthiridine VI exists
in a fast conformational equilibrium of forms
(VIa)<=>(VIb) with the minimum energies of the
preferred conformations equal to 0 and 0.115 kcal mol-1
respectively (Scheme 3). Further the comparison of the
9,
ꢀ
ionization (ESI) obtained on 1-phenyl-6-benzyl- XV and
1-phenyl-6-methyloctahydro-1,6-naphthiridinium XVI
trifluoroacetates the spectra contained the corresponding
molecular ions [M]+ 304 and 228 respectively. Also in
the ESI mass spectrum of trifluoroacetate XV [MH]+
305.20133 and [M2H]++ 306.20470 ions are present in
a ratio 4:1 corresponding to a monoprotonated form (with
the more nucleophilic enamine nitrogen protonated) and
a biprotonated form (the monoprotonated form of
1-phenyl-6-benzyl-1,2,3,4,5,6,7,8-octahydro-1,6-
naphthiridine is presumably stabilized with the second
enamine molecule). The ESI mass spectrum of trifluoro-
acetate XVI turned out to be even more complicated.
Alongside the monoprotonated ion [MH]+ 229.17005 an
ion is present with a mass [MH]+ 571.32595 (their ratio
2:1). This ion may originate from association of a tri-
fluoroacetate anion with two monoprotonated forms (e.g.,
229.170052 + 113.01535 = 571.35545). Quite possible,
that this complex structure of iminium salts can affect
their reactivity.
experimental and calculated for the a and b conforma-
3
tions JH
values revealed that the experimental
H
w
x
3JH
values exactly equaled the sum of the coupling
H
w
x
constants for the pseudoaxial and pseudoequatorial
protons at C7 and C8. Consequently the complicated
pattern of the 1H NMR spectra of the total series of the
octahydro-1,6-naphthiridines is due to the fast con-
formational equilibrium between practically degenerate
semichair-like a and b conformations.
Accordingly, we developed a simple and convenient
synthesis of a series of 1,6-disubstituted 1,2,3,4,5,6,7,8-
Table 2. Chemical shifts in 1H NMR spectra of naphthiridines VI–IX, d, ppm (CDCl3)
&RPSGꢀꢁQRꢀꢁ ꢆꢋ&+ ꢁꢁ ꢇꢋ&+ ꢁꢁ ꢄꢋ&+ ꢁꢁ ꢊꢋ&+ ꢁꢁ ꢅꢋ&+ ꢁꢁ ꢃꢋ&+ ꢁꢁ ꢂꢋ&+ & + ꢁꢁ
2WKHUꢁꢁ
9,ꢀ
ꢂꢀꢉꢌꢁPꢁ ꢂꢀꢌꢇꢁPꢁ ꢃꢀꢂꢈꢁPꢁ ꢃꢀꢅꢊꢁWꢁꢍ- ꢁꢅꢀꢊꢈꢁ+]ꢎꢁ ꢃꢀꢌꢄꢁVꢁ ꢆꢀꢇꢅꢁPꢁ
ꢂꢀꢇꢊꢁPꢁ ꢂꢀꢊꢊꢁPꢁ ꢃꢀꢃꢃꢁPꢁ ꢃꢀꢆꢉꢁWꢁꢍ- ꢁꢅꢀꢊꢈꢁ+]ꢎꢁ ꢃꢀꢄꢇꢁVꢁ ꢆꢀꢆꢂꢁPꢁ
ꢂꢀꢉꢄꢁPꢁ ꢂꢀꢌꢉꢁPꢁ ꢃꢀꢈꢊꢁPꢁ ꢃꢀꢆꢄꢁWꢁꢍ- ꢅꢀꢊꢃꢁ+]ꢎꢁ ꢃꢀꢌꢄꢁVꢁ ꢆꢀꢇꢈꢁPꢁ
ꢂꢀꢊꢈꢁPꢁ ꢂꢀꢌꢆꢁPꢁ ꢃꢀꢈꢈꢁPꢁ ꢃꢀꢅꢃꢁWꢁꢍ- ꢁꢅꢀꢊꢂꢁ+]ꢎꢁ ꢃꢀꢌꢊꢁVꢁ ꢆꢀꢆꢅꢁPꢁ
ꢆꢀꢉꢃꢁ
±ꢁ
ꢆꢀꢉꢈꢁ
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±ꢁ
9,, ꢁ
9,,,ꢀ
,;ꢀ
ꢃꢀꢃꢆꢁVꢁꢍ1ꢋ&+ ꢎꢁ
ꢃꢀꢅꢅꢁVꢁꢍ&+ ꢎꢁ
ꢆꢀꢊꢅꢁVꢁꢍ2&+ ꢎꢁ
a
ꢁ
C6D6
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 5 2006

SYNTHESIS AND CONFORMATIONAL STUDY OF 1,2,3,4,5,6,7,8-OCTAHYDRO-1,6-NAPHTHIRIDINES
745
octahydro-1,6-naphthiridines VI–IX and XIV that
consisted in a sequence of reactions performed without
isolation of intermediate compounds. The target octa-
hydro-1,6-naphthiridines VI–IX and XIV are convenient
synthons for preparation of new biologically active
compounds.
and 6.34 g (51.0 mmol) of p-anisidine we obtained
8.82 g (88%) of compound IV as light-brown crystals,
mp 36.9–38.9°C (from hexane). IR spectrum (mull in
–1
mineral oil), n, cm : 1665 (C=N).
1-Benzyl-4-(1-phenylethylimino)piperidine (V).
In a flat-bottom flask was mixed 3.57 g (19 mmol) of
1-benzyl-4-piperidone and 4.58 g (38 mmol) of 1-phenyl-
ethylamine in 10 ml of anhydrous benzene. The mixture
was stirred for 10 h at room temperature with activated
EXPERIMENTAL
IR spectra were recorded on a spectrophotometer
°
1
UR-20. H and 13C NMR spectra were registered
molecular sieves 3 A(5 ml) in an argon flow. Benzene
was evaporated, excess 1-phenylethylamine was distilled
off in a vacuum, bp 44–45°C (2 mm Hg). We obtained
5.2 g (94%) of crude compound V as a yellow oily
respectively on spectrometers Bruker WM-400
(400 MHz) and Varian VXR-400 (100.58 MHz) using
TMS as an internal reference. GC-MS measurements
were performed on instruments HP5989x-G, Jasco-980
(LC), Fisons Instruments VG Platform 7031 (electron
impact ionization, 70 eV, defector of positive ions) (GC/
MS). High-resolution mass spectra were measured on
spectrometer Bruker FT-ICR MS [electrospray ionization
(ESI)].
–1
substance. IR spectrum (thin film), n, cm : 1670 (C=N).
1-Phenyl-6-benzyl-1,2,3,4,5,6,7,8-octahydro-1,6-
naphthiridine (VI). To a solution of 1.75 ml (17.0 mmol)
of diethylamine in 10 ml of anhydrous THF was slowly
added at –10°C 10.6 ml (17.0 mol) of 1.6 M solution of
n-butyllithium in hexane under an argon atmosphere. The
reaction mixture was stirred for 30 min at –10°C, cooled
to –35°C, a solution of 3 g (11.4 mmol) of compound I in
10 ml of THF was added, and the mixture was stirred for
2 h at –35°C. Then the reaction mixture was cooled to
–78°C, and a solution of 2.7 g (17.0 mmol) of 1-bromo-
3-chloropropane in 5 ml of THF was added, and the
resulting mixture was stirred for 2 h at –50...–35°C. The
temperature was slowly raised to –18°C, the reaction
mixture was maintained at this temperature for 12 h, then
it was slowly warmed to room temperature, and boiled
for 12 h at 66°C. The solvent was evaporated, the residue
was treated with 1 ml of water, acidified with diluted
HCl till pH 3, extracted with ether (3´5 ml), alkalinized
with 20% NaOH till pH 11–12, again extracted with ether
(7´5 ml), the extract was dried with Na2SO4. The solvent
was evaporated to give 2.1 g (60%) of compound VI as
yellow crystals, mp 68.4–69.0°C (from hexane), Rf 0.61
(hexane–acetone, 2:1). IR spectrum (mull in mineral oil),
Thin-layer chromatography was carried out on Silufol
UV-254 plates (Kavaler, Czechia). The column chromato-
graphy was done using Silica gel 60-40 andAluminiumoxid
90 standardisiert Merck (Germany).
1-Benzyl-4-(phenylimino)piperidine (I). Into
a flask equipped with a Dean-Stark trap was charged
10 g (53.0 mmol) of 1-benzyl-4-piperidone, 7.4 g
(79.5 mmol) of freshly distilled aniline, and 100 ml of
anhydrous toluene. The reaction mixture was boiled till
the amount of eliminated water was equal to the calculated
quantity. The toluene was evaporated, the excess aniline
was distilled off in a vacuum, bp 35–36°C (2 mm Hg).
The red-brown oily substance was purified by crystalliza-
tion from hexane. We obtained 8.5 g (61%) of compound
I as light-brown crystals, mp 43.9–45.5°C (from hexane).
–1
IR spectrum (mull in mineral oil), n, cm : 1680 (C=N).
1-Methyl-4-(phenylimino)piperidine (II). In the
same way from 5.65 g (50.0 mmol) of 1-methyl-4-
piperidone and 7.44 g (80.0 mmol) of aniline was obtained
5.63 g (60%) of compound II as a light-yellow oily
substance, bp 118–119°C (1.5 mm Hg). IR spectrum (thin
–1
n, cm : 1690 (N–C=C). 1H NMR spectrum (CDCl3), d,
ppm: 1.69 m (2H, 3CH2), 1.94 m (2H, 4CH2), 2.10 m
(2H, 8CH2), 2.57 t (2H, 7CH2, J 5.70 Hz), 2.98 m (2H,
5CH2), 3.45 m (2H, 2CH2), 3.62 s (2H, CH2C6H6),
7.20 m (10H, C6H5 and CH2C6H5). 13C NMR spectrum
(CDCl3), d, ppm: 20.46 (C3), 25.62 (C8), 27.58 (C4), 50.23
(C2), 52.81 (C7), 56.84 (C5), 62.70 (CH2-Ph), 112.85
(C10), 122.38 (C6H5), 124.64 (C6H5), 127.37 (C6H5),
128.56 (C6H5), 128.96 (C6H5), 129.57 (C6H5), 133.41
(C9), 138.64 (C6H5), 149.1 (C6H5). Mass spectrum, m/z
(Irel, %): 304 (39.2) [M]+, 276 (1.0) [M – 28]+, 213 (17.7)
[M – 91]+, 185 (11.4) [M – 119]+.
–1
film), n, cm : 1680 (C=N).
1-Benzyl-4-(p-tolylimino)piperidine (III). Similarly
from 7.02 g (37.0 mmol) of 1-benzyl-4-piperidone and
6.0 g (56.0 mmol) of p-toluidine we obtained 6.61 g (64%)
of compound III as light-brown crystals, mp 50.7–51.2°C
(from hexane). IR spectrum (mull in mineral oil), n,
cm-1: 1670 (C=N).
1-Benzyl-4-(p-methoxyimino)piperidine (IV).
Similarly from 6.5 g (34.0 mmol) of 1-benzyl-4-piperidone
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 5 2006

ESIPOVA et al.
746
1-Phenyl-6-methyl-1,2,3,4,5,6,7,8-octahydro-1,6-
%): 334 (65.6) [M]+, 243 (24.6) [M – 91]+, 215 (13.1)
[M – 119]+.
Preparation of 1-phenyl-6-benzyl-1,2,3,4,5,6,7,8-
naphthiridine (VII). Similarly from 2.0 g (18.0 mmol)
of compound II and 2.2 ml (22.0 mmol) of 1-bromo-3-
chloropropane we obtained 2.8 g (70%) of compound
VII as an orange oily substance, Rf 0.31 (benzene–
octahydro-1,6-naphthiridine (VI) with the use of
microwave radiation. To a solution of 1.75 ml
(17.0 mmol) diethylamine in 10 ml of anhydrous THF
was slowly added at –10°C 10.6 ml (17.0 mol) of 1.6 M
solution of n-butyllithium in hexane under an argon atmo-
sphere. The reaction mixture was stirred for 30 min at
–10°C, cooled to–35°C, a solution of 3 g (11.4 mmol) of
compound I in 10 ml of THF was added, and the mixture
was stirred for 2 h at –35°C. Then the reaction mixture
was cooled to–78°C, and a solution of 1.68 ml (17.0 mmol)
of 1-bromo-3-chloropropane in 5 ml of THF was added,
and the resulting mixture was stirred for 2 h at
–50...–35°C. Then the temperature was slowly raised to
–18°C, the reaction mixture was maintained at this
temperature for 12 h, then it was slowly warmed to room
temperature, and the solvent was evaporated. The dry
residue was placed into a microwave oven by portions of
200 mg and subjected to irradiation of 90 W power by
short intervals: 30 s + 60 s + 60 s. The powder mixture
obtained was treated with 1 ml of water, acidified with
diluted HCl till pH 3, extracted with ether (3´5 ml),
alkalinized with 20% NaOH till pH 11–12, again extracted
with ether (7´5 ml), the extract was dried with Na2SO4.
The solvent was evaporated, the octahydro-1,6-naphthiri-
dine was recrystallized from hexane to obtain 2.0 g (58%)
of compound VI as yellow crystals.
–1
acetone, 1:1). IR spectrum (thin film), n, cm : 1690
(N–C=C). 1H NMR spectrum (C6D6), d, ppm: 1.47 m
(2H, 3CH2), 1.77 m (2H, 4CH2), 2.22 m (2H, 8CH2),
2.23 s (3H, N–CH3), 2.36 t (2H, 7CH2, 3JH
5.7 Hz),
H
w x
2.84 m (2H, 5CH2), 3.31 m (2H, 2CH2), 7.20 m (5H,
C6H5). Mass spectrum, m/z (Irel, %): 228 (46.2) [M]+,
200 (3.8) [M – 28]+, 213 (3.8) [M – 15]+, 213 (9.6) [M –
43]+.
1-(p-Tolyl)-6-benzyl-1,2,3,4,5,6,7,8-octahydro-
1,6-naphthiridine (VIII) was obtained similarly from
2.0 g (7.2 mmol) of compound III and 1.42 ml (14.4 mmol)
of 1-bromo-3-chloropropane as an orange oily substance.
Yield of crude compound 96%, Rf 0.60 (hexane–acetone,
2:1). 1H NMR spectrum (CDCl3), d, ppm: 1.68 m (2H,
3CH2), 1.96 m (2H, 4CH2), 2.07 m (2H, 8CH2), 2.38 t
(2H, 7CH2, 3JH
5.72 Hz), 2.55 s (3H, CH3), 2.98 m
H
x
w
(2H, 5CH2), 3.40 m (2H, 2CH2), 3.60 s (2H, CH2C6H6),
6.87 d (2H, C6H4-p-CH3, J 8.50 Hz), 7.05 d (2H, C6H4-
p-CH3, J 8.50 Hz), 7.32 m (5H, CH2C6H5). 13C NMR
spectrum (CDCl3), d, ppm: 20.40 (–CH3), 20.47 (C3),
25.64 (C8), 27.70 (C4), 50.30 (C2), 53.03 (C7), 56.98 (C5),
62.78 (CH2–Ph), 112.01 (C10), 124.90 (C6H5), 127.31
(C6H5), 128.55 (C6H5), 129.54 (C6H5), 129.62 (C6H5),
132.23 (C6H5), 133.66 (C9), 138.83 (C6H5), 146.72
(C6H5). Mass spectrum, m/z (Irel, %): 318 (38.1) [M]+,
290 (0.5) [M – 28]+, 227 (28.6) [M – 91]+, 199 (12.5)
[M – 119]+.
Preparation of 1-(1-phenylethyl)-6-benzyl–
1,2,3,4,5,6,7,8-octahydro-1,6-naphthiridine (XIV)
with the use of microwave radiation. To a solution of
1.76 ml (17.0 mmol) of diethylamine in 10 ml of anhydrous
THF at –10°C was slowly added 10.6 ml 17.0 mol) of
1.6 M solution of n-butyllithium in hexane under an argon
atmosphere. The reaction mixture was stirred for 30 min
at –10°C, cooled to –35°C, a solution of 3 g (10.3 mmol)
of compound V in 10 ml of THF was added, and the
mixture was stirred for 2 h at –35°C. Then the reaction
mixture was cooled to–78°C, and a solution of 1.68 ml
(17.0 mmol) of 1-bromo-3-chloropropane in 5 ml of THF
was added, and the resulting mixture was stirred for 2 h
at –50...–35°C. Then the temperature was slowly raised
to –18°C, the reaction mixture was maintained at this
temperature for 12 h, then it was slowly warmed to room
temperature, and the solvent was evaporated. The dry
residue was placed into a microwave oven by portions of
200 mg and subjected to irradiation of 180 W power for
3–3.5 min. The powder mixture obtained was treated
with 1 ml of water, acidified with diluted HCl till pH 3,
1-(4-Methoxyphenyl)-6-benzyl-1,2,3,4,5,6,7,8-
octahydro-1,6-naphthiridine (IX) was obtained
similarly from 3 g(10.2 mmol) of compound IV and
2.0 ml (20.4 mmol) 1-bromo-3-chloropropane as an orange
oily substance. Yield of crude compound 60%, Rf 0.60
1
(hexane–acetone, 2:1). H NMR spectrum (CDCl3), d,
ppm: 1.70 m (2H, 3CH2), 1.93 m (2H, 4CH2), 2.00 m
(2H, 8CH2), 2.52 t (2H, 7CH2, 3JH
5.70 Hz), 2.97 m
H
w x
(2H, 5CH2), 3.35 m (2H, 2CH2), 3.59 s (2H, CH2C6H6),
3.75 s (3H, OCH3), 6.79 d (2H, C6H4-p-CH3, J 8.79 Hz),
6.93 d (2H, C6H4-p-CH3, J 8.80 Hz), 7.32 m (5H,
CH2C6H5). 13C NMR spectrum (CDCl3), d, ppm: 20.92
(C3), 26.01 (C8), 28.21 (C4), 50.63 (C2), 53.56 (C7), 55.67
(O–CH3), 57.29 (C5), 63.03 (CH2–Ph), 110.53 (C10),
114.22 (C6H5), 126.58 (C6H5), 127.32 (C6H5), 128.43
(C6H5), 129.42 (C6H5), 133.79 (C6H5), 138.71 (C9),
142.36 (C6H5), 155.90 (C6H5). Mass spectrum, m/z (Irel,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 5 2006

SYNTHESIS AND CONFORMATIONAL STUDY OF 1,2,3,4,5,6,7,8-OCTAHYDRO-1,6-NAPHTHIRIDINES
747
extracted with ether (3´5 ml), alkalinized with 20% NaOH
till pH 11–12, again extracted with ether (7´5 ml), the
extract was dried with Na2SO4. The solvent was
evaporated to obtain 2.0 g (58%) of compound XIV as
an orange oily substance, Rf 0.54 (hexane–acetone, 1:1).
IR spectrum (thin film), n, cm : 1660 cm . 13C NMR
spectrum (CDCl3, 100.58 MHz), d, ppm: 15.49 (CH3),
22.36 (C3), 25.79 (C8), 27.05 (C4), 41.86 (C2), 50.43 (C7),
53.56 (C5), 57.52 [CH(CH3)Ph], 62.66 (CH2-Ph), 126.37
(C10), 126.48 (C6H5), 126.87 (C6H5), 127.30 (C6H5),
127.99 (C6H5), 128.12 (C6H5), 128.34 (C6H5), 128.77
(C9), 129.03 (C6H5), 129.15 (C6H5). Mass spectrum,
m/z: 332 [M]+.
of 1 g (3.3 mmol) of compound VI in ether cooled to 0°
was added dropwise at cooling a solution of 6.6 mmol of
CF3COOH in anhydrous ether till pH 7. Then a 10%
excess of CF3COOH (0.7 mmol) was added till pH 4.
The solvent was evaporated. The salt was dried in
a vacuum-desiccator over P2O5 and alkali. The residue
obtained was crystallized from ether We obtained 0.88 g
(50%) of compound XV as colorless crystals, mp 112.4–
113.0°C. Mass spectrum, m/z (Irel, %): 304 (7.8) [M]+,
303 (13.5) [M – H]+, 276 (1.4) [M – 28]+, 227 (0.7)
[M – 77]+, 213 (5.7) [M – 91]+, 185 (2.8) [M – 119]+.
Mass spectrum (ESI): MH+ 305.20133, MH+calc 305.19903,
D 0.0023.
–1
–1
1-(1-Phenylethyl)-6-benzyl-1,2,3,4,5,6,7,8-octa-
hydro-1,6-naphthiridine (XIV). To a solution of
1.35 ml diethylamine in 10 ml of anhydrous THF at
–10°C was slowly added 8.0 ml (0.013 mol) of 1.6 M
solution of n-butyllithium in hexane under an argon
atmosphere. The reaction mixture was stirred for 30 min
at –10°C, cooled to –35°C, a solution of 1.905 g
(6.5 mmol) of compound V in 10 ml of THF was added,
and the mixture was stirred for 2 h at –35°C. Then the
reaction mixture was cooled to –78°C, and a solution of
1.3 ml (13.0 mmol) of 1-bromo-3-chloropropane in 5 ml
of THF was added, and the resulting mixture was stirred
for 2 h at –50...–35°C. Then the temperature was slowly
raised to –18°C, the reaction mixture was maintained at
this temperature for 12 h, then it was slowly warmed to
room temperature, and the solvent was evaporated. The
dry residue was dissolved in CH2Cl2, the solution was
applied to an activated sorbent (Al2O3), then the solvent
was evaporated, and the residue was heated to 135°C in
an argon flow for 30 min. The sorbent was washed with
EtOAc (3´5 ml), then with CH2Cl2 saturated with NH3.
The combined methylene extract was dried over Na2SO4.
On evaporating the solvent we obtained 0.580 g (27%)
of compound XIV as an orange oily substance.
1-Phenyl-6-methyl-1,2,3,4,5,6,7,8-octahydro-1,6-
naphthiridinium trifluoroacetate (XVI). Similarly
from 2.8 g (12.0 mmol) of compound VII and 2.85 g
(24.0 mmol) of trifluoroacetic acid we obtained 5.40 g
(99%)of trifluoroacetate of compound XVI as a red oil.
Mass spectrum, m/z (Irel, %): 228 (17.0) [M]+, 227 (36.9)
[M – H]+, 213 (1.4) [M – 15]+, 199 (4.3) [M – 29]+, 184
(10.0) [M – 44]+, 151 (0.7) [M – 77]+. Mass spectrum
(ESI): MH+ 229.17005, MH+calc 229.16993, D 0.00012.
The study was carried out under financial support of
the Russian Foundation for Basic Research (grant no.
05-03-32658a).
REFERENCES
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1998, vol. 27, p. 77670.
2. Sadykov, A.S., Aslanov, Kh.A., and Kushmuradov, Yu.K.,
Alkaloidy khinolizidinovogo ryada. Khimiya. Stereokhi-
miya. Biogenez (Alkaloids of Quinolizidine Series. Chemistry.
Stereochemistry. Biogenesis), Moscow: Nauka, 1975, pp. 125,
261.
3. Evans, D.A., J. Am. Chem. Soc., 1970, vol. 92, p. 7593.
4. Evans, D.A., Bryan, C.A., and Wahl, G.M., J. Org. Chem.,
1970, vol. 35, p. 4122.
1-Phenyl-6-benzyl-1,2,3,4,5,6,7,8-octahydro-1,6-
naphthiridinium trifluoroacetate (XV). To a solution
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 5 2006