Synthesis, stereochemistry and ring-chain tautomerism of some new bis(1,3-perhydrooxazin-2-yl)benzene derivatives

Article abstract of DOI:10.2174/157017811794557886

The synthesis of some new compounds exhibiting two 1,3-perhydrooxazine units connected to the same aromatic ring and of their ditosylated derivatives was carried out in good yields by the direct condensation reaction of the corresponding aminoalcohols wit

Full text of DOI:10.2174/157017811794557886

16
Letters in Organic Chemistry, 2011, 8, 16-21
Synthesis, Stereochemistry and Ring-Chain Tautomerism of Some New
Bis(1,3-perhydrooxazin-2-yl)benzene Derivatives
A. Nana,b, L. Davidb, M. Tintasb, C. Larb and I. Grosu*,b
aNational Institute for Research and Development of Isotopic and Molecular Technologies, 65-103 Donath, 400293,
Cluj Napoca, Romania
b”Babes-Bolyai” University, Organic Chemistry Department and CCOCCAN, 11 Arany Janos str., 400028,
Cluj-Napoca, Romania
Received May 26, 2010: Revised October 31, 2010: Accepted December 10, 2010
Abstract: The synthesis of some new compounds exhibiting two 1,3-perhydrooxazine units connected to the same
aromatic ring and of their ditosylated derivatives was carried out in good yields by the direct condensation reaction of the
corresponding aminoalcohols with aromatic dicarbonyl compounds. The stereochemistry and the ring-chain tautomerism
of these compounds were investigated by NMR and EI-MS.
Keywords: 1,3-perhydrooxazine, ring-chain tautomerism, conformational analysis, like-unlike isomers, NMR, mass-
spectrometry.
INTRODUCTION
linear correlation between the stability of the cyclic form and
the Hammets-Brown parameters of substituents located at
the aryl ring [1]. The shifting of the equilibrium towards the
acyclic tautomer is influenced by the electronic effects of the
substituents of the aromatic unit and by the steric hindrance
of the large substituents located at the 1,3-perdydrooxazine
ring [1]. The ratios between the chain and ring forms were
measured from 1H NMR spectra and the ring–chain
tautomerism was monitored by the cis-trans isomerization
The investigations on the stereochemistry of 1,3-
perhydrooxazines [1-21] were focused on three important
directions: a) the conformational analysis of the compounds
bearing different substituents located at the heterocycle; b)
the determination of the barriers for the flipping of the ring
and for the inversion of configuration at the nitrogen atom
and c) the determination of the kinetic and thermodynamic
parameters for the ring-chain tautomerism. The ring – chain
tautomerism of six membered ring is a process which was
observed for a large number of heterocycles including
sugars, [22] 1,3-oxathiane, [23-25] 1,3-diazine [26-29] and
1,3-perhydrooxazine derivatives [1]
reaction
(e.g.
1,3-diaryl-2,3-dihydro-1H-naphth[1,2-
e][1,3]oxazines and 2,4-diaryl-3,4-dihydro-2H-naphth[2,1-
e][1,3]oxazines) [16, 17].
In previous works [23-25] we successfully investigated
the ring chain tautomerism of some 1,3-oxathiane
compounds including derivatives with two heterocyclic
units. In our experiments we used compounds in which the
ring-chain tautomerism determines the equilibrium between
different diastereoisomers. We investigated spiro-1,3-
oxathiane derivatives exhibiting cis and trans isomers [23,
24] and bis(1,3-oxathian-2-yl)benzene derivatives with two
chiral centers showing like and unlike isomers [25] and we
established, using NMR experiments, the kinetic parameters
of the tautomerization processes.
The conformational analysis of substituted-1,3-
perhydrooxazines [2] revealed high similarity with the
stereochemistry of the corresponding 1,3-dioxane [30, 31] or
1,3-diazine derivatives. [21, 32-34] 2-Aryl-1,3-perhydro-
oxazines (Scheme 1) exhibit anancomeric structures and the
conformational equilibrium (I ꢀ II) of the flipping of the
heterocycle is shifted towards the conformer exhibiting the
aromatic substituent in the equatorial orientation (I).
R
Ar
O
We considered of interest to continue the investigations
of the ring-chain tautomerism in heterocyclic compounds
series using bis(1,3-perhydrooxazin-2-yl)benzene derivatives
(which exhibit like and unlike isomers) and to monitor the
tautomerization processes by NMR and by mass-
spectrometry.
O
Ar
R
N
H
H
R
N
H
H
R
II
I
Scheme 1.
The investigations on the ring-chain tautomerism of 2-
aryl-1,3-perhydrooxazines (IIIꢀIV; Scheme 2) showed the
RESULTS AND DISCUSSION
New 1,3-perhydrooxazine derivatives (1-4) were
obtained in fair to good yields by the condensation reaction
of 3-amino-1-propanol and of its N-tosylated derivative with
*Address correspondence to this author at the”Babes-Bolyai” University,
Organic Chemistry Department and CCOCCAN, 11 Arany Janos str.,
400028, Cluj-Napoca, Romania; Tel: 40264593833; Fax: 40264590818;
E-mail: igrosu@chem.ubbcluj.ro
1570-1786/11 $58.00+.00
© 2011 Bentham Science Publishers Ltd.

Synthesis, Stereochemistry and Ring-Chain Tautomerism
Letters in Organic Chemistry, 2011, Vol. 8, No. 1
17
OH
R
OH
H
Ar O+
R
R
-H+
Ar
H
O
R
R
R
R
H
+H+
H
Ar
Ar
N+
N
R
N
H
H
N
H
H
IV
III
Scheme 2.
R
N
H
H
O
C
NH
OH
R
O
R = H; meta
para
R = Ts; meta
para
1
2
3
4
C
H
O
+
R
N
H
O
Scheme 3.
Table 1. Results of the Synthesis of 1-4
Compound
1
2
3
4
Yields (%)
59
67
52
58
iso-phthaldialdehyde and tere-phthaldialdehyde (Scheme 3,
Table 1).
The NMR spectra of 1 and 2 display three sets of signals
which correspond to the bisperhydrooxazine (cycle-cycle
form, V), the mono-perhydrooxazine, mono-Schiff base
(cycle-chain form, VII) and to the double Schiff base (chain-
Compounds 1-4 were investigated by NMR experiments
and mass-spectrometry (EI). The stereochemistry
investigations of these derivatives reveal the anancomeric
structure of the compounds and the shifting of the
conformational equilibria towards the conformer exhibiting
the aromatic group in equatorial orientation. The
anancomeric structures are suggested by the NMR spectra
which exhibit different signals for the protons located in
axial and equatorial positions. The tosyl groups in 3 and 4
display axial orientations (as expected from literature data)
[35], and they are obtained as single cis-cis isomers (the
aromatic group at position 2 is taken as reference).
1
chain form, VI). Some of the specific signals in the H NMR
spectra, belonging to these very different structures, are very
well separated and the ratio between these three forms could
be measured and the equilibrium constants could be
estimated (Tables 2 and 3). For instance the protons located
at position 2 of the 1,3-perhydrooxazine ring (in the cyclic
form) exhibit a singlet at about 5 ppm, while the same
protons in the Schiff base form (iminic protons) give a more
1
deshielded signal at about 8-9 ppm. H NMR spectrum of 2
(Fig. 1) exhibits two close singlets (ꢀV = 5.18 and ꢀVII = 5.21
ppm) for the protons located at positions 2, 2’ in V and 2 in
VII and two other singlets for the imine protons of isomers
VI and VII (ꢀVI = 8.31 and ꢀVII = 8.28 ppm). The signals
belonging to the chain - ring form VII show the same
The investigations revealed important differences
between the stereochemistry of compounds 1, 2 and 3, 4.
Perhydrooxazines
1
and
2
exhibit the ring-chain
tautomerism, while the tosylated compounds 3 and 4 due to
the substitution at the nitrogen atom, are not involved in
tautomeric equilibria. The tautomeric equilibria for 1 and 2
takes place in solution (e.g. CDCl3 during the NMR
experiments) and they are running between three structures
(bisperhydrooxazine V, double Schiff base VI, and mono-
perhydrooxazine, mono-Schiff base VII; Scheme 4).
HN
H
N
OH
O
H
Ar
Ar
K2
O
H
H
OH
HN
N
The tautomeric equilibria are not completely shifted
towards one of the isomers, the rate of the process is not very
high, and thus all three structures can be easily detected by
NMR and by mass spectrometry. However, the equilibria are
fast enough to incapacitate the chemical or chromatographic
separation of the three tautomers. The two 1,3-oxazine units
are far one of the other and they act independently making
possible the identification of the structure VII.
N
V
VI
K1
OH
H
Ar
O
H
HN
VII
Scheme 4.

18 Letters in Organic Chemistry, 2011, Vol. 8, No. 1
Nan et al.
Fig. (1). 1H NMR spectrum (CDCl3, 300 MHz, relevant fragments).
Table 2. 1H NMR Data (Selected) for Compounds 1 and 2
Compd.
1
Tautomer
2-H
-CH=N-
V
VI
VII
V
5.16
-
-
8.30
8.26
-
5.18
5.18
-
2
VI
VII
8.31
8.27
5.21
Table 3. Thermodynamic Data for the Ring-Chain Tautomerism (Scheme 4) of Compounds 1 and 2
Compd
Ratios (%) of the tautomers with chain and ring forms
K1
K2
ring-ring (V)
ring-chain (VII)
chain-chain (VI)
1
2
20
17
47
54
33
29
2.35
3.17
0.70
0.53
intensities and facilitate their assignment. Similar differences
can be observed in the 13C NMR spectrum, too. It is worthy
to mention the modification of the positions of the signals
belonging to the carbon atoms at position 2, 2’. As an
example, in the case of 2 the 13C NMR spectrum exhibits
two signals (ꢀV = 88.28 and ꢀVII = 88.45ppm) for the
aminoacetalic carbon atoms (V and VII) and other two
signals for the imine carbon atoms of VI and VII (ꢀVI
=
160.9 and ꢀVII = 161.22 ppm). The three tautomeric forms of
2 can be easily observed investigating the signals belonging

Synthesis, Stereochemistry and Ring-Chain Tautomerism
Letters in Organic Chemistry, 2011, Vol. 8, No. 1
19
+
+
O
O
NH
N
CH2
NH
N
H
m/e = 218 (27%)
VIII
m/e = 204 (100%)
IX
+
+
N
CH2
N
CH2
HN
m/e = 118 (85 %)
XI
m/e = 145 (90%)
X
Scheme 5.
1
to the 1,4-phenylene moiety, too. The H NMR spectrum
(Fig. 1) shows only one singlet for the aromatic protons of V
(ꢀV = 7.48 ppm) and of VI (ꢀVI = 7.76 ppm), while for VII
the 1,4-phenylene protons exhibit an AB system (ꢀVII = 7.56,
and the water formed during the reaction was removed using
a Dean-Stark trap. After the water was separated the solvent
was removed and the bis(1,3-perhydrooxazines) were
purified by crystallization.
ꢀVII’ = 7.70 ppm).
1,3-bis(1,3-perhydrooxazin-2-yl)benzene (1)
The EI-MS investigations (using as sample a CHCl3
Yellow crystals, m.p. = 187-188 °C, yields 59%. Anal.
solution of the compounds and the direct introduction
procedure) revealed the molecular ions [M]+ (m/e = 248) and
characteristic fragment ions for the cyclic and iminic
tautomers (Scheme 5). Some of the peaks observed in the
mass spectra of 1 and 2 could be assigned to the double
cycle, cycle-chain or chain-chain forms. In agreement with
the literature data [36] in the EI-MS spectrum of 2 the ion
[M-CH2O]+ (VIII, m/e = 218; 27%) was considered
characteristic for the cycle-cycle form, the peak [M-CH2-
CH2O]+ (IX, m/e = 204; 87%) was associated with the cycle-
imine structure, while the ions [C9H9N2]+ (X, m/e = 145,
100%) and [C8H8N]+ (XI, m/e = 118; 71%) were assigned to
the double imine isomer. In the EI-MS spectrum of 1 the
similar peaks could be observed at comparable relative
intensities: m/e (%) = 218 (29); 204 (81); 145 (100); 118
(69).
Calcd for C14H20N2O2 (248.32): C, 67.71; H, 8.12; N, 11.28;
1
found: C, 67.88; H, 8.26; N, 11.41. H-NMR (CDCl3)(V-
VII): ꢀ (ppm) 1.48-1.95 [4H, overlapped peaks, 5,5’-H (V-
VII)], 3.12-4.24 [8H, overlapped peaks, 4,4’-H, 6,6’-H (V-
VII)], 5.16 [1H, s, 2-H (VII structure), 5.19 [2H, s, 2,2’-H (V
structure)], 7.32-7.72 [4H, overlapped peaks, aromatic
protons (V-VII)], 8.24 [1H, s, 2’-H (VII structure)], 8.28
[2H, s, 2,2’-H (VI structure)]. 13C-NMR (CDCl3)(V-VII): ꢀ
(ppm) 26.30, 29.04, 31.28, 43.79, 58.55, 60.50, 60.71, 67.27
[V-VII], 87.78 [C2,2’, V structure], 87.98 [C2, VII structure],
125.12, 125.59, 127.42, 127.73, 134.83, 137.32, 139.72,
142.49 [V-VII], 160.40 [C2,2’, VI structure], 160.73 [C2’, VII
structure]. EI-MS m/z (%): 248 (42), 218 (29), 204 (81), 145
(100), 130 (32), 118 (69), 117 (27), 91 (22), 79 (15), 77 (17).
1,4-bis(1,3-perhydrooxazin-2-yl)benzene (2)
Yellow crystals, m.p. = 216-217 °C, yields 67%. Anal.
Calcd for C14H20N2O2 (248.32): C, 67.71; H, 8.12; N, 11.28;
found: C, 67.54; H, 7.93; N, 11.49. 1H-NMR (CDCl3)
(structures V-VII): ꢀ (ppm) 1.24-2.03 [4H, overlapped peaks,
5,5’-H (V-VII)], 3.11-4.28 [8H, overlapped peaks, 4,4’-H,
6,6’-H (V-VII)], 5.14 [1H, s, 2-H (VII structure), 5.17 [2H,
s, 2,2’-H (V structure)], 7.45 [4H, s, aromatic protons (V
structure)], 7.52 [2H, d, J = 8.1 Hz, aromatic protons (VII
structure)], 7.66 [2H, d, J = 8.1 Hz, aromatic protons (VII
structure)], 7.72 [4H, s, aromatic protons (VI structure)],
8.23 [1H, s, 2’-H (VII structure)], 8.27 [2H, s, 2,2’-H (VI
structure)]. 13C-NMR (CDCl3)(structures V-VII): ꢀ (ppm)
26.80, 29.54, 33.21, 44.29, 59.05, 60.99, 61.20, 67.77 (V-
VII), 88.28 [C2,2’, V structure], 88.45 [C2, VII structure],
125.61, 126.09, 127.91, 128.23, 135.32, 137.61, 140.21,
142.98 [V-VII], 160.90 [C2,2’, VI structure], 161.22 [C2’, VII
structure]. EI-MS m/z (%): 248 (48), 218 (27), 204 (87), 145
(100), 130 (37), 118 (71), 117 (24), 91 (29), 79 (19), 77 (14).
EXPERIMENTAL SECTION
General
1H and 13C-NMR spectra were recorded at room
temperature using CDCl3 as solvent in 5 mm tubes on a
Varian Gemini spectrometer equipped with a multinuclear
head operating at 300 MHz for protons and 75 MHz for
carbon atoms. The mass spectra have been recorded with a
Varian MAT 311 spectrometer. Melting points were
measured with a Kleinfeld melting point apparatus and they
are uncorrected. Elemental analyses (C, H, N) were
conducted at “Babes-Bolyai” University using a Perkin
Elmer Analyzer; their results were found to be in good
agreement (±0.3%) with the calculated values.
General Procedure for the Synthesis of Compounds 1
and 2
Synthesis of N-tosyl-3-amino-1-propanol
Stoichiometric amounts of 3-amino-1-propanol, and
carbonyl compounds (11 mmol) were refluxed in benzene
To a solution of (10 mmol) 3-amino-1-propanol and (11
mmol) of triethylamine solved in dichloromethane at the -

20
Letters in Organic Chemistry, 2011, Vol. 8, No. 1
Nan et al.
50C, tosylchloride (10 mmol) was slowly added during 24 h
at the same temperature. When the reaction was completed,
20 ml of dichloromethane was added and the reaction
mixture was washed twice with 10 cm3 of sulfuric acid 2N
solution. After drying on Na2SO4 the solvent was removed
in NMR and in MS of different signals for the three different
isomers, but it is too fast for being possible the separation of
the cycle-cycle, cycle-imine or double imine tautomers. The
corresponding N,N-ditosylated derivatives were obtained as
double perhydrooxazine derivatives and they don’t exhibit
tautomers. All investigated cyclic compounds are
anancomeric and the aromatic unit prefers the equatorial
orientation.
and
N-tosyl-3-amino-1-propanol
was
purified
by
crystallization from ethanol.
1H-NMR (CDCl3) ꢀ (ppm): 1.7 [2H , m, -CH2-], 2.43
[3H, s, -CH3], 2.47 [2H, m, -CH2N-], 3.73 [2H, m, -CH2O-],
5.1 [1H, -NH-], 7.75-7.32 [4H, aromatic protons].
ACKNOWLEDGEMENTS
General Procedure for the Synthesis of Compounds 3
and 4
We acknowledge the financial support of this work by
UEFISCSU (IDEI project ID-2278/2008).
Stoichiometric amounts of N-tosyl-3-amino-1-propanol
and carbonyl compounds (11 mmol) and catalytic amounts
(0.05 g) of p-toluenesulfonic acid were refluxed in benzene
and the water formed during the reaction was removed using
a Dean-Stark trap. After the water was separated and the
reaction mixture was cooled to room temperature, the
catalyst was neutralized under stirring with excess of 0.1 M
KOH solution. The organic layer was washed twice with 20
cm3 of water. After drying on Na2SO4 the solvent was
removed and the N-substituted bis(perhidro-1,3-oxazines)
were purified by crystallization from ethanol and/or flash-
chromatography.
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1,3-bis(3-tosyl-1,3-perhydrooxazin-2-yl)benzene (3)
White solid, m.p. = 204-205 °C, Yield 46%. Anal. Calcd
for C28H32N2O6S2 (556.69): C, 60.41; H, 5.79; N, 5.03; S,
1
11.52 found: C, 60.57; H, 5.92; N, 5.22 S, 11.74. H-NMR
(CDCl3) ꢀ (ppm): 1.40 [2H, m, 5,5’-Heq]; 2.47 [6H, s, CH3-
C6H4-], 3.30 [2H, m, 5,5’-Hax], 3.68 [4H, m, 4(4’),6(6’)-Hax],
3.87 [4H, m, 4(4’),6(6’)-Heq], 6.69 [2H, s, 2,2’-H], 7.36 [2H,
d, J = 8 Hz, -C6H4-SO2-], 7.55 [1H, s, m-C6H4-], 7.61 [3H,
overlapped peaks, m-C6H4-], 7.91 [2H, d, J = 8 Hz, -C6H4-
SO2-]. 13C-NMR (CDCl3) ꢀ (ppm): 30.78 [C5,5’], 36.34 [CH3-
C6H4-], 39.98 [C4,4’], 66.03 [C6,6’], 88.19 [C2,2’], 121.96,
126.02, 128.31, 128.37, 129.13, 131.96, 135.67, 136.45,
137.98, 144.31 [aromatic carbon atoms]. EI-MS m/z (%):
401[M-Ts]+ (11), 400 (44), 240 (100), 155 (39), 91 (85).
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White solid, m.p. = 233 - 234 °C, yields 58%. Anal.
Calcd for C28H32N2O6S2 (556.69): C, 60.41; H, 5.79; N, 5.03;
S, 11.52 found: C, 60.60; H, 5.67; N, 4.88 S, 11.29 1H-NMR
(CDCl3) ꢀ (ppm): 1.45 [2H, m, 5,5’-Heq]; 2.46 [6H, s, CH3-
C6H4-], 3.29 [2H, m, 5,5’-Hax], 3.63 [4H, m, 4(4’),6(6’)-Hax]
3.82 [4H, m, 4(4’),6(6’)-Heq], 6.68 [2H, s, 2,2’-H], 7.35 [2H,
d, J = 8 Hz, -C6H4-SO2-], 7.5 [4H, s, -C6H4-], 7.67 [2H, d, J
= 8 Hz, -C6H4-SO2-], 13C-NMR (CDCl3) ꢀ (ppm): 21.57
[C5,5’], 32.13 [CH3-C6H4-], 45.78 [C4,4’], 60.83 [C6,6’], 84.57
[C2,2’], 126.78, 128.31, 128.62, 129.67, 137.06, 137.45,
137.98, 144.31 [aromatic carbon atoms]. EI-MS m/z (%):
401[M-Ts]+ (19), 400 (57), 240 (100), 155 (45), 91 (99).
1,3-oxazine
and
2-(para-nitrophenyl)-5,6-
tetramethylenetetrahydro-1,3-oxazine
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CONCLUSIONS
The NMR and EI-MS investigations of compounds 1 and
2 with two 1,3-perhydrooxazine rings connected to the same
aromatic unit revealed the running ring-chain tautomerism.
This process is slow enough for being possible the recording

Synthesis, Stereochemistry and Ring-Chain Tautomerism
Letters in Organic Chemistry, 2011, Vol. 8, No. 1
21
[16]
Szatmari, I., Martinek, T.A.; Lazar, L.; Fülöp, F. Synthesis of 2,4-
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