Substituent effects in the ring-chain tautomerism of 1-alkyl-3-arylnaphth- [1,2-e][1,3]oxazines

Article abstract of DOI:10.1002/ejoc.200600447

New 1-(1-aminoalkyl)-2-naphthols 8-11 have been synthesised by the condensation of 2-naphthol with aliphatic aldehydes in the presence of ammonia, followed by acidic hydrolysis. The condensation of 7-11 with substituted benzaldehydes after microwave irrad

Full text of DOI:10.1002/ejoc.200600447

FULL PAPER
DOI: 10.1002/ejoc.200600447
Substituent Effects in the Ring–Chain Tautomerism of 1-Alkyl-3-arylnaphth-
[1,2-e][1,3]oxazines
Diána Tóth,[a] István Szatmári,[a] and Ferenc Fülöp*[a]
Dedicated to Professor Erich Kleinpeter on the occasion of his 60th birthday
Keywords: Aminonaphthols / Naphthoxazines / Betti bases / Substituent effects / Ring-chain tautomerism
New 1-(1-aminoalkyl)-2-naphthols 8–11 have been synthe- libria with the aid of two-variant linear equations. A signifi-
sised by the condensation of 2-naphthol with aliphatic
aldehydes in the presence of ammonia, followed by acidic
hydrolysis. The condensation of 7–11 with substituted
benzaldehydes after microwave irradiation led to
1-alkyl-3-aryl-2,3-dihydro-1H-naphth[1,2-e][1,3]oxazines,
which proved to be three-component (rt-o-rc) tautomeric mix-
tures in CDCl3 at 300 K. The electronic effects of the 1-alkyl
and 3-aryl groups on the tautomeric ratios could be deter-
mined for both the ringtrans–chain and the ringcis–chain equi-
cant difference was found between the coefficients of the
Meyer parameter Va, which characterises the volume of the
portion of the alkyl substituent within 0.3 nm of the reaction
centre, for ringtrans–chain and ringcis–chain equilibria, and
this is explained in terms of the stereoelectronic effect caused
by the alkyl substituent at position 1.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
fects of the substituents at positions other than 2 on the
parameters in this equation.[3–8]
Introduction
The structures and reactivities of numerous five- and six-
membered, saturated, 1,3-X,N-heterocycles (X = O, S, NR)
can be characterised by the ring–chain tautomeric equilib-
ria of these heterocycles and the corresponding Schiff bases.
Oxazolidines and tetrahydro-1,3-oxazines are the saturated
1,3-X,N-heterocycles whose ring–chain tautomerism has
been studied most thoroughly. From quantitative studies on
their tautomeric equilibria, it has been concluded that the
tautomeric ratios for oxazolidines and tetrahydro-1,3-oxa-
zines bearing a substituted phenyl group at position 2 can
be characterised by an aromatic substituent dependence
[Equation (1)]
Our quantitative investigations on the ring–chain tauto-
meric equilibria of 1,3-diaryl-2,3-dihydro-1H-naphth[1,2-
e][1,3]oxazines have led to the first precise mathematical
formulae with which to characterise the effects of substitu-
ents situated elsewhere than between the heteroatoms. For
example, we have demonstrated that the tautomeric ratio is
influenced not only by the aryl substituent at position 3,
but also by that at position 1. This additional stabilisation
effect was explained as an anomeric effect in the trans ring
form.[9] When the tautomeric equilibria of 3-alkyl-1-aryl-
2,3-dihydro-1H-naphth[1,2-e][1,3]oxazines were analysed,
the results of multiple linear regression analysis of the
logKR values revealed a significant dependence on the in-
ductive effect of substituent Y (σF), which was further evi-
dence of the anomeric effect in the trans ring form.[9] Sys-
tematic quantitative investigations on the ring–chain tauto-
meric equilibria of 2,4-diarylnaphth[2,1-e][1,3]oxazines
have demonstrated an analogous inductive influence on the
ringtrans–chain tautomeric equilibria.[10]
logKX = ρσ+ + logKX=H
(1)
where KX is the [ring]/[chain] ratio and σ+ is the Hammett–
Brown parameter (electronic character) of substituent X on
the 2-phenyl group.[1,2]
The scope and limitations of Equation (1) have been
thoroughly studied from the point of view of the applica-
bility of this equation in the case of complex tautomeric
The stereoelectronic effect relating to the relative config-
mixtures containing several types of open and/or cyclic urations of C-1 and C-3 in these naphthoxazines could orig-
forms, and the influence of the steric and/or electronic ef- inate from the aryl substituent at position 1. There appears
to be no published examples of the study of such effects of
[a] Institute of Pharmaceutical Chemistry, University of Szeged,
an alkyl group at the same position. We therefore set out
P. O. Box 427, 6701 Szeged, Hungary
to synthesise and investigate the substituent effects in a new
Fax: +36-62-545705
E-mail: fulop@pharm.u-szeged.hu
1,3-disubstituted naphthoxazine model system bearing an
4664
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Substituent Effects in Ring–Chain Tautomerism
FULL PAPER
alkyl substituent at position 1 and an aryl substituent at
position 3.
Results and Discussion
One hundred years ago, Betti reported a straightforward
synthesis of 1-(α-aminobenzyl)-2-naphthol (the Betti base)
from 2-naphthol, benzaldehyde and ammonia.[11] The Betti
procedure can be interpreted as an extension of the Man-
nich condensation, with formaldehyde replaced by an aro-
matic aldehyde, the secondary amine by ammonia and the
C–H acid by an electron-rich aromatic compound, such as
2-naphthol.[11,12] As a consequence of the potential utility
of Mannich-type phenolic bases, the aminoalkylation of
naphthol derivatives is a subject of current chemical inter-
est.[12]
The classical Betti procedure has generally been confined
to the use of aromatic aldehydes (e.g. benzaldehyde) as the
aldehyde component,[12] and only a few examples are
known where benzaldehyde has been replaced by some
other aldehyde. For the synthesis of the desired model com-
pounds, our interest focused on the application of aliphatic
aldehydes in the Betti reaction. Formaldehyde was the first
aliphatic aldehyde to be used in this three-component reac-
tion.[13,14] For the preparation of 1-(1-aminoethyl)-2-naph-
thol, the classical Betti procedure was altered: the interme-
diate naphthoxazine was formed by refluxing 2-naphthol,
acetaldehyde and ammonia in benzene to give 1,3-dimethyl-
2,3-dihydro-1H-naphth[1,2-e][1,3]oxazine. Acidic hydrolysis
of this led to 1-(1-aminoethyl)-2-naphthol hydrochloride in
an overall yield of 70%.[15] A different synthetic pathway
was applied to produce 1-(1-amino-2,2,2-trifluoroethyl)-2-
naphthol, namely the preparation of 1-[2,2,2-trifluoro-1-(1-
naphth-1-yl-ethylamino)ethyl]-2-naphthol, followed by
catalytic hydrogenation.[16,17]
In our experiments, naphthoxazines 2–6 were formed by
the condensation of 2-naphthol (1) and the corresponding
aliphatic aldehyde in the presence of methanolic ammonia
solution in absolute methanol at 60 °C for 6–72 h
(Scheme 1). The acidic hydrolysis of 2–6 led to the desired
aminonaphthol hydrochlorides 7–11 in low yields in a two-
step process. The overall yield was improved considerably
when the solvent was evaporated off after the formation of
the intermediate naphthoxazines (2–6) and the residue was
directly hydrolysed with hydrochloric acid (e.g. for com-
pound 7 the overall yield could be increased from 15% to
95%).
Because of the instability of the Betti base derivatives,
compounds 7–11 were isolated as hydrochlorides, which in
subsequent transformations were basified in situ with tri-
ethylamine. The condensation of aminonaphthols 7–11 with
one equivalent of aromatic aldehyde in absolute methanol
Scheme 1.
16 was successful. After the controlled microwave agitation
(CEM microwave reactor, 10 min at 80 °C), the mixture was
left to stand at room temperature to crystallise.
The 1H NMR spectra of 12–15 reveal that, in CDCl3
solution at 300 K, the members a–g of each set of com-
pounds 12–15 exist in three-component ring–chain tauto-
meric mixtures containing the C-3 epimeric naphthoxazines
(B and C) and also the open tautomer (A). The proportion
of the ring forms decreases as the alkyl substituent at posi-
tion 1 becomes more bulky. Accordingly, for some 1-isopro-
pyl-3-arylnaphthoxazine derivatives (15) the proportions of
the ring forms (B and C) were close to the limiting error
and in the case of 16 only the derivatives 16a, 16e and 16f
were synthesised. As expected, ring forms B and C of com-
pounds 16 (Scheme 2) were not found at all in the tauto-
meric mixture. In order to acquire reliable results, more
sample data were needed and the series of compounds was
therefore expanded to include naphthoxazines 18. The tau-
tomeric behaviour of analogues 18 (18a, 18d–g) is known
from the literature, but compounds 18b and 18c were absent
and were therefore synthesised according to Scheme 3.[14]
Table 1 shows the proportions of the diastereomeric ring
forms (B and C) from the tautomeric equilibria of 12–16
and 18, as determined by integration of the well-separated
O–CHAr–N (ring) and N=CHAr (chain) proton signals in
1
the H NMR spectra. As a consequence of the very similar
NMR spectroscopic characteristics of 1-alkyl-3-aryl-2,3-di-
hydro-1H-naphth[1,2-e][1,3]oxazines 12–16, only the data
for 12a were chosen to illustrate the H NMR spectra of
the prepared tautomeric compounds (see Exp. Sect.).
To study the double substituent dependence of logKB
and logKC, the following Hansch-type quantitative struc-
ture-properties relationship model equation [Equation (2)]
was set up
1
logKB/C = k + ρRPR + ρXσ+X
(2)
in the presence of triethylamine at ambient temperature did where KB = [B]/[A], KC = [C]/[A], PR is an alkyl substituent
not lead to the formation of the desired naphthoxazines. parameter and σ+X is the Hammett–Brown parameter of
This failure was followed by a more modern attempt to syn- the aryl substituent at position 3. In order to find the accu-
thesise our target compounds: microwave irradiation treat- rate dependence of logKB/C, three different alkyl substituent
ment[18] was tried, and in this way the preparation of 12– parameters were studied: Es (calculated from the hydrolysis
Eur. J. Org. Chem. 2006, 4664–4669
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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D. Tóth, I. Szatmári, F. Fülöp
FULL PAPER
Scheme 2.
or aminolysis of esters)[19] and two other steric parameters
Multiple linear regression analysis of Equation (2) was
that are independent of any kinetic data, namely ν, derived performed with the SPSS statistical software, and a value
from the van der Waals radii,[20,21] and Va, the volume of of 0.05 was chosen as the significance level.[23] Good corre-
the portion of the substituent that is within 0.3 nm of the lations were found for all three alkyl substituent parameters.
reaction centre.[22]
The linear regression analysis data for the series 12–15 and
18 are given in Table 2. The best correlations were observed
for the Meyer parameter (Va) of the alkyl substituents, and
this was used for the further examinations.
Table 2. Multiple linear regression analysis of logKB and logKC
values for 12–15 and 18.
k
ρR
ρX
r
PR
=
12–15,18Bh12–15,18A 0.605
–0.320 0.848
0.965
Va
12–15,18Ch12–15,18A 0.413
–0.464 0.978
0.994
0.938
0.992
0.946
0.994
PR = Es 12–15,18Bh12–15,18A 0.609
12–15,18Ch12–15,18A 0.524
0.948
1.442
0.809
0.881
PR = ν 12–15,18Bh12–15,18A 0.624
12–15,18Ch12–15,18A 0.516
–2.250 0.822
–3.356 0.886
The parameters given in Table 2 indicate that the tauto-
meric interconversion (e.g. logKB and logKC values) can be
described by using two substituent parameters (Va and σ+),
Scheme 3.
Table 1. Proportions [%] of the ring-closed tautomeric forms (B and C) in tautomeric equilibria for compounds 12–16 and 18 (CDCl3,
300 K).
18
H
0
12
13
14
15
16
R
Me
2.84
B
Et
Pr
iPr
5.74
B
tBu
7.16
B
Va
σ+
4.31
B
4.78
B
Compound
X
B
C
C
C
C
C
a
b
c
d
e
f
p-NO2 0.79
95.2
86.5
81.1
79.4
72.3
58.3
45.4
70.3
52.8
39.5
39.4
30.4
18.0
10.9
10.0
7.7
6.0
6.3
5.2
2.5
1.7
59.4
21.3
26.5
25.2
18.4
11.6
3.5
4.8
6.8
2.7
2.2
1.9
Ϸ0
Ϸ0
60.3
25.3
23.4
24.8
12.8
9.1
4.4
2.6
1.5
1.5
Ϸ0
Ϸ0
Ϸ0
8.9
3.5
1.2
1.8
Ϸ0
Ϸ0
Ϸ0
Ϸ0
2.5
0.7
1.1
Ϸ0
Ϸ0
Ϸ0
Ϸ0
–
–
Ϸ0
–
–
m-Cl
p-Br
p-Cl
H
0.40
0.15
0.11
0
–
–
Ϸ0
Ϸ0
–
Ϸ0
Ϸ0
–
p-Me
–0.31
g
p-OMe –0.78
3.9
4666
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Substituent Effects in Ring–Chain Tautomerism
FULL PAPER
which means that, when logKB or logKC is plotted against reactions of these aminoalkylnaphthol derivatives with sub-
the Meyer parameter (Va) and the Hammett–Brown param- stituted benzaldehydes lead to 1-alkyl-3-aryl-2,3-dihydro-
eter (σ+), a plane can be fitted to the data points (Figure 1, 1H-naphth[1,2-e][1,3]oxazines, which have proved to be
a and b).
three-component tautomeric mixtures in CDCl3 at 300 K,
involving C-3 epimeric naphthoxazines (B and C) and the
open tautomer (A). The influence of the alkyl substituent
at position 1 on the ring–chain tautomeric equilibria can
be described by the Meyer parameter, and that of the aryl
substituent at position 3 by the Hammett–Brown parameter
(σ+). Linear equations have been found that describe the
double substituent dependence of the equilibrium constants
for both the trans–chain and cis–chain equilibria. The
slopes of the Meyer parameter Va for the trans and cis
forms display a significant difference, which is explained in
terms of an alkyl-substituent-controlled stereoelectronic ef-
fect in the trans ring form. Theoretical examinations of this
alkyl substituent effect and its connection with the pre-
ferred geometry (relating to the relative configurations of
C-1 and C-3) are still in progress.
Experimental Section
Melting points were determined with a Kofler micro melting appa-
ratus and are uncorrected. Elemental analyses were performed with
a Perkin–Elmer 2400 CHNS elemental analyser. Merck Kiesegel 60
F254 plates were used for TLC. The 1H and 13C NMR spectra were
recorded in CDCl3 or in [D6]DMSO solution at 300 K with a
Bruker Avance DRX400 spectrometer at 400.13 (1H) and
100.61 MHz (13C). Chemical shifts are given in δ (ppm) relative to
TMS as internal standard. For the equilibria of tautomeric com-
pounds to be established, the samples were dissolved in CDCl3 and
the solutions were allowed to stand at ambient temperature for 1 d
before the 1H NMR spectra was run. The number of scans was
usually 64.
General Method for the Synthesis of 1-Aminoalkyl-2-naphthols 7–
11: The appropriate aliphatic aldehyde (62.5 mmol) and 25% meth-
anolic ammonia solution (20 mL) were added to a solution of 2-
naphthol (1; 3.6 g, 25 mmol) in absolute MeOH (30 mL). The mix-
ture was then stirred at 60 °C for 4–72 h. The MeOH was removed
under reduced pressure and intermediates 2–6 were suspended in
10% HCl (210 mL). The mixture was stirred and heated for 3 h at
60 °C, and the solvent was evaporated off. The crystalline hydro-
chloride of 7–11 that separated out from EtOAc (50 mL) was fil-
tered off, washed with CHCl3 and Et2O, and recrystallised from
Et2O/MeOH (4:1).
1-(1-Aminoethyl)-2-naphthol Hydrochloride (7): Condensation time:
4 h. White crystals, 5.02 g (95%), m.p. 210–212 °C. 1H NMR ([D6]-
DMSO): δ = 1.62 (d, J = 6.55 Hz, 3 H, CH3), 5.07–5.17 (m, 1 H,
CH3CH), 7.28–7.36 (m, 2 H, naphthyl), 7.52 (t, J = 7.55 Hz, 1 H,
naphthyl), 7.80–7.87 (m, 2 H, naphthyl), 7.98 (d, J = 8.56 Hz, 1 H,
naphthyl), 8.28 (s, 3 H, NH3), 10.84 (s, 1 H, OH) ppm. 13C NMR
([D6]DMSO): δ = 18.4, 44.4, 115.1, 118.6, 121.4, 122.8, 127.0,
Figure 1. (a) Plots of logKB for 12–15B and 18B vs. Meyer (Va)
and Hammett–Brown parameters (σ+). (b) Plots of logKC for 12–
15C and 18C vs. Meyer (Va) and Hammett–Brown parameters (σ+).
The slopes of the alkyl substituent parameters (ρR) for
the equilibria BhA and ChA exhibit a significant differ-
ence (–0.320 vs. –0.464). This difference can be explained 128.0, 128.7, 129.9, 131.4, 153.6 ppm. C12H14ClNO (223.70): calcd.
C 64.43, H 6.31, N 6.26; found C 64.59, H 6.33, N 6.27.
by an additional stabilisation effect caused by the alkyl sub-
stituents.
1-(1-Aminopropyl)-2-naphthol Hydrochloride (8): Condensation
time: 3 h. White crystals, 2.37 g (42%), m.p. 191–193 °C. 1H NMR
([D6]DMSO): δ = 0.79 (t, J = 7.55 Hz, 3 H, CH3), 2.07–2.19 (m, 2
H, CH2), 4.94 (m, 4.83–4.94, 1 H, CH), 7.33 (t, J = 7.55 Hz, 1 H,
naphthyl), 7.39 (d, J = 8.56 Hz, 1 H, naphthyl), 7.50 (t, J = 7.55 Hz,
Conclusions
New alkyl-substituted Betti base analogue aminonaph-
thols have been synthesised from aliphatic aldehydes. The 1 H, naphthyl), 7.83 (t, J = 8.06 Hz, 2 H, naphthyl), 8.02 (d, J =
Eur. J. Org. Chem. 2006, 4664–4669
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D. Tóth, I. Szatmári, F. Fülöp
FULL PAPER
8.56 Hz, 1 H, naphthyl), 8.32 (s, 3 H, NH3), 10.87 (s, 1 H, OH) 1-(1-Amino-2,2-dimethylpropyl)-2-naphthol Hydrochloride (11): 2-
ppm. 13C NMR ([D6]DMSO): δ = 10.5, 25.2, 113.6, 118.4, 121.7,
122.6, 126.8, 127.9, 128.7, 130.0, 132.6, 153.8 ppm. C13H16ClNO
(237.73): calcd. C 65.68, H 6.78, N 5.89; found C 65.45, H 6.77, N
5.89.
Naphthol: 0.56 g (3.88 mmol); condensation time: 72 h. White crys-
tals, 0.39 g (38%), m.p. 236–239 °C. 1H NMR ([D6]DMSO): δ =
1.04 [s, 9 H, (CH3)3C], 4.86 (d, J = 4.03 Hz, 1 H, CCHN), 7.318
(t, J = 7.55 Hz, 1 H, naphthyl), 7.39 (d, J = 9.07 Hz, 1 H, naphthyl),
7.49 (t, J = 7.55 Hz, 1 H, naphthyl), 7.82 (d, J = 9.06 Hz, 2 H,
naphthyl), 8.04 (d, J = 8.56 Hz, 1 H, naphthyl), 8.21 (s, 3 H, NH3),
10.80 (s, 1 H, OH) ppm. 13C NMR ([D6]DMSO): δ = 28.3, 37.9,
57.7, 113.2, 119.8, 123.4, 123.7, 127.5, 128.8, 129.5, 130.9, 134.3,
154.9 ppm. C15H20ClNO (265.2): calcd. C 67.72, H 7.54, N 5.27;
found C 67.49, H 7.53, N 5.28.
1-(1-Aminobutyl)-2-naphthol Hydrochloride (9): Condensation time:
72 h. White crystals, 1.71 g (27%), m.p. 202–204 °C. 1H NMR
([D6]DMSO): δ = 0.82 (t, J = 7.55 Hz, 3 H, CH3), 0.98–1.13 (m, 1
H, CH3CH2), 1.25–1.40 (m, 1 H, CH3CH2), 1.98–2.18 (m, 2 H,
CH2CH), 4.99 (s, 1 H, CH2CH), 7.19–7.52 (m, 3 H, naphthyl), 7.82
(t, J = 9.06 Hz, 2 H, naphthyl), 7.99 (d, J = 8.56 Hz, 1 H, naphthyl),
8.29 (s, 3 H, NH3), 10.82 (s, 1 H, OH) ppm. 13C NMR ([D6]-
DMSO): δ = 13.8, 18.9, 34.2, 113.9, 118.5, 121.9, 122.6, 126.9,
127.9, 128.7 129.9, 133.0, 153.9 ppm. C14H18ClNO (251.75): calcd.
C 66.79, H 7.21, N 5.56; found C 66.81, H 7.22, N 5.57.
General Method for the Synthesis of 1-Alkyl-3-aryl-2,3-dihydro-1H-
naphth[1,2-e][1,3]oxazines (12–16 and 18): The aminonaphthol
(0.39 mmol), one equivalent of X-substituted benzaldehyde,
1.1 equiv. of Et3N and absolute MeOH (7 mL) were mixed in a 10-
mL pressurized reaction vial, which was heated for 10 min at 80 °C
in a CEM microwave reactor. The crystalline product was filtered
off, and washed with MeOH. All of the new compounds 12–16 and
18 gave satisfactory elemental analysis data (C, H, N 0.3%). The
compounds were recrystallised from iPr2O. The physical and ana-
lytical data for compounds 12–16 and 18 are listed in Table 3.
1-(1-Amino-2-methylpropyl)-2-naphthol Hydrochloride (10): Con-
densation time: 72 h. White crystals, 5.03 g (80%), m.p. 229–
232 °C. 1H NMR ([D6]DMSO): δ = 0.65 (d, J = 6.04 Hz, 3 H,
CH3), 1.18 (d, J = 6.56 Hz, 3 H, CH3), 2.26 (s, 1 H, CH3CH), 4.63
(s, 1 H,CH3CHCH), 7.31 (t, J = 7.05 Hz, 2 H, naphthyl), 7.41 (s,
1 H, naphthyl), 7.82 (t, J = 9.06 Hz, 2 H, naphthyl), 8.01 (d, J =
8.05 Hz, 1 H, naphthyl) ppm. 13C NMR ([D6]DMSO): δ = 19.8,
30.4, 54.1, 114.2, 118.5, 121.8, 122.6, 126.8, 127.8, 128.7, 129.9,
132.9, 153.8 ppm. C14H18ClNO (251.75): calcd. C 66.79, H 7.21, N
5.56; found C 66.31, H 7.19, N 5.55.
As regards the similarities in the 1H NMR spectroscopic data, a
full characterisation is reported only for compound 12a. The 1H
NMR chemical shifts of the characteristic O–CHAr–N protons of
Table 3. Physical, analytical and NMR spectroscopic data for naphth[1,2-e][1,3]oxazines 12–16 and 18.
Compd. M.p.
Yield Formula
[%]
MW
Elemental analysis
δ [ppm]
[°C]
C found (calcd.) H found (calcd.) N found (calcd.) N=CH N–CH–O N–CH–O
(A)
(B)
(C)
12a
12b
12c
12d
12e
12f
12g
13a
13b
13c
13d
13e
13f
13g
14a
14b
14c
14d
14e
14f
14g
15a
15b
15c
15d
15e
15f
15g
16a
16e
16f
18b
18c
155–158 64
C19H16N2O3 320.35
71.04 (71.24)
73.02 (73.66)
64.65 (64.42)
73.46 (73.66)
83.05 (82.88)
83.55 (83.01)
78.56 (78.66)
72.01 (71.84)
73.90 (74.18)
65.32 (65.23)
74.42 (74.18)
83.19 (83.01)
82.89 (83.13)
79.13 (78.97)
72.16 (72.40)
74.82 (74.66)
65.98 (66.14)
74.80 (74.66)
83.53 (83.13)
83.74 (83.24)
78.96 (79.25)
72.68 (72.40)
74.39 (74.66)
65.76 (65.98)
74.93 (74.66)
83.11 (83.24)
83.41 (83.01)
79.17 (79.25)
73.16 (72.91)
83.41 (83.24)
83.19 (83.34)
72.95 (73.10)
63.66 (63.55)
5.04 (5.03)
5.21 (5.21)
4.53 (4.55)
5.22 (5.21)
6.23 (6.22)
6.63 (6.62)
6.28 (6.27)
5.42 (5.43)
5.62 (5.60)
4.91 (4.93)
5.62 (5.60)
6.62 (6.62)
6.88 (6.89)
6.64 (6.63)
5.80 (5.79)
5.98 (5.97)
5.27 (5.28)
5.97 (5.97)
6.99 (6.98)
7.29 (7.30)
6.96 (6.95)
5.93 (5.79)
6.09 (5.97)
5.07 (5.27)
5.83 (5.97)
7.38 (7.30)
6.42 (6.62)
6.79 (6.95)
6.12 (6.11)
7.31 (7.30)
7.61 (7.60)
4.76 (4.76)
4.14 (4.15)
8.75 (8.74)
4.52 (4.52)
3.94 (3.95)
4.51 (4.52)
5.11 (5.09)
4.85 (4.84)
4.58 (4.59)
8.39 (8.38)
4.34 (4.33)
3.80 (3.80)
4.34 (4.33)
4.83 (4.84)
4.63 (4.62)
4.41 (4.39)
8.04 (8.04)
4.14 (4.15)
3.65 (3.66)
4.14 (4.15)
4.62 (4.62)
4.40 (4.41)
4.21 (4.20)
8.01 (8.04)
4.21 (4.15)
3.50 (3.66)
4.10 (4.15)
4.59 (4.41)
4.71 (4.84)
4.32 (4.20)
7.73 (7.72)
4.42 (4.41)
4.22 (4.23)
4.75 (4.74)
4.12 (4.11)
8.62
8.44
8.42
8.44
8.46
8.42
8.41
8.56
8.38
8.37
8.37
8.42
8.37
8.32
8.52
8.38
8.36
8.38
8.41
8.35
8.32
8.51
8.34
8.34
8.35
8.36
8.33
8.29
8.51
8.39
8.29
8.43
8.46
6.15
6.03
6.01
6.03
6.06
6.04
6.06
6.09
5.97
5.95
5.99
6.02
5.98
5.96
6.08
5.99
5.98
5.99
6.03
6.00
5.99
6.19
6.10
6.08
6.10
–
5.73
5.60
5.58
5.60
5.53
5.59
5.62
5.72
5.79
5.57
5.60
5.62
–
135–138 59
176–178 51
178–180 60
119–121 56
145–148 54
131–132 67
121–124 71
145–149 33
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
19H16ClNO 309.80
19H16BrNO 354.25
19H16ClNO 309.80
19H17NO
20H19NO
275.35
289.38
20H19NO2 305.38
20H18N2O3 334.38
20H18ClNO 323.83
20H18BrNO 368.28
20H18ClNO 323.83
97–100
55
170–172 32
158–160 56
181–185 15
160–163 42
133–136 76
114–116 33
148–150 47
122–125 43
101–103 20
129–130 21
128–131 38
139–140 52
153–155 48
121–125 36
139–141 45
125–129 34
120–123 16
106–108 26
138–140 61
164–166 81
145–147 73
109–110 64
171–172 93
20H19NO
21H21NO
289.38
303.41
21H21NO2 319.41
21H20N2O3 348.40
21H20ClNO 337.84
21H20BrNO 382.29
21H20ClNO 337.40
–
5.68
5.61
5.58
5.60
–
–
–
–
5.51
5.51
5.52
–
–
–
–
–
–
–
21H21NO
22H23NO
303.40
317.42
22H23NO2 333.42
21H20N2O3 348.41
21H20ClNO 337.85
21H20BrNO 382.30
21H20ClNO 337.85
21H21NO
22H23NO
303.41
289.38
–
–
–
–
–
5.84
5.85
22H23NO2 333.43
22H22N2O3 362.42
22H23NO
23H25NO
317.42
331.45
18H14ClNO 295.76
18H14BrNO 340.21
–
4668
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 4664–4669

Substituent Effects in Ring–Chain Tautomerism
FULL PAPER
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hedron 1993, 49, 2115–2122.
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Chem. 2004, 2231–2238.
each tautomeric form for compounds 12–16 and 18 are given in
Table 3.
1-Methyl-3-p-nitrophenyl-2,3-dihydro-1H-naphth[1,2-e][1,3]oxazine
(12a): A tautomeric mixture of Schiff base 12aA (19.7%), cis-ring
form 12aC (10%) and trans-ring form 12aB (70.3%). Selected sig-
nals: 1H NMR (CDCl3, 300 K): δ = 4.72 (q, J = 7.05 Hz, 1 H,
CH3CHN, Schiff base), 5.06 (q, J = 5.04 Hz, 1 H, CH3CHN, cis),
5.58 (q, J = 7.05 Hz, 1 H, CH3CHNH, Schiff base), 5.73 (s, 1 H,
NCHO, cis), 6.15 (s, 1 H, NCHO, trans), 8.62 (s, 1 H, NCHO,
Schiff base) ppm. 13C NMR (CDCl3, 300 K): δ = 22.5 (trans), 22.8
(cis), 23.1 (Schiff base), 45.8 (trans), 47.9 (cis), 66.8 (Schiff base),
80.7 (trans), 85.5 (cis), and 158.8 (Schiff base) ppm. Assignments
of the aromatic region could not be made because of the low con-
centrations of B and C and the overlapping nature of the signals.
[11] M. Betti, Org. Synth. Coll. Vol. 1 1941, 381–383.
[12] I. Szatmári, F. Fülöp, Curr. Org. Synth. 2004, 1, 155–165.
[13] C. Duff, E. J. Bills, J. Chem. Soc. 1934, 1305–1308.
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2003, 59, 2877–2884.
[15] W. J. Bruke, R. J. Reynolds, J. Am. Chem. Soc. 1954, 76, 1291–
1293.
Acknowledgments
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2127.
[17] Y. Gong, K. Kato, H. Kimoto, Bull. Chem. Soc. Jpn. 2002, 75,
The authors thanks are due to the Hungarian Research Foundation
(OTKA grant D48669) for financial support.
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[23] SPSS Advanced Models 11.0, SPSS Inc., Chicago, IL.
Received: May 23, 2006
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Published Online: August 11, 2006
Eur. J. Org. Chem. 2006, 4664–4669
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4669