Substituent effects in the ring-chain tautomerism of 1,3-diaryl-2,3-dihydro-1H-naphth[1,2-e][1,3]oxazines

Article abstract of DOI:10.1016/S0040-4020(03)00331-4

Condensation of Betti base analogue amino naphthols with substituted benzaldehydes led to 1,3-diaryl-2,3-dihydro-1H-naphth[1,2-e][1,3]oxazines (3-9) which proved to be three-component (r¹-o-r²) tautomeric mixtures in CDCl₃

Full text of DOI:10.1016/S0040-4020(03)00331-4

Tetrahedron 59 (2003) 2877–2884
Substituent effects in the ring-chain tautomerism of 1,3-diaryl-2,3-
dihydro-1H-naphth[1,2-e][1,3]oxazines
*
´ ´ ´ ´ ´ ´ ´
¨
Istvan Szatmari, Tamas A. Martinek, Laszlo Lazar and Ferenc Fu¨lop
Institute of Pharmaceutical Chemistry, University of Szeged, P.O. Box 121, H-6720 Szeged, Hungary
Received 25 October 2002; revised 3 February 2003; accepted 28 February 2003
Abstract—Condensation of Betti base analogue amino naphthols with substituted benzaldehydes led to 1,3-diaryl-2,3-dihydro-1H-
naphth[1,2-e][1,3]oxazines (3–9) which proved to be three-component (r1–o–r2) tautomeric mixtures in CDCl3 at 300 K. The electronic
effects of the 3-aryl groups on the ratios of the ring-chain tautomeric forms at equilibrium could be described by the equation
log KX¼rs þþlog KX¼H. The value of the intercept was found to be strongly influenced by the steric arrangement of the 1,3-diaryl
substituents. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
The investigation of ring-chain tautomeric 2-aryltetrahydro-
1,3-oxazines bearing a substituted phenyl group at position
4 or 6 showed that the substituent on the 4/6-phenyl group
does not exert a significant influence on the parameters in
Eq. (1). However, the presence of the aryl group itself
stabilized the cyclic tautomer, more significantly at position
4 than at position 6.6 The influence of the electronic
character of a substituted phenyl group attached at a position
other than 2 was found to be more pronounced in the ring-
chain tautomeric equilibria of analogous 1,3,4-O,N,N
or-1,3-N,N ring systems. For 4-aryl-2,2-dialkyl-substituted
1,3,4-oxadiazines, the electron-withdrawing groups on the
4-phenyl ring increased the proportions of the ring-closed
tautomers.7 In the ring-chain equilibria of 1,2-diarylimi-
dazolidines, the 2-aryl substituent dependence of which was
observed to follow Eq. (1), electron-donating substituents
on the 1-phenyl ring produced higher values of r.8
The structures and reactivities of numerous five- and six-
membered, saturated, N-unsubstituted 1,3-X,N heterocycles
(X¼O, S, NR) can be characterized by the ring-chain
tautomeric equilibria of the 1,3-X,N heterocycles and the
corresponding Schiff bases.1 The oxazolidines and tetra-
hydro-1,3-oxazines are the saturated 1,3-X,N heterocycles
whose ring-chain tautomerism has been studied most
thoroughly.2 The tautomeric character of 1,3-O,N hetero-
cycles offers a great number of synthetic possibilities, e.g.
they can be used as intermediates in the synthesis of
N-substituted amino alcohols3 or nitrogen-bridged hetero-
cyclic systems4 and they serve as aldehyde sources in
carbon transfer reactions.5
For the tautomeric equilibria of oxazolidines and tetra-
hydro-1,3-oxazines bearing a substituted phenyl group at
position 2, a Hammett-type linear correlation was found
between the log KðK ¼ ½ringŠ=½chainŠÞ values of the equi-
libria and the electronic character (s þ) of the substituents X
on the 2-phenyl group (Eq. (1)), in both the liquid and the gas
phase. The value of r in Eq. (1) proved to be characteristic
of the ring system and dependent on temperature and the
nature of the solvent:1
Our present aim was to study the substituent effects on
the ring-chain tautomerism of naphthalene-condensed
1,3-oxazine derivatives bearing aryl groups at positions 2
and 4, with the aims of a refinement of the scope and
limitations of application of Eq. (1) among six-membered
1,3-O,N heterocycles, and a quantitative characterization of
the effects of both aryl substituents on the ring-chain
equilibria.
log KX ¼ rsþ þ log KX¼H
ð1Þ
In contrast with the great number of studies on the
dependence of the tautomeric equilibria of tetrahydro-1,3-
oxazines on the aromatic substituent at position 2, less is
known on the effects of such substituents at other positions.
2. Results and discussion
Betti’s classical procedure, a Mannich-type aminoalkylation
reaction of 2-naphthol,9 was applied to prepare the starting
materials for the synthesis of the present target compounds.
Condensation of 2-naphthol (1) and benzaldehyde or
substituted benzaldehydes in the presence of ammonia,
Keywords: amino alcohols; oxazines; substituent effects; tautomerism.
*
Corresponding author. Tel.: þ36-62-545564; fax: þ36-62-545705;
e-mail: fulop@pharma.szote.u-szeged.hu
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00331-4

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I. Szatmari et al. / Tetrahedron 59 (2003) 2877–2884
2878
Scheme 1.
and subsequent acidic hydrolysis, gave amino naphthols
3a–f in good yields (Scheme 1). The potential utility of the
Mannich-type phenolic bases makes the aminoalkylation
reaction of naphthol derivatives a subject of current
chemical interest.10 For example, the enantiomers of Betti
base 3d and its N-substituted derivatives were found to be
potent chiral catalysts in additions of dialkylzincs to
aldehydes,11 and this contributed to the enhanced attention
recently paid to the preparation of chiral N-substituted
amino naphthol derivatives.12
naphth[1,2-e][1,3]oxazines, and studied their ring-chain
1
tautomeric equilibria by means of 60 MHz H NMR.13a
They made the assumption that 1,3-diaryl groups prefer
pseudoequatorial and therefore a cis arrangement in the
major ring-closed tautomer. In contrast with this assump-
tion, and the cis position of the diaryl groups found for the
major ring-closed tautomers in both 2,4- and 2,6-diaryl-
perhydro-1,3-oxazines,6 the NOESY spectra of 6a unequi-
vocally showed that the major ring forms in all tautomeric
equilibria (4–9) contain the 1,3-diaryl substituents in the
trans position (B).
Condensations of amino naphthols 3a–f with equivalent
amounts of aromatic aldehydes resulted in naphthoxazine
model compounds 4–9 as crystalline products (Scheme 2).
The 1H NMR spectra of 4–9 revealed that, in CDCl3
solution at 300 K, the a–f members of each set of
compounds 4–9 participated in three-component ring-
chain tautomeric equilibria containing C-3 epimeric
naphthoxazines (B and C) besides the open tautomer (A).
For the 3-(p-dimethylaminophenyl)-substituted derivatives
(4g–9g), the tautomeric equilibria contained only one
ring-closed form (B).
To characterize the effects of the aryl substituent at position
1 on the tautomeric character of this ring system, 1-unsubsti-
tuted 3-aryl-2,3-dihydro-1H-naphth[1,2-e][1,3]oxazines
(11) were also prepared from the readily available14
1-aminomethyl-2-naphthol (10) and aromatic aldehydes.
In CDCl3 at 300 K, 11a–g proved to participate in ring-
chain tautomeric equilibria (Scheme 3).
The proportions of the chain (A) and diastereomeric ring
forms (B and C) of the tautomeric equilibria of 4–9 and 11
(KX) were determined by integration of the well-separated
O–CHAr-N (ring) and NvCHAr (chain) proton singlets or
The intermediate of the Betti reaction was earlier presumed
to have a ring-chain tautomeric character.13 By conden-
sation of the Betti base with aromatic aldehydes, Smith
and Cooper prepared 1-phenyl-3-aryl-2,3-dihydro-1H-
1
doublets (Table 3) in the H NMR spectra (Table 1).
In consequence of the very similar NMR spectroscopic
Scheme 2.

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I. Szatmari et al. / Tetrahedron 59 (2003) 2877–2884
2879
Scheme 3.
Table 1. Proportions (%) of the ring-closed tautomeric forms (B and C) in tautomeric equilibria for compounds 4–9 and 11 (CDCl3, 300 K)
Compound
X
4
5
6
7
(Y¼H),
0
8
9
11,
–
(Y¼mNO2),
(Y¼mBr),
(Y¼pCl),
(Y¼pMe),
(Y¼pOMe),
s þ
0.73
0.405
0.114
20.311
20.778
B
C
B
C
B
C
B
C
B
C
B
C
B
a
b
c
d
e
f
pNO2
mBr
pCl
0.79
0.405
0.114
0
20.311
20.778
21.7
89.0
85.2
80.1
73.6
63.6
47.7
13.3
8.3
8.1
7.5
7.9
6.3
3.7
,0
90.9
82.0
77.3
68.0
57.3
42.1
9.8
7.0
9.5
8.6
8.4
6.6
5.4
,0
93.6
82.0
76.6
70.1
60.0
43.5
10.2
3.6
9.4
8.4
7.8
6.1
4.6
,0
86.1
79.5
72.4
64.4
52.6
37.8
10.4
10.8
10.6
9.7
9.3
7.7
5.9
,0
89.0
76.7
71.7
63.6
50.9
36.6
9.0
7.6
11.3
9.3
8.7
6.8
4.7
,0
88.5
79.5
72.8
62.2
53.2
38.1
8.6
8.3
10.0
9.1
8.2
6.6
5.4
,0
95.2
88.0
79.4
72.3
58.3
45.4
10.3
H
pMe
pOMe
pNMe2
g
characteristics of 1,3-diaryl-2,3-dihydro-2H-naphth[1,2-e]-
[1,3]oxazines 4–9, determination of the relative configu-
rations of the major and minor ring-closed tautomers was
performed only for 6a. Data on 6a, 9g and 11f were chosen
to illustrate the 1H NMR spectra of the prepared tautomeric
compounds (see Experimental). 1,2-Diaryl substituents did
not change the sequence of the chemical shifts of the
characteristic O–CHAr-N and NvCHAr protons. The
configuration of the azomethine double bond was found to
be E, according to the NOE interaction observed between
the Nph–CHAr-N and NvCHAr protons.
parameter s þ of the substituent X on the 3-phenyl group
for 4–9 and 11 (Figure 1 and Table 2).
The linear regression analysis data in Table 2 show that, as
is customary among 2-aryl-1,3-O,N heterocycles,1,2 the
value of r is positive in each case, i.e. electron-withdrawing
substituents on the 3-phenyl ring favour the ring-closed
tautomer. While the value of r for 1-unsubstituted 3-aryl-
2,3-dihydro-2H-naphth[1,2-e][1,3]oxazines (11: 0.81) is the
same (within experimental error) as that for the parent
2-arylperhydro-1,3-oxazines (12: 0.76), the values of r
for 1,3-diaryl-2,3-dihydro-2H-naphth[1,2-e][1,3]oxazines
(4–9: 0.81–1.05) are somewhat higher. The cis or trans
arrangement of the 1,3-diaryl substituents in the ring forms
When Eq. (1) was applied to the log KX values, good linear
correlations were obtained vs the Hammett–Brown
Figure 1. Plots of log KX (in CDCl3) for 4B ( ), 4C (þ), 5B (B), 5C (A), 6B (V), 6C (S), 7B (O), 7C (K), 8B (X), 8C (W), 9B (£), 9C (2), 11B ( ) vs
Hammett–Brown parameter s þ
.

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2880
Table 2. Linear regression data on compounds 4–9, 11, 2-aryl-3,4,5,6-tetrahydro-2H-1,3-oxazines (12), 2-aryl-3,4-dihydro-2H-1,3-benzoxazines (13) and
2-aryl-4-phenyl-3,4,5,6-tetrahydro-2H-1,3-oxazines (14)
Equilibrium
No. of points
Slopea (r)
Intercepta
Correlation coefficient
cb
4AO4B
4AO4C
5AO5B
5AO5C
6AO6B
6AO6C
7AO7B
7AO7C
8AO8B
8AO8C
9AO9B
9AO9C
11AO11B
12AO12Bc
13AO13Bc
14AO14Bd
14AO14Cd
7
6
7
6
7
6
7
6
7
6
7
6
7
7
7
6
6
0.93 (4)
1.04 (2)
1.00 (8)
1.01 (9)
0.96 (5)
0.81 (8)
0.92 (6)
0.98 (9)
0.95 (6)
0.95 (5)
0.95 (6)
0.94 (8)
0.81 (4)
0.74 (6)
0.82 (4)
0.72 (2)
0.99 (4)
0.70 (8)
20.33 (2)
0.64 (15)
20.33 (10)
0.62 (10)
20.42 (10)
0.53 (13)
20.34 (10)
0.49 (12)
20.42 (6)
0.52 (11)
20.40 (9)
0.52 (8)
0.995
0.999
0.985
0.985
0.993
0.979
0.988
0.983
0.989
0.993
0.991
0.986
0.994
0.984
0.995
0.997
0.996
0.85
20.18
0.79
20.18
0.77
20.27
0.68
20.19
0.64
20.27
0.67
20.25
0.67
20.15 (5)
20.66 (3)
0.42 (5)
2
20.51
0.57
20.97
21.12 (8)
a
Standard deviations are given in parentheses.
Relative ring stability constant: see the text.
Data from Ref. 2b.
b
c
d
For compounds 14 (Ref. 6), tautomeric ratios were remeasured and the linear regression analysis was performed separately for the equilibria involving C-2
epimeric ring forms.
of 1,3-diaryl-2,3-dihydro-1H-naphth[1,2-e][1,3]oxazines
does not seem to influence the value of r; the plots for the
equilibria containing C-2 epimeric ring forms of 4–9 (B–A
and C–A) are practically parallel.
naphthoxazines having trans diaryl substituents (4–9 B:
cs¼0.63–0.85), while the negative cs values for the cis
isomers of these compounds (4–9 C: cs¼20.18–20.27)
indicates that the stabilizing effect of the naphthalene ring is
diminished by the unfavourable steric arrangement of the
aryl substituents.
To characterize the effects of the substituents and the
presence of an annelated ring on the stability of the ring
forms, a substitution effect parameter (cs) was calculated as
the difference in the intercepts for the given naphthoxazine
derivative (4–9, 11) and the parent 2-arylperhydro-1,3-
oxazine (12: log K0¼20.15): cs¼log KX¼H2log K0. This
kind of relative ring stability constant was introduced earlier
for the saturated 2-aryl-1,3-O,N heterocycles bearing
substituents at positions 4–6.1b,2b A positive value of cs
means a more stable ring form relative to the corresponding
parent 2-arylperhydro-1,3-O,N heterocycle.
3. Conclusions
Some new Betti base analogue amino naphthols were
obtained by the Mannich-type aminoalkylation of
2-naphthol. The reactions of substituted amino naphthols
and substituted benzaldehydes led to 1,3-diaryl-2,3-dihydro-
1H-naphth[1,2-e][1,3]oxazines which at 300 K proved to be
three-component tautomeric mixtures in CDCl3 containing
C-3 epimeric naphthoxazines (B and C) besides the open
tautomer (A). The influence of aryl substituents at position 3
on the ring-chain tautomeric equilibria could be described
by the Hammett equation. Study of the influence of aryl
substituents at position 1 is still in progress.
While an annelated benzene ring considerably decreased the
stability of the ring form of 2-arylperhydro-1,3-oxazine (13:
cs¼20.66),2b an annelated naphthalene ring caused a
dramatic increase in ring stability (11: cs¼0.67). This
increased stability of the ring form was observed for all

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2881
4. Experimental
129.7, 130.4, 132.4, 134.4, 141.4, 157.5. IR nmax 3345,
1623, 1237, 829 cm21
.
1H NMR spectra (400 MHz) were recorded at 300 K.
Chemical shifts are given in d (ppm) relative to TMS
(CDCl3) as internal standard. For the equilibria to be
established in tautomeric compounds,2 the samples were
dissolved in CDCl3 and the solutions were allowed to stand
at ambient temperature for 1 day before the 1H NMR spectra
were run. The number of scans was usually 32.
4.1.4. Compound 3d. Beige crystals. Yield: 13.94 g (56%),
1
mp 116–1188C (lit.,9 mp 124–1258C). H NMR (CDCl3)
d 6.11 (s, 1H, NCH(Ar)NPh), 7.17 (d, 1H, J¼9.0 Hz,
Nph-H3), 7.20–7.24 (m, 2H, Nph-H6, Ar), 7.29 (d, 2H,
J¼7.5 Hz, Ar), 7.33 (t, 1H, J¼7.5 Hz, Nph-H7), 7.44
(d, 2H, J¼7.5 Hz, Ar), 7.67–7.71 (m, 3H, Nph-H4,
Nph-H5, Nph-H8), 13C NMR (CDCl3) d 56.6, 115.9,
121.0, 121.7, 122.9, 127.1, 127.9, 128.4, 129.1, 129.3,
129.5, 130.8, 132.8, 143.2, 157.8. IR nmax 3296, 1622, 1238,
4.1. General method for the synthesis of 1-(a-amino-Y-
substituted-benzyl)-2-naphthols (3a–f)
770 cm21
.
To a solution of 2-naphthol (1, 14.42 g, 0.1 mol) in absolute
MeOH (50 mL) was added the appropriate aromatic
aldehyde (0.2 mol; for liquid aldehydes, a freshly distilled
sample was used) and 25% methanolic ammonia solution
(20 mL). The mixture was left to stand at ambient
temperature for 2 days, during which a crystalline product
(2a–f) separated out. The crystals were filtered off and
washed with cool MeOH (2£20 mL), dried and suspended
in 20% HCl (200 mL). The mixture was stirred and refluxed
for 3 h, and the crystalline hydrochloride of 3a–f that
separated out was filtered off and washed with EtOAc
(2£25 mL). The hydrochloride was suspended in H2O
(30 mL), and the mixture was treated with conc. NH4OH
(30 mL) and extracted with EtOAc (3£50 mL). After drying
(Na2SO4) and evaporation, crystalline 3a–f was obtained,
which was recrystallized from iPr2O.
4.1.5. Compound 3e. Pale yellow crystals. Yield: 18.67 g
(71%), mp 103–1048C (lit.,16 mp 109.58C). 1H NMR
(CDCl3) d 2.27 (s, 3H, CH3), 6.08 (s, 1H, NCH(Ar)NPh),
7.09 (d, 2H, J¼8.0 Hz, Ar), 7.14 (d, 1H, J¼9.0 Hz,
Nph-H3), 7.21 (t, 1H, J¼9.0 Hz, Nph-H6), 7.31–7.35 (m,
3H, Nph-H7, Ar), 7.69–7.73 (m, 3H, Nph-H4, Nph-H8,
Nph-H5), 13C NMR (CDCl3) d 21.6, 56.1, 115.9, 121.0,
121.7, 122.9, 127.0, 127.6, 129.2, 129.2, 130.0, 130.2,
132.6, 138.2, 140.0, 157.6. IR nmax 3347, 1468, 1235,
814 cm21
.
4.1.6. Compound 3f. Beige crystals. Yield: 12.55 g (45%),
1
mp 117–1188C. H NMR (CDCl3) d 3.71 (s, 3H, OCH3),
6.06 (s, 1H, NCH(Ar)NPh), 6.80 (d, 2H, J¼8.5 Hz, Ar),
7.15 (d, 1H, J¼9.0 Hz, Nph-H3), 7.22 (t, 1H, J¼7.5 Hz,
Nph-H6), 7.32 (t, 1H, J¼7.5 Hz, Nph-H7), 7.35 (d, 2H,
J¼8.5 Hz, Ar), 7.65–7.72 (m, 3H, Nph-H4, Nph-H5,
Nph-H8), 13C NMR (CDCl3) d 55.6, 55.7, 114.5, 115.7,
120.8, 121.5, 122.8, 126.8, 128.8, 128.9, 129.2, 130.0,
132.3, 135.0, 157.1, 159.5. Anal. Calcd for C18H17NO2: C,
77.4; H, 6.13; N, 5.01. Found: C, 77.32; H, 6.23; N, 5.11. IR
4.1.1. Compound 3a. Beige crystals. Yield: 16.76 g (57%),
mp 111–1138C. 1H NMR (CDCl3) d 6.27 (s, 1H,
NCH(Ar)NPh), 7.16 (d, 1H, J¼9.0 Hz, Nph-H3), 7.27 (t,
1H, J¼7.0 Hz, Nph-H6), 7.40 (t, 1H, J¼7.0 Hz, Nph-H7),
7.40 (t, 1H, J¼8.0 Hz, Ar), 7.70 (d, 1H, J¼9.0 Hz,
Nph-H8), 7.71–7.76 (m, 2H, Nph-H4, Nph-H5), 7.77 (d,
1H, J¼8.0 Hz, Ar), 8.10 (d, 1H, J¼8.0 Hz, Ar), 8.38 (s, 1H,
Ar), 13C NMR (CDCl3) d 55.2, 114.5, 121.3, 121.5, 122.9,
123.6, 123.8, 127.9, 129.0, 129.9, 131.0, 131.2, 132.1,
134.5, 144.8, 148.9, 157.2. Anal. Calcd for C17H14N2O3: C,
69.38; H, 4.79; N, 9.52. Found: C, 69.51; H, 4.75; N, 9.64.
nmax 3287, 1510, 1249, 824 cm21
.
4.2. 1-Aminomethyl-2-naphthol (10)
Compound 10 was prepared from 2-naphthol (11.44 g,
0.08 mol) and hexamethylenetetramine (11.20 g, 0.08 mol)
according to Ref. 14a.
IR nmax 3361, 1521, 1347, 730 cm21
.
4.1.2. Compound 3b. White crystals. Yield: 15.42 g (47%),
mp 118–1208C. 1H NMR (CDCl3) d 6.10 (s, 1H,
NCH(Ar)NPh), 7.14–7.17 (m, 2H, Nph-H3, Ar), 7.25 (t,
1H, J¼8.5 Hz, Nph-H6), 7.34–7.38 (m, 3H, Nph-H7, Ar),
7.62 (s, 1H, Ar), 7.66 (d, 1H, J¼8.5 Hz, Nph-H8), 7.71 (d,
1H, J¼8.5 Hz, Nph-H4), 7.73 (d, 1H, J¼8.0 Hz, Nph-H5),
13C NMR (CDCl3) d 55.9, 115.1, 121.1, 121.5, 123.2, 123.5,
126.7, 126.8, 127.2, 129.5, 130.6, 131.1, 131.1, 131.7,
132.5, 145.3, 157.7. Anal. Calcd for C17H14BrNO: C, 62.21;
H, 4.30; N, 4.27. Found: C, 62.39; H, 4.17; N, 4.35. IR nmax
4.2.1. Compound 10. Yellow crystals. Yield: 8.52 g (62%),
mp 131–1338C (lit.,17 mp 135–1388C). 1H NMR (DMSO)
d 4.30 (s, 2H, NCH2NPh), 7.07 (d, 1H, J¼9.0 Hz, Nph-H3),
7.24 (t, 1H, J¼7.5 Hz, Nph-H6), 7.37 (t, 1H, J¼7.5 Hz,
Nph-H7), 7.68 (d, 1H, J¼9.0 Hz, Nph-H4), 7.75 (d, 1H, J¼
8.5 Hz, Nph-H5), 7.87 (d, 1H, J¼8.5 Hz, Nph-H8), 13C
NMR (DMSO) d 45.0, 115.6, 119.5, 122.9, 123.0, 127.1,
129.0, 129.2, 129.5, 134.0, 156.1. IR nmax 1268, 1238, 813,
741 cm21
.
3353, 1436, 1284, 810 cm21
.
4.3. General method for the synthesis of 3-aryl- and
1,3-diaryl-2,3-dihydro-1H-naphth[1,2-e][1,3]oxazines
(4–9 and 11)
4.1.3. Compound 3c. Light beige crystals. Yield: 15.03 g
(53%), mp 109–1118C (lit.,15 mp 1208C). 1H NMR (CDCl3)
d 6.11 (s, 1H, NCH(Ar)NPh), 7.15 (d, 1H, J¼9.0 Hz, Nph-
H3), 7.23–7.28 (m, 3H, Nph-H6, Ar), 7.34 (t, 1H, J¼
8.0 Hz, Nph-H7), 7.39 (d, 2H, J¼8.5 Hz, Ar), 7.66 (d, 1H,
J¼8.5 Hz, Nph-H8), 7.71 (d, 1H, J¼9.0 Hz, Nph-H4), 7.73
(d, 1H, J¼8.0 Hz, Nph-H5), 13C NMR (CDCl3) d 55.8,
115.4, 121.0, 121.4, 123.0, 127.1, 129.2, 129.3, 129.3,
To a solution of the appropriate amino naphthol (3a–f or 10,
1 mmol) in absolute MeOH (20 mL), an equivalent amount
of aromatic aldehyde was added (for liquid aldehydes, a
freshly distilled sample was used), and the mixture was
left to stand at ambient temperature for 24 h. The crystal-
line products were filtered off, washed with Et2O and

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I. Szatmari et al. / Tetrahedron 59 (2003) 2877–2884
2882
Table 3. Physical and analytical data on naphth[1,2-e][1,3]oxazines 4–9 and 11
Compound
Mp (8C)
Yield (%)
Formula
M.W.
C% Found (calculated)
H% Found (calculated)
N% Found (calculated)
4a
4b
4c
4d
4e
207–208a
173–175b
167–168b
146–147a
161–163a
126–128b
201–202b
193–195b
123–125b
163–164b
132–134a
143–145a
108–110a
161–164a
181–182b
147–148a
155–156b,c
154–156a
163–165a
163–164b
177–178b
176–178a,d
153–155a
171–173b,e
146–148a,f
155–157a,g
143–146a,h
225–227a,i
181–183b
116–117b
137–138b
131–133b
148–149b,j
128–132b
197–198b
157–159b
177–178b
180–182a
156–159a
177–178a
182–184a,k
177–179a
161–162b
154–156b
155–157a
109–111a
125–126a
146–147a
152–154a
78
81
69
83
75
86
90
72
67
80
75
82
85
70
81
75
78
85
73
86
88
74
81
86
90
77
81
78
75
92
83
89
77
85
76
84
77
84
93
88
76
79
72
83
78
85
75
80
77
C24H17N3O5
C24H17BrN2O3
C24H17ClN2O3
C24H18N2O3
C25H20N2O3
C25H20N2O4
C26H23N3O3
C24H17BrN2O3
C24H17Br2NO
C24H17BrClNO
C24H18BrNO
C25H20BrNO
C25H20BrNO2
C26H23BrN2O
C24H17ClN2O3
C24H17BrClNO
C24H17Cl2NO
C24H18ClNO
C25H20ClNO
C25H20ClNO2
C26H23ClN2O
C24H18N2O3
C24H18BrNO
C24H18ClNO
C24H19NO
C25H21NO
C25H21NO2
C26H24N2O
C25H20N2O3
C25H20BrNO
C25H20ClNO
C25H21NO
C26H23NO
C26H23NO2
C27H26N2O
C25H20N2O4
C25H20BrNO2
C25H20ClNO2
C25H21NO2
427.41
461.31
416.86
382.41
396.44
412.44
425.48
461.31
495.21
450.76
416.31
430.34
446.34
459.38
416.86
450.76
406.31
371.86
385.89
401.89
414.93
382.41
416.31
371.86
337.42
351.44
367.44
380.48
396.44
430.34
385.89
351.44
365.47
381.47
394.51
412.44
446.34
401.89
367.44
381.47
397.47
410.51
306.32
340.21
295.76
261.32
275.35
291.34
304.39
67.38 (67.44)
62.51 (62.49)
69.12 (69.15)
75.43 (75.38)
75.61 (75.74)
72.68 (72.80)
73.37 (73.40)
62.58 (62.49)
58.30 (58.21)
63.88 (63.95)
69.17 (69.24)
69.85 (69.78)
67.17 (67.27)
67.88 (67.98)
69.09 (69.15)
64.02 (63.95)
70.93 (70.95)
77.48 (77.52)
77.78 (77.81)
74.69 (74.72)
75.31 (75.26)
75.42 (75.38)
69.33 (69.24)
77.45 (77.52)
85.39 (85.43)
85.51 (85.44)
81.84 (81.72)
82.19 (82.07)
75.69 (75.74)
69.71 (69.78)
77.92 (77.81)
85.39 (85.44)
85.52 (85.45)
82.02 (81.86)
82.11 (82.20)
72.75 (72.80)
67.36 (67.27)
74.89 (74.72)
81.68 (81.72)
81.71 (81.86)
78.66 (78.57)
79.11 (79.00)
70.65 (70.58)
63.44 (63.55)
72.97 (73.10)
82.81 (82.73)
82.72 (82.88)
78.48 (78.33)
78.88 (78.92)
4.02 (4.01)
3.70 (3.71)
4.12 (4.11)
4.75 (4.74)
5.09 (5.08)
4.89 (4.89)
5.46 (5.45)
3.70 (3.71)
6.45 (6.46)
3.81 (3.80)
4.37 (4.36)
4.67 (4.68)
4.51 (4.52)
5.06 (5.05)
4.11 (4.11)
3.81 (3.80)
4.23 (4.22)
4.89 (4.88)
5.21 (5.22)
5.01 (5.02)
5.58 (5.59)
4.74 (4.74)
4.36 (4.36)
4.87 (4.88)
5.67 (5.68)
6.03 (6.02)
5.75 (5.76)
6.37 (6.36)
5.09 (5.08)
5.68 (4.68)
5.21 (5.22)
6.02 (6.02)
6.33 (6.34)
6.07 (6.08)
6.65 (6.64)
4.88 (4.89)
4.52 (4.52)
5.01 (5.02)
5.76 (5.76)
6.07 (6.08)
5.84 (5.83)
6.39 (6.38)
4.62 (4.61)
4.15 (4.15)
4.76 (4.77)
5.78 (5.79)
6.23 (6.22)
5.88 (5.88)
6.63 (6.62)
9.81 (9.83)
6.06 (6.07)
6.72 (6.72)
7.33 (7.33)
7.08 (7.07)
6.78 (6.79)
9.88 (9.88)
6.08 (6.07)
2.84 (2.83)
3.12 (3.11)
3.35 (3.36)
3.24 (3.25)
3.13 (3.14)
3.11 (6.10)
6.73 (6.72)
3.11 (3.11)
3.46 (3.45)
3.78 (3.77)
3.64 (3.63)
3.48 (3.49)
3.76 (6.75)
7.34 (7.33)
3.35 (3.36)
3.76 (3.77)
4.15 (4.15)
3.98 (3.99)
3.82 (3.81)
7.35 (7.36)
7.07 (7.07)
3.26 (3.25)
3.64 (3.63)
3.98 (3.99)
3.83 (3.83)
3.68 (3.67)
7.08 (7.10)
6.78 (6.79)
3.13 (3.14)
3.50 (3.49)
3.82 (3.81)
3.66 (3.67)
3.52 (3.52)
6.83 (6.82)
9.16 (9.15)
4.13 (4.12)
4.74 (4.74)
5.36 (5.36)
5.08 (5.09)
4.82 (4.81)
9.21 (9.20)
4f
4g
5a
5b
5c
5d
5e
5f
5g
6a
6b
6c
6d
6e
6f
6g
7a
7b
7c
7d
7e
7f
7g
8a
8b
8c
8d
8e
8f
8g
9a
9b
9c
9d
9e
C26H23NO2
C26H23NO3
9f
9g
11a
11b
11c
11d
11e
11f
11g
C27H26N2O2
C18H14N2O3
C18H14BrNO
C18H14ClNO
C18H15NO
C19H17NO
C19H17NO2
C20H20N2O
a
Recrystallized from iPr2O.
Recrystallized from iPr2O-EtOAc.
Lit.,15 mp 1508C.
b
c
d
e
f
Lit.,13a mp 174–1758C.
Lit.,13a mp 1738C.
Lit.,13a mp 144–1458C.
Lit.,18 mp 1698C.
g
h
i
Lit.,18 mp 958C.
Lit.,13a mp 192–1938C.
Lit.,16 mp 1498C.
j
k
Lit.,16 mp 1818C.
recrystallized. All of the recrystallized new compounds
(4a–g, 5a–g, 6a, 6b, 6d–g, 7b, 8a–d, 8f, 8g, 9a–e, 9g,
11a–g) gave satisfactory data on elemental analysis (C, H,
N^0.3%). The physical and analytical data for compounds
4–9 and 11 are listed in Table 3.
prepared compounds (6a, 9g and 11f). In a consequence of
the very low relative concentrations and the extensive signal
overlaps in the aromatic region, a full NMR characterization
of the minor ring closed tautomers C was not possible. The
1H NMR chemical shifts of the characteristic O–CHAr-N
and NvCHAr protons of each tautomer and the charac-
teristic IR wavenumbers for compounds 4–9 and 11 are
given in Table 4.
1
With regard to the similarities in the H NMR data, full
spectra are described only for three representatives of the

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I. Szatmari et al. / Tetrahedron 59 (2003) 2877–2884
2883
Table 4. NMR and IR spectroscopical data on naphth[1,2-e][1,3]oxazines 4–9 and 11
Compound
dNvCH (A)
dN–CH–O (B)
dN–CH–O (C)
n )
max. (cm21
4a
4b
4c
4d
4e
8.80(s)
8.61(s)
8.64(s)
8.68(s)
8.62(s)
8.55(s)
8.43(s)
8.32(s)
8.55(s)
8.57(s)
8.61(s)
8.55(s)
8.50(s)
8.39(s)
8.73(s)
8.56(s)
8.57(s)
8.60(s)
8.51(s)
8.50(s)
8.39(s)
8.73(s)
8.55(s)
8.62(s)
8.63(s)
8.56(s)
8.53(s)
8.43(s)
8.65(s)
8.55(s)
8.53(s)
8.54(s)
8.52(s)
8.51(s)
8.39(s)
8.69(s)
8.50(s)
8.54(s)
8.55(s)
8.51(s)
8.50(s)
8.40(s)
8.58(s)
8.43(s)
8.46(s)
8.50(s)
8.47(s)
8.39(s)
8.29(s)
5.75(s)
5.68(s)
5.69(s)
5.72(s)
5.70(s)
5.66(s)
5.66(s)
5.69(d)
5.62(s)
5.63(s)
5.65(d)
5.62(s)
5.60(s)
5.60(s)
5.68(s)
5.61(s)
5.60(s)
5.64(s)
5.57(s)
5.60(s)
5.59(s)
5.73(s)
5.63(s)
5.65(s)
5.71(s)
5.65(s)
5.66(s)
5.65(d)
5.72(s)
5.67(s)
5.64(s)
5.68(s)
5.66(s)
5.66(s)
5.63(s)
5.72(s)
5.63(s)
5.64(s)
5.68(s)
5.65(s)
5.65(s)
5.62(s)
5.93(d)
5.84(s)
5.85(s)
5.89(s)
5.87(s)
5.83(s)
5.81(s)
6.04(s)
5.96(d)
5.99(s)
6.03(s)
6.02(s)
5.98(s)
–
5.91(d)
5.87(d)
5.88(d)
5.91(d)
5.90(d)
5.89(s)
–
5.91(d)
5.89(d)
5.90(d)
5.92(d)
5.88(d)
5.91(s)
–
5.94(s)
5.91(d)
5.93(d)
5.97(s)
5.94(d)
5.94(d)
–
5.88(s)
5.89(d)
5.88(d)
5.89(s)
5.90(s)
5.90(s)
–
5.87(s)
5.86(d)
5.87(d)
5.89(d)
5.88(s)
5.89(s)
–
3854, 1598, 1343, 1233
3332, 1527, 1352, 1238
3332, 1527, 1345, 1234
3332, 1525, 1349, 1233
1525, 1468, 1347, 1232
3338, 1526, 1348, 1232
1601, 1344, 1181, 741
1518, 1339, 1232, 753
3322, 1234, 989, 774
33316, 1233, 986, 957
3317, 1467, 1233, 704
3321, 1238, 986, 931
1515, 1251, 1234, 985
3308, 1365, 1233, 955
3320, 1519, 1339, 814
3307, 1233, 990, 825
3320, 1233, 984, 745
3320, 1236, 825, 747
3314, 1233, 985, 745
1515, 1231, 930, 749
3850, 1597, 1367, 1182
3307, 1518, 1340, 1231
3308, 1229, 924, 750
3320, 1235, 984, 750
1236, 932, 743, 698
3320, 1237, 834, 749
3320, 1512, 1169, 983
1602, 1455, 1366, 1181
3311, 1521, 1341, 1233
3317, 1232, 989, 789
3850, 1231, 987, 807
1233, 985, 808, 746
3302, 1233, 987, 746
1450, 1248, 1229, 903
1604, 1365, 1182, 812
3292, 1510, 1342, 1229
3313, 1508, 1247, 1233
3316, 1511, 1247, 1233
3850, 1505, 1454, 942
3320, 1510, 1170, 747
1607, 1511, 1253, 831
1605, 1509, 1251, 811
3314, 1510, 1338, 1224
3308, 1245, 1231, 811
3253, 1225, 951, 818
3248, 1227, 740, 695
1225, 996, 910, 811
4f
4g
5a
5b
5c
5d
5e
5f
5g
6a
6b
6c
6d
6e
6f
6g
7a
7b
7c
7d
7e
7f
7g
8a
8b
8c
8d
8e
8f
8g
9a
9b
9c
9d
9e
9f
9g
11a
11b
11c
11d
11e
11f
11g
–
–
–
–
–
–
–
3266, 1248, 1227, 813
1601, 1368, 1181, 815
1
4.4. H NMR spectroscopic data on 6a, 9g and 11f in
CDCl3
p-N(CH3)2), 3.73 (s, 3H, p-OCH3), 6.31 (s, 1H, NCH
(Ar)NPh), 6.68 (d, 2H, J¼8.5 Hz, Ar), 6.78 (d, 2H,
J¼8.5 Hz, Ar), 7.22 (d, 1H, J¼9.0 Hz, Nph-H3), 7.23–
7.39 (m, 3H, Ar, Nph-H6), 7.37 (t, 1H, J¼7.5 Hz, Nph-H7),
7.63 (d, 2H, J¼8.5 Hz, Ar), 7.72 (d, 1H, J¼9.0 Hz, Nph-
H4), 7.74 (d, 1H, J¼8.0 Hz, Nph-H5), 7.83 (d, 1H, J¼
8.5 Hz, Nph-H8), 8.40 (s, 1H, CHvN), 13C NMR (CDCl3)
d 40.6, 55.7, 74.3, 112.1, 114.6, 120.8, 117.5, 122.2, 122.8,
123.0, 127.6, 129.2, 129.3, 129.4, 129.9, 131.1, 132.5,
134.5, 153.5, 156.3, 159.6, 161.7.
The protons of the open form (A) are numbered according to
the corresponding protons of the naphth[1,2-e][1,3]oxazine
ring form (B, C) (d in ppm, in brackets the multiplicity,
couplings in Hz and assignment, respectively).
1
4.4.1. Compound 6aB. H NMR (CDCl3) d 5.63 (s, 1H,
NCH(Ar)NPh), 5.68 (s, 1H, NCH(Ar)O), 7.24 (d, 1H, J¼
9.0 Hz, H5), 7.27–7.32 (m, 4H, Ar), 7.32–7.35 (m, 3H, H7,
H8, H9), 7.78 (d, 2H, J¼9.0 Hz, Ar), 7.79–7.83 (m, 2H, H6,
H10), 13C NMR (CDCl3) d 53.6, 81.6, 114.6, 119.4, 123.1,
123.8, 124.1, 127.3, 127.8, 129.0, 129.3, 129.5, 130.1,
131.1, 131.2, 131.4, 141.2, 146.1, 148.4, 152.5.
1
4.4.3. Compound 11fA. H NMR (CDCl3) d 3.86 (s, 3H,
OCH3), 5.36 (s, 2H, H1), 6.96 (d, 2H, J¼7.0 Hz, Ar), 7.15
(d, 1H, J¼8.5 Hz, Nph-H3), 7.31 (t, 1H, J¼8.0 Hz, Nph-
H6), 7.48 (t, 1H, J¼8.0 Hz, Nph-H7), 7.68 (d, 1H, J¼
8.5 Hz, Nph-H4), 7.71 (d, 2H, J¼7.0 Hz, Ar), 7.77 (d, 1H,
J¼8.5 Hz, Nph-H5), 7.79 (d, 1H, J¼9.0 Hz, Nph-H8), 8.39
1
4.4.2. Compound 9gA. H NMR (CDCl3) d 3.03 (s, 6H,

´
I. Szatmari et al. / Tetrahedron 59 (2003) 2877–2884
2884
(s, 1H, CHvN), 13C NMR (CDCl3) d 55.9, 60.3, 112.9,
114.7, 120.5, 121.4, 121.5, 123.1, 126.9, 128.0, 128.9,
129.1, 130.8, 132.2, 155.6, 162.3, 163.0.
2002, 526–527. (e) Amat, M.; Canto, M.; Llor, N.; Ponzo, V.;
Perez, M.; Bosch, J. Angew. Chem. Int. Ed. 2002, 41,
335–338.
5. (a) Singh, K.; Singh, J.; Singh, H. Tetrahedron 1989, 45,
3967–3974. (b) Singh, K.; Deb, P. K. Tetrahedron Lett. 2000,
41, 4977–4980. (c) Singh, K.; Deb, P. K.; Venugopalan, P.
Tetrahedron 2001, 57, 7939–7949. (d) Singh, K.; Deb, P. K.;
Behal, S. Heterocycles 2001, 55, 1937–1942.
1
4.4.4. Compound 11fB. H NMR (CDCl3) d 3.82 (s, 3H,
OCH3), 4.37 (d, 1H, J¼17.0 Hz, H1), 4.53 (d, 1H, J¼
17.0 Hz, H1), 5.83 (s, 1H, NCH(Ar)NPh), 6.94 (d, 2H,
J¼7.0 Hz, Ar), 7.14 (d, 1H, J¼9.0 Hz, H5), 7.35 (t, 1H, J¼
8.0 Hz, H8), 7.47 (t, 1H, J¼8.0 Hz, H9), 7.57 (d, 2H,
J¼8.0 Hz, Ar), 7.64 (d, 1H, J¼9.0 Hz, H10), 7.67 (d, 1H,
J¼9.0 Hz, H6), 7.77 (d, 1H, J¼8.5 Hz, H7), 13C NMR
(CDCl3) d 42.7, 55.7, 87.3, 114.0, 114.3, 119.9, 121.6,
121.7, 123.9, 126.9, 128.0, 129.3, 129.4, 131.6, 131.9,
152.7, 160.2.
´ ´ ´
6. Fu¨lop, F.; Lazar, L.; Bernath, G.; Sillanpaa, R.; Pihlaja, K.
¨
¨¨
Tetrahedron 1993, 49, 2115–2122.
7. Milman, B. L.; Potekhin, A. A. Khim. Geterotsikl. Soedin.
1973, 902–907.
´ ´
8. Goblyos, A.; Lazar, L.; Evanics, F.; Fulop, F. Heterocycles
¨ ¨
¨
¨
1999, 51, 2431–2438.
9. Betti, M. Org. Synth. Coll. 1941, 1, 381–383.
10. (a) Grumbach, H.-J.; Arend, M.; Risch, N. Synthesis 1996,
883–887. (b) Katritzky, A. R.; Abdel-Fattah, A. A. A.;
Tymoshenko, D. O.; Belyakov, S. A.; Ghiviriga, I.; Steel, P. J.
J. Org. Chem. 1999, 64, 6071–6075. (c) Saidi, M. R.; Azizi,
N.; Naimi-Jamal, M. R. Tetrahedron Lett. 2001, 42,
8111–8113. (d) Hwang, D.-R.; Uang, B.-J. Org. Lett. 2002,
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Acknowledgements
The author’s thanks are due to the Hungarian Research
Foundation (OTKA No. T034901 and T030452) for
financial support.
11. (a) Cardellicchio, C.; Ciccarella, G.; Naso, F.; Perna, F.;
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