Transformation reactions of the Betti base analog aminonaphthols

Article abstract of DOI:10.1002/jhet.5570410310

By means of simple or domino ring-closure reactions of 1-(α- aminobenzyl)-2-naphthol (Betti base: 1), 1-aminomethyl-2-naphthol (2) and 2-(α-aminobenzyl)-1-naphthol (reverse Betti base: 3) with phosgene, ethyl benzimidate, 2-carboxybenzaldehyde, levulinic

Full text of DOI:10.1002/jhet.5570410310

May-Jun 2004
367
Transformation reactions of the Betti base analog aminonaphthols
István Szatmári, Anasztázia Hetényi, László Lázár and Ferenc Fülöp*
Institute of Pharmaceutical Chemistry, University of Szeged, H-6701, Szeged, POB 121, Hungary
Received January 16, 2004
By means of simple or domino ring-closure reactions of 1-(α-aminobenzyl)-2-naphthol (Betti base: 1), 1-
aminomethyl-2-naphthol (2) and 2-(α-aminobenzyl)-1-naphthol (reverse Betti base: 3) with phosgene, ethyl
benzimidate, 2-carboxybenzaldehyde, levulinic acid, salicylaldehyde/formalin or salicyl-
aldehyde/acetaldehyde, naphth[1,2-e][1,3]oxazine and naphth[2,1-e][1,3]oxazine derivatives were prepared.
All of the nitrogen-bridged polycyclic derivatives of 1 and 3 containing a number of centers of asymmetry
were formed with nearly complete diastereoselectivity. Considerable differences were observed in the ring-
closing abilities of the unsubstituted and phenyl-substituted aminonaphthols 1 and 2 and of the regioisomeric
compounds 1 and 3.
J. Heterocyclic Chem., 41, 367 (2004).
Introduction.
Although Betti's classical procedure for the preparation of
1 - (α-aminobenzyl)-2-naphthol (1: Betti base) was published
more than a century ago [1], the possibilities of the applica-
tion of this versatile synthon in the ring-closure reactions to
give naphthalene-condensed heterocyclic derivatives have
not been thoroughly investigated. The few publications that
have appeared on this topic focus on the reactions of 1 with
aldehydes. Condensation products of 1 and substituted ben-
zaldehydes proved to participate in ring-chain tautomeric
equilibria involving two diastereomeric naphthoxazines and
an open imine form, the ratios of which were strongly influ-
enced by the electronic effects of the substituents on the aro-
matic aldehyde [2-5]. The ring-chain tautomeric character
of these condensation products of 1 and substituted ben-
zaldehydes was utilized by Desai et al. to prepare 4-thiazoli-
done derivatives with antibacterial activity by the addition
of mercaptoacetic acid to the imine forms [6].
Since Naso et al. first reported the application of the
enantiomers of 1 in asymmetric transformations [7,8], a
number of transformation reactions of the enantiopure
Betti base, including ring closures to afford heterocyclic
intermediates have been published. The N-butyl derivative
of (S)-1 was prepared by reductive alkylation via the corre-
sponding ring-chain tautomeric naphthoxazine intermedi-
ate [8]. Nonracemic 1-[α-(1-azacycloalkyl)benzyl]-2-
naphthols were synthetized by Hu et al. via nitrogen-
bridged tetracyclic naphthoxazine derivatives obtained by
reductive cyclization of the enantiomers of 1 with dials in
the presence of NaBH3CN [9, 10].
known procedures [11-13]. Phenyl-substituted regioiso-
meric compounds 1 and 3 were synthesized by Mannich
aminoalkylation of the corresponding 1- or 2-naphthol
with benzaldehyde in the presence of ammonia [11,12].
Acidic hydrolysis of the naphthoxazine intermediates
leads to aminonaphthol 1 or 3, respectively. In conse-
quence of the facile decomposition of the free base, com-
pound 3 was used in further transformations as the
hydrochloride. Aminonaphthol 2 was obtained by the reac-
tion of 2-naphthol and hexamethylenetetramine in acetic
acid, followed by acidic hydrolysis of the intermediate
condensation product [12].
In the first stage of the transformation reactions of com-
pounds 1-3 to yield heterocyclic derivatives, a one-carbon
segment with sp2 configuration was inserted between the
hydroxy and amino groups.
When aminonaphthols 1-3 were treated with phosgene
in the presence of Et3N, the corresponding naphthalene-
condensed 1,3-oxazin-2-ones 4, 5 and 18 were formed in
each case (Schemes 1 and 4). Similar ring closures of the
analogous 2-aminomethylphenol were recently investi-
gated [14]. The reactions of 1-3 with ethyl benzimidate in
boiling EtOH gave the desired 1,3-oxazine derivative 6
only in the case of the unsubstituted aminophenol 2; with
the phenyl-substituted regioisomers 1 and 3, only decom-
position of the starting aminonaphthols was observed
(Scheme 1). Whereas the preparation of dihydro-1,3-
oxazine derivatives by the ring closure of aminoalcohols
with imidates is well known in the literature [15], com-
pound 2 was the first aminophenol for which this transfor-
mation was successfully accomplished.
Our present aim was to extend the synthetic applicability
of aminonaphthol 1 for the preparation of new heterocyclic
derivatives. To investigate the effects of the phenyl sub-
stituent and the chemical behavior of the regioisomeric
structures 1 and 3, these transformations were also per-
formed by starting from aminonaphthols 2 and 3.
Results and Discussion.
The starting aminonaphthols 1-3 were prepared by

368
I. Szatmári, A. Hetényi, L. Lázár and F. Fülöp
Vol. 41
For the preparation of 2-phenylimino-substituted 1,3-
capable of reacting with the amino group of the naphthox-
azine formed, the tautomeric equilibrium can be shifted
completely toward the ring-closed form by this second
ring closure, resulting in nitrogen-bridged heterocycles.
This principle was successfully applied earlier in the
domino ring-closure reactions of N-unsubstituted aminoal-
cohols or aminophenols with γ- or δ-oxoacids [17, 18].
The reactions of aminonaphthols 1-3 with 2-carboxy-
benzaldehyde under mild conditions (r.t.) gave the corre-
sponding isoindole-condensed naphthoxazines 11, 12 and
19 (Schemes 2 and 4). NMR measurements indicated that
pentacycles 11 and 19 were formed with practically com-
plete stereoselectivity, with the relative configurations
depicted in the Schemes; no minor diastereomers were
detected even in the crude products. Similarly high
diastereoselectivity is often observed in the analogous ring
oxazines, aminonaphthols 1-3 were reacted with phenyl
isothiocyanate. In the cases of 1-substituted 2-naphthols 1
and 2, the corresponding thiourea derivatives 7 and 8 were
formed in good yields. Thioureas 7 and 8 were converted
to the corresponding S-methyl isothiourea derivatives with
methyl iodide, and subsequent treatment with methanolic
KOH gave the corresponding 2-arylimino-substituted 1,3-
oxazines 9 and 10 via methyl mercaptan elimination
(Scheme 1). This type of ring closure is well known
among N-thiocarbamoyl-substituted aminoalcohols [16],
but as far as we are aware compounds 9 and 10 are the first
2-arylimino-substituted 1,3-oxazine derivatives formed
from N-thiocarbamoyl-substituted aminophenols.
Endocyclic-exocyclic tautomerism of the C=N bond was
not investigated.
Scheme 1
As mentioned above, the ring closures of N- u n s u b s t i-
tuted aminonaphthols 1-3 with oxo compounds (i. e. the
insertion of a one-carbon segment with sp3 configuration)
result in naphthalene-condensed 1,3-oxazines with a ring-
chain tautomeric character [2-5]. If the oxo compound
used in this reaction contains another functional group
closures of aminoalcohols and is explained as a result of
the kinetic control governing the second ring closures of
the cyclic tautomeric intermediates [19,20].
The analogous reactions of 1-3 with levulinic acid could
not be accomplished under mild conditions, the corre-
sponding pyrrolo-naphthoxazine 13 being produced only
Scheme 2

May-Jun 2004
Transformation reactions of the Betti base analog aminonaphthols
369
in the case of the unsubstituted aminonaphthol 2 (Scheme
2). Elevated temperature again caused the decomposition
of aminonaphthols 1 and 3 instead of cyclization.
17 as crystalline products, whereas the similar transforma-
tions of 15 failed. The difference in cyclization behavior
between 14 and 15 can be explained on the basis of the bet-
ter crystallization ability of the pentacyclic products 16
and 17 formed from 14, which causes a continuous shift of
the tautomeric equilibrium toward the predominant cyclic
tautomer 14B [21,22]. In contrast, Stankevich et al. related
the successful formation of oxazolobenzoxazines in analo-
gous reactions to the increased ratio of the cyclic form in
the tautomeric equilibria of the 2-(o-hydroxyphenyl)-oxa-
zolidine intermediates [23]. According to the NMR data,
pentacycles 16 and 17 were formed with high stereoselec-
tivity (d e ~100%), with the relative configurations
depicted in Scheme 3.
A complete shift of the ring-chain tautomeric equilib-
rium of 1,3-O,N-heterocycles can be achieved by means of
another transformation. If the oxo compound contains
another functional group (e. g. OH) capable of coupling
with the amino group of the ring-closed tautomers via an
appropriate agent, this reaction can be a second ring clo-
sure with another aldehyde. This type of transformation
was exploited earlier in the preparation of 1,3-O,N-hetero-
cycle-condensed 1,3-oxazines by subsequent cyclization
of the aminoalcohols with salicylaldehyde and another
aldehyde [21-23].
When aminonaphthols 1 and 2 were reacted with salicy-
laldehyde, crystalline condensation products 14 and 15
were formed. NMR measurements revealed that the tau-
tomeric equilibrium of 15 in CDCl3 at 300 K was practi-
cally totally shifted toward the open form 15A, while the
phenyl-substituted compound 14 was found to participate
under similar conditions in a three-component tautomeric
equilibrium involving the trans (14B: 56.7%) and the cis
(14C: 8.5%) cyclic diastereomers besides the Schiff base
(14A: 34.8%). These data are in accordance with earlier
observations on the predominance of the open form in the
tautomeric equilibria of the condensation products of 1,2-
and 1,3-aminoalcohols and salicylaldehyde, which is
explained by the stabilization caused by the strong
intramolecular hydrogen bonds [21,22].
Structures.
In the NMR spectra of the products 4-19, proton and car-
bon chemical shifts can be assigned by using COSY,
HSQC and HMBC experiments. The relative configura-
tions of the diastereomers for 11, 14, 16, 17 and 19 were
deduced from the NOESY spectra, in which the cross-peak
for the protons of the chiral C atoms proved their trans
arrangement for all these compounds.
The structures were also confirmed by molecular model-
ing. The conformational protocol comprised a stochastic
search via the Merck Molecular Force Field (MMFF94),
and a subsequent minimization of the resulting low-energy
conformations at the ab initio level, using the HF/3-21G*
basis set for 11, 14, 16, 17 and 19. The resulting structures
Scheme 3
proved to be rigid, since no minor conformation was found
within the 6 kcal/mol energy window. The final conforma-
tions for 11, 16, 17 and 19 are shown in Figure 1.
Treatment of compound 14 with 40% formalin or
ethanolic acetaldehyde solution resulted in the formation
of phenyl-substituted naphthoxazino-benzoxazines 16 and

370
I. Szatmári, A. Hetényi, L. Lázár and F. Fülöp
Scheme 4
Vol. 41
1
on a Bruker Avance DRX400 spectrometer at 400.13 ( H) and
13
100.61 ( C) MHz, with the deuterium signal of the solvent as the
lock and TMS as internal standard. Compounds 1 and 2 were pre-
pared by following literature methods [18]. For the equilibria to be
established in the tautomeric compounds samples were dissolved
in CDCl and the solutions were allowed to stand at ambient tem-
3
perature for 1 day before the VT-NMR spectra were run at 300 K.
1-Phenyl-2,3-dihydro-1H-naphth[1,2-e][1,3]oxazin-3-one (4).
Aminonaphthol 1 (0.30 g, 1.20 mmol) was dissolved in abs.
11
19
toluene (10 mL), and Et N (0.24 g, 2.41 mmol) and phosgene
3
(0.63 mL; 20% in toluene, 1.20 mmol) were added. The mixture
was stirred at r.t. for 3 h and then H O (40 mL) and EtOAc (40
2
mL) were added. The organic layer was separated, dried
(Na SO ) and evaporated. The oily residue crystallized on treat-
ment with Et O (20 mL). The crystalline product was collected
2
4
2
by filtration and recrystallized from iPr O (30 mL). Yield: 0.18 g
1
2
(54%), mp: 210-211 °C; H-NMR (deuteriochloroform): δ 6.08
(1H, d, J = 2.0 Hz, 1-H), 5.96 (1H, bs, NH), 7.24-7.36 (6H, m,
5H, Ph), 7.38-7.44 (2H, m, 8-H, 9-H), 7.54-7.59 (1H, m, 6-H),
13
7.81-7.89 (2H, m, 7-H, 10-H); C-NMR (deuteriochloroform): δ
56.6 (1-C), 113.2 (10b-C), 117.4 (5-C), 123.0 (10-C), 125.4
(4'-C), 127.2 (2'-C, 6'-C), 127.4 (6a-C), 127.7 (8-C), 129.0 (9-C),
129.1 (6-C), 129.7 (3'-C, 5'-C), 130.9 (7-C), 131.2 (10a-C), 141.9
(1'-C), 148.4 (4a-C), 150.4 (3-C).
Anal. Calcd. for C H NO (275.31): C, 78.53; H, 4.76; N,
18 13 2
5.09. Found: C, 78.75; H, 4.75; N, 5.09.
16
17
Figure 1. Final predominant minimum energy molecular structures for 11,
16, 17 and 19, obtained by using ab initio HF/3-21G* calculations.
2,3-Dihydro-1H-naphth[1,2-e][1,3]oxazin-3-one (5).
Aminonaphthol 2 (0.30 g, 1.73 mmol) was dissolved in abs.
toluene (10 mL) and Et N (0.35 g, 3.47 mmol) and phosgene
Our results prove that the Betti base 1 and its amino-
naphthol analogs 2 and 3 are useful starting materials for
the preparation of naphthalene-condensed tri-, tetra- or pen-
tacyclic 1,3-oxazine derivatives. The ring closures of 1 and
3 to furnish tetra- and pentacycles were found to be charac-
terized by virtually complete diastereoselectivity. Probably
as a result of the different chemical stabilities of 1-3, con-
siderable differences wereobserved in the cyclization abili-
ties of the unsubstituted and phenyl-substituted amino-
naphthols 1 and 2 and of the regioisomeric compounds 1
and 3.
3
(20% in toluene, 0.90 mL; 1.73 mmol) were added. The mixture
was stirred at r.t. for 4 h and then H O (40 mL) and EtOAc (40
2
mL) were added. The organic layer was separated, dried
(Na SO ) and evaporated. The oily residue crystallized on treat-
ment with n-hexane (20 mL). The crystalline product was col-
2
4
lected by filtration and recrystallized from n-hexane-iPr O (4:1,
1
2
50 mL). Yield: 0.11 g (32%), mp: 166-168 °C; H-NMR (deu-
teriochloroform): δ 4.94 (2H, s, 2 x 1-H), 5.72 (1H, bs, NH),
7.22 (1H, d, J = 9.1 Hz, 5-H), 7.46-7.60 (3H, m, 8-H, 9-H, 10-
H), 7.81 (1H, d, J = 8.8 Hz, 6-H), 7.87 (1H, d, J = 8.1 Hz, 7-H);
13
C-NMR (deuteriochloroform): δ 41.5 (1-C), 108.7 (10b-C),
EXPERIMENTAL
117.3 (5-C), 121.8 (10-C), 125.6 (8-C), 127.8 (9-C), 129.1 (7-
C), 129.3 (6a-C), 130.1 (6-C), 133.2 (10a-C), 147.4 (4a-C),
150.6 (3-C).
Melting points were determined on a Kofler micro melting
apparatus and are uncorrected. Elemental analyses were per-
formed with a Perkin-Elmer 2400 CHNS elemental analyzer.
Anal. Calcd. for C H NO (199.21): C, 72.35; H, 4.55; N,
12
7.03. Found: C, 72.19; H, 4.54; N, 7.01.
9
2
Merck Kieselgel 60F plates were used for TLC: the eluent was
254
3-Phenyl-1H-naphth[1,2-e][1,3]oxazine (6).
1
13
toluene-methanol 4:1. The H- and C-NMR spectra were
recorded in CDCl solution in 5 mm tubes, at room temperature,
A mixture of aminonaphthol 2 (0.40 g, 2.31 mmol) and ethyl
3

May-Jun 2004
Transformation reactions of the Betti base analog aminonaphthols
371
benzimidate (0.31 g, 2.31 mmol) was refluxed in EtOH (20
mL)
treatment with Et O (20 mL). The crystalline product was col-
was extracted with CHCl (3 x 20 mL). After drying (Na SO )
3
and evaporation of the solvent, the crystalline oxazine was
2
4
for 8 h. After evaporation, the residue crystallized on
obtained on treatment with n-hexane (20 mL); it was collected by
filtration and recrystallized from n-hexane-iPr O (5:1, 36 mL).
2
lected by filtration and recrystallized from iPr O (30 mL).
1
2
Yield: 0.15 g (55%), mp: 156-158 °C; H-NMR (deuteriochloro-
2
Yield: 0.22 g (37%), mp: 161-162 °C; H-NMR (deuteriochlo-
1
form): δ 6.27 (1H, bs, 1-H), 7.01 (1H, t, J = 7.3 Hz, 4'-H), 7.16-
7.47 (12H, m, 5-H, 8-H, 9-H, 2'-H, 3'-H, 5'-H, 6'-H, N-Ph), 7.67-
roform): δ 5.13 (2H, s, 2 x 1-H), 7.21 (1H, d, J = 8.8 Hz, 5-H),
7.39-7.51 (4H, m, 8-H, 3'-H, 4'-H, 5'-H), 7.55 (1H, t, J = 7.8
Hz, 9-H), 7.67 (1H, d, J = 8.8 Hz, 6-H), 7.75 (1H, d, J = 8.8 Hz,
7-H), 7.82 (1H, d, J = 8.1 Hz, 8-H), 8.10-8.15 (2H, m, 2'-H, 6'-
13
7.71 (1H, m, 6-H), 7.79-7.84 (2H, m, 7-H, 10-H); C-NMR
(deuteriochloroform): δ 56.0 (1-C), 114.7 (10b-C), 116.4 (5-C),
119.4 (5-C), 122.7 (10-C), 123.1 (8-C), 123.3 (6-C), 124.5 (7-C),
125.1 (2''-C, 6''-C), 127.4 (4''-C), 127.6 (3''-C, 5''-C), 128.8 (4'-
C), 129.0 (2'-C, 6'-C), 129.2 (3'-C, 5'-C), 129.6 (6a-C), 131.3
(10a-C), 139.7 (1'-C), 143.8 (N-C(Ph)), 144.7 (4a-C), 147.0
(C=N).
13
H); C-NMR (deuteriochloroform): δ 43.5 (1-C), 110.9 (10b-
C), 116.7 (5-C), 122.3 (10-C), 125.1 (8-C), 127.2 (9-C), 127.5
(3'-C, 5'-C), 128.5 (2'-C, 6'-C), 128.8 (6-C), 128.9 (7-C), 130.1
(6a-C), 131.3 (4'-C), 132.3 (10a-C), 146.6 (1'-C), 152.6 (4a-C),
154.4 (3-C).
Anal. Calcd. for C H N O (350.42): C, 82.26; H, 5.18; N,
Anal. Calcd. for C H NO (259.31): C, 83.38; H, 5.05; N,
18 13
5.40. Found: C, 83.61; H, 5.04; N, 5.41.
24 18
7.99. Found: C, 82.48; H, 5.17; N, 7.97.
2
1
N -[α-(2-Hydroxy-1-naphthyl)benzyl]-N -phenylthiourea (7).
2
3-Phenylimino-2,3-dihydro-1H-naphth[1,2-e][1,3]oxazine (10).
To a solution of thiourea 8 (0.40 g, 1.30 mmol) in MeOH (10
mL), MeI (0.50 mL, 8.03 mmol) was added and the solution was
stirred for 2 h. After evaporation of the solvent, the residue was
stirred in 3 M methanolic KOH (20 mL) for 4 h. Following evap-
A mixture of aminonaphthol 1 (0.50 g, 2.00 mmol) and phenyl
isothiocyanate (0.35 mL, 2.93 mmol) in abs. toluene (20 mL) was
stirred for 1 day. The crystals that separated out were collected by
filtration and washed with toluene (2 x 20 mL) and used in the
next step without further purification. Yield: 0.35 g (45%), mp:
oration, H O (30 mL) was added to the residue and the mixture
2
was extracted with CHCl (3 x 20 mL). After drying (Na SO )
1
177-179 °C; H-NMR (deuteriochloroform): δ 6.11 (1H, bs, CH-
NH), 7.07-7.47 (10H, m, 3-H, 2'-H, 3'-H, 5'-H, 6'-H, NH-Ph),
7.54 (1H, t, J = 7.3 Hz, 4'-H), 7.60-7.69 (1H, m, 6-H), 7.69-7.94
3
and evaporation of the solvent, the crystalline oxazine was
2
4
obtained on treatment with n-hexane (20 mL); it was collected by
filtration and recrystallized from n-hexane-iPr O (3:1, 40 mL).
13
(4H, m, 4-H, 5-H, 7-H, 8-H); C-NMR (deuteriochloroform): δ
2
Yield: 0.20 g (56%), mp: 158-160 °C; H-NMR (deuteriochloro-
1
55.8 (CH-NH), 109.7 (3-C), 118.0 (8-C), 118.9 (1-C), 123.9 (4''-
C), 125.3 (2''-C, 6''-C), 126.3 (3''-C, 5''-C), 126.7 (6-C), 128.0 (7-
C), 128.7 (2'-C, 6'-C), 129.2 (4-C), 130.0 (4'-C), 130.3 (3'-C, 5'-
C), 132.3 (4a-C), 134.7 (5-C), 135.8 (8a-C), 136.5 (1''-C), 152.0
(1'-C), 153.4 (2-C), 192.3 (NH-C=S-NH).
form): δ 4.97 (2H, s, 2 x 1H), 5.12 (1H, bs, NH), 7.05 (1H, t, J =
7.3 Hz, 4'-H), 7.10 (1H, d, J = 9.3 Hz, 5-H), 7.33 (2H, t, J = 7.8
Hz, 2'-H, 6'-H), 7.41-7.50 (3H, m, 8-H, 3'-H, 5'-H), 7.55 (1H, t, J
= 7.8 Hz, 9-H), 7.66 (1H, d, J = 8.3 Hz, 6-H), 7.73 (1H, d, 9.1 Hz,
13
7-H), 7.82 (1H, d, J = 8.3 Hz, 10-H); C-NMR (deuteriochloro-
Anal. Calcd. for C H N OS (384.50): C, 74.97; H, 5.24; N,
24 20
7.29. Found: C, 74.76; H, 5.22; N, 7.31.
2
form): δ 42.2 (1-C), 112.3 (10b-C), 116.4 (5-C), 119.7 (10-C),
122.3 (8-C), 122.8 (9-C), 125.0 (4'-C), 127.2 (6-C), 128.8 (2'-C,
6'-C), 129.2 (3'-C, 5'-C), 130.2 (6a-C), 130.9 (10a-C), 139.0 (7-
C), 145.7 (1'-C), 146.9 (4a-C), 185.2 (3-C)
1
N -(2-Hydroxy-1-naphthyl)methyl-N -phenylthiourea (8)
2
A mixture of aminonaphthol 2 (0.50 g, 2.89 mmol) and phenyl
isothiocyanate (0.40 mL, 3.34 mmol) in abs. toluene (20 mL) was
stirred for 1 day. The crystals that separated out were filtered off
and washed with toluene (2 x 20 mL) and used in the next step
without further purification. Yield: 0.42 g (47%), mp: 152-155
Anal. Calcd. for C H N O (274.33): C, 78.81; H, 5.14; N,
18 14
10.21. Found: C, 78.70; H, 5.14; N, 10.16.
2
(7aR*, 14S*)-14-Phenyl-7aH, 12H, 14H-naphth[1', 2':5, 6][1, 3]-
oxazino[2,3-a]isoindol-12-one (11).
1
°C; H-NMR (deuteriochloroform): δ 4.80 (1H, bs, NH), 5.27
(2H, d, J = 4.3 Hz, CH -NH), 6.88 (1H, bs, NH), 7.12 (2H, d, J =
To a solution of aminonaphthol 1 (0.50 g, 2.00 mmol) in abs.
toluene (20 mL), 2-carboxybenzaldehyde (0.30 g, 2.01 mmol)
was added. The mixture was stirred at r.t. for 5 days, during
which a white solid separated out. The solvent was evaporated
off and the residue crystallized on treatment with Et O (20 mL).
2
The crystalline product was collected by filtration and recrystal-
2
7.8 Hz, 2'-H, 6'-H), 7.19 (1H, d, J = 8.8 Hz, 3-H), 7.23-7.40 (4H,
m, 6-H, 7-H, 3'-H, 5'-H), 7.44 (1H, t, J = 8.1 Hz, 4'-H), 7.67 (1H,
d, J = 5.3 Hz, 4-H), 7.69 (1H, d, J = 6.0 Hz, 5-H), 7.75 (1H, d, J =
13
8.1 Hz, 8-H); C-NMR (deuteriochloroform): δ 40.8 (CH -NH),
2
115.0 (1-C), 120.5 (3-C), 121.2 (8-C), 123.4 (6-C), 125.4 (2'-C,
6'-C), 127.3 (4'-C), 128.0 (7-C), 129.3 (5-C), 129.4 (4a-C), 130.5
(4-C), 130.6 (3'-C, 5'-C), 133.3 (8a-C), 135.6 (1'-C), 153.7 (2-C),
180.3 (NH-C=S-NH).
lized from iPr O (30 mL). Yield: 0.45 g (62%), mp: 221-222 °C;
1
2
H-NMR (deuteriochloroform): δ 6.09 (1H, s, 14-H), 6.95 (1H, s,
7a-H), 7.19 (1H, d, J = 9.1 Hz, 6-H), 7.22-7.33 (5H, m, Ph), 7.42-
7.47 (2H, m, 2-H, 3-H), 7.48-7.61 (3H, m, 8-H, 9-H, 10-H), 7.70
(1H, d, J = 7.3 Hz, 5-H), 7.73-7.79 (2H, m, 4-H, 1-H), 7.87 (1H,
Anal. Calcd. for C H N OS (308.41): C, 70.10; H, 5.23; N,
18 16
9.08. Found: C, 69.92; H, 5.23; N, 9.06.
2
13
d, J = 7.1 Hz, 11-H); C-NMR (deuteriochloroform): δ 50.7 (14-
1-Phenyl-3-phenylimino-2, 3-dihydro-1H-naphth[1, 2- e] [ 1 , 3 ]-
oxazine (9).
C), 79.2 (7a-C), 111.9 (14a-C), 118.7 (6-C), 123.8 (1-C), 124.0
(3-C), 124.3 (4'-C), 124.4 (2-C), 127.2 (10-C), 128.3 (11-C),
128.6 (5-C), 128.7 (2'-C, 6'-C), 129.1 (3'-C, 5'-C), 129.9 (4a-C),
130.2 (8-C), 130.6 (4-C), 131.5 (14b-C), 132.5 (9-C), 132.6 (11a-
C), 140.7 (7b-C), 141.9 (1'-C), 151.4 (6a-C), 165.4 (12-C).
Anal. Calcd. for C H NO (363.42): C, 82.63; H, 4.72; N,
To a solution of thiourea 7 (0.30 g, 0.78 mmol) in MeOH (10
mL), MeI (0.40 mL, 6.43 mmol) was added and the solution was
stirred for 2 h. After evaporation of the solvent, the residue was
stirred in 3 M methanolic KOH (20 mL) for 4 h. Following evap-
25 17
2
3.85. Found: C, 82.45; H, 4.72; N, 3.84.
oration, H O (30 mL) was added to the residue and the mixture
2

372
I. Szatmári, A. Hetényi, L. Lázár and F. Fülöp
Vol. 41
7 aH, 1 2H,14H-Naphth[1', 2':5, 6][1, 3]oxazino[2, 3-a]isoindol-12-
one (12).
collected by filtration and recrystallized from iPr O-EtOAc (6:1,
1
2
70 mL). Yield: 1.45 g (67%), mp: 175-177 °C; H-NMR (deuteri-
ochloroform): δ 5.30 (2H, s, CH -N=CH), 6.79 (1H, t, J = 7.6 Hz,
2
To a solution of aminonaphthol 2 (0.30 g, 1.73 mmol) in abs.
toluene (20 mL), 2-carboxybenzaldehyde (0.26 g, 1.73 mmol)
was added. The mixture was stirred at r.t. for 1 day, during which
white solid separated out. The solvent was evaporated off and the
residue crystallized on treatment with Et O (20 mL). The crys-
2
talline product was collected by filtration and recrystallized twice
3'-H), 6.90 (1H, d, J = 8.1 Hz, 3-H), 7.00 (1H, t, J = 8.1 Hz, 4'-H),
7.08 (1H, d, J = 8.6 Hz, 5'-H), 7.10 (1H, d, J = 8.1 Hz, 4-H), 7.36
(1H, t, J = 7.8 Hz, 6-H), 7.52 (1H, t, J =8.6 Hz, 7-H), 7.72 (1H, d,
J = 8.8 Hz, 6'-H), 7.79 (1H, d, J = 7.8 Hz, 5-H), 7.99 (1H, d, J = 8.6
13
Hz, 8-H), 8.37 (1H, s, N=CH); C-NMR (deuteriochloroform): δ
51.8 (CH -N=CH), 114.9 (1-C), 115.5 (1'-C), 117.5 (5'-C), 118.0
2
from iPr O-EtOAc (3:1, 40 mL). Yield: 0.18 g (36%), mp: 176-
2
1
178 °C; H-NMR (deuteriochloroform): δ 4.90 (1H, d, J = 16.9
(3-C), 118.4 (3'-C), 122.9 (8-C), 123.7 (6-C), 127.5 (7-C), 128.9
(4-C), 130.2 (5-C), 131.8 (2'-C), 132.7 (4'-C), 133.2 (4a-C), 135.6
(8a-C), 151.9 (2-C), 163.0 (6'-C), 166.4 (N=CH ) .
Hz, 14-H), 5.52 (1H, d, J = 16.9 Hz, 14-H), 6.08 (1H, s, 7a-H),
7.17 (1H, d, J = 9.1 Hz, 6-H), 7.45 (1H, t, J = 7.3 Hz, 10-H), 7.54-
7.86 (7H, m, 1-H, 2-H, 3-H, 4-H, 5-H, 8-H, 9-H), 7.94 (1H, d, J =
Anal. Calcd. for C H NO (277.33): C, 77.96; H, 5.45; N,
18 15
5.05. Found: C, 78.14; H, 5.45; N, 5.06%
2
13
7.3 Hz, 11-H); C-NMR (deuteriochloroform): δ 38.0 (14-C),
82.2 (7a-C), 111.1 (14a-C), 119.0 (6-C), 121.6 (1-C), 124.1 (3-
C), 124.2 (2-C), 124.8 (10-C), 127.5 (11-C), 128.9 (5-C), 129.3
(8-C), 130.8 (4-C), 132.5 (9-C), 135.8 (4a-C), 140.7 (14b-C),
143.2 (11a-C), 149.6 (7b-C), 149.9 (6a-C), 168.6 (12-C).
Anal. Calcd. for C H NO (287.32): C, 79.43; H, 4.56; N,
19 13 2
4.87. Found: C, 79.58; H, 4.55; N, 4.87%
(7aR* , 1 5S*)-15-Phenyl-7aH, 13H, 15H-naphth[1', 2':5, 6][1, 3]-
oxazino[3,2-c][1,3]benzoxazine (16).
To a solution of 14 (0.30 g, 0.85 mmol) in EtOH (20 mL), 40%
aqueous formaldehyde (2.5 mL) was added. The mixture was
stirred at r.t. for 30 min., during which white crystals separated
out. The crystalline product was collected by filtration, and
7a-Methyl-8,9-dihydro-7aH,10H, 1 2H-naphth[1,2-e]pyrrolo[2,1-b]-
[1,3]oxazin-10-one (1 3).
recrystallized from iPr O-EtOAc (3:1, 40 mL). Yield: 0.29 g
1
2
(93%), mp: 214-216 °C; H-NMR (deuteriochloroform): δ 4.91
(1H, d, J = 6.8 Hz, 13-H), 4.96 (1H, d, J = 6.8 Hz, 13-H), 5.53
(1H, s, 15-H), 5.61 (1H, s, 7a-H), 6.92-7.01 (2H, m, 11-H, 9-H),
7.13 (1H, d, J = 9.0 Hz, 6-H), 7.22-7.36 (9H, m, 2-H, 3-H, 8-H,
10-H, Ph), 7.38-7.42 (1H, m, 5-H), 7.74-7.81 (2H, m, 1-H, 4-H);
To a solution of aminonaphthol 2 (0.40 g, 2.31 mmol) in abs.
toluene (10 mL), levulinic acid (0.27 g, 2.31 mmol) was added.
The mixture was refluxed for 3 h, and the solvent was evaporated
off. The product was purified by column chromatography (silica
gel, eluent: toluene-MeOH, 14:1). Yield: 0.09 g (17%), mp: 104-
13
C-NMR (deuteriochloroform): δ 57.9 (15-C), 77.9 (13-C), 78.7
(7a-C), 111.3 (15a-C), 117.2 (11-C), 119.1 (6-C), 120.3 (7b-C),
121.3 (9-C), 122.8 (1-C), 123.8 (3-C), 127.1 (2-C), 128.0 (5-C),
128.7 (2'-C, 6'-C), 128.9 (4'-C), 129.3 (10-C), 129.4 (3'-C, 5'-C),
130.0 (4-C), 130.8 (8-C), 132.0 (4a-C), 2 x 141.5 (15b-C, 1'-C),
150.7 (6a-C), 153.3 (11a-C).
1
106 °C; H-NMR (deuteriochloroform): δ 1.62 (3H, s, Me), 2.17-
2.28 (1H, m, 9-H), 2.43-2.67 (3H, m, 9-H, 2 x 8-H), 4.43 (1H, d,
J = 16.6 Hz, 12-H), 5.41 (1H, d, J = 16.6 Hz, 12-H), 6.99 (1H, d,
J = 8.8 Hz, 6-H), 7.37 (1H, t, J = 7.3 Hz, 3-H), 7.50 (1H, t, J = 7.6
Hz, 2-H), 7.65 (1H, d, J = 9.1 Hz, 5-H), 7.70 (1H, d, J = 8.3 Hz,
Anal. Calcd. for C H NO (365.44): C, 82.17; H, 5.24; N,
13
25 19
3.83. Found: C, 82.39; H, 5.25; N, 3.82%
2
4-H), 7.76 (1H, d, J = 8.3 Hz, 1-H); C-NMR (deuteriochloro-
form): δ 22.8 (Me), 29.3 (9-C), 31.8 (8-C), 36.2 (12-C), 91.1 (7a-
C), 109.9 (12a-C), 119.4 (6-C), 121.4 (1-C), 124.2 (3-C), 127.1
(2-C), 128.7 (4-C), 129.0 (5-C), 129.2 (4a-C), 131.0 (12b-C),
149.9 (6a-C), 174.8 (10-C).
( 7 aR*, 13R* , 1 5S*)-13-Methyl-15-phenyl-7aH, 1 3H, 1 5H-naphth-
[1',2':5,6][1,3]oxazino[3,2-c][1,3]benzoxazine (17).
A mixture of compound 14 (0.30 g, 0.85 mmol), EtOH (20 mL)
and acetaldehyde (2 mL) was stirred at r.t. until the TLC showed no
more starting material (for ca. 10 h). The solvent was evaporated off
and the residue crystallized on treatment with Et O (30 mL). The
2
crystalline product was collected by filtration and recrystallized
Anal. Calcd. for C H NO (253.30): C, 75.87; H, 5.97; N,
16 15 2
5.53. Found: C, 76.08; H, 5.96; N, 5.54.
3-(2-Hydroxyphenyl)-1-phenyl-2,3-dihydro-1H-naphth[1,2-e]-
[1,3]oxazine (14).
from iP r O-EtOAc (4:1, 50 mL). Yield: 0.25 g (78%), mp: 226-228
1
A solution of aminonaphthol 1 (1.50 g, 6.03 mmol) and salicy-
laldehyde (0.74 g, 6.03 mmol) in MeOH (40 mL) was stirred at
r.t. for 1 h. The solvent was evaporated off and the residue crys-
2
°C; H-NMR (deuteriochloroform): δ 1.78 (3H, d, J = 5.5 Hz, Me),
5.15 (1H, q, J = 5.5 Hz, 13-H), 5.70 (1H, s, 15-H), 5.89 (1H, s, 7a-
H), 6.94-7.07 (2H, m, 9-H, 11-H), 7.19 (1H, d, J = 9.1 Hz, 6-H),
7.27-7.41 (9H, m, 2-H, 3-H, 8-H, 10-H, Ph), 7.44-7.49 (1H, m, 5-
tallized on treatment with Et O (40 mL). The crystalline product
2
was collected by filtration and recrystallized from iPr O-EtOAc
2
(3:1, 80 mL). Yield: 1.83 g (86%), mp: 180-181 °C; H-NMR
13
1
H), 7.80-7.86 (2H, m, 3-H, 4-H); C-NMR(deuteriochloroform):δ
19.8 (Me), 54.7 (15-C), 79.4 (13-C), 81.1 (7a-C), 111.0 (15a-C),
116.8 (11-C), 119.1 (6-C), 120.3 (7b-C), 121.0 (9-C), 122.3 (1-C),
123.7 (3-C), 128.6 (2-C), 128.7 (5-C), 128.9 (2'-C, 6'-C), 129.0
(4'-C), 129.4 (10-C), 129.5 (3'-C, 5'-C), 130.0 (4-C), 130.6 (8-C),
132.1 (4a-C), 2 x 141.9 (15b-C, 1'-C), 151.5 (6a-C), 153.7 (11a-C).
(deuteriochloroform): δ 5.68 and 5.78 (trans diastereomer, major
compound), 5.88 and 5.95 (cis diastereomer, minor compound),
13
8.60 (Schiff base); C-NMR (deuteriochloroform): δ 54.2 and
79.0 for the trans diastereomer, 57.0 and 83.7 for cis diastere-
omer, and 166.9 for the Schiff base.
Anal. Calcd. for C H NO (379.46): C, 82.30; H, 5.58; N,
26 21
3.69. Found: C, 82.49; H, 5.56; N, 3.70.
2
3-(2-Hydroxyphenyl)-2,3-dihydro-1H-naphth[1,2-e][1,3]oxazine
(15).
4-Phenyl-3,4-dihydro-2H-naphth[2,1-e][1,3]oxazin-2-one (18).
Aminonaphthol hydrochloride 3 (0.30 g, 1.05 mmol) was sus-
pended in abs. toluene (10 mL), and Et N (0.34 g, 3.15 mmol) and
A solution of aminonaphthol 2 (1.50 g, 8.67 mmol) and salicy-
laldehyde (1.06 g, 8.67 mmol) in MeOH (40 mL) was stirred at r.t.
for 1 h. The solvent was evaporated off and the residue crystal-
3
phosgene (0.55 mL; 20% in toluene, 1.05 mmol) were added. The
lized on treatment with Et O (40 mL). The crystalline product was
2

May-Jun 2004
Transformation reactions of the Betti base analog aminonaphthols
373
REFERENCES AND NOTES
mixture was stirred at r.t. for 4 h and then EtOAc (40 mL) and
H O (40 mL) were added. The organic layer was separated, dried
2
(Na SO ) and evaporated. The oily residue crystallized on treat-
[*] Author to whom correspondence should be addressed. E-
mail: fulop@pharma.szote.u-szeged.hu
2
ment with n-hexane (20 mL). The crystalline product was filtered
4
o ff and recrystallized from n-hexane-iPr O (40-10 mL). Yield:
1
[1] M. Betti, Gazz. Chim. Ital., 30 II., 310 (1900).
[2] H. E. Smith and N. E. Cooper, J. Org. Chem., 35, 2212
(1970).
[3] H. Möhrle, C. Miller and D. Wendisch, Chem. Ber., 107,
2675 (1974).
2
0.09 g (31%), mp: 196-198 °C; H-NMR (deuteriochloroform): δ
5.78 (1H, s, 4-H), 5.97 (1H, bs, NH), 6.93 (1H, d, J = 8.6 Hz, 5-H),
7.31-7.41 (5H, m, Ph), 7.49-7.62 (3H, m, 6-H, 8-H, 9-H), 7.78
13
(1H, d, J = 7.8 Hz, 7-H), 8.36 (1H, d, J = 8.6 Hz, 10-H); C-NMR
(deuteriochloroform): δ 58.6 (4-C), 114.8 (4a-C), 121.7 (6-C),
123.5 (10-C), 124.6 (8-C), 127.1 (9-C), 127.4 (7-C), 127.7 (4'-C),
127.8 (2'-C, 6'-C), 129.1 (5-C), 129.5 (3'-C, 5'-C), 133.9 (10a-C),
141.8 (6a-C), 142.9 (1'-C), 144.4 (10b-C), 150.3 (2-C)
[4] I. Szatmári, T. A. Martinek, L. Lázár and F. Fülöp,
Tetrahedron, 59, 2877 (2003).
[5] I. Szatmári, T. A. Martinek, L. Lázár, A. Koch, E.
Kleinpeter, K. Neuvonen and F. Fülöp, J. Org. Chem., in press.
[6] N. C. Desai, H. K. Shukla, N. A. Langalia and K. A.
Thaker, J. Indian Chem. Soc., 61, 711 (1984).
[7] C. Cardellicchio, G. Ciccarella, F. Naso, E. Schingaro and
F. Scordari, Tetrahedron: Asymmetry, 9, 3667 (1998).
[8] C. Cardellicchio, G. Ciccarella, F. Naso, F. Perna and P.
Tortorella, Tetrahedron, 55, 14685 (1999).
[9] J. Lu, X. Xu, C. Wang, J. He, Y. Hu and H. Hu,
Tetrahedron Lett., 43, 8367 (2002).
[10] J. Lu, X. Xu, S. Wang, C. Wang, Y. Hu and H. Hu, J.
Chem. Soc., Perkin Trans. 1, 2900 (2002).
Anal. Calcd. for C H NO (275.31): C, 78.53; H, 4.76; N,
18 13
5.09. Found: C, 78.32; H, 4.75; N, 5.08%
2
(7 S*, 13b R*)-7-Phenyl-7H, 9H, 13bH-naphth[2', 1':5, 6][1, 3] -
oxazino[2,3-a]isoindol-9-one (19).
To a suspension of aminonaphthol hydrochloride 3 (0.50 g,
1.75 mmol) in abs. toluene (20 mL), 2-carboxybenzaldehyde
(0.27 g, 1.73 mmol) and Et N (0.20 g, 1.98 mmol) were added.
3
The mixture was stirred at r.t. for 8 days and then was washed
consecutively with H O (50 mL) and with 2 M HCl solution (50
2
mL) after adding of EtOAc (50 mL). The organic layer was sepa-
rated, dried (Na SO ) and evaporated. The oily residue crystal-
[11] M. Betti, Org. Synth. Coll. Vol. 1, 381 (1941).
[12] J. C. Duff and E. J. Bills, J. Chem. Soc., 1305 (1934).
[13] I. Szatmári, T. A. Martinek, L. Lázár and F. Fülöp, Eur. J.
Org. Chem., in press.
[14] J. Mindl, O. Hrabik, V. Sterba and J. Kavalek, Coll. Czech.
Chem. Commun., 65, 1262 (2000).
[15] F. Fülöp, G. Bernáth and K. Pihlaja, Adv. Heterocyclic
Chem., 69, 349 (1998).
[16] F. Fülöp, G. Bernáth and P. Sohár, Tetrahedron, 41, 5981
(1985).
2
4
lized on treatment with n-hexane (20 mL). The crystalline prod-
uct was collected by filtration and recrystallized from n-hexane-
1
iPr O (8:1, 45 mL). Yield: 0.27 g (42%), mp: 156-158 °C; H-
2
NMR (deuteriochloroform): δ 6.17 (1H, s, 7-H), 6.51 (1H, s, 13b-
H), 7.10 (1H, d, J = 8.6 Hz, 6-H), 7.25-7.37 (3H, m, 2'-H, 4'-H, 6'-
H), 7.42-7.58 (7H, m, 2-H, 3-H, 5-H, 13-H, 3'-H, 5'-H), 7.63 (1H,
t, J = 7.6 Hz, 11-H), 7.76-7.89 (3H, m, 4-H, 10-H, 12-H), 8.24-
13
8.30 (1H, m, 1-H); C-NMR (deuteriochloroform): δ 52.9 (7-C),
80.2 (13b-C), 114.6 (6a-C), 121.7 (5-C), 121.9 (1-C), 124.0 (2-
C), 124.2 (3-C), 125.2 (14b-C), 126.0 (4'-C), 126.2 (11-C), 127.0
(10-C), 127.8 (4-C), 128.4 (6-C), 129.0 (13-C), 129.1 (2'-C, 6'-
C), 130.7 (3'-C, 5'-C), 132.5 (12-C), 132.8 (4a-C), 133.9 (9a-C),
140.7 (13a-C), 142.0 (1'-C), 148.5 (14a-C), 166.1 (9-C).
[17] F. Csende and G. Stájer, Heterocycles, 53, 1379 (2000).
[18] T. Ito, N. Yamazaki and C. Kibayashi, Synlett, 10, 1506
(2001).
[19] I. Meyers, S. V. Downing and M. J. Weiser, J. Org. Chem.,
66, 1413 (2001).
Anal. Calcd. for C H NO (363.42): C, 82.63; H, 4.72; N,
25 17
3.85. Found: C, 82.86; H, 4.73; N, 3.86.
2
[20] L. Lázár and F. Fülöp, Eur. J. Org. Chem., 3025 (2003).
[21] F. Fülöp, L. Lázár, I. Pelczer and G. Bernáth, Tetrahedron,
44, 2993 (1988).
[22] L. Lázár, F. Fülöp, G. Bernáth, A. Kálmán and G. Argay,
J. Heterocyclic Chem., 28, 1213 (1991).
Acknowledgement.
The author's thanks are due to the Hungarian Research
Foundation (OTKA grants T034901 and T030452) for financial
support.
[23] B. F. Kukharev, V. K. Stankevich, G. R. Klimenko, V. V.
Bayandin and A. I. Albanov, Arkivoc, xiii, 166 (2003).