Facile synthesis of 1,3,6-oxadiazepines from 2,2′-(1,2-ethanediyldiimino)bisphenols

Article abstract of DOI:10.1016/S0040-4020(00)00984-4

A useful sequence of reactions for the syntheses of a variety of heterocyclic systems including an oxadiazepine ring is described. The key step involves the condensation of substituted 2,2′-(1,2-ethanediyldiimino)bisphenols with ethanedial to provide stereoselectively the 6a,7a-trans-6,6a,7a,8,15,16-hexahydro[1,4]benzoxazine[4′,3′:6,7] [1,3,6]oxadiazepino[2,3-c][1,4]-benzoxazine-6,8-diol framework, as established by X-ray diffraction analyses.

Full text of DOI:10.1016/S0040-4020(00)00984-4

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 55±64
Facile synthesis of 1,3,6-oxadiazepines from
2,20-(1,2-ethanediyldiimino)bisphenols
a
Ma. Eugenia Ochoa, Susana Rojas-Lima, Herbert Hop¯, Patricia Rodrõguez, Dolores Castillo,
b
c
c
a
Â
È
Norberto Farfan and Rosa Santillan
a
a,
*
Â
a
  Â
 Â
Â
Departamento de Quõmica, Centro de Investigacion y de Estudios Avanzados del IPN, Apartado Postal 14-740, 07000 Mexico D. F., Mexico
b
Universidad Autonoma del Estado de Hidalgo, Centro de Investigaciones Quõmicas, Carretera Pachuca-Tulancingo Km 4.5,
Â
Ciudad Universitaria, 42076 Pachuca de Soto, Hidalgo, Mexico
 Â
Centro de Investigaciones Quõmicas, Universidad Autonoma del Estado de Morelos, Av. Universidad 1001, 62210 Cuernavaca, Mexico
c
Â
Received 28 March 2000; revised 15 October 2000; accepted 18 October 2000
AbstractÐA useful sequence of reactions for the syntheses of a variety of heterocyclic systems including an oxadiazepine ring is
described. The key step involves the condensation of substituted 2,20-(1,2-ethanediyldiimino)bisphenols with ethanedial to provide stereo-
selectively the 6a,7a-trans-6,6a,7a,8,15,16-hexahydro[1,4]benzoxazine[40,30:6,7][1,3,6]oxadiazepino[2,3-c][1,4]-benzoxazine-6,8-diol
framework, as established by X-ray diffraction analyses. q 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
thermal ring contraction of oxygenated pyrazines.19 The
related 4,5-dihydro-1,3,6-oxadiazepine-2-thione has
5
been detected as a metabolite of manganous ethylenebis-
(dithiocarbamate), a common fungicide used for controlling
crop diseases.20 An alternative method described in the
literature for the synthesis of the saturated heterocycles
(6) involves condensation of bis(chloromethyl)ether with
aliphatic amines.21 The related 4,5-benz[d][1,3,6]oxa-
diazepines (7) have been obtained by photolysis of quinoxa-
line N-oxides.22±24
a-Dicarbonyl compounds are valuable synthons for the
preparation of heterocyclic molecules because of their
high reactivity towards nucleophiles.1±4
Thus, many polyfunctionalized compounds having amino,
hydroxyl and thiol groups react with a-dicarbonyl
compounds to give a variety of bicyclic,5 tricyclic,6±9
tetracyclic10 and cage11 compounds, often with high stereo-
selectivity.
Our interest in the reactions of o-aminophenols with
various dicarbonyl compounds is focused on the highly
Polyheterocyclic seven-membered rings of the 1,3,6-
oxadiazepine type containing one methylene group between
the oxygen and the two nitrogen atoms have been described
so far only sporadically in the literature.12 The ®rst studies
reported are related to the preparation of 1,5-dinitro-3-oxa-
1,5-diazacycloheptane13±15 (1) by the reversible reaction of
formaldehyde with nitroamines13,14. In 1957, Daeniker16
reported the synthesis of the oxadiazepine 2 while investi-
gating the chemotherapeutic use of a series of heterocycles
and the synthesis was patented in view of the fact that the
ethylene bis-phthalazinium chloride precursor possesses
bacteriostatic activity.17 Intramolecular Mannich reactions
of 2-alkylaminomethylbenzimidazoles led to the prepara-
tion of compounds 3a±3d,18 and the intermediate oxa-
diazepines 4a±4d were characterized during a study of the
Keywords: condensations; aminoalcohols; diazepines; X-ray crystal
structures.
* Corresponding author. Fax: 152-5747-7113;
e-mail: rsantill@mail.cinvestav.mx
0040±4020/01/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00984-4

56
M. E. Ochoa et al. / Tetrahedron 57 (2001) 55±64
Scheme 1. Preparation of benzoxazino-benzoxazines (8), oxadiazepines (10) and bisoxazolidines (12).
mixtures of benzene±ethanol at re¯ux for 5±12 h to give
the cis-benzoxazino±benzoxazines 8a±8g in yields of 43±
86% (Scheme 1). The structures of 8a±8g were established
by two-dimensional NMR experiments and compared with
the data described for analogous compounds.5,26±28 The 13C
NMR spectra of 8a±8g showed only one half of the total
number of expected carbons consistent with a structure of
C2 symmetry. Further evidence for the formation of these
bicycles is the characteristic shift of the methine carbon at
1
about 76 ppm. In the H NMR spectra the signals for these
methine protons are located between 5.17 and 5.66 ppm. In
all cases the mass spectra showed peaks both for the
molecular ion and the ion corresponding to half of the
molecule.29
Reduction of the benzoxazino±benzoxazines 8a±8g with
2 equiv. of BH3±THF gave the corresponding 2,20-(1,2-
ethanediyldiimino)bisphenols 9a±9g. Thereby, it is worth
noting that the analogous N-hydroxyalkylethylenediamines
possess antimycobacterial activity.30 Furthermore, metal
complexes of such bisphenols are useful models for the
simulation of enzymatic systems.31
stereoselective preparation of different heterocyclic
systems.5,8,9,25 In the present contribution a useful method
for the synthesis of 1,3,6-oxadiazepines is presented with
2,20-(1,2-ethanediyldiimino)bisphenols and glyoxal as start-
ing materials. An interesting feature of the reaction is the
stereoselective transformation of glyoxal. Moreover, 1,3,6-
oxadiazepine derivatives are structurally related to known
pharmacologically active molecules and the method of
synthesis described in here should provide an easy route
to the preparation of analogous molecules.
Although the syntheses of several bisphenols32±36 have
already been reported, their spectroscopic characterization
has not been described previously. The 1H NMR spectra of
9a±9g show a characteristic singlet for the CH2N group
between 3.16 and 3.38 ppm. The mass spectra display
peaks for the M1 and half of the molecule which in the
case of 9a, 9c, 9e, 9g correspond to the base peak. The
X-ray structure of 9g (Fig. 1) was determined and normal
bond distances and angles are observed. The C±O bond
2. Results and discussion
The reactions between 1 equiv. of various o-aminophenol
derivatives and glyoxal were carried out in benzene or
Ê
length is 1.374 (3) A, the N±Carom bond (N1±C2

M. E. Ochoa et al. / Tetrahedron 57 (2001) 55±64
57
derivatives 10a±10e (Scheme 2). It is worth mentioning
that the modest yields are due to the fact that a mixture of
products containing bisoxazolidines 12, oxadiazepines 10
and traces of piperazinones 13 is formed which was
separated by fractional crystallization.
In what follows the NMR and mass spectrometric data of
compound 10a will be discussed representatively for
1
compounds 10a±10e. The H NMR spectrum of 10a in
DMSO-d6 shows a doublet at 7.01 ppm (Jˆ5.4 Hz) for the
hydroxyl groups, a doublet at 5.31 ppm (Jˆ5.8 Hz) for H-6
and H-8, a singlet at 4.19 ppm for H-6a and H-7a, as well as
an AA0BB0 system at 3.23 and 4.14 for the H-15,16 hydro-
gens. Concerning the stereochemistry at carbons C-6 and C-8,
the observation that the signals for these protons do not show
coupling with H-6a and H-7a, respectively, allows one to
deduce a gauche conformation according to the Karplus equa-
tion.39 The COSY spectrum shows correlation between the
hydroxyl protons and the H-6 and H-8 hydrogens.
Figure 1. ORTEP drawing of compound 9g showing atomic labeling and
thermal ellipsoids at the 25% probability level. The symmetry transforma-
tion to generate the unlabeled atoms is A: 2x11, y, 2z11/2
Ê
1.433(3) A) is shorter than the N±Caliph bond (N1±C7,
Ê
1.468(3) A). The orientation of the nitrogen atoms is gauche
with the N1±C7±C70 ±N10 torsion angle being 2648. The
torsion angle between the aromatic ring and the N-methyl-
ene groups (C1±C2±N1±C7) is 1088 and that of the
O1±C1±C2±N1 fragment is 68.
The aromatic part of the 13C NMR spectrum of 10a was
assigned by comparison with the starting materials and by
use of two-dimensional experiments. The quaternary carbon
C-4a (141.5 ppm) correlated with H-6 in a COLOC experi-
ment. The mass spectrum of 10a shows a peak for the mole-
cular ion at m/zˆ342, and peaks corresponding to the loss of
fragments with m/zˆ18. For compound 10a there exist two
possible structures, one possessing a plane of symmetry
where all substituents are located on the same side of the
molecule (all cis) and another one with a C2 axis where the
substituents are on opposite sides. Molecular modelling
shows that the trans-substituted heterocycle is favored
over the cis-substitued one by steric reasons. In order to
con®rm this statement, an X-ray crystallographic study
was undertaken, whereby it was unambiguously established
Based on the strategy described in a prior work for the
synthesis of chiral piperazines,25 and knowing that the
course of the condensations with a-dicarbonyl derivatives
is extremely sensitive to the reaction conditions, the conden-
sation reactions of compounds 9a±9g with glyoxal were
carried out ®rst with 2 equiv. of this reagent in ethanol±
ethyl acetate (9:1). Thereby, the 1,3,6-oxadiazepines 10a±
10e were obtained in yields of 24±38%. It can be proposed
that the reaction of 9a±9e with glyoxal leads ®rst to a tetra-
hydroxylated intermediate similar to the one described by
Alcaide37 and Chassonnery38 that undergoes a highly stereo-
selective ring closure to provide the 1,3,6-oxadiazepine
Scheme 2. Reaction Scheme for the formation of 10, 12 and 13.

58
M. E. Ochoa et al. / Tetrahedron 57 (2001) 55±64
Figure 2. ORTEP drawing of compounds 10c and 10e showing atomic labeling and thermal ellipsoids at the 25% probability level. Compound 10c crystallized
with a molecule of EtOH.
that the benzoxazinol moieties are joined in a trans con-
®guration. The X-ray structures of 10c and 10e (Fig. 2)
show that the seven-membered rings adopt the most stable
twist-chair (TC) conformation.40 The N14-C7a and N17-
C6a bond distances are 1.428(5) and 1.425(5) A for 10c
Ê
and 1.421(6) and 1.417(6) A for 10e which are shorter
from 2,20-(1,2-ethanediyldiimino)bisphenols and glyoxal as
starting materials. The sequence of reactions described in
this report is useful for the preparation of a variety of hetero-
cyclic systems with potential bioactivity like bisoxazoli-
dines, piperazines, oxadiazepines and benzoxazinols. The
preparation of the 1,3,6-oxadiazepine provides the 6a,7a-
trans-substituted seven-membered ring, as demonstrated
by X-ray crystallography.
Ê
3
3
41
Ê
than the mean Csp ±Nsp distances (1.469(14) A). The
six-membered rings adopt half-chair conformations with
the oxygen atoms in pseudoaxial (anti) and the hydrogens
in pseudoequatorial positions (gauche). The corresponding
C±O distances are within the expected values.41 The
pseudoaxial hydroxyl groups at C-6 and C-8 have C±O
4. Experimental
Ê
distances of 1.397(5) and 1.400(5) A for 10c and 1.396(6)
Ê
and 1.403(6) A for 10e. The O9±C8 and O5±C6 distances
NMR spectra were recorded on Jeol GLX 270, Jeol
Eclipse1400 and Bruker Avance DPX spectrometers.
Special techniques (APT, COSY, HMQC, HMBC,
COLOC) were used to assign the spectra. Chemical shifts
are stated in ppm with reference to TMS. IR spectra have
been recorded on a Perkin±Elmer 16F-PC FT-IR spectro-
photometer with KBr pellets. Mass spectra were obtained on
a HP 5989A spectrometer using electron impact ionization
(EI). Elemental analyses were carried out by Oneida
Research Services, Whitesboro, N.Y. 13492. HRMS were
determined on a Jeol 102A spectrometer at the Instituto de
Ê
are 1.413(5)/1.411(5) A and 1.428(7)/1.404(7) for 10c and
10e, respectively.
Reduction of 10a and 10b with BH3THF gives the corre-
sponding benzoxazinols 11a and 11b in yields of 48 and
73%, respectively. The H NMR spectrum of 11a shows a
1
doublet at 5.28 ppm (Jˆ4.8 Hz) for H-2, the diastereotopic
protons at position 3 give rise to signals at 3.12 and
3.38 ppm and the broad signal at 3.45 ppm was assigned
to the methylene group at C-9. In the 13C NMR spectra of
11a two distinct signals are observed for both C-9 (47.5 and
47.4 ppm) and C-3 (52.5 and 52.4 ppm). Again in the mass
spectrum both the molecular ion at m/zˆ328 and an ion at
m/zˆ164 corresponding to half of the molecule are present.
Â
Quõmica, UNAM.
X-Ray diffraction studies of monocrystals were performed
on an Enraf±Nonius CAD4 diffractometer (lMoKa
ˆ
Ê
0.71069 A). A selected crystal was set upon a diffract-
ometer, unit cell dimensions with estimated standard devia-
tions were obtained from least-squares re®nements of the
setting angles of 25 well centered re¯ections. Three
standard re¯ections were monitored periodically; they
showed no change during data collection. Corrections
were made for Lorentz and polarization effects. Absorption
correction was not necessary. The structures of 9g, 10c and
10e were determined by direct methods. Computations for
all structures were performed with SHELXL (Sheldrick,
1993).42 Atomic form factors for neutral C, N, O and H
were taken from Ref. 43. Hydrogen atoms were calculated.
Anisotropic temperature factors were introduced for all non-
hydrogen atoms. Least-squares re®nements were carried out
by minimizing Sw(uFou2uFcu)2, where Fo and Fc are the
observed and calculated structure factors. Weights were
used. Models reached convergence with RˆS(iFou2uFci)/
SuFou and RwˆSw(iFou2uFci)2/Sw(Fo)2]1/2. Criteria for a
As expected, the formation of bisoxazolidines (12b±12c,
12e and 12f) was preferred when the reaction between
bisphenols 9b, 9c, 9e and 9f and glyoxal was carried out
in a 1:1 molar ratio in benzene:ethanol (9:1). The structures
of these compounds were established by NMR spectroscopy
in comparison with similar derivatives.25 The formation of
these compounds could be evidenced by the signal around
93 ppm for C-2. In solution, these bisoxazolidine type
derivatives are in equilibrium with the starting materials
(Scheme 2) thus precluding their puri®cation by chromato-
graphic procedures.
3. Conclusion
A series of ®ve new 1,3,6-oxadiazepines have been prepared

M. E. Ochoa et al. / Tetrahedron 57 (2001) 55±64
59
satisfactory complete analysis were the ratios of rms shifts
to standard deviation being less than 0.1 and no signi®cant
features in the ®nal difference Fourier map.
(47), 65 (26); Anal. calcd for C16H16N2O2: C, 71.64; H, 5.97;
N, 10.45; Found: C, 71.72; H, 6.08; N, 10.35.
4.1.3. cis-5a,6,11a,12-Tetrahydro-3,9-dimethyl-[1,4]benz-
oxazino[3,2-b][1,4]benzoxazine (8c). Glyoxal (1.2 g,
8.1 mmol) was added to 2-amino-5-methylphenol (2.0 g,
16.3 mmol) in 35 mL benzene to yield 1.8 g (83%) of 8c
which was recrystallized from acetone, mp 231±2328C. IR
(KBr) 3376, 3030, 2964, 2920, 2854, 1598, 1518, 1488,
1448, 1420, 1292, 1266, 1232, 1142, 1128 1010, 980, 874,
858, 800, 786, 756, 578 cm21; 1H NMR (300 MHz, DMSO-
d6) d 7.12 (2H, d, Jˆ4.0 Hz, NH-6,12), 6.56 (4H, AB,
Jˆ7.7 Hz, H-1,7, H-2,8), 6.46 (2H, s, H-4,10), 5.20 (2H,
d, Jˆ4.0 Hz, H-5a,11a), 2.12 (6H, s, CH3-3,9); 13C NMR
(75.5 MHz, DMSO-d6) d 142.2 (C-4a), 128.4 and 128.3
(C-3 and C-12a), 122.5 (C-2), 117.3 (C-4), 114.9 (C-1),
76.3 (C-5a), 21.1 (CH3); MS (EI, 70 eV) m/z (%): 268
(M1, 66), 269 (M111, 11), 148 (10), 147 (87), 146 (82),
134 (M1/2, 100), 118 (25), 91 (23), 77 (34), 65 (18); Anal.
calcd for C16H16N2O2: C, 71.64; H, 5.97; N, 10.44. Found:
C, 71.62; H, 6.17; N, 10.33.
Crystal data for 9g: C16H20N2O2, Mˆ272.34 g/mol, mono-
Ê
clinic, space group C2/c, with aˆ25.137 (5) A, bˆ6.053
Ê
Ê
Ê 3
(1) A, cˆ9.617 (2) A, bˆ103.88 (3)8, Vˆ1420.5 (5) A ,
Zˆ4, dcalcˆ1.273 g cm23, mˆ0.085 cm21. A total of 1585
re¯ections were collected, from which 1552 were unique
(Rint 0.02), 960 re¯ections were considered observed,
F.4s(F), 91 parameters, ®nal Rˆ0.061, Rwˆ0.188.
Weighting scheme w21ˆs2F2o1(0.1150 P)211.3815 P
where Pˆ(F2o12Fc2)/3.
Crystal
data
for
10c:
C20H22N2O5
C2H5OH,
Mˆ416.46 g/mol, monoclinic, space group P21/a, with
Ê
Ê
Ê
aˆ12.928 (1) A, bˆ8.363 (1) A, cˆ19.319 (1) A,
bˆ91.706 (1)8, Vˆ2087.8 (3) A , Zˆ4, dcalcˆ1.325 g cm23
,
Ê 3
mˆ0.097 cm21. A total of 1782 re¯ections were collected,
from which 1700 were considered observed (Rint 0.032)
F.4s(F), 271 parameters, ®nal Rˆ0.049, Rwˆ0.133.
Weighting scheme: w21ˆs2F2o1(0.0744 P)211.7055 P
where Pˆ(F2o12Fc2)/3.
4.1.4. cis-5a,6,11a,12-Tetrahydro-2,8-dinitro-[1,4]benz-
oxazino[3,2-b][1,4]benzoxazine (8d). Glyoxal (1.3 ,
8.1 mmol) was added to 2-amino-4-nitrophenol (2.5 g,
16.2 mmol) in 30 mL benzene and re¯uxed for 10 h to
yield 2.3 g (86%) of 8d which was recrystallized from
acetone, mp 241±2428C. IR (KBr) 3420, 1522, 1518,
Crystal data for 10e: C18H16Cl2N2O5, Mˆ411.23 g/mol,
Ê
trigonal, space group P3, with aˆ15.066 (2) A, bˆ15.066
Ê
Ê
(2) A, cˆ6.8860 (10) A, aˆbˆ90.08, gˆ120.08, Vˆ
1353.6 (3) A , Zˆ3, dcalcˆ1.513 g cm23, mˆ0.393 mm21
.
Ê 3
1
A total of 3008 re¯ections were collected, from which
1934 were unique (Rint 0.044), 1316 re¯ections were con-
sidered observed, F.4s(F), 244 parameters, ®nal
1514, 1340, 1322, 1268, 1248, 1226, 1150, 968 cm21; H
NMR (270 MHz, DMSO-d6) d 8.13 (2H, d, Jˆ4.3 Hz, NH-
6,12), 7.65 (2H, d, Jˆ2.7 Hz, H-1,7), 7.58 (2H, dd, Jˆ8.6,
2.7 Hz, H-3,9), 6.91 (2H, d, Jˆ8.6 Hz, H-4,10), 5.66 (2H, d,
Jˆ4.4 Hz, H-5a,11a); 13C NMR (75.5 MHz, DMSO-d6) d
148.3 (C-4a), 142.5 (C-2), 131.0 (C-12a), 117.3 (C-4), 116.2
(C-3), 109.9 (C-1), 76.0 (C-5a); MS (EI, 70eV) m/z (%) 330
(M1, 3), 98 (6), 73 (15), 60 (16), 55 (21), 45 (27), 44 (100);
HRMS calcd for C14H10N4O6: 330.0600. Found: 330.0587.
Error 24.1 ppm.
Rˆ0.041, Rwˆ0.105. Weighting scheme: w21
ˆ
s2Fo21(0.0618 P)210.1600 P where Pˆ(Fo212F2c)/3.
4.1. General procedure for the preparation of
benzoxazino±benzoxazines (8)
To a solution of the appropriate o-aminophenol (1.0 mmol)
in benzene was added dropwise 40% aqueous glyoxal
(0.5 mmol) and the solution was kept under re¯ux for 5 h
using a Dean Stark trap. The solvent was evaporated in
vacuum and the solid washed with ether and recrystallized
from an appropriate solvent.
4.1.5. cis-5a,6,11a,12-Tetrahydro-2,8-dichloro[1,4]benz-
oxazino[3,2-b][1,4]benzoxazine (8e). Glyoxal (1.1 g,
7.0 mmol) was added to 2-amino-4-chlorophenol (2.0 g,
14.0 mmol) in 30 mL benzene and re¯uxed for 8 h to
yield 1.64 g (76%) of 8e, recrystallized from acetone, mp
202±2038C. IR (KBr) 3376, 1606, 1496, 1304, 1270, 1244,
4.1.1. cis-5a,6,11a,12-Tetrahydro [1,4] benzoxazino [3,2-
b][1,4]benzoxazine (8a). Mp 202±2048C lit27 2318C.
1
1208, 1150, 1120, 898, 844, 808 21; H NMR (300 MHz,
DMSO-d6) d 7.63 (2H, d, Jˆ3.2 Hz, NH-6,12), 6.72 (2H, d,
Jˆ2.0 Hz, H-1,7), 6.68 (2H, d, Jˆ8.4 Hz, H-4,10), 6.62
(2H, dd, Jˆ8.4, 2.0 Hz, H-3,9), 5.31 (2H, d, Jˆ4.0 Hz,
H-5a,11a). 13C NMR (75.5 MHz, DMSO-d6) d 140.9
(C-4a), 132.4 (C-12a), 125.8 (C-2), 118.9 (C-3), 118.3
(C-4), 114.2 (C-1), 75.6 (C-5a); MS (EI, 70 eV) m/z (%):
308 (M1, 56), 309 (M111, 10), 310 (M112, 37), 311
(M113, 6), 312 (M114, 6), 167 (77), 166 (52), 154
(M1/2, 100), 156 (40), 155 (39), 142 (29), 138 (28), 78
(16), 77 (19), 63 (29); Anal. calcd for C14H10N2O2Cl2: C,
54.40; H, 3.23; N, 9.06; Cl, 22.92; Found: C, 54.00; H, 3.28;
N, 8.87; Cl, 22.86.
4.1.2. cis-5a,6,11a,12-Tetrahydro-2,8-dimethyl-[1,4]benz-
oxazino[3,2-b][1,4]benzoxazine (8b). Glyoxal (2.4 g,
16.3 mmol) was added to 2-amino-4-methylphenol (4.0 g,
32.5 mmol) in 50 mL of a mixture of benzene-ethanol (9:1)
to give 3.4 g (78%) of 8b which was recrystallized from
acetone, mp 236±2378C. IR (KBr) 3374, 3304, 1618,
1604, 1506, 1310, 1288, 1258, 1216, 1140, 1126, 936,
1
848, 796 cm21; H NMR (400 MHz, DMSO-d6) d 7.18
(2H, d, Jˆ4.0 Hz, NH-6,12), 6.51 (2H, d, Jˆ8.0 Hz,
H-4,10), 6.48 (2H, s, H-1,7), 6.39 (2H, d, Jˆ8.0 Hz,
H-3,9), 5.17 (2H, d, Jˆ4.0 Hz, H-5a, 11a), 2.14 (6H, s,
CH3-2,8); 13C NMR (100 MHz, DMSO-d6) d 139.6
(C-4a), 130.5 and 130.3 (C-2, C-12a,), 119.5 (C-3), 116.2
(C-4), 115.1 (C-1), 75.8 (C-5a), 21.0 (CH3); MS (EI, 70 eV)
m/z (%): 268 (M1, 76), 269 (M111, 14), 147 (88), 146 (63),
134 (M1/2, 100), 122 (33), 118 (32), 107 (21), 91 (29), 77
4.1.6. cis-5a,6,11a,12-Tetrahydro-2,8-ditert-butyl[1,4]benz-
oxazino[3,2-b][1,4]benzoxazine (8f). Glyoxal (0.4 g,
3.03 mmol) was added to 2-amino-4-tertbutylphenol
(1.0 g, 6.06 mmol) in 50 mL of a mixture of benzene:

60
M. E. Ochoa et al. / Tetrahedron 57 (2001) 55±64
ethanol (9:1) and re¯uxed for 12 h to yield 0.46 g (43%) of
8f, recrystallized from methanol, mp 223±2248C (dec). IR
(KBr) 3420, 3370, 2950, 1522, 1498, 1342, 1310, 1288,
acetone, mp 238±2408C. IR (KBr) 3304, 3048, 2920,
2850, 1596, 1524, 1420, 1302, 1278, 1250, 1230, 1208,
1
1124, 860, 810 cm21; H NMR (400 MHz, DMSO-d6) d
1
1264, 1220, 1156, 1132, 1104 cm21; H NMR (270 MHz,
8.95 (2H, s, NH), 6.51 (2H, d, Jˆ8.0 Hz, H-6,60), 6.36
(2H, s, H-3,30), 6.19 (2H, d, Jˆ8.0 Hz, H-5,50), 4.72 (2H,
s, OH), 3.33 (4H, s, (CH2)2), 2.13 (6H, s, CH3-4,40); 13C
NMR (100 MHz, DMSO-d6) d 142.7 (C-1), 138.0 (C-2),
128.9 (C-4), 116.7 (C-5), 114.1 (C-6), 111.4 (C-3), 43.0
(CH2). 21.8 (CH3); MS (EI, 70 eV) m/z (%) 272 (M1, 21),
273 (M111, 5), 138 (95), 137 (100), 136 (M1/2, 94), 134
(23), 109 (49), 91 (27), 77 (24), 65 (16); Anal. calcd for
C16H20N2O2: C, 70.59; H, 7.35; N, 10.29; Found: C, 70.55;
H, 7.50; N, 10.19.
DMSO-d6) d 7.17 (2H, d, Jˆ4.0 Hz, NH-6,12), 6.70 (2H, d,
Jˆ2.0 Hz, H-1,7), 6.62 (2H, dd, Jˆ8.4, 2.0 Hz, H-3,9), 6.54
(2H, d, Jˆ8.4 Hz, H-4,10), 5.20 (2H, d, Jˆ4.0 Hz,
H-5a,11a), 1.22 (18H, s, C(CH3)3); 13C NMR (67.8 MHz,
DMSO-d6) d 144.3 (C-2), 139.6 (C-4a), 129.9 (C-12a),
115.9 (C-3,4), 111.8 (C-1), 75.9 (C-5a), 34.4 (C-CH3)3),
32.0 (CH3); MS (EI, 70 eV) m/z (%): 352 (M1, 100), 353
(M111, 25), 189 (59), 188 (47), 176 (M1/2, 27), 162 (26),
105 (6), 91 (9), 77 (10), 65 (5); HRMS calcd for
C22H28N2O2: 352.2151. Found: 352.2162. Error 13.2 ppm.
4.2.3. 2,20-(1,2-Ethanediyldiimino)-5,50-dimethylbisphe-
nol (9c). To a solution of 8c (2.7 g, 10.1 mmol) in 50 mL
THF, 10.1 mL (20.14 mmol) of BH3±THF was added, 3 h
re¯ux. After work-up 2.16 g (79%) of 9c were obtained that
was recrystallized from acetone, mp 246±2488C (dec). IR
(KBr) 3302, 3040, 2918, 2860, 1522, 1506, 1498, 1422,
4.1.7. cis-5a,6,11a,12-Tetrahydro-1,7-dimethyl-[1,4]benz-
oxazino-[3,2-b][1,4]benzoxazine (8g). Glyoxal (0.6 g,
4.1 mmol) was added to 2-amino-m-cresol (1.0 g, 8 mmol)
in 15 mL benzene to yield 800 mg (74%) of 8g, mp 2438C.
IR (KBr) 3422, 1524, 1484, 1238, 1162, 768 cm21;1H NMR
(270 MHz, DMSO-d6) d 6.81 (2H, d, Jˆ4.0 Hz, NH-6,12),
6.63 (2H, dd, Jˆ4.8, 4.0 Hz, H-3,9), 6.53 (2H, d, Jˆ4.0 Hz,
H-2,8 and H-4,10), 5.23 (2H, d, Jˆ4.0 Hz, H-5a,11a), 2.12
(6H, s, CH3-1,7); 13C NMR (67.8 MHz, DMSO-d6) d 141.5
(C-4a), 128.6 (C-12a), 123.3 (C-3), 122.7 (C-1), 118.7
(C-2), 114.5 (C-4), 75.5 (C-5a), 17.5 (CH3); MS (EI,
70 eV) m/z (%): 268 (M1, 89), 269 (M111, 16), 147 (92),
134 (M1/2, 100), 122 (34), 118 (29), 91 (27), 77 (33); Anal.
calcd for: C16H16N2O2: C, 71.64; H, 5.97; N, 10.44; Found:
C, 71.66; H, 6.17; N, 10.41.
1
1216, 1208, 1122, 798, 796 cm21; H NMR (400 MHz,
DMSO-d6) d 9.10 (2H, s, NH), 6.48 (2H, s, H-6,60), 6.43
(2H, d, Jˆ10.0 Hz, H-3,30) and 6.42 (2H, Jˆ10 Hz, H-4,40),
4.54 (2H, br, OH), 3.21 (4H, s, (CH2)2), 2.01 (6H, s,
CH3-5,50); 13C NMR (100 MHz, DMSO-d6) d 144.6 (C-1),
135.5 (C-2), 124.9 (C-5), 120.3 (C-4), 115.0 (C-6), 110.3
(C-3), 43.1 (CH2), 20.8 (CH3); MS (EI, 70 eV) m/z (%) 272
(M1, 16), 273 (M111, 3), 137 (92), 136 (M1/2, 100), 134
(20), 109 (33), 91 (24), 77 (23), 65 (16); Anal. calcd for
C16H20N2O2: C, 70.59; H, 7.35; N, 10.29; Found: C, 70.52;
H, 7.41; N,10.28.
4.2. General procedure for the preparation of 2,20-(1,2-
ethanediyldiimino)bisphenols (9)
4.2.4. 2,20-(1,2-Ethanediyldiimino)-4,40-dinitrobisphenol
(9d). To a solution of 8d (1.94 g, 5.9 mmol) in 50 mL THF,
5.9 mL (11.7 mmol) of BH3±THF was added, 3 h re¯ux.
After work-up 1.5 g (77%) of 9d were obtained that was
recrystallized from acetone, mp 220±2228C (dec). IR
(KBr) 3386, 3228, 2920, 1530, 1502, 1472, 1458, 1344,
To a solution of the appropriate benzoxazino±benzoxazine
(1.0 mmol) in 50 mL THF, 2.0 mmol of BH3±THF was
added and the solution was re¯uxed for 5 h. The excess
borane was destroyed with a few drops of 10% NaOH, the
solution was dried over Na2SO4 and the solvent evaporated
under vacuum. The solid was washed with acetone and
recrystallized as described below.
1
1224, 744 cm21; H NMR (400 MHz, DMSO-d6) d 11.01
(2H, br, NH), 7.43 (2H, dd, Jˆ8.4, 2.6 Hz, H-5,50), 7.30
(2H, d, Jˆ2.6 Hz, H-3,30), 6.78 (2H, d, Jˆ8.4 Hz, H-6,60),
5.63 (2H, br, OH), 3.38 (4H, s, (CH2)2); 13C NMR
(67.9 MHz, DMSO-d6) d 151.5 (C-1), 141.2 (C-4), 138.3
(C-2), 113.5 (C-5), 112.7 (C-6), 103.3 (C-3), 41.8 (CH2);
MS (EI, 70 eV) m/z % 334 (M1, 1), 330 (3), 289 (8), 168
(12), 165 (20), 123 (16), 122 (100), 121 (25), 120 (16), 108
(11), 95 (20), 77 (20), 65 (21), 63 (13), 53 (32), 52 (22), 51
(21); HRMS calcd for C14H14N4O6: 334.0913. Found:
334.0908. Error 21.5 ppm.
4.2.1. 2,20-(1,2-Ethanediyldiimino)bisphenol30,32,35 (9a).
To a solution of 8a (4.3 g, 17.9 mmol) in 50 mL THF,
17.9 mL (35.8 mmol) BH3±THF was added. The product
was recrystallized from ethanol±chloroform to yield 4.1 g
(94%) of 9a, mp 236±237 8C [Lit30 228±2328C, Lit32 225±
2278C, Lit35 214±2178C dec]. IR (KBr) 3308, 1510, 1446,
1
1110, 742 cm21; H NMR (400 MHz, DMSO-d6) d 9.18
(2H, s, NH), 6.65 (2H, d, Jˆ7.6 Hz, H-6,60), 6.63 (2H, dd,
Jˆ8.0, 7.3 Hz, H-4,40), 6.53 (2H, d, Jˆ7.0 Hz, H-3,30), 6.40
(2H, ddd, Jˆ7.6, 7.3, 1.1 Hz, H-5,50), 4.70 (2H, s, OH), 3.27
(4H, s, (CH2)2); 13C NMR (100 MHz, DMSO-d6) d 144.6
(C-1), 137.9 (C-2), 120.2 (C-4), 116.2 (C-5), 113.9 (C-6),
110.2 (C-3), 42.7 (CH2); MS (EI, 70 eV) m/z (%): 244 (M1,
24), 245 (M111, 5), 123 (87), 122 (M1/2, 100), 120 (16),
95 (28), 94 (15), 77 (29), 65 (16).
4.2.5. 2,20-(1,2-Ethanediyldiimino)-4,40-dichlorobisphe-
nol34 (9e). To a solution of 8e (1.0 g, 3.25 mmol) in
50 mL THF, 3.24 mL (6.5 mmol) of BH3±THF was
added. After work-up the product was washed with etha-
nol/hexane to yield 1.0 g (99%) of 9e that was recrystallized
from acetone, mp 205±2078C (dec). IR (KBr) 3301, 3040,
3020, 2918, 2850, 1616, 1612, 1596, 1522, 1508, 1498,
1472, 1458, 1436, 1420, 1298, 1290, 1256, 1216, 1208,
1158, 1122, 860, 798, 734, 688, 668 cm21 1H NMR
;
4.2.2. 2,20-(1,2-Ethanediyldiimino)-4,40-dimethylbisphe-
nol34 (9b). To a solution of 8b (3.7 g, 13.8 mmol) in
50 mL THF, 13.5 mL (27.6 mmol) of BH3±THF was
added. After work-up the solid was washed with acetone
to give 3.5 g (93%) of 9b, that was recrystallized from
(400 MHz, DMSO-d6) d 9.54 (2H, s, NH), 6.60 (2H, d,
Jˆ8.4 Hz, H-6,60), 6.51 (2H, d, Jˆ1.8 Hz, H-3,30), 6.38
(2H, dd, Jˆ8.4 Hz, 1.8, H-5,50), 3.67 (2H, brs, OH), 3.24
(4H, s, (CH2)2); 13C NMR (100 MHz, DMSO-d6) d 143.4

M. E. Ochoa et al. / Tetrahedron 57 (2001) 55±64
61
(C-1), 139.3 (C-2), 124.0 (C-4), 114.9 (C-6), 114.4 (C-3),
109.2 (C-5), 41.9 (CH2); MS (EI, 70 eV) m/z (%) 312 (M1,
30), 313 (M111, 8), 314 (M112, 20), 315 (M113, 5), 316
(M114, 4), 159 (27), 158 (40), 157 (78), 156 (M1/2, 100),
129 (25), 93 (18); Anal. calcd for C14H14N2O2Cl2: C, 53.70;
H, 4.47; N, 8.95; Cl, 22.69; Found: C, 53.6; H, 4.47; N, 8.81.
7.3 Hz, H-3,11), 5.31 (2H, d, Jˆ5.8 Hz, H-6,8), 4.19 (2H, s,
H-6a,7a), 4.14 (2H, AA0BB0, H-15,16) 3.23 (2H, AA0BB0,
H-150,160); 13C NMR (100 MHz, DMSO-d6) d 141.5
(C-4a), 130.4 (C-13a), 122.0 (C-2), 119.0 (C-3), 117.1
(C-4), 111.4 (C-1), 89.0 (C-6), 82.3 (C-6a), 46.8 (C-15);
MS (EI, 70eV) m/z (%) 342 (M1, 27), 343 (M111, 6),
324 (M1-H2O, 5), 284 (19), 266 (42), 221 (23), 175 (3),
147 (18), 121 (6), 119 (100), 93 (15), 91 (28), 65 (34);
Anal. calcd for C18H18N2O5: C, 63.16; H, 5.29; N, 8.18;
Found: C, 62.85; H, 5.26; N, 8.11.
4.2.6. 2,20-(1,2-Ethanediyldiimino)-4,40-tert-butylbisphe-
nol36 (9f). To a solution of 8f (1.0 g, 2.84 mmol) in 50 mL
THF, 2.8 mL (5.68 mmol) of BH3±THF was added, 4 h
re¯ux, 0.72 g (68%) yield that was recrystallized from
ethanol, mp 180±1828C [Lit36 mp 1958C]. IR (KBr) 3368,
3332, 3220, 3068, 2962, 2906, 1598, 1524, 1500, 1464,
4.3.2. 6,6a,7a,8,15,16-Hexahydro-2,12-dimethyl-[1,4]benz-
oxazino[40,30:6,7][1,3,6]-oxadiazepino[2,3-c][1,4]benzoxa-
zine-6,8-diol (10b). Glyoxal (1.1 g, 9.55 mmol) was added to
9b (1.3 g, 4.78 mmol) to yield 660 mg (36 %) of 10b that was
recrystallized from EtOH, mp 210±2128C. IR (KBr) 3334,
2918, 2360, 1616, 1514, 1466, 1346, 1276, 1254, 1216,
1200, 1096, 1052, 1042, 998, 668 cm21;1H NMR
(400 MHz, DMSO-d6) d 6.89 (2H, d, Jˆ5.5 Hz, OH-6,8),
6.75 (2H, s, H-1,13), 6.64 (2H, d, Jˆ8.0 Hz, H-4,12), 6.48
(2H, d, Jˆ8 Hz, H-3,11), 5.23 (2H, d, Jˆ5.5 Hz, H-6,8), 4.15
(2H, s, H-6a,7a), 4.11 (2H, AA0BB0, H-15,16), 3.20 (2H,
AA0BB0, H-150,160), 2.23 (6H, s, CH3-2,12); 13C NMR
(100 MHz, DMSO-d6) d 139.3 (C-4a), 130.7 (C-13a), 130.1
(C-2), 119.2 (C-2), 116.7 (C-4), 111.9 (C-1), 88.9 (C-6), 82.3
(C-6a), 46.7 (C-15), 21.3 (CH3-2,12); MS (EI, 70 eV) m/z (%)
371 (M111, 9), 370 (M1, 40), 323 (14), 312 (34), 294 (20),
249 (40), 176 (21), 160 (22), 148 (30), 134,(98), 133 (100), 77
(64), 65 (30); Anal. calcd for C20H22N2O5.H2O: C, 61.85; H,
6.18; N, 7.21; Found: C, 61.87; H, 6.18; N, 7.06.
1414, 1362, 1278, 1264, 1192, 1132 cm21 1H NMR
;
(270 MHz, DMSO-d6) d 9.04 (2H, s, NH), 6.57 (2H, d,
Jˆ1.0 Hz, H-3,30), 6.56 (2H, d, Jˆ8.0 Hz, H-6,60), 6.42
(2H, dd, Jˆ8.0, 1.0 Hz, H-5,50), 4.91 (2H, br, OH), 3.31
(4H, s, (CH2)2), 1.21 (18H, s, C(CH3)3-4,40); 13C NMR
(67.9 MHz, DMSO-d6) d 142.6 and 142.3 (C-1 and C-4),
137.0 (C-2), 113.4 (C-6), 112.9 (C-5), 108.0 (C-3), 43.0
(CH2). 34.4 (C(CH3)3), 32.1 (C(CH3)3); MS (EI, 70 eV)
m/z (%) 356 (M1, 29), 357 (M111, 9), 179 (100), 164
(20), 162 (12), 148 (8), 133 (8), 122 (9), 57 (18). HRMS
calcd for C22H32N2O2: 356.2464. Found: 356.2460. Error
21.1 ppm.
4.2.7. 2,20-(1,2-Ethanediyldiimino)-3,30-dimethylbisphe-
nol (9g). To a solution of 8g (1.0 g, 3.73 mmol) in 50 mL
THF, 3.73 mL (7.46 mmol) of BH3±THF was added, 530
mg (52%) yield that was recrystallized from acetone, mp
170±1738C (dec). IR (KBr) 3330, 3050, 2982, 2940, 2850,
2674, 1586, 1482, 1454, 1352, 1338, 1270, 1240, 1186,
4.3.3. 6,6a,7a,8,15,16-Hexahydro-3,11-dimethyl-[1,4]benz-
oxazino[40,30:6,7][1,3,6]oxadiazepino[2,3-c][1,4]benzoxa-
zine-6,8-diol (10c). Glyoxal (0.85 g, 5.88 mmol) was added
to 9c. (0.8 g, 2.94 mmol), 260 mg (24%) of 10c were
obtained, mp 178±1798C, that was recystallized from ethanol.
IR (KBr) 3416, 1514, 1286, 1244, 1184, 1062, 996,
1108, 1014, 946, 932, 788, 778, 772, 748, 738, 662 cm21
;
1H NMR (400 MHz, acetone-d6) d 6.77 (2H, dd, Jˆ8.0,
7.7 Hz, H-5,50), 6.65 (2H, d, Jˆ8.0 Hz, H-6,60), 6.61 (2H,
d, Jˆ7.7 Hz, H-4,40), 3.16 (4H, s, (CH2)2), 2.31 (6H, s, CH3-
3,30); 13C NMR (100 MHz, DMSO-d6) d 149.6 (C-1), 135.8
(C-2), 129.9 (C-3), 122.1 (C-5), 121.4 (C-4), 113.3 (C-6),
48.3 (CH2), 18.6 (CH3); MS (EI, 70 eV,) m/z (%) 272 (M1,
22), 273 (M111, 15), 137 (79), 136 (100), 109 (24), 91 (15),
77 (16), 65 (10); HRMS calcd for C16H20N2O2: 272.1525.
Found: 272.1527. Error 20.9 ppm.
1
878, cm21; H NMR (270 MHz,DMSO-d6) d 6.94 (2H, d,
Jˆ5.5 Hz, OH-6,8), 6.81 (2H, d, Jˆ8.2 Hz, H-1,13), 6.67
(2H, d, Jˆ8.2 Hz, H-2,12), 6.62 (2H, s. H-4,10), 5.27 (2H,
d, Jˆ5.5 Hz, H-6,8), 4.15 (2H, s, H-6a,7a), 4.07 (2H,
AA0BB0,H-15,16), 3.20 (2H, AA0BB0, H-150,160), 2.14 (6H,
s, CH3-3,11); 13C NMR (67.9 MHz, DMSO-d6) d 141.5
(C-4a), 128.1 and 127.9 (C-3 and C-13a), 122.3 (C-2),
117.7 (C-4), 111.3 (C-1), 89.3 (C-6), 82.4 (C-6a), 46.71
(C-15), 20.7 (CH3-3); MS (EI, 70 eV) m/z (%) 370 (M1,
19), 371 (M111, 4), 312 (22), 295 (11), 294 (26), 249 (24),
176 (11), 161 (14), 160 (12), 148 (14), 147 (11), 134 (50), 133
(100), 132 (22), 107 (13), 106 (12), 79 (15), 78 (20), 77 (25),
65 (12), 43 (22). HRMS calcd for C20H22N2O5: 370.1529.
Found: 370.1531. Error 20.6 ppm.
4.3. General procedure for the preparation of 6,6a,7a,8,
15,16-hexahydro[1,4]benzoxazino[40,30:6,7][1,3,6]-
oxadiazepino[2,3-c][1,4]benzoxazine-6,8-diol (10)
To a solution of 2,20-(1,2-ethanediyldiimino)bisphenol (1.0
mmol) in 25 mL of EtOH±ethyl acetate (9:1) 2.0 mmol of
40% aqueous glyoxal was added dropwise and the solution
was re¯uxed for 5 h. The solution was concentrated, the
precipitate washed with EtOH and the product recrystallized
from ethanol.
4.3.4. 6,6a,7a,8,15,16-Hexahydro-2,12-dinitro-[1,4]benz-
oxazino[40,30:6,7][1,3,6]-oxadiazepino[2,3-c][1,4]benz-
oxazine-6,8-diol (10d). Glyoxal (0.54, 3.7 mmol) was
added to 9d (0.62 g, 1.85 mmol). After work-up 300 mg
(37%) of 10d were obtained, mp 211±2138C. IR (KBr)
3412, 1518, 1344, 1316, 1272, 1246, 1228, 1056,
4.3.1. 6,6a,7a,8,15,16-Hexahydro[1,4]benzoxazino[40,30:
6,7][1,3,6]oxadiazepino[2,3-c][1,4]benzoxazine-6,8-diol
(10a). Glyoxal (0.59 g, 4.1 mmol) was added to 9a (0.5 g,
2.04 mmol) to yield 0.26 g (38%) of 10a that was recrystal-
lized from EtOH, mp 2018C. IR (KBr) 3252, 1506, 1350,
1
994 cm1; H NMR (400 MHz, DMSO-d6) d 7.78 (2H, d,
1238, 1216, 1058, 1042, 1010, 742 cm21
;
1H NMR
Jˆ2.5 Hz, H-1,13), 7.68 (2H, dd, Jˆ8.6, 2.5 Hz, H-3,11),
7.55 (2H, d, Jˆ5.7 Hz, OH), 7.03 (2H, d, Jˆ8.6 Hz,
H-4,10), 5.46 (2H, d, Jˆ5.7 Hz, H-6,8), 4.36 (2H, s,
H-6a,7a), 4.34 (2H, AA0BB0, H-15,16), 3.41 (2H, AA0BB0,
(400 MHz, DMSO-d6) d 7.01 (2H, d, Jˆ5.4 Hz, OH),
6.94 (2H, d, Jˆ7.7 Hz, H-1,13), 6.87 (2H, t, Jˆ7.7 Hz, H-
2,12), 6.80 (2H, d, Jˆ7.3 Hz, H-4,10), 6.70 (2H, dd, Jˆ7.7,

62
M. E. Ochoa et al. / Tetrahedron 57 (2001) 55±64
H-150,160); 13C NMR (100 MHz, DMSO-d6) d 147.4
(C-4a), 142.5 (C-2), 130.9 (C-13a), 117.4 (C-4), 115.5
(C-3), 106.6 (C-1), 89.64 (C-6), 81.8 (C-6a), 47.0 (C-15);
MS (EI, 70eV, DIP) m/z (%) 414 (M1-H2O, 0.4), 385 (2),
356 (26), 207(27), 192 (19), 178 (11), 165 (20), 164 (47),
134 (14), 73 (11), 70(21), 61 (25), 45 (39), 44 (52), 43 (100);
Anal. calcd for C18H16N4O9: C, 50.00; H, 3.70; N, 12.96;
Found: C, 49.93; H, 4.08; N, 12.17.
After work-up 220 mg (73%) of 11b were obtained, mp 187±
1888C. IR (KBr) 3336, 3032, 2916, 2852, 1610, 1516, 1458,
1438, 1368, 1354, 1312, 1278, 1208, 1190, 1102, 1054, 1038,
1
930, 796 cm21; H NMR (300 MHz, DMSO-d6) d 7.05(2H,
br, OH), 6.55 (2H, d, Jˆ7.9 Hz, H-8,80), 6.48 (2H, s, H-5,50),
6.32 (2H, d, Jˆ7.9 Hz, H-7,70), 5.21 (2H, t, Jˆ2.5 Hz,
H-2,20), 3.43 (4H, s, (CH2)2), 3.11 (4H, br, H-3a,3b,3a0,3b0),
2.13 (6H, s, Me); 13C NMR (75.5 MHz, DMSO-d6) d 140.4
(C-8a), 134.7 (C-4a), 130.7 (C-6), 118.0 (C-7), 116.8 (C-8),
112.6 (C-5), 90.1 (C-2), 52.9 (C-3) 47.6 (C-9). 21.7 (CH3);
MS (EI, 70 eV, DIP) m/z (%) 356 (M111, 38), 179 (12), 178
(M1/2, 100), 148 (52), 91 (10), 79 (12), 77 (16). Anal. calcd
for C20H24N2O4: C, 67.41; H, 6.74; N,7.86; Found: C, 67.18;
H, 6.72; N, 7.79.
4.3.5. 6,6a,7a,8,15,16-Hexahydro-2,12-dichloro-[1,4]benz-
oxazino[40,30:6,7][1,3,6] oxadiazepino [2,3-c][1,4]benzoxa-
zine-6,8-diol (10e). Glyoxal (0.78 g, 5.4 mmol) was added to
9e (0.85 g, 2.72 mmol), 36% (400 mg) yield of 10e, mp 219±
222 8C (dec). IR (KBr) 3288, 1676, 1604, 1502, 1354, 1214,
1
1206, 1096, 1052, 1040, 1000, 836, 804 cm21; H NMR
(300 MHz, DMSO-d6) d 7.40 (2H, brs, OH), 7.03 (2H, d,
Jˆ2.2 Hz, H-1,13), 6.79 (2H, d, Jˆ8.5 Hz, H-4,10), 6.71
(2H, dd, Jˆ8.5, 2.2 Hz, H-3,11), 5.31 (2H, d, Jˆ1.3 Hz,
H-6,8), 4.22 (2H, d, Jˆ1.3 Hz, H-6a,7a), 4.16 (2H,
AA0BB0,H-15,16), 3.23 (2H, AA0BB0, H-150,160); 13C
NMR (75.5 MHz, DMSO-d6) d 140.6 (C-4a), 132.2
(C-13a), 126.2 (C-2), 118.7 (C-3,4), 111.5 (C-1), 89.2
(C-6), 82.4 (C-6a), 47.3 (C-15); MS (EI, 70 eV, DIP) m/z
(%) 412 (M111), 352 (35), 334 (27), 289 (33), 153 (100),
77 (17); Anal. calcd for C18H16N2O5Cl2: C, 52.58; H, 3.89; N,
6.81; Found: C, 52.46; H, 3.91; N, 7.06.
4.5. General procedure for the preparation of N,N0-
ethylene-2,20-bisbenzoxazolidines (12)
To a solution of the appropriate bisphenol (1.0 mmol)
1.0 mmol of 40% aqueous glyoxal was added dropwise
and the solution was re¯uxed for 24 h using a Dean Stark
trap. The solvent was evaporated under vacuum and the
residue washed with acetone. Attempts to recrystallize the
products by column chromatography or crystallization
caused extensive hydrolysis and recovery of the starting
materials.
4.4. General procedure for the preparation of 4,40-(1,2-
ethanediyl)-bis(3,4)dihydro-2H-benzo[1,4]-oxazin-2-ol
(11)
4.5.1. N,N0-Ethylene-2,20-bisbenzoxazolidine (12a). It
was prepared as reported.25
4.5.2. N,N0-Ethylene-5,50-dimethyl-2,20-bisbenzoxazoli-
dine (12b). Glyoxal (0.16 g, 1.10 mmol) was added to 9b
(0.3 g, 1.10 mmol) in 25 mL toluene:ethanol (9:1) and the
solution was re¯uxed 4 h. After work-up 150 mg (47%) of
12b were obtained, mp 168±1708C. IR (KBr) 2918, 2854,
1612, 1508, 1496, 1472, 1464, 1442, 1370, 1352, 1336,
To a solution of the appropriate oxadiazepine (1.0 mmol) in
20 mL of THF, 1.46 mmol of BH3±THF was added drop-
wise and the reaction was kept under re¯ux for 2 h. After
cooling to room temperature, a few drops of 10% NaOH
were added, the solution was dried over Na2SO4 and the
solvent was evaporated under vacuum. The solid residue
was washed with ethanol.
1
1276, 1262, 1218, 1180, 982 cm21; H NMR (DMSO-d6,
270 MHz) d 6.60 (2H, d, Jˆ7.9 Hz, H-7,70), 6.47 (2H, s,
H-4,40), 6.37 (2H, d, Jˆ7.9 Hz, H-6,60), 5.39 (2H, s,
H-2,20), 3.67 and 3.16 (4H, AA0BB0, H-8a,8a0,8b,8b0),
2.17 (6H, s, CH3); 13C NMR (DMSO-d6, 67.9 MHz) d
147.9 (C-7a), 138.2 (C-3a), 131.6 (C-5), 119.0 (C-6),
108.1 (C-7), 107.9 (C-4), 93.6 (C-2), 42.0 (C-8), 21.5
(CH3); MS (EI, 70 eV, DIP) m/z (%) 294 (M1, 45), 295
(M111, 9), 161 (25), 133 (100), 132 (20), 91 (5), 78 (18)
77 (14), 65 (10).
4.4.1. 4,40-(1,2-Ethanediyl-bis(3,4)dihydro-2H-benzo[1,4]-
oxazin-2-ol (11a). Prepared from 10a (0.25 g, 0.73 mmol)
and 0.73 mL (1.46 mmol) of BH3±THF. The solid residue
was washed with ethanol to yield 122 mg (48%) of 11a,
mp 120±1218C. IR (KBr) 3446, 3216, 2918, 2850, 1606,
1504, 1470, 1458, 1358, 1282, 1238, 1200, 1170, 1110,
1048, 932, 816, 806, 740 cm21; 1H NMR (400 MHz,
DMSO-d6) d 7.12 (2H, d, Jˆ2.6 Hz, OH), 7,10 (2H, d,
Jˆ2.6 Hz, OH), 6.74 (2H, ddd, Jˆ8.0, 7.6, 1.5 Hz, H-6,60),
6.68 (2H, dd, Jˆ8.0, 1.5 Hz, H-5,50), 6.67 (2H, dd, Jˆ7.6,
1.5 Hz, H-8,80), 6.53 (2H, ddd, Jˆ7.6, 1.5 Hz, H-7,70), 5.28
(2H, d, Jˆ4.8 Hz, H-2,20), 3.45 (4H, brs, (CH2)2), 3.38 (2H,
d, Jˆ11.5 Hz, H-3a,3a0), 3.12 (2H, dt, Jˆ11.5, 4.8 Hz,
H-3b,3b0); 13C NMR (100 MHz, DMSO-d6) d 142.3
(C-8a), 134.7 (C-4a), 121.8 (C-6), 117.3 (C-7), 116.7 (C-8),
111.6 (C-5), 89.8 (C-2), 52.5 and 52.4 (C-3) 47.5 and 47.4
(C-9); MS (EI, 70 eV, DIP) m/z (%) 328 (M1, 26), 329
(M111, 5), 165 (11), 164 (M1/2, 100), 134 (70), 106 (22),
93 (11), 77 (14), 65 (23). HRMS calcd for C18H20N2O4:
328.1423. Found: 328.142. Error 20.6 ppm
4.5.3. N,N0-Ethylene-6,60dimethyl-2,20-bisbenzoxazoli-
dine (12c). Glyoxal (0.26 g, 1.83 mmol) was added to 9c
(0.5 g, 1.83 mmol) in benzene±ethanol (9:1), 4 h re¯ux. The
residue washed with hexane: ethyl acetate to yield 220 mg
(41%) of 12c, mp 172±173 8C. IR (KBr) 2918, 2850, 1506,
1494, 1472 cm21;1H NMR (CDCl3, 300 MHz) d 6.62 (2H,
d, Jˆ7.8 Hz, H-5,50), 6.61 (2H, brs, H-7,70), 6.37 (2H, d,
Jˆ7.8 Hz, H-4,40), 5.44 (2H, s H-2,20), 3.50 and 3.32 (4H,
AA0BB0, H-8a,8b,8a0,8b0). 13C NMR (CDCl3, 75.5 MHz) d
150.5 (C-7a), 135.9 (C-3a), 129.9 (C-6), 122.2 (C-5), 110.3
(C-7), 106.5 (C-4), 94.2 (C-2), 43.0 (C-8), 21.5 (CH3); MS
(EI, 70 eV, DIP) m/z (%) 294 (M1, 32), 295 (M111, 7), 161
(17), 134 (12), 133 (100), 132 (20), 106 (9), 78 (21), 77 (15).
4.4.2. 4,40-(1,2)-Ethanediyl-bis(3,4)dihydro-2H-benzo[1,4]-
oxazin-6-methyl-2-ol (11b). Prepared from oxadiazepine 10b
(0.31 g, 0.84 mmol) and 0.84 mL (1.7 mmol) of BH3±THF.
4.5.4. N,N0-Ethylene-5,50dichloro-2,20-bisbenzoxazoli-
dine (12e). Glyoxal (0.25 ml, 2.24 mmol) was added to 9e

M. E. Ochoa et al. / Tetrahedron 57 (2001) 55±64
63
7. Le Rouzic, A.; Maunaye, M.; L'Haridon, P. J. Chem. Res. (S)
1985, 35.
  Â
8. Farfan, N.; Santillan, R.; Guzman, J.; Castillo, B.; Ortõz, A.;
(0.7 g, 2.24 mmol) in ethyl acetate. The residue was washed
with ethyl acetate to yield 489 mg (62%) of 12e, mp 205±
2068C. IR (KBr) 2922, 2360, 1486, 1254, 1236, 1184 cm21
;
1H NMR (DMSO-d6, 400 MHz) d 6.75 (2H, d, Jˆ1.8 Hz,
H-4,40), 6.71 (2H, d, Jˆ8.0 Hz, H-7,70), 6.56 (2H, dd,
Jˆ8.0, 1.8 Hz, H-6,60), 5.61 (2H, s H-2,20), 3.79 and 3.21
(2H each, AA0BB0, H-8a,8b,8a0,8b0). 13C NMR (DMSO-d6,
100 MHz) d 148.9 (C-7a), 139.6 (C-3a), 126.5 (C-5), 117.8
(C-6), 109.1 (C-7), 106.7 (C-4), 93.8 (C-2), 40.2 (C-8); MS
(EI, 70eV, DIP) m/z (%)338 (M114, 2) 337 (M113, 3),
336(M112, 14), 335 (M111, 4), 334 (M1, 21), 181 (20),
155 (32), 153 (100), 125 (14), 63 (25). HRMS 334.0276.
Calcd for C16H12Cl2N2O2. Found: 334.0280. Error
11.3 ppm.
Daran, J.-C.; Robert, F.; Halut, S. Tetrahedron 1994, 50, 9951.
È
 Â
9. Ortõz, A.; Carrasco, J.; Hop¯, H.; Santillan, R.; Farfan, N.
Synth. Commun. 1998, 28, 1293.
10. Weisman, G. R.; Ho, S. C. H.; Johnson, V. Tetrahedron Lett.
1980, 21, 335.
11. Nielsen, A. T.; Nissan, R. A.; Vanderah, D. J.; Coon, C. L.;
Giraldi, R. D.; George, C. F.; Flippen-Anderson, J. J. Org.
Chem. 1990, 55, 1459.
12. Tkaczynska, D. Wiad. Chem. 1972, 26, 755; Chem. Abs. 1973,
78: R 29649q.
13. Woodcock, D. J. Chem. Soc. 1949, 1635.
14. Myers, G. S.; Wright, G. F. Can. J. Res. 1949, 27B, 489;
Chem. Abs. 1949, 43: 9074d.
4.5.5. N,N0-Ethylene-5,50-ditertbutyl-2,20-bisbenzoxazol-
idine (12f). Glyoxal (0.24 g, 1.68 mmol) was added to 9f
(0.6 g, 1.68 mmol) in benzene:ethanol (9:1), 4 h re¯ux. The
residue was washed with hexane: ethyl acetate to yield
200 mg (32%) of 12f, mp 204±2058C. IR (KBr) 2958,
2918, 2850, 1636, 1622, 1616, 1604, 1540, 1522, 1500,
1474, 1466, 1458, 1436, 1354, 1290, 1268, 1248, 1218,
15. Majer, J.; Denkstein, J. Coll. Czech. Chem. Commun. 1966,
31, 2547; Chem. Abs. 1966, 65: 7042d.
16. Daeniker, H. U.; Druey, J. Helv. Chim. Acta 1957, 40,
918.
17. Druey, J.; Daeniker, H. U. Swiss P1962, 358, 430; Chem. Abs.
1963, 59: P11530a.
;
1192, 1144, 1050, 816 cm21 1H NMR (DMSO-d6,
18. Ishiwata, S.; Shiokawa, Y. Chem. Pharm. Bull. 1970, 18,
1245.
400 MHz) d 6.71 (2H, s, H-4,40), 6.62 (2H, d, Jˆ8.0 Hz,
H-7,70), 6.55 (2H, d, Jˆ8.0 Hz, H-6,60), 5.42 (2H, s,
H-2,20), 3.68 and 3.26 (2H each, AA0BB0, H-8a,8b,8a08b0),
1.23 (18H, s, C(CH3)3). 13C NMR (DMSO-d6, 100 MHz) d
147.7 (C-7a), 145.4 (C-5), 137.9 (C-3a), 115.1 (C-6), 107.4
(C-7), 104.6 (C-4), 93.8 (C-2), 42.1 (C-8), 34.8 (C(CH3)3),
32.0 (C(CH3)3); MS (EI, 70eV, DIP) m/z (%) 379 (M111,
9), 378 (M1, 33), 203 (M, 22), 175 (M, 23), 161 (14), 160
(100), 132 (18), 41 (12). HRMS 378.2307. Calcd for
C24H30N2O2 Found: 378.2319. Error 13.1 ppm.
19. O'Connell, A. J; Peck, C. J.; Sammes, P. G. J. Chem. Soc.
Chem. Commun. 1983, 399.
20. Autio, K.; Pyysalo, H. J. Agri. Food. Chem. 1983, 31,
568.
21. Krakowiak, K.; Idowski, P.; Kotelko, B. Polish J. Chem. 1984,
58, 251; Chem. Abs. 1985, 103, 37462y.
22. Kaneko, C.; Yamada, S.; Yokoe, I.; Ishikawa, M. Tetrahedron
Lett. 1967, 1873.
23. Buchardt, O.; Feeney, J. Acta Chem. Scand. 1967, 21,
1899.
24. Buchardt, O.; Jensen, B. Acta Chem. Scand. 1968, 22,
877.
5. Supporting information available
 Â
25. Ortõz, A.; Farfan, N.; Hop¯, H.; Santillan, R.; Ochoa, M. E.;
È
Tables of atomic coordinates, thermal parameters, bond
lengths and angles and observed and calculated structure
factors have been deposited at the Cambridge Crystallo-
graphic Data Center.
Â
Gutierrez, A. Tetrahedron: Asymmetry 1999, 10, 799.
26. Barluenga, J.; Aznar, F.; Liz, R.; Cabal, M.-P.; Cano, F. H.;
Foces-Foces, C. Chem. Ber. 1986, 119, 887.
27. Tauer, E.; Grellmann, K.-H.; Kaufmann, E.; Noltemeyer, M.
Chem. Ber. 1986, 119, 3316.
28. Tauer, E.; Grellmann, K.-H. Chem. Ber. 1990, 123, 1149.
29. Fuchs, B. Tetrahedron Lett. 1970, 1747.
Acknowledgements
30. Wilkinson, R. G.; Cantrall, M. B.; Shepherd, R. G. J. Med.
Pharm. Chem. 1962, 5, 835.
Financial support from CONACYT is gratefully acknowl-
 Â
edged. The authors wish to thank Marõa Luisa Rodrõguez for
NMR spectra.
31. Hinshaw, C. J.; Peng, G.; Singh, R.; Spence, J. T.; Enemark,
J. H.; Bruck, M.; Kristofzski, J.; Merbs, S. L.; Ortega, R. B.;
Wexler, P. A. Inorg. Chem. 1989, 28, 4483.
32. Hunig, S.; Scheutzow, D.; Schlaf, H.; Quast, H. Liebigs Ann.
Chem. 1972, 765, 110.
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