A convenient methodology for the in situ oxidation of 4-substituted urazoles. Setting UP a one-pot procedure for the efficient protection of dienes

Article abstract of DOI:10.3987/COM-12-12637

The oxidation of 4-substituted urazoles to the corresponding 1,2,4-triazoline-3,5-diones can be performed selectively in the presence of dienic systems by the action of the nitrosonium ion, formed in situ by stoichiometric amounts of sodium nitrite and ac

Full text of DOI:10.3987/COM-12-12637

HETEROCYCLES, Vol. 87, No. 3, 2013, pp. -. © The Japan Institute of Heterocyclic Chemistry
Received, 25th November, 2012, Accepted, 11th January, 2013, Published online, 16th January, 2013
DOI: 10.3987/COM-12-12637
A CONVENIENT METHODOLOGY FOR THE IN SITU OXIDATION OF
4-SUBSTITUTED URAZOLES. SETTING UP A ONE-POT PROCEDURE
FOR THE EFFICIENT PROTECTION OF DIENES
María A. Fernández-Herrera, Jesús Sandoval-Ramírez,* Sara Montiel-Smith,
and Socorro Meza-Reyes
Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla,
72570 Puebla, Pue., Mexico; E-mail: jesus.sandoval@correo.buap.mx
Abstract – The oxidation of 4-substituted urazoles to the corresponding
1,2,4-triazoline-3,5-diones can be performed selectively in the presence of dienic
systems by the action of the nitrosonium ion, formed in situ by stoichiometric
amounts of sodium nitrite and acetic acid. This convenient methodology is mild,
fast, and allows the efficient protection of dienic systems in a one-pot procedure.
The dienes were not affected whatsoever by the nitrosonium ion, and react
extremely fast with triazolinediones; promptly forming the corresponding
Diels-Alder cycloadducts in good to excellent yields. The reaction medium did
not affect steroids having an extra double bond at the side chain or an acid-labile
spiroketal moiety.
INTRODUCTION
The 4-substituted 1,2,4-triazoline-3,5-diones (TADs) are very versatile reagents in various organic
reactions including Diels-Alder reactions,1 electrophilic aromatic substitutions,2 dehydrogenations,3
oxidations of alcohols or thiols,4 and condensations.5 The formation of Diels-Alder cycloadducts is
essential, for instance, for multicomponent strategies and in the field of the chemistry of protecting groups,
among others. In order to protect labile dienes, many dienophiles have been employed, and among them
4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) displayed notable preference because its ability to form
Diels-Alder cycloadducts at low temperatures; although it might participate in ene reactions.6 It has been
reported that PTAD; the “Cookson reagent”,7 is an extremely reactive dienophile; for example, it has
demonstrated to be 1000 times more reactive than tetracyanoethylene,8 and 2000 times more reactive than
maleic anhydride.9 Most of TADs are obtained in moderate to good yields; however, in spite of the fact
that a variety of methodologies for the preparation of TADs have been reported so far, this transformation
is challenging. Commonly, TADs are prepared from the oxidation of the corresponding urazoles and

several reagents for the oxidation of urazoles have been reported, such as
1,3,4,6-tetrachloro-3α,6α-diphenylglycoluril (also known as iodogen),10 iodobenzene diacetate,11 t-butyl
hypochlorite,12 calcium hypochlorite,13 potassium dichromate,14 phenylseleninic anhydride and
phenylseleninic acid,15 NBS,16 OXONE (potassium peroxomonosulfate),17 triphenylbismuth carbonate,18
among others. Many of those reagents involve: long reaction times, special care to be manipulated, high
costs, higroscopicity, photosensitivity, lack of selectivity, dangerousness, and tedious or fancy
preparation/work-up procedures. To date, most reagents currently used in the preparation of TADs result
in the formation of by-products that either decompose or are difficult to remove. TADs are very useful
but highly reactive and sensitive. It is of interest, therefore, to search for new mild synthetic methods.
RESULTS AND DISCUSSION
We were interested in developing a mild method for the preparation of 1,2,4-triazoline-3,5-dione
derivatives. For this purpose, we found that upon stoichiometric quantities of nitrosonium ion (generated
from sodium nitrite and acetic acid), urazoles 1a-d can readily be transformed into the corresponding
TADs 2a-d. A plausible mechanism for this reaction involves the in situ generation of the nitrosonium ion
acting as the oxidizing species. Subsequent elimination of nitroxyl then yields the
1,2,4-triazoline-3,5-dione moiety (Scheme 1). The oxidation reactions were performed in ethyl acetate at
room temperature, since urazoles exhibited high solubility under such conditions. In our hands, ethyl
acetate showed to be the best solvent for urazoles, providing excellent yields and reaction times. Other
solvents currently employed (as methylene chloride or THF), did not dissolve urazoles rapidly; hence
poor yields and long reaction times were obtained instead.
Nitrosonium ion formation from NaNO2 and AcOH
O
O
H
O
H
O
Na+
N
N
N
N
O
O+
-H2O
HO
O+
H2O
O
O
O
O
Urazole oxidation
H
O
O
H
N
H
H
H
H
N
N
N
N
N
N
N
N
N
N
O
O
-HNO
N
R
O
O
O
O
O
N
R
N
R
N
R
TAD (2)
4-substituted urazole (1)
OMe
c
a
R=
R=
b
N
R=
NO2
d
R=
N
Scheme 1. A plausible mechanism for the formation of the nitrosonium ion, and the subsequent oxidation
of urazoles to TADs.

Due to their high reactivity, TADs are difficult to purify and decompose easily. Nevertheless, we trapped
such dienophiles in situ through a Diels-Alder cycloaddition using the dienes ergosteryl benzoate (3),
(25R)-spirosta-5,7-dien-3-yl benzoate (4), and anthracene (5). This convenient one-pot method made
available a series of cycloadducts (6-8) in excellent yields, involving two in situ reactions and without
by-products. Reactions were readily performed at room temperature, and the resulting cycloadducts were
purified by column chromatography and properly characterized (Scheme 2).
H
H
N
N
NaNO2/AcOH
AcOEt
O
O
N
R
N
BzO
O
N
1a-d
BzO
N
ergosteryl benzoate (3)
a R = C6H5
b R = C6H4-p-NO2
c R = N=CHC6H5
O
R
6a d
-
d R = N=CHC6H4-p-OMe
O
O
H
H
N
N
NaNO2/AcOH
AcOEt
O
O
O
O
N
R
N
N
1a-d
BzO
BzO
(25R)-spirosta-5,7-dien-3 -yl benzoate ( )
O
N

4
O
R
7a d
-
R
N
H
H
O
N N
N
NaNO2/AcOH
AcOEt
N
O
O
O
N
R
1a-d
anthracene (5)
8a d
-
Scheme 2. In situ formation of Diels-Alder cycloadducts.
The reaction times and yields of the resulting Diels-Alder cycloadducts using 4-substituted urazoles are
presented in Table 1. Entries 1-4 and 5-8 show cycloadducts derived from steroidal dienes (3 and 4)
showing excellent yields in short reaction times. For anthracene cycloadducts (entries 9-12), yields were
lower under the same tested conditions. Anthracene (5) is a more stable diene which was slowly dissolved
in ethyl acetate, and when a mixture of solvents was used in equal amounts (EtOH/CH2Cl2 1:1)
anthracene cycloadducts were improved obtaining quantitative yields.

Table 1. Reaction times and yields for the Diels-Alder cycloadducts series 6-8.
Entry
Urazole
Diene
Cycloadduct
Time (min) Yield (%)a
1
2
1a
1b
1c
1d
1a
1b
1c
1d
1a
1b
1c
1d
6a
6b
6c
6d
7a
7b
7c
7d
8a
8b
8c
8d
5
7
98
99
98
96
97
96
98
98
88
80
82
75
3
3
5
4
5
5
5
6
7
4
7
5
8
5
9
8
10
11
12
15
12
12
5
a Yields are reported after purification by column chromatography.
It is worth noting that for urazoles 1c-d, the imino group was not attacked by the nitrosonium ion in any
case. In this fashion, substituted arylidenaminourazoles could be selectively obtained, due to the fact that
4-aminourazole can be easily synthesized from non-expensive reagents, and readily reacts with
aldehydes.19 In order to evaluate the selective oxidation of urazoles and the subsequent formation of the
corresponding cycloadducts, the NMR spectra of all products were recorded. The C-22 double bond of 3
did not undergo the addition of the nitrosonium ion. In the case of spirostans, it is reported that, in the
presence of an acidic medium, the C-23 could be rapidly attacked by the nitrosonium ion; and the
resulting intermediate can be hydrolyzed to provide 23-oxospirostans.20 NBS could have reacted in allylic
positions of 3 and 4. On the other hand, oxidizing agents like OXONE, t-butyl hypochlorite, and
potassium dichromate readily react with the spiroketal moiety of 4. These side-reactions were not
observed when the steroidal dienes were employed under the abovementioned conditions; hence, high
regioselectivity was found in the proposed methodology; since most of oxidizing agents are not selective

with other functional groups. It means that the nitrosonium ion exclusively and rapidly reacts with
urazoles. In our hands, PTAD was isolated,21 but yields were poor. If TADs are trapped in situ as the
proposed methodology suggests, yields of the cycloadducts become excellent instead. The formation of
the steroidal cycloadducts can be confirmed by the characteristic signals for H-6 and H-7 for 6a and 7a
which are shifted towards 6.20-6.50 ppm as an AB system. For 8a the signal for H-9 and H-10 is
displayed in 6.34 ppm as a sharp singlet. In the range of 7.00-8.00 ppm, aromatic protons appear for all
compounds. The steroidal angular methyls (Me-18 and Me-19) showed singlet signals for a unique
compound. The same condition was observed for the doublets assigned to Me-21, Me-241, Me-26 and
Me-27.
To the best of our knowledge, the protective power of urazoles is related to the substituent at position 4;
thus, an electron withdrawing group diminishes the electron density of the resulting double bond in the
cycloadduct. In the same way, deprotection reactions are facilitated by the presence of such electron
withdrawing group.22 In this context, the retro-Diels-Alder reactions were performed for all adducts,
under the action of DBU in toluene, and in all cases the starting dienes 3-5 were successfully recovered.
CONCLUSIONS
The oxidation of 4-substituted urazoles under the action of the nitrosonium ion provides an efficient, mild
and rapid methodology to successfully attain TADs. The one-pot procedure developed here allowed the in
situ formation of the nitrosonium ion (using sodium nitrite and acetic acid in stoichiometric amounts), the
chemo-oxidation of the urazole building blocks, and the subsequent formation of the corresponding
cycloadducts in a rapid and stereoselective way. Furthermore, the retro-Diels-Alder reaction proceeded
successfully under standard basic conditions, providing the regeneration of dienes. The labile groups
attached in the steroidal side chains were not affected at all.
EXPERIMENTAL
General
1H and 13C-NMR spectra were recorded at 400 and 100 MHz respectively on a Varian Mercury
spectrometer. The spectra were registered in CDCl3 and referenced to TMS. The chemical shift values are
reported as ppm units and coupling constants are expressed in Hertz (Hz). All assignments were
confirmed with the aid of two dimensional experiments (COSY, HSQC and HMBC). HRMS data were
obtained from a JEOL The MStation spectrometer. Infrared spectra were recorded on a Nicolet 380 FT-IR
spectrometer. UV-Visible data were recorded on a Beckman DU-7500 UV-Vis spectrophotometer.
4-aminourazole (p-urazine) was prepared according to the procedure described by Lenoir.19

General procedure for the synthesis of arylideniminourazoles
4-Aminourazole (8.6 mmol) was dissolved in 30 mL of hot water. Then the corresponding aldehyde
(benzaldehyde or anisaldehyde, 17.2 mmol) was added dropwise. The reaction mixture was refluxed for
30 min, next cooled and the resulting precipitate was filtered off, washed with ethyl ether and dried under
vacuum to yield quantitatively 1c-d as thin needles.
General procedure for the synthesis of cycloadducts
To a solution of the selected diene (3-5, 0.18 mmol) in 0.5 mL of EtOAc, urazole (1a-d, 0.18 mmol) and
NaNO2 (12.4 mg, 0.18 mmol) were added. The reaction mixture was maintained under an argon
atmosphere and then, AcOH (20.5 µL, 0.36 mmol) was added. The resulting solution was stirred at room
temperature for an established period of time (Table 1) where the formation of the nitrosonium ion can be
observed (brown gas) and the characteristic red color of the corresponding TAD appeared next but readily
vanished.21 The crude was washed once with a saturated aqueous solution of NaHCO3 (30 mL) and once
with distilled water (30 mL), dried over Na2SO4, and evaporated under reduced pressure. The resulting
product was purified by column chromatography over silica gel (hexane/EtOAc, 8:2) generating 6-8 in
good to excellent yields (see Table 1).
(22E)-5α,8α-(4'-Phenyl)urazoloergosta-6,22-dien-3β-yl benzoate (6a).23 1H-NMR (400 MHz, CDCl3)
 8.03 (2H, m, H-ortho Bz), 7.52 (1H, m, H-para Bz), 7.42 (2H, m, H-ortho), 7.42 (2H, m, H-meta Bz),
7.42 (2H, m, H-meta), 7.28 (1H, m, H-para), 6.43 (1H, d, J7-6 = 8.3 Hz, H-7), 6.26 (1H, d, J6-7 = 8.3 Hz,
H-6), 5.73 (1H, m, H-3), 5.24 (1H, m, H-23), 5.18 (1H, m, H-22), 3.39 (1H, dd, J4eq-3 = 4.5 Hz, Jgem
=
13.9 Hz, H-4eq), 2.51 (1H, m, H-15a), 2.36 (1H, m, H-14), 2.36 (1H, m, H-4ax), 2.27 (1H, m, H-2eq),
2.06 (1H, m, H-20), 2.06 (1H, m, H-12eq), 1.04 (3H, d, J21-20 = 6.0 Hz, CH3-21), 1.04 (3H, s, CH3-19),
1
0.91 (3H, d, J24 -24 = 6.8 Hz, CH3-241), 0.83 (3H, d, J26-25 = 6.9 Hz, CH3-26), 0.82 (3H, s, CH3-18), 0.82
(3H, d, J27-25 = 6.8 Hz, CH3-27). 13C-NMR (100 MHz, CDCl3)  33.6 (C-1), 26.0 (C-2), 71.1 (C-3), 31.0
(C-4), 41.1 (C-5), 135.0 (C-6), 129.2 (C-7), 43.8 (C-8), 52.8 (C-9), 65.3 (C-10), 22.3 (C-11), 38.0 (C-12),
64.8 (C-13), 49.2 (C-14), 23.3 (C-15), 27.4 (C-16), 55.0 (C-17), 13.2 (C-18), 17.4 (C-19), 39.5 (C-20),
21.2 (C-21), 135.1 (C-22), 132.3 (C-23), 42.7 (C-24), 17.5 (C-241), 33.0 (C-25), 19.9 (C-26), 19.6 (C-27),
165.5 (PhCO2-3), 148.9 (C-3’), 146.4 (C-5’), 132.6 (C-para Bz), 131.7 (C-ipso), 130.6 (C-ipso Bz), 129.5
(C-ortho Bz), 128.7 (C-meta Bz), 128.1 (C-ortho), 126.1 (C-meta), 127.6 (C-para). HRMS: calcd. for
C43H54N3O4, 676.4114, [M+H]+; found, 676.4107. [α]D = -89.7º (1.0 CHCl3). IR 3049, 2926, 1774, 1714,
1603 cm-1.
1
(22E)-5α,8α-(4'-p-Nitrophenyl)urazoloergosta-6,22-dien-3β-yl benzoate (6b). H-NMR (400 MHz,
CDCl3)  8.26 (2H, m, H-meta), 8.04 (2H, m, H-ortho Bz), 7.84 (2H, m, H-ortho), 7.55 (1H, m, H-para
Bz), 7.43 (2H, m, H-meta Bz), 6.47 (1H, d, J7-6 = 8.3 Hz, H-7), 6.31 (1H, d, J6-7 = 8.3 Hz, H-6), 5.72 (1H,

m, H-3), 5.25 (1H, m, H-23), 5.20 (1H, m, H-22), 3.36 (1H, dd, J4eq-3 = 4.4 Hz, Jgem = 14.0 Hz, H-4eq),
1
1.07 (3H, s, CH3-19), 1.05 (3H, d, J21-20 = 6.8 Hz, CH3-21), 0.91 (3H, d, J24 -24 = 6.8 Hz, CH3-241), 0.84
13
(3H, d, J26-25 = 6.8 Hz, CH3-26), 0.83 (3H, s, CH3-18), 0.82 (3H, d, J27-25 = 6.8 Hz, CH3-27). C-NMR
(100 MHz, CDCl3)  33.6 (C-1), 25.7 (C-2), 70.8 (C-3), 30.9 (C-4), 41.2 (C-5), 135.4 (C-6), 129.3 (C-7),
43.8 (C-8), 52.7 (C-9), 65.6 (C-10), 22.4 (C-11), 37.9 (C-12), 65.2 (C-13), 49.1 (C-14), 23.3 (C-15), 27.5
(C-16), 55.0 (C-17), 13.1 (C-18), 17.5 (C-19), 39.6 (C-20), 21.2 (C-21), 134.9 (C-22), 132.4 (C-23), 42.7
(C-24), 17.5 (C-241), 33.0 (C-25), 19.9 (C-26), 19.6 (C-27), 165.6 (PhCO2-3), 147.5 (C-NO2), 145.9
(C-3’), 144.8 (C-5’), 137.7 (C-ipso), 132.8 (C-para Bz), 130.4 (C-ipso Bz), 129.6 (C-ortho Bz), 128.2
(C-meta Bz), 125.7 (C-ortho), 124.0 (C-meta). HRMS calcd. for C43H53N4O6, 721.3965, [M+H]+; found,
721.3960. [α]D = -34.6º (1.0 CHCl3). IR 3048, 2928, 1750, 1705, 1600, 1523, 1347, 748 cm-1.
1
(22E)-5α,8α-(4'-Benzalamino)urazoloergosta-6,22-dien-3β-yl benzoate (6c). H-NMR (400 MHz,
CDCl3)  9.47 (1H, s, H-imine), 8.06 (2H, m, H-ortho Bz), 7.80 (2H, m, H-ortho), 7.55 (1H, m, H-para
Bz), 7.41 (2H, m, H-meta Bz), 7.41 (2H, m, H-meta), 7.41 (1H, m, H-para), 6.41 (1H, d, J7-6 = 8.3 Hz,
H-7), 6.23 (1H, d, J6-7 = 8.3 Hz, H-6), 5.76 (1H, m, H-3), 5.25 (1H, m, H-23), 5.19 (1H, m, H-22), 3.38
(1H, dd, J4eq-3 = 5.0 Hz, Jgem = 14.0 Hz, H-4eq), 2.52 (1H, m, H-15a), 2.36 (1H, m, H-14), 2.36 (1H, m,
H-4ax), 2.26 (1H, m, H-2eq), 2.06 (1H, m, H-20), 2.06 (1H, m, H-12eq), 1.04 (3H, d, J21-20 = 6.8 Hz,
1
CH3-21), 1.03 (3H, s, CH3-19), 0.92 (3H, d, J24 -24 = 6.8 Hz, CH3-241), 0.85 (3H, d, J26-25 = 6.7 Hz,
CH3-26), 0.83 (3H, d, J27-25 = 6.8 Hz, CH3-27), 0.82 (3H, s, CH3-18). 13C-NMR (100 MHz, CDCl3)  33.5
(C-1), 25.9 (C-2), 70.9 (C-3), 30.9 (C-4), 41.1 (C-5), 135.1 (C-6), 129.2 (C-7), 43.8 (C-8), 52.7 (C-9),
65.3 (C-10), 22.4 (C-11), 38.0 (C-12), 64.9 (C-13), 49.1 (C-14), 23.2 (C-15), 27.5 (C-16), 55.0 (C-17),
13.2 (C-18), 17.5 (C-19), 39.5 (C-20), 21.2 (C-21), 135.1 (C-22), 132.3 (C-23), 42.7 (C-24), 17.5 (C-241),
33.0 (C-25), 19.9 (C-26), 19.6 (C-27), 165.5 (PhCO2-3), 156.2 (C-imine), 147.2 (C-3’), 144.6 (C-5’),
133.8 (C-ipso), 132.7 (C-para Bz), 131.1 (C-para), 130.6 (C-ipso Bz), 129.6 (C-ortho Bz), 128.5 (C-meta
Bz), 128.2 (C-ortho), 128.1 (C-meta). HRMS calcd. for C44H55N4O4, 703.4223, [M+H]+; found, 703.4214.
[α]D = -40.7º (1.0 CHCl3). IR 3279, 3050, 2925, 1760, 1710, 1605, 1052, 806 cm-1.
1
(22E)-5α,8α-(4'-Anisalamino)urazoloergosta-6,22-dien-3β-yl benzoate (6d). H-NMR (400 MHz,
CDCl3)  9.33 (1H, s, H-imine), 8.06 (2H, m, H-ortho Bz), 7.75 (2H, m, H-ortho), 7.54 (1H, m, H-para
Bz), 7.43 (2H, m, H-meta Bz), 6.90 (2H, m, H-meta), 6.40 (1H, d, J7-6 = 8.3 Hz, H-7), 6.23 (1H, d, J6-7
=
8.2 Hz, H-6), 5.75 (1H, m, H-3), 5.25 (1H, m, H-23), 5.19 (1H, m, H-22), 3.83 (3H, s, OCH3), 3.38 (1H,
dd, J4eq-3 = 4.9 Hz, Jgem = 13.9 Hz, H-4eq), 2.53 (1H, m, H-15a), 2.35 (1H, m, H-14), 2.35 (1H, m, H-4ax),
2.26 (1H, m, H-2eq), 2.04 (1H, m, H-20), 2.04 (1H, m, H-12eq), 1.04 (3H, d, J21-20 = 7.6 Hz, CH3-21),
1.03 (3H, s, CH3-19), 0.92 (3H, d, J24 -24 = 6.8 Hz, CH3-241), 0.84 (3H, d, J26-25 = 6.7 Hz, CH3-26), 0.83
1
13
(3H, d, J27-25 = 7.0 Hz, CH3-27), 0.82 (3H, s, CH3-18). C-NMR (100 MHz, CDCl3)  33.6 (C-1), 26.0

(C-2), 71.0 (C-3), 30.9 (C-4), 41.1 (C-5), 135.1 (C-6), 129.2 (C-7), 43.8 (C-8), 52.7 (C-9), 65.3 (C-10),
22.4 (C-11), 38.0 (C-12), 64.9 (C-13), 49.2 (C-14), 23.2 (C-15), 27.5 (C-16), 55.0 (C-17), 13.2 (C-18),
17.5 (C-19), 39.5 (C-20), 21.2 (C-21), 135.1 (C-22), 132.3 (C-23), 42.7 (C-24), 17.5 (C-241), 33.0 (C-25),
19.9 (C-26), 19.6 (C-27), 165.5 (PhCO2-3), 156.7 (C-imine), 147.4 (C-3’), 144.9 (C-5’), 126.4 (C-ipso),
132.7 (C-para Bz), 162.1 (C-OCH3), 55.3 (OCH3), 130.6 (C-ipso Bz), 129.6 (C-ortho Bz), 128.2 (C-meta
Bz), 129.9 (C-ortho), 114.0 (C-meta). HRMS calcd. for C45H57N4O5, 733.4329, [M+H]+; found, 733.4319.
[α]D = -24.9º (1.0 CHCl3). IR 3290, 3048, 2926, 1760, 1715, 1615, 1247, 1051, 1040, 860 cm-1.
1
(25R)-5α,8α-(4'-Phenyl)urazolospirost-6-en-3β-yl benzoate (7a). H-NMR (400 MHz, CDCl3)  8.03
(2H, m, H-ortho Bz), 7.53 (1H, m, H-para Bz), 7.42 (2H, m, H-ortho), 7.42 (2H, m, H-meta Bz), 7.42
(2H, m, H-meta), 7.30 (1H, m, H-para), 6.43 (1H, d, J7-6 = 8.3 Hz, H-7), 6.27 (1H, d, J6-7 = 8.2 Hz, H-6),
5.71 (1H, m, H-3), 4.58 (1H, dd, J16-17 = 14.8 Hz, J16-15 = 7.1 Hz, H-16), 3.45 (1H, ddd, J26eq-25 = 4.4 Hz,
Jgem = 12.8 Hz, J26eq-24eq = 1.6 Hz, H-26eq), 3.41 (1H, ddd, J4eq-3 = 4.8 Hz, Jgem = 14.0 Hz, J4eq-2eq = 1.2
Hz, H-4eq), 3.33 (1H, dd, J26ax-25 = 11.0 Hz, Jgem = 12.8 Hz, H-26ax), 2.90 (1H, ddd, J15-14 = 4.8 Hz, J15-16
= 7.1 Hz, Jgem = 11.8 Hz, H-15a), 2.44 (1H, dd, J14-15a = 4.8 Hz, J14-15b = 13.2 Hz, H-14), 2.38 (1H, dd,
J4ax-3 = 11.6 Hz, Jgem = 14.0 Hz, H-4ax), 2.27 (1H, m, H-2eq), 1.04 (3H, s, CH3-19), 1.00 (3H, d, J21-20
=
6.6 Hz, CH3-21), 0.91 (3H, s, CH3-18), 0.78 (3H, d, J27-25 = 6.4 Hz, CH3-27). 13C-NMR (100 MHz,
CDCl3)  33.7 (C-1), 26.1 (C-2), 71.0 (C-3), 31.3 (C-4), 41.2 (C-5), 135.0 (C-6), 129.1 (C-7), 41.1 (C-8),
52.6 (C-9), 65.6 (C-10), 22.0 (C-11), 38.3 (C-12), 63.9 (C-13), 48.7 (C-14), 31.1 (C-15), 79.5 (C-16),
61.2 (C-17), 17.2 (C-18), 17.5 (C-19), 41.1 (C-20), 14.5 (C-21), 109.1 (C-22), 31.5 (C-23), 28.7 (C-24),
30.2 (C-25), 66.6 (C-26), 17.1 (C-27), 165.5 (PhCO2-3), 149.6 (C-3’), 147.0 (C-5’), 132.7 (C-para Bz),
131.6 (C-ipso), 130.6 (C-ipso Bz), 129.5 (C-ortho Bz), 128.8 (C-meta), 128.1 (C-para), 127.7 (C-meta
Bz), 126.1 (C-ortho). HRMS calcd. for C42H50N3O6, 692.3700, [M+H]+; found, 692.3695. [α]D = -72.9º
(1.0 CHCl3). IR 3047, 2925, 1770, 1718, 1602 cm-1.
1
(25R)-5α,8α-(4'-p-Nitrophenyl)urazolospirost-6-en-3β-yl benzoate (7b). H-NMR (400 MHz, CDCl3)
 8.26 (2H, m, H-meta), 8.04 (2H, m, H-ortho Bz), 7.84 (2H, m, H-ortho), 7.55 (1H, m, H-para Bz), 7.43
(2H, m, H-meta Bz), 6.46 (1H, d, J7-6 = 8.3 Hz, H-7), 6.30 (1H, d, J6-7 = 8.2 Hz, H-6), 5.72 (1H, m, H-3),
4.61 (1H, dd, J16-17 = 14.8 Hz, J16-15 = 7.2 Hz, H-16), 3.47 (1H, dd, J26eq-25 = 4.0 Hz, Jgem = 10.8 Hz,
H-26eq), 3.38 (1H, m, H-4eq), 3.36 (1H, dd, J26ax-25 = 11.2 Hz, Jgem = 10.8 Hz, H-26ax), 2.83 (1H, ddd,
J15-14 = 4.8 Hz, J15-16 = 7.2 Hz, Jgem = 11.6 Hz, H-15a), 2.45 (1H, m, H-14), 2.40 (1H, m, H-4ax), 2.25
(1H, m, H-2eq), 1.06 (3H, s, CH3-19), 1.01 (3H, d, J21-20 = 6.5 Hz, CH3-21), 0.92 (3H, s, CH3-18), 0.79
(3H, d, J27-25 = 6.3 Hz, CH3-27). 13C-NMR (100 MHz, CDCl3)  33.6 (C-1), 26.0 (C-2), 70.7 (C-3), 31.2
(C-4), 41.2 (C-5), 135.3 (C-6), 129.3 (C-7), 41.2 (C-8), 52.6 (C-9), 66.0 (C-10), 22.1 (C-11), 38.3 (C-12),
64.2 (C-13), 48.5 (C-14), 31.0 (C-15), 79.5 (C-16), 61.2 (C-17), 17.2 (C-18), 17.5 (C-19), 41.2 (C-20),

14.5 (C-21), 109.3 (C-22), 31.5 (C-23), 28.7 (C-24), 30.2 (C-25), 66.7 (C-26), 17.1 (C-27), 165.6
(PhCO2-3), 148.2 (C-NO2), 146.0 (C-3’), 145.4 (C-5’), 137.7 (C-ipso), 132.8 (C-para Bz), 130.5 (C-ipso
Bz), 129.6 (C-ortho Bz), 128.2 (C-meta Bz), 125.7 (C-ortho), 124.0 (C-meta). HRMS calcd. for
C42H49N4O8, 737.3550, [M+H]+; found, 737.3543. [α]D = -67.4º (1.0 CHCl3). IR 3079, 2926, 1765, 1700,
1612, 1520, 1342, 751 cm-1.
1
(25R)-5α,8α-(4'-Benzalamino)urazolospirost-6-en-3β-yl benzoate (7c). H-NMR (400 MHz, CDCl3) 
9.46 (1H, s, H-imine), 8.06 (2H, m, H-ortho Bz), 7.81 (2H, m, H-ortho), 7.55 (1H, m, H-para Bz), 7.42
(2H, m, H-meta Bz), 7.42 (2H, m, H-meta), 7.42 (1H, m, H-para), 6.41 (1H, d, J7-6 = 8.3 Hz, H-7), 6.24
(1H, d, J6-7 = 8.2 Hz, H-6), 5.74 (1H, m, H-3), 4.62 (1H, dd, J16-17 = 14.4 Hz, J16-15 = 7.6 Hz, H-16), 3.49
(1H, dd, J26eq-25 = 3.6 Hz, Jgem = 10.8 Hz, H-26eq), 3.38 (1H, dd, J26ax-25 = Jgem = 10.8 Hz, H-26ax), 3.38
(1H, m, H-4eq), 2.93 (1H, ddd, J15-14 = 4.9 Hz, J15-16 = 7.6 Hz, Jgem = 11.6 Hz, H-15a), 2.45 (1H, dd,
J14-15a = 4.9 Hz, J14-15b = 14.0 Hz, H-14), 2.38 (1H, dd, J4ax-3 = 11.4 Hz, Jgem = 13.2 Hz, H-4ax), 2.26 (1H,
m, H-2eq), 1.04 (3H, s, CH3-19), 1.01 (3H, d, J21-20 = 6.5 Hz, CH3-21), 0.90 (3H, s, CH3-18), 0.80 (3H, d,
13
J27-25 = 6.3 Hz, CH3-27). C-NMR (100 MHz, CDCl3)  33.6 (C-1), 26.0 (C-2), 70.9 (C-3), 31.3 (C-4),
41.2 (C-5), 135.0 (C-6), 129.1 (C-7), 41.1 (C-8), 52.5 (C-9), 65.7 (C-10), 22.0 (C-11), 38.3 (C-12), 64.0
(C-13), 48.6 (C-14), 31.0 (C-15), 79.6 (C-16), 61.2 (C-17), 17.2 (C-18), 17.5 (C-19), 41.1 (C-20), 14.5
(C-21), 109.2 (C-22), 31.5 (C-23), 28.8 (C-24), 30.2 (C-25), 66.7 (C-26), 17.1 (C-27), 165.5 (PhCO2-3),
156.5 (C-imine), 147.8 (C-3’), 145.2 (C-5’), 133.7 (C-ipso), 132.7 (C-para Bz), 131.2 (C-para), 130.6
(C-ipso Bz), 129.6 (C-ortho Bz), 128.5 (C-meta Bz), 128.2 (C-ortho), 128.2 (C-meta). HRMS calcd. for
C43H51N4O6, 719.3809, [M+H]+; found, 719.3801. [α]D = -76.4º (1.0 CHCl3). IR 2924, 1763, 1710, 1610,
1047, 865 cm-1.
1
(25R)-5α,8α-(4'-Anisalamino)urazolospirost-6-en-3β-yl benzoate (7d). H-NMR (400 MHz, CDCl3) 
9.27 (1H, s, H-imine), 8.01 (2H, m, H-ortho Bz), 7.71 (2H, m, H-ortho), 7.50 (1H, m, H-para Bz), 7.39
(2H, m, H-meta Bz), 6.86 (2H, m, H-meta), 6.35 (1H, d, J7-6 = 8.3 Hz, H-7), 6.19 (1H, d, J6-7 = 8.2 Hz,
H-6), 5.68 (1H, m, H-3), 4.58 (1H, m, H-16), 3.78 (3H, s, OCH3), 3.44 (1H, ddd, J26eq-25 = 3.6 Hz, Jgem
11.2 Hz, J26eq-24eq = 1.6 Hz, H-26eq), 3.34 (1H, dd, J26ax-25 = Jgem = 11.2 Hz, H-26ax), 3.34 (1H, m,
H-4eq), 2.89 (1H, m, H-15a), 2.40 (1H, dd, J14-15a = 4.8 Hz, J14-15b = 13.2 Hz, H-14), 2.33 (1H, dd, J4ax-3
gem = 14.0 Hz, H-4ax), 2.21 (1H, m, H-2eq), 1.03 (3H, s, CH3-19), 0.97 (3H, d, J21-20 = 6.6 Hz, CH3-21),
=
=
J
13
0.90 (3H, s, CH3-18), 0.76 (3H, d, J27-25 = 6.3 Hz, CH3-27). C-NMR (100 MHz, CDCl3)  33.5 (C-1),
26.0 (C-2), 70.9 (C-3), 31.2 (C-4), 41.1 (C-5), 134.9 (C-6), 129.0 (C-7), 41.1 (C-8), 52.5 (C-9), 65.6
(C-10), 21.9 (C-11), 38.2 (C-12), 63.9 (C-13), 48.5 (C-14), 31.0 (C-15), 79.5 (C-16), 61.1 (C-17), 17.2
(C-18), 17.4 (C-19), 41.0 (C-20), 14.5 (C-21), 109.1 (C-22), 31.4 (C-23), 28.7 (C-24), 30.1 (C-25), 66.7
(C-26), 17.1 (C-27), 165.5 (PhCO2-3), 156.8 (C-imine), 148.0 (C-3’), 145.4 (C-5’), 126.3 (C-ipso), 132.7

(C-para Bz), 162.1 (C-OCH3), 55.3 (OCH3), 130.5 (C-ipso Bz), 129.5 (C-ortho Bz), 128.1 (C-meta Bz),
129.9 (C-ortho), 113.9 (C-meta). HRMS calcd. for C44H53N4O7, 749.3914, [M+H]+; found, 749.3908.
[α]D = -72.0º (1.0 CHCl3). IR 2926, 1760, 1713, 1604, 1274, 1100, 1010, 858 cm-1.
1
9,10-(4’-Phenyl)urazolo-9,10-dihydroanthracene (8a). H-NMR (400 MHz, CDCl3)  7.48 (4H, m,
aromatics), 7.34 (2H, m, H-meta), 7.29 (4H, m, aromatics), 7.29 (1H, m, H-para), 7.19 (2H, m, ortho),
6.34 (2H, s, H-9 and H-10). 13C-NMR (100 MHz, CDCl3)  156.0 (C-3’, C-5’), 136.4 (C-4a, C-8a, C-9a,
C-10a), 131.0 (C-ipso), 128.3 and 124.0 (C-1 and C-8), 125.3 (C-ortho), 129.0 (C-meta), 128.3 (C-para),
60.4 (C-9 and C-10). HRMS calcd. for C22H16N3O2, 354.1243, [M+H]+; found, 354.1237. IR 3054, 2927,
1757, 1703, 1612 cm-1.
9,10-(4’-p-Nitrophenyl)urazolo-9,10-dihydroanthracene (8b). 1H-NMR (400 MHz, CDCl3)  8.22 (2H,
m, H-meta), 7.66 (2H, m, H-ortho), 7.54-7.27 (8H, m, H-aromatics), 6.35 (2H, s, H-9 and H-10).
13C-NMR (100 MHz, CDCl3)  154.3 (C-3’, C-5’), 146.3 (C-NO2), 137.1 (C-ipso), 136.4 (C-4a, C-8a,
C-9a, C-10a), 128.6 and 124.1 (C-1 and C-8), 124.7 (C-ortho), 124.3 (C-meta), 60.4 (C-9 and C-10).
HRMS calcd. for C22H15N4O4, 399.1093, [M+H]+; found, 399.1085. IR 2926, 1765, 1695, 1451, 1395,
732 cm-1.
1
9,10-(4’-Benzalamino)urazolo-9,10-dihydroanthracene (8c). H-NMR (400 MHz, CDCl3)  9.28 (1H,
s, H-imine), 7.74 (2H, d, J = 7.4 Hz, H-ortho), 7.52 and 7.24 (8H, m, H-aromatics), 7.42 (1H, m, H-para),
7.40 (2H, m, H-meta), 6.32 (2H, s, H-9 and H-10). 13C-NMR (100 MHz, CDCl3)  157.5 (C-imine),
153.9 (C-3’, C-5’), 136.5 (C-4a, C-8a, C-9a, C-10a), 132.9 (C-ipso), 131.8 (C-para), 128.6 (C-meta),
128.5 and 124.1 (C-1 and C-8), 128.4 (C-ortho), 60.2 (C-9 and C-10). HRMS calcd. for C23H17N4O2,
381.1352, [M+H]+; found, 381.1347. IR 3290, 2925, 1760, 1705, 1040, 845 cm-1.
1
9,10-(4’-Anisalamino)urazolo-9,10-dihydroanthracene (8d). H-NMR (400 MHz, CDCl3)  9.14 (1H,
s, H-imine), 7.69 (2H, m, H-ortho), 7.47 and 7.28 (8H, m, H-aromatics), 6.88 (2H, m, H-meta), 6.32 (2H,
s, H-9 and H-10), 3.82 (3H, s, OCH3). 13C-NMR (100 MHz, CDCl3)  157.7 (C-imine), 154.1 (C-3’,
C-5’), 136.5 (C-4a, C-8a, C-9a, C-10a), 125.5 (C-ipso), 128.8 (C-para), 114.1 (C-meta), 128.4 and 124.1
(C-1 and C-8), 130.2 (C-ortho), 60.2 (C-9 and C-10), 55.3 (OCH3). HRMS calcd. for C24H19N4O3,
411.1457, [M+H]+; found, 411.1452. IR 3287, 2920, 1762, 1711, 1250, 1045, 1038, 855 cm-1.
ACKNOWLEDGEMENTS
The authors gratefully thank CONACYT for grant 84380 to JSR and the Repatriation grant 166040 to
MAFH. We also thank PROMEP for the grant 103.5/12/4367 BUAP-PTC-301 to MAFH.

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