HNO2-Assisted Triazine Cycle Contraction in 3-oxo-,3-thioxo- and 3-imino-5,7-dimethyl-4a,7a-diphenyl-perhydroimidazo[4,5-e][1,2,4]triazin-6-ones

Article abstract of DOI:10.1016/j.mencom.2012.11.006

Treatment of 3-oxo-, 3-thioxo- and 3-imino-5,7-dimethyl-4a,7a- diphenylperhydroimidazo[4,5-e][1,2,4]triazin-6-ones with NaNO₂ in the presence of AcOH caused contraction of the perhydrotriazine cycle to the imidazolidine one. The products were t

Full text of DOI:10.1016/j.mencom.2012.11.006

Mendeleev
Communications
Mendeleev Commun., 2012, 22, 299–301
HNO2-assisted triazine cycle contraction in 3-oxo-,
3-thioxo- and 3-imino-5,7-dimethyl-4a,7a-diphenyl-
perhydroimidazo[4,5-e][1,2,4]triazin-6-ones
Angelina N. Kravchenko,*a Galina A. Gazieva,a Sergei V. Vasilevskii,a
Pavel A. Belyakova and Yulia V. Nelyubinab
a N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian
Federation. Fax: +7 499 135 5328; e-mail: kani@server.ioc.ac.ru
b A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119991 Moscow,
Russian Federation. Fax: +7 499 135 5085; e-mail: unelya@xrlab.ineos.ac.ru
DOI: 10.1016/j.mencom.2012.11.006
Treatment of 3-oxo-, 3-thioxo- and 3-imino-5,7-dimethyl-4a,7a-diphenylperhydroimidazo[4,5-e][1,2,4]triazin-6-ones with NaNO2 in
the presence of AcOH caused contraction of the perhydrotriazine cycle to the imidazolidine one. The products were transformed into
glycolurils and their analogues.
Me
A triazine cycle is known to reduce to an imidazolidine one on
impact of benzaldehyde.1 We have recently demonstrated that
imidazotriazines 1 in reactions with aromatic aldehydes 2 trans-
form to N-benzylidenamino-5-thioxohexahydroimidazo[4,5-d]-
imidazol-2(1H)-ones (thioglycolurils) 3 (Scheme 1).2,3
Ph
H2N
H2N
N
OH
OH
i
NH
O
N
X
Ph
Me
4
Ar
Me
Me
H
N
Ph
Ph
H
N
R
R
N
N
N
N
H
N
NH
ii
ArCHO
2
N
O
X
N
O
NH
O
N
N
H
O
S
N
N
H
X
HCl, MeOH, ∆
Ph
Ph
N
N
N
H
N
H
S
Me
Me
R
R
1a–c
5a–c
1
3
a X = S
b X = O
c X = NH· HCl
Scheme 1
This research unexpectedly revealed a similar process while
examining nitrosation of 3-thioxo-, 3-oxo- and 3-iminoimidazo-
[4,5-e][1,2,4]trazin-6-ones 1a–c, although initially we aimed to
introduce a nitroso group at triazine nitrogen atoms.4
We examined a reaction between imidazotriazines 1a–c and
sodium nitrite in acids using the classic nitrosation procedure.5
The starting compounds 1a–c were synthesized by our original
procedure through a-ureidoalkylation of thiosemicarbazide, semi-
carbazide and aminoguanidine hydrochloride, respectively, with
4,5-dihydroxy-1,3-dimethyl-4,5-diphenylimidazolidin-2-one
(DHI) 46 (Scheme 2).
The first tests were run for imidazotriazine 1a using sodium
nitrite, 10% hydrochloric acid or glacial AcOH. Instead of the
anticipated N-nitroso derivative of imidazotriazine 1a, the final
product appeared to be unknown thioglycoluril 5a, which
apparently originated from the triazine cycle contraction to the
imidazolidine one. The yields of thioglycoluril 5a were 93%
(AcOH) and 70% (aqueous HCl).
Scheme 2 Reagents and conditions: i, MeOH, HCl, ii, NaNO2, AcOH,
room temperature, 2 h or NaNO2, 10% HCl, room temperature, 2 h.
N(1)H nitrosation occurred, next, cleavage of N(1)–C(7a) bond
took place, and finally, the new intermediate cyclized with the
N2O release.
To verify the structures of compounds 5 we attempted to
performe their independent syntheses by DHI a-ureidoalkyla-
O
H
N
Me
Me
H
N
Ph
Ph
N
N
N
NH
HNO2
NH
O
O
N
N
N
H
X
N
H
X
Ph
Ph
Me
Me
1a–c
O
H
N
In order to expand the scope of the discovered reaction, we
subjected 3-oxo- and 3-imino-5,7-dimethyl-4a,7a-diphenylper-
hydroimidazo[4,5-e][1,2,4]triazin-6-ones 1b,c to analogous trans-
formations and obtained glycoluril 5b (yield 89%) described in
literature7–9 (the yield was not reported) and new iminoglycoluril
5c (yield 85%), respectively.
N
Me
Me
Ph
Ph
N
N
N
NH
NH
N
H
O
O
X
– N2O, – H+
N
N
X
Ph
H
Ph
Me
Me
5a–c
Based on the classic mechanism of N-nitrosation, we suggested
a probable mechanism for 1®5 transformation (Scheme 3). First,
Scheme 3
© 2012 Mendeleev Communications. All rights reserved.
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Mendeleev Commun., 2012, 22, 299–301
O(1)
N(1)
O(2)
O(1)
C(2)
tion of the corresponding substrates under the acidic catalytic
(a)
(b)
C(18)
C(4)
N(1)
C(2)
N(2)
conditions, similarly to the known synthesis of compound 5b.7
As for compound 5c, aminoguanidine hydrochloride did not
react with DHI 4.
N(3)
C(5)
C(4)
N(2)
C(17)
C(6)
N(4)
C(3)
C(3)
C(6)
C(1)
C(12)
C(1)
Reactions of DHI 4 with either urea or thiourea in boiling
MeOH for 30 min appeared to give the same product – glycoluril
5b in 85% and 79% yields, respectively (Scheme 4). The yield
of compound 5b prepared by nitrosation was higher (93%). The
second reaction product was 1,3-dimethyl-4,5-diphenyl-1,3-di-
hydro-2H-imidazol-2-one 6.10 It was absolutely unpredictable
that the DHI 4 reaction with thiourea would produce glycoluril 5b.
Furthermore, in the test experiment when thioglycoluril 5a was
subjected to the reaction conditions (see Scheme 4) no replacement
of sulfur with oxygen occurred.
C(7)
C(11)
C(12)
C(5)
C(10)
C(16)
C(17)
C(16)
C(11)
C(13)
C(14)
C(15)
C(7)
C(8)
C(15)
C(10)
C(13)
C(9)
C(8)
C(9)
C(14)
Figure 1 General views of compounds (a) 5b and (b) 6. The hydrogen
atoms of the molecule 5b, except for those of the NH groups, are omitted for
clarity.
tion,14,15 we suggest that acid-promoted condensation of DHI 4
with thiourea (Scheme 5) produces the carbenium-iminium ion A
(shown as two resonance structures), which in turn traps thiourea
molecule by the sulfur atom to form intermediate B. This inter-
mediate can interact with the second molecule of DHI to afford
a bicyclic product (5b) and intermediate (C) which on loss of
elemental sulfur yields imidazolone 6.
The structures of compounds 5a–c and 6 were confirmed by
elemental analysis and 1H and 13C NMR spectroscopy.† Structures
of 5b and 6 were ultimately established by X-ray diffraction.‡ As
Me
Ph
N
H2N
H2N
OH
OH
i
O
+
X
N
Ph
Me
X = S, O
4
Me
Me
Ph
Ph
Ph
N
N
N
NH
NH
1
signals from NH group protons are not visible in the H NMR
O
+
O
O
N
The 1H and 13C NMR spectra were recorded on a Bruker AM-300
†
Ph
Me
Me
spectrometer (300.13 MHz for 1H and 75.47 MHz for 13C NMR spectra).
Chemical shifts were measured with reference to the residual protons of
a [2H6]DMSO solvent (d 2.50 ppm). Melting points were determined with
a GALLENKAMP instrument (Sanyo). Commercial compounds (benzil,
1,3-dimethylurea, and semicarbazide hydrochloride) supplied by ACROS
and thiosemicarbazide, dihydrate of aminoguanidine hydrochloride (IREA)
were used in the syntheses. The solvents were used as purchased. Starting
DHI 4 was synthesized by analogy with the procedure for the benzil
condensation with 1,3-dimethylurea.16
5b
6
Scheme 4 Reagents and conditions: i, MeOH, HCl, reflux, 30 min.
On the basis of our experimental data and in terms of the
classic understanding of the acid-catalyzed a-amidoalkylation
mechanism,11,12 the mechanism proposed by Butler,13 and com-
munications on processes of the thiirane building and destruc-
Compounds 5a–c (general procedure). Sodium nitrite (0.28 g, 4 mmol)
was added portionwise to the suspension of 5,7-dimethyl-4a,7a-diphenyl-
perhydroimidazo[4,5-e][1,2,4]triazine-3,6-dione 1a (4 mmol) or its thio
or imino analogue 1b,c in glacial AcOH (30 ml) at room temperature, and
the mixture was stirred for 2 h. The precipitate formed was filtered off,
washed with AcOH and water to afford products 5a–c.
Me
Me
Ph
Ph
Ph
N
N
OH
OH
OH
– H2O
H2O
H+
O
O
OH2
N
N
Ph
Me
Me
All compounds 5a–c gave satisfactory elemental analysis data.
For 5a: yield 93%, mp 336–338°C (AcOH). 1H NMR, d: 2.61 (s, 6H,
MeN), 6.82–7.19 (m, 10H, 2Ph), 9.96 (s, 2H, NH). 13C {1H} NMR, d:
26.8 (NMe), 87.5 (CPh), 127.1 (Ph), 127.9 (Ph), 128.4 (Ph), 133.9 (Ph),
158.5 (C=O), 183.1 (C=S).
For 5b: yield 89%, mp 324–326°C (AcOH). 1H NMR, d: 2.56 (s, 6H,
MeN), 6.91–7.21 (m, 10H, 2Ph), 8.31 (s, 2H, NH). 13C {1H} NMR, d:
26.2 (NMe), 83.7 (CPh), 127.3 (Ph), 127.7 (Ph), 128.2 (Ph), 135.3 (Ph),
159.0 (C=O), 160.1 (C=O).
For 5c: yield 85%, mp 332–334°C (AcOH). 1H NMR, d: 2.69 (s, 6H,
MeN), 6.92–7.23 (m, 10H, 2Ph). 13C {1H} NMR, d: 27.0 (NMe), 87.3
(CPh), 127.2 (Ph), 128.1 (Ph), 128.7 (Ph), 133.6 (Ph), 158.3 (C=O), 159.1
(C=NH). LS/MS, m/z: 322.1 [M+H]+ (C36H30N6O3S).
Parallel syntheses of 2,4-dimethyl-1,5-diphenylglycoluril 5b by a-ureido-
alkylation of urea and thiourea using DHI 4. Procedure A: MeOH (10 ml)
was poured to the mixture of DHI 4 (0.7 g, 2.34 mmol) and urea (0.14 g,
2.34 mmol). One drop of conc. HCl was added, and the mixture was boiled
for 0.5 h. Precipitation started after 20 min of boiling, and the boiling was
continued for more 10 min, and then cooled. The precipitate was filtered
off and washed with methanol to produce 0.64 g (85%) of 5b, white
crystals, mp 324–326°C (MeOH).
4
Me
Me
Ph
Ph
Ph
N
N
OH
S
OH
– H+
O
O
Ph
N
N
Me
Me
NH2
NH2
A
Me
Me
Me
Ph
Ph
H
N
N
O
S
4, H+
N
N
NH2
NH2
O
O
O
N
N
H
Ph
Ph
Me
5b
B
– (H2N)2CO
Me
Me
Procedure B: MeOH (25 ml) was poured to the mixture of DHI 4 (1.19 g,
4 mmol) and thiourea (0.3 g, 4 mmol). Two drops of conc. HCl were
added, the mixture was boiled for 1 h, and then cooled. The precipitate
was filtered off and washed with methanol. Yield of 5b, 1.01 g (79%),
white crystals, mp 324–326°C (MeOH). The filtrate was kept for 2 days.
The crystals that formed were filtered off to give 0.13 g (12%) of 1,3-di-
methyl-4,5-diphenyl-1,3-dihydro-2H-imidazol-2-one 6, mp 184–186°C
(MeOH) (lit.,10 185–187°C).
Ph
S
Ph
Ph
N
N
O
Sx
O
N
N
Ph
Me
Me
C
6
Scheme 5
– 300 –

Mendeleev Commun., 2012, 22, 299–301
spectrum of 5c (Y = +NH2Cl–), an LC/MS analysis was performed
imidazolone cycle in 6 [Figure 1(b)] is planar (within 0.01 Å).
The torsion angle C(6)C(3)C(1)C(12) that characterizes the mutual
disposition of phenyl substituents in 6 is 3.8(3)°, with the angle
between their mean planes being 66.0(3)°. As the molecule lacks
any convenient proton donors, in a crystal it forms weak C–H···O
and C–H···p contacts only.
In summary, the herein discovered contraction of the perhydro-
triazine cycle in 3-oxo-, 3-thioxo- and 3-iminoperhydroimidazo-
[4,5-e][1,2,4]triazin-6-ones to the imidazolidine cycle may serve
as a new synthetic pathway to prepare glycolurils and their analogues,
which may promote their wider use in medicinal chemistry and
related areas.
that confirmed a presence of the molecular ion with m/z 322.1.
According to the X-ray data, compound 5b [Figure 1(a)] crys-
tallizes in a centrosymmetric space group Pbca. The imidazolidine
cycles in this bicyclic system have an envelope conformation
with the atoms C(1) and C(3) deviated by 0.43(1) and 0.41(1) Å
in dimethyl-substituted and NH containing fragments, respec-
tively; the angle between their mean planes being 71.8(2)°. The
pseudotorsion angle C(5)C(1)C(3)C(11) is equal to 26.3(2)°; the
angle between the phenyl rings is 46.9(2)°.
In a crystal of 5b, the molecules are held together by N(3)–
H···O(2) and N(4)–H···O(1) hydrogen bonds of intermediate
strength [N···O 2.804(2) and 2.867(2) Å, ÐNHO 176(1) and
160(1)°]. The resulting H-bonded chains are assembled in a 3D
framework by various weak interactions of C–H···O and C–H···p
types.
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‡
Crystallographic data.
Crystals of 5b (C18H18N4O2, M = 322.36) are orthorhombic, space group
Pbca, at 120 K: a = 16.405(5), b = 11.891(4) and c = 16.595(5) Å, V =
= 3237.2(17) Å3, Z = 8 (Z' = 1), dcalc = 1.323 g cm–3, m(MoKa) = 0.89 cm–1,
F(000) = 1360.
Crystals of 6 (C17H16N2O, M = 264.32) are monoclinic, space group
P21/n, at 120 K: a = 5.9478(6), b = 16.7752(18) and c = 13.4216(14) Å,
b = 90.408(2)°, V = 1339.1(2) Å3, Z = 4 (Z' = 1), dcalc = 1.311 g cm–3,
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and GOF = 1.001 for all the independent reflections [R1 = 0.0541 was
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the refinement converged to wR2 = 0.1043 and GOF = 1.002 for all the
independent reflections [R1 = 0.0428 was calculated against F for 2203
observed reflections with I > 2s(I)]. All calculations were performed
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CCDC 907773 and 907774 contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
For details, see ‘Notice to Authors’, Mendeleev Commun., Issue 1, 2012.
Received: 30th May 2012; Com. 12/3934
– 301 –