Synthesis of N-{5-Oxo-2-thioxo(2,5-dithioxo)hexahydroimidazo-[4,5-d]imidazol-1(2H)-yl}formamides

Article abstract of DOI:10.1055/s-0036-1588388

A synthetic route to novel N-{5-oxo-2-thioxo(2,5-dithioxo)hexahydroimidazo[4,5-d]imidazol-1(2H)-yl}formamides, by a tandem N-formylation and ring-contraction reaction of 5,7-disubstituted 3-thioxoperhydroimidazo[4,5-e]-1,2,4-triazine-6-ones(thiones) with formic acid, has been developed.

Full text of DOI:10.1055/s-0036-1588388

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–E
letter
A
G. A. Gazieva et al.
Letter
Synlett
Synthesis of N-{5-Oxo-2-thioxo(2,5-dithioxo)hexahydroimidazo-
[4,5-d]imidazol-1(2H)-yl}formamides
Galina A. Gazieva*a
R1
N
R1
N
HCOOH,
Me2CO,
55 °C, 2 h
HN
N
H
N
Tatyana B. Karpovaa
Tatyana V. Nechaevaa,b
Yulia V. Nelyubina*c
Igor E. Zanind
O
S
NH
X
X
N
N
R3
N
N
R3
S
R2
R2
9 examples
19–70% yield
X = O, S; R1 = Me, Et; R2 = Me, Et, Ph; R3 = H, Me
Angelina N. Kravchenkoa
a N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of
Sciences, Leninsky Prosp. 47, 119991 Moscow, Russian Federation
gaz@ioc.ac.ru
b D. Mendeleev University of Chemical Technology of Russia,
Miusskaya Sq. 9, 125047 Moscow, Russian Federation
c A.N. Nesmeyanov Institute of Organoelement Compounds,
Russian Academy of Sciences, Vavilova Str. 28, 119991 Moscow,
Russian Federation
unelya@xrlab.ineos.ac.ru
d Voronezh State University, Universitetskaya Sq. 1, 394000
Voronezh, Russian Federation
Received: 06.10.2016
Accepted after revision: 04.12.2016
Published online: 10.01.2017
One of the approaches to the synthesis of mono- and
dithio analogues of glycolurils is the triazine ring-contrac-
tion reaction of 5,7-dialkyl-3-thioxoperhydroimidazo[4,5-
e]-1,2,4-triazin-6-ones(thiones) 1 with (hetero)aromatic al-
dehydes in acid medium (HCl) or with nitrous acid.10,12,14 In
general, triazine ring contraction to the imidazolidine ring
takes place upon treatment of the corresponding 1,2,4-tri-
azine derivatives with reagents such as sodium dithionite
or zinc in acetic acid,15 benzaldehyde derivatives in acidic
medium,12,14a,16 hydroxylamine-O-sulfonic acid,17 mercu-
ric(II) oxide,18 or organolithium reagents.19 There are a few
examples of 1,2,4-triazine ring contraction in the reaction
with hydrochloric, acetic, or formic acids.16,20 For example,
attempts to bring about acid hydrolysis of the 7-chloro-1,2-
dihydropyrimido[5,4-e]-1,2,4-triazines 2 in aqueous formic
acid led to ring-contraction products 3 in around 6% yield
(Scheme 1).20b
DOI: 10.1055/s-0036-1588388; Art ID: st-2016-d0667-l
Abstract A synthetic route to novel N-{5-oxo-2-thioxo(2,5-dithi-
oxo)hexahydroimidazo[4,5-d]imidazol-1(2H)-yl}formamides, by a tan-
dem N-formylation and ring-contraction reaction of 5,7-disubstituted
3-thioxoperhydroimidazo[4,5-e]-1,2,4-triazine-6-ones(thiones)
formic acid, has been developed.
with
Key words N-heterocycles, thioanalogues of glycolurils, formylation,
ring contraction, tandem reaction
Glycolurils
(tetrahydroimidazo[4,5-d]imidazole-
2,5(1H,3H)-diones) possess a wide range of biological activ-
ities1 and have found applications as anion-binding recep-
tors and molecular capsules,2 molecular templates for in-
tramolecular Claisen-type condensation,3 and as precursors
in combinatorial4 and supramolecular chemistry.5
O
Mono- and dithio analogues of glycolurils (5-thioxo-
hexahydroimidazo[4,5-d]imidazol-2(1H)-ones and tetra-
hydroimidazo[4,5-d]imidazole-2,5(1H,3H)-dithiones) have
been studied to a considerably lesser extent. However, they
have already been recognized as substrates for the tem-
plate-directed crossed-Claisen condensation,6 organocata-
lysts for N-Boc protection of amines7 or α-monobromina-
tion of 1,3-dicarbonyl compounds,8 and as building blocks
for the synthesis of semithiobambusurils.9 Some monothio
analogues of glycolurils demonstrate sedative,10 anxiolyt-
ic,11 and cytotoxic12 activities. While glycolurils are easily
accessible compounds, their thio analogues represent a yet
unfulfilled synthetic challenge.13
HN
N
H
N
H
N
Cl
N
R
90% HCOOH
reflux, 10 h
O
NH
N
N
N
N
R
2
3
R = H, Me
Scheme 1 Ring contraction of compounds 2
Earlier, upon treatment of several compounds 1 with
hydrochloric acid, 1,2,4-triazine ring contraction was not
observed.12,14b To the best of our knowledge, formic acid has
not yet used specifically for this purpose. Furthermore, for-
mic acid is not only an acid and acylating agent, but also a
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

B
G. A. Gazieva et al.
Letter
Synlett
R1
N
R2
N
R1
N
H
N
H
N
EtOH–H2O–HCl (100:10:1)
OH
H2N
Δ
NH
NH
NH
+
X
X
X
+
N
R2
N
N
N
R3
S
N
R3
S
OH
HN
R3
S
R1
R2
1'c,d,h,i
5a–i
1a–i
O
H2O, HCl,
70 °C
for
S
S
R1
N
5f,g
– PhCHNNHC(S)NH2
Ph
H
N
N
H
NH2
NH2
S
1f,g
H
N
R2
N
N
H
1,5: X = O, R3 = H, R1 = R2 = Me (a), Et (b), R2 = Ph, R1 = Me (c), Et (d), R1 - R3 = Me (e);
X = S, R3 = H, R1 = R2 = Me (f), Et (g), R2 = Ph, R1 = Me (h), Et (i)
Scheme 2 Synthesis of starting compounds 1
R1
reducing agent, for example, in the Leuckart–Wallach reac-
tion.21 Accordingly, an investigation into the reaction of
compounds 1 with formic acid became our objective.
Herein, we report the first synthesis of N-(5-oxo-2-thi-
oxo(2,5-dithioxo)hexahydroimidazo[4,5-d]imidazol-1(2H)-
yl)formamides 4 by tandem N-formylation and triazine
ring-contraction reaction of 5,7-disubstituted 3-thioxoper-
hydroimidazo[4,5-e]-1,2,4-triazin-6-ones(thiones) 1 with
formic acid.
O
Ph
N
Me
HN
N
Me
Me
R2
H
N
N
O
S
N
N
N
NH
6a–c
O
S
O
O
HCOOH
N
N
H
N
N
H
N
H
S
N
Me
Me
Me
1a
4a
7
6a: R1 = H, R2 = Ph, 6b: R1 = R2 = Me, 6c: R1 = Me, R2 = Et
Scheme 3 Reaction of compound 1a with carbonyl compound and
HCOOH
The starting materials 1 were prepared by cyclization of
4,5-dihydroxyimidazolidine-2-ones 5a–i with thiosemicar-
bazide following procedures described earlier (Scheme
2).14d,22 Known compounds 1a,b,e–g were obtained in 36–
70% yields. The yields of the major regioisomers (R1 = Alk,
R2 = Ph) of the novel unsymmetrically substituted imidaz-
otriazines 1c,d,h,i were 39–63% (minor regioisomers
1′c,d,h,i were not isolated). The structures and purity of
compounds 1c,d,h,i were ascertained by elemental analysis,
IR, 1H NMR, 13C NMR, and NOESY spectroscopic analyses
(see Supporting Information).23
Heating imidazotriazine 1a to reflux in 90% formic acid
led to its decomposition (Table 1, entry 1). When com-
pound 1a was heated to reflux in a mixture of 90% formic
acid and acetone, 6b, in the ratio 1:1, 1:3, and 1:5, product
4a was formed in 29–55% yields. It is evident that a reduc-
tion in temperature with the increasing proportion of ace-
Table 1 Optimization of the Reaction Conditions for the Imidazotri-
azine 1a
With this set of imidazotriazines in hand, we examined
their reaction with formic acid and carbonyl compounds 6.
Our investigations were initiated with the reaction of model
compound 1a, benzaldehyde 6a, and excess of formic acid
under heating (Scheme 3), when a mixture of two com-
pounds in a ratio 1:6 was obtained, as evidenced by NMR
spectroscopic analysis. The minor product was the known
(E)-4-(benzylideneamino)-1,3-dimethyl-5-thioxohexahydro-
imidazo[4,5-d]imidazol-2(1H)-one (7).22b The major prod-
uct turned out novel compound 4a resulting from tandem
N-formylation and triazine ring contraction of imidazotri-
azine 1a. The yield of the major compound 4a was 25%. In
an attempt to avoid the formation of products resulting
from tandem hydrazone formation–ring contraction, we
used ketones 6b,c. However, the reaction of one equivalent
each of 1a and 6b in excess of formic acids led to formamide
4a in low yield and no other products were isolated. To op-
timize the reaction conditions, solvent, reaction time, and
temperature were varied (Table 1).
Entry Solvent
Temp (°C) Time (h) Yield of 4a (%)a
1
2
HCOOH
reflux
reflux
reflux
reflux
55
2
2
0
29
54
55
70
67
46
70
56
40
41
45
0
HCOOH–acetone (1:1)
HCOOH–acetone (1:3)
HCOOH–acetone (1:5)
HCOOH–acetone (1:3)
HCOOH–acetone (1:5)
HCOOH–acetone (1:3)
HCOOH–acetone (1:3)
HCOOH–acetone (1:3)
HCOOH–butan-2-one (1:5)
HCOOH–butan-2-one (1:5)
HCOOH–butan-2-one (1:3)
HCOOH–MeOH (1:3)
3
2
4
2
5
2
6
55
2
7
50
2
8
55
3
9
r.t.
24
2
10
11
12
13
reflux
55
2
55
2
55
2
a Isolated yield.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

C
G. A. Gazieva et al.
Letter
Synlett
tone in the mixture of solvents resulted in an increase of
the product yield (Table 1, entries 2–4). Further investiga-
tions showed that formamide 4a was formed at 55 °C, 50 °C,
and room temperature in good yields for 2–24 hours (Table
1, entries 5–9). The optimal yield was obtained at 55 °C for
two hours (Table 1, entry 5). Carrying out reaction in a mix-
ture of formic acid with other solvents (butanone and
MeOH) did not lead to improvement of the product yield
(Table 1, entries 10–12), or compound 4a was not formed at
all (Table 1, entry 13).
The scope of the tandem N-formylation–triazine ring-
contraction reaction of imidazotriazines 1 was subsequent-
ly investigated under the optimized conditions. All the
studied compounds 1a–i reacted with formic acid to give
the corresponding formamides 4a–i (Scheme 4).24 Products
4a–d,f–i obtained from starting materials 1a–d,f–i without
substituents in the triazine ring were obtained in 54–70%
yields; however, introducing a methyl group at N(4) atom of
imidazotriazine 1e led to a dramatic decrease in the yield of
compound 4e (19%).
Figure 1 ORTEP view of 4b with nonhydrogen atoms as thermal ellip-
soids (p = 50%)
Results of the analysis of the experimental powder dif-
fraction patterns of the compounds 4a,b,f–i show that the
investigated samples were single-phase (see Supporting In-
formation).
A plausible mechanism for the formation of compounds
4 is depicted in Scheme 5 and includes a tandem sequence
of N-formylation of imidazotriazine 1 at N(1) and subse-
quent triazinane ring contraction to the imidazolidine. The
proposed pathway of the reaction is based on the fact that
intermediates 8 were identified by 1H NMR analysis or iso-
lated in some experiments. For example, stirring imidazo-
triazine 1a in 90% formic acid at room temperature for two
hours gave derivative 8a (X = O, R1 = R2 = Me) in 26% yield
(see Supporting Information).
R1
R1
N
HN
N
H
N
Me2CO, HCOOH,
55 °C, 2 h
N
O
S
NH
X
X
N
N
R3
N
R3
S
N
R2
R2
1a–i
4a–i
Me
HN
N
Et
HN
N
Me
HN
O
S
O
S
O
S
N
N
N
N
N
O
O
O
N
N
H
N
N
H
N
H
Me
Et
Ph
4a 70%
4b 68%
4c 57%
R1
N
R1
N
HN
N
H
N
O
S
HCOOH
NH
X
X
Et
HN
N
Me
HN
N
Me
HN
N
N
R2
N
R2
N
H
O
S
O
S
O
S
N
H
S
N
N
N
O
O
S
N
N
H
N
N
N
N
H
1
4
Ph
Me
Me
Me
HCOOH
– H2O
H
O
4d 65%
4e 19%
4f 61%
R1
N
N
H
S
Et
HN
N
Me
HN
N
Et
HN
N
N
X
O
S
O
S
O
S
N
N
N
N
N
S
S
S
H
R2
N
N
H
N
N
H
N
N
H
8
Et
Ph
Ph
4g 63%
4h 54%
4i 63%
Scheme 5 Proposed mechanism for the formation of compounds 4
Scheme 4 Synthesis of N-{5-oxo-2-thioxo(2,5-dithioxo)hexahydroim-
idazo[4,5-d]imidazol-1(2H)-yl}formamides 4a–i
In conclusion, we have developed a simple protocol for
the synthesis of novel mono- and dithio analogues of gly-
colurils possessing the formamide function. Novel N-{5-
oxo-2-thioxo(2,5-dithioxo)hexahydroimidazo[4,5-d]imid-
azol-1(2H)-yl}formamides were synthesized by the reac-
tion of 5,7-disubstituted 3-thioxoperhydroimidazo[4,5-e]-
1,2,4-triazine-6-ones(thiones) with formic acid in moder-
ate to good yields. The compounds synthesized may be
used as precursors of hitherto unknown thio analogues of
N-aminoglycolurils.
All compounds 4a–i were characterized by IR, NMR, and
1
HRMS analysis. In the H NMR and 13C NMR spectra of for-
mamides 4a–i in DMSO-d6, signals for two rotamers were
observed. The signals were assigned using {1H-13С} and {1H-
15N} HSQC methods. The single-crystal structure of com-
pound 4b was also obtained (Figure 1).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

D
G. A. Gazieva et al.
Letter
Synlett
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Acknowledgment
High-resolution mass spectra were recorded in the Department of
Structural Studies of N.D. Zelinsky Institute of Organic Chemistry,
Moscow.
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Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588388.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
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7-Methyl-5-phenyl-3-thioxoperhydroimidazo[4,5-e]-1,2,4-
triazin-6-one (1c)
White solid; yield 0.537 g (51%); mp 258–260 °С (decomp.). 1H
NMR (300 MHz, DMSO-d6): δ = 2.73 (s, 3 H, Me), 5.02 (d, J = 8.5
Hz, 1 H, CH), 5.45–5.48 (dd, J = 8.5, 1.9 Hz, 1 H, CH), 5.86 (br s, 1
H, N(1)H), 7.13 (t, J = 7.2 Hz, 1 H, p-PhH), 7.35 (t, J = 7.8 Hz, 2 H,
m-PhH), 7.48 (d, J = 8.1 Hz, 2 H, o-PhH), 8.62 (s, 1 H, N(4)H), 9.52
(s, 1 H, N(2)H). 13C NMR (75 MHz, DMSO-d6): δ = 27.0, 62.1,
69.0, 122.0, 123.9, 128.6, 137.5, 155.8, 184.9. IR: 3208, 2971,
1698, 1595, 1529, 1500, 1477, 1439, 1396, 1303, 1261, 1147,
1120, 746. ESI-HRMS: m/z [M + H] calcd for C11H13N5OS:
264.0914; found: 264.0907.
7-Methyl-5-phenylperhydroimidazo[4,5-e]-1,2,4-triazin-3,6-
dithione (1h)
Yellowish solid; yield 0.514 (46%); mp 216–218 °С (decomp.).
1H NMR (500 MHz, DMSO-d6): δ = 3.05 (s, 3 H, Me), 5.32–5.38
(m, 2 H, CH), 5.97 (s, 1 H, N(1)H), 7.30 (d, J = 7.6 Hz, 2 H, o-PhH),
7.33 (t, J = 7.4 Hz, 1 H, p-PhH), 7.42 (t, J = 7.6 Hz, 2 H, m-PhH),
8.70 (s, 1 H, N(4)H), 9.65 (s, 1 H, N(2)H). 13C NMR (75 MHz,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

E
G. A. Gazieva et al.
Letter
Synlett
DMSO-d6): δ = 31.1, 66.7, 73.8, 127.2, 128.6, 129.1, 138.2, 181.1,
186.3. IR: 3177, 2959, 1595, 1554, 1500, 1407, 1388, 1335,
1293, 1265, 1213, 1136, 1108, 698. Anal. Calcd for C11H13N5S2:
C, 47.29; H, 4.69; N, 25.07; S, 22.95. Found: C, 47.32; H, 4.70; N,
25.05; S, 22.91.
cis). 13C NMR (75 MHz, DMSO-d6): δ = 28.08 (NMe, trans), 28.12
(NMe, cis), 28.9 (NMe, cis), 29.6 (NMe, trans), 68.1 (CH, trans),
68.3 (CH, cis), 75.2 (CH, cis), 76.3 (CH, trans), 157.3 (CO, cis),
157.4 (CO, trans), 159.9 (HNCO, cis), 167.5 (HNCO, trans), 183.4
(CS, cis), 184.4 (CS, trans). IR: 3258, 2944, 2891, 1703, 1680,
1520, 1486, 1419, 1253, 1220, 1047, 754. ESI-HRMS: m/z [M +
H] calcd for C7H11N5O2S: 230.0706; found: 230.0700.
(24) Synthesis of N-{4,6-Disubstituted 5-Oxo-2-thioxo(2,5-dithi-
oxo)hexahydroimidazo[4,5-d]imidazol-1(2H)-yl}forma-
mides 4a–i; General Procedure
N-{4,6-Diethyl-5-oxo-2-thioxohexahydroimidazo[4,5-d]-
imidazol-1(2H)-yl}formamide (4b)
White solid; yield: 0.35 g (68%); mp 228–229 °С (decomp.). H
To a solution (or suspension) of imidazotriazine 1 (2 mmol) in
acetone (22.5 mL) was added 90% formic acid (7.5 mL). The
resulting mixture was heated to 55 °C and stirred for 2 h. Then
the reaction mixture was cooled to r.t. and allowed to stand for
72 h to attain complete precipitation. The precipitate of com-
pound 4 was filtered, washed with MeOH, and dried.
Representative Analytical Data
1
NMR (300 MHz, DMSO-d6): 70:30 (cis/trans): δ = 1.02–1.07 (m,
6 H, Me), 3.06–3.41 (m, 4 H, NCH2), 5.45–5.58 (m, 2 H, CHCH),
8.06 (d, J = 10.3 Hz, 0.3 H, HCO, trans), 8.13 (s, 0.7 H, HCO, cis),
9.94 (d, J = 10.3 Hz, 0.3 H, NNH, trans), 9.95 (s, 0.7 H, NH, cis),
10.05 (s, 0.3 H, NH, trans), 10.56 (s, 0.7 H, NNH, cis). 13C NMR
(75 MHz, DMSO-d6): δ = 12.76 (Me, trans), 12.86 (Me, cis), 12.92
(Me), 36.0 (NCH2), 36.6 (NCH2, cis), 37.0 (NCH2, trans), 66.5 (CH,
trans), 66.6 (CH, cis), 73.2 (CH, cis), 74.2 (CH, trans), 156.8 (CO,
cis), 157.0 (CO, trans), 160.2 (HNCO, cis), 167.8 (HNCO, trans),
183.7 (CS, cis), 184.6 (CS, trans). IR: 3200, 2988, 2973, 1709,
1677, 1539, 1501, 1470, 1436, 1252, 1229, 1068, 756. ESI-
HRMS: m/z [M + H] calcd for C9H15N5O2S: 258.1019; found:
258.1021.
N-{4,6-Dimethyl-5-oxo-2-thioxohexahydroimidazo[4,5-d]-
imidazol-1(2H)-yl}formamide (4a)
White solid; yield 0.321 g (70%); mp 231–233 °С (decomp.). 1H
NMR (300 MHz, DMSO-d6): 70:30 (cis/trans): δ = 2.71 (s, 3 H,
NMe), 2.78 (s, 2.1 H, NMe, cis), 2.81 (s, 0.9 H, NMe, trans), 5.34–
5.45 (m, 2 H, CHCH), 8.08 (d, J = 10.5 Hz, 0.3 H, HCO, trans), 8.12
(s, 0.7 H, HCO, cis), 9.93 (s, 0.7 H, NH, cis), 9.97 (d, J = 10.5 Hz, 0.3
H, NNH, trans), 10.04 (s, 0.3 H, NH, trans), 10.52 (s, 0.7 H, NNH,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E