Base-promoted ring expansion of 3-aminopyrimidine-2-thiones into 1,2,4-triazepine-3-thiones

Article abstract of DOI:10.1016/j.tet.2016.03.082

A base-promoted ring expansion of 3-amino-4-hydroxyhexahydropyrimidine-2-thiones into 2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thiones has been developed. Experimental data and DFT calculations showed that the reaction proceeded through fast formation of intermediate acyclic isomers of pyrimidines followed by their slow cyclization into triazepines. The starting hydroxypyrimidines were prepared by reaction of α,β-unsaturated ketones or β-alkoxy ketones with HNCS followed by treatment of the obtained β-isothiocyanato ketones with hydrazine. Triazepine-3-thiones were transformed into their 3-oxo analogs by oxidation with H₂O₂ under basic conditions.

Full text of DOI:10.1016/j.tet.2016.03.082

Tetrahedron xxx (2016) 1e14
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Base-promoted ring expansion of 3-aminopyrimidine-2-thiones into
1,2,4-triazepine-3-thiones
*
Anastasia A. Fesenko, Anatoly D. Shutalev
Department of Organic Chemistry, Moscow Technological University, 86 Vernadsky Avenue, 119571 Moscow, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
A base-promoted ring expansion of 3-amino-4-hydroxyhexahydropyrimidine-2-thiones into 2,4,5,6-
tetrahydro-3H-1,2,4-triazepine-3-thiones has been developed. Experimental data and DFT calculations
showed that the reaction proceeded through fast formation of intermediate acyclic isomers of pyrimi-
dines followed by their slow cyclization into triazepines. The starting hydroxypyrimidines were prepared
Received 8 January 2016
Received in revised form 14 March 2016
Accepted 24 March 2016
Available online xxx
by reaction of
obtained -isothiocyanato ketones with hydrazine. Triazepine-3-thiones were transformed into their 3-
oxo analogs by oxidation with H2O2 under basic conditions.
a,b-unsaturated ketones or b-alkoxy ketones with HNCS followed by treatment of the
b
Keywords:
Isothiocyanato ketones
Thiosemicarbazides
Pyrimidines
Ó 2016 Elsevier Ltd. All rights reserved.
Ring expansion
1,2,4-Triazepines
1. Introduction
analogs, 2,4,5,6-tetrahydro-3H-1,2,4-triazepin-3-ones and their 3-
thioxo derivatives. From the literature data2,5 we suggested that
a straightforward and general approach to these heterocycles is
Rare heterocyclic scaffolds are of great interest from the view-
point of synthetic, theoretical, and medicinal chemistry. With the
exception of benzo- and hetero-fused derivatives, 1,2,4-triazepines,
particularly 1,2,4-triazepin-2-ones/thiones are representative of
these scaffolds.1 Methods for the preparation of a few 1,2,4-
triazepin-2-ones/thiones include reaction of arylidene ketones
based on the reaction of b-isothiocyanato ketones with hydrazines.
This reaction was performed with 3-isothiocyanato-1,3-
diphenylpropan-1-one,5b,c 2-(1-isothiocyanatocyclopentyl)cyclo-
pentanone,5c,d and the readily available 4-isothiocyanato-4-
methylpentan-2-one5d,e (1, Scheme 1) under neutral, acidic, or
basic conditions.
with N2H4$2HNCS,2 addition of (thio)semicarbazides to
saturated ketones or their synthetic equivalents,3 reaction of
isocyanato or
-isothiocyanato ketones with hydrazines,4,5 con-
a,b-un-
b
-
b
densation of 1,3-dicarbonyl compounds with (thio)semi-
carbazides,6 CDI-mediated cyclization of 3-hydrazino-substituted
amines,7 and reaction of thiosemicarbazides with dimethyl acety-
lenedicarboxylate and dibenzoyl acetylene.8 The disadvantages of
these methods are low availability of starting compounds, multi-
step reaction sequences, poor yields, limited synthetic flexibility,
laborious procedures, etc. It should be noted that some 1,2,4-
triazepin-2-ones are useful in the treatment of HIV infection.7
However, low availability of non-fused 1,2,4-triazepin-2-ones/thi-
ones hampers the progress of their investigation and application.
In continuation of our research into the synthesis of 2,3,4,5-
tetrahydro-1H-1,3-diazepin-2-ones using a ring expansion meth-
odology,9 we were interested in the preparation of their aza-
Scheme 1. Reaction of isothiocyanate 1 with hydrazine.
It was demonstrated that isothiocyanate 1 reacts with hydrazine
hydrate under heating in water in the presence of mineral acid to
yield pyrimidine derivative 2 (Scheme 1).10 Later it was reported
that the product of this reaction is not the pyrimidine 2 but tri-
azepine 3 which can also be prepared by reaction of isothiocyanate
1 with hydrazine hydrate in refluxing benzene using a DeaneStark
trap.5e In contrast, under the given conditions5e,10 we obtained 3-
* Corresponding author. Tel.: þ7 495 246 0555x908; fax: þ7 495 246 0555x909;
e-mail addresses: anatshu@gmail.com, shutalev@orc.ru (A.D. Shutalev).
http://dx.doi.org/10.1016/j.tet.2016.03.082
0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Fesenko, A. A.; Shutalev, A. D., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.03.082

2
A.A. Fesenko, A.D. Shutalev / Tetrahedron xxx (2016) 1e14
aminopyrimidine-2-thione 4 as the major compound, and the
amount of triazepinethione 3 did not exceed 5% and 15%, re-
spectively (according to 1H NMR spectra of the isolated crude
products). This indicates that rapid cyclization of the intermediate
thiosemicarbazide 5 into pyrimidine derivative 4 is followed by its
slow transformation into triazepinethione 3 via ring expansion
with nitrogen insertion. Therefore, results of the reaction of iso-
thiocyanato ketones with hydrazines do not appear to be so clear as
available. As for other isothiocyanates, their synthesis was either
not reported previously (for 6d,h,i),17,25 or they were obtained only
as crude products (for 6eeg),5a,18,19 or procedures for their prepa-
ration were far from optimal (for 6b,c).15b,20
reported previously.2,5,10 Indeed, the initially formed 4-(
g-oxoalkyl)
thiosemicarbazides (e.g., 5) can undergo various transformations,
including cyclization into 1,2,4-triazepine-3-thiones, derivatives of
pyrimidine, fused heterocyclic systems, macrocyclic compounds,
etc.11
Based on the reported data and our experience, we hypothe-
sized that 3-amino-4-hydroxyhexahydropyrimidine-2-thiones ob-
Scheme 2. Synthesis of b-isothiocyanato carbonyl compounds 6aej.
Two alternative methods were used for the synthesis of starting
isothiocyanates 6aej. The first method was based on the addition of
HNCS to unsaturated carbonyl compounds 7aej, and the second
tained by the reaction of b-isothiocyanato ketones with hydrazines
was our original method involving the reaction of HNCS with b-
can serve as starting compounds for the preparation of 2,4,5,6-
tetrahydro-3H-1,2,4-triazepine-3-thiones. Here, we report the
synthesis of 2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thiones by
base-promoted ring expansion of 3-amino-4-hydroxyhexa-
hydropyrimidine-2-thiones, a plausible pathway of this trans-
formation based on experimental data and DFT calculations, and
oxidative transformation of the obtained 1,2,4-triazepine-3-thiones
into the corresponding 3-oxo derivatives. Two preparative pro-
alkoxy ketones 8aed (Scheme 2).
b
-Alkoxy ketones 8aed were prepared by directed aldol type
condensation of TMS ethers of acetone, cyclopentanone, or cy-
clohexanone with acetone dimethyl acetal or acetaldehyde
diethyl acetal in the presence of ZnCl2 in AcOEt.21 During the
reaction and vacuum distillation,
b-alkoxy ketones 8aec partly
converted into the corresponding unsaturated ketones 7b,d,h.
Compounds 6aej were synthesized by reacting 7aej, 8d or mix-
tures of 7b,d,h and 8aec with NH4SCN in the presence of H2SO4
in water. The ratio of the reagents, the reaction temperature and
time were optimized to achieve maximum conversion of starting
compounds (92e100% according to 1H NMR spectra of the crude
products) (Table 1).
cedures for the synthesis of
reported.
b-isothiocyanato ketones are also
2. Results and discussion
Under improved reaction conditions mesityl oxide (7a) reacted
with HNCS (1.05 equiv) for 15 min upon heating at 70e80 ꢀC to give
isothiocyanate 6a in 75% isolated yield (Table 1, entry 1). Iso-
thiocyanato ketones 6bee,h,i were prepared using a greater excess
of HNCS (1.96e3.01 equiv) and heating at 60 ꢀC for 3e7 h (entries
2e5, 8, and 9). The same temperature was used for the preparation
of isothiocyanate 6g from ketone 7g (entry 7). In contrast, the ad-
dition of HNCS to ketone 7f smoothly proceeded at 5 ꢀC for 25 h
(entry 6). The amount of isothiocyanate 6f in the isolated crude
product significantly decreased within the reaction temperature
range of 20e90 ꢀC (1H NMR spectroscopic data). Mild reaction
conditions were applied for the synthesis of isothiocyanate 6j from
aldehyde 7j (entry 10). Compounds 6c,d,g,h with two stereocenters
formed as diastereomeric mixtures (Table 1). The isothiocyanates
6aej obtained were purified by vacuum distillation. Partial elimi-
nation of HNCS proceeded during distillation of 6d,e,f,h to give an
admixture of the corresponding unsaturated ketone 7d,e,f,h
(3e21%) in the resulting product. The amount of this admixture was
taken into account in the following synthetic step.
2.1. Synthesis of starting
compounds
b-isothiocyanato carbonyl
Preparation of b-isothiocyanato aldehydes and ketones was the
first step of the triazepine synthesis. These isothiocyanates have
been the focus of considerable attention since 1946,12 and they
have found a broad application as versatile precursors in organic
synthesis.13 The most general and straightforward preparative
route to these compounds involves the addition of HNCS generated
by treatment of thiocyanate salts with strong mineral acids to a,b-
unsaturated aldehydes and ketones in water.14e16 Success of this
reaction is highly dependent on the substrate structure, particularly
on the nature of the substituents.14,15b Therefore, in each particular
case, careful optimization of reaction conditions should be carried
out. As a consequence it is not surprising that the number of b-
isothiocyanato aldehydes and ketones described still remains
somewhat limited. For the present study, isothiocyanates 6aej
were chosen as a starting material (Scheme 2, Table 1). Among
them, only compounds 6a,j could be considered to be synthetically
Table 1
Optimized reaction conditions for the synthesis of b
-isothiocyanato carbonyl compounds 6aej.a
Entry
7 or/and 8 (7/8 ratio)
Reagents ratiob
R
R1
R2
R3
R4
Temp (ꢀC)c
Time (h)
6
Yield (%)d
Isomer ratioe
1
2
3
4
5
6
7
8
9
7a
1.05:0.53:1
2.03:1.02:1
2.53:1.27:1
2.11:1.06:1
3.01:1.51:1
2.50:1.25:1
1.05:1.05:1
1.96:0.98:1
2.05:1.02:1
1.41:0.71:1
Me
Me
Me
Me
Me
CH2CH2CH2
H
Me
Me
Me
Me
H
H
H
Me
H
H
Me
CH2CH2CH2
CH2CH2CH2
CH2CH2CH2
Me
Me
Me
d
70e80
60
60
60
60
5
60
60
0.25
3
4
4
7
25
4
3
6a
6b
6c
6d
6e
6f
6g
6h
6i
75
81
86
74
74
62
59
90
90
56
d
7bþ8a (3:97)
OEt
d
d
7c
60:40
70:30
d
7dþ8b (55:45)
OEt
d
7e
7f
7g
d
d
CH2CH2CH2CH2
H
Me
H
Me
d
56:44
63:37
d
7hþ8c (13:87)
CH2CH2CH2CH2
CH2CH2CH2CH2
H
OEt
OMe
d
8d
7j
60
3
10
H
rt, then 40
1, then 1
6j
d
a
Level of conversion of the starting material is 100% (entries 1, 2, 8e10), 96% (entry 3), 95% (entries 4, 5), and 92% (entry 6).
NH4SCN/H2SO4/substrate molar ratio.
Bath temperature.
Isolated yield (after vacuum distillation).
After vacuum distillation.
b
c
d
e
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A.A. Fesenko, A.D. Shutalev / Tetrahedron xxx (2016) 1e14
3
2.2. Synthesis of 3-amino-4-hydroxyhexahydropyrimidine-2-
thiones
The reaction between isothiocyanates 6aej and hydrazine hydrate
(1 equiv) readily proceeded in MeCN or EtOH at room temperature to
give the corresponding 3-amino-4-hydroxyhexahydropyrimidine-2-
thiones 10aej in 74e97% yields (Scheme 3, Table 2) via intermediate
formation of 4-(g-oxoalkyl)thiosemicarbazides 9aej. Cyclization of
the latter with participation of the amino group was not observed.
Reaction of 6bej with hydrazine afforded pyrimidines as mix-
tures of two (for 10b,e,f,i,j) or four diastereomers (for 10c,d,g,h).
This reaction proceeded under thermodynamic control, which was
confirmed by data in entries 3 and 4, and by the presence of acyclic
isomers 9bed,g along with pyrimidines 10bed,g (entries 2e5, 8) in
the isolated products.
Scheme 4. Base-promoted ring expansion of pyrimidines 10aej into triazepines 11aej.
and reflux of the reaction mixture led to formation of a considerable
amount of impurities (entry 12). No reaction proceeded with py-
rimidine 10g under the action of DBU in MeCN at room temperature
(entry 11).
Treatment of perhydroquinazolines 10h,i with KOH in EtOH
upon heating (entries 14e16, 24), KOH in H2O at room temperature
(entry 17), NaH in THF at room temperature (entry 25), DBU in
refluxing MeCN, pyridine, or toluene (entries 19e20, 27e29) did
not result in formation of the target bicyclic triazepines 11h,i. Un-
expected dehydration of compounds 10h,i into the corresponding
products 12a,b, 13a,b proceeded in refluxing pyridine (entries 18,
26) while in the presence of DBU this reaction was completely
suppressed (entries 19, 27). Triazepines 11h,i were prepared from
perhydroquinazolines 10h,i in refluxing MeOH in the presence of
MeONa in 93e94% yields (entries 13, 21). It should be noted that
complete conversion of 10h required a greater amount of MeONa
(5.08 equiv) compared with 10i (2.56 equiv) (entry 13 vs entry 21;
entry 21 vs entry 22 vs entry 23). Our attempts to obtain triazepine
11j from 10j under various conditions failed. Either the starting
material was recovered or a complex mixture of unidentified
products was formed (see, for example, entries 30 and 31).
Monocyclic triazepines 11aec were also prepared using a one-
Scheme 3. Reaction b-isothiocyanato carbonyl compounds 6aej with hydrazine.
Table 2
Synthesis of 3-amino-4-hydroxyhexahydropyrimidine-2-thionesa
Entry
6
Solvent Time (h)b Product(s) Yield (%)c Isomer ratio for 10d
1
2
3
4
5
6
7
8
6a EtOH
6b MeCN
6c MeCN
6c EtOH
6d MeCN
6e MeCN
6f MeCN
6g MeCN
6h MeCN
6i MeCN
6j EtOH
1
1
1
1
1.5
2
0.17
1
2.33
2
1
10a
93
93
91
90
82
96
93
88
96
97
74
d
10bþ9be
10cþ9cf
10cþ9cf
10dþ9dg
10e
75:25
45:26:18:11
46:26:19:9
71:26:2:1
60:40
pot procedure from b-isothiocyanato ketones 6aec without iso-
10f
60:40
lation of the intermediate pyrimidines 10aec (Scheme 5).
Compounds 11aec were prepared in 75%, 61% and 42% isolated
yield, respectively, by treatment of 6aec with hydrazine hydrate
(1.02e1.11 equiv) in the presence of NaOH (0.68e1.01 equiv) in H2O
at room temperature for 1.5e6 h. Obviously, this transformation
proceeds via fast reaction of N2H4 with isothiocyanato ketones
6aec to give pyrimidines 10aec followed by their slow conversion
into the target products promoted with NaOH.
Thus, we have shown that 3-amino-4-hydroxyhexa-
hydropyrimidine-2-thiones undergo previously unknown ring ex-
pansion to produce 2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-
thiones in the presence of bases. Based on the experimental data
shown in Table 3 and quantum chemical calculations at the B3LYP/
6-311þþG(d,p) level of theory using the PCM solvation model
performed for the transformation of pyrimidine 10a into triazepine
11a, we suggest that this reaction includes initial deprotonation of
compound 10a under the action of a base to give one of three
possible anions A, B, or C (Scheme 6).
10gþ9gh
50:29:13:8
36:35:27:2
84:16
9
10
11
10h
10i
10j
90:10
a
A slight excess of N2H4$H2O (up to 1.07 equiv) was used, except for entry 6
(0.98 equiv).
b
c
At rt (entries 1e6, 8e11) or 0 ꢀC (entry 7).
Isolated yield (for 10 or 10þ9).
d
e
f
According to 1H NMR spectroscopic data for the crude product.
10b/9b¼90:10.
10c/9c (two isomers, 78:22)¼89:11.
10d/9d (a single isomer)¼97:3.
g
h
10g/9g (two isomers, 56:44)¼97:3.
2.3. Synthesis of 2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-
thiones/ones
Pyrimidines 10aej were converted into the corresponding
2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thiones 11aej under the
action of bases (Scheme 4). Table 3 shows selected experimental
data for this transformation.
Monocyclic pyrimidines 10aec afforded triazepines 11aec in
78e93% yields after treatment with aqueous NaOH (0.74e1 equiv)
at room temperature (entries 1e3). Transformation of bicyclic py-
rimidines 10deg into triazepines 11deg did not proceed under
these conditions (entry 10). The use of alcoholic KOH
(2.49e2.51 equiv) and heating the reaction mixture at 40 ꢀC for 4 h
led to smooth formation of triazepines 11deg (entries 4e6, 8). For
these starting compounds the reaction rate decreased with a de-
crease in temperature (entry 6 vs entry 7, and entry 8 vs entry 9),
The calculations showed that anion B is the most unstable
compared with anions A and C (
298 K and 1 atm), therefore its formation can be excluded. Anions A
and C are very close in energy (
D
G¼11.1e11.3 kcal/mol in EtOH,
D
G¼0.2 kcal/mol in EtOH), and they
can form an equilibrium mixture upon deprotonation of 10a. Since
the only way for conjugated base C to be transformed into tri-
azepine 11a involves cleavage of C2eN3 bond with a high energy
barrier, this anion seems to be the unreactive species. Anion A has
an extraordinarily long N3eC4 bond and short CeO bond (1.625
ꢀ
and 1.316 A in EtOH, respectively) compared with the lengths of the
ꢀ
corresponding bonds in 10a (1.484 and 1.426 A in EtOH). Therefore,
we suppose that deprotonation of 10a to give anion A followed by
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4
A.A. Fesenko, A.D. Shutalev / Tetrahedron xxx (2016) 1e14
Table 3
Base-promoted ring expansion of pyrimidines 10aej into triazepines 11aej
Entry
10a
Solvent
Base (equiv)
Reaction conditions
Conv. (%)b
Product(s)
Isolated yield (%)
Isomers ratiob
1
2
3
4
5
6
7
8
10a
10b
10c
10d
10e
10f
10f
10g
10g
10g
10g
10g
10h
10h
10h
10h
10h
10h
10h
10h
10i
H2O
H2O
H2O
NaOH (0.74)
NaOH (0.75)
NaOH (1.00)
KOH (2.51)
KOH (2.49)
KOH (2.50)
KOH (2.52)
KOH (2.50)
KOH (2.02)
NaOH (0.77)
DBU (0.54)
NaOH (1.02)
MeONa (2.56)
KOH (2.45)
KOH (3.02)
KOH (3.04)
KOH (3.00)
d
rt, 1.33 h
rt, 3 h
rt, 6 h
40 ꢀC, 4 h
40 ꢀC, 4 h
40 ꢀC, 4 h
rt, 3 h
40 ꢀC, 5.5 h
rt, 4 h
rt, 1.5 h
100
100
100
100
100
100
50
100
24
0
11a
11b
11c
11d
11e
11f
93
83
78
90
91
93
d
93
d
d
d
d
93
d
d
d
d
d
d
d
94
d
d
d
d
d
d
d
d
d
d
d
d
55:45
92:8
d
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
H2O
MeCN
EtOHeH2O (10:1)
MeOH
EtOH
EtOH
H2O
EtOH
py
py
MeCN
MeOH
MeOH
MeOH
EtOH
THF
d
11f
d
11g
11g
d
93:7
92:8
d
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
rt, 3 h
0
d
d
rt, 3.33 h, then reflux, 0.5 h
reflux, 5.5 h
40 ꢀC, 5.5 h
60 ꢀC, 5.5 h
rt, 7 h 16 min
40 ꢀC, 24 h
reflux, 3.42 h
reflux, 3.42 h
reflux, 2 h
reflux, 8 h
reflux, 7 h
reflux, 6.75 h
40 ꢀC, 5.5 h
rt, 6.42 h
90
100
52
100
0
70
100
0
11gc
11h
11h
11hd
d
76:24
60:40
59:41
62:38
d
11he
12aþ13af
d
60:40
d
DBU (0.25)
DBU (0.24)
MeONa (5.08)
MeONa (5.01)
MeONa (2.67)
KOH (2.52)
NaH (1.08)
d
d
0
d
d
100
96
81
5
3
99
0
0
0
80
90
11ig
11ig
11ih
11i
d
10i
10i
10i
10i
10i
10i
10i
10i
d
d
d
11i
d
py
py
MeCN
toluene
MeOH
EtOH
reflux, 3.58 h
reflux, 3.58 h
reflux, 3 h
reflux, 3 h
40 ꢀC, 5 h
12bþ13bi
d
d
DBU (0.23)
DBU (0.25)
DBU (0.25)
MeONa (2.48)
LPO (2.86)
d
d
d
d
ej
ej
d
10j
10j
d
40 ꢀC, 4 h
d
a
The crude products obtained by the reaction of 6aej with N2H4 were used (see Table 2).
Level of conversion according to 1H NMR spectroscopy of the crude product.
With considerable amount of impurities (about 55 mol %).
With considerable amount of impurities (about 70 mol %).
With considerable amount of impurities (about 66 mol %).
A mixture of 12a (R1¼H, two isomers, 56:27) and 13a (R1¼H) in a ratio of 83:17.
Plus 4 mol % of a mixture of 12b and 13b (R1¼Me).
b
c
d
e
f
g
h
i
Plus 5 mol % of a mixture of 12b and 13b (R1¼Me).
A mixture of 12b and 13b (R1¼Me) in a ratio of 61:39.
j
A complex mixture of unidentified products.
cleavage of the N3eC4 bond is the most preferable initiation of the
ring expansion.
Transformation of anion A into the anion of acyclic form D
proceeds via the transition state TS with low activation energy
(electronic energy 0.5 kcal/mol in EtOH, the Gibbs free energy
z0 kcal/mol in EtOH, 298 K and 1 atm). Further detailed calcula-
tions using the OH-anion as a base showed that the complex of
anion A with H2O obtained after deprotonation of 10a with hy-
droxide undergoes N3eC4 bond cleavage with an activation barrier
Scheme 5. One-pot synthesis of triazepinethiones 11aec from isothiocyanates 6aec.
of
D
G¼2.4 kcal/mol (EtOH, 298 K, 1 atm) to give the complex of
anion D with H2O. This reaction proceeds with a
DG value of
of side products from 10j rather then triazepine 11j, since the al-
dehyde group in the intermediate acyclic form 9j is highly reactive
under strongly basic conditions.
3-Oxo-analogs of the obtained 1,2,4-triazepine-3-thiones can be
readily prepared by oxidation.
Compounds 11a,f,g,i were oxidized with H2O2 in H2OeEtOH
solution in the presence of KOH to give the corresponding 1,2,4-
triazepin-3-ones 15aed in high yields (Scheme 7).
ꢁ1.1 kcal/mol. The IRC analysis demonstrated that the found tran-
sition state connects the desired minima. Anion D after protonation
followed by cyclization of the obtained thiosemicarbazide 9a into
triazepine 14 and dehydration gives the target product 11a. For-
mation of triazepine 11a from pyrimidine 10a is a thermodynami-
cally favorable process with
DG¼ꢁ12 kcal/mol (EtOH, 298 K, 1 atm).
We suppose that the base-promoted transformation of other
pyrimidines 10bei into the corresponding triazepines 11bei pro-
ceeds via acyclic isomers 9bei analogously, as described for 10a.
Although the acyclic isomers 9aei rapidly form from pyrimidines
10aei, their cyclization into 14aei, which proceeds with partici-
pation of the most nucleophilic nitrogen of the thiosemicarbazide
moiety,22 seems to be slow and strongly dependent on the struc-
ture of the starting compound (Table 3). This explains the formation
3. Conclusion
An efficient synthesis of the rare heterocyclic scaffold, 2,4,5,6-
tetrahydro-3H-1,2,4-triazepine-3-thione has been developed. The
key step of the synthesis is the ring expansion of 3-amino-4-
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A.A. Fesenko, A.D. Shutalev / Tetrahedron xxx (2016) 1e14
5
spectrophotometer. Band characteristics in the IR spectra are de-
fined as very strong (vs), strong (s), medium (m), weak (w), and
shoulder (sh). 1H NMR and proton decoupled 13C NMR spectra
(solutions in DMSO-d6 or CDCl3) were acquired using a Bruker DPX
300 spectrometer at 300.13 MHz (1H) and 75.48 MHz (13C). 1H NMR
chemical shifts are referenced to the residual proton signal in
DMSO-d6 (2.50 ppm) or CDCl3 (7.24 ppm). In 13C NMR spectra,
central signals of DMSO-d6 (39.50 ppm) or CDCl3 (77.23 ppm) were
used as references. Multiplicities are reported as singlet (s), doublet
(d), triplet (t), quartet (q), and some combinations of these, mul-
tiplet (m). Selective 1He1H decoupling and DEPT-135 experiments
were used to aid in the assignment of 1H and 13C NMR signals. 2D
NMR experiments (1He13C HSQC, 1He13C HMBC) for compounds
11aec (solutions in DMSO-d6) were carried out using a Bruker
Avance-600 spectrometer at 600.13 MHz (1H) and 150.91 MHz
(
13C). Mass spectra were obtained on a Finnigan MAT INCOS 50
Scheme 6. A plausible pathway for pyrimidine ring expansion.
instrument (electron impact, 70 eV). Elemental analyses (CHN)
were performed using a Thermo Finnigan Flash EA1112 apparatus.
Thin-layer chromatography was carried out on Aldrich silica gel 60
F254 aluminum backed plates in CHCl3/MeOH (9:1, v/v) and CHCl3/
MeOH (5:1, v/v) as solvent systems. Spots were visualized with UV
light or iodine vapors. Column chromatography was performed
with MachereyeNagel silica gel 60 (0.063e0.200 mm). All yields
refer to isolated, spectroscopically and TLC pure compounds. The
color of solid substances was white, if not otherwise mentioned. pH
of aqueous solutions was measured with universal indicator paper.
4.2. Synthesis of
b-isothiocyanato carbonyl compounds
Scheme 7. Oxidation of triazepinethiones 11a,f,g,i into triazepinones 15aed.
4.2.1. 4-Isothiocyanato-4-methylpentan-2-one (6a). To
a
stirred
mixture of 4-methylpent-3-en-2-one (7a) (131.24 g, 1.337 mol) and
NH4SCN (106.91 g, 1.404 mol) in H2O (130 mL) was added a cooled
(10e15 ꢀC) solution of H2SO4 (40.0 mL, 0.702 mol; d¼1.831 g/mL,
94%) in H2O (40 mL) over 5 min. The obtained emulsion was heated
in a water bath (70e80 ꢀC, temperature of bath) under intense
stirring for 15 min, and cooled. The organic layer was separated,
and the aqueous layer was extracted with ether (2ꢂ45 mL). The
combined organic layer was neutralized with 7% aqueous Na2CO3 to
pH 8, washed with H2O, brine, and dried over Na2SO4. The solvent
was removed under vacuum, and the residue was distilled under
vacuum to give compound 6a (158.71 g, 75%) as a slightly yellow
liquid. Bp 102e113 ꢀC/20 mmHg; nD20 1.5008 (lit.23 1.5030). 1H NMR
hydroxyhexahydropyrimidine-2-thiones under the action of bases.
The proposed reaction pathway based on experimental data and
DFT calculations included fast formation of intermediate acyclic
isomers followed by their slow cyclization into triazepines. Starting
hydroxypyrimidines were prepared by reaction of
ketones or -alkoxy ketones with thiocyanic acid followed by
treatment of the obtained -isothiocyanato ketones with hydra-
zine. 3-Oxo-analogs were readily obtained from triazepine-3-
thiones by oxidation with H2O2. Since various -alkoxy ketones
a,b-unsaturated
b
b
b
can be prepared using directed aldol condensation of TMS ethers of
ketones and acetals of carbonyl compounds, a large variety of tri-
azepines can be obtained and subsequently modified. We believe
that this methodology will be helpful for further research into the
chemistry and applications of 1,2,4-triazepines.
(300.13 MHz, CDCl3) d: 2.69 (2H, s, CH2), 2.15 (3H, s, CH3C]O), 1.46
(6H, s, 2CH3).
4.2.2. 4-Isothiocyanatopentan-2-one (6b). To a stirred solution of
a 97:3 mixture of 4-ethoxypentan-2-one (8a) and pent-3-en-2-one
(7b) (19.92 g, 154.65 mmol total) and NH4SCN (23.90 g,
313.97 mmol) in H2O (70 mL) was added a cooled (10e15 ꢀC) so-
lution of H2SO4 (9 mL, 158.07 mmol; d¼1.831 g/mL, 94%) in H2O
(35 mL) over 5 min. The obtained emulsion was heated in a water
bath (60 ꢀC, temperature of bath) under intense stirring for 3 h, and
cooled. The resulting mixture was extracted with ether (100 mL,
2ꢂ50 mL) using 0.5 L separatory funnel. To the combined organic
layer was gradually added saturated aqueous NaHCO3 (50 mL) and
then solid NaHCO3 was added in small portions so that the foam
formation was not too intense. After the neutralization was almost
completed, which could be detected by the fading of gas evolution,
the aqueous layer was separated, and the organic layer was addi-
tionally washed with saturated aqueous NaHCO3 (2ꢂ50 mL, 25 mL)
to pH 8, H2O (2ꢂ50 mL), brine (2ꢂ50 mL), and dried over Na2SO4.
The solvent was removed under vacuum, and the residue was
distilled under vacuum with argon bleed to give compound 6b
(18.03 g, 81%) as a slightly yellow liquid in thick layer. Bp 58e67 ꢀC/
0.1 mmHg, n2D0 1.5079 (lit.20 1.5074). After about 4 weeks of storage
at 5e7 ꢀC the color of liquid becomes more intense, which has no
4. Experimental section
4.1. General
All solvents were distilled before use. 95% EtOH was used unless
otherwise indicated. The petroleum ether had a distillation range of
40e60 ꢀC. 100% hydrazine hydrate was used. Mixtures of 8a and 7b
(97:3), 8b and 7d (45:55), and 8c and 7h (87:13) were prepared
according to the literature procedure21 by the reaction of acetal-
dehyde diethyl acetal with the TMS ethers of acetone, cyclo-
pentanone, and cyclohexanone, respectively, in the presence of
ZnCl2 in AcOEt followed by vacuum distillation of the resulting
products (see Supplementary data). Compounds 7e and 8d were
obtained analogously by condensation of acetone dimethyl acetal
with the TMS ethers of cyclopentanone and cyclohexanone (see
Supplementary data). All other reagents were purchased from
commercial sources and used without additional purification. IR
spectra (Nujol) were recorded using
a
BrukerVector 22
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6
A.A. Fesenko, A.D. Shutalev / Tetrahedron xxx (2016) 1e14
effect on the yields or color of products prepared from it. 1H NMR
144.77 mmol; d¼1.831 g/mL, 94%) in H2O (25 mL) over 4 min. The
obtained emulsion was heated in a water bath (60 ꢀC, temperature
of bath) under intense stirring for 7 h, and cooled. The resulting
mixture was extracted with ether (50 mL, 3ꢂ30 mL). Neutralization
of combined organic layer was performed as described for com-
pound 6b. After neutralization, the organic layer was washed with
H2O (3ꢂ30 mL), brine (2ꢂ30 mL), and dried over Na2SO4. The sol-
vent was removed under vacuum, and the residue containing 6e
and 7e in a ratio of 95:5 was distilled twice under vacuum from the
flask equipped with a short-path distillation head and argon bleed
tube (first distillation gave a brown colored material; second dis-
tillation afforded a slightly yellow liquid in a thick layer) to give
a 92:8 mixture (13.71 g) of compound 6e and 7e. Partial elimination
of HNCS proceeded during distillation. The calculated yield of 6e is
74% (12.95 g). Bp (first distillation) 81e102 ꢀC/0.1 mmHg, bp (sec-
ond distillation) 89e91 ꢀC/0.1 mmHg; nD20¼1.5239. 1H NMR
(300.13 MHz, CDCl3)
d
: 4.21 (1H, ddq, 3J¼7.2, 3J¼6.6, 3J¼5.9 Hz,
CHN), 2.83 (1H, dd, 2J¼17.5, 3J¼7.2 Hz, HA in CH2), 2.60 (1H, dd,
2J¼17.5, 3J¼5.9 Hz, HB in CH2), 2.15 (3H, s, CH3C]O), 1.34 (3H, d,
3J¼6.6 Hz, CH3).
4.2.3. 4-Isothiocyanato-3-methylpentan-2-one (6c). To
a stirred
mixture of 3-methylpent-3-en-2-one (7c) (24.88 g, 253.52 mmol)
and NH4SCN (48.86 g, 641.88 mmol) in H2O (100 mL) was added
a cooled (10e15 ꢀC) solution of H2SO4 (18.3 mL, 321.13 mmol;
d¼1.831 g/mL, 94%) in H2O (50 mL) in small portions (0.5e1 mL)
over 7 min. The obtained emulsion was heated in a water bath
(60 ꢀC, temperature of bath) under intense stirring for 4 h, and
cooled. The resulting mixture was extracted with ether (100 mL,
3ꢂ50 mL). Neutralization of combined organic layer was performed
as described for compound 6b. After neutralization the organic
layer was washed with H2O (2ꢂ50 mL), brine (2ꢂ50 mL, 25 mL),
and dried over Na2SO4. The solvent was removed under vacuum,
and the residue containing 6c (two isomers, 63:37) and 7c in a ratio
of 96:4 was distilled under vacuum with argon bleed to give
compound 6c (34.27 g, 86%; a slightly yellow liquid in a thick layer)
as a 60:40 mixture of two isomers. Bp 65e75 ꢀC/0.1 mmHg;
n2D0¼1.5072 (lit.20 1.5078). 1H NMR of the major isomer
(300.13 MHz, CDCl3)
d: 1.57e2.33 (7H, m, CH2CH2CH2 and CHC]O),
1.45 (3H, s CH3), 1.42 (3H, s CH3); 13C NMR (75.48 MHz, CDCl3)
d
:
215.98 (C]O), 131.97 br (NCS), 61.77 (CeN), 57.19 (CHC]O), 39.76
(CH2), 28.96 (CH3), 26.70 (CH2), 26.37 (CH3), 19.77 (CH2).
4.2.6. 2-(1-Isothiocyanatocyclopentyl)cyclopentanone
(6f). To
a
cooled (ice bath), stirred mixture of 2-cyclopentylidenec
(300.13 MHz, DMSO-d6)
d
: 4.06 (1H, dq, 3J¼7.1, 3J¼6.5 Hz, CHN),
yclopentanone (7f) (15.18 g, 101.05 mmol) and NH4SCN (19.24 g,
252.75 mmol) in H2O (40 mL) was added a cooled (10e15 ꢀC) so-
lution of H2SO4 (7.4 mL, 126.68 mmol; d¼1.825 g/mL, 92%) in H2O
(20 mL) over 7 min. The obtained emulsion was stirred in an ice
bath for 2 h, and then allowed to stand at 5e7 ꢀC (refrigerator) for
23 h. The resulting mixture was extracted with ether (60 mL,
2ꢂ20 mL). Neutralization of the combined organic layer was per-
formed as described for compound 6b. After neutralization the
organic layer was washed with H2O (3ꢂ25 mL), brine (2ꢂ25 mL),
and dried over Na2SO4. The solvent was removed under vacuum,
and the residue containing 6f and 7f in a ratio of 92:8 was distilled
under vacuum from the flask equipped with a short-path distilla-
tion head and argon bleed tube to give a 79:21 mixture (15.68 g) of
compound 6f and 7f as a slightly yellow liquid in a thick layer.
Partial elimination of HNCS proceeded during distillation. The cal-
culated yield of 6f is 62% (13.17 g). Bp 106e118 ꢀC/0.1 mmHg;
2.60 (1H, dq, 3J¼7.1, 3J¼7.1 Hz, CHC]O), 2.15 (3H, s, CH3C]O), 1.30
(3H, d, 3J¼6.5 Hz, CH3CHN), 1.21 (3H, d, 3J¼7.1 Hz, CH3CHC]O); 1H
NMR of the minor isomer (300.13 MHz, DMSO-d6) d: 4.00 (1H, dq,
3J¼7.2, 3J¼6.6 Hz, CHN), 2.73 (1H, dq, 3J¼7.2, 3J¼7.2 Hz, CHC]O),
2.17 (3H, s, CH3C]O), 1.30 (3H, d, 3J¼6.6 Hz, CH3CHN), 1.10 (3H, d,
3J¼7.2 Hz, CH3CHC]O); 13C NMR of the major isomer (75.48 MHz,
CDCl3) d: 208.58 (C]O),132.01 (NCS), 54.86 (CHN), 52.54 (CHC]O),
29.38 (CH3C]O), 20.51 (CH3CHN), 13.39 (CH3CHC]O); 13C NMR of
the minor isomer (75.48 MHz, CDCl3) : 208.78 (C]O), 132.28
d
(NCS), 54.59 (CHN), 52.30 (CHC]O), 29.36 (CH3C]O), 18.71
(CH3CHN), 12.84 (CH3CHC]O).
4.2.4. 2-(1-Isothiocyanatoethyl)cyclopentanone (6d). To a stirred
45:55 mixture of 2-(1-ethoxyethyl)cyclopentanone (8b) and 2-
ethylidenecyclopentanone (7d) (38.74 g, 295.98 mmol in total)
and NH4SCN (47.48 g, 623.75 mmol) in H2O (120 mL) was added
a cooled (10e15 ꢀC) solution of H2SO4 (17.8 mL, 312.36 mmol;
d¼1.831 g/mL, 94%) in H2O (50 mL) over 5 min. The obtained
emulsion was heated in a water bath (60 ꢀC, temperature of bath)
under intense stirring for 4 h, and cooled. The resulting mixture
was extracted with ether (150 mL, 2ꢂ50 mL). Neutralization of the
combined organic layer was performed as described for compound
6b. After neutralization the organic layer was washed with H2O
(3ꢂ50 mL), brine (2ꢂ30 mL, 15 mL), and dried over Na2SO4. The
solvent was removed under vacuum, and the residue containing 6d
(two isomers, 68:32) and 7d in a ratio of 95:5 was distilled under
vacuum from the flask equipped with a short-path distillation head
and argon bleed tube to give a 88:12 mixture (40.34 g) of com-
pound 6d (two isomers, 70:30) and 7d as a yellow liquid. Partial
elimination of HNCS proceeded during distillation. The calculated
yield of 6d is 74% (37.05 g). Bp 72e97 ꢀC/0.1 mmHg; nD20¼1.5277. 1H
n2D0¼1.5433. 1H NMR (300.13 MHz, CDCl3)
d
: 1.59e2.42 (15H, m, all
protons); 13C NMR (75.48 MHz, CDCl3)
d: 216.43 (C]O), 132.62 br
(NCS), 72.84 (CeN), 55.92 (CH2), 39.88 (CH2), 39.32 (CH2), 38.42
(CH2), 27.12 (CH2), 23.40 (CH2), 22.23 (CH2), 20.30 (CH2).
4.2.7. 1-Acetyl-2-isothiocyanatocyclohexane (6g). To a stirred mix-
ture of 1-acetylcyclohexene (7g) (16.75 g, 134.88 mmol) and
NH4SCN (10.78 g, 141.61 mmol) in H2O (11 mL) was added a cooled
(10e15 ꢀC) solution of H2SO4 (8.3 mL, 142.09 mmol; d¼1.825 g/mL,
92%) in H2O (15 mL) over 30 min. The obtained emulsion was
heated in a water bath (60 ꢀC, temperature of bath) under intense
stirring for 4 h, and cooled. The resulting mixture was extracted
with ether (20 mL, 2ꢂ10 mL). Neutralization of the combined or-
ganic layer was performed as described for compound 6b. After
neutralization the organic layer was washed with H2O (3ꢂ20 mL),
brine (2ꢂ20 mL), and dried over Na2SO4. The solvent was removed
under vacuum, and the residue was distilled under vacuum from
the flask equipped with a short-path distillation head and argon
bleed tube to give compound 6g (14.47 g, 59%; a yellow liquid) as
a mixture of two diastereomers in a ratio of 56:44. Bp 90e114 ꢀC/
0.1 mmHg. 1H NMR of the 56:44 isomer mixture (300.13 MHz,
NMR of the 70:30 isomer mixture (300.13 MHz, DMSO-d6) d: 4.26
(0.7H, dq, 3J¼6.8, 3J¼3.4 Hz, CHN in the major isomer), 4.08 (0.3H,
dq, 3J¼6.7, 3J¼4.3 Hz, CHN in the minor isomer), 1.37 (2.1H, d,
3J¼6.8 Hz, CH3 in the major isomer), 1.29 (0.9H, d, 3J¼6.7 Hz, CH3 in
the minor isomer), 1.98e2.57, 1.66e1.93 (5H and 2H respectively,
two m, CH2CH2CH2 and CHC]O in the both isomers).
CDCl3) d: 4.36 (0.56H, unresolved m, half-width at half-height value
of 8.0 Hz, CHN in the major isomer), 3.79 (0.44H, ddd, 3J¼10.9,
3J¼10.0, 3J¼4.2 Hz, CHN in the minor isomer), 2.62 (0.44H, ddd,
3J¼11.2, 3J¼10.0, 3J¼3.8 Hz, CHC]O in the minor isomer), 2.36
(0.56H, ddd, 3J¼12.1, 3J¼3.6, 3J¼3.0 Hz, CHC]O in the major iso-
mer), 2.20 (1.32H, s, CH3 in the minor isomer), 2.16 (1.68H, s, CH3 in
4.2.5. 2-(2-Isothiocyanatoprop-2-yl)cyclopentanone (6e). To a stir-
red mixture of 2-isopropylidenecyclopentanone (7e) (11.89 g,
95.71 mmol) and NH4SCN (21.91 g, 287.83 mmol) in H2O (45 mL)
was added a cooled (10e15 ꢀC) solution of H2SO4 (8.25 mL,
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A.A. Fesenko, A.D. Shutalev / Tetrahedron xxx (2016) 1e14
7
the major isomer), 1.15e2.23 (8H, m, CH2CH2CH2CH2 in the both
isomers); 13C NMR of the major isomer (75.48 MHz, CDCl3)
207.52 (C]O), 56.43 (CHN), 53.78 (CHC]O), 32.24 (CH2), 28.04
(CH3), 24.68 (CH2), 22.95 (CH2), 20.38 (CH2), signal of the C]S
carbon was not detected in the spectrum; 13C NMR of the minor
isomer (75.48 MHz, CDCl3) d: 208.91 (C]O), 56.17 (CHN), 54.82
(CHC]O), 32.88 (CH2), 29.69 (CH3), 27.99 (CH2), 24.47 (CH2), 24.03
(CH2), signal of the C]S carbon was not detected in the spectrum.
2ꢂ50 mL). Neutralization of the combined organic layer was per-
formed as described for compound 6b. After the neutralization was
completed, the organic layer was washed with H2O, brine, and
dried over MgSO4. The solvent was removed under vacuum, and the
residue was distilled under vacuum from the flask equipped with
a short-path distillation head and argon bleed tube to give com-
pound 6j (30.94 g, 56%) as a slightly yellow liquid. Bp 54e64 ꢀC/
d:
0.1 mmHg; 1H NMR (300.13 MHz, CDCl3)
d
: 9.73 (1H, dd, 3J¼1.3,
3J¼1.0 Hz, CH]O), 4.28 (1H, ddq, 3J¼7.3, 3J¼6.6, 3J¼5.7 Hz, CHN),
2.82 (1H, ddd, 2J¼17.8, 3J¼7.3, 3J¼1.3 Hz, HA in CH2), 2.66 (1H, ddd,
2J¼17.8, 3J¼5.7, 3J¼1.0 Hz, HB in CH2), 1.40 (3H, d, 3J¼6.6 Hz, CH3).
4.2.8. 2-(1-Isothiocyanatoethyl)cyclohexanone (6h). To
a stirred
87:13 mixture of 2-(1-ethoxyethyl)cyclohexanone (8c) and 2-
ethylidenecyclohexanone (7h) (35.69 g, 217.27 mmol total) and
NH4SCN (32.35 g, 424.98 mmol) in H2O (100 mL) was added
a cooled (10e15 ꢀC) solution of H2SO4 (12.15 mL, 213.21 mmol;
d¼1.831 g/mL, 94%) in H2O (50 mL) over 10 min. The obtained
emulsion was heated in a water bath (60 ꢀC, temperature of bath)
under intense stirring for 3 h, and cooled. The resulting mixture
was extracted with ether (150 mL, 2ꢂ50 mL). Neutralization of the
combined organic layer was performed as described for compound
6b in a 1 L separatory funnel. After neutralization the organic layer
was washed with H2O (3ꢂ50 mL), brine (2ꢂ50 mL), and dried over
Na2SO4. The solvent was removed under vacuum, and the residue
containing 6h (two isomers, 62:38) was distilled under vacuum
from the flask equipped with a short-path distillation head and
argon bleed tube to give a 97:3 mixture (36.58 g) of compound 6h
(two isomers, 63:37) and 7h as a yellow liquid. Partial elimination
of HNCS proceeded during distillation. The calculated yield of 6h is
90% (35.83 g). Bp 95e115 ꢀC/0.1 mmHg; n2D0¼1.5359. 1H NMR of the
4.3. Synthesis of 3-amino-4-hydroxyhexahydropyrimidine-2-
thiones
4.3.1. 3-Amino-4-hydroxy-4,6,6-trimethylhexahydropyrimidine-2-
thione (10a). Pyrimidine 10a (3.451 g, 93%) was prepared from
freshly distilled isothiocyanate 6a (3.073 g, 19.54 mmol) and
N2H4$H2O (1.030 g, 20.57 mmol) in EtOH (20 mL) (20 ꢀC, 1 h) as
described for compound 10c in Method A. Mp 143.5e145.5 ꢀC (dec,
MeCN) (lit.24 153e154 ꢀC). IR (Nujol) , cmꢁ1: 3525 (m), 3390 (br
n
m), 3339 (m), 3221 (br vs), 3168 (m), 3140 (m), 1619 (m), 1512 (s),
1270 (s), 1195 (s); 1H NMR (300.13 MHz, DMSO-d6)
d: 8.17 (1H, br s,
N
(1)H), 5.91 (1H, d, 4J¼1.2 Hz, OH), 4.89 (2H, br s, NH2), 2.00 (1H, dd,
2J¼13.9, 4J¼1.7 Hz, 5-He), 1.89 (1H, dd, 2J¼13.9, 4J¼1.2 Hz, 5-Ha),1.48
(3H, s, 4-CH3), 1.28 (3H, s, 6-CH3), 1.14 (3H, s, 6-CH3); 13C NMR
(75.48 MHz, DMSO-d6) d: 176.31 (C-3), 82.68 (C-4), 49.30 (C-6),
47.14 (C-5), 30.02 (CH3), 28.80 (CH3), 28.14 (CH3).
63:37 isomer mixture (300.13 MHz, CDCl3) d: 4.25 (0.63H, dq,
3J¼6.6, 3J¼5.7 Hz, CHN in the major isomer), 4.21 (0.37H, dq, 3J¼6.7,
3J¼4.6 Hz, CHN in the minor isomer), 2.60 (0.37H, dddd, 3J¼12.7,
3J¼5.4, 3J¼4.6, 4J¼1.1 Hz, CHC]O in the minor isomer), 1.88e2.45,
1.43e1.75 (5.63H, and 3H, respectively, two m, CH2CH2CH2CH2 in
the both isomers and CHC]O in the major isomer), 1.35 (1.89H, d,
3J¼6.6 Hz, CH3 in the major isomer), 1.31 (1.11H, d, 3J¼6.7 Hz, CH3 in
the minor isomer).
4.3.2. 3-Amino-4-hydroxy-4,6-dimethylhexahydropyrimidine-2-
thione (10b) and 4-(4-oxopent-2-yl)thiosemicarbazide (9b). To
a cooled in an ice bath, stirred solution of freshly distilled iso-
thiocyanate 6b (6.588 g, 46.01 mmol) in MeCN (23 mL) was added
N2H4$H2O (2.324 g, 46.42 mmol) dropwise over 5 min. White solid
started to precipitate during the addition. The ice bath was re-
moved and the resulting suspension was stirred at room temper-
ature for 1 h. The solvent was removed under vacuum to a half
volume and the obtained dense suspension was cooled to ꢁ18 ꢀC.
The precipitate was filtered on a cold (ꢁ18 ꢀC) filter, rapidly washed
with cold (ꢁ18 ꢀC) MeCN (2ꢂ10 mL), cold (ꢁ18 ꢀC) ether
(2ꢂ20 mL), and dried to give product (7.485 g, 93%) as a 90:10
mixture of pyrimidine 10b (two diastereomers, 75:25) and its
acyclic isomer 9b. After crystallization from EtOH the ratio of iso-
mers did not change (68:22:10, respectively). Mp 119.5e122.5 ꢀC
4.2.9. 2-(2-Isothiocyanatoprop-2-yl)cyclohexanone (6i). To a stirred
mixture of 2-(2-methoxyprop-2-yl)cyclohexanone (8d) (23.77 g,
139.62 mmol) and NH4SCN (21.76 g, 285.86 mmol) in H2O (65 mL)
was added a cooled (10e15 ꢀC) solution of H2SO4 (8.15 mL,
143.02 mmol; d¼1.831 g/mL, 94%) in H2O (35 mL) in small portions
(0.3e0.5 mL) over 5 min. The obtained emulsion was heated in
a water bath (60 ꢀC, temperature of bath) under intensive stirring
for 3 h, and cooled. The resulting mixture was extracted with ether
(75 mL, 2ꢂ50 mL). Neutralization of the combined organic layer
was performed as described for compound 6b. After neutralization
the organic layer was washed with H2O (2ꢂ50 mL), brine
(2ꢂ30 mL), and dried over Na2SO4. The solvent was removed under
vacuum, and the residue was distilled under vacuum from the flask
equipped with a short-path distillation head and argon bleed tube
to give compound 6i (24.84 g, 90%) as a slightly yellow liquid in
thick layer. Bp 90e104 ꢀC/0.1 mmHg; n2D0¼1.5302. 1H NMR
(dec, EtOH). IR (Nujol)
n
, cmꢁ1: 3276 (br vs), 3239 (br vs), 1617 (m),
1527 (s), 1485 (s), 1264 (s), 1056 (s); 1H NMR of the major isomer of
pyrimidine 10b (300.13 MHz, DMSO-d6) d: 8.12 (1H, br s, N(1)H),
6.06 (1H, d, 4J¼1.2 Hz, OH), 4.85 (2H, br s, NH2), 3.51 (1H, ddq,
3J¼12.3, 3J¼6.4, 3J¼3.5 Hz, 6-H), 1.92 (1H, ddd, 2J¼13.2, 3J¼3.5,
4J¼2.1 Hz, 5-He), 1.57 (1H, ddd, 2J¼13.2, 3J¼12.3, 4J¼1.2 Hz, 5-Ha),
1.48 (3H, s, 4-CH3), 1.08 (3H, d, 3J¼6.4 Hz, 6-CH3); 1H NMR of the
minor isomer of pyrimidine 10b (300.13 MHz, DMSO-d6) d: 7.94
(1H, br s, N(1)H), 6.01 (1H, s, OH), 4.91 (2H, br s, NH2), 3.38 (1H, ddq,
3J¼11.3, 3J¼6.4, 3J¼3.6 Hz, 6-H), 2.04 (1H, ddd, 2J¼13.2, 3J¼3.6,
4J¼1.8 Hz, 5-He), 1.73 (1H, dd, 2J¼13.2, 3J¼11.3 Hz, 5-Ha), 1.44 (3H, s,
4-CH3), 1.10 (3H, d, 3J¼6.4 Hz, 6-CH3); 1H NMR of the acyclic isomer
(300.13 MHz, CDCl3)
d
: 2.52 (1H, ddd, 3J¼12.5, 3J¼4.9, 4J¼1.0 Hz,
CHC]O), 2.22e2.38, 1.88e2.14, 1.52e1.75 (3H, 2H, and 3H, re-
spectively, three m, CH2CH2CH2CH2), 1.51 (3H, s, CH3), 1.46 (3H, s,
CH3).
9b (300.13 MHz, DMSO-d6) d: 8.61 (1H, br s, NHNH2), 7.72 (1H, br d,
3J¼8.9 Hz, NH), 4.67 (1H, dddq, 3J¼8.9, 3J¼6.9, 3J¼6.6, 3J¼5.7 Hz,
CHN), 4.42 (2H, br s, NH2), 2.78 (1H, dd, 2J¼16.3, 3J¼5.7 Hz, HA in
CH2C]O), 2.61 (1H, dd, 2J¼16.3, 3J¼6.9 Hz, HB in CH2C]O), 2.10
(3H, s, CH3C]O), 1.11 (3H, d, 3J¼6.6 Hz, CH3); 13C NMR of the major
4.2.10. 3-Isothiocyanatobutanal (6j). To a cooled in an ice bath,
stirred mixture of but-2-enal (7j) (29.89 g, 426.45 mmol) and
NH4SCN (45.77 g, 601.27 mmol) in H2O (30 mL) under argon at-
mosphere was added a solution of H2SO4 (17.15 mL, 300.95 mmol;
d¼1.831 g/mL, 94%) in H2O (18 mL) over 35 min. The resulting
emulsion was stirred at room temperature for 1 h, then in a water
bath (40 ꢀC, temperature of bath) for additional 1 h, and cooled to
room temperature. The mixture was extracted with ether (100 mL,
isomer of pyrimidine 10b (75.48 MHz, DMSO-d6) d: 177.56 (C-2),
82.15 (C-4), 43.62 (C-5), 42.24 (C-6), 27.50 (4-CH3), 19.86 (6-CH3);
13C NMR of the minor isomer of pyrimidine 10b (75.48 MHz, DMSO-
d6)
d: 175.32 (C-2), 83.75 (C-4), 43.78 (C-6), 43.62 (C-5), 26.23 (4-
CH3), 20.33 (6-CH3); 13C NMR of the acyclic isomer 9b
Please cite this article in press as: Fesenko, A. A.; Shutalev, A. D., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.03.082

8
A.A. Fesenko, A.D. Shutalev / Tetrahedron xxx (2016) 1e14
(75.48 MHz, DMSO-d6)
d
: 207.58 (C]O), 180.08 (C]S), 48.97
13C NMR of the first minor isomer (26%) of pyrimidine 10c
(CH2C]O), 45.34 (CHN), 30.27 (CH3C]O), 20.19 (CH3CH). Anal.
Calcd for C6H13N3OS: C, 41.12; H, 7.48; N, 23.98. Found: C, 41.32; H,
7.47; N, 23.84.
(75.48 MHz, DMSO-d6) d: 177.04 (C-2), 84.92 (C-4), 47.43 (C-6),
43.82 (C-5), 24.28 (4-CH3), 18.42 (6-CH3), 11.86 (5-CH3); 13C NMR of
the second minor isomer (19%) of pyrimidine 10c (75.48 MHz,
DMSO-d6)
(4-CH3), 18.73 (6-CH3), 11.66 (5-CH3); 13C NMR of the third minor
isomer (9%) of pyrimidine 10c (75.48 MHz, DMSO-d6) : 175.39 (C-
d: 174.15 (C-2), 86.58 (C-4), 49.17 (C-6), 44.23 (C-5), 20.00
4.3.3. 3-Amino-4-hydroxy-4,5,6-trimethylhexahydropyrimidine-2-
thione (10c) and 4-(3-methyl-4-oxopent-2-yl)thiosemicarbazide
(9c). Method A: To a cooled in an ice bath, stirred solution of freshly
distilled isothiocyanate 6c (10.112 g, 64.36 mmol) in MeCN (50 mL)
was added N2H4$H2O (3.242 g, 64.76 mmol) dropwise over 5 min.
White solid started to precipitate during the addition. The ice bath
was removed and the resulting suspension was stirred at room
temperature for 1 h. The solvent was removed under vacuum, the
residue was triturated with ether until crystallization was com-
plete, the obtained suspension was cooled (ꢁ18 ꢀC). The precipitate
was filtered, washed with cold ether (4ꢂ25 mL), and dried to give
product (11.079 g, 91%) as a 89:11 mixture of pyrimidine 10c (four
diastereomers, 45:26:18:11) and its acyclic isomer 9c (two di-
astereomers, 78:22).
d
2), 85.79 (C-4), 47.37 (C-6), 40.46 (C-5), 26.59 (4-CH3), 16.72 (6-
CH3), 8.54 (5-CH3); 13C NMR of the major isomer of thio-
semicarbazide 9c (75.48 MHz, DMSO-d6) d: 210.74 (C]O), 50.91
(CHN), 49.87 (CHC]O), 29.29 (CH3C]O), 18.55 (CH3CHN), 12.65
(CH3CHC]O), signal of the C]S carbon was not detected in the
spectrum. Anal. Calcd for C7H15N3OS: C, 44.42; H, 7.99; N, 22.20.
Found: C, 44.47; H, 8.22; N, 22.08.
4.3.4. 1-Amino-7a-hydroxy-4-methyloctahydro-2H-cyclopenta[d]py-
rimidine-2-thione (10d) and 4-[1-(2-oxocyclopentyl)ethyl]thio-
semicarbazide (9d). This product (2.089 g, 82%) as a 97:3 mixture of
pyrimidine 10d (four diastereomers, 71:26:2:1) and its acyclic
isomer 9d (a single diastereomer) was prepared from 2.331 g of
freshly distilled isothiocyanate 6d (88 mol % in a mixture with 7d;
2.141 g, 12.64 mmol) and N2H4$H2O (0.633 g, 12.64 mmol) in MeCN
(10 mL) (20 ꢀC, 1 h 30 min) as described for compound 10c in
Method A. The analytically pure sample (0.099 g) as a 96:4 mixture
of pyrimidine 10d (two diastereomers, 96:0:0:4, respectively) and
its acyclic isomer 9d (a single diastereomer) was obtained from
0.304 g of the crude product after crystallization from MeCN (3 mL)
in the presence of DBU (0.058 mL). (Note: crystallization from
MeCN without DBU led to partial dehydration of the product). Mp
Method B: This product (0.791 g, 90%) as a 89:11 mixture of
pyrimidine 10c (four diastereomers, 46:26:19:9) and its acyclic
isomer 9c (two diastereomers, 78:22) was prepared from freshly
distilled isothiocyanate 6c (0.730 g, 4.64 mmol) and N2H4$H2O
(0.248 g, 4.95 mmol) in EtOH (5 mL) (20 ꢀC, 1 h) as described in
Method A. The analytically pure sample (0.136 g) as a 89:11 mixture
of pyrimidine 10c (four diastereomers, 46:24:17:12) and its acyclic
isomer 9c (two diastereomers, 80:20) was obtained from 0.356 g of
the crude product using crystallization from MeCN (3 mL) in the
presence of DBU (0.070 mL). (Note: crystallization from MeCN or
EtOH without DBU led to partial dehydration of the product). Mp
146e147.5 ꢀC (dec, MeCN). IR (Nujol) , cmꢁ1: 3296 (br s), 3231 (br
n
109.5e113.5 ꢀC (dec, MeCN). IR (Nujol)
n
, cmꢁ1: 3327 (s), 3311 (s),
s), 3147 (s), 1603 (s), 1496 (s), 1230 (s), 1093 (s), 1050 (s); 1H NMR of
3288 (s), 3252 (s), 3230 (s), 3136 (s), 1620 (m), 1523 (s), 1495 (s),
the major isomer (71%) of pyrimidine 10d (300.13 MHz, DMSO-d6)
1256 (s), 1041 (s); 1H NMR of the major isomer (46%) of pyrimidine
d
: 8.10 (1H, br s, N(3)H), 6.20 (1H, s, OH), 4.95 (2H, br s, NH2), 3.52
10c (300.13 MHz, DMSO-d6)
d
: 7.98 (1H, br d, 4J¼1.8 Hz, N(1)H), 6.16
(1H, dq, 3J¼6.7, 3J¼3.5 Hz, 4-H), 2.07 (1H, ddt, 3J1þ3J2¼18.5, 3J¼3.5,
4J¼1.8 Hz, 4a-H), 2.37e2.53, 1.48e1.72, and 1.19e1.41 (1H, 3H, and
2H, respectively, three m, 5-H, 6-H, and 7-H), 1.02 (3H, d, 3J¼6.7 Hz,
CH3); 1H NMR of the first minor isomer (26%) of pyrimidine 10d
(1H, s, OH), 4.89 (2H, br s, NH2), 3.85 (1H, ddq, 3J¼6.9, 3J¼3.5,
4J¼0.8 Hz, 6-H), 1.67 (1H, ddq, 3J¼7.0, 3J¼3.5, 4J¼1.8 Hz, 5-H), 1.47
(3H, s, 4-CH3), 1.02 (3H, d, 3J¼6.9 Hz, 6-CH3), 0.71 (3H, d, 3J¼7.0 Hz,
5-CH3); 1H NMR of the first minor isomer (26%) of pyrimidine 10c
(300.13 MHz, DMSO-d6) d: 8.10 (1H, br s, N(3)H), 5.93 (1H, s, OH),
(300.13 MHz, DMSO-d6)
d
: 8.09 (1H, br s, N(1)H), 5.89 (1H, d,
4.93 (2H, br s, NH2), 3.31e3.41 (1H, m, 4-H, signals partly overlap
with signal of HOD in solvent), 1.08 (3H, d, 3J¼6.5 Hz, CH3), signals
of other protons overlap with proton signals of the other isomers;
1H NMR of the second minor isomer (2%) of pyrimidine 10d
4J¼0.9 Hz, OH), 4.90 (2H, br s, NH2), 3.10 (1H, dq, 3J¼11.0, 3J¼6.5 Hz,
6-H), 1.48 (1H, ddq, 3J¼11.0, 3J¼6.7, 4J¼0.9 Hz, 5-H), 1.48 (3H, s, 4-
CH3), 1.09 (3H, d, 3J¼6.5 Hz, 6-CH3), 0.90 (3H, d, 3J¼6.7 Hz, 5-
CH3); 1H NMR of the second minor isomer (19%) of pyrimidine
(300.13 MHz, DMSO-d6)
d
: 8.35 (1H, br d, 3J¼3.6 Hz, N(3)H), 5.76
10c (300.13 MHz, DMSO-d6)
d
: 7.86 (1H, br s, N(1)H), 5.97 (1H, s,
(1H, d, 4J¼1.4 Hz, OH), 1.18 (3H, d, 3J¼6.9 Hz, CH3), signals of other
protons overlap with proton signals of the other isomers; 1H NMR
of the third minor isomer (1%) of pyrimidine 10d (300.13 MHz,
OH), 4.97 (2H, br s, NH2), 3.06 (1H, dq, 3J¼10.8, 3J¼6.5 Hz, 6-H), 1.70
(1H, dq, 3J¼10.8, 3J¼6.9 Hz, 5-H), 1.26 (3H, s, 4-CH3), 1.09 (3H, d,
3J¼6.5 Hz, 6-CH3, signals overlap with signals of the 6-CH3 group of
the major isomer), 0.91 (3H, d, 3J¼6.9 Hz, 5-CH3); 1H NMR of the
third minor isomer (9%) of pyrimidine 10c (300.13 MHz, DMSO-d6)
DMSO-d6) d: 8.31 (1H, br s, N(3)H), 5.79 (1H, s, OH), 4.91 (2H, br s,
NH2), 2.85 (1H, ddq, 3J¼9.9, 3J¼6.6, 3J¼1.3 Hz, 4-H), 1.08 (3H, d,
3J¼6.6 Hz, CH3), signals of other protons overlap with proton signals
of the other isomers; 1H NMR of the acyclic isomer 9d (300.13 MHz,
d
: 7.95 (1H, br s, N(1)H), 5.95 (1H, br s, OH), 4.88 (2H, br s, NH2), 3.49
(1H, ddq, 3J¼6.7, 3J¼4.1, 4J¼1.9 Hz, 4-H), 1.90 (1H, ddq, 3J¼6.9,
3J¼4.1, 4J¼1.0 Hz, 5-H),1.47 (3H, s, 4-CH3, signal partly overlaps with
signal of the 4-CH3 group of the major isomer), 1.06 (3H, d,
3J¼6.7 Hz, 6-CH3), 0.88 (3H, d, 3J¼6.9 Hz, 5-CH3); 1H NMR of the
DMSO-d6)
d
: 8.66 (1H, br s, NHNH2), 4.51 (1H, ddq, 3J¼9.2, 3J¼6.5,
3J¼6.5 Hz, CHN), 4.47 (2H, br s, NH2), 1.08 (3H, d, 3J¼6.5 Hz, CH3),
signals of other protons overlap with proton signals of the cyclic
isomers; 13C NMR of the major isomer (71%) of pyrimidine 10d
major isomer of thiosemicarbazide 9c (300.13 MHz, DMSO-d6)
d:
(75.48 MHz, DMSO-d6) d: 177.04 (C-2), 92.90 (C-7a), 48.84 (C-4),
8.67 (1H, br s, NHNH2), 7.65 (1H, br d, 3J¼9.5 Hz, NHCH), 4.69 (1H,
ddq, 3J¼9.5, 3J¼7.0, 3J¼6.6 Hz, CHN), 4.47 (2H, br s, NH2), 2.82 (1H,
dq, 3J¼7.0, 3J¼7.0 Hz, CHC]O), 2.14 (3H, s, CH3C]O), 1.05 (3H, d,
3J¼6.6 Hz, CH3CHC]O), 0.99 (3H, d, 3J¼7.0 Hz, CH3CHN); 1H NMR of
the minor isomer of thiosemicarbazide 9c (300.13 MHz, DMSO-d6)
43.28 (C-4a), 36.01 (CH2), 21.24 (CH2), 19.47 (CH2), 17.27 (CH3). Anal.
Calcd for C8H15N3OS: C, 47.74; H, 7.51; N, 20.88. Found: C, 47.79; H,
7.47; N, 20.85.
4.3.5. 1-Amino-7a-hydroxy-4,4-dimethyloctahydro-2H-cyclopenta
[d]pyrimidine-2-thione (10e). This product (10.487 g, 96%) as
a mixture of two isomers in a ratio of 60:40 was prepared from
10.024 g of freshly distilled isothiocyanate 6e (92 mol % in a mixture
with 7e; 9.466 g, 51.65 mmol) and N2H4$H2O (2.539 g, 50.73 mmol)
in MeCN (50 mL) (20 ꢀC, 2 h 5 min) as described for compound 10c
in Method A. After crystallization from EtOH the diastereomeric
d
: 8.69 (1H, br s, NHNH2), 4.53e4.65 (1H, m, CHN), 2.95 (1H, dq,
3J¼7.1, 3J¼5.5 Hz, CHC]O), 2.15 (3H, s, CH3C]O), 0.97 (3H, d,
3J¼7.1 Hz, CH3CHN), signals of other protons overlap with proton
signals of the other isomers; 13C NMR of the major isomer (46%) of
pyrimidine 10c (75.48 MHz, DMSO-d6)
44.72 (C-6), 41.51 (C-5), 25.60 (4-CH3), 16.34 (6-CH3), 8.21 (5-CH3);
d: 176.97 (C-2), 85.43 (C-4),
Please cite this article in press as: Fesenko, A. A.; Shutalev, A. D., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.03.082

A.A. Fesenko, A.D. Shutalev / Tetrahedron xxx (2016) 1e14
9
ratio changed to 93:7, respectively. Mp 146e148 ꢀC (dec, EtOH)
(rate of heating was more than 1 ꢀC/10e20 s), Mp 176.5e178 ꢀC
(s), 1065 (s), 1049 (s); 1H NMR of the major isomer (50%) of py-
rimidine 10g (300.13 MHz, DMSO-d6)
d
: 8.02 (1H, br d, 3J¼1.7 Hz,
(dec, EtOH) (rate of heating was 1 ꢀC/1 min). IR (Nujol)
n
, cmꢁ1
:
N(1)H), 6.09 (1H, s, OH), 4.88 (2H, br s, NH2), 3.76e3.81 (1H, m, 8a-
3303 (sh), 3288 (s), 3223 (br s), 3144 (m), 3023 (m), 1610 (m), 1531
H), 1.42 (3H, s, CH3), 0.81e2.06 (9H, m, 4a-H, 5-H, 6-H, 7-H, and 8-
(s), 1216 (s), 1077 (s), 1054 (m); 1H NMR of the 60:40 diastereomeric
H); 1H NMR of the first minor isomer (29%) of pyrimidine 10g
mixture (300.13 MHz, DMSO-d6)
d
: 8.22 (0.6H, br s, N(3)H in the
(300.13 MHz, DMSO-d6) d: 8.15 (1H, br s, N(1)H), 5.92 (1H, d,
major isomer), 8.09 (0.4H, br s, N(3)H in the minor isomer), 6.07
(0.4H, s, OH in the minor isomer), 5.81 (0.6H, d, 4J¼1.3 Hz, OH in the
major isomer), 4.97 (0.8H, br s, NH2 in the minor isomer), 4.92
(1.2H, br s, NH2 in the major isomer), 1.28e2.31 (7H, m, 4a-H, 5-H,
6-H, 7-H in the both isomers), 1.25 (1.2H, s, 4-CH3 in the minor
isomer), 1.24 (1.8H, s, 4-CH3 in the major isomer), 1.15 (1.8H, s, 4-
CH3 in the major isomer), 1.04 (1.2H, s, 4-CH3 in the minor iso-
4J¼0.8 Hz, OH), 4.89 (2H, br s, NH2), 3.02 (1H, ddd, 3J¼11.0, 3J¼11.0,
3J¼4.1 Hz, 8a-H),1.46 (3H, s, CH3), 0.96e2.06 (9H, m, 4a-H, 5-H, 6-H,
7-H, and 8-H, signals overlap with proton signals of the other iso-
mers); 1H NMR of the second minor isomer (13%) of pyrimidine 10g
(300.13 MHz, DMSO-d6) d: 7.91 (1H, br s, N(1)H), 5.96 (1H, s, OH),
4.95 (2H, br s, NH2), 2.94 (1H, ddd, 3J¼11.0, 3J¼11.0, 3J¼4.0 Hz, 8a-
H),1.29 (3H, s, CH3), 0.96e2.06 (9H, m, 4a-H, 5-H, 6-H, 7-H, and 8-H,
signals overlap with proton signals of the other isomers); 1H NMR
of the third minor isomer (8%) of pyrimidine 10g (300.13 MHz,
mer); 13C NMR of the major isomer (75.48 MHz, DMSO-d6)
d: 178.24
(C-2), 88.89 (C-7a), 54.42 (C-4), 52.25 (C-4a), 36.88 (CH2), 30.85 (4-
CH3), 23.22 (4-CH3), 22.44 (CH2), 19.58 (CH2); 13C NMR of the minor
DMSO-d6) d: 7.79 (1H, br s, N(1)H), 5.94 (1H, s, OH), 3.61e3.66 (1H,
isomer (75.48 MHz, DMSO-d6)
d
: 176.52 (C-2), 93.06 (C-7a), 52.93
m, 8a-H), 1.44 (3H, s, CH3), signals of other protons overlap with
(C-4a), 50.88 (C-4), 38.71 (CH2), 27.40 (4-CH3), 25.91 (CH2), 25.85
(4-CH3), 19.96 (CH2). Anal. Calcd for C9H17N3OS: C, 50.20; H, 7.96; N,
19.52. Found: C, 50.37; H, 8.35; N, 19.12.
proton signals of the other isomers; 1H NMR of the major isomer
(56%) of thiosemicarbazide 9g (300.13 MHz, DMSO-d6) d: 8.75 (1H,
br s, NHNH2), 4.49 (2H, br s, NH2), 2.83 (1H, ddd, 3J¼6.7, 3J¼6.7,
3J¼4.0 Hz, CHC]O), 2.12 (3H, s, CH3), signals of other protons
overlap with proton signals of the cyclic isomers; 1H NMR of the
minor isomer (44%) of thiosemicarbazide 9g (300.13 MHz, DMSO-
4.3.6. 10-Amino-7a0-hydroxyhexahydrospiro[cyclopentane-1,4’-cyclo-
penta[d]pyrimidine]-20(30H)-thione (10f). To a cooled in an ice bath,
stirred solution of freshly distilled isothiocyanate 6f (8.400 g,
79 mol % in a mixture with 7f; 7.054 g, 33.70 mmol) in MeCN
(30 mL) was added N2H4$H2O (1.808 g, 36.12 mmol) dropwise over
3 min. White solid started to precipitate during the addition. The
resulting suspension was stirred in an ice bath for 10 min, and
cooled to ꢁ18 ꢀC. The precipitate was filtered on a cold (ꢁ18 ꢀC)
filter, rapidly washed with cold (ꢁ18 ꢀC) MeCN (10 mL), cold
(ꢁ18 ꢀC) ether (3ꢂ20 mL), and dried to give compound 10f (7.548 g,
93%) as a mixture of two isomers in a ratio of 60:40. After crystal-
lization from MeCN the diastereomeric ratio did not change. Mp
d6)
d
: 8.61 (1H, br s, NHNH2), 7.66 (1H, br d, 3J¼8.9 Hz, NHCH), 4.43
(2H, br s, NH2), 2.64 (1H, ddd, 3J¼10.5, 3J¼10.5, 3J¼3.8 Hz, CHC]O),
2.10 (3H, s, CH3), signals of other protons overlap with proton sig-
nals of the cyclic isomers; 13C NMR of the major isomer (50%) of
pyrimidine 10g (75.48 MHz, DMSO-d6) d: 177.38 (C-2), 84.67 (C-4),
45.15 (C-8a), 43.35 (C-4a), 27.89 (CH2), 25.10 (CH3), 24.11 (CH2),
22.23 (CH2), 19.39 (CH2); 13C NMR of the first minor isomer (29%) of
pyrimidine 10g (75.48 MHz, DMSO-d6) d: 176.88 (C-2), 84.51 (C-4),
49.46 (C-8a), 47.00 (C-4a), 30.88 (CH2), 24.76 (CH2), 24.50 (CH2),
23.64 (CH3), 23.46 (CH2); 13C NMR of the second minor isomer
125e126.5 ꢀC (dec, MeCN); IR (Nujol)
s), 3162 (m), 1614 (m), 1517 (s), 1247 (s), 1200 (s); 1H NMR of the
61:39 diastereomeric mixture (300.13 MHz, DMSO-d6) : 8.23 (1H,
n
, cmꢁ1: 3280 (br s), 3209 (br
(13%) of pyrimidine 10g (75.48 MHz, DMSO-d6) d: 174.38 (C-2),
86.15 (C-4), 50.79 (C-8a), 47.80 (C-4a), 31.42 (CH2), 24.87 (CH2),
d
24.41 (CH2), 23.50 (CH2), 20.88 (CH3); 13C NMR of the third minor
br s, N(3)H in both isomers), 6.02 (0.61H, s, OH in the major isomer),
5.73 (0.39H, d, 4J¼1.3 Hz, OH in the minor isomer), 4.97 (1.22H, br s,
NH2 in the major isomer), 4.92 (0.78H, br s, NH2 in the minor iso-
mer), 2.07e2.36, 1.22e1.99 (2H, and 13H, respectively, two m, 4a-H,
5-H, 6-H, 7-H, and CH2CH2CH2CH2 in both isomers); 13C NMR of the
isomer (8%) of pyrimidine 10g (75.48 MHz, DMSO-d6) d: 174.03 (C-
2), 85.50 (C-4), 47.11 (C-8a), 42.83 (C-4a), 28.47 (CH2), 28.41 (CH2),
26.66 (CH3), 20.64 (CH2), 19.47 (CH2). Anal. Calcd for C9H17N3OS: C,
50.20; H, 7.96; N, 19.52. Found: C, 50.32; H, 7.80; N, 19.51.
major isomer (75.48 MHz, DMSO-d6)
d
: 176.51 (C-2), 93.49 (C-7a),
4.3.8. 1-Amino-8a-hydroxy-4-methyldecahydroquinazoline-2-thione
(10h). Pyrimidine 10h (4.576 g, 96%) as a mixture of four isomers in
a ratio of 36:35:27:2 was prepared from 4.159 g of freshly distilled
isothiocyanate 6h (97 mol % in a mixture with 7h; 4.074 g,
22.23 mmol) and N2H4$H2O (1.163 g, 23.23 mmol) in MeCN (21 mL)
(20 ꢀC, 2 h 20 min) as described for compound 10c in Method A. The
analytically pure sample (0.158 g) as a mixture of three isomers in
a ratio of 0:53:42:5, respectively, was obtained from 0.398 g of the
crude 10h after crystallization from MeCN (3.6 mL) in the presence
of DBU (0.070 mL). (Note: crystallization from MeCN or EtOH
without DBU led to partial formation of the dehydration products).
61.73 (C-4), 51.79 (C-4a), 38.03 (CH2), 37.38 (CH2), 35.58 (CH2),
25.89 (CH2), 23.56 (CH2), 22.28 (CH2), 20.14 (CH2); 13C NMR of the
minor isomer (75.48 MHz, DMSO-d6) d: 177.67 (C-2), 88.84 (C-7a),
64.36 (C-4), 51.21 (C-4a), 40.26 (CH2), 36.63 (CH2), 33.77 (CH2),
24.99 (CH2), 23.07 (CH2), 23.04 (CH2), 19.75 (CH2). Anal. Calcd for
C
11H19N3OS: C, 54.74; H, 7.93; N, 17.41. Found: C, 54.82; H, 8.15; N,
17.61.
4.3.7. 3-Amino-4-hydroxy-4-methyldecahydroquinazoline-2-thione
(10g) and 4-(2-acetylcyclohexyl)thiosemicarbazide (9g). To a cooled
in an ice bath, stirred solution of freshly distilled isothiocyanate 6g
(7.022 g, 38.32 mmol) in MeCN (19 mL) was added N2H4$H2O
(2.015 g, 40.24 mmol) dropwise over 5 min. White solid started to
precipitate during the addition. The resulting suspension was stir-
red at room temperature for 1 h, and cooled to ꢁ18 ꢀC. The pre-
cipitate was filtered on a cold (ꢁ18 ꢀC) filter, rapidly washed with
cold (ꢁ18 ꢀC) MeCN (3ꢂ10 mL), and dried to give product (7.225 g,
88%) as a 97:3 mixture of pyrimidine 10g (four diastereomers,
50:29:13:8) and its acyclic isomer 9g (two diastereomers, 56:44).
Crystallization from MeCN gave the analytically pure sample as
a 97:3 mixture of pyrimidine 10g (four diastereomers, 32:42:20:6,
respectively) and its acyclic isomer 9g (two diastereomers, 27:73,
Mp 139.5e145 ꢀC (dec, MeCN). IR (Nujol)
(m), 3142 (s), 1625 (m),1530 (s), 1489 (s), 1258 (s), 1071 (s), 1028 (s);
1H NMR of the major isomer (36%) (300.13 MHz, DMSO-d6)
: 8.34
n
, cmꢁ1: 3303 (br s), 3237
d
(1H, br d, 3J¼3.8 Hz, N(3)H), 5.71 (1H, d, 4J¼1.6 Hz, OH), 4.82 (2H, br
s, NH2), 3.23 (1H, ddq, 3J¼6.8, 3J¼6.2, 3J¼3.8 Hz, 4-H), 2.33e2.41
(1H, m, 8-Heq), 1.83e1.92 (1H, m, 8-Hax), 1.10e1.71 (6H, m, 5-H, 6-H,
7-H, signals overlap with proton signals of the other isomers), 1.13
(3H, d, 3J¼6.8 Hz, CH3); 1H NMR of the first minor isomer (35%)
(300.13 MHz, DMSO-d6)
d: 8.08 (1H, br s, N(3)H), 5.88 (1H, d,
4J¼1.2 Hz, OH), 4.83 (2H, br s, NH2), 3.17 (1H, dq, 3J¼10.9, 3J¼6.4 Hz,
4-H), 2.39e2.48 (1H, m, 8-Heq), 1.10e1.71 (7H, m, 8-Hax, 5-H, 6-H, 7-
H, signals overlap with proton signals of the other isomers), 1.06
(3H, d, 3J¼6.4 Hz, CH3); 1H NMR of the second minor isomer (27%)
respectively). Mp 127e140 ꢀC (dec, MeCN); IR (Nujol)
(br vs), 3123 (m),1598 (m),1545 (s), 1530 (s), 1258 (s), 1097 (s), 1080
n
, cmꢁ1: 3232
(300.13 MHz, DMSO-d6) d: 8.07 (1H, br s, N(3)H), 6.04 (1H, s, OH),
Please cite this article in press as: Fesenko, A. A.; Shutalev, A. D., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.03.082

10
A.A. Fesenko, A.D. Shutalev / Tetrahedron xxx (2016) 1e14
4.77 (2H, br s, NH2), 3.86 (1H, dq, 3J¼6.9, 3J¼3.3 Hz, 4-H), 2.60e2.68
(1H, m, 8-Heq), 0.76e1.71 (7H, m, 8-Hax, 5-H, 6-H, 7-H, signals
overlap with proton signals of the other isomers), 1.00 (3H, d,
3J¼6.9 Hz, CH3); 1H NMR of the third minor isomer (2%)
C5H11N3OS: C, 37.25; H, 6.88; N, 26.06. Found: C, 37.62; H, 7.18; N,
25.80.
4.4. Synthesis of 2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-
thiones
(300.13 MHz, DMSO-d6)
d: 8.02 (1H, br s, N(3)H), 5.48 (1H, s, OH),
4.85 (2H, br s, NH2), signals of other protons overlap with proton
signals of the other isomers; 13C NMR of the major isomer (36%)
(75.48 MHz, DMSO-d6) d: 176.59 (C-2), 83.84 (C-8a), 48.57 (C-4),
4.4.1. 5,5,7-Trimethyl-2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-
thione (11a). Method A: To a cooled in an ice bath, stirred emulsion
of isothiocyanate 6a (34.80 g, 221.32 mmol) in H2O (240 mL) was
added a solution of NaOH (6.04 g, 151.00 mmol) and N2H4$H2O
(12.25 g, 244.71 mmol) in H2O (60 mL) over 18 min, then the ice
bath was removed. After addition the starting isothiocyanate al-
most dissolved and the solid material started to precipitate in
5 min. The resulting suspension was stirred at room temperature
for 1.5 h, cooled in an ice bath for 2 min, and then AcOH (8.75 mL,
152.88 mmol) was gradually added. The mixture was stirred for
additional 2 min and cooled. The precipitate was filtered, washed
with ice cold H2O (6ꢂ75 mL), petroleum ether (2ꢂ50 mL), cold
ether (4ꢂ50 mL), and dried to give triazepine 11a (28.28 g, 75%).
Method B: Triazepine 11a (0.872 g, 93%) was prepared from
pyrimidine 10a (1.035 g, 5.47 mmol) and NaOH (0.161 g, 4.03 mmol)
in H2O (7 mL) (rt, 1 h 20 min) as described for compound 11b in
Method B. Mp 213e213.5 ꢀC (dec, EtOH) (lit.5e 209e210 ꢀC). IR
42.36 (C-4a), 36.06 (CH2), 24.78 (CH2), 24.18 (CH2), 21.69 (CH2),
17.29 (4-CH3); 13C NMR of two minor isomers (35 and 27%)
(75.48 MHz, DMSO-d6) d: 178.43, 177.45 (C-2), 84.24, 82.62 (C-8a),
46.96, 46.64 (C-4), 44.10, 43.70 (C-4a), 36.37, 34.50, 24.20, 24.11,
23.61, 22.36, 21.52, 21.06 (CH2CH2CH2CH2), 17.99, 15.71 (4-CH3).
Anal. Calcd for C9H17N3OS: C, 50.20; H, 7.96; N, 19.52. Found: C,
50.28; H, 7.99; N, 19.47.
4.3.9. 1-Amino-8a-hydroxy-4,4-dimethyldecahydroquinazoline-2-
thione (10i). Pyrimidine 10i (5.163 g, 97%) as a mixture of two
isomers in a ratio of 84:16 was prepared from freshly distilled
isothiocyanate 6i (4.603 g, 23.33 mmol) and N2H4$H2O (1.196 g,
23.90 mmol) in MeCN (20 mL) (20 ꢀC, 2 h) as described for com-
pound 10c in Method A. After crystallization from EtOH the di-
astereomeric ratio changed to 95:5, respectively. Mp 188e188.5 ꢀC
(dec, EtOH). IR (Nujol)
n
, cmꢁ1: 3326 (m), 3231 (br s), 3029 (m),
(Nujol) n
, cmꢁ1: 3264 (s), 3220 (br vs), 3097 (w), 1674 (m), 1561 (s),
1624 (m), 1535 (s), 1286 (s), 1216 (s); 1H NMR of the major isomer
1191 (s); 1H NMR (300.13 MHz, DMSO-d6)
d: 10.13 (1H, br d,
(300.13 MHz, DMSO-d6)
d
: 8.17 (1H, br s, N(3)H), 5.74 (1H, d,
4J¼2.0 Hz, N(2)H), 8.24 (1H, unresolved br d, N(4)H), 2.55 (2H, d,
4J¼1.5 Hz, OH), 4.83 (2H, br s, NH2), 2.37e2.45 (1H, m, 8-Heq),
1.09e1.74 (8H, m, 4a-H, 5-H, 6-H, 7-H, 8-Hax), 1.17 (3H, s, 4-CH3),
1.13 (3H, s, 4-CH3); 1H NMR of the minor isomer (300.13 MHz,
4J¼0.8 Hz, 6-H), 1.99 (3H, s, 7-CH3), 1.21 (6H, s, 5-CH3); 13C NMR
(75.48 MHz, DMSO-d6) d: 175.32 (C-3), 161.53 (C-7), 57.64 (C-5),
44.38 (C-6), 29.71 (5-CH3), 25.43 (7-CH3); MS (EI) m/z 173 [3,
(Mþ2)þ], 172 [8, (Mþ1)þ], 171 (59, Mþ), 156 (1), 117 (3), 116 (12), 115
(100), 100 (60), 97 (32), 89 (13), 83 (12), 72 (24), 60 (15), 59 (16), 58
(14), 57 (16), 56 (32), 55 (15), 42 (18), 41 (24), 39 (11), 28 (10).
DMSO-d6) d: 8.13 (1H, br s, N(3)H), 5.76 (1H, s, OH), 4.78 (2H, br s,
NH2), 2.50e2.59 (1H, m, 8-Heq, signals partly overlap with proton
signals of the solvent),1.46 (3H, s, 4-CH3),1.08 (3H, s, 4-CH3), signals
of other protons overlap with protons signals of the major isomer;
13C NMR of the major isomer (75.48 MHz, DMSO-d6)
d
: 176.31 (C-2),
4.4.2. 5,7-Dimethyl-2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thione
(11b). Method A: To a cooled in an ice bath, stirred emulsion of
isothiocyanate 6b (0.453 g, 3.16 mmol) in H2O (3 mL) was added
a solution of NaOH (0.095 g, 2.37 mmol) and N2H4$H2O (0.162 g,
3.24 mmol) in H2O (1 mL) over 1 min, then the ice bath was re-
moved. After addition the starting isothiocyanate almost dissolved
and the solid material started to precipitate in 5 min. The resulting
suspension was stirred at room temperature for 3 h, then AcOH
(0.140 mL, 2.45 mmol) and saturated aqueous NaHCO3 (1 mL) were
subsequently added, and the suspension was cooled. The pre-
cipitate was filtered, washed with cold H2O, petroleum ether, and
dried to give triazepine 11b (0.306 g, 61%).
83.44 (C-8a), 52.96 (C-4), 49.14 (C-4a), 36.26 (CH2), 29.53 (4-CH3),
24.93 (CH2), 23.71 (4-CH3), 22.36 (CH2), 21.81 (CH2). Anal. Calcd for
C
10H19N3OS: C, 52.37; H, 8.35; N, 18.32. Found: C, 52.31; H, 8.54; N,
18.24.
4.3.10. 3-Amino-4-hydroxy-6-methylhexahydropyrimidine-2-thione
(10j). To a cooled in an ice bath, stirred solution of isothiocyanate 6j
(8.581 g, 66.43 mmol) in EtOH (50 mL) was added N2H4$H2O
(3.360 g, 67.11 mmol) dropwise over 5 min. White solid started to
precipitate during the addition. The ice bath was removed and the
resulting suspension was stirred for 1 h at room temperature. The
obtained suspension was cooled to ꢁ18 ꢀC. The precipitate was
filtered on a cold (ꢁ18 ꢀC) filter, rapidly washed with cold (ꢁ18 ꢀC)
EtOH (3ꢂ20 mL), cold (ꢁ18 ꢀC) ether (2ꢂ20 mL), and dried to give
pyrimidine 10j (7.977 g, 74%) as a mixture of two diastereomers in
a ratio of 90:10. After crystallization from EtOH the ratio of isomers
Method B: To a stirred solution of NaOH (0.191 g, 4.78 mmol) in
H2O (7 mL) was added pyrimidine 10b (1.122 g, 6.40 mmol), the
resulting suspension was stirred at room temperature for 3 h, then
AcOH (0.280 mL, 4.89 mmol) and saturated aqueous NaHCO3 (1 mL)
were subsequently added, and the suspension was cooled. The pre-
cipitate was filtered, washed with cold H2O, petroleum ether, and
dried to give triazepine 11b (0.837 g, 83%). Mp 198 ꢀC (dec, EtOH). IR
did not change. Mp 143.5e144 ꢀC (dec, EtOH). IR (Nujol)
3234 (br vs), 1622 (m), 1604 (m), 1531 (s), 1502 (m), 1486 (m), 1265
(s), 1037 (s); 1H NMR of the major isomer (300.13 MHz, DMSO-d6)
n :
, cmꢁ1
d:
(Nujol) n
, cmꢁ1: 3222 (br s), 3176 (br s), 3134 (br s), 3014 (m), 1667
8.14 (1H, br s, N(1)H), 6.39 (1H, dd, 3J¼4.8, 4J¼1.0 Hz, OH), 5.15 (2H,
br s, NH2), 4.88 (1H, ddd, 3J¼4.8, 3J¼3.4, 3J¼2.2 Hz, 4-H), 3.49 (1H,
ddq, 3J¼12.2, 3J¼6.4, 3J¼3.5 Hz, 6-H), 1.84 (1H, dddd, 2J¼13.3,
3J¼3.5, 3J¼2.2, 4J¼2.0 Hz, 5-He), 1.52 (1H, dddd, 2J¼13.3, 3J¼12.2,
3J¼3.4, 4J¼1.0 Hz, 5-Ha), 1.11 (3H, d, 3J¼6.4 Hz, CH3); 1H NMR of the
(m), 1576 (m), 1557 (w), 1490 (s), 1210 (s); 1H NMR (300.13 MHz,
DMSO-d6)
d
: 10.11 (1H, br d, 4J¼2.1 Hz, N(2)H), 8.43 (1H, br dd, 3J¼3.5,
4J¼2.1 Hz, N(4)H), 3.62 (1H, dddq, 3J¼7.0, 3J¼6.5, 3J¼3.5, 3J¼2.7 Hz, 5-
H), 2.58 (1H, dd, 2J¼14.6, 3J¼2.7 Hz, 6-HA), 2.49 (1H, dd, 2J¼14.6,
3J¼7.0 Hz, 6-HB),1.96 (3H, s, 7-CH3),1.13 (3H, d, 3J¼6.5 Hz, 5-CH3); 13
C
minor isomer (300.13 MHz, DMSO-d6)
d
: 8.06 (1H, br s, N(1)H), 6.36
NMR (75.48 MHz, DMSO-d6) d: 176.42 (C-3),161.04 (C-7), 50.74 (C-5),
(1H, d, 3J¼5.5 Hz, OH), 5.13 (2H, br s, NH2), 4.94 (1H, ddd, 3J¼6.3,
3J¼5.5, 3J¼5.1 Hz, 4-H), 2.11 (1H, dddd, 2J¼13.5, 3J¼5.1, 3J¼4.4,
4J¼1.0 Hz, 5-He), 1.68 (1H, ddd, 2J¼13.5, 3J¼7.8, 3J¼6.3 Hz, 5-Ha), 1.14
(3H, d, 3J¼6.5 Hz, CH3), signals of the 6-H proton completely
overlap with signals of the analogous proton of the major isomer;
39.61 (C-6), 25.13 (7-CH3), 22.22 (5-CH3); MS (EI) m/z 159 [4,
(Mþ2)þ],158 [9, (Mþ1)þ],157 (100, Mþ),142 (2),124 (4),115 (13),101
(8), 97 (11), 99 (35), 89 (15), 86 (57), 83 (36), 82 (18), 81 (9), 74 (10), 72
(23), 71 (84), 69 (21), 68 (9), 67 (13), 60 (64), 59 (52), 57 (38), 56 (75),
54 (23), 53 (21), 44 (27), 43 (27), 42 (75), 41 (83), 39 (46), 30 (13), 29
(11), 28 (30), 27 (19). Anal. Calcd for C6H11N3S: C, 45.83; H, 7.05; N,
26.72. Found: C, 45.72; H, 7.17; N, 26.75.
13C NMR of the major isomer (75.48 MHz, DMSO-d6)
d
: 176.57 (C-2),
78.35 (C-4), 41.89 (C-6), 36.65 (C-5), 19.83 (CH3). Anal. Calcd for
Please cite this article in press as: Fesenko, A. A.; Shutalev, A. D., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.03.082

A.A. Fesenko, A.D. Shutalev / Tetrahedron xxx (2016) 1e14
11
4.4.3. 5,6,7-Trimethyl-2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-
thione (11c). Method A: Triazepine 11c (0.188 g, 42%) as a mixture of
two isomers in a ratio of 65:35 was prepared from of isothiocyanate
6c (0.414 g, 2.63 mmol), NaOH (0.106 g, 2.67 mmol) and N2H4$H2O
(0.146 g, 2.91 mmol) in H2O (3.5 mL) (rt, 7 h) as described for
compound 11b in Method A.
Method B: Triazepine 11c (0.962 g, 78%) as a mixture of two
isomers in a ratio of 55:45 was prepared from pyrimidine 10c
(1.368 g, 7.22 mmol) and NaOH (0.290 g, 7.25 mmol) in H2O (11 mL)
(rt, 6 h) as described for compound 11b in Method B. After crys-
tallization from EtOH the diastereomeric ratio changed to 64:36,
temperature of bath) for 4 h. At the beginning of the reaction the
clear solution formed and the solid material started to precipitate
after 15 min. When the reaction was completed, the obtained
suspension was cooled, AcOH (1.15 mL, 20.09 mmol) was added,
and the solvent was removed under vacuum. To the residue was
added saturated aqueous NaHCO3 (5 mL), the mixture was tritu-
rated until crystallization was completed, and the obtained sus-
pension was cooled. The precipitate was filtered, washed with ice
cold H2O, petroleum ether, and dried to give triazepine 11e (1.439 g,
91%). Mp 254 ꢀC (dec, MeCN) (lit.5a 225e228 ꢀC). IR (Nujol) , cmꢁ1
n :
3250 (sh), 3223 (sh), 3187 (br vs), 3091 (m), 1686 (m), 1562 (s), 1196
respectively. Mp 175.5e181 ꢀC (EtOH). IR (Nujol)
n
, cmꢁ1: 3276 (s),
(s); 1H NMR (300.13 MHz, DMSO-d6)
N
5a-H), 2.29e2.38 (2H, m, 8-H), 1.89e2.03, 1.70e1.84, 1.41e1.63 (1H,
d
: 10.37 (1H, br d, 4J¼2.1 Hz,
3190 (br vs), 3106 (m), 1666 (m), 1568 (s), 1196 (s); 1H NMR of the
(2)H), 8.41 (1H, br d, 4J¼2.1 Hz, N(4)H), 2.74 (1H, t, 3J1þ3J2¼17.4 Hz,
major isomer (300.13 MHz, DMSO-d6)
N
d
: 10.14 (1H, br d, 4J¼2.2 Hz,
(2)H), 8.52 (1H, br dd, 3J¼4.1, 4J¼2.2 Hz, N(4)H), 3.57 (1H, ddq,
1H, and 2H, respectively, three m, 6-H and 7-H), 1.20 (3H, s, 5-CH3),
3J¼6.7, 3J¼4.1, 3J¼1.7 Hz, 5-H), 2.73 (1H, dq, 3J¼7.2, 3J¼1.7 Hz, 6-H),
1.91 (3H, s, 7-CH3), 1.06 (3H, d, 3J¼6.7 Hz, 5-CH3), 1.02 (3H, d,
3J¼7.2 Hz, 6-CH3); 1H NMR of the minor isomer (300.13 MHz,
1.05 (3H, s, 5-CH3); 13C NMR (75.48 MHz, DMSO-d6)
d: 175.16 (C-3),
165.94 (C-8a), 57.69 (C-5), 52.92 (C-5a), 34.49 (CH2), 28.42 (CH2),
27.46 (5-CH3), 24.48 (5-CH3), 23.14 (CH2); MS (EI) m/z 199 [5,
(Mþ2)þ], 198 [9, (Mþ1)þ], 197 (100, Mþ), 182 (6), 164 (9), 128 (12),
123 (6), 116 (5), 115 (67), 100 (16), 97 (16), 95 (5), 94 (6), 84 (7), 83
(18), 82 (21), 81 (7), 80 (6), 79 (7), 60 (6), 59 (7), 58 (13), 55 (6), 54
(6), 53 (7), 43 (5), 42 (10), 41 (14), 39 (9), 28 (9). Anal. Calcd for
C9H15N3S: C, 54.79; H, 7.66; N, 21.30. Found: C, 54.70; H, 7.60; N,
21.30.
DMSO-d6)
d
: 10.27 (1H, br d, 4J¼2.3 Hz, N(2)H), 8.73 (1H, br ddd,
3J¼6.2, 4J¼2.3, 4J¼1.0 Hz, N(4)H), 3.22 (1H, ddq, 3J¼6.7, 3J¼6.2,
3J¼4.4 Hz, 5-H), 2.63 (1H, ddq, 3J¼7.1, 3J¼4.4, 4J¼1.0 Hz, 6-H), 1.95
(3H, s, 7-CH3), 1.05 (3H, d, 3J¼6.7 Hz, 5-CH3), 1.01 (3H, d, 3J¼7.1 Hz,
6-CH3); 13C NMR of the major isomer (75.48 MHz, DMSO-d6)
d:
176.08 (C-3), 162.25 (C-7), 53.82 (C-5), 42.57 (C-6), 23.40 (7-CH3),
18.26 (5-CH3), 11.85 (6-CH3); 13C NMR of the minor isomer
(75.48 MHz, DMSO-d6)
d
: 176.31 (C-3), 159.37 (C-7), 53.42 (C-5),
4.4.6. 5a0,60,70,80-Tetrahydro-20H-spiro[cyclopentane-1,5’-cyclopenta
[f][1,2,4]triazepine]-30(40H)-thione (11f). Triazepine 11f (4.125 g,
93%) was prepared from pyrimidine 10f (4.805 g, 19.91 mmol) and
KOH (2.790 g, 49.72 mmol) in EtOH (50 mL) (40 ꢀC, 4 h) as described
44.48 (C-6), 25.29 (7-CH3), 21.32 (5-CH3),14.85 (6-CH3); MS (EI) m/z
173 [6, (Mþ2)þ], 172 [10, (Mþ1)þ], 171 (100, Mþ), 115 (32), 103 (41),
97 (22), 96 (9), 95 (16), 86 (43), 85 (86), 83 (10), 75 (12), 74 (10), 71
(12), 70 (48), 69 (36), 68 (63), 60 (36), 59 (28), 57 (16), 56 (41), 55
(38), 53 (16), 44 (32), 43 (19), 42 (39), 41 (26), 39 (13), 29 (11), 28
(17), 27 (13). Anal. Calcd for C7H13N3S: C, 49.09; H, 7.65; N, 24.54.
Found: C, 49.15; H, 7.80; N, 24.27.
for compound 11e. Mp 237e237.5 ꢀC (dec, EtOH). IR (Nujol)
3247 (br vs), 3170 (br vs), 3086 (br m), 1673 (m), 1561 (s), 1539 (m),
n :
, cmꢁ1
1216 (s); 1H NMR (300.13 MHz, DMSO-d6)
d: 10.47 (1H, br d,
4J¼2.1 Hz, N(2)H), 8.56 (1H, br d, 4J¼2.1 Hz, N(4)H), 2.82 (1H, ddd,
J¼10.2, J¼8.0, J¼1.8 Hz, 5a-H), 2.27e2.45 (2H, m, 8-H), 1.70e2.04,
1.35e1.68 (4H, and 8H respectively, two m, 6-H, 7-H,
4.4.4. 5-Methyl-2,3,4,5,5a,6,7,8-octahydrocyclopenta[f][1,2,4]tri-
azepine-3-thione (11d). Triazepine 11d (1.292 g, 90%) as a mixture
of two isomers in a ratio of 92:8 was prepared from pyrimidine 10d
(1.573 g, 7.81 mmol) and KOH (1.100 g,19.60 mmol) in EtOH (24 mL)
(40 ꢀC, 4 h) as described for compound 11e. After crystallization
from MeCN the diastereomeric ratio changed to 97:3, respectively.
CH2CH2CH2CH2); 13C NMR (75.48 MHz, DMSO-d6)
d: 175.60 (C-3),
165.85 (C-8a), 67.28 (C-5), 52.54 (C-5a), 36.56 (CH2), 34.76 (CH2),
34.56 (CH2), 28.79 (CH2), 24.73 (CH2), 23.97 (CH2), 22.88 (CH2); MS
(EI) m/z 225 [4, (Mþ2)þ], 224 [15, (Mþ1)þ], 223 (100, Mþ), 194 (5),
191 (6), 190 (44), 155 (11), 129 (9), 128 (19), 116 (5), 115 (81), 110 (8),
109 (9), 97 (12), 91 (7), 84 (10), 83 (8), 82 (20), 80 (8), 79 (12), 77
(12), 67 (25), 60 (10), 59 (6), 55 (7), 54 (7), 53 (6), 41 (12), 28 (11).
Anal. Calcd for C11H17N3S: C, 59.16; H, 7.67; N,18.81. Found: C, 59.11;
H, 7.80; N, 18.96.
Mp 210.5 ꢀC (dec, MeCN). IR (Nujol)
m), 3011 (m), 1667 (m), 1573 (s), 1557 (m), 1492 (s), 1216 (s); 1H
NMR of the major isomer (300.13 MHz, DMSO-d6) : 10.29 (1H, br d,
n
, cmꢁ1: 3188 (br vs), 3140 (br
d
4J¼2.1 Hz, N(2)H), 8.25 (1H, br dd, 4J¼2.1, 3J¼1.5 Hz, N(4)H), 3.33 (1H,
ddq, 3J¼8.7, 3J¼6.4, 3J¼1.5 Hz, 5-H), 2.49e2.59 (1H, m, 5a-H),
2.26e2.44 (2H, m, 8-H), 1.89e2.01, 1.69e1.82, 1.47e1.63, 1.32e1.45
(1H, 1H, 1H, and 1H respectively, four m, 6-H and 7-H), 1.15 (3H, d,
3J¼6.4 Hz, CH3); 1H NMR of the minor isomer (300.13 MHz, DMSO-
4.4.7. 5-Methyl-1,3,5a,6,7,8,9,9a-octahydro-2H-benzo[e][1,2,4]tri-
azepine-2-thione (11g). Triazepine 11g (2.346 g, 93%) as a mixture
of two isomers in a ratio of 93:7 was prepared from pyrimidine 10g
(2.765 g, 12.84 mmol) and KOH (1.801 g, 32.10 mmol) in EtOH
(33 mL) (40 ꢀC, 5 h 30 min) as described for compound 11e. The
analytically pure sample (0.163 g, a 97:3 diastereomeric mixture)
was obtained from 0.408 g of crude 11g using column chroma-
tography on silica gel 60 (12.72 g) eluting with petroleum ether/
CHCl3 (from 1:1 to 1:4) followed by crystallization of the obtained
solid (0.344 g) from EtOH (9 mL). Mp 210.5e211.5 ꢀC (dec, EtOH). IR
d6)
d
: 10.34 (1H, br d, 4J¼2.1 Hz, N(2)H), 8.90 (1H, br dd, 3J¼6.6,
4J¼2.1 Hz, N(4)H), 3.45 (1H, ddq, 3J¼6.6, 3J¼6.6, 3J¼3.0 Hz, 5-H), 2.88
(1H, dt, 3J1þ3J2¼17.2, 3J¼3.0 Hz, 5a-H), 0.99 (3H, d, 3J¼6.6 Hz, CH3),
signals of other protons overlap with protons signals of the major
isomer; 13C NMR of the major isomer (75.48 MHz, DMSO-d6)
d:
176.14 (C-3), 167.55 (C-8a), 54.34 (C-5), 49.20 (C-5a), 33.41 (CH2),
29.56 (CH2), 22.74 (CH2), 19.82 (CH3); MS (EI) m/z 185 [7, (Mþ2)þ],
184 [12, (Mþ1)þ], 183 (100, Mþ), 168 (12), 128 (7), 115 (39), 114 (15),
112 (6), 109 (9), 97 (62), 95 (11), 86 (16), 82 (43), 81 (19), 80 (23), 79
(10), 77 (10), 70 (41), 69 (24), 67 (22), 65 (9), 60 (16), 59 (17), 55 (19),
54 (14), 53 (14), 44 (20), 42 (11), 41 (27), 39 (15), 28 (16). Anal. Calcd
for C8H13N3S: C, 52.43; H, 7.15; N, 22.93. Found: C, 52.43; H, 7.14; N,
22.97.
(Nujol) n
, cmꢁ1: 3215 (br vs), 3190 (br vs), 3120 (br m), 3019 (m),
1657 (m), 1580 (m), 1549 (s), 1185 (s), 1171 (s); 1H NMR of the major
isomer (300.13 MHz, DMSO-d6)
d
: 10.03 (1H, br d, 4J¼2.1 Hz, N(3)H),
7.90 (1H, br d, 4J¼2.1 Hz, N(1)H), 3.29 (1H, ddd, 3J¼10.6, 3J¼10.2,
3J¼4.1 Hz, 9a-H), 2.68 (1H, ddd, 3J¼12.2, 3J¼10.6, 3J¼3.8 Hz, 5a-H),
1.99e2.11, 1.83e1.93, 1.51e1.69, 1.08e1.40 (1H, 1H, 2H, and 4H, re-
spectively, four m, 6-H, 7-H, 8-H, and 9-H), 1.92 (3H, s, CH3); 1H
4.4.5. 5,5-Dimethyl-2,3,4,5,5a,6,7,8-octahydrocyclopenta[f][1,2,4]tri-
azepine-3-thione (11e). To a solution of KOH (1.116 g, 19.88 mmol)
in EtOH (25 mL) was added pyrimidine 10e (1.718 g, 7.98 mmol) and
NMR of the minor isomer (300.13 MHz, DMSO-d6) d: 10.17 (1H, br d,
4J¼2.2 Hz, N(3)H), 8.26 (1H, br s, N(1)H), 3.75e3.80 (1H, unresolved
m, half-width at half-height value of 7.4 Hz, 9a-H), 1.90 (3H, s, CH3),
signals of other protons overlap with protons signals of the major
the resulting mixture was stirred in
a
water bath (40 ꢀC,
Please cite this article in press as: Fesenko, A. A.; Shutalev, A. D., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.03.082

12
A.A. Fesenko, A.D. Shutalev / Tetrahedron xxx (2016) 1e14
isomer; 13C NMR of the major isomer (75.48 MHz, DMSO-d6)
d:
H), 1.24 (3H, s, 5-CH3), 1.15 (3H, s, 5-CH3); 13C NMR (75.48 MHz,
DMSO-d6) : 177.92 (C-3), 162.96 (C-9a), 58.03 (C-5), 50.39 (C-5a),
177.66 (C-2), 168.05 (C-5), 60.03 (C-9a), 42.96 (C-5a), 35.01 (CH2),
27.15 (CH2), 23.95 (CH2), 23.46 (CH2), 20.06 (CH3); MS (EI) m/z 199
[4, (Mþ2)þ], 198 [13, (Mþ1)þ], 197 (100, Mþ), 182 (3), 164 (7), 140
(8), 139 (65), 137 (13), 128 (16), 127 (15), 123 (10), 122 (15), 116 (7),
115 (12), 114 (8), 110 (8), 109 (33), 107 (9), 98 (12), 97 (18), 96 (26),
95 (62), 91 (11), 85 (12), 83 (20), 82 (26), 81 (77), 79 (43), 77 (24), 72
(14), 70 (14), 69 (29), 68 (19), 67 (46), 65 (17), 60 (32), 59 (24), 57
(17), 56 (18), 55 (24), 54 (21), 53 (19), 42 (22), 41 (42), 40 (10), 39
(23), 29 (11), 28 (19), 27 (11). Anal. Calcd for C9H15N3S: C, 54.79; H,
7.66; N, 21.30. Found: C, 54.83; H, 7.89; N, 21.15.
d
34.70 (CH2), 27.54 (5-CH3), 27.03 (CH2), 25.71 (5-CH3), 25.10 (CH2),
22.96 (CH2); MS (EI) m/z 213 [3, (Mþ2)þ], 212 [10, (Mþ1)þ], 211 (73,
Mþ), 196 (8), 178 (7), 168 (6), 155 (8), 137 (14), 129 (79), 128 (48), 115
(79), 114 (47), 113 (15), 112 (10), 111 (41), 109 (14), 101 (14), 100 (59),
97 (16), 96 (100), 95 (49), 94 (30), 91 (15), 84 (55), 83 (59), 82 (22),
81 (33), 80 (17), 79 (35), 77 (21), 70 (9), 69 (26), 68 (15), 67 (44), 65
(13), 60 (23), 59 (19), 58 (43), 56 (9), 55 (25), 54 (14), 53 (17), 43
(12), 42 (26), 41 (51), 39 (15), 28 (12). Anal. Calcd for C10H17N3S: C,
56.84; H, 8.11; N, 19.88. Found: C, 56.85; H, 8.13; N, 20.01.
4.4.8. 5-Methyl-2,4,5,5a,6,7,8,9-octahydro-3H-benzo[f][1,2,4]tri-
azepine-3-thione (11h). Triazepine 11h (1.110 g, 93%) as a mixture of
two isomers in a ratio of 58:42 was prepared from pyrimidine 10h
(1.307 g, 6.07 mmol) and Na (0.357 g, 15.55 mmol) in anhydrous
MeOH (24 mL) (reflux, 5 h 20 min) as described for compound 11i.
The analytically pure sample (0.224 g, a 76:24 diastereomeric
mixture) was obtained from 0.504 g of crude 11h using column
chromatography on silica gel 60 (9.98 g) eluting with petroleum
ether/CHCl3 (from 1:1 to 1:2) followed by crystallization of the
obtained solid (0.472 g) from EtOH (8 mL). Mp 170e179.5 ꢀC (dec,
4.5. Synthesis of 2,4,5,6-tetrahydro-3H-1,2,4-triazepin-3-ones
4.5.1. 5,5,7-Trimethyl-2,4,5,6-tetrahydro-3H-1,2,4-triazepin-3-one
(15a). A 250-mL round bottom flask equipped with magnetic
stirrer, thermometer and dropping funnel was charged with a so-
lution of KOH (13.67 g, 243.63 mmol) in H2O (70 mL), tri-
azepinethione 11a (11.92 g, 69.60 mmol) and EtOH (70 mL). To the
resulting stirred suspension was added H2O2 (28.0 mL,
415.96 mmol; d¼1.175 g/mL, 43%) dropwise so that the internal
temperature was maintained below 30 ꢀC. Then the reaction mix-
ture was cooled to 20 ꢀC, stirred at room temperature for 1 h, and
neutralized with concentrated aqueous HCl to pH 7 upon cooling in
an ice bath. The precipitate was filtered, washed with ice cold H2O,
petroleum ether, and dried to give triazepinone 15a (10.28 g, 95%).
EtOH). IR (Nujol)
n
, cmꢁ1: 3210 (br vs), 1660 (m), 1553 (s), 1202 (vs);
: 10.00 (1H,
1H NMR of the major isomer (300.13 MHz, DMSO-d6)
d
br d, 4J¼2.5 Hz, N(2)H), 8.58 (1H, br dd, 3J¼4.8, 4J¼2.5 Hz, N(4)H),
3.34 (1H, ddq, 3J¼6.8, 3J¼6.1, 3J¼4.8 Hz, 5-H), 2.34 (1H, ddd, 3J¼11.8,
3J¼6.1, 3J¼4.3 Hz, 5a-H), 1.21e2.07 (8H, 6-H, 7-H, 8-H, and 9-H,
signals overlap with signals of analogous protons of the minor
isomer), 1.16 (3H, d, 3J¼6.8 Hz, CH3); 1H NMR of the minor isomer
Mp 233e234 ꢀC (H2O) (lit.5e 214 ꢀC). IR (Nujol) , cmꢁ1: 3235 (br s),
n
(300.13 MHz, DMSO-d6)
d
: 9.91 (1H, br d, 4J¼2.5 Hz, N(2)H), 8.72
3167 (m), 3098 (br s), 3024 (m), 1682 (s), 1651 (s); 1H NMR
(1H, br dd, 3J¼4.7, 4J¼2.5 Hz, N(4)H), 3.81 (1H, ddq, 3J¼6.9, 3J¼4.7,
3J¼2.7 Hz, 5-H), 2.49 (1H, ddd, 3J¼12.7, 3J¼4.6, 3J¼2.7 Hz, 5a-H,
signals partly overlap with proton signals of the solvent), 1.21e2.07
(8H, 6-H, 7-H, 8-H, and 9-H, signals overlap with signals of analo-
(300.13 MHz, DMSO-d6)
d
: 8.81 (1H, br d, 4J¼2.1 Hz, N(2)H), 6.63
(1H, unresolved br d, N(4)H), 2.45 (2H, d, 4J¼0.8 Hz, H-6), 1.95 (3H, s,
7-CH3), 1.16 (6H, s, 5-CH3); 13C NMR (75.48 MHz, DMSO-d6)
d:
157.41, 155.17 (C-3, C-7), 53.56 (C-5), 43.94 (C-6), 30.23 (5-CH3),
25.49 (7-CH3); MS (EI) m/z 156 [1, (Mþ1)þ], 155 (6, Mþ), 140 (1), 100
(12), 99 (100), 97 (33), 84 (45), 72 (41), 70 (7), 67 (5), 58 (11), 57
(13), 56 (32), 53 (5), 43 (5), 42 (19), 41 (18), 39 (10), 29 (5), 28 (6).
gous protons of the major isomer), 1.09 (3H, d, 3J¼6.9 Hz, CH3); 13
C
NMR of the major isomer (75.48 MHz, DMSO-d6) d: 182.52 (C-3),
160.90 (C-9a), 53.23 (C-5), 47.91 (C-5a), 37.03 (CH2), 32.31 (CH2),
27.37 (CH2), 24.51 (CH2), 18.92 (CH3); 13C NMR of the minor isomer
(75.48 MHz, DMSO-d6)
d
: 181.18 br (C-3), 160.85 (C-9a), 51.63 (C-5),
4.5.2. 5a0,60,70,80-Tetrahydro-20H-spiro[cyclopentane-1,50-cyclopenta
[f][1,2,4]triazepine]-30(40H)-one (15b). To a stirred solution of KOH
(0.816 g, 14.55 mmol) in H2O (3 mL) were added triazepinethione
11f (0.646 g, 2.89 mmol) and EtOH (11 mL). To the resulting sus-
pension was added H2O2 (1.95 mL, 28.97 mmol; d¼1.175 g/mL, 43%)
over 1 min. After 10e15 min the reaction mixture began to warm,
starting material gradually dissolved and new precipitate formed.
(Note: With increased charges the internal temperature of reaction
mixture should be maintained below 55 ꢀC). The obtained sus-
pension was stirred at room temperature for 1.5 h, AcOH (0.7 mL,
12.23 mmol) was added, and the solvent was removed under vac-
uum (temperature of bath below 35 ꢀC). To the residue was added
saturated aqueous NaHCO3 (3 mL), and the obtained suspension
was cooled. The precipitate was filtered, washed with ice cold H2O,
petroleum ether, and dried to give triazepinone 15b (0.539 g, 90%).
45.99 (C-5a), 36.05 (CH2), 27.12 (CH2), 25.99 br (CH2), 23.70 (CH2),
16.77 (CH3); MS (EI) m/z 199 [6, (Mþ2)þ], 198 [11, (Mþ1)þ], 197
(100, Mþ), 182 (12), 164 (4), 154 (5), 129 (23), 115 (13), 114 (19), 113
(9), 111 (18), 101 (7), 96 (35), 95 (15), 94 (11), 91 (9), 86 (9), 84 (10),
81 (16), 79 (12), 77 (11), 70 (33), 69 (19), 67 (26), 65 (9), 60 (13), 59
(10), 55 (14), 54 (9), 53 (11), 44 (20), 42 (15), 41 (26), 39 (12), 28 (18).
Anal. Calcd for C9H15N3S: C, 54.79; H, 7.66; N, 21.30. Found: C,
54.81; H, 7.68; N, 21.28.
4.4.9. 5,5-Dimethyl-2,4,5,5a,6,7,8,9-octahydro-3H-benzo[f][1,2,4]tri-
azepine-3-thione (11i). To a solution of Na (0.589 g, 25.63 mmol) in
anhydrous MeOH (25 mL) was added pyrimidine 10i (1.156 g,
5.04 mmol) and the resulting mixture was refluxed under stirring
for 8 h with the protection from air moisture (CaCl2-tube). The
obtained solution was cooled, AcOH (1.55 mL, 27.08 mmol) was
added, and the solvent was removed under vacuum. To the residue
was added saturated aqueous NaHCO3 (5 mL), the mixture was
triturated until crystallization was completed, and the obtained
suspension was cooled. The precipitate was filtered, washed with
ice cold H2O, petroleum ether, and dried to give triazepine 11i
Mp 233.5e234.5 ꢀC (dec, EtOH). IR (Nujol) , cmꢁ1: 3281 (br s),
n
3205 (br s), 3125 (s), 3079 (br s), 1691 (s), 1655 (s); 1H NMR
(300.13 MHz, DMSO-d6)
d
: 9.18 (1H, br d, 4J¼2.4 Hz, N(2)H), 7.06 (1H,
br d, 4J¼2.4 Hz, N(4)H), 2.69 (1H, ddd, J¼10.9, J¼8.1, J¼1.8 Hz, 5a-H),
2.24e2.38 (2H, m, 8-H), 1.92e2.03, 1.33e1.85 (1H, and 11H, re-
spectively, two m, 6-H, 7-H, CH2CH2CH2CH2); 13C NMR (75.48 MHz,
(1.002 g, 94%). Mp 188e191 ꢀC (EtOH). IR (Nujol)
vs), 3163 (br vs), 3125 (m), 3100 (br s), 1658 (m), 1568 (s), 1548 (m),
n
, cmꢁ1: 3217 (br
DMSO-d6) d: 158.31, 155.44 (C-3, C-8a), 62.06 (C-5), 51.76 (C-5a),
36.95 (CH2), 34.52 (2CH2), 28.84 (CH2), 24.28 (CH2), 23.78 (CH2),
22.40 (CH2); MS (EI) m/z 208 [37, (Mþ1)þ], 207 (100, Mþ), 190 (25),
178 (8), 135 (12), 122 (9), 121 (11), 112 (28), 109 (21), 108 (12), 107
(11), 100 (15), 99 (88), 97 (12), 94 (12), 93 (12), 91 (22), 84 (61), 82
(18), 81 (16), 80 (18), 79 (23), 78 (11), 77 (19), 68 (12), 67 (60), 65
(21), 55 (20), 54 (37), 53 (23), 42 (15), 41 (46), 39 (20), 28 (14). Anal.
1483 (s), 1198 (s); 1H NMR (300.13 MHz, DMSO-d6)
d: 10.21 (1H, br
d, 4J¼2.3 Hz, N(2)H), 8.19 (1H, br d, 4J¼2.3 Hz, N(4)H), 2.49 (1H, dd,
3J¼11.1, 3J¼4.9 Hz, 5a-H, signals partly overlap with proton signals
of the solvent), 2.13e2.34 (2H, m, 9-H), 1.68e1.91, 1.48e1.64,
1.28e1.46 (3H, 1H, and 2H, respectively, three m, 6-H, 7-H, and 8-
Please cite this article in press as: Fesenko, A. A.; Shutalev, A. D., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.03.082

A.A. Fesenko, A.D. Shutalev / Tetrahedron xxx (2016) 1e14
13
Calcd for C11H17N3O: C, 63.74; H, 8.27; N, 20.27. Found: C, 63.75; H,
8.24; N, 20.32.
vacuum (temperature of bath below 35 ꢀC). To the residue was
added saturated aqueous NaHCO3, and the obtained suspension
was cooled. The precipitate was filtered, washed with ice cold H2O,
petroleum ether, and dried to give triazepinone 15d (0.582 g, 84%).
4.5.3. 5-Methyl-1,3,5a,6,7,8,9,9a-octahydro-2H-benzo[e][1,2,4]tri-
azepin-2-one (15c). To
a
stirred solution of KOH (0.885 g,
Mp 195e196 ꢀC (EtOH). IR (Nujol)
n
, cmꢁ1: 3253 (br vs), 3120 (br s),
15.78 mmol) in H2O (5 mL) were added triazepinethione 11g
(1.038 g, 5.26 mmol; a 93:7 diastereomeric mixture) and EtOH
(15 mL) and the resulting suspension was cooled in an ice bath.
Then H2O2 (2.2 mL, 32.68 mmol; d¼1.175 g/mL, 43%) was added
over 9 min. During the addition the solid material dissolved and
almost at the same time the new precipitate formed. The ice bath
was removed after 5 min from the completion of the addition.
(Note: With increased charges the internal temperature of reaction
mixture should be maintained below 20 ꢀC). The obtained sus-
pension was stirred at room temperature for 1 h, AcOH (0.80 mL,
13.97 mmol) was added, solid NaHCO3 was added until pH of the
reaction mixture was 8. The solvent was removed under vacuum,
the wet residue was co-evaporated with toluene (2ꢂ15 mL), and
then the flask with the residue was dried in a vacuum desiccator
(over P2O5) to constant weight. The obtained material was purified
using column chromatography on silica gel 60 (18.41 g) eluting
with MeOH/CHCl3 (from 1:100 to 1:50). The main fraction was
concentrated, the residual foam was triturated with ether until
crystallization was complete, the resulting suspension was cooled
(ꢁ18 ꢀC). The precipitate was filtered, washed with cold (ꢁ18 ꢀC)
ether (3ꢂ2 mL), and dried to give triazepinone 15c (0.563 g, 59%) as
a mixture of two isomers in a ratio of 95:5. (Note: compound 15c is
water soluble, isolation of product as described for other tri-
azepinones afforded 15c in 39% yield). Crystallization from EtOH
gave triazepinone 15c as a single diastereomer. Mp 226e227 ꢀC
1689 (vs), 1645 (s); 1H NMR (300.13 MHz, DMSO-d6)
d: 8.93 (1H, br
d, 4J¼2.5 Hz, N2H), 6.61 (1H, br d, 4J¼2.5 Hz, N4H), 2.22e2.35,
2.07e2.18, 1.71e1.88, 1.22e1.55 (2H, 1H, 3H, and 3H, respectively,
four m, 5a-H, 6-H, 7-H, 8-H, and 9-H), 1.22 (3H, s, 5-CH3), 1.10 (3H, s,
5-CH3); 13C NMR (75.48 MHz, DMSO-d6)
d: 157.39 br, 157.21 (C-3, C-
9a), 52.34 (C-5), 51.05 (C-5a), 36.46 (CH2), 28.49 (5-CH3), 27.81
(CH2), 26.53 (CH2), 25.96 (5-CH3), 24.13 (CH2); MS (EI) m/z 196 [5,
(Mþ1)þ], 195 (37, Mþ), 180 (6), 166 (2), 152 (12), 139 (9), 138 (11),
137 (16), 127 (7), 126 (6), 113 (24), 112 (63), 111 (58), 109 (10), 99
(95), 96 (14), 95 (25), 94 (14), 93 (9), 91 (10), 84 (45), 82 (14), 81
(29), 80 (12), 79 (26), 77 (18), 69 (15), 68 (10), 67 (32), 65 (11), 58
(100), 55 (19), 54 (11), 53 (17), 43 (8), 42 (18), 41 (24), 39 (9), 28 (9).
Anal. Calcd for C10H17N3O: C, 61.51; H, 8.78; N, 21.52. Found: C,
61.51; H, 8.69; N, 21.49.
Acknowledgements
This research was financially supported by the Russian Foun-
dation for Basic Research (Grant No. 15-03-07564) and the Ministry
of Education and Science of the Russian Federation (project part of
government order, 4.1849.2014/K). We thank Dmitry A. Cheshkov
for registration of 2D NMR spectra.
Supplementary data
(EtOH). IR (Nujol) n
, cmꢁ1: 3225 (br vs), 3089 (br vs),1685 (vs),1632
Supplementary data (procedures for directed aldol type con-
densations, copies of IR, 1H and 13C NMR spectra of synthesized
compounds, 2D NMR spectra of compounds 11aec, computational
details) associated with this article can be found in the online
version, at http://dx.doi.org/10.1016/j.tet.2016.03.082. These data
include MOL files and InChiKeys of the most important compounds
described in this article.
(m); 1H NMR of the major isomer (300.13 MHz, DMSO-d6)
d: 8.64
(1H, br d, 4J¼2.1 Hz, N(3)H), 6.38 (1H, br d, 4J¼2.1 Hz, N(1)H), 3.11
3
(1H, ddd, 3J¼11.0, 3J¼10.3, 3J¼4.1 Hz, 9a-H), 2.58 (1H, ddd, J¼12.1,
3J¼11.0, 3J¼3.6 Hz, 5a-H), 1.89 (3H, s, CH3), 1.82e1.97, 1.55e1.69,
1.09e1.39 (2H, 2H, and 4H respectively, three m, 6-H, 7-H, 8-H, and
9-H); 1H NMR of the minor isomer (300.13 MHz, DMSO-d6)
d: 8.85
(1H, br d, 4J¼2.5 Hz, N(3)H), 6.80 (1H, br s, N(1)H), 3.63e3.68 (1H,
unresolved m, half-width at half-height value of 7.4 Hz, 9a-H), 1.83
(3H, s, CH3), signals of other protons overlap with protons signals of
the major isomer; 13C NMR of the major isomer (75.48 MHz, DMSO-
References and notes
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