Straightforward Three-Component Synthesis of N′,N′′-Disubstituted N -Alkyl-1,3,5-Triazinanes

Article abstract of DOI:10.1055/s-0039-1690900

Efficient approaches towards the synthesis of various N-substituted 1,3,5-triazinanes based on a transformation of N -alkyl-1,5,3-dioxazepanes or on a domino reaction involving condensation of various amines, amides, and paraformaldehyde are described for the first time. Mg(ClO 4) 2 was shown to be one of the most potent additives for the condensation. The proposed approaches permit the synthesis of a broad spectrum of substituted sym -triazinanes in good yields with relatively easy workup. In the case of the multicomponent reaction, the approach allows the preparation of the target substances from simple and easily accessible reagents. The representatives of the resulting compounds were found to possess no antimicrobial or cytotoxic activity in in vitro bioassays.

Full text of DOI:10.1055/s-0039-1690900

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2020, 31, A–F
letter
A
en
A. V. Kletskov et al.
Letter
Synlett
Straightforward Three-Component Synthesis of N′,N′′-Disubsti-
tuted N-Alkyl-1,3,5-Triazinanes
Alexey V. Kletskov*a
Antonio Fronterab
Anna A. Sinelshchikovac
Mikhail S. Grigorievc
Vladimir P. Zaytseva
Mariya V. Grudovaa
Alexander S. Bunevd
Sofia Presnukhinae
Anton Shetneve
0
0
0
0-0
0
0
2-6
9
7
9-
5
4
5
X
Lewis acid
easy
ArSO2-NH2 + Alkyl-NH2
r.t. or reflux workup
one step
yields up to 84%
X = CH2, C=S
R = H, SO2Ar
no antimicrobial or
cytotoxic activity
+
R
X
N
R
CHCl3
(CH2O)n
N
N
Lewis acid
reflux
easy
workup
Alkyl
0
0
0
0-
0
0
0
1-9
1
7
5-7
5
8
3
S=C(NH2)2 + Alkyl-NH2
+
CHCl3
(CH2O)n
0
0
0
0-0
0
0
1-
6
4
0
8-8
3
2
9
Fedor I. Zubkova
0
0
0
0-0
0
0
2-
0
2
8
9-0
8
3
1
a Organic Chemistry Department, Faculty of Science, Peoples’
Friendship University of Russia (RUDN University), 6 Miklukho-
Maklaya St., Moscow 117198, Russian Federation
avkletskov@gmail.com
b Department of Chemistry, Universitat de les Illes Balears, Crta.
de Valldemossa km 7.7, 07122 Palma de Mallorca (Baleares),
Spain
c Frumkin Institute of Physical Chemistry and Electrochemistry,
Russian Academy of Sciences, Leninsky pr. 31, bld. 4, Moscow
119071, Russian Federation
d Medicinal Chemistry Center, Togliatti State University,
14 Belorusskaya St., 445020 Togliatti, Russian Federation
e Pharmaceutical Technology Transfer Center, Yaroslavl State
Pedagogical University named after K. D. Ushinsky,
108 Respublikanskaya St., Yaroslavl, 150000, Russian Federation
Received: 03.03.2020
Accepted after revision: 30.03.2020
Published online: 17.04.2020
triazinanes. The reported methods have various disadvan-
tages; some give mixtures of products, others require wa-
ter-soluble starting materials, and some involve relatively
harsh conditions that are not tolerated by some functional
groups.6–8 For instance, three N-tert-butyl-N′,N′′-sulfonyl-
triazinanes have been synthesized from N-tert-butylmeth-
animine and various sulfonamides in refluxing benzene in
the presence of an equimolar quantity of acetic anhydride
(Figure 1).8 Moreover, possible applications of such tri-
azinanes in both organic synthesis and as bioactive sub-
stances remain underexplored.
DOI: 10.1055/s-0039-1690900; Art ID: st-2020-k0126-l
Abstract Efficient approaches towards the synthesis of various N-sub-
stituted 1,3,5-triazinanes based on a transformation of N-alkyl-1,5,3-di-
oxazepanes or on a domino reaction involving condensation of various
amines, amides, and paraformaldehyde are described for the first time.
Mg(ClO4)2 was shown to be one of the most potent additives for the
condensation. The proposed approaches permit the synthesis of a
broad spectrum of substituted sym-triazinanes in good yields with rela-
tively easy workup. In the case of the multicomponent reaction, the ap-
proach allows the preparation of the target substances from simple and
easily accessible reagents. The representatives of the resulting com-
pounds were found to possess no antimicrobial or cytotoxic activity in
in vitro bioassays.
O
O
O
O
O
R
R
S
S
Δ
N
N
O
O
N
RSO2NH2
+
+
N
benzene
Key words triazinanes, domino reaction, sulfonamides, amides,
amines, thiourea
R = Ph, 4-MeC6H4, CH2Ph
Figure 1 Synthesis of N-tert-butyl-N′,N′′-sulfonyltriazinanes
Symmetrical N-substituted 1,3,5-triazinanes have been
shown to be useful intermediates in organic synthesis,
serving as synthons for the corresponding aldimines, which
can be generated in situ for further chemical transforma-
tions.1–4 1,3,5-Triazinanes have found practical use as ele-
ments of synergistic antimicrobial compositions.5 However,
little information is available on straightforward approach-
es to the synthesis of unsymmetrically N-substituted 1,3,5-
A key problem in the synthesis of polysubstituted mole-
cules is the need for sufficiently complex reagents, which
usually are not readily available. Therefore, the develop-
ment of efficient methods for obtaining complex molecules
from simple and widely available starting materials through
multicomponent reactions remains a primary goal of mod-
ern synthetic organic chemistry. Here we report a straight-
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
A. V. Kletskov et al.
Letter
Synlett
forward approach to the synthesis of various N-substituted
triazinanes by a one-pot multicomponent reaction of para-
formaldehyde, alkylamines, and sulfonamides or thiourea.
There is good reason to believe that the high yields of the
target products combined with the easy workup procedure
of the method, the revealed lack of toxicity of the products,
and the sufficiently broad scope of their possible applica-
tions will render N-alkyltriazinanes eye-catching products
for a broad range of researchers.
During our attempt to synthesize 3-[(4-chlorophe-
nyl)sulfonyl]-1,5,3-dioxazepane (1) by the reaction of 3-
tert-butyl-1,5,3-dioxazepane (2a) with 4-chlorobenzene-
sulfonamide (3a) under conditions previously described for
the transamination of 3-tert-butyl-1,5,3-dioxazepane with
(het)arylamines, we found that the reaction instead gave of
1-(tert-butyl)-3,5-bis[(4-chlorophenyl)sulfonyl]-1,3,5-tri-
azinane (4a) exclusively (Scheme 1).9
conditions from simpler more-accessible reagents and vari-
ous additives, including some rare-earth metal salts
through a one-pot domino process. We established that
corresponding triazinanes could be obtained by reaction of
tert-butylamine, paraformaldehyde, and various sulfon-
amides in the presence of an acidic catalyst (samarium ni-
trate) in chloroform at r.t. Our subsequent efforts focused
on the optimization of the reaction conditions. Condensa-
tion of 4-toluensulfonamide (3b) with butylamine and
paraformaldehyde to give triazinane 4g (Scheme 3) was
chosen as a model reaction for the optimization of the syn-
thesis conditions.
O
O
O
S
S
S
O
NH2
N
N
O
conditions
O
+ BuNH2 + (CH2O)n
N
3b
4g
Scheme 3 Example chosen for the optimization of conditions for the
Cl
three-component reaction
O
S
O
NH2
O
S
N
O
O
Cl
We established that practically any acid (Lewis or Brøn-
sted type) promoted this reaction (Table 1). Moreover, the
three-component condensation proceeded with a satisfac-
tory yield even in the absence of a catalyst (Table 1, entries
4 and 5). The presence of water in crystalline hydrate cata-
lysts did not have a noticeable effect on their activity (en-
tries 13 and 15). Eventually, acetic acid (entry 20) and mag-
nesium perchlorate (entries 21 and 22) were found to dis-
play the highest catalytic activity.
3a
1
Sm(NO3)3·6H2O
CHCl3, r.t
O
+
Cl
Cl
O
O
S
O
S
N
N
O
O
N
O
N
4a
2a
Scheme 1 Unexpected formation of the 1,3,5-triazinane 4a
Presumably, the formation of the 1,3,5-triazine ring
proceeds through double alkylation of two molecules of the
sulfonamide with 3-tert-butyl-1,5,3-dioxazepane (2a) un-
der catalysis by samarium trinitrate hexahydrate and a fur-
ther interaction of the resulting intermediate with formal-
dehyde formed as a result of catalytic decomposition of 3-
tert-butyl-1,5,3-dioxazepane (2a). To demonstrate the suit-
ability of the method for the preparation of the 1,3,5-tri-
azinanes, we expanded this approach to the synthesis of
triazinane derivatives 4b–f (Scheme 2).
Interestingly, the addition of copper(II) chloride inhibit-
ed the formation of the desired product 4g (Table1, entry 2).
This might be explained by partial hydrolysis of copper(II)
chloride under the reaction conditions with the formation
of copper(II) hydroxide, which, in turn, decomposes the tri-
azinane, thereby shifting the equilibrium of the reaction to-
ward the starting materials. This fact might be used in fu-
ture research on the activation of the corresponding sym-
triazinane systems toward further chemical transforma-
tions.
We then decided to investigate the possibility of synthe-
sizing the N-substituted-1,3,5-triazinanes under milder
It should be mentioned here that according to the stoi-
chiometry of the reaction (Scheme 3), the ratio of its com-
ponents should be primary amine/sulfonamide/formalde-
hyde = 1:2:3; however, it was established experimentally
that the highest yield of the target triazine 4g was achieved
when the ratio of the reagents was 1.05:2.00:3.75, respec-
tively. We also established that an increase in the reaction
time to three hours moderately increased the yield of com-
pound 4g to 76%. Consequently, this reaction time was used
in subsequent syntheses.
O
R1
R1
N
R2
+
O
O
O
Sm(NO3)3·6H2O
CHCl3, r.t., 36 h
2a,b
S
S
N
N
O
O
O
NH2
N
R2
S
O
R1
4a–f
3a–e
The assumed mechanism for the multicomponent reac-
tion of sulfonamides, primary amines, and formaldehyde is
presented in Scheme 4. The key steps of the transformation
are (i) condensation of an amine with formaldehyde to give
R1 = Me (3b, 4b, 4f), F (3c, 4c), Cl (3a, 4a), Br (3d, 4d), I (3e, 4e)
R2 = t-Bu (2a, 4b, 4c, 4d, 4e), Bn (2b, 4f)
Scheme 2 Two-component synthesis of triazinanes 4a–f by the reac-
tion of sulfonamides 3 with dioxazepanes 2
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

C
A. V. Kletskov et al.
Letter
Synlett
Table 1 Optimization of Conditions for the Synthesis of Triazinane 4g
with diethyl ether when magnesium perchlorate or another
salt is used as the catalyst. The workup in the case of acetic
acid appears to be slightly more complicated, and involves
an additional step for the neutralization of the acid.
Entry Additivea
Solvent
Temp
Time (h) Yieldb (%)
1
2
KOH
H2O
r.t
36
2
–
Some of the products shown in Scheme 5 were synthe-
sized by both the multicomponent reaction (Method a) and
from dioxazepanes 2 (Method b; see Scheme 2). Although
Method b for the synthesis of 1,3,5-triazinanes 4 from 3-al-
kyl-1,5,3-dioxazepanes 2 generally gave slightly higher
yields, we believe that the multicomponent reaction ap-
proach is preferable because it does not require the synthe-
sis of the corresponding 3-alkyl-1,5,3-dioxazepane 2. The
proposed conditions for the multicomponent reaction tol-
erate chiral amines as initial substrates; thus, chiral tri-
azinanes 4j, 4k, 4n and 4o were obtained from the corre-
sponding optically active phenethylamines. The conditions
also permitted the preparation of derivatives containing
alkenyl, alkynyl, or hydroxy groups (4l, 4p, and 4w, respec-
tively) from on corresponding amines. The use of an argon
atmosphere did not generally affect the yield of the prod-
uct, although it reduced the slight coloration of the reaction
mixtures and crude products. A study of this reaction of
various substituted anilines is currently ongoing in our
group.
As our preliminary experiments showed, the method
for the preparation of triazinanes 4 from sulfonamides 3
could be extended to other amides, particularly thiourea
(Scheme 6). Replacement of sulfonamide 3 with thiourea
permitted easy access to 1,3,5-triazinane-2-thiones 5 in
comparatively high yields (Scheme 6). Representative ex-
amples of these products have been shown to possess anti-
oxidant activity.10 We deliberately chose the previously
known triazinane-2-thiones 5 to demonstrate the capabili-
ties of the method and to permit comparison of the
yields.10–14 Compounds 5a–d were previously synthesized
by a two-step procedure using different conditions to those
reported here. Generally, the lower yields of the previous
syntheses (given in square brackets) can be explained either
by the use of different solvent systems and catalysts, or by
the absence of a catalyst in the case of compound 5d. Com-
pound 5e was synthesized for the first time. It is also worth
mentioning that thiourea is prone to react with acid anhy-
drides;15,16 consequently, the corresponding derivatives are
CuCl2
CHCl3
EtOH
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
reflux
r.t
11
38
41
54
45
48
48
55
57
57
59
59
60
60
63
65
65
66
70
71
76
3
KOH
36
2
4
–
reflux
reflux
reflux
reflux
reflux
r.t
5
–
4
6
NiClO4·6H2O
LiClO4
2
7
2
8
ZnO
2
9
SmF3
36
2
10
11
12
13
14
15
16
17
18
19
20
21
22
NdCl3
reflux
reflux
r.t
MnCl2
2.5
Sm(NO3)3·6H2O
NiCl2
36
2
reflux
r.t
SmCl3·6H2O
NiCl2·6H2O
Sm(NO3)3·6H2O
CoCl2·6H2O
Pr(NO3)3·6H2O
Ni(OAc)2
AcOH
36
2
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
2
2
2
2
2
Mg(ClO4)2
Mg(ClO4)2
2
3
a 10 mol%.
b Isolated yield.
imine A; (ii) nucleophilic addition of a molecule of the sul-
fonamide to the C=N double bond to give diamine B. (iii) ad-
dition of a second molecule of formaldehyde to the diamine
B, followed by Lewis acid catalyzed nucleophilic substitu-
tion of an OH group by a second molecule of the sulfon-
amide to give triamine C; and (iv) cyclization of the inter-
mediate C by the action of a third molecule of formalde-
hyde.
The workup involves simple filtration of the reaction
mixture through a thin layer of silica gel, partial evapora-
tion of chloroform, and further precipitation of the product
LA
H2CO, LA
R'NH2, LA
NH
O
H2N R'
R
NH2
R
N
R
NH R'
– LA
– H2O
– LA
R N
H
R
H
A
B
R
NH2
LA
H2CO, LA
R'
R'
LA OH
LA
H
H2CO, LA
N
NH
R'NH2
O
R
N
N
R
N
H2N R'
R
NH
– H2O
– LA
N
R'
NH
R'
– H2O
– LA
NH
R'
NH H
R'
4
C
Scheme 4 Possible mechanism for the multicomponent synthesis of substituted triazinanes by a domino reaction of formaldehyde, amines, and sul-
fonamides (R = alkyl; R' = SO2Ar); LA = Lewis acid.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

D
A. V. Kletskov et al.
Letter
Synlett
O
O
Ar
Ar
4
S
S
Mg(ClO4)2 (10 mol%)
3N
N
O
O
5
6
AlkylNH2 + (CH2O)n + ArSO2-NH2
2
CHCl3, Δ, 3 h, 9–84 %
N 1
4
Alkyl
Cl
Cl
F
F
Br
Br
O
O
O
O
O
O
N
O
O
S
S
S
S
S
S
O
S
S
N
N
N
N
N
N
N
O
O
O
O
O
O
O
N
N
N
N
4b 84% (90%) [95%]8
4a 71% (79%)
4c 69% (60%)
4d 64% (68%)
I
I
O
O
O
O
O
O
O
O
S
S
S
S
S
S
N
N
N
N
N
N
S
O
S
O
O
O
O
O
O
O
O
N
N
O
N
N
N
N
4e 75% (80%)
4f 58% (68%)
4g 76%
4h 59%
N
Bn
O
O
O
O
O
O
S
S
S
S
S
S
N
N
N
N
N
N
O
O
O
O
O
O
O
O
S
S
O
N
N
N
N
N
N
O
O
H
H
4i 61% (70%)
4j 57%
4k 58%
4l 45%
Bn
Ph
O
Me
Ph
O
Me
N
N
O
O
N
O
O
O
O
S
S
S
S
S
S
N
S
S
O
N
N
N
N
O
O
O
O
N
N
N
4m 77%
4n 58%
4o 57%
4p 9%
H
H
Ph
O
Me
O
Ph
O
Me
MeO
OMe
MeO
OMe
Cl
Cl
Cl
Cl
O
O
N
O
N
O
O
S
S
O
S
S
S
S
S
S
N
N
N
N
N
N
O
O
O
O
O
O
O
N
N
N
N
4q 61%
4r 58%
4s 70%
4t 65%
O
S
O
O
O
S
O
O
O
N
S
S
S
S
N
N
O
N
O
N
N
O
O
O
N
N
N
4u 76%
4v 58%
4w 27%
HO
Scheme 5 Synthesized N,N′-disulfonamidotriazinanes 4. Yields from dioxazepanes 2 (Method b) are shown in parentheses. Yields of previous prepara-
tions are shown in square brackets with references to the original work.
unlikely to be easily obtained if acetic anhydride is used as a
reagent.8 Our multicomponent approach therefore has
greater synthetic versatility. We are currently studying the
possibility of applying this approach in the synthesis of var-
ious N,N′,N′′-trisubstituted 1,3,5-triazinane-2-thiones.
Formamide also reacted successfully under the condi-
tions described above (Scheme 7). In this case, however, one
amide and two amine fragments entered the resulting
product 6. The reasons for the difference in these results
from the outcomes shown in Scheme 5 are unclear at pres-
ent, and will be clarified in subsequent publications.
An X-ray crystallographic study confirmed that mole-
cules 4i and 4r contain a 1,3,5-triazinane system with three
substituents on the nitrogen atoms (Figure 2).17 The general
geometrical features of these systems are similar. The six-
membered rings of both molecules have the usual slightly
distorted chair conformation in which the N-alkyl substitu-
ent (CH2Bn or Bu) occupies the axial position and the two
N-sulfonamide fragments adopt the sterically favored pseu-
doequatorial orientation.
The N-1 nitrogen atoms bound with the alkyl substitu-
ents have to be sp3-hybridized and have a pyramidal config-
uration, whereas the other two N-3 and N-5 nitrogen atoms
belonging to the sulfonamide groups have to be sp2-hybrid-
ized and, therefore, have a flat configuration in the tri-
azinane ring. For these reasons, triazinanes 4i and 4r should
both have a plane of symmetry passing through the N-1 ni-
trogen atom and the C-4 carbon atom. However, the X-ray
crystal structure analysis revealed that in the solid state,
the configurations of the N-3 and N-5 sulfonamide nitro-
gens are different; one of these atoms has an sp3-hybridiza-
tion and is pyramidal [the sum of the valence angles around
N-3 is 344.1(2)° for 4i and 352.9(8)° for 4r], whereas the
other is sp2-hybridized and nearly flat [the sum of valence
angles around N-5 is 359.9(6)° for 4i and 357.9(4)° for 4r].
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

E
A. V. Kletskov et al.
Letter
Synlett
S
N
Mg(ClO4)2 (10 mol%)
N
N
Mg(ClO4)2 (10 mol%)
HN
NH
AlkylNH2 + (CH2O)n + CS(NH2)2
t-Bu-NH2 + (CH2O)n + O=CH-NH2
N
CHCl3, Δ, 4.5 h
CHCl3, Δ, 3 h, 54–81%
5
Alkyl
O
6 84% [99%]14
S
S
N
Scheme 7 An extension of the three-component reaction to forma-
mide. The ratio of the amine, formamide, and formaldehyde was
2.05:1.00:3.10. The yield from a previous synthesis is shown in square
brackets.
HN
NH
HN
NH
N
S
HN
NH
5a 80% [85%]11
5b 62% [25%]11
N
In conclusion, various N-substituted triazinanes were
obtained by a multicomponent reaction of paraformalde-
hyde, alkylamines, and sulfonamides or thiourea in the
presence of various additives, among which Mg(ClO4)2 was
shown to be the most potent.18 Formamide also reacted
successfully under the conditions described. Representa-
tives of the synthesized compound did not show any no-
ticeable antimicrobial or cytostatic activity. However, they
represent interesting targets for further screening for anti-
fungal, herbicidal, or possibly antiviral activities. Tri-
azinanes are known to decompose to give formaldehyde as
well as reactive Schiff base intermediates; this limits their
widespread application as disinfectants due to associated
mutagenicity in some cases.19 The fact that the tested rep-
resentative examples of N-substituted 1,3,5-triazinanes did
not show noticeable antimicrobial or cytotoxic activity in-
dicates their stability towards decomposition in aqueous
media under biotesting conditions, which makes them at-
tractive targets for further careful evaluation of their bioac-
tivities. This will include in silico studies, due to the practice
of sorting out the 1,3,5-triazinane core as a potential source
of formaldehyde or reactive Schiff bases in the initial stages
of screening of molecular libraries.
S
S
HN
NH
HN
NH
N
OH
5e 54%
N
5c 70% [25%]11, [30%]12
5d 81% [35%]10
Scheme 6 Synthesis of 5-alkyl-1,3,5-triazinane-2-thiones 5. The ratio
of the amine, paraformaldehyde, and thiourea reactants was
1.05:2.00:1.00. Yields from previous syntheses are shown in square
brackets.
These structural peculiarities lead to a violation of the sym-
metry of the molecules in the crystal, and might be studied
in detail in further publications. Complete crystallographic
data for the molecules 4i and 4r are given in the Supporting
Information (SI; Tables 3S–9S).
Representative examples of the synthesized compounds
were evaluated for their in vitro antimicrobial activity
against Gram-positive and Gram-negative bacteria and
their cytotoxicity against selected human cancer lines. They
generally showed neither antimicrobial activity nor signifi-
cant cytotoxic activity, apparently due to their stability to-
wards hydrolysis under the biotesting conditions. Only
compound 4f exhibited a moderate cytotoxic activity
against the HT 1080 cell line. Details of the biotesting are
provided in the SI (Tables 1S and 2S).
Funding Information
The publication has been prepared with the support of the RUDN Uni-
versity Program 5-100 and the Russian Foundation for Basic Research
(project No 19-03-00807 A). A.F. thanks MICIU/AEI of Spain (projects
CTQ2017-85821-R and RED2018-102331-T, FEDER funds) for finan-
cial support.
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Acknowledgment
The XRD measurements were performed by using the equipment of
CKP FMI IPCE RAS.
Supporting Information
Supporting information for this article is available online at
Figure 2 X-ray crystal structures of 1,3,5-trizinanes 4i (left) and 4r
(right)
https://doi.org/10.1055/s-0039-1690900.
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© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

F
A. V. Kletskov et al.
Letter
Synlett
References and Notes
ing solution was cooled to –20 °C and the precipitate was col-
lected by filtration, washed with a small amount of cold EtOH
and dried, initially in air and then in a vacuum desiccator over
P2O5. Workup for products 4l, 4p, and 4w after concentration of
the filtrate included extraction of the crude viscous product
with boiling hexane–Et2O (1:2), followed by slow evaporation of
the resulting extract, initially at r.t. and then at 0 °C, resulting in
slow precipitation of the products as white solids. The resulting
solids were collected by filtration and dried in air and then in a
vacuum desiccator over P2O5. Compound 5e precipitated from
CHCl3. The crude product was collected by filtration, washed
with acetone, and dissolved in EtOH. The solution was filtered
through a fritted glass filter with minimal porosity, evaporated,
and treated with CHCl3 (5 mL). The precipitate was collected by
filtration and dried in air and then in a vacuum desiccator over
P2O5. In the case of 3,5-di-tert-butyl-1,3,5-triazinane-1-carbal-
dehyde (6), 2.05 equivalents of the amine were used under the
optimal conditions, as the use of equimolar combinations of
formamide and tert-butylamine gave 6 in a lower yield. Pure
compound 6 was obtained immediately after evaporation of the
filtrate under reduced pressure. The use of an argon atmosphere
did not generally affect the yields of the products, but did
reduce the slight coloration of the reaction mixtures and the
crude products.
(1) Ha, H.-J.; Lee, W. K. Heterocycles 2002, 57, 1525.
(2) Ji, D.; Sun, J. Org. Lett. 2018, 20, 2745.
(3) Ji, D.; Wang, C.; Sun, J. Org. Lett. 2018, 20, 3710.
(4) Chen, L.; Liu, K.; Sun, J. RSC Adv. 2018, 8, 5532.
(5) Yin, B. WO 2011049761, 2005.
(6) Flores-Parra, A.; Sánchez-Ruíz, S. A. Heterocycles 1999, 51, 2079.
(7) Tartakovsky, V. A.; Ermakov, A. S.; Sigai, N. V.; Vinogradov, D. B.
Russ. Chem. Bull. 2000, 49, 1082.
(8) Ziegler, E.; Rüf, W. Z. Naturforsch., B 1975, 30, 951.
(9) Makhmudiyarova, N. N.; Prokof’ev, K. I.; Mudarisova, L. V.;
Ibragimov, A. G.; Dzhemilev, U. M. Russ. J. Org. Chem. 2013, 49,
750.
(10) Garibov, E. N.; Rzaeva, I. A.; Shykhaliev, N. G.; Kuliev, A. I.;
Farzaliev, V. M.; Allakhverdiev, M. A. Russ. J. Appl. Chem. 2010,
83, 707.
(11) Lazarev, D. B.; Ramsh, S. M.; Ivanenko, A. G. Zh. Obshch. Khim.
2000, 3, 442.
(12) Khairullina, R. R.; Geniyatova, A. R.; Ibragimov, A. G.; Dzhemilev,
U. M. Russ. J. Org. Chem. 2013, 49, 904.
(13) Khairullina, R. R.; Geniyatova, A. R.; Meshcheryakova, E. S.;
Khalilov, L. M.; Ibragimov, A. G.; Dzhemilev, U. M. Russ. J. Org.
Chem. 2015, 51, 116.
(14) Kovalenko, A. L.; Serov, Y. V.; Tselinskii, I. V. Zh. Obshch. Khim.
1990, 26, 1240.
Typical Procedure Method b (from 1,5,3-Dioxazepanes)
The appropriate 3-alkyl-1,5,3-dioxazepane (1.57 mmol) was
added to the amide (1.57 mmol) and Sm(NO3)3·6H2O (71 mg,
0.16 mmol) in CHCl3 (5 mL), and the mixture was stirred for 36
h at r.t. CHCl3 (35 mL) was added and the mixture was washed
twice with H2O in a separatory funnel. The organic layer was
separated, dried (Na2SO4), and filtered through a thin layer of
silica gel. Further workup of the filtrate was similar to that
described in Method A.
(15) Khalifeh, M.; Abbasi, R. Beilstein J. Org. Chem. 2015, 11, 1265.
(16) Hugershoff, A. Ber. Dtsch. Chem. Ges. B 1925, 58, 2477.
(17) CCDC 1984058 and 1984059 contain the supplementary crys-
tallographic data for compounds 4a and 4r, respectively. The
data can be obtained free of charge from The Cambridge Crys-
tallographic Data Centre via www.ccdc.cam.ac.uk/getstruc-
tures.
(18) 1,3,5-Triazinanes 4–6; Typical Procedure Method a (Multi-
component Approach)
1-(tert-Butyl)-3,5-bis[(4-chlorophenyl)sulfonyl]-1,3,5-tri-
azinane (4a)
Paraformaldehyde (90 mg, 3.00 mmol; 94.3 mg, 3.14 mmol in
the case of thiourea derivatives) (based of formaldehyde) and
Mg(ClO4)2 (36 mg, 0.157 mmol) were added to a solution the
appropriate amide (1.57 mmol) in CHCl3 (5 mL). The appropri-
ate amine (0.8 mmol; 1.60 mmol in the case of thiourea) was
then added, and the mixture stirred under reflux for 3 h in air or
under argon. (A sealed vessel at 66 °С in oil bath was used in the
case of t-BuNH2 or i-PrNH2. Refluxing for 4.5 h was required for
derivative 6). The mixture was then cooled to r.t. and filtered
through a thin layer of silica gel. In the case of compounds 4u
and 4v, the reaction was quenched with hot acetone (25 mL),
due to the low solubility of corresponding compounds in CHCl3,
and filtered through a fritted glass filter with minimal porosity.
The filtrate was concentrated to approximately 0.5–0.7 mL
under reduced pressure, and Et2O (5 mL) was added. The result-
White powder; yield: 274 mg (71%; Method a); 304 mg (79%;
Method b); mp 185–186 ℃. IR (KBr): 3089, 3067 (CHarom), 2974
(alkyl), 1347, 1161 (SO2N) cm–1 1H NMR (600.2 MHz, CDCl3):
.
 = 7.73 (app. d, J ≈ 8.6 Hz, 4 Harom), 7.49 (app. d, J ≈ 8.6 Hz,
4 Harom), 4.64 (s, 2 H, CH2), 4.16 (s, 4 H, 2CH2), 1.05 (s, 9 H, 3CH3).
13C NMR (150.9 MHz, CDCl3):  = 139.87 (2 Cquat), 137.07
(2 Cquat), 129.57 (4 CHarom), 129.09 (4 CHarom), 62.56 (2 CH2),
60.89 (CH2), 54.23 (Cquat), 27.35 (3 CH3). MS (ESI): m/z = 494.0
[M + H, 37Cl, 37Cl]+, 493.1, [M + H, 35Cl, 37Cl]+, 492.1 [M + H, 35Cl,
35Cl]+. Anal. Calcd for C19H23Cl2N3O4S2: C, 46.34; H, 4.71; N, 8.53;
S, 13.02. Found: C, 46.33; H, 4.59; N, 8.58; S, 12.94.
(19) Kleber, M.; Blaszkewicz, M.; Lucas, S.; Bolt, H. M.; Föllmann, W.
Toxicol. Ind. Health 2002, 18, 425.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F