Multicomponent reactions of amino alcohols with CH2O and dithiols in the synthesis of 1,3,5-dithiazepanes and macroheterocycles

Article abstract of DOI:10.1016/j.tet.2014.03.053

A series of new hydroxyl-substituted 1,3,5-dithiazepanes and N,N′-(2-hydroxyethyl)tetrathiadiazacycloalkanes were synthesized by the multicomponent reactions ₍MCRs) of amino alcohols with formaldehyde and α,ω-dithiols. The MCR with 1,2-dithiol proceeds via a (1+2+1)-cyclocondensation with selective formation of 1,3,5-dithiazepanes. Stereochemistry of the dithiazepane ring was determined by X-ray diffraction. The reaction with higher α,ω-dithiols (1,3-propane-, 1,4-butane-, 1,5-pentane-, 1,6-hexanedithiol and 2-[2-(2-sulfanyletoxy)ethoxy]-1-ethanethiol) yielded OH-substituted macroheterocycles as a result of (2+4+2)- cyclocondensation. The structure of the latter was determined by NMR spectroscopy, MALDI-TOF and electrospray ionization methods. The doubly charged ions like [M+2H]²⁺ are found in the ESI spectra of the macrocycles.

Full text of DOI:10.1016/j.tet.2014.03.053

Tetrahedron 70 (2014) 3502e3509
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Multicomponent reactions of amino alcohols with CH2O and dithiols
in the synthesis of 1,3,5-dithiazepanes and macroheterocycles
,
b
Guzel R. Khabibullina a, Vnira R. Akhmetova a , Marat F. Abdullin ,
Tatiana V. Tyumkina a, Leonard M. Khalilov a, Askhat G. Ibragimova,
Usein M. Dzhemileva
*
a Institute of Petrochemistry and Catalysis, Russian Academy of Sciences, 141 Prospekt Oktyabrya, 450075 Ufa, Russian Federation
b Ufa Scientific Centre of Russian Academy of Sciences, Institute of Organic Chemistry, 71 Prospekt Oktyabrya, 450054 Ufa, Russian Federation
a r t i c l e i n f o
a b s t r a c t
A series of new hydroxyl-substituted 1,3,5-dithiazepanes and N,N0-(2-hydroxyethyl)tetrathiadiazacy-
Article history:
Received 2 December 2013
Received in revised form 5 March 2014
Accepted 17 March 2014
cloalkanes were synthesized by the multicomponent reactions (MCRs) of amino alcohols with formal-
dehyde and
selective formation of 1,3,5-dithiazepanes. Stereochemistry of the dithiazepane ring was determined by
X-ray diffraction. The reaction with higher -dithiols (1,3-propane-, 1,4-butane-, 1,5-pentane-, 1,6-
a
,u
-dithiols. The MCR with 1,2-dithiol proceeds via a (1þ2þ1)-cyclocondensation with
Available online 25 March 2014
a,u
hexanedithiol and 2-[2-(2-sulfanyletoxy)ethoxy]-1-ethanethiol) yielded OH-substituted macrohetero-
cycles as a result of (2þ4þ2)-cyclocondensation. The structure of the latter was determined by NMR
spectroscopy, MALDIeTOF and electrospray ionization methods. The doubly charged ions like [Mþ2H]2þ
are found in the ESI spectra of the macrocycles.
Keywords:
Amino alcohols
Cyclization
Macrocycles
Multicomponent reaction
Sulfur heterocycles
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
We noticed that the MCR of amino alcohols with SO2P and
dithiols proceeds via an intra- or inter-molecular heterocyclization
Sulfur- and nitrogen-containing macrocycles, due to stereo-
chemical features and the presence of heteroatoms in a molecule,
are perspective complexons, extracting agents for heavy metals,
ionophores,1 bioregulators and agents for supramolecular struc-
tures.2 Among existing methods for one-pot synthesis of macro-
heterocycles, an especially attractive route is the cyclo-coupling of
two bifunctional monomers, containing different heteroatoms,
performed by template synthesis3 or catalysis.4 In recent years
macrocyclization strategies have successfully involved MCRs with
participation of bifunctional monomers and aldehydes;5 including
the Ugi reaction in tandem with intermolecular [3þ2]-
cycloaddition as well as two-component multimolecular (2þ2)-
cyclocondensation.6
depending on the length of the hydrocarbon chain connecting two
thiol groups in the initial -dithiols.
a,u
2. Results and discussion
In order to expand the aforementioned research, and further
elaborate an efficient one-pot method for the synthesis of OH-
substituted S,N-hetero and macrocycles, we examined MCR of
amino alcohols (NH2OH, NH2(CH2)mOH, m¼2,4) with formaldehyde
and
a
,
u
-dithiols HS(CH2)nSH (n¼2e6). The used amino alcohols
opens up the possibility for further functionalization of hetero- and
macro-cycles onto the hydroxyl-groups.
We have found that the multicomponent heterocyclization
There are several examples of MCR of amines with CH2O and
could be implemented at 20 ꢀS by admixing
a,u-dithiol to an
a,u
-dithiols to give the 1,5,3-dithiazepanes,7 and one example
aqueous solution of CH2O with subsequent introduction of a cor-
responding amino alcohol into the reaction mixture at ratio of the
starting reagents equal to 1:2:1. Seven- or macrocyclic N,S-con-
taining heterocycles are formed under the indicated conditions,
leading to sulfur- and nitrogen-containing macroheterocycles with
an uracil fragment as a result of intramolecular heterocyclization at
the NH2-group of amines.8
depending on the structure of the initial a,u-dithiols (Scheme 1).
Thus, reaction of 1,2-ethanedithiol 2a with amino alcohols 1aee
and CH2O proceeds as intramolecular heterocyclization with the
formation of 1,5,3-dithiazepan-3-ol (3a), 2-(1,5,3-dithiazepan-3-
* Corresponding author. Tel./fax: þ7 3472 842750; e-mail address: vnirara@
gmail.com (V.R. Akhmetova).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.03.053

G.R. Khabibullina et al. / Tetrahedron 70 (2014) 3502e3509
3503
a two singlets in the regions dO 2.90e3.02 and dO 3.93e4.40, re-
spectively, with an integrated intensity ratio of 1:1. On the basis of
the data for compounds 3aec it is possible to propose a structure
for the compound forming upon both (1þ2þ1) and (2þ4þ2)
cyclocondensation processes, which would display similar sets of
1H and 13C NMR signals. Electron ionization (EI) mass spectrometry
of the heterocycle 3b shows a molecular ion peak [M]þ at m/z 179.
In MALDI TOF spectra for the compounds 3s,d the presence of peaks
[MꢁH]þ is observed at m/z 206.356 and 192.270, respectively,
whereas the same for the compound 3e shows a molecular ion peak
[MþH]þ at m/z 256.247, which proves the formation of (1þ2þ1)
cyclization products. For the compound 3a a molecular ion in the
mass spectra could not be registered, so the structure of 3a was
confirmed by X-ray diffraction (Fig. 1). Therefore taking into ac-
count the above-mentioned facts, the 1,5,3-dithiazepane structure
can be attributed to the heterocycles 3aee.
Scheme 1. Synthesis of 1,3,5-dithiazepanes and tetrathiadiazamacroheterocycles by
MCR of amino alcohols with SO2P and aliphatic -dithiols.
a,u
yl)-1-ethanol (3b) 4-(1,5,3-dithiazepan-3-yl)-1-butanol (3c), 1-
(1,5,3-dithiazepan-3-yl)-2-propanol (3d), and 2-(1,5,3-dithiazepan
-3-yl)-1-phenyl-1-ethanol (3e) with 90e98% yields (Scheme 1).
Thus MCR of amino alcohols 1aee, CH2O and 1,2-fthandithiols
proceeds via an intramolecular type (1þ2þ1)-cyclocondensation.
At the same time, the reaction of amino alcohols 1aec with CH2O
and
a,u-dithiols 2bee, having longer chains, proceeds as in-
termolecular condensation of two molecules of 1aec, four mole-
cules of SO2P and two molecules of 2bee, i.e., in accordance to
three-component multimolecular (2þ4þ2)-cyclocondensation
resulting in the formation of 16-, 18-, 20- and 22-membered tet-
rathiadiazamacrocycloalkanes 4 to 6aed, whose increase in size is
accompanied by yield drop from 86 to 60%. Reaction of alkyl(-
phenyl)substituted amino alcohols 1d,e with CH2O and a,u-dithiols
2bee proceeds with the formation of product mixture, probably
due to steric effects of the substituents.
It should be noted that upon interaction of amino alcohols 1aec
with CH2O and 1,6-hexandithiol 2f, along with tetrathiadiazama-
crocycloalkanes 4e6d, 1,12-dioxa-3,10,14,21-tetrathiacyclodocozan
(7) has also been isolated in an amount of about w12%, wherein
the latter forms as a consequence of intermolecular (2þ4)-cyclo-
condensation of dithiol 2f with CH2O. Based on this fact one may
assume that the reaction proceeds via the formation of in-
termediate dioxatetrathiamacrocycles, which are exposed in the
reaction conditions to an action of amino alcohols with further
formation of tetrathiadiazamacrocycloalkanes. In order to confirm
that assumption, isolated from the reaction mixture 1,12-dioxa-
3,10,14,21-tetrathiacyclodocosane (7) was reacted with 2-
aminoethanol. As a result, the expected macroheterocycle 5d
was obtained, in accordance with (2þ4þ2)-cyclocondensation
(Scheme 2).
Fig. 1. Structure of two independent molecules 3aA and 3aB according to the X-ray
diffraction data.
X-ray diffraction analysis of compound 3a demonstrates that the
1,3,5-dithiazepane fragment has a distorted chair conformation
with atoms S(3) and S(4) transcending the C(8)C(11)C(3)C(6)N(2)
ꢀ
ꢀ
plane by 1.086 A and ꢁ1.112 A, respectively. Lengths of the CeN
ꢀ
bonds in the 1,5,3-diazepane fragment constitute 1.456 A and
1.460 A and correspond to simple CeN bonds. The length of the
NeO bond constitutes 1.467 A, which is much greater than that for
ꢀ
ꢀ
simple NeO bonds. In heterocycle 3a the hydroxyl group at a ni-
trogen atom occupies an axial position (anomeric effect). Such
anomeric interaction of an unshared nitrogen atom N(1) pair (Lp)
with antibonding
s*
orbitals of CeS bonds is characteristic for
CeS
NCH2S systems in 1,3,5-dithiazinans.9
Molecular packing for compound 3a is represented by two di-
astereoisomers 3aA and 3aB (Fig. 1). Bond angle S(3)eS(4)eC(11)
for the first molecule constitutes 100.359ꢀ, whereas bond angle
S(6)eS(3)eC(8) constitutes 101.019ꢀ. In the second molecule 3aB
bond angles S(7)eS(1)eC(10) and C(12)eS(2)eC(9) constitute
101.402ꢀ and 100.079ꢀ, respectively. Inclination angle of the hy-
droxyl group with regards to the ring plane comprises 78.865ꢀ in
the first molecule and 82.252ꢀ in the second. The hydroxyl group is
inclined towards atom S(10) by 1.813ꢀ more than towards atom
C(9) in the first molecule, whereas in the second molecule the
hydroxyl group inclination towards atom S(6) by 4.078ꢀ exceeds
that towards atom S(3). Also, hydroxyl group protons of two
Scheme 2. Synthesis of compound 5d.
The 13C NMR spectra of compounds 3aec show the two char-
acteristic signals of C atoms of methylene groups S(CH2)2S and
NCH2S in the regions dS 35.87e36.01 and
d 59.08e62.71, re-
spectively. The resonance of the magnetically equivalent methylene
protons in 1,3,5-dithiazepane ring appears in the 1H NMR spectra as

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G.R. Khabibullina et al. / Tetrahedron 70 (2014) 3502e3509
neighbouring molecules are oriented in opposite directions. In
equivalence in constitutional parameters of diastereoisomers re-
lates, probably, to a varying degree of crystallinity existing there
between. Crystal structure is therefore stipulated by the existence
of a stacking effect between the molecules.
between the nitrogen atom and a hydroxyl group N/HeO (Fig. 3),
resulting in a five-membered pseudocycle. The value of spinespin
coupling constant (3Jaa¼10.0 Hz) indicated that the tertiary proton
occupies a pseudoaxial location and the phenyl substituent adopts
the equatorial position in the newly formed pseudocycle (Fig. 3).
Indeed, this structure is the lowest conformer on the potential
energy surface (PES) according to our calculations by PBE/3z
(Priroda 6.0).10
The scanning of PES at rotation along the C8eC9 bond showed
that there are three minima corresponding to three stable rotam-
ers. The (þsc)-rotamer of compound 3e with a five-membered
pseudocyclic system corresponds the global minimum (Fig. 4).
By contrast, in the 1O NMR spectrum of compound 5f, the cor-
responding HO(Ph)CHCH2 and NCH2S protons appear as a multiplet
Note that in the 1H NMR spectra of the 1-(1,5,3-dithiazepan-3-
yl)-2-propanol 3d and the 2-(1,5,3-dithiazepan-3-yl)-1-phenyl-
1-ethanol 3e, methylene protons between the N and S atoms are
magnetically nonequivalent, and their signals appears as dou-
blets with geminal constant 2J¼14 Hz (Fig. 4, a), unlike narrow
singlets in the series of compounds 3aes. It demonstrates a shift
of the conformational equilibrium to a ‘chairechair’ conformation
of the dithiazepane fragment in solution at room temperature
(Fig. 2, a).
at dH 4.73 and a broadened singlet at
d 4.06, due to more confor-
mational flexibility (Fig. 2, b). Fig. 5 shows one of the stable con-
formers of 18-membered macrocycle 5f with different
conformational states of two SCH2NCH2S fragments, formed by
(2þ4þ2)-cyclocondensation of the initial reagents.
Fig. 2. The fragments 1O NMR spectra of compounds 3e (a) and 5f (b).
Fig. 5. Conformer of compound 5f (three-dimensional geometric structure visualiza-
tion performed by the program ChemCraft 1.6).11
Typically, in the 1H and 13C NMR spectra (CDCl3, DMSO-d6) of all
macroheterocycles, the signals are shown as singlets due to the
conformational mobility. For macroheterocycles 4 to 6aed analysis
of one- and two-dimensional (COSY, HSQC, HMBC) spectra have
shown that all signals with the expected chemical shifts were ob-
served in the NMR spectra for each compound, and the ratio of
integral intensities thereof in the 1H NMR spectra corresponds to
the suggested structures. Due to the molecules symmetry, in the 1H
and 13C NMR spectra of the 16- and 18-membered macrohetero-
cycles 4e6a,b cyclic hydrogen and carbon atoms are observed as
three resonance signals, and in the spectra of the 20- and 22-
membered macroheterocycles 4e6c,ddas four signals, re-
spectively. Thus, signals for the ring atoms in compound 5b in the
1H NMR spectrum in DMSO-d6 have the following chemical shifts:
1.60, 2.54 and 4.01 ppm; the intensity ratio is 1:1:1. In the HSQC
spectrum these refer to signals dC 29.27, 31.07 and 57.40 ppm, re-
spectively. The hydroxyethyl substituent, whose signals also are
located in the middle region of the spectrum, was identified by
characteristic cross-peaks in the COSY HH spectrum, observed be-
tween vicinal partners (vicinal J SpineSpin Coupling Constants) in
a NeCH2eCH2eOH fragment at dH 2.85, 3.62 ppm and dC 54.11 and
59.24 ppm. HMBC experimental data confirms the presence of
a SH2NCH2SCH2 fragment and the two types of SH2NCH2 frag-
ments in the molecule (Fig. 6).
Fig. 3. Predominant conformer of compound 3e (three-dimensional structure visual-
ization performed by the program ChemCraft 1.6).11
Fig. 4. Newman projection of the rotamers for compound 3e and calculated relative
values of Gibbs energy.
According to a NOE-diff experiment, the observed 1Oe1O-in-
teractions are indicative of a spatial closeness of the methylene
protons NSO2S with both endo- and with exo-cyclic protons.
As a result, methylene hydrogen and carbon atoms, localized in
the macroheterocycles 4e6a,b between atoms N and S, are ob-
served as a singlet in the region dH 3.96e4.18 in the 1H NMR spectra
Moreover, we observed in the 1H NMR spectrum of heterocycle
3e, the doublet of doublets of the HO(Ph)CHCH2 tertiary proton
3
(3Jaa¼10.0 Hz, Jae¼3.2 Hz), which is indicative of the hindered ro-
ꢀ
tation of the N-substituent due to hydrogen bonding (2.144 A)

G.R. Khabibullina et al. / Tetrahedron 70 (2014) 3502e3509
3505
In order to confirm the structure of 1,5,9,13-tetrathia-3,11-
diazacyclohexadecan-3,11-diol (4a) with greater reliability, acyla-
tion thereof by means of Ac2O in pyridine solution has been carried
out, resulting in the formation of 3,11-bis(acetoxy)-1,5,9,13-
tetrathia-3,11-diazacyclohexadecan (8) (Scheme 3).
Fig. 6. The HMBC (plain lines) key correlations and the observed NOEs (dashed lines)
for the macrocycle 5b (protons are omitted for clarity).
and dC 56.82e59.82din the 13C NMR spectra. The other macro-
heterocycles were identified in similar manner.
Scheme 3. Acylation of the compound 4a.
Electrospray ionization (ESI) mass spectrometry indicated the
formation of macroheterocycles 4aed, 5aed and 6aed. Peaks of
varying intensity for molecular ions, formed due to addition of Hþ-,
Naþ-, Kþ-cations and Clꢁ anions, were registered. Except for com-
pound 5a, in all other cases low-intensity (0.5e6%) peaks of
[MþH]þ molecular ions were observed (4bed). Abundant
[MþNa]þ, [MþK]þ molecular ions were registered only in the mass
spectra of the compounds 5bed. Concerning ions [MþCl]ꢁ, ob-
served in the mass spectra of macroheterocycles 4aed, 5a,s and 6s,
it should be noted that those are formed primarily from the com-
pounds having low gas phase acidity.12 Such kinds of compounds
give low-intensity mass spectrum peaks for [MꢁH]ꢁ ions or do not
produce any peaks at all. Clꢁ anions could possibly originate from
the solvent since we have utilized a methanol/chloroform mixture
in order to improve sample solubility. However, the presence of
[MþCl]ꢁ ions could be attributed also to contamination of the ion
source.12 Ions [MþCl]ꢁ produce intense peaks in the mass spectra of
compounds 4aec, 5a, 5c and 6c. In case of compound 4d the peak
has low intensity (16%). In all other cases ions [MþCl]ꢁ could not be
observed.
A characteristic feature of the compounds 4aed, 5bed and
6aed is the formation of doubly charged [Mþ2H]2þ ions under ESI
conditions. At the same time, relative peak intensities for these ions
in the mass spectra of all three groups of compounds differ one
from the other. The most intense peaks for these ions (60e100%)
are registered in the case of 5bed. In the mass spectra of com-
pounds 4aed and 6aed, peak intensities for [Mþ2H]2þ ions are
approximately equal (Fig. 7). However, in the case of 6aed, peak
intensities are varied for ions [Mþ2H]2 from 12% to 31%.
In the 1O and 13S NMR spectra of product 8, along with the
signals for the methylene hydrogen and carbon atoms of the
macrocycle (dO 1.91, 2.76 and 4.19 ppm and dS 29.39, 31.19 and
57.80 ppm), signals at dO 2.04 ppm and at dS 19.55, 168.80 ppm,
corresponding to the acyl substituents, are present. Elemental
analysis corresponds to a molecular formula of S14O26P4S4N2,
while the IR spectrum of compound 8 (film) exhibits intense bands
at 1681 and 1759 cmꢁ1, which are indicative of the presence of
a eC]O group and its enol form in the heterocyclic molecule. ESI
mass spectrometry of product 8 contains a low-intensity peak at m/
z 437, corresponding to the [MþNa]þ ion. The data obtained are
indicative of the formation of macroheterocycle 4a upon conden-
sation of muriatic hydroxylamine with formaldehyde and 1,3-
propanedithiol.
To extend the application scope of the MCR occurring between
primary amine alcohols, CH2O and a,u-dithiols, and to develop an
efficient method to design macroheterocycles of varied structure,
we have studied the reactivity of oxygen-containing dithiols, such
as 3,6-dioxa-1,8-octandithiol 9a and 4,40-dimercaptodiphenyloxide
9b. The reaction of 9a with CH2O and monoethanolamine gave 2-
[19-(2-hydroxyethyl)-1,11,14,24-tetraoxa-4,8,17,21-tetrathia-6,19-
diazacyclohexacozanyl]
(10a)
and
1,6,9,14,19,22-hexaoxa-
3,12,16,25-tetrathiacyclohexacozan (11a) with yields 79 and 9%,
respectively (Scheme 4).
Inten. (x100,000)
222
4.0
3.0
2.0
1.0
0.0
[M+Na]+
[M+2H]2+
S
S
S
S
H
OH
465
N
N
HO
H
[M+K]+
210
481
377
307
356
345
505
497
254
323
286
194
245
395
422
407
274
443
200.0 225.0 250.0 275.0 300.0 325.0 350.0 375.0 400.0 425.0 450.0 475.0
m/z
Fig. 7. ESI spectrum of the macrocycle 5s.
The formation of complexes of macroheterocycles with cations,
anions and O2P is characteristic under conditions of chemical
ionization in ESI mode; also known the is formation of doubly
charged complexes with cyclic oligopeptides.13 It should be noted
that in case of compounds 4aed, the capability thereof to interact
with two cations decreases along with an increase of macrocycle
size. For products 5bed this capability is shown the greatest
extent.14
Cryoscopic determination of the molecular weight of compound
Scheme 4. Synthesis of macroheterocycles by condensation of monoethanolamine
with SO2P and oxygen-containing dithiols.
4b gives a value of 354ꢂ10.15

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G.R. Khabibullina et al. / Tetrahedron 70 (2014) 3502e3509
It is essential to note that under selected conditions, 4,40-
ionizing capillary potential of 4.5 kV and ꢁ3.5 kV, respectively.
The temperature and voltage of the interface capillary under APCI
(ESI) conditions was 230 ꢀC and 5 (25) to ꢁ5 (ꢁ25) V, respectively.
The nebulizer gas (nitrogen) flow rate was 0.5 (1.5) L/min. The
high-frequency lenses (Q-array) voltage was 5 to ꢁ5 V. Sample
solution (direct syringe sample inlet) under APCI (ESI) conditions
was in methanol (acetonitrile), mobile phase was methanol
(acetonitrile/water, 75/25). The mobile phase flow rate was 20
dimercaptodiphenyloxide 9b, comprising a conformationally ‘rigid’
diphenyloxide, reacts with SO2P and monoethanolamine, giving
a macroheterocycle 10b (62%), constructed of three molecules of
the monoethanolamine, six molecules of SO2P and three mole-
cules of dithiols, i.f., in accordance to (3þ6þ3)-cyclocondensation,
as well as 11b (20%), formed by cyclocondensation of dithiol 9b
with SO2P.
Peaks for doubly charged ions were observed in the ESI mass
spectrum of compound 10a, those with maximal intensity corre-
spond to ions [Mþ2H]2þ at m/z 268 and [Mþ2Na]2þ (19%) at m/z
290. Peaks for ions [MþK]þ at m/z 573 (9%), [MþNa]þ at m/z 557
(47%) and [MþCl]ꢁ at m/z 569 (100%) were also observed.
MALDIeTOF spectra of the compounds 10b and 11b contain
peaks at 981.919 and 909.357, which probably correspond to
[NþNa]þ and [NþH2OþKþNa]þ ions. The molecular ion [MþH]þ
for 11a is observed in the MALDIeTOF spectrum at m/z 450.27 and
in the atmospheric pressure chemical ionization (ESI) mass spec-
trum at m/z 450.
(50) mL/min. Mass spectra of the compound 3cee (in chloroform)
and compounds 4a, 5a, 6c, 7, 10b, 11a and 11b (in DMSO) were
recorded on a spectrometer ‘MALDIeTOF Autoflex III’ (Bruker,
Germany) with
a-cyano-4-hydroxycinnamic acid as a matrix.
Samples of the compounds were prepared by the ‘dried droplet
method’ (1:10). The elemental analysis were determined on
a Carlo Erba Model 1106 CHNS analyzer. The content of S in
compounds 3c, 4a, 4b and 5b was determined by the Shenigers
method.15 The melting points were determined on an RNMK 80/
2617 hot stage. Column chromatography was performed on silica
gel. All starting amino alcohols and dithiols are commercially
available.
3. Conclusions
All calculations were carried out using a program PRIRODA-06
developed by Laikov.10,16 Geometric parameter optimization, vi-
brational frequency analysis, and calculation of entropy and ther-
modynamic corrections to the total energy of the compounds were
carried out on the DFT level with the PerdeweBurkeeErnzerhof
In summary, MCR of amine alcohols with formaldehyde and 1,2-
ethanedithiol proceeds with the selective formation of OH-
substituted 1,5,3-dithiazepanes in a (1þ2þ1)-cyclocondensation.
It was shown that the reaction of aliphatic
a
,u
-dithiols (1,3-
(PBE) functional in combination with a 3z
basis set.17 Thermody-
propane-, 1,4-butane-, 1,5-pentane-, 1,6-hexanedithiol and 2-[2-
(2-sulfanyletoxy)ethoxy]-1-ethanethiol) with formaldehyde and
amine alcohols allows gives products of intermolecular three-
component (2þ4þ2)-cyclocondensation with the formation of
novel S,N-macroheterocycles. Upon interaction of 4,40-dimercap-
todiphenyloxide with formaldehyde and monoethanolamine,
a product of multimolecular (3þ6þ3)-cyclocondensation is formed.
Thus, a novel, simple and efficient procedure for the preparation of
S,N-macrocycles was demonstrated.
namic parameters and activation energies were determined at
298 K. The minima were confirmed through the calculation of the
force constant (Hessian) matrix and the analysis of the resulting
frequencies. Visualization of quantum chemical data was carried
out with the programs ChemCraft.18
4.2. Preparation of 1,5,3-dithiazepanes 3aee and macro-
heterocycles 4aed, 5aef, 6aed and 10a,b
Dithiol 2aee or 9a,b (1 mmol) was mixed with a 37% solution of
formaldehyde (0.15 mL, 2 mmol), and ethanol (3 mL) at room
temperature over a period of 20 min. A solution of 0.07 g (1 mmol)
of hydroxylamine hydrochloride 1a in water (3 mL) was added to
the reaction mixture and the mixture was stirred for 3e4 h at room
temperature. The product obtained from hydroxylamine hydro-
chloride was neutralized with a 10% solution of NaOH. White pre-
cipitate that formed was filtered off and washed with H2O
(3*15 mL) then dried. The corresponding amino alcohol 1bee
(1 mmol) in CHCl3 (15 mL) was added dropwise to the reaction
mixture and the mixture was stirred for 3e4 h at room tempera-
ture. The water was removed and the solution was dried with an-
hydrous MgSO4. Solvent was removed, and the crude product was
separated by column chromatography to give a pure sample 3aee,
5aef and 6aed, which was analyzed by NMR spectroscopy. The
precipitate that formed from dithiol 2bee and hydroxylamine hy-
drochloride 1a was filtered off, then was washed with water and
dried. The product was washed with CHCl3 and dried. The details of
further purification performed for the new compounds are de-
scribed in Product Data.
4. Experimental section
4.1. General
All reactions were performed at room temperature under air
atmosphere in a round bottom flask equipped with magnetic stir
bar. New compounds were characterized by 1H (100.62 MHz), 13
C
(400.13 MHz), 1He1HCOSY, HSQC, HMBC, IR, GCeMS, LS-MS (APCI,
ESI), MALDIeTOF, and elemental analysis. 1H and 13C NMR spectra
were recorded using a Bruker Avance 400 MHz NMR spectrometer
and referenced to 7.28 ppm and 77.10 ppm for chloroform, or to
2.50 ppm and 39.50 ppm for DMSO-d6. IR spectra were recorded
as thin films or from samples dispersed in mineral oil with
a Bruker Vertex 70 v spectrometer. Electron ionization (70 eV)
spectrum of compound 3b was obtained on a Finnigan 4021 gas
chromatography-mass spectrometer (HP-5 glass capillary column,
50,000ꢃ0.25 mm; carrier gas helium; oven temperature pro-
gramming from 50 to 300 ꢀC at a rate of 5 ꢀ/min; injector tem-
perature 280 ꢀC; ion source temperature 250 ꢀC). Electron
ionization (70 eV) spectrum of compound 3see was obtained on
a GCMS-QP2010 Ultra (Shimadzu) gas chromatography-mass
spectrometer (Supelco 5 ms capillary column, 60,000ꢃ0.25; car-
rier gas helium; oven temperature programming from 40 ꢀS to
150 ꢀS at a rate of 10 ꢀ/min; injector temperature 260 ꢀC; ion
source temperature 200 ꢀC). Atmospheric pressure chemical
ionization (APCI) mass spectrum of the compound 5a and elec-
trospray ionization (ESI) mass spectra of the compounds 4aed,
4.2.1. 1,5,3-Dithiazepan-3-ol (3a). White solid, yield 0.15 g (98%), Rf
0.74 (hexane/ethyl acetate/chloroform, 1:4:1); mp 94e95 ꢀS
(94e95 ꢀS)7a dH (400 MHz, CDCl3, 25 ꢀC) 3.02 (4H, s, SCH2), 4.40
;
(4H, s, NCH2), 6.67 (1H, br s, OH); dC (100 MHz, CDCl3) 36.0 (SCH2),
62.7 (NCH2).
4.2.2. 8-(1,5,3-Dithiazepan-3-yl)-9-ethanol (3b). Colourless oil,
yield 0.33 g (93%), Rf 0.67 (SH2Sl2/1,4-dioxane, 10:1); vmax (liquid
5bef, 6aed, 7, 8, 10a,b were obtained on
spectrometer LCMS-2010EV (Shimadzu) in positive and negative
ions mode at the corona discharge needle ionizing electrode and
a HPLC mass-
film) 677 (CeS), 1051, 1273 (CeN), 1426, 2911, 3400 (OH) cmꢁ1
.
dH
(400 MHz, CDCl3, 25 ꢀC) 2.70 (2H, t, J 5.2, NCH2CH2), 2.90 (4H, s,

G.R. Khabibullina et al. / Tetrahedron 70 (2014) 3502e3509
3507
SCH2CH2), 3.49 (2O, t, J 5.2, HOCH2CH2), 4.05 (1H, s, HO), 3.93 (4O, s,
NCH2S); dC (100 MHz, CDCl3) 35.9 (SCH2CH2), 53.1 (NCH2CH2), 58.7
(HOCH2CH2), 59.4 (NCH2S); m/z (%): 179 (30) [M]þ, 148 (30)
[MꢁCH2OH]þ,105 (15) [SCH2CH2SCH2]þ, 42 (100) [CHCH2N]þ. Anal.
Calcd for C6H13NOS2: C, 40.19; H, 7.31; N, 7.81; S, 35.77. Found: C,
40.15; H, 7.55; N, 7.60; S, 35.48.
[Mþ2H]2þ; Ncr¼354ꢂ10.19 Anal. Calcd for S12O26N2O2S4: S, 40.19;
O, 7.31; N, 7.81; S, 35.77. Found: S, 40.26; O, 7.11; N, 7.85; S, 35.85.
4.2.8. 1,5,11,15-Tetrathia-3,13-diazacycloicozane-3,13-diol
(4c). White solid, yield (0.15 g) 76%, mp 111e112 ꢀS. vmax (Nujol)
666 (eCeSe), 1179 cmꢁ1 dH (400 MHz, DMSO-d6, 25 ꢀC) 1.40 (4H,
;
br s, S(CH2)2CH2), 1.54 (8H, br s, SCH2CH2), 2.63 (8O, br s, SCH2CH2),
4.07 (8H, s, NCH2S); dC (100 MHz, DMSO-d6) 27.9 (S(CH2)2CH2), 29.4
(SCH2CH2), 32.4 (SCH2CH2), 59.7 (NCH2S). ESI (70 eV); m/z (%): 421
(100) [MþCl]ꢁ, 387 (6) [MþH]þ, 194 (6) [Mþ2H]2þ. Anal. Calcd for
4.2.3. 4-(1,5,3-Dithiazepan-3-yl)-1-butanol (3c). Colourless oil,
yield 0.37 g (96%), Rf 0.80 (hexane/ethyl acetate/chloroform,
1:4:1); vmax (liquid film) 675 (CeS), 1067, 1273 (CeN), 1427, 2934,
3367 (OH) cmꢁ1
;
dH (400 MHz, CDCl3, 25 ꢀC) 1.50e1.58 (4H, m,
S14O30N2O2S4: S, 43.49; O, 7.82; N, 7.24; S, 33.17. Found: S, 43.52;
NCH2CH2CH2); 2.64 (2H, t, J 6.6, NCH2CH2); 2.98 (4O, s, SCH2CH2);
3.57 (2O, t, J 5.8, HOCH2CH2); 4.12 (4O, s, NCH2S); dC (100 MHz,
CDCl3) 23.9 (NCH2CH2); 30.8 (HOCH2CH2); 36.0 (SCH2CH2); 51.2
(NCH2CH2); 59.1 (NCH2S); 62.4 (HOCH2CH2); m/z (%): 207 (10)
[M]þ, 114 (100) [MꢁSCH2CH2SH]þ; MALDI TOF, m/z: 206.356
[NꢁH]þ. Anal. Calcd for S8O17NOS2: S, 46.34; O, 8.26; N, 6.75; S,
30.93. Found: S, 46.56; O, 8.40; N, 6.90; S, 31.01.
O, 7.71; N, 7.25; S, 33.53.
4.2.9. 1,5,12,16-Tetrathia-3,14-diazacyclodocozane-3,14-diol
(4d). White solid, yield (0.17 g) 83%, mp 90e93 ꢀS. vmax (Nujol) 722
(CeS), 1077 (CeN) cmꢁ1 dH (400 MHz, DMSO-d6, 25 ꢀC) 1.33 (8H, br
;
s, S(CH2)2CH2), 1.53 (8H, br s, SCH2CH2), 2.61 (8O, t, 3J 7.2, SCH2CH2),
4.02 (8H, s, NCH2S); dC (100 MHz, DMSO-d6) 28.32 (S(CH2)2CH2),
29.8 (SCH2CH2), 32.3 (SCH2CH2), 59.8 (NCH2S). ESI (70 eV); m/z (%):
449 (16) [MþCl]ꢁ, 453 (8) [MþK]þ, 455 (6); [MþNa]þ, 208 (3)
[Mþ2H]2þ. Anal. Calcd for S16O34N2O2S4: S, 46.34; O, 8.26; N, 6.75;
S, 30.93. Found: S, 46.26; O, 8.11; N, 6.62; S, 30.92.
4.2.4. 1-(1,5,3-Dithiazepan-3-yl)-2-propanol (3d). Colourless oil,
yield 0.17 g (85%), Rf 0.70 (ethyl acetate/hexane/chloroform, 4:2:1).
vmax (liquid film) 678 (CeS), 1066, 1273 (CeN), 1449, 2911, 2966,
3421 (OH) cmꢁ1
;
dH (400 MHz, CDCl3, 25 ꢀC) 1.11 (3O, d, J 6.4, Me);
2.27 (1H, dd, 2J 13.2, Jaa 10.0, NSOaObCH); 2.89 (1H, dd, 2J 13.2,
3Jae 2.8, NSOaObCH); 2.94e3.05 (4H, m, SCH2CH2); 3.77 (1H, ddd,
3J 10.0, 3J 6.8, 3J 2.8, CHMe); 4.09 (2H, d, 2J 14.0, NCHaS); 4.15 (2H,
d, 2J 14.0, NCHbS); dC (100 MHz, CDCl3) 21.2 (Me); 37.0 (SCH2CH2);
60.21 (CHMe); 60.8 (NCH2S); 64.4 (NCH2CH). m/z (%): 193 (36)
[M]þ, 148 (71) [MꢁCH(CH3)OH]þ, 100 (100) [Mꢁ(CH2S)2]þ, 42
(100) [CHCH2N]þ. MALDI TOF, m/z: 192.270 [NꢁH]þ. GCeMS
(70 eV); Anal. Calcd for C7H15NOS2: C, 43.49; H, 7.82; N, 7.24; S,
33.17. Found: C, 43.56; H, 7.94; N, 7.16; S, 33.09.
4.2.10. 2-[11-(2-Hydroxyethyl)-1,5,9,13-tetrathia-3,11-
diazacyclohexadecanyl]-1-ethanol (5a). Colourless oil, yield (0.16 g)
82%, Rf 0.72 (SH2Sl2/EtOH, 5:1). vmax (liquid film) 666 (eCeSe),
1096, 1456, 2927 (eOH); dH (400 MHz, CDCl3, 25 ꢀC) 1.77 (4O, m,
SCH2CH2), 2.57 (8O, m, SCH2CH2), 2.76 (4O, t, 3J 5.4, HOCH2), 3.54
(4O, t, 3J 5.4, NCH2CH2), 3.96 (8O, s, NCH2S); dC (100 MHz, CDCl3)
29.9 (SCH2CH2), 30.3 (SCH2CH2), 53.6 (HOCH2); 56.9 (NCH2S), 59.0
(NCH2CH2); dH (400 MHz, DMSO-d6, 25 ꢀC) 1.60 (4O, m, SCH2CH2),
2.54 (8O, m, SCH2CH2), 2.70 (4O, t, 3J 5.4, HOCH2), 3.47 (4O, t, 3J 5.4,
NCH2CH2), 4.01 (8O, s, CH2, NCH2S); dC (100 MHz, DMSO-d6) 29.3
(SCH2CH2), 31.1 (SCH2CH2), 53.8 (HOCH2), 57.4 (NCH2S), 59.8
(NCH2CH2). MALDI TOF, m/z: 386.414 [N]þ. APCI (70 eV); m/z (%):
421 (100) [MþSl]ꢁ, 387 (41) [MþH]þ. Anal. Calcd for
3
4. 2. 5. 2-(1, 5, 3-Dithiazepan-3-yl)-1-phenyl-1-ethanol
(3e). Colourless oil, yield 0.24 g (92%), Rf 0.65 (ethyl acetate/hex-
ane/chloroform, 4:2:1). vmax (liquid film) 701 (CeS), 1097, 1273,
1427, 1665, 2912, 2966, 3436 (OH) cmꢁ1
;
dH (400 MHz, CDCl3,
S14O30N2P2S4: S, 43.49; O, 7.82; N, 7.24; S, 33.17. Found: S, 43.23;
O, 7.81; N, 7.29; S, 33.50.
3
25 ꢀC) 2.56 (1H, dd, 2J 13.4, Jaa 9.8, NCHaHbCH), 2.96 (4H, s,
3
SCH2CH2), 3.10 (1H, dd, 2J 13.4, Jae 3.4, NCHaHbCH), 4.16 (2O, d, 2J
14.0, NCHaHbS), 4.24 (2O, d, 2J 14.0, NCHaHbS), 4.71 (1H, dd, 3Ja
10.0, 3Je 3.2, HOCHPh), 7.25e7.35 (5O, m, Ph); dC (100 MHz, CDCl3)
36.9 (SCH2CH2), 60.6 (NCH2CH), 60.7 (NCH2S), 70.9 (HOCHPh),
127.0, 129.0, 129.5, 142.9 (CHPh); m/z (%): 163 [HOCH(Ph)
CH2N(CH2)2], 148 [CH2N(CH2SCH2)2], 134 [N(CH2SCH2)2]; no mo-
lecular ion peak was observed. MALDI TOF, m/z: 256.247 [NþH]þ;
ESI (70 eV); m/z (%): 256 (100) [MþH]þ. Anal. Calcd for
4.2.11. 2-[12-(2-Hydroxyethyl)-1,5,1,14-tetrathia-3,12-
diazacyclopctadecanyl]-1-ethanol (5b). Colourless oil, yield (0.16 g)
77%, Rf 0.65 (SH2Sl2/EtOH, 5:1). vmax (liquid film) 662 (eCeSe),
1050, 1436, 2925; dH (400 MHz, CDCl3, 25 ꢀC) 1.67 (8O, s, SCH2CH2),
2.66 (8O, s, SCH2CH2), 2.85 (4O, t, 3J 5.4, HOCH2), 3.62 (4O, t, 3J 5.4,
NCH2CH2), 4.03 (8O, s, NCH2S); dC (100 MHz, CDCl3) 29.1 (SCH2CH2),
31.6 (SCH2CH2), 54.1 (HOCH2), 57.1 (NCH2S), 59.2 (NCH2CH2); ESI
(70 eV); m/z (%): 437 (22) [MþNa]þ, 208 (60) [Mþ2H]2þ. Anal. Calcd
for S16O34N2P2S4: S, 46.34; O, 8.26; N, 6.75; S, 30.93. Found: S,
46.40; O, 8.60; N, 7.00; S, 30.86.
C
12H17NOS2: C, 56.43; H, 6.71; N, 5.48. Found: C, 56.47; H, 6.68; N,
5.54.
4.2.6. 1,5,9,13-Tetrathia-3,11-diazacyclohexadecane-3,11-diol
(4a). White solid, yield (0.16 g) 96%, mp 140e142 ꢀS. vmax (Nujol)
4.2.12. 2-[13-(2-Hydroxyethyl)-1,5,11,15-tetrathia-3,13-
diazacycloicosanyl]-1-ethanol (5c). Colourless oil, yield (0.15 g) 68%,
Rf 0.27 (C6H14/CH3CO2Et/EtOH, 1:4:0.5). vmax (liquid film) 665
722 (CeS), 1246, 3200 cmꢁ1 dH (400 MHz, DMSO-d6, 25 ꢀC) 1.83
;
(4H; p, 3J 7.2, CH2CH2CH2), 2.75 (8O, t, 3J 7.2, SCH2CH2), 4.18 (8H, s,
NCH2S); dC (100 MHz, DMSO-d6) 29.8 (CH2CH2CH2), 31.5 (SCH2CH2),
59.8 (NCH2S). MALDI TOF, m/z: 329.384 [NꢁH]þ (calcd for
(eCeSe), 1049, 1435, 3436 cmꢁ1 dH (400 MHz, CDCl3, 25 ꢀC) 1.46
;
(4O, m, S(CH2)2CH2); 1.58 (8O, m, SCH2CH2); 2.54 (8O, t, SCH2CH2);
2.85 (4O, t, 3J 5.4, HOCH2); 3.62 (4O, t, 3J 5.4, NCH2CH2); 4.02 (8O, s,
NCH2S); dC (100 MHz, CDCl3) 28.1 (S(CH2)2CH2); 29.6 (SCH2CH2);
31.9 (SCH2CH2); 54.1 (HOCH2); 57.2 (NCH2S); 59.2 (NCH2CH2); ESI
(70 eV); m/z (%): 477 (100) [MþCl]ꢁ, 481 (23) [MþK]þ, 465 (73)
[MþNa]þ, 222 (100) [Mþ2H]2þ. Anal. Calcd for S18O38N2P2S4: S,
48.83; O, 8.65; N, 6.33; S, 28.97. Found: S, 48.84; O, 8.56; N, 6.35; S,
29.02.
S
10O21N2O2S4, 329.550). ESI, (70 eV); m/z (%): 367 (51%) [MþCl]ꢁ;
365 (100) [M]þ, 166 (37) [Mþ2H]2þ. Anal. Calcd for S10O22N2O2S4:
S, 36.33; O, 6.71; N, 8.47; S, 38.80. Found: S, 36.36; O, 6.75; N, 8.54;
S, 38.73.
4.2.7. 1,5,10,14-Tetrathia-3,12-diazacyclooctadecane-3,12-diol
(4b). White solid, yield (0.10 g) 67%, mp 103e104 ꢀS. vmax (Nujol)
724 (CeS), 1110, 3326 cmꢁ1 dH (400 MHz, DMSO-d6, 25 ꢀC) 1.62
;
(8H, br s, SCH2CH2), 2.63 (8O, br s, SCH2CH2), 4.02 (8H, s, NCH2S); dC
(100 MHz, DMSO-d6) 29.0 (SCH2CH2), 31.9 (SCH2CH2), 59.8 (NCH2S).
ESI (70 eV); m/z (%): 393 (71) [MþCl]ꢁ, 359 (5) [MþH]þ; 180 (20)
4.2.13. 2-[14-(2-Hydroxyethyl)-1,5,12,16-tetrathia-3,14-
diazacyclodocosanyl]-1-ethanol (5d). Colourless oil, yield (0.14 g)
60%, Rf 0.44 (C6H14/CH3CO2Et/EtOH, 3:3:1). vmax (liquid film) 665

3508
G.R. Khabibullina et al. / Tetrahedron 70 (2014) 3502e3509
(eCeSe), 1040, 1455, 3401 cmꢁ1 dH (400 MHz, CDCl3, 25 ꢀC) 1.36
(8O, br s, S(CH2)2CH2); 1.56 (8O, m, SCH2CH2); 2.53 (8O, t,
SCH2CH2); 2.84 (4O, t, 3J 5.4, HOCH2); 3.61 (4O, t, 3J 5.4, NCH2CH2);
4.01 (8O, s, NCH2S); dC (100 MHz, CDCl3) 28.4 (S(CH2)2CH2); 29.9
(SCH2CH2); 32.0 (SCH2CH2); 54.1 (HOCH2); 57.2 (NCH2S); 59.1
(NCH2CH2); ESI (70 eV); m/z (%): 509 (36) [MþK]þ, 493 (59)
[MþNa]þ, 236 (100) [Mþ2H]2þ. Anal. Calcd for S20O42N2P2S4: S,
51.02; O, 8.99; N, 5.95; S, 27.24. Found: S, 51.05; O, 9.01; N, 6.03; S,
27.19.
(70 eV); m/z (%): 533 (46) [MþSl]ꢁ, 497 (8) [MꢁH]ꢁ, 250 (20)
[Mþ2H]2þ. Anal. Calcd for S22O46N2P2S4: S, 52.97; O, 9.29; N,
5.62; S, 25.71. Found: S, 53.02; O, 9.31; N, 5.56; S, 25.78.
4.2.19. 2-[14-(2-Hydroxyethyl)-1,5,12,16-tetrathia-3,14-
diazacyclodocosanyl]-1-ethanol (6d). Colourless oil, yield (0.22 g)
83%; vmax (liquid film) 650 (CeS), 1061, 1266, 1435, 3367 cmꢁ1
; dH
(400 MHz, CDCl3, 25 ꢀC) 1.34 (8H, br s, S(CH2)2CH2), 1.53 (16H, br s,
SCH2CH2 and NCH2(CH2)2CH2OH), 2.50 (8H, t, 3J 7.6, SCH2CH2), 2.64
(4O, s, 3J 5.4, NCH2CH2), 3.56 (4H, t, HOCH2), 3.95 (8H, s, NCH2S); dC
(100 MHz, CDCl3) 24.5 (S(CH2)2CH2), 28.4 (NCH2CH2), 30.0
(SCH2CH2), 30.6 (HOCH2CH2), 32.0 (SCH2CH2), 51.6 (NCH2CH2), 56.7
(NCH2S), 62.4 (HOCH2); ESI (70 eV); m/z (%): 675 (33)
4.2.14. 1-[11-(2-Hydroxypropyl)-1,5,9,13-tetrathia-3,11-
diazacyclohexadecanyl]-2-propanol (5e). Colourless oil, yield
(0.13 g) 62%, Rf 0.65 (ethyl acetate/hexane/chloroform, 4:2:1);
vmax (liquid film) 751 (CeS), 1059, 2926, 3426 cmꢁ1
;
dH (400 MHz,
[Mþ(CH2)6(SH)2eH]ꢁ, 264 (14) [Mþ2H]2þ
. Anal. Calcd for
S24O50N2P2S4: S, 54.70; O, 9.56; N, 5.32; S, 24.37. Found: S, 54.68;
CDCl3, 25 ꢀC) 1.00 (6O, d, J 6, Me), 1.62 (4H, m, CH2CH2CH2), 2.28
(2O, m, NCHaCH), 2.42 (8O, m, SCH2CH2), 2.50 (2H, m, NCHbCH),
3.60 (2O, m, CH2CH(OH)CH3), 3.81 (8O, br s, NCH2S); dC (100 MHz,
CDCl3) 20.5 (Me), 30.1 (CH2CH2CH2), 30.6 (SCH2CH2), 57.3 (NCH2S),
59.8 (NCH2CH), 64.0 (CH2CH(OH)CH3); ESI (70 eV); m/z (%): 208
(50) [Mþ2H]2þ. Anal. Calcd for S16O34N2P2S4: S, 46.34; O, 8.26;
N, 6.75; S, 30.93. Found: S, 46.40; O, 8.22; N, 6.71; S, 30.87.
O, 9.57; N, 5.36; S, 24.42.
4. 2. 20. 1,12-Dioxa-3,10,14, 21-tetrathiacyclodocosane
(7). Compound 7 was obtained together with 5d and isolated by
column chromatography with (C6H14/CH3CO2Et/EtOH, 3:3:1) as the
eluent. Colourless oil, yield (0.02 g) 12%, Rf 0.25; vmax (liquid film)
655 (eSeCe), 1112, 1445 cmꢁ1 dH (400 MHz, CDCl3, 25 ꢀC) 1.43
;
4.2.15. 2-[11-(2-Hydroxy-2-phenylethyl)-1,5,9,13-tetrathia-3,11-
diazacyclohexadecanyl]-1-phenyl-1-ethanol (5f). Colourless oil,
yield (0.18 g) 68%, Rf 0.62 (Cl4/2-propanols, 1:1); vmax (liquid film)
(8O, m, S(CH2)2CH2), 1.66 (8O, m, SCH2CH2), 2.70 (8O, t, 3J 7.6,
SCH2CH2), 4.72 (8O, s, OCH2S); dC (100 MHz, CDCl3) 28.3
(S(CH2)2CH2), 29.7 (SCH2CH2), 30.6 (SCH2CH2), 66.0 (OCH2S);
MALDI TOF, m/z: 384.204 [N]þ. Anal. Calcd for S16O32O2S4: S,
49.96; O, 8.38; S, 33.34. Found: S, 50.12; O, 8.35; S, 32.95.
701 (CeS), 1060, 1248, 1660, 3434 cmꢁ1 dH (400 MHz, CDCl3, 25 ꢀC)
;
1.85 (4O, m, CH2CH2CH2), 2.63 (8O, br s, SCH2CH2), 2.78 (2O, m,
NCHaCH), 2.97 (2H, m, NCHbCH), 4.06 (8H, br s, NCH2S), 4.73 (2O, m,
CH2CH(OH)Ph), 7.30-7.38 (10O, m, CHPh), dC (100 MHz, CDCl3) 23.8
(CH2CH2CH2), 31.2 (SCH2CH2), 57.8 (NCH2S), 60.7 (NCH2CH), 71.0
(CH2CH(OH)Ph), 126.4 (CHPh), 128.1 (CHPh), 128.8 (CHPh), 142.2
(CHPh); ESI (70 eV); m/z (%): 270 (100) [Mþ2H]2þ. Anal. Calcd for
4 . 2 . 21. 3 ,11 - B i s ( a c e t yl o x y ) - 1, 5 , 9 ,13 - t e t ra t h i a - 3 ,11 -
diazacyclohexadecane (8). A mixture of compound 4a (0.1 g,
0.3 mmol) in pyridine (2 mL) and Ac2O (1 mL) was stirred at
room temperature during 24 h, then CH2Cl2 (5 mL) was added.
The solution was washed by NH4Cl (10%) (3*5 mL) and with
water, then dried with Na2CO3. The solution was evaporated.
Brown oil, yield (0.09 g) 73%, vmax (liquid film) 650 (CeS), 1196,
S
26O38N2P2S4: S, 57.95; O, 7.11; N, 5.20; S, 23.80. Found: S, 57.89;
O, 7.16; N, 5.26; S, 23.74.
4.2.16. 4-[11-(4-Hydroxybutyl)-1,5,9,13-tetrathia-3,11-
diazacyclohexadecanyl]-1-butanol (6a). Colourless crystal, yield
(0.14 g) 62%, mp 238e240 ꢀS; vmax (liquid film) 665 (CeS), 1062,
1681 (eC]O) cmꢁ1 dH (400 MHz, CDCl3, 25 ꢀC) 1.91 (4H, t, 3J 6.8,
;
SCH2CH2), 2.04 (6H, s, Me), 2.76 (8O, t, 3J 6.8, SCH2CH2), 4.19 (8H,
s, NCH2S); dC (100 MHz, CDCl3) 19.6 (Me), 29.4 (SCH2CH2), 31.2
(SCH2CH2), 57.8 (NCH2S), 168.8 (COMe). Anal. Calcd for
1244, 1434, 3367 cmꢁ1 dH (400 MHz, CDCl3, 25 ꢀC) 1.53 (8H, br s,
;
NCH2(CH2)2CH2OH), 1.81 (4H, pent, J 7.2, SCH2CH2), 2.57e2.65
(12O, m, SCH2CH2 and NCH2CH2), 3.57 (4H, s, HOCH2CH2), 3.97 (8H,
s, NCH2S); dC (100 MHz, CDCl3) 24.0, 30.5, 51.5, 62.3 (N(CH2)4OH),
30.4 (SCH2CH2), 30.9 (SCH2CH2), 56.8 (NCH2S); ESI (70 eV); m/z
(%):222 (31) [Mþ2H]2þ. Anal. Calcd for S18O38N2P2S4: S, 48.83; O,
8.65; N, 6.33; S, 28.97. Found: S, 48.85; O, 8.71; N, 6.36; S, 28.99.
S14O26N2O4S4: S, 40.55; O, 6.32; N, 6.76; S, 30.93. Found: S,
40.71; O, 6.26; N, 6.69; S, 30.90.
4.2.22. 2-[19-(2-Hydroxyethyl)-1,11,14,24-tetraoxa-4,8,17,21-
tetrathia-6,19-diazacyclohexacosanyl]-1-ethanol (10a). Colourless
oil, yield (0.21 g) 79%, Rf 0.68 (CH2Cl2/hexane/CH3CO2Et, 3:3:1);
vmax (liquid film) 754 (eCeSeCe), 1040, 1110, 3444 cmꢁ1
; dH
4.2.17. 4-[12-(4-Hydroxybutyl)-1,5,10,14-tetrathia-3,12-
(400 MHz, CDCl3, 25 ꢀC) 2.71 (8O, s, SCH2CH2), 2.83 (4O, t,
NCH2CH2), 3.57 (8O, s, NCH2S), 3.59 (8O, t, OCH2CH2O), 3.62 (4O, t,
CH2, HOCH2), 4.08 (8O, s, OCH2CH2S); dC (100 MHz, CDCl3) 31.0
(SCH2CH2), 54.0 (NCH2CH2), 57.5 (NCH2S), 59.3 (HOCH2), 70.2
(OCH2CH2S), 71.5 (OCH2CH2O); ESI (70 eV); m/z (%): 573 (9)
[MþK]þ, 557 (47) [MþNa]þ, 290 (19) [Mþ2Na]2þ, 268 (100)
[Mþ2H]2þ, 569 (100) [MþSl]ꢁ. Anal. Calcd for S20O42N2P6S4: S,
44.91; O, 7.92; N, 5.24; S, 23.98. Found: S, 44.93; O, 7.85; N, 5.19; S,
24.04.
diazacyclooctadecanyl]-1-butanol (6b). Colourless oil, yield (0.20 g)
86%; vmax (liquid film) 649 (CeS), 1076, 1269, 1455, 3401 cmꢁ1
; dH
(400 MHz, CDCl3, 25 ꢀC) 1.54 (8H, br s, NCH2(CH2)2CH2OH), 1.65
(8H, br s, SCH2CH2), 2.53 (8O, br s, SCH2CH2), 2.63 (4O, s, NCH2CH2),
3.58 (4H, s, HOCH2CH2), 3.97 (8H, s, NCH2S); dC (100 MHz, CDCl3)
24.1 (NCH2CH2), 29.2 (SCH2CH2), 30.6 (HOCH2CH2), 31.6 (SCH2CH2),
51.6 (NCH2CH2), 56.7 (NCH2S), 62.3 (CH2OH); ESI (70 eV); m/z (%):
236 (12) [Mþ2H]2þ. Anal. Calcd for S20O42N2P2S4: S, 51.02; O,
8.99; N, 5.95; S, 27.24. Found: S, 50.98; O, 8.84; N, 5.96; S, 27.34.
4.2.23. 2-[18-(2-Hydroxyethyl)-11,25-dioxa-2,6,16,20-tetrathia-4,18-
diazapentacyclo[24.2.2.27 ,10.212,15 .221, 24 ]hexatryaconta-
1(28),7,9,12,14,21,23,26,29,31,33,35-dodecaen-4-yl]-1-ethanol
(10b). Colourless crystal, yield (0.19 g) 62%, mp 94e95 ꢀS. Rf
0.40 (CH2Cl2/hexane/CH3CO2Et, 3:3:1:1); vmax (Nujol) 750 (CeS),
4.2.18. 4-[13-(4-Hydroxybutyl)-1,5,11,15-tetrathia-3,13-
diazacycloicosanyl]-1-butanol (6c). Colourless oil, yield (0.17 g) 67%,
vmax (liquid film) 756 (CeS), 1060, 1216, 3400 cmꢁ1
; dH (400 MHz,
CDCl3, 25 ꢀC) 1.45 (4H, br s, S(CH2)2CH2), 1.56 (16H, br s, SCH2CH2
and NCH2(CH2)2CH2OH), 2.52 (8H, br s, SCH2CH2), 2.63 (4O, s,
NCH2(CH2)2CH2OH), 3.58 (4H, s, HOCH2), 3.96 (8H, s, NCH2S); dC
(100 MHz, CDCl3) 24.1 (S(CH2)2CH2), 28.1 (NCH2CH2), 29.7
(SCH2CH2), 30.6 (HOCH2CH2), 31.9 (SCH2CH2), 51.6 (NCH2CH2), 56.7
(NCH2S), 62.4 (HOCH2); MALDI TOF, m/z: 250.112 [N/2þO]þ; ESI
1150,1470 cmꢁ1 dH (400 MHz, CDCl3, 25 ꢀC) 2.89 (6H, m, NCH2CH2),
;
3.46 (6O, m, CH2CH2OH), 4.41 (12H, s, NCH2S), 4.99 (3H, br s, OH),
6.95 (12H, d, 3J 6.8, Ph), 7.43 (12H, d, 3J 6.8, Ph); dC (100 MHz, CDCl3)
54.1 (NCH2C), 58.7 (CH2SH2OH), 61.8 (NSH2S), 119.7, 131.8, 134.5,
156.6 (Ph); MALDI TOF, m/z: 981.919 [NþNa]þ. Anal. Calcd for

G.R. Khabibullina et al. / Tetrahedron 70 (2014) 3502e3509
3509
C48H51N3S6O6: C 60.16, H 5.36, N 4.38, S 20.08. Found: C 60.17, H
Supplementary data
5.29, N 4.40, S 20.11.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.03.053.
4.2.24. 1,6,9,14,19,22-Hexaoxa-3,12,16,25-tetrathiacyclohexacosane
(11a). Colourless oil, yield (0.02 g) 9%, Rf 0.43 (CH2Cl2/hexane/
CH3CO2Et/EtOH, 3:3:1:1). vmax (liquid film) 649 (eSeCe), 1109,
References and notes
1455 cmꢁ1 dH (400 MHz, CDCl3, 25 ꢀC) 2.69 (8O, m, SCH2CH2O),
;
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isova, N. E.; Reshetova, M. D.; Ustynyuk, Y. A. Russ. Chem. Rev. 2007, 76,
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pp 135e182.
3.55 (16O, m, SCH2CH2 and O(CH2)2O), 4.58 (8O, br s, OCH2S); dC
(100 MHz, CDCl3) 32.5 (SCH2CH2), 67.2 (SCH2CH2), 69.7 (O(CH2)2O),
71.8 (OCH2S); MALDI TOF, m/z: 450.27. ESI (70 eV); m/z (%): 484 (32)
[MþSl]ꢁ, 450 (54) [MþH]þ, 448 [MꢁH]ꢁ. Anal. Calcd for
ꢁ
ꢂ
S
16O32P6S4: C 42.83; O, 7.19; S, 28.59. Found: C 42.79; O, 7.23; S,
28.65.
4.2.25. 4,11,18,25,32,39-Hexaoxa-2,6,16,20,30,34-hexathiaheptacyclo
[38.2.2.27,10.212,15.221,24.226.29.235,38]tetrapentaconta-1(42),7(54),8,10
(53),12,14,21,23,26,28,35,37,40,43,45,47,49,51-pctadecane
(11b). White solid, yield (0.06 g) 20%, mp 65e67 ꢀS. Rf 0.15
(CH2Cl2/hexane/CH3CO2Et/EtOH, 3:3:1:1); vmax (Nujol) 896, 1092,
1580, 3059 cmꢁ1 dH (400 MHz, CDCl3, 25 ꢀC) 4.99 (12H, s, SCH2O),
;
6.99 (12H, d, J 8.6, Ph), 7.51 (12H, d, J 8.6, Ph); dC (100 MHz, CDCl3)
69.2 (SCH2O), 119.6, 131.8, 133.4, 156.7 (CPh). MALDI TOF, m/z:
909.357 [NþKþNaþH2O]þ. Anal. Calcd for S42O36P6S6: C 60.84; O,
4.38; S, 23.20. Found: C 60.89; O, 4.36; S, 23.11.
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4.3. Crystal structure analysis of compound 3a
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The 0.24ꢃ0.36ꢃ0.4 single crystal of 3a was prepared by slow
evaporation of a hexane/ethyl acetate/chloroform (1:4:1) solution at
room temperature. X-ray diffraction data was collected on a XCalibur
Eos diffractometer with graphite monochromated Mo-Ka radiation
ꢀ
(
l
¼0.71073 A). Collection and processing of data was performed
using the program CrysAlisPro Oxford Diffraction Ltd., Version
1.171.33.66. The structure was solved by direct methods as imple-
mented in the program SHELXS-97.20 The refinement was carried
out using SHELXL-97.21 The structure was refined by a full-matrix
least-square technique using anisotropic thermal parameters for
non-hydrogen atoms and a riding model for hydrogen atoms.
Crystal structure data of 3a: C4H9NS2O, M¼100.84, triclinic, P1
ꢀ
ꢀ
ꢀ
8. Fattakhov, S. G.; Solov’eva, S. E.; Efremov, Y. Y.; Rizvanov, I. K.; Reznic, V. S. Russ.
J. Gen. Chem. 2001, 71, 469e470.
(no. 1), a¼6.5991(7) A, b¼6.9097(7) A, c¼8.2602(9) A,
3
ꢀ
a
¼109.839(10)ꢀ,
b
¼95.545(9)ꢀ,
g
¼94.714(8)ꢀ, V¼349.97(7) A ,
9. (a) Hansen, T. J.; Angeles, R. M.; Keefer, L. K.; Day, C. S.; Gaffield, W. Tetrahedron
1981, 37, 4143e4149; (b) Walba, D. M.; Wand, M. D. Tetrahedron Lett. 1982, 23,
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marinov, I. S.; Borisova, A. O.; Starikova, Z. A.; Korzhova, L. F.; Kunakova, R. V.
Russ. Chem. Bull. Int. Ed. 2010, 59, 1002e1009.
T¼239.(2),
Dcalcd¼1.4353
mg/mm3,
Z¼3,
reflections
collected¼5222, independent reflections¼3814 (Rint¼0.0196), final
R index [I 2
s
(I)]: R1¼0.035372; R index (all data): wR2¼0.1103.
Crystallographic data for the structure of 3a have been deposited in
the Cambridge Crystallographic Data Centre as a CIF deposition
with file number CCDC 948885. Copies of these data can be ob-
tained free of change on application to CCDC, 12, Union Road,
Cambridge, CB2 1EZ, UK (fax: þ44 1223 336033, e-mail: depos-
it@ccdc.cam.ac.uk) or from http://www.ccdc.cam.ac.uk/data_-
request/cif.
10. Laikov, D. N. Chem. Phys. Lett. 1997, 281, 151e156.
11. Zhurko, G. A. ChemCraft V. 1.6, www.chemcraftprog.com.
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B.; Zhan, Q.-W.; Hong, S.-J.; Li, P.; Li, S.-P.; Wang, Y.-T. Molecules 2012, 17,
5836e5853.
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trom. 1999, 5, 81e88.
15. Gelman, N. E. Metody kolichtestvennogo organitcheskogo elementnogo micro-
analiza (Methods of quantification organic elemental microanalysis); Chimiya:
Moscow, 1987; pp 149e154.
Acknowledgements
16. Laikov, D. N.; Ustynyuk, Y. A. Russ. Chem. Bull. Int. Ed. 2005, 54, 820e826.
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18. Zhurko, G. A.; Zhurko D. A. ChemCraft 1.6, 2009.
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ucts); Gostoptekhizdat: Moscow, 1962, Vol. 5, p 887.
20. SHELXS Sheldrick, G. M. Acta Crystallogr. 2008, A64, 11e122.
21. SHELXL Sheldrick, G. M. Acta Crystallogr. 2008, A64, 11e122.
This work was supported by Russian Foundation for Basic
ꢀ
ꢀ
Research (RFBR projects No. N 14-03-00240-a, N 14-03-97023-
r_Povolzh’f_a) and Governments of the Russian Federation (NSh-
2136.2014.3 and grant of the President of the Russian Federation to
the young scientist and graduate students (SP-2161.2012.4)).