Comparative reactivity of hydroxyketones and their derivatives in the reactions with N,S-nucleophiles

Article abstract of DOI:10.1007/s11172-018-2188-2

The reactions of thiosemicarbazide (TSC), thiocarbohydrazide, and hydrazine thiocarbamate with oxyketones, haloketones, and derivatives of acetylenic alcohols were studied. Thiadiazines bearing exocyclic thio and hydrazo groups were synthesized. Acetylenic alcohols react with TSC to give the corresponding thiazolidines. The reactions of halo derivatives of acetylenic alcohols with TSC are complicated by side reactions.

Full text of DOI:10.1007/s11172-018-2188-2

110 6
Russian Chemical Bulletin, International Edition, Vol. 67, No. 6, pp. 1106—1109, June, 2018
Comparative reactivity of hydroxyketones and their derivatives
in the reactions with N,S-nucleophiles
E. Kh. Pulatov, M. D. Isobaev, B. G. Mavlonov, and T. Kh. Abdullaev
V. I. Nikitin Institute of Chemistry, Academy of Sciences of the Republic of Tajikistan,
2
99/2 ul. Aini, 734063 Dushanbe, Tajikistan.
Fax: +992 (37) 225 8095. E-mail: coordin@yandex.ru
The reactions of thiosemicarbazide (TSC), thiocarbohydrazide, and hydrazine thiocarbamate
with oxyketones, haloketones, and derivatives of acetylenic alcohols were studied. Thiadiazines
bearing exocyclic thio and hydrazo groups were synthesized. Acetylenic alcohols react with TSC
to give the corresponding thiazolidines. The reactions of halo derivatives of acetylenic alcohols
with TSC are complicated by side reactions.
Key words: monohalo- and dihalo-substituted acetylenic alcohols, oxyketones, thiosemi-
carbazide, thiocarbohydrazide, thiocarbamic acid.
At present, there are data showing promise for applica-
The structure of compound 2a was established by IR
1
1
tion of the six-membered heterocycles as anticoagulant
agents.1 This prompted the development of new synthetic
approaches towards these type of compounds. We believe
that derivatives of acetylenic alcohols are the promising
and H NMR spectroscopy. H NMR spectrum of com-
pound 2a exhibits a broadened singlet at δ 13.04 with
integral intensity of 1 H attributed to the SH group proton.
A singlet signal at δ 2.10 was ascribed to the C(5) methyl
group protons. A signal of the C(6) methyl group protons
appeared at δ 1.35.
,2
3
building blocks to solve this problem. Earlier, we have
shown that hydroxy ketones react with thiosemicarbazide
to give 2-amino- and 5-alkoxy-substituted thiadiazine
derivatives. With the aim to extend the scope of this reac-
tion, in the present work we studied the reactions of
Ketone 1a reacts with TCH in the presence of
CF COOH to give thiadiazine 2b bearing an endocyclic
3
hydrazo group. Thiadiazine 2b is likely formed by the
3
3
-hydroxy-3-methylbutan-2-one (1a) and 1-bromo-3-
mechanism described by us earlier (Scheme 2).
hydroxy-3-methylbutan-2-one (1b) with thiocarbohydr-
azide (TCH) and hydrazine dithiocarbamate (HDTC).
Acid-catalyzed reaction of ketone 1a with HDTC in
dioxane at room temperature produces six-membered
heterocyclic compound, 5,6,6-trimethyl-3,6-dihydro-2H-
Analysis of the directions of the competitive reactions of
bifunctional reagents with the compounds bearing simul-
taneously hydroxy and haloalkyl groups is of special inter-
est. If the compound contains hydroxy and bromomethyl
groups that can compete upon the reaction, the latter group
is generally more reactive. Bromo-substituted derivatives
1,3,4-thiadiazine-2-thiol (2a) (Scheme 1).
4
,5
of oxyketones were synthesized by known procedures.
It follows from the analysis of the reaction products
that cyclization of 1-bromo-3-hydroxy-3-methylbutan-2-
one (1b) upon the reaction with TCH proceeds via sub-
stitution of the bromine atom to give 2-hydrazinyl-5-(2-
hydroxypropan-2-yl)-3,6-dihydro-2H-1,3,4-thiadiazine
Scheme 1
(
2c) (Scheme 3).
To reliably explain this reaction pathway, we calculated
the electron density distribution and minimum-energy
geometries for molecules 1a, 1b, and 1b´ at the DFT/
6
,7
B3LYP/3-21G level of theory using Gaussian software
(
Fig. 1).
The computations indicate that the difference in the
energies for molecules 1a, 1b, and 1´b does not explain
their reactivity. Apparently, the formation of the intramo-
lecular H-bond between the OH-group proton and the
lone electron pair of the intermediate hydrazone nitrogen
+
Conditions: i. H , dioxane.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1106—1109, June, 2018.
066-5285/18/6706-1106 © 2018 Springer Science+Business Media, Inc.
1

Reactivity oxyketones with N,S-nucleophiles
Russ. Chem. Bull., Int. Ed., Vol. 67, No. 6, June, 2018
1107
Scheme 2
Reagents and conditions: i. CF COOH, H O, reflux.
3
2
Scheme 3
Reagents and conditions: i. CF COOH, H O, reflux.
3
2
atom has a greater effect (see Scheme 3). This conforma-
tion favors spatial proximity of the thiol group and the
bromomethyl group carbon atom.
range characteristic of the C—SH bond was observed only
in the IR spectrum of compound 2a but not in the IR
spectrum of compounds 2b,c. In the IR spectra of
compounds 2a—c, the absorptions at the ranges of
The structures of compounds 2b,c were established by
1
–1
H NMR and IR spectroscopy. IR spectra of compounds
1701—1650 (2a,b) and 1701—1628 cm (2c) were at-
1
2
b,c show new absorption bands at 3385 and 3088 cm–
tributed to the endocyclic N=C bond vibrations and
–
1
characteristic of the vibrations of the NH group of the
hydrazino moiety. Absorption band at the 600—700 cm
the intense absorption at the 1520—1504 cm range
was ascribed to the vibrations of endo- and exocyclic
N—N bond. In the case of compound 2c, a broadened
absorption band at 3358 cm– was ascribed to the
OH group vibrations.
2
–
1
1
1H NMR spectra of compounds 2b,c exhibit the broad-
ened singlets of the NH and NH group protons at about
2
1
δ 7.05 and 7.35, respectively. In H NMR spectrum of
E = –21.61 kcal mol–1
E = –182.03 kcal mol–1
compound 2b, the C(5) and C(6) methyl group protons
1
resonate at δ 2.05 and 1.33, respectively. H NMR spec-
trum of compound 2c shows a new signal at δ 4.40 attrib-
uted to the CH S group protons, a signal of the C(6) methyl
2
group protons at δ 1.39, and a broadened signal of the
OH group at δ 6.28.
The reaction of 1,3-dibromopropyne with TSC in
E = –182.03 kcal mol–1
aqueous EtOH to give thiazolidines is known. Hennion
8
9
and Boisselle described the synthesis of functionalized
Fig. 1. Quantum-chemical calculations of the molecules of
oxyketone (1a) and bromo-substituted oxyketone (1b). Charges
on the carbon atoms of the carboxyl and bromomethyl groups
are given in a.u.
iminodihydrofurans by the reaction of chloro derivative of
cyanoacetylenic alcohols with TSC under mild conditions.
To compare the reaction pathways, we involved 3-hydroxy-

1108
Russ. Chem. Bull., Int. Ed., Vol. 67, No. 6, June, 2018
Pulatov et al.
Scheme 4
Reagents and conditions: i. CF COOH (2 equiv.), dioxane, H O, 70 °C, 8 h; ii. TSC, Et N, dioxane, 70 °C, 8 h.
3
2
3
3
-methylbut-1-yne (3a) and 3-chloro-3-methylbut-1-yne
These compounds were synthesized as earlier de-
1
1—13
(
3b) in the reactions with TSC.
scribed
by the replacement of the terminal hydrogen
It was found that 3-hydroxy-3-methylbut-1-yne (3a)
atom of 3-hydroxy-3-methylbut-1-yne (1a) with molecu-
lar bromine in aqueous basic medium followed by the
replacement of the α-hydroxy group of a newly formed
derivative 3c with the bromine atom in acetic medium.
The reactions of acetylenic halo derivatives 3c,d with TSC
were unsuccessful due to resinification of the reaction
mixture.
reacts with TSC in aqueous CF CO H to produce 2-hy-
3
2
drazono-5,5-dimethyl-4-methylene-1,3-thiazolidine (4).
At the same time, the same product 4 was obtained by the
reaction of chloro-substituted acetylenic alcohol, 3-chloro-
3
-methylbut-1-yne (3b), with TSC in the presence of
triethylamine in refluxing dioxane (Scheme 4).
In the case of 3-hydroxy-3-methylbut-1-yne (3a), the
reaction is initiated by the protonation of the OH group
In summary, the present work reveals that the reactions
of acetylenic alcohols and oxy- and halo-substituted ke-
tones with thiosemicarbazide, thiocarbohydrazide, and
hydrazine dithiocarbamate result in cyclic products —
thiazolidines and thiadiazines. In contrast, the same reac-
tions with halo-substituted acetylenic alcohols failed to
give the desired products due to resinification.
3
,10
of CF CO H via the known mechanism
that involves
3
2
elimination of the water molecule; while, in the case of
3
-chloro-3-methylbut-1-yne (3b), the abstraction of HCl
in the presence of Et N occurs. In both cases, the reaction
3
involves nucleophilic attack of the thiol group of TSC on
an electron-deficient C(3) carbon atom to give intermedi-
ate S-alkylation product and subsequent intramolecular
addition of the thiosemicarbazide amino group to the
triple bond to produce thiazolidine 4.
Experimental
1H NMR spectra were recorded with an XTIPC VARIAN
MR-400 instrument (working frequency of 400 MHz) in
The structure of the synthesized compound 4 was
1
confirmed by H NMR and IR spectroscopy. IR spectrum
DMSO-d . The chemical shifts are given in the δ scale relative
6
of compound 4 exhibits the absorptions at 1668, 1574, and
to Me Si (internal standard).
–
1
4
1
510 cm attributed, respectively, to the vibrations of the
IR spectra were obtained on a Perkin—Elmer Spectrum-65
exocyclic C=C, C=N, and N—N bonds. The absorptions
instrument. Elemental analysis was performed with a Perkin—
–
1
at 3181 and 2973 cm were ascribed to the stretching
Elmer-2400 analyzer. Melting points were measured on a Boetius
1
–1
vibrations of the endo- and exocyclic amino groups. In H
apparatus at heating rate of 4 °C min
.
NMR spectrum of compound 4, the protons of the C(5)
dimethyl groups resonate at δ 1.83 and two signals of the
3-Chloro-3-methylbut-1-yne (1d) was synthesized from the
1
1—13
corresponding acetylenic alcohol as earlier described.
1
-Bromo-3-hydroxy-3-methylbutan-2-one (1b) was synthe-
geminal protons of exocyclic =CH groups at the C(4)
2
4
,5
sized following known procedures.
appear at δ 5.88 and 7.47 with integral intensity of 1 H
each. The signals observed at δ 11.02 and 8.04 were at-
tributed to the protons of the endocyclic NH and exocyclic
1
-Bromo-3-hydroxy-3-methylbut-1-yne (3c) and 1,3-dibro-
mo-3-methylbut-1-yne (3d) were synthesized similarly to known
11—13
procedures.
NH groups.
2
5,6,6-Trimethyl-3,6-dihydro-2H-1,3,4-thiadiazine-2-thiol
(2a). To a solution of 3-hydroxy-3-methylbutan-2-one (1a)
(1.02 g, 0.01 mol) in water (100 mL), hydrazine dithiocarbamate
(1.40 g, 0.01 mol) in water—dioxane (1 : 1, 20 mL) was added
We failed to involve TSC in the reaction with acetylenic
halo derivatives, e.g., 1-bromo-3-hydroxy-3-methylbut-
-yne (3c) and 1,3-dibromo-3-methylbut-1-yne (3d).
1

Reactivity oxyketones with N,S-nucleophiles
Russ. Chem. Bull., Int. Ed., Vol. 67, No. 6, June, 2018
110 9
and the reaction mixture was refluxed for 8 h in the presence of
(32%). Physicochemical properties of compound 4 obtained by
methods A and B are identical.
catalytic amounts of H SO . After three-fourth of the solvent
2
4
was removed, the residue was neutralized with a NaHCO solu-
3
tion. The light yellow precipitate formed was collected by filtra-
References
tion and recrystallized from water—dioxane (1 : 1). Yield 1.07 g
(
62%), m.p. 115 °C (from water—dioxane, 1 : 1). Found (%):
1
. T. M. Vasil´eva, V. A. Makarov, O. N. Chupakhin, L. P.
C, 41.31; H, 5.69; N, 16.02; S, 36.71. C H N S . Calculated (%):
6
10
2 2
–
1
Sidorova, N. M. Perova, V. L. Rusinov, Gematologiya i
Transfuziologia [Gematology and Transfusion Medicine], 2008,
53, No. 4, 12—15 (in Russian).
C, 41.38; H, 5.75; N, 16.09; S, 36.78. IR (KBr), ν/cm : 1325,
1
170 (C—C); 1565 (C—N); 1520 (N—N); 1650 (C=N); 750
1
(
C—S); 1265 (C=S). H NMR, δ: 1.35 (s, 6 H, 2 Me); 2.10 (s, 3 H,
Me); 13.05 (s, 1 H, SH).
-Hydrazinyl-5,6,6-trimethyl-6H-1,3,4-thiadiazine (2b). To
a solution of 3-hydroxy-3-methylbutan-2-one (1a) (1.02 g,
2
3
. Par. RF 2379306.
. E. Kh. Pulatov, M. J. Isobaev, B. G. Mavlonov, Russ. Chem.
Bull., 2016, 65, 2473.
2
4
. I. N. Nazarov, M. S. Burmistrova, A. A. Akhrem, Zh. Org.
Khim. [Russ. J. Org. Chem.], 1959, 29, 735 (in Russian).
. S. Kroiss, W. Steglich, Tetrahedron, 2004, 60, 4921.
. M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, J. A. Montgomery, Jr.,
T. Vreven, K. N. Kudin, J. C. Burant, J. M. Millam, S. S.
Iyengar, J. Tomasi, V. Barone, B. Mennucci, M. Cossi,
G. Scalmani, N. Rega, G. A. Petersson, H. Nakatsuji, M. Hada,
M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida,
T. Nakajima, Y. Honda, O. Kitao, H. Nakai, M. Klene,
X. Li, J. E. Knox, H. P. Hratchian, J. B. Cross, C. Adamo,
J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev,
A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, P. Y. Ayala,
K. Morokuma, G. A. Voth, P. Salvador, J. J. Dannenberg,
V. G. Zakrzewski, S. Dapprich, A. D. Daniels, M. C. Strain,
O. Farkas, D. K. Malick, A. D. Rabuck, K. Raghavachari,
J. B. Foresman, J. V. Ortiz, Q. Cui, A. G. Baboul, S. Clifford,
J. Cioslowski, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz,
I. Komaromi, R. L. Martin, D. J. Fox, T. Keith, M. A. Al-
Laham, C. Y. Peng, A. Nanayakkara, M. Challacombe,
P. M. W. Gill, B. Johnson, W. Chen, M. W. Wong, C. Gonzalez,
J. A. Pople, Gaussian 03, Revision A.1, Gaussian, Inc.,
Pittsburgh (PA), 2003.
0
0
.01 mol) in 1.5% aqueous CF CO H (100 mL), TCH (1.06 g,
3 2
.01 mol) in water (20 mL) was added. The mixture was refluxed
5
6
for 8 h, cooled down, and neutralized with a chilled aqueous
NaHCO . The precipitate formed was collected by filtration and
3
crystallized from water. Yield 1.27 g (74%), m.p. 124 °C (from
water). Found (%): C, 41.78; H, 6.90; N, 32.49; S, 18.54.
C H N S. Calculated (%): C, 41.86; H, 6.97; N, 32.56; S, 18.60.
6
12
4
–
1
IR (KBr), ν/cm : 1323, 1167 (C—C); 1564 (C—N); 1517
1
(
2
N—N); 1650 (C=N); 750 (C—S). H NMR, δ: 1.33 (s, 6 H,
Me); 2.05 (s, 3 H, Me); 7.05 (s, 1 H, NH); 7.35 (s, 2 H, NH ).
2
2
-Hydrazinyl-5-(1-hydroxy-1-methylethyl)-6H-1,3,4-thia-
diazine (2c). To a stirred solution of 1-bromo-3-hydroxy-3-
methylbutan-2-one (1b) (1.81 g, 0.01 mol) in 1.5% aqueous
CF CO H (30 mL), TCH (1.06 g, 0.01 mol) in hot water (20 mL)
3
2
was added. The mixture was refluxed for 8 h and neutralized with
a NaHCO3 solution. The precipitate formed was refluxed in
water (70 mL per 1 g of the precipitate) with activated charcoal,
filtered, and precipitated. Yield 1.55 g (82%), m.p. 112 °C.
Found (%): C, 37.81; H, 5.18; N, 14.66; S, 33.61. C H N OS .
6
10
2
2
Calculated (%): C, 37.89; H, 5.26; N, 14.73; S, 33.68. IR (KBr),
–
1
ν/cm : 1056, 1280 (C—C); 1434 (C—N); 1504—1512 (N—N);
628—1701 (C=N); 736 (C—S); 3340—3200 (NH—NH ), 3358
1
2
1
(
OH), 1262. H NMR, δ: 1.39 (s, 6 H, 2 Me); 3.20 (s, 1 H, OH);
7. E. V. Butyrskaya, Komp´yuternaya khimiya: osnovy teorii i
4
.40 (s, 2 H, CH ); 7.06 (s, 1 H, NH); 7.36 (s, 2 H, NH ).
2
2
rabota s programmami Gaussian i Gauss View [Computational
Chemistry. Theory and Running Gaussian and Gauss View
Software], Solon-Press, Moscow, 2011, 224 pp. (in Russian).
. K. A. Volkova, A. S. Nachmanovich, S. A. Amasova, Russ.
J. Org. Chem., 2007, 43, 1379.
. A. P. Borisova, O. A. Shemyakina, A. G. Mal´kina, V. A.
Nasyreva, B. A. Trofimov, Proc. Int. Conf. on Organic
Chemistry "Organic Chemistry from Butlerov and Beilstein to
Modern Times"] (St. Petersburg, Russia, 2006), St. Petersburg,
p. 230 (in Russian).
2
-Hydrazono-5,5-dimethyl-4-methylenethiazolidine (4). A. To
a solution of 3-hydroxy-3-methylbut-1-yne (3a) (0.84 g, 0.01 mol)
and CF CO H (3 mL) in water, a solution of TSC (0.91 g,
3
2
8
9
0
.01 mol) in water—dioxane (1 : 1) was added portionwise. The
mixture was heated at 70 °C for 8 h and concentrated in vacuo.
The residue was cooled to 0 °C, the precipitate formed was col-
lected by filtration and crystallized from water. Yield 0.9 g (48%),
m.p. 168—169 °C (from water—ethanol, 1 : 1). Found (%):
C, 45.79; H, 6.93; N, 26.68; S, 20.31. C H N S. Calculated (%):
6
11
3
–
1
C, 45.86; H, 7.00; N, 26.75; S, 20.38. IR (KBr), ν/cm : 3182,
1
0. M. M. Krayushkin, B. V. Lichitskii, A. P. Mikhalev, A. A.
Dudinov, S. N. Ivanov, Russ. J. Org. Chem., 2005, 41, 87].
1. G. F. Hennion, A. P. Boisselle, J. Org. Chem., 1961, 26, 725.
2. E. Kumarasamya, J. Sivaguru, Chem. Commun., 2013,
9, 4346.
2
973 (NH, NH ); 1668 (C=C, C=N); 1368 (C(CH ) ); 1268
2
3 2
1
(
C—N); 1574, 1510 (N—N). H NMR, δ: 1.83 (s, 6 H, 2 Me);
1
1
5
.88 and 7.47 (both s, 1 H each, =CH ); 11.02 (s, 1 H, NH), 8.04
2
(
s, 2 H, NH ).
2
4
B. To a solution of TSC (0.91 g, 0.01 mol) in dioxane (20 mL),
13. L. Brandsma, Synthesis of Acetylenes, Allenes and Cumulenes.
a solution of 3-chloro-3-methylbut-1-yne (3b) (1.02 g, 0.01 mol)
in dioxane was added portionwise and the reaction mixture was
heated at 70 °C for 8 h in the presence of triethylamine as
a catalyst. The mixture was cooled down to 0 °C and neutralized
with an HCl solution. The precipitate formed was collected by
filtration and crystallized from water—ethanol (1 : 1). Yield 0.6 g
Methods and Techniques, Elsevier, Oxford, 2004, 502 pp.
Received May 10, 2017;
in revised form October 18, 2017;
accepted December 27, 2017