Versatile approaches to a library of building blocks based on 5-acylthiazole skeleton

Article abstract of DOI:10.1080/00397911.2020.1808224

Thiazole derivatives represent an important class of azole heterocycles with a broad spectrum of biological activity and, therefore, the synthesis of these compounds is of remarkable concern. We present here practical and reliable protocol for synthesis of some 5-acylthiazoles and demonstrate their utility in the preparation of several new series of thiazole-containing building blocks through transformation of 5-acyl function. Specifically, thiazole-based alcohols, oximes, primary, and secondary amines were successively synthesized in good to excellent yields. The chemical structures of obtained compounds were confirmed by ¹H and ¹³C NMR-spectroscopy, elemental analysis, and mass-spectrometry.

Full text of DOI:10.1080/00397911.2020.1808224

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Versatile approaches to a library of building blocks
based on 5-acylthiazole skeleton
Olesia G. Kulyk , Dmytro A. Biloborodov , Maksim A. Cherevatenko , Yevhen
Y. Shyriakin , Alexander Yu. Lyapunov , Alexander V. Mazepa , Valerii V.
Vashchenko , Valeriy D. Orlov & Maksim A. Kolosov
To cite this article: Olesia G. Kulyk , Dmytro A. Biloborodov , Maksim A. Cherevatenko , Yevhen
Y. Shyriakin , Alexander Yu. Lyapunov , Alexander V. Mazepa , Valerii V. Vashchenko , Valeriy D.
Orlov & Maksim A. Kolosov (2020): Versatile approaches to a library of building blocks based on 5-
acylthiazole skeleton, Synthetic Communications, DOI: 10.1080/00397911.2020.1808224
To link to this article: https://doi.org/10.1080/00397911.2020.1808224
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https://doi.org/10.1080/00397911.2020.1808224
Versatile approaches to a library of building blocks based
on 5-acylthiazole skeleton
Olesia G. Kulyka , Dmytro A. Biloborodova, Maksim A. Cherevatenkoa,
Yevhen Y. Shyriakina, Alexander Yu. Lyapunovb , Alexander V. Mazepac,
Valerii V. Vashchenkod , Valeriy D. Orlova , and Maksim A. Kolosova
b
aSchool of Chemistry, V. N. Karazin Kharkiv National University, Kharkiv, Ukraine; Enamine Ltd., Kyiv,
c
d
Ukraine; A.V. Bogatsky Physico-Chemical Institute of the NAS of Ukraine, Odesa, Ukraine; Department
of Technology of Organic Materials, State Scientific Institution, Institute for Single Crystals, NAS of
Ukraine, Kharkiv, Ukraine
ABSTRACT
ARTICLE HISTORY
Received 26 June 2020
Thiazole derivatives represent an important class of azole hetero-
cycles with a broad spectrum of biological activity and, therefore,
the synthesis of these compounds is of remarkable concern. We pre-
sent here practical and reliable protocol for synthesis of some
5-acylthiazoles and demonstrate their utility in the preparation of
several new series of thiazole-containing building blocks through
transformation of 5-acyl function. Specifically, thiazole-based alco-
hols, oximes, primary, and secondary amines were successively syn-
thesized in good to excellent yields. The chemical structures of
obtained compounds were confirmed by 1H and 13C NMR-spectros-
copy, elemental analysis, and mass-spectrometry.
KEYWORDS
Building blocks; Hantzsch
thiazole synthesis;
Leuckart–Wallach reaction;
oxime; thiazole
GRAPHICAL ABSTRACT
CONTACT Olesia G. Kulyk
University, Kharkiv, Ukraine; Maksim A. Kolosov
olesia.g.kulyk@karazin.ua
School of Chemistry, V. N. Karazin Kharkiv National
School of
kolosov@univer.kharkov.ua; kolosov@karazin.ua
Chemistry, V. N. Karazin Kharkiv National University, Kharkiv, Ukraine.
Supplemental data for this article can be accessed on the publisher’s website
ß 2020 Taylor & Francis Group, LLC

2
O. G. KULYK ET AL.
Introduction
Thiazole and its derivatives attracted tremendous attention over the years because of
their presence as a key structural motif in the pharmaceutically and biologically relevant
compounds.[1] Indeed, the thiazole ring is an important subunit in a large number of
bioactive natural compounds such as thiamin (vitamin B1), thiamin pyrophosphate,[2]
mycothiazole,[3] macrocyclic thiopeptide antibiotics,[4] thiostrepton,[5] micrococcin P1,[6]
epothilones (Fig. 1a).[7] Furthermore, a plethora of thiazole-comprising synthetic drugs
were developed, which are commercially available nowadays (for some selected examples
see Fig. 1b).[8] Such enormous interest in these compounds is due to a broad range of
their biological properties, including antiviral,[9] antibacterial,[10] anti-tubercular,[11]
antifungal,[12] anti-inflammatory,[13] antimalarial,[14] anticancer,[15] and anticonvulsant
activities.[16] Additionally, thiazole derivatives are found applications as fluorescent
dyes,[17] polymers,[18] liquid crystals,[19] insecticides etc.[20]
A number of synthetic strategies for the preparation of various thiazole derivatives
were developed.[1c,21–24] Among them, classical Hantzsch,[22] Gabriel,[23] and
Cook–Heilborn[24] reactions are the most widely used approaches (Scheme 1).
Although a lot of thiazole-based building blocks were described in the literature, derivatives
of 5-acylthiazoles are quite rare among them. Meanwhile, the 5-acyl group in thiazole ring
makes it an appealing precursor in the synthesis of wide range building blocks demonstrating
various types of bioactivity.[25] In most cases, Hantzsch ring closure reaction was used for the
synthesis of 5-acylthiazoles,[25,26] however, main attention in the cited Refs. was given to the
Figure 1. Selected examples of bioactive thiazole-comprising compounds: (a) natural and (b) synthetic.

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Scheme 1. General approaches toward the synthesis of thiazole derivatives.
Figure 2. Library structures derived from 5-acylthiazoles 3.
further transformations of these derivatives, i.e. synthesis of chalcones,[26a,e] bisthiazoles,[26b]
thiazolyl dihydroisoxazoles,[26c] thiazolyl pyrimidines,[26f] etc. Therefore, the protocols of 5-
acylthiazoles synthesis were not properly detailed or rather controversial (e.g. purification of
thiazole hydrochlorides by flash chromatography on silica using non-polar eluent,[25c] etc.).
Thus, pursuing the aim to expand the molecular diversity of the 2,4,5-trisubstituted thiazole
library (Fig. 2), in this work, we are focusing on the elaboration of general, reliable, and con-
venient method of 5-acylthiazole synthesis and further demonstrating their utility in the prep-
aration of corresponding alcohols, oximes, primary, and secondary amines.
Results and discussion
We adopted Hantzsch-type cyclocondensation of a-halodiketones 1 with thioamides 2 as a
route to 5-acylthiazole derivatives 3. To its optimization the interaction of a-halodiketones
1a or 1b with thioamide 2a were chosen as a model reaction (Scheme 2).

4
O. G. KULYK ET AL.
Scheme 2. Model reactions for the optimization of 5-acylthiazole synthesis.
Table 1. Optimization of the reaction conditionsa.
Entry
Solvent
Reaction conditions, i
Yield, %b
1
2
3
4
5
6
7
8
Toluene
Xylene
i-PrOH
BuOH
i-AmOH
Acetone
Neat
Reflux, 2 h
Reflux, 20 min
Reflux, 1 h
Reflux, 1 h
Reflux, 6 h
Reflux, 1 h
Melting
Traces
–
24
37
46
6
46
68
NA
(1) Fusion (neat) at 140 ꢀC; (2) toluene, reflux, 2 h
aReagents ratio: 1b (1 eq.), 2a (1.05 eq.).
bIsolated yield.
The entry with the optimum conditions for the preparation of target compound is in bold.
In the case of reaction of open-chain a-halodiketone 1a under the typical Hantzsch proto-
col (reflux in ethanol),[26c] the thiazole 3aa was obtained in only moderate yield (43%). A
simple modification of the process by facilitation of the water removal deploying refluxing
toluene with Dean-Stark water trap following by the treatment of as-formed thiazole hydro-
chloride with aqueous Na2CO3 allowed us to improve the yield of 3aa up to 80%.
However, the reaction of 2-chlorocyclohexane-1,3-dione 1b with 2a in the same con-
ditions (toluene, Dean-Stark water trap) yielded only traces of target compound 3ba as
1
it was detected by H NMR-spectroscopy (Table 1, entry 1). To improve the yield, vari-
ous solvents such as xylene, i-propanol, n-butanol, i-amyl alcohol, and acetone were
examined. An attempt to carry out the reaction in higher boiling non-polar solvent
(xylene) turned to failure, resulted in the formation of an inseparable mixture (entry 2).
On the contrary, carrying out the reaction in polar protic solvent (i-propanol) furnished
the desired product 3ba in 24% yield (entry 3). Further increasing the boiling point of

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Figure 3. Substrate scope for the synthesis of thiazole-based building blocks.
Table 2. Prepared library of 5-acylthiazoles 3xy (x corresponds to a-halodiketones 1a or 1b, while y
– to thioamides 2, see Fig. 3).
Entry
Product
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
i
Yield, %
80
Entry
Product
3aj
3al
3am
3an
3ao
3ba
3bb
3bc
3bd
i
Yield, %
Entry
Product
3be
3bf
3bg
3bh
3bk
3bl
i
Yield, %
1
2
3
4
5
6
7
8
9
a
a
a
a
a
a
a
a
a
10
11
12
13
14
15
16
17
18
a
a
b
b
c
d
d
d
d
57
78
74
74
60
68
57
67
73
19
20
21
22
23
24
25
d
d
d
d
d
a
a
61
60
58
52
48
44
45
97
75
83
73
70
77
70
68
3bm
Reaction conditions i¼a: toluene, reflux; b: EtOH, reflux; c: K2CO3, EtOH, r.t.; d: (1) fusion (neat), (2) toluene, reflux.
protic solvents increased the yield of the product up to 46% (entries 4 and 5). On the
other hand, the use of aprotic polar solvent such as acetone was unsuccessful, yield of
3ba was only 6% (entry 6). Excluding the solvent, i.e. fusing the thoroughly grounded
mixture of 1b with 2a, similarly to Mu€hlstadt and Borde,[27] afforded the target product
3ba in 46% yield (entry 7). To further enhance the yield, the preliminary fused mixture
of 1b (1 eq.) and 2a (1.05 eq) was then refluxed in toluene with Dean-Stark water trap
(entry 8) followed by treatment with Na2CO3 to afford 3ba in 68% yield.
With the established conditions, their scope for the synthesis of various 5-acylthiazoles
was studied. The two diversity points in reaction products 3 were generated by the com-
bination of 3-chloropentane-2,4-dione 1a or 2-chlorocyclohexane-1,3-dione 1b with various
thioamides 2 (Fig. 3). The cyclocondensation proceeded smoothly when ortho- or para-
substituted aryl 2a–i, heteroaryl 2j,k and alkyl 2l thioamides were used (Table 2). However,
this strategy did not work properly when longer alkyl tail thioamides 2m-o were employed.
Fortunately, the typical Hantzsch protocol (reflux in ethanol following by common work-
up) allowed us to obtain target thiazolyl ketones 3am, 3an, and 3ao (Table 2, entries 12,
13, and 14).

6
O. G. KULYK ET AL.
Table 3. Prepared library of thiazole-based alcohols 4xy (x corresponds to a-halodiketones 1a or 1b,
while y – to thioamides 2, see Fig. 3).
Entry
Product
Yield, %
Entry
Product
Yield, %
1
2
3
4
5
6
7
4aa
4ab
4ad
4af
4ag
4ah
4ai
92
94
97
96
91
95
80
8
9
4am
4an
4ao
4ba
4bc
4bl
92
96
95
90
91
81
96
10
11
12
13
14
4bm
It should be noted that yields for the reactions utilizing 2-chlorocyclohexane-1,3-
dione 1b were lower than those when 3-chloropentane-2,4-dione 1a was used.
Apparently, the structural portions of an intermediate (a-thiodiketone), formed by the
nucleophilic attack of sulfur atom of thioamide on the a-carbon atom of 2-chlorocyclo-
€
hexane-1,3-dione, caused steric hindrance (according to the Burgi–Dunitz trajectory) of
subsequent intramolecular nucleophilic attack of nitrogen atom on the carbonyl
group,[28] thus, reducing the yield of the target compound.
For the construction of diversity-oriented library, 5-acylthiazoles 3 were further
exploited for the synthesis of thiazole-containing alcohols 4, oximes 5, primary 6, and
secondary 8 amines (Fig. 2).
The reduction of thiazolyl ketones 3 to the corresponding alcohols 4 was smoothly
carried out by the stepwise addition of NaBH4 to the ice-cold solution of compounds 3
in methanol. When the conversion was completed (as it was monitored by TLC) the
reaction mixture was worked up to afford desired alcohols 4 in high yields (80–97%),
which are pure enough for further use without additional purification (Table 3).
For the preparation of primary amines 6, the Leuckart–Wallach reductive amination of
ketones using ammonium formate was initially chosen.[29] The optimization of the reaction
conditions was carried out taken as a model reaction the fusing of ketone 3aa (component
A, see Table 4) with ammonium formate (component B). The fusing the mixture of A and B
at 150–5 ꢀC for 1 h, then at 180–5 ꢀC for 3.5 h followed by the treatment of as-formed N-for-
myl derivative with conc. HCl at 85–90 ꢀC for 1 h resulted in only 40% conversion of the
starting 3aa to 6aa, as it was determined by 1H NMR spectroscopy (Table 4, entry 1). Simple
increasing the excess of ammonium formate (B) could only slightly improve the conversion,
up to 50% (entries 2 and 3). The changing of heating regime appeared to be more successful
(entry 4). Thus, the best result was obtained by three-cycle heating 3aa with ammonium for-
mate, which was added in the excessive amount at the beginning of each of cycles (entry 5).
The yield of the target product 6aa after usual work-up raised up to 79%.
We explored the scope of the optimized above conditions with various thiazolyl
ketones 3 (Table 5). However, we have found that this approach was applicable only
with 2-aryl substituted thiazolyl ketones 3 providing the desired primary amines 6ab,
6ad–ah, and 6bc in good yields (55–76%), whereas with 2-alkyl substituted thiazolyl
ketones 3ai, 3al, and 3bl the inseparable mixtures of target and side products were

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Table 4. Optimization of the Leuckart–Wallach reductive amination reaction.
Entry
1
A (eq.) : B (eq.)
Reaction conditions, i
Result
1 : 4
1 : 9
1 : 15
150–5 ꢀC, 1.5 h
Mixture of A : C (1.5 : 1)a
180–5 ꢀC, 3.5 h
2
3
4
150–5 ꢀC, 1.5 h
Mixture of A : C (1.1 : 1)a
Mixture of A : C (1 : 1)a
30%b
180–5 ꢀC, 3.5 h
150–5 ꢀC, 1.5 h
180–5 ꢀC, 3.5 h
1 : 24 (in four equal portions)
160–5 ꢀC, þ B (6 eq.), 1 h
190–5 ꢀC, þ B (6 eq.), 2 h
190–5 ꢀC, þ B (6 eq.), 2 h
190–5 ꢀC, þ B (6 eq.), 2 h
160–5 ꢀC, þ B (10.5 eq.), 1 h
190–5 ꢀC, 3 h
5
1 : 21
79%b
160–5 ꢀC, þ B (6 eq.), 1 h
190–5 ꢀC, 3 h
160–5 ꢀC, þ B (4.5 eq.), 1 h
190–5 ꢀC, 3 h
aDetermined by H NMR spectroscopy.
1
bIsolated yield of 6aa.
Table 5. Prepared library of thiazole-based oximes 5xy, primary 6xy and secondary 8xy amines
(x corresponds to a-halodiketones 1a or 1b, while y – to thioamides 2, see Fig. 3).
Entry
Product
R1, R2
R
Yield, %
1
2
3
4
5
6
7
8
5aa
5ae
5af
5ai
R1 ¼ R2 ¼ CH3
R1 ¼ R2 ¼ CH3
R1 ¼ R2 ¼ CH3
R1 ¼ R2 ¼ CH3
R1 ¼ R2 ¼ CH3
R1, R2 ¼ -(CH2)3-
R1, R2 ¼ -(CH2)3-
R1 ¼ R2 ¼ CH3
R1 ¼ R2 ¼ CH3
R1 ¼ R2 ¼ CH3
R1 ¼ R2 ¼ CH3
R1 ¼ R2 ¼ CH3
R1 ¼ R2 ¼ CH3
R1 ¼ R2 ¼ CH3
R1 ¼ R2 ¼ CH3
R1, R2 ¼ -(CH2)3-
R1 ¼ R2 ¼ CH3
R1, R2 ¼ -(CH2)3-
R1 ¼ R2 ¼ CH3
R1 ¼ R2 ¼ CH3
R1 ¼ R2 ¼ CH3
R1 ¼ R2 ¼ CH3
R1, R2 ¼ -(CH2)3-
R1, R2 ¼ -(CH2)3-
Ph
85
96
93
91
87
81
73
79
64
55
64
63
68
74
63
66
76
79
77
89
90
84
92
96
o-FC6H4
p-ClC6H4
CH2C6H4
CH3
5al
5bb
5bl
6aa
6ab
6ad
6ae
6af
6ag
6ah
6ai
p-CH3C6H4
CH3
Ph
9
p-CH3C6H4
p-FC6H4
o-FC6H4
p-ClC6H4
p-BrC6H4
o-BrC6H4
CH2C6H4
CH3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
6al
6bc
6bl
8ab
8al
p-OCH3C6H4
CH3
p-CH3C6H4
CH3
C2H5
CH(CH3)2
CH3
C2H5
8am
8an
8bl
8bm

8
O. G. KULYK ET AL.
Scheme 3. Alternative approach toward the synthesis of primary amines 6.
Scheme 4. Synthesis of secondary thiazolyl amines 8
obtained. Apparently, too high CH-activity of 2-alkyl group under applied conditions
caused the side processes. To circumvent this limitation, two-step pathway to com-
pounds 6 in milder conditions, including the conversion of ketone 3 to oxime 5 fol-
lowed by the reduction of the latter into amine 6 was proposed (Scheme 3).
The condensation of thiazolyl ketones 3ai, 3al, or 3bl (1 eq.) with hydroxylamine hydro-
chloride (1.2 eq.) produced corresponding ketoximes 5ai, 5al, or 5bl in good yields.
Subsequent reduction with zinc dust yielded desired amines 6ai, 6al, or 6bl in 63%, 66%, and
79% yields, respectively. Additionally, 2-aryl substituted thiazolyl ketoximes 5aa, 5ae, 5af,
and 5bb were also successfully obtained following the same protocol (Table 5 and Scheme 3).
The mono-N-alkyl derivatives could be obtained by mono-alkylation of primary amines 6,
however, such reaction often accompanied with dialkylation. Thus, as more selective way to
N-alkylamines 8 we proposed here the one-pot reaction of ketones 3 (1 eq.) with 20% solution
of methylamine in methanol (10.5 eq.), followed by reduction of formed imine by NaBH4. In
such a way, secondary thiazolyl amines 8 were obtained in high yields (Scheme 4 and Table
5). It is worth noting that an excess of methylamine is crucial in this case since the equimolar
ratio of starting reagents or a slight excess (1.5–3 eq.) of methylamine yielded the mixture of
target amines with secondary alcohols type 4 as determined by 1H NMR spectroscopy.
As was expected, the synthesis and purification of primary thiazolyl amines appeared
to be more complicated compared to secondary thiazolyl amines. Specifically, secondary
amines 8 were easily obtained in one-pot reaction without further purification, while
primary amines 6 were purified as hydrochlorides by refluxing the solution of thiazolyl
amine hydrochlorides in MeOH with activated charcoal followed by filtration and pre-
cipitation from filtrate with acetone.
Conclusion
In summary, a general and practical method of 5-acylthiazole synthesis based on reflux-
ing the corresponding thioamides and a-halo-1,3-diketones in toluene with Dean-Stark

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9
water trap have been developed. We have found that the preliminary fusion of starting
thioamides with 2-chlorocyclohexane-1,3-dione is crucial to provide high yields in the
synthesis of 5,6-dihydrobenzo[d]thiazole derivatives The obtained thiazolyl ketones 3
were successfully employed for the synthesis of thiazolyl alcohols 4 by reduction of
ketones 3 with NaBH4, primary thiazolyl amines 6 by either one-step Leuckart–Wallach
reductive amination of ketones 3 or by reduction of ketoximes 5, secondary thiazolyl
amines 8 by one-pot amination of ketones 3 followed by reduction of formed imines
with NaBH4. Noteworthy, 2-alkyl substituted thiazolyl ketones, alcohols, and amines
represent the valuable building blocks with the lowest molar weight in this series.
Experimental part
General procedure for the synthesis of thiazolyl ketones 3aa-al
To a boiling mixture of the corresponding thioamide 2 (1 eq.) and toluene (ca. 700 mL
per 1 mol of 1a), 3-chloropentane-2,4-dione 1a (1.05 eq.) was added dropwise, and the
resulting mixture refluxed using Dean-Stark water trap for 2 h. After cooling to r.t.,
reaction mixture was washed with 10% solution of Na2CO3 to adjust the pH of aqueous
phase to ca. 7. The organic layer was then washed with brine, dried over Na2SO4, fil-
tered and concentrated to 2/3 volume. The extract was purged with dry HCl while stir-
ring at r.t. The formed thiazolyl ketone hydrochloride was filtered off, washed with
toluene and hexane, dried under air and recrystallized from EtOH or acetone. The
obtained hydrochloride was quenched with a mixture of saturated aqueous solution of
Na2CO3/CHCl3 (3:1), and the resulting suspension stirred at r.t. until the complete dis-
solving of the solid. The aqueous phase was separated and extracted with CHCl3. The
combined organic layers were washed with brine, dried over Na2SO4, filtered and con-
centrated under reduced pressure to yield pure target thiazolyl ketones.
General procedure for the synthesis of 5,6-dihydrobenzo[d]thiazole derivatives
3ba–bh and 3bk
A mixture of 2-chlorocyclohexane-1,3-dione 1 b (1 eq.) and thioamide 2 (1.05 eq.) was
thoroughly grounded in a mortar, and the resulting powder carefully melted at 140 ꢀC.
If necessary, the powder of starting compounds was divided into three portions and
melted in a stepwise manner with the aim to not overheat the mixture. To a resulting
fused mixture toluene (ca. 500 mL per 1 mol of 1 b) was added, and the reaction mix-
ture refluxed while stirring using Dean-Stark water trap. When no further water was
trapped, the reaction mixture was worked up similarly as described for the synthesis of
thiazolyl ketones 3aa–al.
General procedure for the synthesis of thiazolyl alcohols 4
To a solution of corresponding thiazolyl ketone 3 (1 eq.) in MeOH (ca. 150–200 mL per
0.1 mol of 3), NaBH4 (1.1 eq.) was added at 0 ꢀC in a stepwise manner under argon.
The reaction mixture was stirred at r.t. until complete consumption of the ketone as
determined by TLC (eluent: EtOAc/n-hexane 2:1). The reaction mixture was then

10
O. G. KULYK ET AL.
evaporated to dryness, 10% solution of Na2CO3 (1–1.5 L per 1 mol of starting ketone)
was added and a mixture was extracted with CHCl3. The extract was washed with brine
and dried over Na2SO4, filtered and concentrated under reduced pressure to give alco-
hols 4.
General procedure for the synthesis of thiazolyl oximes 5
To a suspension of appropriate thiazolyl ketone 3 (1 eq.) in water (ca. 150 mL per
0.5 mol of 3) hydroxylamine hydrochloride (1.2 eq) was added. The pH of reaction mix-
ture was adjusted to ca. 7–8 by the addition of a 20% solution of NaOH in water. Then
EtOH (ca. 500 mL per 0.5 mol of 3) was added, and the resulting mixture refluxed for
6 h. After cooling to r.t., the formed precipitate was filtered off, washed with water,
EtOH/H2O (1:1) mixture and EtOH, and air-dried without further purification.
General procedure for reduction of thiazolyl oximes 5 to primary thiazolyl
amines 6
To a well-stirred solution of ketoxime 5ai, 5al, or 5bl (1 eq.) in a mixture of HOAc (24
eq.) and conc. HCl (30 eq.), Zn dust (7 eq.) was added at 0 ꢀC, and the reaction mixture
stirred for 4 h at r.t. The pH of resulting slurry was adjusted to ca. 10–12 by the add-
ition of a 20% solution of NaOH in water, and the mixture was stirred at r.t. for
15 min. Then, the resultant solution was extracted with benzene, washed with brine,
dried over K2CO3, filtered and concentrated under reduced pressure to give target pri-
mary amines 6ai, 6al, or 6bl in 63, 66, and 79% yields, respectively.
General procedure for Leuckart–Wallach reductive amination of thiazolyl ketones
3 to primary thiazolyl amines 6
A mixture of thiazolyl ketone 3 (1 eq.) and ammonium formate (10.5 eq.) was heated at
160–5 ꢀC for 1 h, then at 190–5 ꢀC for 3 h under neat conditions. After cooling to ca.
100 ꢀC, a second portion of ammonium formate (6 eq.) was added, and the reaction
mixture again heated at 160–5 ꢀC for 1 h and at 190–5 ꢀC for 3 h. After cooling to ca.
100 ꢀC, the third portion of ammonium formate (4.5 eq.) was added, and the analogous
cycle of heating run. Portions of ketone which distilled off with water vapor were
returned to the flask during the cycles of heating. After cooling to ca. 50 ꢀC, conc. HCl
(17.5 eq.) was added, and the reaction mixture heated at 85–90 ꢀC for 1 h to hydrolyze
the intermediate (corresponding formamide). After being cooled to r.t., the reaction
mixture was made alkaline with 10% aqueous solution of NaOH and the dark oil thus
produced extracted with toluene. The combined organic layers were washed with brine,
dried over Na2SO4, filtered and concentrated to 2/3 volume. The extract was purged
with dry HCl while stirring at r.t. The formed precipitate of crude thiazole hydrochlor-
ide was filtered off, washed with toluene and hexane, and dried under air. The crude
was purified through dissolving in minimum amount of MeOH and heating at reflux
with activated charcoal for 1 h. After cooling to r.t., charcoal was filtered off and washed
with MeOH. The filtrate was concentrated to minimal volume in vacuo, and then

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precipitated by the addition of excess of acetone to the hot methanol solution affording
thiazolyl amine hydrochloride. The conversion of hydrochloride into base was carried
out similarly as described for thiazolyl ketones 3.
General procedure for the synthesis of secondary thiazolyl amines 8
A mixture of corresponding thiazolyl ketone 3 (1 eq.) and MeNH2 (20% solution in
MeOH, 10.5 eq.) was magnetically stirred in a hermetically stopped flask at r.t. for 16 h.
Then the reaction mixture was cooled to 0 ꢀC and NaBH4 (1.05 eq.) added in three por-
tions under argon. After completion of the reaction as determined by TLC, the reaction
mixture was evaporated to dryness, saturated aqueous solution of Na2CO3 was added
and a mixture was extracted with CHCl3. The extract was washed with water, brine,
dried over K2CO3, filtered, and concentrated under reduced pressure to give target sec-
ondary amines 8.
Supplemental data associated with this article (Full experimental detail, characteristics
1
for all new compounds, copies of H and 13C NMR, LRMS spectral data) can be found
via the “Supplementary Content” section of this article’s webpage.
Acknowledgments
The authors thank V. I. Musatov, E. V. Vashchenko (STC “Institute for Single Crystals” NAS of
Ukraine, Kharkiv, Ukraine), and A. V. Borisov (Enamine Ltd., Kiev, Ukraine) for spectroscopic
measurements.
Funding
The research was supported by [Grant 0118U002025] of Ministry of Education and Science of
Ukraine and by [Grants 811H/11–09, 811H/38–09, 811H/26–10 and 811 H/19–12] of V.N.
Karazin Kharkiv National University.
ORCID
Olesia G. Kulyk
http://orcid.org/0000-0003-0303-6941
Alexander Yu. Lyapunov
Valerii V. Vashchenko
http://orcid.org/0000-0002-7538-303X
http://orcid.org/0000-0003-0831-1949
Valeriy D. Orlov
Maksim A. Kolosov
http://orcid.org/0000-0002-8670-5348
http://orcid.org/0000-0002-6714-0513
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