Unusual product from the acid-catalyzed one-pot, multicomponent reaction of thiocarbohydrazide, aldehydes, and phenacyl bromides

Article abstract of DOI:10.1080/00397911.2017.1332225

A one-pot, three-component protocol for the synthesis of novel five-membered thiazole ring bonded to two hydrazone motifs is described. The acid-catalyzed reaction of one equivalent of thiocarbohydrazide, two equivalents of aromatic aldehydes, and one equivalent of phenacyl bromides afforded the five-membered thiazole ring. The reactions proceed with novel chemoselectivity. Similar reported protocols have always afforded 1,3,4-thiadiazines.

Full text of DOI:10.1080/00397911.2017.1332225

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Unusual Product From the Acid Catalyzed One Pot,
Multi-Component Reaction of Thiocarbohydrazide,
Aldehydes and Phenacyl Bromides
Mohanad shkoor, Ayahtallah al-abade, Ibtesam Aleteiwib, Mahmoud Al-Talib
& Hasan Tashtoush
To cite this article: Mohanad shkoor, Ayahtallah al-abade, Ibtesam Aleteiwib, Mahmoud Al-Talib
& Hasan Tashtoush (2017): Unusual Product From the Acid Catalyzed One Pot, Multi-Component
Reaction of Thiocarbohydrazide, Aldehydes and Phenacyl Bromides, Synthetic Communications,
DOI: 10.1080/00397911.2017.1332225
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1332225
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Date: 25 May 2017, At: 12:10

Unusual Product from the Acid Catalyzed One Pot, Multi-Component Reaction of
Thiocarbohydrazide, Aldehydes and Phenacyl bromides
Mohanad shkoor1, Ayahtallah al-abade2, Ibtesam Aleteiwib2, Mahmoud Al-Talib2, Hasan
Tashtoush2
1Department of Chemistry and Earth Sciences, Qatar University, Doha, Qatar, 2Chemistry
Department, Yarmouk University, Irbid, Jordan
Abstract
A one-pot, three-component protocol for the synthesis of novel five membered thiazole
ring bonded to two hydrazone motifs is described. The acid catalyzed reaction of one
equivalent of thiocarbohydrazide, two equivalents of aromatic aldehydes and one
equivalent of phenacyl bromides afforded the five membered thiazole ring. The reactions
proceed with novel chemoselectivity. Similar reported protocols have always afforded
1,3,4-thiadiazines.
Graphical Abstract
1

KEYWORDS: hydrazones, thiocarbohydrazide, thiocarbohydrazone, thiazole,
multicomponent reaction, chemoselectivity
Multicomponent reactions (MCRs) have become increasingly preferred and reliable
synthetic tools for synthetic organic and green chemists. Their efficiency stems from the
ability of construction of wide range of complex molecules from readily available and
easily accessible building blocks in mostly simple single step, atomic economic, time
efficient and cost effective procedures. As a result, there will be continuous demand for
the discovery and development of new MCRs reactions.1
Hydrazones exhibit a wide range of pharmaceutical activities.2 Among these hydrazones,
thiazol-2-yl hydrazones have attracted the attention for their diverse medicinal properties
including: anti-tuberculosis,3 antibacterial,4 anti-malarial,5 antifungal activity,6 histone
acetyltransferase anhibitors,7 human monoamine oxidase (hMAO) A and B enzymes
inhibitors,8 anti-tumor,9 and many others.
Thiocarbohydrazide has been extensively employed for the construction of heterocyclic
compounds with biological and pharmacological interest.12
In the course of our research in exploiting thiocarbohydrazide in the construction of
substituted thiazoles,13 we targeted molecules that contain thiazole ring bearing two
hydrazine moieties on hope that the additional hydrazone motif will enhance the
biological activities of the thiazolyl hydrazone according to the general principles of drug
design and discovery.
2

The step-wise synthesis of thiazole ring attached to two hydrazone motifs has been
reported14, Scheme 1. The bis-thiocarbohydrazone was cyclized with phenacyl choride to
provide the thiazole compound. This type of cyclization is straightforward and no
chemoselectivity is involved. Although this two-step synthesis provided the target
compound in very good yield, a one-pot multicomponent route would be advantageous
since it eliminates the synthesis and purification of the thiocarbohydrazones.
A literature survey revealed that one pot multi-component reaction of one equivalent of
thiosemicarbazide, two equivalents of aldehydes or ketones and one equivalent of
phenacyl halides afforded thiazol-2-yl hydrazones.15 Surprisingly the one pot multi-
component reactions of thiocarbohydrazide (structurally similar to thiosemicarbazide)
with aldehydes or ketones and phenacyl bromides in (1: 2<: 1) equivalent ratios provided
always substituted 1, 3, 4-thiadiazine,16 Scheme 2. The same multicomponent reactions
in (1:1:1) equivalent ratios also provided 1, 3, 4-thiadiazine as main product.17 These
reactions proceed by formation of the 2-hydrazino-1,3,4-thiadiazine which then
undergoes condensation with aldehydes or ketones.
The reported literature suggested that the only route to thiazole compounds with two
hydrazine motifs is only a step-wise synthesis. However, we decided to investigate a one
pot multicomponent route to these compounds. At the onset of our experiments, A
mixture of thiocarbohydrazide, phenacyl bromide and benzaldehyde (1:1:2) in ethanol
was heated at 60°C for two hours in the presence of catalytic amount of acetic acid (20
3

mol%), after which TLC indicated full consumption of thiocarbohydrazide, scheme 3.
The product precipitated on cooling and was recrystallized from ethanol.
The 1HNMR spectrum for the solid (compound 4a) showed a singlet at 6.80 ppm (See
supporting info.) which accounts for the five membered ring product. 1HNMR spectrum
for the crude solid did not show any signal corresponds to the six membered thiadiazine
rings. In all other experiments, Scheme 3, that provided compounds (4a-j), table 1,
singlet in the range of δ 6.16-7.14 ppm was observed. 1HNMR of crude reactions
mixtures showed no thiadiazine ring formation. When the reaction was repeated with
catalytic amount of sodium acetate AcONa (20 mol%), same product was obtained with
almost the same yield (70%) after two hours heating at 60°C . The increase in the catalyst
loading of acetic acid (30 mol%) did not improve the yield. Surprisingly, when the
reaction was repeated employing similar procedure reported by Vedula group16a,b, Only
and exclusively the thiazole compound 4a formed. The reaction afforded compound 4a
upon refluxing for three hours without any catalyst.
A plausible mechanism of the formation of compound 4a is depicted in Scheme 4. We
believe that the reaction starts by the acid catalyzed condensation of thiocarbohydrazide
with two equivalents of the aromatic aldehydes to form bis-thiocarbohydrazone. The SN2
type attack of bis-thiocarbohydrazone sulfur on the C-Br gives intermediate A.
Subsequent attack of NH nitrogen on the C=O of the phenacyl bromide leads to the
formation of intermediate B which undergoes acid catalyzed dehydration to form
compound 4a.
4

The mechanism was proposed based on a set of control experiments, scheme 5. The
results of the control experiments suggest that in order to form the five membered
thiazole ring in all cases, bis-thiocarbohydrazones must form initially followed by
cyclization with phenacyl bromide.
The reaction of thiocarbohydrazide 1 with phenacyl bromide 3a provided 2-hydrazino-
1,3,4-thiadiazine 9, which implies that the first step in the mechanism should not involve
this type of cyclization. The cyclization of the mono-thiocarbohydrazones 5 with
phenacyl bromide 3a afforded substituted thiazole 10. While the mono-
thiocarbohydrazones 6 afforded 1,3,4-thiadiazine 11. Both chemoselectivities were
reported in literature 18. These different chemoselectivities suggest that reaction pathway
should not involve this type of cyclization since all products were five membered thiazole
ring exclusively.
The cyclization of bis-thiocarbohydrazones 7 and 8 with phenacyl bromide 3a provided
substituted thiazole ring 4a and 4h respectively in slightly higher yields than the
multicomponent protocol. This was an additional proof of the suggested structure resulted
from the one-pot multicomponent protocol. These results imply that the mechanism of
the reaction involves the cyclization of bis-thiocarbohydrazones with phencyl bromides.
5

The results also prove that the one pot multicomponent synthesis is more efficient than
the cyclization of bis-thiocarbohydrazones with phenacyl bromides since it reduces
number of steps and minimizes purification efforts without significantly affecting the
yield
To the best of our knowledge, this is the first report where a one pot-multicomponent
reaction of an aldehyde, phenacyl bromide and thiocarbohydrazide provides a five
membered thiazole ring.
In conclusion, in contrast of the reported examples, the acid catalyzed one-pot multi-
component reaction of one equivalent of thiocarbohydrazide, two equivalents of aromatic
aldehydes and one equivalent of phenacyl bromides afforded the five membered thiazole
ring bonded to two hydrazone moieties.
Procedure For The Synthesis Of Compound 4c: (Detailed Procedures And
Spectroscopic Data Are Provided In The Supporting Information)
a mixture of 4-anisaldehyde (1.36 gm, 1.22 mL, 10 mmol), thiocarbohydrazide (0.53 gm,
5 mmol), phenacyl bromide (1.00 gm, 5 mmol) and catalytic amount (20 mol%) of acetic
acid in ethanol (15 mL) was heated at 60o C for 2 hours. The progress of the reaction was
monitored by TLC. After reaction completion, the mixture was cooled down and the solid
obtained was filtered off and recrystallized from ethanol to give 4c as ligh yellow
needles, mp 147-148 oC, 1.79 gm, 81% yield. 1H NMR (CDCl3, 400 MHz) δ 3.81 (s, 3H,
OCH3), 3.83 (s, 3H, OCH3), 6.88-6.92 (m, 5H CH), 7.39 (m, 5H, CH), 7.69 (d, J= 8.8 Hz
, 2H, CH), 7.88 (d, J= 8.8 Hz , 2H, CH), 8.02 (s, 1H, NCH), 9.50 (s, 1H, NCH). 13C
6

NMR (CDCl3, 100 MHz): 55.4, 55.5, 106.6, 114.2, 114.4, 122.8, 125.5, 127.2, 129.2,
129.8, 130.2, 132.9, 140.1, 153.3, 162.1, 162.5, 164.2, 169.9. IR (KBr) cm-1: 1603(C=N),
1568, 1512 (C=C) aromatic. Anal. calcd for C25H22N4O2S: C, 67.85; H, 5.01; N, 12.66;
S, 7.25. Found: C, 67.60; H, 5.33; N, 12.69; S, 7.05.
ACKNOWLEDGMENT
The financial support of this work by the Deanship of Graduate Studies and Research at
Yarmouk University is highly acknowledged (project No. 29/2014). Hasan Tashtoush
thanks Jordan University of Science and Technology for his sabbatical stay.
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9

Table 1 Acid catalyzed three-component reaction of thiocarbohydrazide with aldehydes
and phenacyl bromides
Comp.
2a, 4a
2a, 4b
2b, 4c
2b, 4d
2c, 4e
2c, 4f
Ar
X
H
Br
H
Yield%a
C6H5-
72
68
81
76
74
72
64
C6H5-
p-CH3OC6H4-
p-CH3OC6H4- Br
p-CH3C6H4-
p-CH3C6H4-
p-
H
Br
Br
2d, 4g
(CH3)2NC6H4-
2-furyl-
Br
H
86
88
85
2e, 4h
2f, 4i
2f, 4j
2-thienyl-
2-thienyl-
Br
aIsolated yield
10

Scheme 1 The step-wise synthesis of thiazole ring
11

Scheme 2 Reported one pot-multi component reactions of thiocarbohydrazide with
excess of aldehydes or ketones and phenacyl bromides
12

Scheme 3 One pot multi-component reaction of thiocarbohydrazide with aromatic
aldehydes and phenacyl bromides.
13

Scheme 4 A plausible mechanism for the acid catalyzed one pot three-component
formation of compounds 4a.
14

Scheme 5 Control experiments to probe the mechanism of formation of compounds 4.
15

Figure 1. Thiazol-2-yl hydrazones of reported biological activities
16