Sequential change in one-pot, three-component protocol: A stepping stone in heterocyclic synthesis

Article abstract of DOI:10.1080/00397911.2016.1178775

Two different heterocycles, thiazole-2-imines and imidazole-2-thiones, have been conveniently synthesized by just altering the sequential order (1+2+3 or 1+3+2) when combining the same components [aryl amine (1), aryl isothiocyanate (2), and phenacyl bromide (3)] in one-pot, three-component protocols. The third possible sequential order of combination (2+3+1) chemoselectively affords thiazole-2-imine. The finding is a stepping stone in the synthetic applicability of sequential one-pot, three-component protocols.

Full text of DOI:10.1080/00397911.2016.1178775

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
Sequential Change in One Pot Three Component
Protocol – a Stepping Stone in Heterocyclic
Synthesis
Ranganathan Raja, Dinesh Murugan, Archana Sivasubramaniyan, Jaabil
George, Sakthivel Perumal, Ponnuswamy Alagusundaram, Mohan Raj
Jayakumar & Murugavel Saminathan
To cite this article: Ranganathan Raja, Dinesh Murugan, Archana Sivasubramaniyan,
Jaabil George, Sakthivel Perumal, Ponnuswamy Alagusundaram, Mohan Raj Jayakumar
& Murugavel Saminathan (2016): Sequential Change in One Pot Three Component
Protocol – a Stepping Stone in Heterocyclic Synthesis, Synthetic Communications, DOI:
10.1080/00397911.2016.1178775
To link to this article: http://dx.doi.org/10.1080/00397911.2016.1178775
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Date: 01 May 2016, At: 23:08

SEQUENTIAL CHANGE IN ONE POT THREE COMPONENT PROTOCOL – A
STEPPING STONE IN HETEROCYCLIC SYNTHESIS
Ranganathan Raja1, Dinesh Murugan1, Archana Sivasubramaniyan1, Jaabil George1,
Sakthivel Perumal1, Ponnuswamy Alagusundaram1,, Mohan Raj Jayakumar2, Murugavel
Saminathan2
1Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University,
Madurai, India, 2Department of Physics, Thanthai Periyar Government Institute of
Technology, Vellore, Tamilnadu, India
Address Correspondance to Ponnuswamy Alagusundaram: Department of Organic
Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai-625021, India.
E-mail: ramradkrish@yahoo.co.in
Abstract
As a novel synthetic diversity, two different heterocycles viz. thiazole-2-imines and
imidazole-2-thiones have been conveniently synthesized by just altering the sequential
order (1+2+3 or 1+3+2) of combining the same components viz. aryl amine (1), aryl
isothiocyanate (2) and phenacyl bromide (3) in one pot three component protocols. The
third possible sequential order of combination (2+3+1) chemoselectively affords thiazole-
2-imine. The finding is a stepping stone in the synthetic applicability of sequential one-
pot three component protocols.
1

KEYWORDS: stepping stone, sequential change, thiazole-2-imine, imidazole-2-thione,
one-pot, three components
INTRODUCTION
Imidazole-2-thione and thiazole-2-imine derivatives possess a variety of bioactivity.[1–3]
There are many protocols for the synthesis of thiazole-2-imine derivatives[4–16] and
imidazole-2-thione derivatives[17–25] from different starting materials. However, to the
best of our knowledge, there is only a single report,[26] wherein two different five
membered heterocycles have been prepared by using the same components. Herein, we
report a novel observation, that is, the synthesis of two different heterocycles from the
same components by taking into account the various possible inter-component reactivities
and subsequently changing the sequence of their combination in a one pot three
component reaction.
Three component reactions have emerged as a potential tool in organic syntheses.
Some named reactions such as Biginelli condensation, Mannich, Hantzsch, Petasis,
Passerini and Strecker reactions have paved the way for the synthesis of diversified
heterocyclic compounds. These one pot reactions generally involve the combination of
the components giving little importance to the various possible inter-reactivity of the
individual components with each of the other components combined. Hence, little
emphasis is being given to the sequence of combining the components in many multi-
component reactions. One such three component reactions involving aryl amine, aryl
isothiocyanate and phenacyl bromide as the components has been reported to afford
2

thiazole-2-imine.[4–16] On the other hand, in contrast to this Zeng.et.al. have reported that
the same three component reaction yield imidazole-2-thione and not the thiazole-2-imine
as reported.[24] In continuation of this controversy, Singh. et. al. have revisited to the
same three component reaction once again re-establishing their original claim that is the
product formed is thiazole-2-imine and not imidazole-2-thione.[27] Though all these
reports have resulted in the synthesis of thiazole-2-imine alone via. the three component
protocol, we herein report that by considering the inter-component reactivities and
changing their sequence of combination, it is possible to synthesize both the above said
heterocycles viz. thiozole-2-imine and imidazole-2-thione.
RESULTS AND DISCUSSION
From a deeper look on these components, it could be envisaged that aryl amine will react
with both aryl isothiocyanate and phenacyl bromide separately to afford thiourea and
mono phenacyl amine respectively which can further react with the third component to
afford two different heterocycles viz. thiazole-2-imine (4) and imidazole-2-thione (5)
derivatives respectively (Scheme 1).
In view of the above presumption, the three components were combined by two different
sequential orders as shown in Scheme 1 affording 4 and 5 in excellent yields, the details
of which are presented vide infra.
At the outset, the first sequential order (1+2+3) of combining the components was
attempted i.e. aryl amine (1) was added to aryl isothiocyanate (2) in ethanol to afford
3

thiourea immediately (as monitored by TLC) to which was added the third component
viz. phenacyl bromide (3) and the mixture was refluxed for about 30 minutes to afford the
corresponding thiazole-2-imines in good to excellent yields (Table 1).
On the other hand, the second sequential order of combination (1+3+2) of the above said
components was attempted i.e. aryl amine (1) was added to ethanolic solution of
phenacyl bromide (3) and refluxed for 30 minutes and then aryl isothiocyanate (2) was
added and further refluxed for 20 minutes. To our delight, this change in the sequential
order resulted in the formation of the corresponding imidazole-2-thione (5) in good to
excellent yield (Table 2).
As a representative example, the intermediate viz. 1,3-diphenylthiourea formed by
reaction of aniline (1a) and phenyl isothiocyanate (2a) has been isolated. Similarly, the
intermediate viz. mono phenacyl aniline by the reaction of aniline (1a) and phenacyl
bromide (3a) has been isolated. These intermediates on reaction with the third
component afford the expected products viz. thiazole-2-imine (4a) and imidazole-2-
thione (5a) respectively. The intermediates were characterized by comparison of their
physical and spectral data with that of the authentic samples.
Finally, the third possible sequential order of combining the three components (2+3+1)
was also attempted i.e. aryl isothiocyanate (2) was added to a solution of phenacyl
bromide (3) in ethanol followed by the addition of aryl amine (1) and the mixture was
refluxed. This resulted in the formation thiazole-2-imine (4) as the exclusive product
4

indicating that aryl amine (1) chemoselectively reacts with aryl isothiocyanate (2) to
afford the thiourea which subsequently reacts with phenacyl bromide (3) to give the
product.
Of the compounds synthesized, except two heterocycles (4a and 4b)[16], others are
hitherto unknown. All the synthesized compounds were characterized by 1H and 13C
NMR (1D & 2D). X-ray crystal structure of a representative compounds (4k and 5k)
unambiguously confirms the structural assignment.
CONCLUSION
The novelty of synthesizing two different heterocycles viz.thiazole-2-imines and
imidazole-2-thiones from the same components viz. aryl amine, aryl isothiocyanate and
phenacyl bromide through one-pot protocol by just changing the sequential order of
combining the components is reported. This interesting observation is a stepping stone in
the synthetic applicability of one pot sequential three component protocols in
heterocyclic synthesis. It conveys that looking at the various possible inter-component
reactivities before planning a multicomponent reaction may pave the way for newer
synthetic applicability.
EXPERIMENTAL SECTION
General Procedure For The Synthesis Of Thioazole-2-Imine Derivatives (4)
To the amine (1, 1 mmol) in ethanol (3mL), aryl isothiocyanate (2, 1 mmol) was added
followed by phenacyl bromide (3, 1 mmol) and the solution was refluxed for 30 minutes.
5

After the completion of the reaction (as monitored by TLC), the reaction mixture was
cooled to room temperature and poured onto excess of crushed ice to afford the
corresponding thioazole-2-imine (4) as a solid which was filtered and recrystallized from
distilled ethanol.
(Z)-N-(3,4-Diphenylthiazol-2(3H)-Ylidene)Aniline (4a)[16]
1
Obtained as a white solid; Mp.191-193 ºC. H NMR (300 MHz, CDCl3: δ 7.33 – 7.17
(m, 10H), 7.09 – 6.98 (m, 5H), 5.94 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 159.96,
151.84, 139.93, 138.06, 131.69, 129.33, 128.85, 128.77, 128.23, 128.18, 127.44, 123.14,
121.56, 97.21.
General Procedure For The Synthesis Of Imidazole -2-Thione Derivatives (5)
To the amine (1, 1 mmol) in ethanol (3mL), phenacyl bromide (3, 1 mmol) was added
and refluxed for 30 minutes and then aryl isothiocyanate (2, 1 mmol) was added to the
solution and further refluxed for 20 minutes. After the completion of the reaction (as
monitored by TLC), the reaction mixture was cooled to room temperature and poured
onto excess of crushed ice to afford the corresponding imidazole-2-thione (5) as a solid
which was filtered and recrystallized from distilled ethanol.
1, 3, 4-Triphenyl-1H-Imidazole-2(3H)-Thione (5a)
1
Obtained as a white solid; Mp.171-172 ºC. H NMR (300 MHz, CDCl3: δ 7.72 – 7.69 (m,
2H), 7.55 – 7.29 (m, 8H), 7.25 – 7.13 (m, 3H), 7.08 – 6.98 (m, 3H). 13C NMR (75 MHz,
CDCl3): δ 165.47, 138.04, 136.78, 131.46, 128.85, 128.83, 128.70, 128.48, 128.29,
6

128.20, 128.12, 127.69, 125.96, 116.10. Anal. Calc. for C21H16N2S: C, 76.80; H, 4.91; N,
8.53; S, 9.76. Found: C, 76.95; H, 4.90; N, 8.52; S, 9.75.
ACKNOWLEDGEMENTS
The authors thank to the Department of Science and Technology and UGC, New Delhi,
India for the financial support by sanctioning the UGC (BSR-meritorious) fellowship and
DST-PURSE programme and the IRHPA program for the purchase of a NMR
spectrometer.
SUPPORTING INFORMATION
Supplemental data for this article can be accessed on the publisher’s website
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Scheme 1. Sequential of the same components in the synthesis of different heterocycles
(4 & 5)
10

Table 1. One-pot three component synthesis of thiazole-2-imine derivatives (4a-m). a
aReaction conditions: To the amine (1, 1 mmol) in ethanol (3mL), aryl isothiocyanate (2, 1 mmol)
was added followed by phenacyl bromide (3, 1 mmol) and the solution was refluxed for 30 minutes.
11

Table 2. One-pot three component synthesis of imidazole-2-thione derivatives (5a-o). b
bReaction conditions: To the amine (1, 1 mmol) in ethanol (3mL), phenacyl bromide (3, 1 mmol)
was added and refluxed for 30 minutes and then aryl isothiocyanate (2, 1 mmol) was added to the solution
and further refluxed for 20 minutes.
12

Figure 1. X-ray crystal structure of the compound 4k[28]: Ellipsoid probability level 30%
13

Figure 2. X-ray crystal structure of the compound 5k[29] : Ellipsoid probability level 30%
14