Straightforward Approach Toward Dihydrothiazoles via Intramolecular Bromocyclization

Article abstract of DOI:10.1080/00397911.2015.1067707

An intramolecular bromonium ion-assisted cyclization with sulfur as an internal nucleophile is described. Starting from benzoyl chlorides, this method provides an easy procedure for the synthesis of dihydrothiazole derivatives in moderate to good yields.

Full text of DOI:10.1080/00397911.2015.1067707

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Straightforward Approach Toward
Dihydrothiazoles via Intramolecular
Bromocyclization
Seyed Esmail Sadat-Ebrahimia, Marzieh Ganjizadeh Zarja, Setareh
Moghimib, Azadeh Yahya-Meymandia, Mohammad Mahdavib, Saman
Arabb, Abbas Shafieeb & Alireza Foroumadib
a School of Pharmacy, International Campus, Tehran University of
Medical Sciences, Tehran, Iran
Click for updates
b Department of Medicinal Chemistry, Faculty of Pharmacy and
Pharmaceutical Sciences Research Center, Tehran University of
Medical Sciences, Tehran, Iran
Accepted author version posted online: 15 Jul 2015.Published
online: 15 Jul 2015.
To cite this article: Seyed Esmail Sadat-Ebrahimi, Marzieh Ganjizadeh Zarj, Setareh Moghimi, Azadeh
Yahya-Meymandi, Mohammad Mahdavi, Saman Arab, Abbas Shafiee & Alireza Foroumadi (2015):
Straightforward Approach Toward Dihydrothiazoles via Intramolecular Bromocyclization, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
DOI: 10.1080/00397911.2015.1067707
To link to this article: http://dx.doi.org/10.1080/00397911.2015.1067707
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Synthetic Communications1, 0: 1–6, 2015
Copyright © Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397911.2015.1067707
STRAIGHTFORWARD APPROACH TOWARD
DIHYDROTHIAZOLES VIA INTRAMOLECULAR
BROMOCYCLIZATION
Seyed Esmail Sadat-Ebrahimi,1 Marzieh Ganjizadeh Zarj,1
Setareh Moghimi,2 Azadeh Yahya-Meymandi,1
Mohammad Mahdavi,2 Saman Arab,2 Abbas Shafiee,2 and
Alireza Foroumadi2
1School of Pharmacy, International Campus, Tehran University of Medical
Sciences, Tehran, Iran
2Department of Medicinal Chemistry, Faculty of Pharmacy and
Pharmaceutical Sciences Research Center, Tehran University of Medical
Sciences, Tehran, Iran
GRAPHICAL ABSTRACT
Abstract An intramolecular bromonium ion–assisted cyclization with sulfur as an internal
nucleophile is described. Starting from benzoyl chlorides, this method provides an easy
procedure for the synthesis of dihydrothiazole derivatives in moderate to good yields.
Keywords Benzoyl chloride; bromocyclization; dihydrothiazole; N-bromosuccinimide
(NBS)
INTRODUCTION
The electrophilic addition of halogens to alkenes has been utilized by chemists
since 1851.[1] The resulting intermediate exhibited considerable synthetic applications
to access further functionality or complexity.[2] In particular, the nucleophilic attack
to this reactive intermediate, the halonium electrophile, in an intra- or intermolecular
fashion afforded an array of useful products. Halocyclization is a well-known
intramolecular attack to halogen-activated double bonds for the construction of het-
erocyclic compounds[3] even with asymmetric induction.[4] In this protocol, different
Received January 18, 2015.
Address correspondence to Alireza Foroumadi, Department of Medicinal Chemistry, Faculty of
Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran,
Iran. E-mail: aforoumadi@yahoo.com
1

2
S. E. SADAT-EBRAHIMI ET AL.
nucleophiles such as carbon, nitrogen, and oxygen are applicable and make this
method more attractive for the construction of halogenated natural products.[5]
2-Aminothiazolines have been regarded as privileged scaffolds possessing a wide
range of biological activities, including neuronal acetylcholine receptor modulators,[6]
antimicotic agents,[7] antimicrobial agents,[8] and nitric oxide synthase inhibitors.[9]
Thiazolines were also investigated as an alternative substituent to find new riluzol-like
drugs. Riluzol is known as the only drug for the suppression of amyotrophic lateral
sclerosis (ALS) progress.[10] Among the molecular recognition processes based on
the photophysical behaviors,[11] thiazoline-metal-based receptors have found an
important place as fluorescent probe for specific anion species in biomedical studies.[12]
The predominant strategy toward the thiazoline core involves dehydrative
cyclization of hydroxyethyl-thioureas using HCl[13] and carbonyl- and thiocarbonyl-
diimidazoles.[14] The Mitsunobu reaction is also considered as an alternative method
but tends to produce mixtures of N and S cyclization products.[15] With these results
in hand, finding new approaches to this valuable core seems inevitable. Accordingly,
we tried to investigate the intramolecular addition of sulfur to the activated double
bond to synthesize 2-aminothiazoline derivatives containing possible handles for
further derivatization.
RESULTS AND DISCUSSION
In continuation of our previous efforts to report versatile methodologies for the
synthesis of heterocycles,[16] herein we report a straightforward approach for the syn-
thesis of N-(5-(bromomethyl)-4,5-dihydrothiazol-2-yl)benzamide derivatives 4a–g.
Based on the application of N,N-disubstituted thiourea derivatives,[17] which
were identified as potentially useful substrates in the synthesis of thiazoles,[18] we
tried to generate a molecule containing thiourea and a double bond at the same time.
Focusing on this strategy, the reaction of benzoyl isothiocyanate derivatives,
prepared in situ by the reaction of benzoyl chlorides and ammonium thiocyanate,
with allyl amine in a one-pot manner was chosen.[19] Then, adducts 3a–g were sepa-
rated and subjected without further purification to 1 equiv. of N-bromosuccinimide
(NBS) in refluxing acetone to afford 4a–g in 50–77% yields (Scheme 1). Among dif-
ferent double-bond activators, we have chosen NBS as an inexpensive, commercially
available, and effective cyclization reagent.[20]
Scheme 1. Synthesis of N-(5-(bromomethyl)-4,5-dihydrothiazol-2-yl)benzamides 4a–g.

STRAIGHTFORWARD ROUTE TOWARD DIHYDROTHIAZOLES
3
Table 1. Effect of various solvents on reactiona
Entry
Solvent
Temp. (°C)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
CH3CN
THF
1,4-Dioxane
Dichloromethane
DMF
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
Reflux
12
12
12
12
12
12
12
1.5
46
31
44
29
39
33
53
73
DMSO
Acetone
Acetone
aReaction condition: N-(allylcarbamothioyl)benzamidec (1 equiv.), NBS (1 equiv.), solvent (3 mL).
bIsolated yields.
cPrepared according to Ref. [17].
A survey on the solvent and temperature in the cyclization step revealed that
acetone at room temperature is the best solvent among tetrahydrofuran (THF),
dimethylformamide (DMF), dimethylsulfoxide (DMSO), dioxane, dichloromethane,
and acetonitrile after 12 h (Table 1, entries 1–7). It is noteworthy that increasing
the temperature led to the reaction completion within 1.5 h and afforded the desired
product in improved yields (Table 1, entry 8).
After optimization, we turned our attention to evaluate the generality of
this reaction. A series of benzoyl chlorides were investigated for the synthesis of
substituted thiazolines. It was found that the introduction of different electron-
withdrawing groups in either the ortho, meta, or para positions did not affect the
isolated yield and the reaction time, just in the case of fluorine as substituent
a significant drop in yield was observed (Table 2).
The structures of compounds 4a–g were determined from their infrared (IR),
1
mass spectroscopic (MS), and H and 13C NMR spectral data. The molecular ion
peak at m=z 331, 11 distinct signals in 13C NMR spectrum, and the broad peak
1
at 8.73 ppm in H NMR confirmed the proposed structure of 4c. The absorption
bonds at 3307, 1703 cmꢀ1 related to secondary amide proton and C=O are also in
agreement with the desired product.
Table 2. Scope of the synthesis of thiazolines
Entry
Product
Ar
Time (min)
Yield (%)a
1
2
3
4
5
6
7
4a
4b
4c
4d
4e
4f
C6H5
90
75
80
83
72
85
73
73
70
77
65
50
68
74
2-Cl-C6H4
3-Cl-C6H4
4-Cl-C6H4
2-F-C6H4
3-NO2-C6H4
4-NO2-C6H4
4 g
aIsolated yields.

4
S. E. SADAT-EBRAHIMI ET AL.
CONCLUSION
In conclusion, we have reported the NBS-driven intramolecular 5-exo attack
heterocyclization of N-(allylcarbamothioyl)benzamides. The presence of halogens
on the phenyl ring and in the side chain made this product amenable for further func-
tionalizations, considering the fact that the thiazoline core along with other hetero-
cyclic units would be useful for biological responses or lowering toxicity. Further
applications of this scaffold in medicinal chemistry are in progress in our laboratory.
EXPERIMENTAL
Melting points were taken on a Kofler hot-stage apparatus and are uncorrected.
1H and 13C NMR spectra were recorded on Bruker FT-400 and 500 instruments,
using tetramethylsilane (TMS) as an internal standard. The infrared (IR) spectra
were obtained on a Nicolet Magna FTIR 550 spectrophotometer (KBr disks). Mass
spectra were recorded on an Agilent Technology (HP) mass spectrometer operating
at an ionization potential of 70 eV. Elemental analyses were carried out with
a Perkin-Elmer model 240-C apparatus.
Synthesis of N-(5-(Bromomethyl)-4,5-dihydrothiazol-2-yl)
Benzamide Derivatives
Benzoyl chloride derivatives (1 mmol) were added to a solution of ammonium
thiocyanate (1 mmol) in 3 mL dry acetone. After 30 min stirring in refluxing acetone,
the solution was cooled to 0–5 °C and allyl amine (1 mmol) was added dropwise and
stirred at room temperature. After completion, the solution was poured into cold
water and the precipitate was filtered off. NBS (1 mmol) was added to the crude
product (1 mmol) dissolved in 3 mL dry acetone. Then, the temperature was increased
to reflux and continued for the appropriate time. After this time, the residue was
purified by column chromatography on silica gel by petroleum ether=ethyl acetate
(PE=EA) 15:1 to afford 4a–g as a white powder.
N -(5-(Bromomethyl)-4,5-dihydrothiazol-2-yl)-2-chlorobenzamide (4b)
Yield: 0.23 g (70%); white powder; mp 118–119 °C. IR (KBr): 3303, 1695, 1607,
1
1441, 1295, 1083, 756 cmꢀ1. H NMR (500 MHz, DMSO-d6): d ¼ 3.67 (d, J ¼ 11.9
Hz, 2H), 3.74–3.81 (m, 2H), 4.12–4.21 (m, 1H), 7.38–7.39 (m, 1H), 7.45–7.47 (m,
2H), 7.65 (d, J ¼ 7.3 Hz, 1H), 10.39 (brs, 1H). 13C NMR (125 MHz, DMSO-d6):
d ¼ 36.0, 47.0, 50.8, 126.9, 130.0, 130.1, 130.6, 131.3, 136.7, 169.5, 173.3. Anal. calcd.
for C11H10BrClN2OS: C, 39.60; H, 3.02; N, 8.40. Found: C, 39.39; H, 2.90; N, 8.12.
FUNDING
This work was supported by a grant from the research council of Tehran
University of Medical Sciences, International Campus.

STRAIGHTFORWARD ROUTE TOWARD DIHYDROTHIAZOLES
5
SUPPLEMENTAL MATERIAL
1
Full experimental details and H and 13C NMR spectra for this article can be
accessed on the publisher’s website.
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