Acid mediated synthesis of thiazolines, thiazoles and enamide derivatives from methyl enol ethers: Application towards synthesis of wilsoniamine B

Article abstract of DOI:10.1016/j.tetlet.2020.151675

An efficient metal-free synthesis of thiazolines, dihydrothiazole and enureas or thioureas from methyl enol ether with urea or thiourea derivatives in the presence of TFA (trifluoroacetic acid) are reported here. This synthetic protocol involves the formation of two bonds, C–N as well as C–S, in one step for the synthesis of thiazoline derivatives, dihydrothiazoles and a direct C–N bond for the synthesis of enamides with good to excellent yields. Further, this method was employed for the synthesis of wilsoniamine B alkaloid.

Full text of DOI:10.1016/j.tetlet.2020.151675

Journal Pre-proofs
Acid mediated synthesis of thiazolines, thiazoles and enamide derivatives from
methyl enol ethers: application towards synthesis of wilsoniamine B
Tapan Kumar Jena, Faiz Ahmed Khan
PII:
S0040-4039(20)30094-0
DOI:
https://doi.org/10.1016/j.tetlet.2020.151675
TETL 151675
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
26 December 2019
21 January 2020
23 January 2020
Please cite this article as: Jena, T.K., Khan, F.A., Acid mediated synthesis of thiazolines, thiazoles and enamide
derivatives from methyl enol ethers: application towards synthesis of wilsoniamine B, Tetrahedron Letters (2020),
doi: https://doi.org/10.1016/j.tetlet.2020.151675
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Acid mediated synthesis of thiazolines,
thiazoles and enamide derivatives from
methyl enol ethers: application towards
synthesis of wilsoniamine B
Leave this area blank for abstract info.
Tapan Kumar Jena and Faiz Ahmed Khan*
R1
R1
N
R2
X
X
R
R
1,2-DCE
R
R
S
S
OMe
R2
NH2
R1
or
NH
or
N
H
R1
TFA, 40 oC- 50 o
6-8 h
C
R2
N
X= O,S
X= O or S
R= H, Me, Et, Ph
C-S, C-N bond formation
Direct Enamide synthesis
Urea, thiourea as a nucleophile
Broad substrate scope
R1= Ar- (H, Alkyl, OMe, F, Br, NO2)
R= R1= (Cycloheptenyl)
R2= Ph, Ph-NH, NH2
Br
OMe
Br
Br
Me
O
N
Me
N
H
Application towards Wilsoniamine B

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Acid mediated synthesis of thiazolines, thiazoles and enamide derivatives from
methyl enol ethers: application towards synthesis of wilsoniamine B
Tapan Kumar Jena, Faiz Ahmed Khan
Department of Chemistry, Indian Institute of Technology Hyderabad, Kandi, Sangareddy, Telangana 502285, India
———
ARTICLE INFO
ABSTRACT
 Corresponding author. Tel.: (040) 2301 6084; e-mail: faiz@iith.ac.in
Article history:
Received
An efficient metal-free synthesis of thiazolines, dihydrothiazole and enureas or thioureas from
methyl enol ether with urea or thiourea derivatives in the presence of TFA (trifluoroacetic acid)
Received in revised form
Accepted
Available online
are reported here. This synthetic protocol involves the formation of two bonds, C-N as well as
C-S, in one step for the synthesis of thiazoline derivatives, dihydrothiazoles and a direct C-N
bond for the synthesis of enamides with good to excellent yields. Further, this method was
employed for the synthesis of wilsoniamine B alkaloid.
2009 Elsevier Ltd. All rights reserved.
Keywords:
Methyl enol ethers
Thiazolines
C-N, C-S bond
Wilsoniamine B alkaloid
by Zhang and co-worker from vinyl azides and potassium
thiocyanates in the presence of Pd-catalyst.7 An one-pot, three-
Introduction:-
Thiazoline derivatives which contain a nitrogen-sulfur (N-S)
bond are known to have promising anti-HIV, antibacterial,
antiviral, anticancer, antifungal activities1,2 and expanded
applications in peptide synthesis.3 2-Aminothiazoline moiety is
an important pharmacophore among nitrogen and sulfur-
containing heterocycles with wide spectrum of pharmaceutical
agents such as cefotaxime,4a meloxicam,4b nitazoxanide with
novel potent antiprotozoal agent, and compound showcasing
herbicidal activity4c (Figure 1). Thus, N-S containing bonds are
functionally and biologically important.
component reaction for the syntheses of thiazolidin-4-ol
derivatives,8a and one-pot synthesis of glycothiazolines from
glycals have also been reported in the literature.8b Copper-
catalyzed coupling reaction also established for the synthesis of
2-aminothiazole.9 Enantiospecific synthesis of thiazolidine
derivatives from inactivated chiral aziridines with isothiocyanates
were also exploited in the literature.10 Triflouromethylation of
alkenes with thiourea from Togni reagent were used for the
syntheses of thiazolines and thiazines by intramolecular C-S
bond formation.11 Recently, a radical pathway was employed for
the syntheses of 2-aminothiazoles from active methylene
compound and thiourea in the presence of TBHP/AIBN.12 Cross-
dehydrogenative coupling reaction was also used for the
synthesis of iminothiazolines.13 Similarly, enureas or thioureas
(enamides) motifs are found in several biologically active
molecules,14a and in important organic substrates.14b The
conventional method involves their synthesis from the reaction of
imine with isocyanates.15 The reported drawback in these
reactions is the toxicity of isocyanates and removal of water
during the reactions. Other methods have also been developed for
their synthesis, such as, carbolithilation of amines,16 Pd-catalyzed
C-N coupling reaction of alkenyl tosylates or mesylates with urea
derivatives,17 reaction of acylamino alcohols with Lawesson’s
reagent,18 hydroalumination of ketenimines.19 Although,
syntheses of thiazoline core containing compounds have been
known in the literature, to the best of our knowledge, there has
O
O
O
N
O
O
N
O
OH
H
NO2
O
S
N
S
N
H
O
HN
(Nitazoxanide)
(Herbicidal activity)
(Latrunculin A)
S
O
Figure 1. Biologically important natural products and drugs.
Due to their biological significance, syntheses of thiazoline
containing scaffolds has been attractive goal.5 For example,
several strategies have been developed for the syntheses of such
heterocycles containing derivatives and the most common
methods are summarized in Scheme 1. Among them, compound
with α-halo carbonyl and thiourea are the common methods
utilized for synthesizing these derivatives.6 An alternative method
for the synthesis of 4-substituted 2-aminothiazole was reported

2
Tetrahedron
been no method reported for direct synthesis of thiazolines,
best-optimized condition were identified as 2.0 equivalent of
TFA as a reagent and 1,2-DCE at 40 oC for 8 h.
dihydrothiazoles and unsaturated enamides from methyl enol
ethers. Methyl enol ethers are good starting materials because
they can act as both electrophile as well as nucleophile20 and also
easy to prepare. In continuation to our previous work, where enol
ethers were used as a nucleophile, whereas in this work methyl
enol ether acts as an electrophile. This method also provides an
alternative to the existing methods where halogen containing
compounds are generally required. Therefore, we report a metal
free, acid-mediated method for the synthesis of thiazolines,
enamides from enol ethers via C-S and C-N bond formation.
Table-1. Optimization conditionsa,b
OMe
S
Me
Me
S
NH2
O
NH
Reagent
NH
MeO
solvent,
temperature
2a
1a
N
3a
entry
Reagent
(equiv.)
Solvent
Temp.
Time
(h)
Yield
(%)b
OH
CF3
N
O
(oC)
rt
DMF
rt
S
C
RNH2
S
Br
N
F3C
N
R
Ref. 8
1
2
BF3-OEt2
(1.0)
CH3NO2
CH3NO2
24
24
ND
ND
OAc
N
S
O
R1
R2
R
R2
LG
Ref. 9
S
N
Ref.6
R1
Bi(OTf)3
(0.5)
rt
R1
RNCS
H2N
NH2
NH
R2
3
4
FeCl3 (0.2)
Toluene
CH3CN
rt
24
12
ND
ND
O
O
NH2
NH
OTs
N
H
N
Pd
H
MeSO3H
(0.5)
rt- reflux
Ligand, base
Ref. 17
5
6
7
8
TfOH (0.5)
TfOH (0.5)
TFA (0.5)
TFA (1)
1,2-DCE
CHCl3
rt
40
rt
24
14
23
18
54
66
88
90
Scheme 1: Previous reports
This work: Methyl enol ether as electrophile
R1
R
R1
R
1,2-DCE
1.2-DCE
X
R2
NH
X
R
R
S
1,2-DCE
TFA
S
OMe
R1
R2
NH2
R1
N
N
R2
N
H
40
R2 = NH2, Ph-NH, Ph
X = S, O
Result and Discussion:
9
TFA (2)
1,2-DCE
40
8
90
To investigate the reaction condition, we selected enol ether (1a)
and N-phenyl thiourea (2a) as model substrates (Table 1).
Optimization of the reaction condition was carried out by
changing solvents, temperatures, and reagents. First, the reaction
was conducted in CH3NO2 as solvent with Lewis acids like BF3-
OEt2, Bi(OTf)3 as catalysts but the reaction didn’t work (Table 1,
entry 1-2). So we changed various types of catalysts and solvents
to check the feasibility of reaction and it was found that solvent
plays an important role in the formation of the desired product
(Table 1, entry 3-5). After observing product formation in
chlorinated solvents like 1,2-DCE, and CHCl3, we screened for a
suitable catalyst to improve the yield. When reaction was carried
out at room temperature in the presence of Bronsted acid like
TfOH (0.5 equivalents), we observed 54% yield with longer
reaction time (Table 1, entry 5). Similarly, when the reaction was
performed by using CHCl3 as a solvent yield has improved to
66% in 14 hours (entry 6). When trifluoroacetic acid (TFA) was
used in 1,2-DCE as a solvent at room temperature, the reaction
proceeded well with improvement of yield in longer reaction time
(entry 7). After observing very good yield, we thought of
increasing the catalyst to reduce the reaction time. When the
catalyst was increased to 1.0 equivalent or 2.0 equivalent reaction
time has reduced drastically with improvement in yield as well
(entries 8-9). Triflic acid (TfOH) in dichloromethane (DCM) also
gave the product in moderate yield (entry 10). In summary, the
10
TfOH (1.5)
DCM
rt
8
37
aReaction conditions: 1a (0.4 mmol), 2a (0.4 mmol), 1,2-DCE (4 ml).
bIsolated yields. ND = Not detected.
Under the optimized condition, the substrate scope of the reaction
were studied using a series of enol ethers with respect to different
thiourea or thiobenzamide derivatives (Table 2). As shown in
Table 2, different substituted enol ethers were converted into
corresponding thiazolines and thiazole derivatives in good to
excellent yield. First, the effect of the substituent on enol ethers
were explored. Substrate with electron-donating group like –
OMe, at different positions on aromatic ring of enol ethers (1a-
1d) were screened under the optimum condition with respect to
2a, affording the corresponding desired product in good yields
(3a-3d, Table 2). Similarly, alkyl substituent derived enol ether
1e reacted well with compound 2a to afford compound 3e in 68%
yield. Enol ether (1f) having fluoro substituent also gave the
product as expected in fair yield with 56% (3f), which was
further confirmed with single crystal X-ray analysis (Table 2).
Enol ether 1g (R=ethyl and R1=aryl) also converted into the
product (3g) with very well in 89% yield. Further, benzophenone
derived enol ethers (1h-1i) with electron-donating substituent

3
were tested, which afforded the expected product in good yield
(3h, 3i). While in the case of enol ether with 1j, both cyclization
(3j) and enthiourea (3j’) products were observed in 21% and
54% yields respectively.
substituent (2e) also reacted well with compound 1a and
afforded the product in excellent yield (4f).
Table-3: Direct Synthesis of Enureas or thioureas (Enamides).
X
a
,b
R2
X
2
R
Table-2. Scope of Enol ethers and Thioureas
R
1,2-DCE
OMe
NH
R2
NH2
R1
R1
TFA, 40 oC- 50 o
6-8 h
C
R1
5
1
R1
R
R
S
2
S
R
1,2-DCE
S
OMe
R2
NH2
N
4
R1
or
TFA, 40 oC- 50 o
6-8 h
C
N
N
H
S
S
1
3
S
NH
NH
Me
N
N
N
N
H
H
H
H
OMe
OMe
OMe
OMe
Me
MeO
F
F
NO2
, 42%
5c
, 75%
5b
, 71%
5a
Me
Me
Me
Me
S
OMe
OMe
S
S
S
NH
NH
NH
NH
84%
O
O
O
N
N
N
N
3a,
3b,
3c,
3d,
90%
91%
95%
NH
NH
NH
N
N
N
H
H
H
Me
Me
F
OMe
OMe
Me
Me
MeO
OMe
MeO
5d
, 72%
5f
, 80%
5e
, 88%
Me
S
Me
Me
O
S
O
S
N
S
S
OMe
NH
NH
NH
NH
NH
HN
NH
N
N
N
OMe
5g
H
N
3e,
68%
3f,
3g,
89%
56%
3h,
96%
MeO
OMe
MeO
OMe
OMe
OMe
Me
MeO
, 55%
5i
, 96%
5h
, 50%
S
MeO
Me
NH
N
H
aReaction conditions: 1 (0.4 mmol), 2 (0.4 mmol), 1,2-DCE (4 ml), TFA (2.0
equiv), for 6-12 h at 40-50 oC. bIsolated yields after silica gel column
chromatography.
OMe
S
N
S
N
S
NH
NH
Me
Me
N
3i,
3j,
3j',
54%
4a
, 37%
82%
21%
OMe
OMe
MeO
MeO
OMe
Me
Me
MeO
Me
S
OMe
S
S
After successfully synthesizing thiazolines and thiazoles, we
moved to synthesize enamide derivatives directly from enol
ethers because it serves as important building block in many
natural products22 as well as polymer synthesis. Different enol
ethers having donating as well as withdrawing substituents were
treated with urea, thiourea or benzamide derivatives for its
synthesis (Table 3). Enol ether 1k with –NO2 substituent when
treated with compound 2a, gave the enamide derivatives as E/Z
mixture in moderate yield (5a, Table 3). Compound 2a also
reacted well with benzophenone derived enol ethers 1l and 1m
having substituent like (-H, -F) and gave the products 5b, 5c in
71% and 75% yields respectively and compound 5c was further
determined by single crystal X-ray structure (Table 3). N-phenyl
urea (2f) derivative also gave the enamide derivatives (5d-5g) in
good to moderate yields. Even cyclic aliphatic enol ether 1n also
reacted with compound 2c and gave the product in 50% yield
(5h). Simple benzamide 2g derivative also underwent reaction
with enol ether 1h and delivered the product 5i in 96% yield.
Under similar reaction condition, compound 5c and 5d were
further reacted to check the feasibility of cyclization, however,
we didn’t observe any cyclized products after 24 h (starting
material recovered). The substrate scope in Table 2 and Table 3
indicates that the electron-rich enol ethers gave only cyclized
product with thiourea (thiazoline derivatives), whereas urea
derivative gave only enamide derivatives.
N
N
S
NH
S
N
N
N
O2N
H2N
4ec
4d
MeO
4f,
95%
, 30%
4c
, 33%
4b
, 24%
MeO
, 80%
MeO
aReaction conditions: 1 (0.4 mmol), 2 (0.4 mmol), 1,2-DCE (4 ml), TFA (2.0
equiv), for 6-8 h. bIsolated yields after silica gel column chromatography.
cReaction was carriedout at 60 oC.
In order to broaden the scope of this reaction, dihydrothiazoles
were also prepared by using simple benzothioamide derivatives
(2b, 2c, 2d, Table 2) with enol ethers. When compound 1h
reacted with benzothioamide 2b, a new product dihydrothiazole
(4a) formation was observed in moderate yield. Surprisingly,
when 1h was reacted with compound 2c, a new product (4b)
formation was achieved with aryl group migration in low yield.
1
The characteristic aryl attached C-H proton in H nmr appeared
at 5.66 (d, J = 6.6 Hz, 1H), 4.82 (d, J = 6.6 Hz, 1H) while the C-
H attached carbon in 13C appeared at δ 88.6 and 62.6. These
values are in agreement with the core structure containing 2,4-
diaryl thiazoline reported by Couture group.21 To check whether
migration will occur in acetophenone derived enol ethers or not,
compound 1a and 1g were treated similarly with compound 2c,
but we ended up with simple dihydrothiazole derivatives (4c and
4d) without migration of any group in 33% and 30% yields
respectively. Simple thiourea 2d also reacted well with enol ether
1h to give the product (4e) in 80% yield. To our delight electron-
withdrawing substituted thiourea derivative having –NO2

4
Tetrahedron
R1
R1
R1
R1
also could be used for the straightforward synthesis of
wilsoniamine B and the results were depicted in Scheme 3. When
the enol ether 1o was reacted with compound 2h in the presence
of trifluoroacetic acid in a sealed tube, resulted compound 6 in
77% yield. Further, wilsoniamine B (7) can be achieved by
employing the known protocol for methyl quaternization of
compound 6.23b
CF3-COO
CF3COOH
OMe
OMe
X
MeOH
OMe
H
N
X
HN
R
R
R
H
R
B
A
N
NH2
HN
HN
H-O-C-CF3
O
1
X
2
X=S or O
R1
R1
R1
S
X=S
H
H
N
HN
HN
X
HN
X
NH
R
R
R
3
5
C
HN
CONCLUSION:
In conclusion, we have disclosed a new strategy for the synthesis
of thiazoline, dihydrothiazole using urea or thiourea derivatives
as nucleophile with methyl enol ethers in good to excellent
yields. This method also involves metal free direct synthesis of
enureas or thioureas (enamides) derivatives. Further, the
applicability of this methodology was illustrated by synthesizing
wilsoniamine B marine natural product. This protocol also
provides an alternative route for the construction of quaternary
center.
Scheme 2. Plausible Mechanism for Direct Synthesis of
Enamides and Thiazolines
On the basis of observation from the substrate scope of the
reaction, a possible mechanism for direct synthesis of thiazoline
derivatives, enamide derivatives is shown in Scheme 2. First,
compound 1 will be protonated in the presence of trifluoroacetic
acid and further attack of nitrogen nucleophile of compound 2 at
the α-position of enol ether would take place to give the
intermediate (A), which may undergo -MeOH elimination to
furnish the compound 5, after tautomerization from intermediate
B. Next, the protonation of an alkene moiety may occur to give
benzylic carbocation intermediate C, and then intramolecular
nucleophilic attack of sulfur atom to the carbocation center will
take place to give thiazoline derivatives 3.
Acknowledgments
We gratefully acknowledge Department of Science and
Technology, Science and Engineering Research Board
(EMR/2017/003484), India for financial support. TKJ thanks
MHRD, India for the award of the research fellowship.
References and notes
From the substrate scope for the synthesis of enamide
derivatives which indicates nitrogen source as a nucleophile, we
further testified the utility of this methodology towards the
synthesis of alkaloid wilsoniamine B23a from enol ether 1o.
Wilsoniamine B possesses a unique hyxahydro-1H-pyrrolo[1,2-
c]imidazole-1-one ring system and was isolated from the
bryozoan species.
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Retrosynthesis:
Br
Br
OMe
OMe
Br
Me
OMe
3.
4.
NH
O
Br
Me
Br
N
Br
O
H
N
Me
O
Br
Br
Br
N
H
N
OMe
Me
N
H
Wilsoniamine B
Synthetic approach:
5.
6.
(a) D’hooghe, M.; Kimpe, N. D. Tetrahedron 2006, 62, 513–535.
(b) Albrecht, U.; Freifeld, I.; Reinke, H.; Langer, P. Tetrahedron
2006, 62, 5775–5786. (c) Sengoden, M.; Vijay, M.; Balakumar,
E.; Punniyamurthy, T. RSC Adv. 2014, 4, 54149-54157. (d)
Kumar, S. V.; Muthusubramanian, S.; Perumal, S. RSC Adv.,
2015, 5, 90451–90456.
(a) Zhu, Y. P; Yuan, J. J.; Zhao, Q.; Lian, M.; Gao, Q. H.; Liu, M.
C.; Yang, Y.; Wu, A. X. Tetrahedron 2012, 62 173-178. (b) King,
L. C.; Hlavacek, R. J. J. Am. Chem. Soc.1950, 72, 3722-3725. (c)
Wipf, P.; Aslan, D. C.; Southwick, E. C.; Lazo, J. S. Bioorg. Med.
Chem. Lett. 2001, 11, 313–317.
Br
OMe
Br
Br
OMe
Br
Br
OMe
HN Me
Br
Me
1,2-DCE
ref. 23b
Me
O
O
H
N
N
Br
N
Br
Br
O
TFA (2 equiv),
sealed tube,
100 o C, 12 h,
77%
H
Me
N
N
H
OMe
1o
6
2h
7
This approach
Wilsoniamine B
TFA, toluene
reflux, 30 h, 52%
Br
Br
OMe
ref. 23b
O
7.
8.
Chen, B.; Guo, S.; Guo, X.; Zhang, G.; Yu, Y. Org. Lett. 2015, 17,
4698-4701.
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Kumbhare, R. M. Eur. J. Org. Chem. 2014, 2468–2479, (b) Reid,
E. M.; Vigneau, E. S.; Gratia, S. S.; Marzabadi, C. H.; Castro M.
D. Eur. J. Org. Chem., 2012, 17, 3295-3303.
Br
Br
Br
Br
OMe
Our previous approach
OMe
Scheme 3. Synthetic Application
Previously, our group also reported its synthesis23b from
brominated homologated aldehyde with (S)-N-methylpyrrolidine-
2-carboxamide (2h). However, we envisaged that compound 1o
9.
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180-183.
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81, 11508-11513.

5
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6
Tetrahedron
Declaration of interests
☒ The authors declare that they have no known
competing financial interests or personal
relationships that could have appeared to influence
the work reported in this paper.
☐The authors declare the following financial
interests/personal relationships which may be
considered as potential competing interests:

7
Research Highlights
 Acid mediated synthesis of thiazolines and
enamide derivatives from methyl enol
ethers.
 Enol ethers acts as an electrophile.
 C-N and C-S bond formation was achieved.
 Application towards wilsoniamine
B
alkaloid.