One-Pot Strategy for Thiazoline Synthesis from Alkenes and Thioamides

Article abstract of DOI:10.1021/acs.orglett.7b00079

A convenient synthesis of a privileged pharmaceutical motif, thiazoline is accomplished. This reaction utilizes simple and readily available alkene and thioamide substrates in an intermolecular fashion via a simple one-pot procedure. A wide range of functional groups is tolerated, and the thiazoline product has been further utilized for the synthesis of the corresponding β-aminothiol and thiazole from routine hydrolysis and oxidation protocols.

Full text of DOI:10.1021/acs.orglett.7b00079

Letter
pubs.acs.org/OrgLett
One-Pot Strategy for Thiazoline Synthesis from Alkenes and
Thioamides
Nur-E Alom, Fan Wu, and Wei Li*
Department of Chemistry and Biochemistry, School of Green Chemistry and Engineering, The University of Toledo, 2801 West
Bancroft Street, Toledo, Ohio 43606, United States
S
* Supporting Information
ABSTRACT: A convenient synthesis of a privileged pharma-
ceutical motif, thiazoline is accomplished. This reaction utilizes
simple and readily available alkene and thioamide substrates in
an intermolecular fashion via a simple one-pot procedure. A
wide range of functional groups is tolerated, and the thiazoline
product has been further utilized for the synthesis of the
corresponding β-aminothiol and thiazole from routine
hydrolysis and oxidation protocols.
ligands in transition-metal-catalyzed coupling reactions.5 To
xpediting access to heterocycles, common structural motifs
Ein natural products and pharmaceuticals, directly from
gain access to this useful heterocyclic core, several synthetic
methods have been established.6 Currently, the condensation of
simple feedstock is an attractive synthetic strategy. Nitrogen-
cysteamine with nitriles, esters, or imidates represents the
method of choice for thiazoline synthesis (Scheme 1b).
However, limited availability of the β-aminothiols often hinders
the versatility of this method in accessing a diverse array of
thiazolines, particularly when potential structure−activity
relationship (SAR) studies are desired. Oftentimes, multistep
syntheses are required to gain access to the desired aminothiol
precursor. To partially circumvent the β-aminothiol availability
problem, methods involving condensation of β-amino alcohols
with carbonyl surrogates, followed by thionation of the amide
intermediate, and eventual ring closure to provide the
thiazolines have also been developed.7 Finally, intramolecular
strategies or α-halo carbonyl precursors have also been utilized
to construct the thiazoline core.8
and sulfur-containing thiazolines and their derivatives are
important classes of compounds owing to their frequent
appearances in bioactive natural products and pharmaceuticals.1
These molecules often exhibit a wide range of bioactivities
including anticancer, anti-HIV, antibiotic, and neurological
activities.2 For example, ritonavir, an antiretroviral drug
containing two thiazoles, has been indicated to treat HIV.2d
Firefly luciferin is also well known for its role in the
bioluminescence of fireflies (Scheme 1a).3 In addition, a
number of interesting natural products such as largazole,
curacin A, and tantazole B contain one or more thiazoline
subunits.4 Moreover, thiazolines have also been utilized as
Scheme 1. Direct Coupling of Alkene and Thioamide
Alkenes are highly versatile synthetic substrates for classic
reactions such as epoxidation, dihydroxylation, bromination,
etc. The synthetic utility of alkenes is further augmented by
their availability from commercial sources or reliable synthetic
operations.9 A range of thioamides are also commercially
available or readily synthesized from their amide counterparts
with sulfurating agents.10 To circumvent the β-aminothiol
availability problem in thiazoline synthesis, the development of
a general coupling reaction between alkenes and thioamides
would provide versatile access to a wide array of thiazoline
structures (Scheme 1c).11 Herein, we report our findings of a
convenient one-pot reaction of alkenes and thioamides to
enable the construction of a variety of thiazolines in addition to
demonstrating the derivatizations of the thiazoline product to
useful thiol-amine and thiazole motifs.
Received: January 12, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00079
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Organic Letters
Letter
a
We initially hypothesized that generation of 1,2-dibromoal-
kanes from halogenation of alkenes could be followed by
nucleophilic additions of thioamides to afford the desired
thiazoline products. Although 1,2-dihalogenoalkanes were often
considered as poor electrophiles due to competing elimination
or alkene reversion reactions, the utilization of a soft
nucleophile such as a thioamide in the absence of a strong
base might alleviate these deleterious pathways.12 To validate
our hypothesis, we synthesized 1,2-dibromoethylbenzene in
94% yield from simple dibromination of styrene 1a in
acetonitrile. To our delight, when the 1,2-dibromoalkane was
treated with thiobenzamide 2a, thiazoline 3a formation was
observed in 63% yield in acetonitrile at 80 °C (Figure 1). This
Table 1. Optimization of Reaction Conditions
entry
halogen
Br2
acid
solvent
base
yield (%)
1
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
39
7
2
LiBr/H2O2(aq)
LiBr/H2O2(aq)
LiBr/oxone
LiBr/UHP
NaBr/UHP
KBr/UHP
LiBr/UHP
LiBr/UHP
LiBr/UHP
LiBr/UHP
LiBr/UHP
LiBr/UHP
LiBr/UHP
LiBr/UHP
LiBr/UHP
LiBr/UHP
LiBr/UHP
LiBr/UHP
LiBr/UHP
LiBr/UHP
LiBr/UHP
3
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
AcOH
TsOH
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
50
6
4
5
56
21
11
10
2
6
7
8
9
DCE
10
11
12
toluene
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
25
52
23
52
60
66
60
66
44
69
73 (71)
66
49
b
13
14
15
16
17
LiOAc
NaOAc
Figure 1. Validation of hypothesis.
Na2CO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
c
result clearly demonstrated that a common solvent acetonitrile
could be used for both 1,2-dibromoalkane formation and
subsequent nucleophilic displacements; thus, suggesting a one-
pot procedure directly from simple alkene precursors was
indeed plausible. A time study showed that the dibromination
reaction went to completion within 1 h. Therefore, the one-pot
reaction was conducted by adding the thioamide to the
dibromoethylbenzene mixture after 1 h. Gratifyingly, this
procedure produced the desired thiazoline 3a in 39% yield,
validating our initial hypothesis (Table 1, entry 1).
18
d
19
e
e
e
,
,
,
f
20
21
22
g
h
a
Reaction conditions: styrene 1a (1.0 equiv, 0.5 mmol), halide (2.2
equiv), oxidant (1.0 equiv), acid (2.0 equiv), solvent (1 M) at 80 °C
for 1 h, then thioamide 2a (3.0 equiv) and base (3.0 equiv) for 15 h at
80 °C. 1,3-Benzodioxole is used as the internal standard. TFA (1.5
equiv). NaHCO3 (1.0 equiv). NaHCO3 (3.0 equiv). Conditions:
LiBr (3.0 equiv), UHP (1.5 equiv), NaHCO3 (3.0 equiv). Isolated
b
c
d
e
f
Interested in further optimizing this reaction, we considered
the utilization of alternative bromine sources. Specifically, in
situ generated bromine equivalent by oxidation of halide salts
was attractive by avoiding the use of corrosive bromine. This
oxidative strategy had been extensively utilized for the
bromination of alkenes and arenes.13 A combination of lithium
bromide (LiBr) and aqueous hydrogen peroxide was selected as
a starting point. Using this approach, the thiazoline product was
produced in only 7% yield (Table 1, entry 2). The presence of
an acid additive was crucial to promote the yield to 50%,
presumably to promote the oxidation of the halide salts (Table
1, entry 3). Further time optimization revealed that the
dibromination of styrene went to completion within 1 h.
Screening different halides and oxidants demonstrated that the
LiBr and urea·hydrogen peroxide (UHP) combination was the
optimal choice to provide 56% desired product (Table 1,
entries 3−7). Solvent and acid evaluation showed that
acetonitrile (1 M) and 2 equiv of trifluoroacetic acid (TFA)
gave the highest yield (Table 1, entries 8−13). We reasoned
that perhaps residual acid from the dibromination process
could be detrimental to the subsequent nucleophilic sub-
stitution reactions. To validate this hypothesis, a base was
added along with the thioamide nucleophile. Indeed, addition
of 2 equiv of LiOAc improved the yield to 60% (Table 1, entry
14). Encouraged by this result, a series of mild inorganic bases
and fine-tuning of base stoichiometry were examined to further
increase the yield to 69%, with 3 equiv of NaHCO3 being the
most optimal (Table 1, entries 14−19). Finally, increasing the
halide source to 3.0 equiv provided the best yield for this
reaction at 73% (Table 1, entry 20). Increasing the
g
h
yield in parentheses. CH3CN (1.5 M). 50 °C.
concentration or lowering the temperature, however, lead to
decreased efficiency (Table 1, entries 21 and 22).
With the optimized conditions in hand, the alkene substrate
scope was evaluated. As the examples below illustrate, a notable
feature of this reaction was the ability to introduce a broad
range of thioamides without decomposition by the bromine
source. A range of styrene derivatives achieved moderate to
good yields of the desired thiazolines (Scheme 2, entries 3a−
i,l).14 For example, substitutions at the para position of the
benzene ring with electron-neutral or -donating groups worked
efficiently (Scheme 2, products 3a−c,f,l). On the other hand,
tethering an electron-withdrawing group at the para position
resulted in diminishing yield (Scheme 2, product 3d).
Additionally, halogen substitutions at either the ortho or para
position produced good yields of the thiazolines (Scheme 2,
products 3e,g−i). Aliphatic alkenes with alkyl, alcohol, ether,
ester, and imide functionalities were also viable substrates in
this reaction (Scheme 2, products 3j,k,m−r). In terms of
regioselectivity for the aliphatic alkenes, the initial nucleophilic
addition was reversed compared to the styrene derivatives
presumably due to the primary C−Br bond being the more
electrophilic site for aliphatic alkenes, whereas the secondary
benzylic C−Br bond is the more electrophilic position for the
styrene derivatives.
For the thioamide substrate scope, substitution of a methyl
group at either the ortho or para position afforded the products
in good yields (Scheme 3, products 4a and 4b). Electron-
B
DOI: 10.1021/acs.orglett.7b00079
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Scheme 2. Alkene Substrate Scope
Scheme 3. Thioamide Substrate Scope
a
Standard reaction condition unless otherwise noted. For detailed
b
conditions, see the Supporting Information. Major regioisomer is as
shown. Regioisomeric ratios are determined by crude NMR and >95:5
unless noted in parentheses.
a
Standard reaction condition unless otherwise noted. For detailed
ology in providing beneficial structures for potential SAR
studies. Finally, alkylthioamide could also furnish the respective
thiazoline compound (Scheme 3, entry 4r).
b
conditions, see the Supporting Information. Major regioisomer was
shown. Regioisomeric ratios were determined by crude NMR and
>95:5 unless noted in parentheses. Propionitrile, 100 °C. Several
c
d
After demonstrating a broad substrate scope for thiazoline
synthesis, we set out to explore its utility in further synthetic
elaborations. In this case, gram-scale synthesis of 3a was
accomplished in 61% yield using the standard reaction
conditions (Figure 2). Upon refluxing 3a in 5 M HCl,
hydrolysis of the ring structure occurred to generate the desired
β-aminothiol 5 in 92% yield, thus providing an efficient two-
step method for the highly regioselective thioamination of
terminal alkenes.15 On the other hand, oxidation of 3a by DDQ
in dichloromethane provided the heteroaromatic thiazole 6 in
95% yield.16 These derivatizations offered pathways to a
number of useful nitrogen-containing compounds, further
highlighting the synthetic advantages of this one-pot procedure.
In conclusion, we have developed a practical and reliable
procedure for the synthesis of thiazolines by oxidatively
coupling alkenes and thioamides. This intermolecular reaction
minor regioisomers were isolated and reported as 3m′, 3n′, 3o′, 3p′,
e
and 3q′. Bromine was used for the dibromination reaction.
donating groups such as alcohol, ether, and amine proceeded in
moderate yields (Scheme 3, products 4c,j,l). In addition,
halogen substitutions at the ortho, meta, or para positions
afforded the thiazoline products in good efficiency while
containing functionalities for further synthetic operation
(Scheme 3, products 4e−i,n). Moreover, thioamides including
electron-deficient aromatics such as pyridines and pyrimidine
could also provide the desired products, albeit in lower yields
(Scheme 3, products 4m,o−q). Notably, 2-pyridinethioamide
proceeded smoothly to afford a structure resembling a common
ligand framework. Furthermore, inclusion of these heteroar-
omatic examples demonstrated the versatility of this method-
C
DOI: 10.1021/acs.orglett.7b00079
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Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
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■
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00079.
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Experimental procedure and characterization data of the
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: wei.li@utoledo.edu.
ORCID
Wei Li: 0000-0002-8038-5574
Notes
The authors declare no competing financial interest.
(14) 1,2-Disubstituted cis-stilbene (15%) and trans-β-methylstyrene
(<10%) work with low efficiency and stereospecificity.
ACKNOWLEDGMENTS
We gratefully acknowledge the University of Toledo for
financial support with a start-up fund.
■
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DOI: 10.1021/acs.orglett.7b00079
Org. Lett. XXXX, XXX, XXX−XXX