Four-component thiazole formation from simple chemicals under metal-free conditions

Article abstract of DOI:10.1039/c8gc03895c

Multi-component reactions for the synthesis of polysubstituted thiazoles from simple chemicals are described. Under metal-free reaction conditions, cheap and easily available ketones, aldehydes, ammonium salt, and elemental sulfur are self-assembled to provide entries to three thiazoles in moderate to good yield with a range of functionalities tolerated.

Full text of DOI:10.1039/c8gc03895c

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COMMUNICATION
Four-component thiazole formation from simple chemicals
under metal-free conditions
Received 00th January 20xx,
Accepted 00th January 20xx
Jingjing Jiang, Huawen Huang,* and Guo-Jun Deng*
DOI: 10.1039/x0xx00000x
www.rsc.org/
(a) Common entries for thiazole formation
Multi-component reactions for the synthesis of polysubstituted
thiazoles from simple chemicals are described. Under metal-free
reaction conditions cheap and easily available ketones, aldehydes,
ammonium salt, and elemental sulfur are self-assembled to
provide entries to three thiazoles in moderate to good yield with
a range of functionalities tolerated.
O
O
'Br' reagent
Br
R1
R1
R1
R2
H
H
R2
R2
TM catalysis
N
S
N
S
base
R3
H
+
Lawesson
reagent
S
O
R3
NH2
R3
NH2
(b) Thiazole formation with elemental sulfur (two-component)
The one-pot consecutive multi-component assembly is an
important principle in nature for the construction of bonds in
the biosynthesis of numerous natural products with the
assistance of enzymes. Due to the featured productivity, yield,
convergence and facile execution, it is also considered as a
powerful strategy to the preparation of valuable compounds in
molecular synthesis.1 Thus the design and discovery of novel
multi-component reactions (MCR) have been drawing intensive
interests from synthetic chemistry.1-2
R3
R2
FeCl3 (10 mol%)
DMSO, air, 140 o
N
R3
O
+
S8
R1
C
S
R1
N
R2
O
H
(c) Thiazole formation with elemental sulfur (three-component)
CuBr2 (20 mol%)
N
1,10-Phen (20 mol%)
R2
CHO
R1
NH2
+
+
S8
R1
R2
DBU (2.0 equiv)
O2 (1 atm)
S
DMSO, 80 o
C
Thiazole is an important five-membered heterocycle, which
as a key unit widely exists in pharmaceuticals,3 naturally
occurring products,4 and functional materials.5 The versatile
bio-activities of thiazole compounds in metabolism have
triggered considerable efforts on the structural and synthetic
development. While cyclization between highly functionalized
α-bromoketones and thioamides under base conditions is
considered as the most common method to construct thiazole
ring,6 noble-metal-catalyzed sequentially stepwise thiazole C–H
functionalization provides an alternative entry to multi-
substituted thiazoles (Figure 1, a).7 Regarding multi-component
reactions for the construction of thiazoles, in 2015, Miura et al.
reported a sequential procedure for the synthesis of 2,5-
disubstituted thiazoles from terminal alkynes, sulfonyl azides,
and thionoesters, in which copper(I)-catalyzed 1,3-dipolar
cycloaddition of terminal alkynes with sulfonyl azides followed
by rhodium(II)-catalyzed coupling with thionoesters and
(d) Thiazole formation with elemental sulfur (four-component)
R1
R2
O
metal- and base-free
+
R3CHO
+
NH4+X-
+
S8
this work
R1
R1
R2
Ar
N
N
N
Ar
or
or
Ar
Ar
Ar
S
R1
S
S
R1 = Ar; R2 = H
R1 = alkyl; R2 = H
R1, R2 = Ar or alkyl
Figure 1. Methods for thiazole formation. (TM = transition
metal)
deprotective aromatization.8 In 2018, Guo and co-workers have
developed base-promoted metal-/oxidant-free three-component
tandem annulations the construction of 2,4,5 ‐ trisubstituted
thiazoles via C−N bond cleavage of amidines.9 While
benzothiazoles have been intensively constructed with cheap
and bench-stable elemental sulfur,10 thiazole formation is rare.
In 2018, Yan et al. reported an iron-catalyzed atom economical
approach for the synthesis of substituted thiazoles starting from
enamines and elemental sulfur through the C-H
functionalization/C-S bond formation (Figure 1, b).11 And Jiao
group has recently disclosed a copper-catalyzed aerobic three-
Key Laboratory of Environmentally Friendly Chemistry and Application of Ministry
of Education, College of Chemistry, Xiangtan University, Xiangtan 411105, China;
Fax:
(+86)0731-5829-2251;
Tel:
(+86)0731-5829-8601;
E-mail:
hwhuang@xtu.edu.cn, gjdeng@xtu.edu.cn
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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component annulation for the synthesis of 2,5-disubstituted benzaldehyde (2a-d1) excluded the intramolecuVlaierw AhrtyicdleroOgnleinne
thiazoles (Figure 1, c).12 In spite of these proven utilities, the 1,2- and 1,5-migration, respectively. The result with the
DOI: 10.1039/C8GC03895C
synthetic development of a more straightforward route from addition of deuterium oxide instead of water also supported an
simple chemicals to trisubstituted thiazoles remains highly intermolecular protonation in the final transformation (Figure
desirable. Herein, we have now revealed a four-component 3).
Ph
2a
NH4I, S8
HN
reaction which obviates the needs of prefunctionalized starting
materials and metal catalysts (Figure 1, d). By this protocol, the
concise formation of three trisubstituted thiazoles is selectively
realized through the condensation with different ketones. Hence,
the reactions with methyl ketones afford benzyl and vinyl
thiazoles via sequentially five-molecular assembly.
Initially, the one-pot condensation reaction of acetophenone
(1a), benzaldehyde (2a), ammonium iodide, and elemental
sulfur in pyridine revealed a five-molecular assembly to afford
2,4-diphenyl-5-benzylthiazole (3a), even with equally
stoichiometric amounts of 1a and 2a (Figure 2, path a). The
kinetic studies on this transformation indicated that the
dehydrative Aldol condensation of 1a and 2a to form chalcone
A occurred very fast (complete within 10 min), which therefore
prohibited the interaction of 1a, ammonium, and sulfur
(Willgerodt reaction). In the optimization of reaction conditions
(See ESI for details), pyridine as the reaction media
dramatically enhanced the yield. In this regard, pyridine
C6D5
O
O
N
S
Ph
C6D5
C6D5
CD3
pyridine/H2O
150 °C, 20 h
Ph
D
S
Py
Ph
1a-d8
C-d6
no D incorporation
D
Ph
1a
NH4I, S8
HN
O
D
Ph
N
O
S
Ph
Ph
Ph
pyridine/H2O
150 °C, 20 h
Ph
Ph
D
Ph
C-d2
S
Py
2a-d1
32% D
Ph
O
N
S
S8
+
Ph
NH4I
+
+
PhCHO
Ph
pyridine/D2O
150 °C, 20 h
1a
2a
38% D
Figure 3. Isotope labeling experiments.
The attempts on the sequential five-component reaction with
two different aldehydes were failed either in one-pot or by a
two-step operation due to the fast reversible Aldol reaction in
present system. In this regard, four substituted thiazoles were
generally generated with poor chemoselectivity (Figure 4). We
also found that it was ammonium iodide that led to a fast retro
Aldol reaction/benzaldehyde exchange.
probably served as
a Michael donor to facilicate the
nucleophilic attack of A to sulfur, thus leading to the formation
of the pyridinium intermediate B. Besides, the solubilities of
inorganic ammonium iodide and elemental sulfur were
improved by the addition of water, which thereby led to a
further yield enhancement. On the other hand, in the same
pyridine/H2O system the treatment of propiophenone (1q) with
2a, ammonium iodide, and elemental sulfur afforded the
expected trisubstituted thiazole 4a in a moderate yield.
Mechanistically, this oxidative annulation probably proceeds
through the intermediates D-G and involves a key Willgerodt-
type sulfuration (Figure 2, path b).
O
Ph
CHO
Cl
NH4I, S8
N
Ph
+
(2-ClPh)Ph
pyridine/H2O
150 °C, 20 h
Ph(2-ClPh)
S
Ph
2j
without
with : four thiazoles formed
2j
A
2j 3a
formed (52%)
:
O
O
CHO
Cl
NH4I
Ph
Ph
Cl
+
pyridine/H2O
Ph
150 °C, 10 min
2j
A
18%
no exchange (w.o. NH4I)
Ph
Ph
Ph
Ph
N
N
HO
N
N
S8
Figure 4. Thiazole formation from chalcone.
S
S
Ph
Ph
Ph
Ph
-H2O
NH
Me
Ph
Me
Me
[O]
Me
E
With the optimized pyridine/H2O reaction system in hand, the
substrate scope of the four-component thiazole formation was
explored (Figure 5). First, methyl aromatic ketones such as
substituted acetophenones reacted smoothly to give 5-
benzylthiazoles 3a-3m in moderate to good yields with a broad
tolerance of functionalities such as alkyl, alkoxy, halo (F, Cl,
Br), and even alkynyl (3i). Among them, the substrates bearing
electron-donating groups including methoxy afforded the
corresponding thiazole in a relatively lower yield (3g). Besides,
ortho-methylacetophenone (3m) showed much lower reactivity
than its meta- and para-isomers, featuring an obvious steric
hindrance effect. The naphthyl variant was also accommodated
to give 3n in 70% yield. Then, heteroaromatic ketones with
thiophenyl and furanyl motifs furnished 3o and 3p, respectively,
in modest yields. The robust nature of the present five-
molecular system was further reflected by the effective gram-
scale preparation, in which, for example, 3a was isolated in
65% yield.
D
G
F
R = Me
path b
Ph
O
N
R'
3a
S8
NH4I
+
+
+
PhCHO
Ph
Ph
pyridine/H2O
150 °C, 20 h
S
R
, R' = Ph, 77%
, R' = H, 50%
1a 1q
or
2a
4a
-H2O, -Py
-H2O path a
R = H
Ph
O
O
HN
O
NH
Ph
S
S8
S
Ph
Ph
Ph
:
Py
Ph
Py
B
Ph
Py
Ph
C
A
Figure 2. Formation of thiazoles by four-component reactions.
Given the tentative proposal of reaction mechanism based on
condensation, we were intrigued by revealing the hydrogen
absorption process at the C5 benzylic position of 3a. Regarding
the proposed intermediate C, the isotope labeling experiments
with deuterated acetophonone (1a-d8) and deuterated
2 | J. Name., 2012, 00, 1-3
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Subsequently, the generality and limitation of aldehyde benzaldehydes such as halo (Cl and Br) were acommodated
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DOI: 10.1039/C8GC03895C
components was studied. Notably, in all cases only aromatic with the present system (4i-4j).
R1
aldehydes were productive in present stage, while aliphatic
O
N
NH4I
R2
ArCHO
S8
aldehydes generally resulted in an elusive complex mixture.
Regarding to substituted benzaldehydes, the desired products
were smoothly obtained with yields ranging from 40% to 84%
(3q-3ac). Among them, halo functionalities (F, Cl, Br) attached
at the benzene ring were well tolerated (3t-3v, 3y-3z, and 3ab-
3ac). Interestingly, the configuration of an ortho-substituent
could improve the reactivity of benzaldehydes, probably due to
an effect of neighbouring group participation. For example, 2-
chloro- and 2-bromobenzaldehyde featured obviously higher
efficiency than their 4- and 3-substituted isomers (3y versus 3u
and 3ab; 3z versus 3v and 3ac). Then, thiophene carbaldehydes
were accommodated to afford twofold thiophen-decorated
thiazoles 3ad and 3ae, albeit in moderate yields. Finally, the
bulky 2-naphthaldehyde gave the corresponding product 3af in
75% yield.
R2
Ar
R1
pyridine/H2O
150 oC, 20 h
S
4
1
2
n-Pr
Ph
H3C
Ph
Ph
N
N
N
N
Et
Ph
Ph
S
Ph
Ph
n
S
S
S
4d
4a
4b
, 52%
, 50%
4c
, 49%
n = 1, , 44%
4e
n = 2, , 63%
4f
n = 3, , 68%
4g
n = 7, , 64%
Cl
N
N
S
S
R
4h
R = OMe, , 80%
R = Br,
4j
, 65%
4i
, 59%
Figure 6. Four-molecular formation of trisubstituted thiazoles.
To our delight, when we subjected aliphatic methylketones to
the pyridine system, 4-vinylthiazoles were furnished as the
main product. In complementary to the results of above two
thiazole formation, this reaction represents another sequential
five-molecular assembly. The present observation also revealed
in the sulfuration process the methylene adjacent to carbonyl
groups was inherently higher reactive upon vinyl groups. Thus
the unique reactive selectivity led to a new entry to structurally
significant vinylthiazoles that cannot be easily obtained by
known synthetic methods. In the modification of reaction
conditions (See ESI for details), the addition of BzOH
facilitated this thiazole formation. Thereafter, this reaction
found to smoothly tolerate a range of aliphatic methylketones
and aromatic aldehydes, giving 4-vinylthiazoles 5a-5l in
generally moderate yields (Figure 7).
Ar1
O
N
+ 2 Ar2CHO
NH4I
S8
Ar1
Ar2
pyridine/H2O
150 oC, 20 h
S
Ar2
1
2
3
a
3a
R = H,
, 77%
, 66%
, 65%
, 65%
, 73%
, 69%
, 65%
R
CH3
R
3b
3c
3d
3e
3f
R = CH3,
R = Ph,
R = F,
R = Cl,
R = Br,
N
N
N
Ph
Ph
S
S
Ph
Ph
Ph
R = CH3, , 73%
3k
S
3g
R = OCH3, , 55%
3h
R = OCF3, , 75%
3j
R = CF3, , 70%
3m
, 42 %
Ph
3i
R = CCPh, , 75%
3l
R = Cl,
, 63%
S
O
N
N
N
Ph
Ph
Ph
S
S
S
Ph
Ph
Ph
3p
, 40%
3n
3o
, 70%
, 61%
Ar
Ph
O
Ph
Ph
BzOH
N
N
N
N
S8
+
NH4I
2 ArCHO
R
pyridine/H2O
120 oC, 5 h
R
Ar
N
S
S
S
S
R
1
2
5
R
R
3q
3r
R = CH3,
R = Ph,
R = OCH3,
R = F,
R = Cl,
R = Br,
, 68%
, 70%
, 71%
, 62%
, 71%
, 76%
, 40%
R
Ar
Ph
Ar
Ph
R
3s
3t
R
3aa
3ab
3ac
3x
R = CH3, , 73%
R = Cl,
R = Br,
R = CH3,
R = Cl,
R = Br,
, 70%
, 58%
, 57%
N
N
3y
3z
, 84%
, 80%
3u
3v
3w
Ar
Ph
n-Bu
Ar
R
S
S
S
R = CF3,
Ph
5a
5b
5g
, 52%
5h
Ar = 4-ClC6H4, , 63%
5i
Ar = 4-CH3C6H4, , 40%
R = n-Pr,
R = n-Bu,
, 51%
, 56%
Ar = 4-FC6H4,
N
S
Ph
S
Ph
5j
5k
5l
Ar = 4-FC6H4,
Ar = 4-ClC6H4,
Ar = 4-BrC6H4,
, 37%
, 53%
, 42%
N
N
5c
R = n-pentyl, , 51%
5d
R = n-heptyl, , 60%
S
S
5e
, 56%
, 58%
R = i-Bu,
R = Bn,
S
S
5f
S
Figure 7. Synthesis of 4-vinylthiazoles from methyl aliphatic
3ad
, 45%
3ae
, 36%
3af
, 75%
ketones.
Figure 5. Five-molecular formation of 2,4-diaryl-5-
benzylthiazoles. a Yield of five mmol scale reaction.
To further explore the utility and versatility of the present
thiazole formation, the late-stage oxidation of the resultant 5-
benzylthiazoles was performed (Figure 8). In a modified
CuI/TBHP system, while 3a was oxidized into 6a with good
yield, excellent levels of chemoselectivity was observed when
4-vinyl-5-benzylthiazole 5f was subjected to this system. Thus,
the present protocol provides a stepwise method for 5-
benzoylthiazole construction.
As shown above, non-methyl ketones gave formal tetra-
substituted thiazoles. The scope of this thiazole formation was
then studied (Figure 6). Generally, moderate yields were
observed with propiophenone (4a), 1,2-diphenylethanone (4b),
heptan-4-one (4c), and some cyclic ketones (4d-4g). Notably,
the condensation annulation of 4-methoxybenzaldehyde and
cyclooctanone afforded the corresponding product 4h in 80%
yield. Synthetically useful functionalities attached to
This journal is © The Royal Society of Chemistry 20xx
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CuI (50 mol %)
AcOH (3 equiv)
TBHP (6 equiv)
Scearce-Levie, C. Patrick, A. Adame, F. Giorgini, S.
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R
R
N
N
O
Ph
Ph
S
DMSO (1 mL)
100 oC, air, 12 h
S
Ph
Ph
6a
6b
3a
, R = Ph
, R = Ph, 73%
, R = styryl, 53%
5f
, R = styryl
Figure 8. Benzylic oxidation of 5-benzylthiazoles.
Conclusions
4
In summary, we have developed a modular multi-component
system for the effective synthesis of 2,4,5-trisubstituted
thiazoles by the combination of Debus-Radziszewski imidazole
synthesis and Gewald thiophene formation. This metal-free
assembly of thiazoles has been oriented by the use of different
ketone substrates, i.e. aromatic methylketones, aliphatic
methylketones, and non-methylketones. Thus, three substituent-
varied thiazoles were afforded with a broad substrate scope.
This multi-component protocol that was inspired by classic
name reactions represents one of significant progress on
reaction discovery with the combinatorial strategy.
5
Conflicts of interest
There are no conflicts of interest to declare.
Acknowledgements
Support by the National Natural Science Foundation of China
(21871226, 21572194, 21602187) and the Collaborative Innovation
Center of New Chemical Technologies for Environmental Benignity
and Efficient Resource Utilization is gratefully acknowledged.
6
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