N-Heterocyclic Carbene-Catalyzed in situ Activation of Alkynyl Acids for C?S Bond Formation: Access to Imidazo[2,1-b][1,3]thiazinones

Article abstract of DOI:10.1002/adsc.201800857

Alkynyl acids are first utilized as alkynyl acylazolium precursors through an in situ activation strategy for the efficient construction of carbon-sulfur bond in a formal [3+3] annulation. This protocol offers a direct and rapid pathway for the synthesis of imidazo[2,1-b][1,3]thiazinone skeleton, a useful heterocyclic class frequently found in many bioactive compounds. This reaction also has the advantages of scalability, readily available materials, and simple manipulation in open air. (Figure presented.).

Full text of DOI:10.1002/adsc.201800857

Title: N-Heterocyclic Carbene-Catalyzed in situ Activation of Alkynyl
Acids for C-S Bond Formation: Access to Imidazo[2,1-b]
[1,3]thiazinones
Authors: Ding Du, Kewen Sun, Shiyi Jin, Jindong Zhu, Xinmiao Zhang,
Maoyu Gao, Wanqi Zhang, and Tao Lu
This manuscript has been accepted after peer review and appears as an
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content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800857
Link to VoR: http://dx.doi.org/10.1002/adsc.201800857

10.1002/adsc.201800857
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
N-Heterocyclic Carbene-Catalyzed in situ Activation of Alkynyl
Acids for C-S Bond Formation: Access to Imidazo[2,1-
b][1,3]thiazinones
Kewen Sun,a Shiyi Jin,a Jindong Zhu,a Xinmiao Zhang,a Maoyu Gao,a Wanqi Zhang,a
Tao Lu a and Ding Du a*
a
State Key Laboratory of Natural Medicines, Department of Organic Chemistry, China Pharmaceutical University,
Nanjing, 210009, P. R. China. Email: ddmn9999@cpu.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. Alkynyl acids are first utilized as alkynyl This reaction also has the advantages of scalability, readily
acylazolium precursors through an in situ activation strategy available materials, and simple manipulation in open air.
for the efficient construction of carbon-sulfur bond in a formal
[3+3] annulation. This protocol offers a direct and rapid
pathway for the synthesis of imidazo[2,1-b][1,3]thiazinone
skeleton, a useful heterocyclic class frequently found in many
bioactive compounds.
Keywords: carbene; alkynyl acid; in situ activation; C-S
bond formation; heterocyclic compounds
esters as the alkynyl acylazolium precursors to
undergo two different NHC-catalyzed annulations,
affording a series of functionalized pyridines and (Z)-
5-amino-3-furanones, respectively. Very recently,
Wang and co-workers [3c, 3d]reported two formal [3+3]
Introduction
Over the last decade, N-heterocyclic carbenes (NHCs)
have been used as efficient organocatalysts to enable
numerous unconventional transformations due to their
unique reactivity. Among these transformations,
nucleophilic NHCs can combine with different
carbonyl compounds to generate several key NHC-
bound intermediates like homoenolates, enolates,
alkenyl acylazoliums and vinyl enolates that have been
extensively studied and applied in diverse annulation
reactions to access a variety of heterocyclic
compounds (Figure 1). [1]
Figure 1. Extensively studied NHC-bound intermediates.
However, as another important type of NHC-bound
intermediate, alkynyl acylazoliums I were rarely
investigated,[2] and limited annulation reactions with
diverse binucleophiles were documented (Scheme
1a).[3] In 2017, Chi’s group[3a] and our
group[3b]independently applied p-nitrophenyl alkynyl
Scheme 1. Generation and reactions of alkynyl
acylazoliums.
1
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10.1002/adsc.201800857
Advanced Synthesis & Catalysis
Table 1. Optimization of the reaction conditions[a]
annulations of alkynyl acylazoliums I derived from
ynals under oxidative NHC conditions, giving rise to
axially chiral -pyrone-aryls and trisubstituted
pyrimidin-4-ones, respectively. Therefore, it is still in
demand to further investigate the reactivity of alkynyl
acylazoliums I and enrich their applications in the
organic synthesis.
In the field of NHC organocatalysis, compared to
frequently used ester and aldehyde substrates,
carboxylic acids are more readily available and easier
to handle. In recent years, saturated[4]and -
unsaturated alkenyl[5]carboxylic acids have been
applied to generate some important NHC-bound
intermediates such as enolates, alkenyl acylazoliums
and vinyl enolates through an in situ activation
strategy. Therefore, we reasoned that in situ activation
of alkynyl acids 1 with NHC catalysis might afford
alkynyl acylazoliums I in a direct manner (Scheme 1b).
The construction of carbon-sulfur (C-S) bond has been
one of the research interests in organic synthesis owing
to wide prevalence of C-S bond in many biologically
active molecules.[6] However, there are limited
examples of C-S bond construction in the field of NHC
catalysis.[7] We envisioned that the combination of
Entry Cat.
PCR
Base
Solvent Yield [%][b]
1
A
B
C
D
E
F
pyBOP DIPEA
pyBOP DIPEA
pyBOP DIPEA
pyBOP DIPEA
pyBOP DIPEA
pyBOP DIPEA
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
63
41
65
41
82
83
0
2
3
alkynyl
acylazoliums
I
with
2-
mercaptobenzimidazoles or 2-mercaptoimidazoles 2
might undergo a Michael addition to construct the C-S
bond followed by lactam formation to afford a series
of imidazo[2,1-b][1,3]thiazinones 3 (Scheme 1b).
Notably, the imidazo[2,1-b][1,3]thiazinone skeleton is
an interesting structure widely found in organic
compounds possessing important pharmacological
activities (Figure 2), [8]and thus, the synthesis of this
4
5
6
7
none pyBOP DIPEA
8
F
F
F
F
F
F
F
F
F
pyBOP DBU
pyBOP Et3N
36
69
54
57
80
[9]
skeleton has evoked much interest of chemists.
9
Herein, we report an efficient and rapid pathway to
access functionalized imidazo [2,1-b][1,3]thiazinones
from simple and readily available starting materials
with NHC catalysis.
10
11
12
13
14
15
16c
pyBOP Cs2CO3 PhMe
pyBOP DIPEA
pyBOP DIPEA
pyBOP DIPEA
THF
DCM
CH3CN 92
CH3CN 12
CH3CN 82
CH3CN 92
CDI
DIPEA
DIPEA
HATU
pyBOP DIPEA
[a]All reactions were performed on a 0.15 mmol scale with
1.2 equiv of 1a, 1.0 equiv of 2a, 1.5 equiv of a PCR, 3.0
equiv of a base, 10 mol % of a NHC precursor, 150 mg of
4Å MS (molecular sieves), in an anhydrous solvent (3 mL)
at rt for 3-4 h under N2.
Figure 2. Representative bioactive compounds with the
imidazo[2,1-b][1,3]thiazinone skeleton.
[b]Isolated yields based on 2a.
[c]The reaction was carried out in open air. Mes = 2,4,6-
(CH3)3C6H2.
Results and Discussion
that the reaction with NHC catalysis could afford the
desired product 3a in moderate to good yields (entries
1-6), while the reaction did not work in the absence of
an NHC precursor (entry 7). Further examination of
the bases and solvents in the presence of catalyst F
(entries 8-13) revealed that DIPEA and CH3CN are the
Commercially available 3-phenylpropiolic acid 1a
and 2-mercaptobenzimidazole 2a were used as the
model substrates for our initial attempt (Table 1). The
reaction between 1a and 2a was carried out in the
presence of a series of NHC precursors A-F using
pyBOP as the peptide coupling reagent (PCR) and
DIPEA as a base under N2 atmosphere. It was found
2
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10.1002/adsc.201800857
Advanced Synthesis & Catalysis
Table 2. The scope of the reaction between symmetric 2-mercaptobenzimidazoles or 2-mercaptoimidazoles 2 and diverse
alkynyl acids 1 [a]
[a]All reactions were performed on a 0.15 mmol scale with 1.2 equiv of 1, 1.0 equiv of 2, 1.5 equiv of pyBOP, 3.0 equiv of
DIPEA, 10 mol % of F, 150 mg of 4Å MS, in anhydrous CH3CN (3 mL) at rt for 3-4 h in open air. All yields are isolated
yields based on 2.
optimal base and solvent, respectively, and the desired
product 3a was obtained in 92% yield (entry 13). We
also tested other PCRs such as CDI and HATU, but
resulting in decreased yields (entries 14-15). We were
happy to find that the reaction carried out in open air
without nitrogen protection had no influence on the
reaction yield (entry 16). Therefore, the optimal
reaction conditions were established as that in entry 16
for further scope exploration.
With the optimal reaction conditions in hand, we
moved our attention to explore the scope of this
reaction (Table 2). Initially, a wide range of 3-
arylpropiolic acids 1 were examined. The reaction
could accommodate various 3-(substituted phenyl)
propiolic acids with diverse substituents at different
positions on the phenyl ring, affording the
corresponding products 3b-k in moderate to high
yields. However, 3-(2-methylphenyl)propiolic acid
was not tolerated probably due to the steric effect of
the more hindered 2-methyl group. Similarly, the more
hindered 3-(naphthalen-1-yl)propiolic acid was also
unsuitable to this protocol, but the less hindered 3-
(naphthalen-2-yl)propiolic acid as well as 3-(thiophen-
2-yl)propiolic acid were well tolerated under the
optimal reaction conditions, affording products 3n and
3o, respectively, in moderate yields. Then, 3-alkyl-
substituted alkynyl acids were tested. It was gratifying
3
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10.1002/adsc.201800857
Advanced Synthesis & Catalysis
of each 5-substituted substrate were obtained almost in
the same ratio. It is also noteworthy that isomers 3ba
and 3bb can be separated by column chromatography
while other isomers are inseparable.
that the size and length of the alkyl groups had little
impact on the reaction results and the desired products
3p-s were obtained in moderate yields. However, an
aryl or an alkyl group at the 3-position of the acids
proved essential to this protocol since 3t was not
formed when propiolic acid was used as the substrate.
We also carried out the reaction of 2-
hydroxybenzimidazole 4 with 1a under the standard
conditions (Scheme 2a). Fortunately, this protocol was
equally applicable to substrate 4, although product 5
was obtained in 54% yield. Since p-nitrophenyl
alkynyl esters have been successfully used as alkynyl
acylazolium precursors in our previous work, [3b] we
then tested the reaction of 4-nitrophenyl 3-
phenylpropiolate 6 with 2a using F as the catalyst
(Scheme 2b). It was found that higher reaction
temperature was essential for the complete conversion
of substrate 6, however, desired product 3a was
isolated in only 36% yield. [10] Furthermore, a scale-up
synthesis of product 3a and a derivatization of 3a were
carried out. Product 3a was obtained in a maintained
yield with a 1.5 mmol scale under the standard
conditions (Scheme 2c). Reduction of compound 3a
with LiAlH4 gave rise to product 7 in 56% yield whose
carbonyl group and C=C double bond were reduced at
the same time (Scheme 2d).
Finally,
two
4,5-disubstituted
2-
mercaptobenzimidazoles were used to further explore
the generality of this reaction. The electronic nature of
the substituents seemed to have great influence on the
reaction results. The reaction of 5,6-dimethyl-2-
mercaptobenzimidazole gave product 3u in a high
yield,
while
substrate
5,6-dibromo-2-
mercaptobenzimidazole was unsuitable to this
protocol. Moreover, the reactions of two 2-
mercaptoimidazoles with 1a were examined. As a
result,
the
reaction
of
unsubstituted
2-
mercaptoimidazole afforded product 3w in 73% yield,
while the reaction of 4,5-diphenylmercaptoimidazole
afforded product 3x in 38% yield.
Table 3. The reactions of unsymmetrical 2-
mercaptobenzimidazoles with acid 1a.
Scheme 2. Further scope exploration and synthetic
application.
Conclusion
To further expand the synthetic utility of this
protocol, the reactions of several unsymmetrically
monosubstituted 2-mercaptobenzimidazoles were
tested under the standard conditions (Table 3). The
In summary, we have demonstrated an NHC-
catalyzed formal [3+3] annulation of 2-
mercaptobenzimidazoles or 2-mercaptoimidazoles
with alkynyl acylazoliums that were directly generated
from alkynyl carboxylic acids for the first time through
an in situ activation strategy. This protocol offers a
simple and rapid access to a broad range of
functionalized imidazo[2,1-b][1,3]thiazin-4-ones, a
class of skeletally interesting heterocyclic compounds.
Furthermore, this protocol has the advantages of
reaction
of
4-methyl-2-mercaptobenzimidazole
afforded 3aa and 3ab in 80% combined yield with
good regioselectivity (3aa:3ab = 6.3:1). However, the
reaction of 5-substituted 2-mercaptobenzimidazoles
afforded the desired products in high yields but with
poor regioselectivity. The two isomers of the reaction
4
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10.1002/adsc.201800857
Advanced Synthesis & Catalysis
7.2 Hz, 1H), 7.80 (d, J = 6.9 Hz, 1H), 7.74-7.66 (m, 2H),
7.56-7.40 (m, 2H), 7.29-7.20 (m, 2H), 6.87 (s, 1H). 13C
NMR (75 MHz, CDCl3) δ 164.9 (d, J = 252.7 Hz), 159.8,
149.4, 146.4, 142.7, 131.1, 130.9, 129.1 (d, J = 8.8 Hz),
126.0, 124.5, 118.8, 116.9 (d, J = 22.1 Hz), 116.2, 114.0.
HRMS (ESI) calcd for C16H10FN2OS (M+H)+: 297.0498,
found 297.0491.
scalability and simple manipulation in open air without
inert air protection. Further investigation and
application of alkynyl acylazoliums in the synthesis of
diverse heterocyclic motifs are currently underway in
our laboratory.
2-(p-Chloro)-4H-benzo[4,5]imidazo[2,1-b][1,3]thiazin-
4-one (3e). 35 mg, 74%. Yellowish solid, mp: 256-258oC.
1H NMR (300 MHz, CDCl3) δ 8.60 (d, J = 7.2 Hz, 1H), 7.81
(d, J = 7.9 Hz, 1H), 7.65 (d, J = 8.6 Hz, 2H), 7.57-7.43 (m,
4H), 6.90 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 159.7,
149.3, 146.3, 142.7, 138.3, 133.1, 131.1, 129.9, 128.2, 126.1,
124.5, 118.8, 116.2, 114.1. HRMS (ESI) calcd for
C16H10ClN2OS (M+H)+: 313.0202, found 313.0195.
2-(p-Bromo)-4H-benzo[4,5]imidazo[2,1-b][1,3]thiazin-4-
one (3f). 40 mg, 75%. Yellowish solid, mp: 250-252oC. 1H
NMR (300 MHz, CDCl3) δ 8.59 (d, J = 7.9 Hz, 1H), 7.81 (d,
J = 7.7 Hz, 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 8.4
Hz, 2H), 7.52-7.43 (m, 2H), 6.90 (s, 1H). 13C NMR (75 MHz,
CDCl3) δ 159.7, 149.4, 146.2, 142.7, 133.6, 132.9, 131.1,
128.3, 126.6, 126.1, 124.5, 118.8, 116.2, 114.2. HRMS
(ESI) calcd for C16H10BrN2OS (M+H)+: 356.9697, found
356.9689.
Experimental Section
General Methods and Materials.
All reactions were carried out in dry glassware, and were
monitored by analytical thin-layer chromatography (TLC),
which was visualized by ultraviolet light (254 nm). All
solvents were obtained from commercial sources and were
purified according to standard procedures. Alkynyl
carboxylic acids 1[11] and substrates 2[12] are commercially
available or prepared according to known procedures.
Purification of the products was accomplished by flash
chromatography using silica gel (200-300 mesh). All NMR
spectra were recorded on Bruker spectrometers, running at
300 MHz or 500 MHz for 1H and 75 MHz or 125 MHz for
13C respectively. Chemical shifts (δ) and coupling constants
(J) are reported in ppm and Hz respectively. The solvent
signals were used as references (residual CHCl3 in CDCl3:
δH = 7.26 ppm, δc = 77.0 ppm; residual residue DMSO in
DMSO-d6: δH = 3.3 ppm, δc = 39.5 ppm). The following
abbreviations are used to indicate the multiplicity in NMR
spectra: s (singlet); d (doublet); t (triplet); q (quartet); m
(multiplet). High resolution mass spectrometry (HRMS)
was recorded on TOF perimer for ESI+.
2-(3-Chlorophenyl)-4H-benzo[4,5]imidazo[2,1-
b][1,3]thiazin-4-one (3g). 41 mg, 88%. Yellowish solid,
mp: 192-194oC. 1H NMR (300 MHz, CDCl3) δ 8.57 (d, J =
7.6 Hz, 1H), 7.79 (d, J = 7.4 Hz, 1H), 7.66 (s, 1H), 7.61-
7.39 (m, 5H), 6.88 (s, 1H). 13C NMR (75 MHz, CDCl3) δ
159.6, 148.9, 146.1, 142.5, 136.2, 135.7, 131.7, 130.9, 130.8,
127.0, 126.1, 125.1, 124.5, 118.7, 116.1, 114.5. HRMS
(ESI) calcd for C16H10ClN2OS (M+H)+: 313.0202, found
313.0190.
2-(m-Tolyl)-4H-benzo[4,5]imidazo[2,1-b][1,3]thiazin-4-
one (3h). 37 mg, 85%. Yellowish solid, mp: 178-180oC. 1H
NMR (300 MHz, CDCl3) δ 8.58 (d, J = 7.6 Hz, 1H), 7.79 (d,
J = 7.6 Hz, 1H), 7.56-7.30 (m, 6H), 6.89 (s, 1H), 2.45 (s,
3H). 13C NMR (75 MHz, CDCl3) δ 159.9, 150.8, 146.8,
142.6, 139.6, 134.5, 132.5, 131.0, 129.4, 127.4, 125.9, 124.2,
124.0, 118.6, 116.1, 113.6, 21.4. HRMS (ESI) calcd for
C17H13N2OS (M+H)+: 293.0749, found 293.0735.
General experimental procedure for the
synthesis of 3
To an oven-dried 10 mL flask was charged with an acid 1
(0.18 mmol), substrate 2 (0.15 mmol), pyBOP (117 mg,
0.225 mmol), catalyst F (4.95 mg, 0.015 mmol), 150 mg of
4 Å MS and DIPEA (79 μL, 0.45 mmol). Then anhydrous
CH3CN (3 mL) was added to the flask and the resulting
mixture was stirred in open air for typically 3-4 h until the
completion of the reaction as monitored by TLC. The
mixture was filtered and the filtrate was concentrated under
reduced pressure. The residue was purified by
chromatography on silica gel using hexane/acetone (50:1)
as the eluent to afford products 3.
2-(o-Fluorophenyl)-4H-benzo[4,5]imidazo[2,1-
b][1,3]thiazin-4-one (3i). 30 mg, 68%. Yellowish solid,
mp: 144-146oC. 1H NMR (300 MHz, CDCl3) δ 8.59 (d, J =
7.4 Hz, 1H), 7.80 (d, J = 7.3 Hz, 1H), 7.63 -7.40 (m, 4H),
7.36-7.22 (m, 2H), 6.92 (s, 1H). 13C NMR (75 MHz, CDCl3)
δ 159.6, 159.2 (d, J = 252.3 Hz), 146.7, 144.4, 142.4, 133.0
(d, J = 8.5 Hz), 130.9, 129.7, 126.0, 125.1 (d, J = 3.7 Hz),
124.3, 122.4 (d, J = 12.7 Hz), 118.6, 117.5 (d, J = 5.0 Hz),
117.0 (d, J = 21.7 Hz), 116.1. HRMS (ESI) calcd for
C16H10FN2OS (M+H)+: 297.0498, found 296.0491.
2-(2-Chlorophenyl)-4H-benzo[4,5]imidazo[2,1-
2-Phenyl-4H-benzo[4,5]imidazo[2,1-b][1,3]thiazin-4-one
(3a). 38 mg, 92%. Yellowish solid, mp: 177-179oC. H
1
b][1,3]thiazin-4-one (3j). 35 mg, 75%. Yellowish solid,
mp: 135-137oC. 1H NMR (300 MHz, CDCl3) δ 8.61 (d, J =
7.1 Hz, 1H), 7.81 (d, J = 6.8 Hz, 1H), 7.61-7.36 (m, 6H),
6.75 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 159.5, 147.9,
146.8, 142.4, 133.3, 132.5, 131.9, 130.9, 130.7, 130.4, 127.4,
126.0, 124.3, 118.7, 118.2, 116.2. HRMS (ESI) calcd for
C16H10ClN2OS (M+H)+: 313.0202, found 313.0197.
2-(2-Bromophenyl)-4H-benzo[4,5]imidazo[2,1-
NMR (300 MHz, CDCl3) δ 8.65-8.52 (m, 1H), 7.79 (d, J =
7.3 Hz, 1H), 7.70-7.67 (m, 2H), 7.61-7.40 (m, 5H), 6.91 (s,
1H). 13C NMR (75 MHz, CDCl3) δ 159.9, 150.6, 146.7,
142.6, 134.6, 131.7, 131.0, 129.6, 126.9, 125.9, 124.3, 118.7,
116.1, 113.8. HRMS (ESI) calcd for C16H11N2OS (M+H)+:
279.0592, found 279.0590.
2-(p-Tolyl)-4H-benzo[4,5]imidazo[2,1-b][1,3]thiazin-4-
one (3b). 42 mg, 96%. Yellowish solid, mp: 203-205oC. 1H
NMR (300 MHz, CDCl3) δ 8.58 (d, J = 7.5 Hz, 1H), 7.78 (d,
J = 7.5 Hz, 1H), 7.58 (d, J = 8.2 Hz, 2H), 7.52-7.39 (m, 2H),
7.32 (d, J = 8.0 Hz, 2H), 6.88 (s, 1H), 2.42 (s, 3H). 13C NMR
(75 MHz, CDCl3) δ 160.0, 150.6, 146.8, 142.60, 142.55,
131.6, 131.0, 130.2, 126.7, 125.8, 124.2, 118.6, 116.1, 113.0,
21.4. HRMS (ESI) calcd for C17H13N2OS (M+H)+:
293.0749, found 293.0740.
b][1,3]thiazin-4-one (3k). 39 mg, 73%. Yellowish solid,
mp: 137-139oC. 1H NMR (300 MHz, CDCl3) δ 8.60 (d, J =
7.4 Hz, 1H), 7.80 (d, J = 7.3 Hz, 1H), 7.73 (d, J = 6.6 Hz,
1H), 7.54-7.36 (m, 5H), 6.71 (s, 1H). 13C NMR (75 MHz,
CDCl3) δ 159.5, 149.6, 146.7, 142.4, 135.3, 133.9, 131.9,
130.9, 130.4, 127.9, 126.0, 124.4, 121.9, 118.7, 118.2, 116.2.
HRMS (ESI) calcd for C16H10BrN2OS (M+H)+: 356.9697,
found 356.9691.
2-(p-Methoxyphenyl)-4H-benzo[4,5]imidazo[2,1-
b][1,3]thiazin-4-one (3c). 21 mg, 45%. Yellowish solid,
mp: 223-225oC. 1H NMR (300 MHz, CDCl3) δ 8.59 (d, J =
7.4 Hz, 1H), 7.79 (d, J = 7.4 Hz, 1H), 7.66 (d, J = 6.9 Hz,
2H), 7.55-7.38 (m, 2H), 7.04 (d, J = 8.8 Hz, 2H), 6.86 (s,
1H), 3.89 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 162.6,
160.2, 150.2, 142.6, 132.5, 131.0, 128.4, 126.7, 125.8, 124.2,
118.6, 116.1, 114.9, 112.1, 55.6. HRMS (ESI) calcd for
C17H13N2O2S (M+H)+: 309.0698, found 309.0697.
2-(Naphthalen-2-yl)-4H-benzo[4,5]imidazo[2,1-
b][1,3]thiazin-4-one (3n). 36 mg, 73%. Yellowish solid,
mp: 207-209oC. 1H NMR (300 MHz, CDCl3) δ 8.62 (d, J =
6.7 Hz, 1H), 8.20 (s, 1H), 8.00-7.87 (m, 3H), 7.83 (d, J =
8.0 Hz, 1H), 7.74 (d, J = 8.7 Hz, 1H), 7.66-7.41 (m, 4H),
7.04 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 159.9, 150.5,
146.7, 142.7, 134.6, 133.0, 131.8, 131.1, 129.6, 128.9, 128.2,
127.8, 127.5, 127.3, 125.9, 124.3, 123.2, 118.7, 116.2, 114.0.
HRMS (ESI) calcd for C20H13N2OS (M+H)+: 329.0749,
found 329.0742.
2-(p-Fluorophenyl)-4H-benzo[4,5]imidazo[2,1-
b][1,3]thiazin-4-one (3d). 36 mg, 82%. Yellowish solid,
2-(Thiophen-2-yl)-4H-benzo[4,5]imidazo[2,1-
b][1,3]thiazin-4-one (3o). 32 mg, 75%. Yellowish solid,
mp: 246-248oC. 1H NMR (300 MHz, CDCl3) δ 8.59 (d, J =
5
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10.1002/adsc.201800857
Advanced Synthesis & Catalysis
mp: 251-253oC. 1H NMR (300 MHz, CDCl3) δ 8.57 (d, J =
7.4 Hz, 1H), 7.78 (d, J = 7.3 Hz, 1H), 7.59 (d, J = 4.4 Hz,
2H), 7.53-7.39 (m, 2H), 7.19 (t, J = 4.4 Hz, 1H), 6.91 (s,
1H). 13C NMR (75 MHz, CDCl3) δ 159.8, 145.9, 143.0,
158.5, 150.3, 147.0, 143.8, 134.6, 131.7, 129.6, 126.9, 125.3,
116.6, 113.7, 113.5, 101.2, 55.7. HRMS (ESI) calcd for
C17H13N2O2S (M+H)+: 309.0698, found 309.0695.
7-Methoxy-2-phenyl-4H-benzo[4,5]imidazo[2,1-
142.7, 137.0, 130.4, 128.9, 128.7, 125.9, 124.4, 118.7, 116.1, b][1,3]thiazin-4-one (3bb). 22 mg, 48% yield. Yellowish
111.7. HRMS (ESI) calcd for C14H9N2OS2 (M+H)+:
285.0156, found 285.0155.
solid, mp: 174-176oC.1H NMR (500 MHz, CDCl3) δ 8.13 (d,
J = 2.5 Hz, 1H), 7.72-7.68 (m, 2H), 7.67 (d, J = 8.9 Hz, 1H),
7.58-7.52 (m, 3H), 7.12 (dd, J = 8.8, 2.5 Hz, 1H), 6.89 (s,
1H), 3.94 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 160.3,
157.3, 150.9, 144.7, 136.9, 134.6, 131.8, 131.7, 129.9, 126.9,
119.1, 115.5, 113.5, 99.5, 56.0. HRMS (ESI) calcd for
2-Methyl-4H-benzo[4,5]imidazo[2,1-b][1,3]thiazin-4-
one (3p). 22 mg, 69%. Yellowish solid, mp: 162-164oC. 1H
NMR (300 MHz, CDCl3) δ 8.53 (d, J = 7.5 Hz, 1H), 7.75 (d,
J = 7.4 Hz, 1H), 7.49-7.38 (m, 2H), 6.52 (d, J = 1.1 Hz, 1H),
2.47 (d, J = 1.0 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 159.6, C17H13N2O2S (M+H)+: 309.0698, found 309.0697.
148.7, 146.7, 142.3, 131.0, 125.8, 124.1, 118.6, 116.0, 115.5, 8-Methyl-2-phenyl-4H-benzo[4,5]imidazo[2,1-
22.7. HRMS (ESI) calcd for C11H9N2OS (M+H)+: 217.0436,
found 217.0433.
b][1,3]thiazin-4-one (3ca) and 7-methyl-2-phenyl-4H-
benzo[4,5]imidazo[2,1-b][1,3]thiazin-4-one (3cb) (1:1
mixture). 40 mg, 91% combined yield. Yellowish solid,
mp: 208-210oC. 1H NMR (500 MHz, CDCl3) δ 8.43 (d, J =
8.3 Hz, 1H, 3ca), 8.39 (s, 1H, 3cb), 7.71-7.64 (m, 5H,
3ca+3cb), 7.58-7.50 (m, 7H, 3ca+3cb), 7.30 (d, J = 8.2 Hz,
1H, 3cb), 7.25 (d, J = 9.0 Hz, 1H, 3ca), 6.89 (s, 2H, 3ca+3cb),
2.55 (s, 3H, 3cb), 2.52 (s, 3H, 3ca). 13C NMR (75 MHz,
CDCl3) δ 160.1, 159.8, 150.6, 150.4, 145.9, 143.4, 140.7,
136.1, 134.60, 134.58, 131.7, 131.1, 129.5, 127.4, 126.9,
125.7, 118.5, 118.1, 116.1, 115.6, 113.75, 113.71, 21.82,
21.75. HRMS (ESI) calcd for C17H13N2OS (M+H)+:
293.0749, found 293.0740.
2-Ethyl-4H-benzo[4,5]imidazo[2,1-b][1,3]thiazin-4-one
1
(3q). 19 mg, 55%. Yellowish solid, mp: 118-120oC. H
NMR (300 MHz, CDCl3) δ 8.55 (d, J = 7.9 Hz, 1H), 7.76 (d,
J = 7.3 Hz, 1H), 7.54-7.35 (m, 2H), 6.57 (s, 1H), 2.75 (q, J
= 7.3 Hz, 2H), 1.39 (t, J = 6.2 Hz, 3H). 13C NMR (75 MHz,
CDCl3) δ 159.9, 155.2, 146.8, 142.4, 131.0, 125.8, 124.1,
118.5, 116.0, 113.9, 30.0, 13.5. HRMS (ESI) calcd for
C12H11N2OS (M+H)+: 231.0592, found 231.0582.
2-Pentyl-4H-benzo[4,5]imidazo[2,1-b][1,3]thiazin-4-one
1
(3r). 26 mg, 64%. Yellowish solid, mp: 77-79oC. H NMR
(300 MHz, CDCl3) δ 8.54 (dd, J = 7.4, 1.3 Hz, 1H), 7.76 (dd,
J = 7.2, 1.0 Hz, 1H), 7.49-7.38 (m, 2H), 6.54 (s, 1H), 2.70
(t, J = 7.9 Hz, 2H), 1.81-1.71 (m, 2H), 1.44-1.35 (m, 4H),
0.92 (t, J = 7.0 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 159.8,
8-Chloro-2-phenyl-4H-benzo[4,5]imidazo[2,1-
b][1,3]thiazin-4-one (3da) and 7-chloro-2-phenyl-4H-
benzo[4,5]imidazo[2,1-b][1,3]thiazin-4-one (3db) (1:1
154.0, 146.8, 142.4, 131.0, 125.8, 124.1, 118.5, 116.1, 114.6, mixture). 42 mg, 90% combined yield. Yellowish solid,
36.7, 30.8, 28.8, 22.2, 13.8. HRMS (ESI) calcd for
mp: 228-232oC.1H NMR (500 MHz, CDCl3) δ 8.62 (d, J =
2.0 Hz, 1H, 3db), 8.51 (d, J = 8.7 Hz, 1H, 3da), 7.77 (d, J =
1.9 Hz, 1H, 3da), 7.73-7.67 (m, 5H, 3da+3db), 7.61-7.52 (m,
6H, 3da+3db), 7.47 (dd, J = 8.6, 2.1 Hz, 1H, 3da or 3db),
7.42 (dd, J = 8.7, 2.0 Hz, 1H, 3da or 3db), 6.931 (s, 1H, 3da
or 3db), 6.929 (s, 1H, 3da or 3db). 13C NMR (75 MHz,
CDCl3) δ 159.67, 159.62, 151.1, 151.0, 147.4, 143.4, 141.2,
134.4, 132.0, 131.7, 131.4, 130.1, 129.7, 126.9, 126.6, 124.7,
119.4, 118.6, 116.8, 116.3, 113.7, 113.6. HRMS (ESI) calcd
for C16H10ClN2OS (M+H)+: 313.0202, found 313.0197.
2-Phenyl-4H-benzo[4,5]imidazo[2,1-b][1,3]oxazin-4-one
(5). 21 mg, 54%. Yellowish solid, mp: 186-188oC. 1H NMR
(300 MHz, CDCl3) δ 8.33 (d, J = 7.3 Hz, 1H), 7.98-7.95 (m,
2H), 7.76 (d, J = 7.7 Hz, 1H), 7.66-7.53 (m, 3H), 7.49 (td, J
= 7.7, 1.3 Hz, 1H), 7.42 (td, J = 7.7, 1.2 Hz, 1H), 6.58 (s,
C15H17N2OS (M+H)+: 273.1062, found 273.1054.
2-Cyclopropyl-4H-benzo[4,5]imidazo[2,1-b][1,3]thiazin-
4-one (3s). 23 mg, 64%. Yellowish solid, mp: 112-114oC.
1H NMR (300 MHz, CDCl3) δ 8.52 (d, J = 7.6 Hz, 1H), 7.74
(d, J = 7.4 Hz, 1H), 7.54 -7.33 (m, 2H), 6.44 (s, 1H), 2.08-
1.89 (m, 1H), 1.24-1.19 (m, 2H), 1.10-1.02 (m, 2H). 13C
NMR (75 MHz, CDCl3) δ 159.6, 156.4, 146.4, 142.5, 131.1,
125.7, 124.1, 118.5, 116.0, 111.7, 17.4, 10.3. HRMS (ESI)
calcd for C13H11N2OS (M+H)+: 243.0592, found 243.0588.
7,8-Dimethyl-2-phenyl-4H-benzo[4,5]imidazo[2,1-
b][1,3]thiazin-4-one (3u). 41 mg, 90%. Yellowish solid,
mp: 235-237oC. 1H NMR (300 MHz, CDCl3) δ 8.37 (s, 1H),
7.74-7.66 (m, 2H), 7.60-7.51 (m, 4H), 6.91 (s, 1H), 2.45,
2.43 (s×2, 2CH3). 13C NMR (75 MHz, CDCl3) δ 159.9,
150.4, 141.3, 135.1, 134.8, 133.6, 131.6, 130.3, 129.5, 129.3, 1H). 13C NMR (75 MHz, CDCl3) δ 162.3, 157.2, 151.4,
126.9, 118.8, 116.2, 113.8, 20.42, 20.37. HRMS (ESI) calcd
for C18H15N2OS (M+H)+: 307.0905, found 307.0898.
7-Phenyl-5H-imidazo[2,1-b][1,3]thiazin-5-one (3w). 25
139.2, 132.8, 129.3, 129.1, 128.1, 126.5, 126.0, 123.9, 119.1,
115.0, 97.2. HRMS (ESI) calcd for C16H11N2O2 (M+H)+:
263.0821, found 263.0824.
1
mg, 73%. Yellowish solid, mp: 143-145oC. H NMR (300
MHz, DMSO) δ8.00 (d, J = 1.6 Hz, 1H), 7.70-7.63 (m, 2H),
7.59-7.48 (m, 3H), 7.43 (d, J = 1.6 Hz, 1H), 6.89 (s, 1H).
13C NMR (75 MHz, CDCl3) δ 158.2, 152.5, 140.3, 134.9,
131.8, 131.7, 129.6, 127.0, 114.8, 112.1. HRMS (ESI) calcd
for C12H9N2OS (M+H)+: 229.0436, found 229.0426.
Procedure for the reduction of 3a with LiAlH4
To a 25 mL round-bottom flask was charged with 3a (41.7
mg, 0.15 mmol), 46 mg of LiAlH4 (1.2 mmol) and
anhydrous 4 mL of THF. The mixture was stirred at room
temperature for 1h. The mixture was concentrated and the
residue was purified by chromatography on silica gel using
hexane/EtOAc (6:1) as the eluent to afford 22 mg of
compound 5.
2,3,7-Triphenyl-5H-imidazo[2,1-b][1,3]thiazin-5-one
1
(3x). 22 mg, 38%. Yellowish solid, mp: 230-232oC. H
NMR (300 MHz, CDCl3) δ 7.72-7.62 (m, 2H), 7.60-7.52 (m,
3H), 7.51-7.47 (m, 2H), 7.47-7.39 (m, 5H), 7.26-7.21 (m,
3H), 6.73 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 159.2,
150.6, 141.0, 140.8, 134.7, 132.5, 131.6, 130.9, 129.5, 128.6,
128.2, 128.1, 127.8, 127.7, 126.80, 126.76, 113.2. HRMS
(ESI) calcd for C24H17N2OS (M+H)+: 381.1062, found
381.1057.
2-Phenyl-3,4-dihydro-2H-benzo[4,5]imidazo[2,1-
b][1,3]thiazine (5). 22 mg, 56%. Yellowish solid, mp: 164-
1
166oC. H NMR (300 MHz, DMSO) δ 7.64-7.36 (m, 4H),
7.31 (t, J = 7.4 Hz, 2H), 7.25-7.20 (m, 1H), 7.17-7.07 (m,
2H), 5.12 (t, J = 7.7 Hz, 1H), 3.49-3.31 (m, 2H), 2.35-2.07
(m, 2H). 13C NMR (75 MHz, CDCl3) δ 148.9, 143.7, 141.6,
135.3, 128.5, 127.6, 127.4, 121.8, 121.3, 117.6, 110.5, 58.2,
47.4, 39.1. HRMS (ESI) calcd for C16H15N2S (M+H)+:
267.0956, found 267.0960..
9-Methyl-2-phenyl-4H-benzo[4,5]imidazo[2,1-
b][1,3]thiazin-4-one
and
8-chloro-2-phenyl-4H-
benzo[4,5]imidazo[2,1-b][1,3]thiazin-4-one (3aa). 35 mg,
80% combined yield. Yellowish solid, mp: 213-215oC.1H
NMR (500 MHz, CDCl3) δ 8.46-8.38 (m, 1H), 7.73-7.66 (m,
2H), 7.61-7.51 (m, 3H), 7.39-7.28 (m, 2H), 6.91 (s, 1H),
2.70 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 160.1, 150.6,
145.8, 141.8, 134.6, 131.7, 130.7, 129.6, 128.6, 126.9, 126.4,
124.3, 113.8, 113.6, 16.6. HRMS (ESI) calcd for
C17H13N2OS (M+H)+: 293.0749, found 293.0743.
Acknowledgements
This work is funded by the National Natural Science Foundation
of China (No. 21572270), the Qing Lan Project of Jiangsu
Province, the Priority Academic Program Development of Jiangsu
Higher Education Institutions, and the College Students
Innovation Project for the R&D of Novel Drugs (J1310032).
8-Methoxy-2-phenyl-4H-benzo[4,5]imidazo[2,1-
b][1,3]thiazin-4-one (3ba). 23 mg, 50% yield. Yellowish
1
solid, mp: 161-163oC. H NMR (500 MHz, CDCl3) δ 8.45
(d, J = 8.9 Hz, 1H), 7.73-7.66 (m, 2H), 7.60-7.51 (m, 3H),
7.25 (d, J = 2.4 Hz, 1H), 7.05 (dd, J = 8.9, 2.4 Hz, 1H), 6.91
(s, 1H), 3.90 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 159.7,
6
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10.1002/adsc.201800857
Advanced Synthesis & Catalysis
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7
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10.1002/adsc.201800857
Advanced Synthesis & Catalysis
FULL PAPER
N-Heterocyclic Carbene-Catalyzed in situ
Activation of Alkynyl Acids for C-S Bond
Formation: Access to Imidazo[2,1-
b][1,3]thiazinones
Adv. Synth. Catal. Year, Volume, Page – Page
Kewen Sun, Shiyi Jin, Jindong Zhu, Xinmiao
Zhang, Maoyu Gao, Wanqi Zhang, Tao Lu and
Ding Du *
8
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