Synthesis of benzothiazonine by rhodium-catalyzed denitrogenative transannulation of 1-sulfonyl-1,2,3-triazole and thiochromone

Article abstract of DOI:10.1039/d1ob00419k

A facile synthesis of multi-functionalized benzothiazonine was achieved by the rhodium-catalyzed denitrogenative annulation of 1-sulfonyl-1,2,3-triazole and thiochromone. In view of the excellent atom economy, broad substrate scope and easy availability of starting materials, the protocol provided an efficient strategy for the construction of mediumN,S-heterocycles.

Full text of DOI:10.1039/d1ob00419k

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Biomolecular Chemistry
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Synthesis of benzothiazonine by rhodium-
catalyzed denitrogenative transannulation of
1-sulfonyl-1,2,3-triazole and thiochromone†
Cite this: Org. Biomol. Chem., 2021,
19, 5758
Received 4th March 2021,
Accepted 4th May 2021
Saygbechi T. Jablasone, Jr, Zihang Ye, Shengguo Duan, Ze-Feng Xu * and
DOI: 10.1039/d1ob00419k
Chuan-Ying Li
*
rsc.li/obc
A facile synthesis of multi-functionalized benzothiazonine was quetiapine.5 To the best of our knowledge, medium N,S-het-
achieved by the rhodium-catalyzed denitrogenative annulation of erocycles are still unknown as drugs; however, benefitting
1-sulfonyl-1,2,3-triazole and thiochromone. In view of the excel- from the ring strain, medium-sized N,S-heterocycles usually
lent atom economy, broad substrate scope and easy availability of bear a unique conformation, which is important in drug dis-
starting materials, the protocol provided an efficient strategy for
the construction of medium N,S-heterocycles.
1,2,3-Triazole, which can be synthesized via click reaction, is a
very important heteroarene acting as a widespread motif in
bioactive molecules and drugs, as a linker in materials
science, in biological studies and so on.1 Furthermore, a
Dimroth equilibrium could be established between triazole 1
and α-diazo imine 2 (Scheme 1A) when an electron-withdraw-
ing group was attached at the 1-position of 1,2,3-triazole.
Consequently, Gevorgyan, Fokin and co-workers reported in
2008 that with a rhodium catalyst, 1-sulfonyl-1,2,3-triazole
could act as a precursor of α-imino rhodium carbene 3 to react
with nitrile producing imidazole (Scheme 1B).2 α-Imino
rhodium carbene 3 is electrophilic at carbene carbon and
nucleophilic at imine nitrogen, making it a useful 1,3-dipole
synthon in organic synthesis. Following the landmark work,
various groups investigated the transformations of 1-sulfonyl-
1,2,3-triazole, and α-imino rhodium carbene 3 has become
one of the most important intermediates in the synthesis of
nitrogen-containing compounds, especially in the construction
of 5- and 6-membered (hetero)cycles.3,4 However, a rare case of
medium ring synthesis employing 3 was reported.
The N,S-heterocycle is a prevalent skeleton in many drugs
(Fig. 1). For instance, there is a 5-membered N,S-heterocycle in
famotidine and oxacillin; cephalexin, trifluoperazine and
chlormezanone contain
a
6-membered N,S-heterocycle.
7-Membered N,S-heterocycles can be found in diltiazem and
Department of Chemistry, Key Laboratory of Surface & Interface Science of Polymer
Materials of Zhejiang Province, Zhejiang Sci-Tech University, Xiasha West Higher
Education District, Hangzhou, 310018, China. E-mail: xuzefeng@zstu.edu.cn,
licy@zstu.edu.cn; Tel: (+86)-571-86843094
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
d1ob00419k
Scheme 1 Background and reaction design.
5758 | Org. Biomol. Chem., 2021, 19, 5758–5761
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Table 1 Optimization of reaction conditionsa
Entry
1b : 6a
[Rh]
Solvent
Temp. (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
2 : 1
2 : 1
2 : 1
2 : 1
2 : 1
2 : 1
2 : 1
1.4 : 1
1.4 : 1
1.4 : 1
1.4 : 1
1.4 : 1
1.4 : 1
1.4 : 1
Rh2(OAc)4
Rh2(esp)2
Rh2(esp)2
Rh2(piv)4
Rh2(oct)4
Rh2(tfa)4
Rh2(dpf)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
Toluene
TCE
CHCl3
DCM
Toluene
Toluene
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
80
65
78
73
74
80
—
—
84
87
79
74
—
93
98
Fig. 1 Representative N,S-heterocycle-containing drugs.
covery. Thus, efficient synthetic methodology for medium N,S-
heterocycles is highly desirable. The conformational strain and
entropic factor in the transition state make it difficult to con-
struct medium rings,6 and only a few protocols have been
developed to afford 8- or 9-membered N,S-heterocycles, includ-
ing intramolecular F–C reaction, metathesis, nucleophilic
cyclization and so on.7 Accordingly, new and efficient synthetic
methods for medium-sized N,S-heterocycles are still needed.
As mentioned, transannulation of 1-sulfonyl-1,2,3-triazole
was an effective strategy to produce N-heterocycles. In the pre-
vious reports, sulfur could attack the carbene carbon in
α-imino rhodium carbene 3 and the following cleavage of the
C–S bond would finally yield the C–S insertion product
(Scheme 1C).8 Accordingly, a synthetic protocol for 9-mem-
bered N,S-heterocycle thiazonine was designed (Scheme 1D).
The nucleophilic addition of sulfur in thiochromone 6 to
9
10
11
12
13c
14c
80
Reflux
Reflux
80
90
a General conditions: 1b, 6a (0.2 mmol), [Rh] (3 mol%), and solvent
(1 mL) at reflux. b Isolated yield. c [Rh] (5 mol%) was used. Ts = tosyl,
OAc = acetate, esp = α,α,α′,α′-tetramethyl-1,3-benzenedipropionate, adc
= 1-adamantanecarboxylate, piv = pivalate, oct = octanoate, tfa = tri-
fluoroacetate, dpf = N,N′-diphenylformamidinate, DCE = 1,2-dichlor-
oethane, TCE = 1,1,2-trichloroethane, and DCM = dichloromethane.
The investigation of the transannulation reaction scope
carbene carbon would give sulfur ylide 7 and intramolecular (Scheme 2) under the optimal conditions began with testing
Michael addition of 7 would produce 8. The following depar- various sulfonyls. Generally, sulfonyl groups influence the
ture of sulfur furnishes the desired 9-membered thiazonine 9. reaction to some extent: electron-abundant arylsulfonyl substi-
Herein, we report our successful establishment of the protocol tuted benzothiazonines 9a–d could be generated in 75%–99%
for medium-sized N,S-heterocyclic benzothiazonine synthesis.
yields, and electron-deficient arylsulfonyl substituted ben-
With triazole 1b and thiochromone 6a as model substrates, zothiazonines 9e and 9f could be formed in 81% and 91%
the reaction was first tried in DCE with 3 mol% Rh2(OAc)4 as yields, respectively. The steric effect of the sulfonyl would
the catalyst, and benzothiazonine 9b was isolated in 65% yield depress the reaction and as a result, the yields of 9c and 9g
as depicted in entry 1, Table 1. Based on the initial result, the were reduced to 75% and 70%, respectively; the mesyl substi-
screening of reaction conditions was performed by evaluating tuted product 9h was obtained in 90% yield. The substituents
various rhodium catalysts. Common rhodium(II) salts, such as on 4-aryl of the triazole affected the reaction remarkably: alkyl
Rh2(OAc)4, Rh2(esp)2, Rh2(adc)4, Rh2(piv)4 and Rh2(oct)4, could substituted benzothiazonine 9i was delivered in 81% yield but
catalyse the reaction, and the desired benzothiazonine 9b was a strong electron-donating group destabilized the triazole and
obtained in good yields (entries 1–5) except for Rh2(tfa)4 and the corresponding product 9j was obtained in only 29% yield.
Rh2(dpf)4, in which cases, no reaction occurred and triazole 1b When methyl was located at the ortho-position, 9k was pro-
decomposed gradually (entries 6, 7). Although Rh2(oct)4 per- duced in 69% yield. Normally, the electron-withdrawing
formed best (entry 5), Rh2(OAc)4 was selected for further screen- groups retarded the reaction and 9l–o were isolated in moder-
ing because an improved yield of 9b can be achieved when redu- ate to good yields (48%–73%); however, 9p was obtained in
cing the dosage of triazole 1b to 1.4 equivalents (84%, entry 8). 87% yield, which means that the ester group was well compati-
Further screening of solvents (entries 9–12) revealed that ble. 1-Naphthyl substituted 9q was generated in 81% yield,
toluene was the most suitable solvent in which 9b was gener- and considering the lower yield of 9k, it is difficult to ascertain
ated in 87% yield; no reaction took place in reflux DCM. When the impact of the steric effect on the reaction. Gratifyingly, the
the dosage of Rh2(OAc)4 was increased to 5 mol%, 9b was heteroaryl group could be tolerated and 9r could be afforded
obtained in 93% yield (entry 13) and when the temperature was in an acceptable yield (67%). The substituents on the thiochro-
elevated to 90 °C, 9b could be obtained almost quantitatively mone were also evaluated; methoxy and fluoro substituted pro-
(entry 14), and these were selected as the optimal conditions.
ducts were formed in excellent yields (9s: 90% and 9u: 92%),
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tron withdrawing group (benzoyl) on the aryl group of thio-
chromone was not compatible and only a complicated mixture
was obtained.
It is worth mentioning that a sulfur atom was essential to
the reaction, and when it was replaced with oxygen (chromone)
or nitrogen (quinolin-4(1H)-one), no desired similar hetero-
cycle was generated and triazole 1b was decomposed gradually.
When benzothiopyran-4-one was employed, only an unrecog-
nizable mixture was obtained, indicating the necessity of the
double bond.
Several experiments were conducted to illustrate the poten-
tial of the protocol in organic synthesis. The reaction could be
extended to a 1 mmol scale and the yields of the desired ben-
zothiazonines 9b and 9w were still satisfactory (81% and 73%
respectively, eqn (1)). A one-pot procedure starting from an
alkyne was also established, in which triazole was formed via
click reaction between the alkyne and sulfonyl azide under the
catalysis of CuTc; 6a and Rh2(OAc)4 were added and allowed to
react at 90 °C for 1 h, and finally, 9b was isolated in 71% yield
(eqn (2)). The sulfur could be oxidized to sulfone 10 by
m-CPBA (eqn (3)). Moreover, Suzuki coupling of 9w with
boronic acid gave the biphenyl product 11 in quantitative yield
(eqn (4)).
ð1Þ
ð2Þ
ð3Þ
Scheme 2 Reaction scope.
whereas chloro and bromo substituted 9v and 9w were
obtained in lower yields (73% and 71%). Thiochromone
without any substituents led to the formation of 9t in 85%
yield. When methyl was present at the ortho-position to sulfur,
the reaction was hampered seriously and only a 16% yield of
9x was achieved, illustrating the vital influence of the steric
effect around the sulfur atom on the reaction. The strong elec-
ð4Þ
In summary, we have established a practical synthetic pro-
tocol for medium-sized N,S-heterocycles, and functionalized
benzothiazonine was afforded in a quantitative yield with a
broad scope. Synthetic applications were also conducted illus-
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trating the potential of the method. Based on the excellent
atom economy and easy availability of the starting materials,
the protocol provided an efficient strategy for the construction
of medium heterocycles and could find more applications in
organic synthesis.
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We are grateful for the support of this work by the National
Natural Science Foundation of China (21871235, 21801224 and
21901230), the Fundamental Research Funds of Zhejiang
Sci-Tech University (2019Y003) and the Science Foundation
of Zhejiang Sci-Tech University (ZSTU) under Grant No.
18062301-Y.
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