Pyridinium 1,4-zwitterionic thiolates as a useful class of sulfur-containing synthons: application to the synthesis of 2,5-dihydro-1,4,5-thiadiazepines

Article abstract of DOI:10.1039/c9cc08326j

A novel [4+3] cascade cyclization reaction of pyridinium 1,4-zwitterionic thiolates with azoalkenes derived from α-halo hydrazones in situ has been developed. This reaction was found to allow expedient access to an array of 2,5-dihydro-1,4,5-thiadiazepine

Full text of DOI:10.1039/c9cc08326j

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Pyridinium 1,4-zwitterionic thiolates as a useful
class of sulfur-containing synthons: application to
the synthesis of 2,5-dihydro-1,4,5-thiadiazepines†
ab
Cite this: Chem. Commun., 2019,
55, 14606
Received 24th October 2019,
Accepted 5th November 2019
Bin Cheng,
*
Yuntong Li,‡b Taimin Wang,‡a Xinping Zhang,ab Hui Li,ab
b
Yun Li
and Hongbin Zhai*abc
DOI: 10.1039/c9cc08326j
rsc.li/chemcomm
A novel [4+3] cascade cyclization reaction of pyridinium 1,4-zwitterionic The commonly used pyridinium zwitterions mainly include A1–A3
thiolates with azoalkenes derived from a-halo hydrazones in situ has and their analogues (Scheme 1), one of the important applications
been developed. This reaction was found to allow expedient access of which was using them as 1,3-dipoles to produce diversified
to an array of 2,5-dihydro-1,4,5-thiadiazepines. Libraries of highly heterocyclic compounds, where the pyridine moiety was retained
functionalized sulfoxide and sulfone analogues of 2,5-dihydro- in the target molecules. Recently, Yoo reported the pyridinium
1,4,5-thiadiazepines were also obtained via selective oxidation with 1,4-zwitterionic compounds A4 (Scheme 1) and successfully applied
m-CPBA.
them to a series of cycloaddition reactions (e.g., [5+2], [5+3]) to
access unusual medium-sized heterocycles, where the pyridine part
Sulfur is a chemical element closely involved in various aspects of A4 was also incorporated into the target products.8 In 2011,
of human life, as it is ubiquitous in natural products,1 pharma- Bazgir reported an efficient and simple synthesis of pyridinium
ceutical molecules,2 functional materials3 and almost all living 1,4-zwitterionic thiolates A5 (Scheme 1) from dialkyl acetylenedicarb-
organisms.4 Organosulfur compounds are found in a variety of oxylates, elemental sulfur, and pyridine.9 However, 1,4-zwitterionic
forms (e.g., thioethers, sulfoxides, and sulfones, among others) thiolates of this class have not yet been recognized as useful and
that serve various functions in agrochemistry, medicinal chemistry, versatile synthons to the best of our knowledge. In this context,
material chemistry and food chemistry. Thus, many efficient meth- intrigued by their unique structures, we envisaged that the reactive
ods have been developed to introduce sulfur atoms into target intermediates could be used to prepare sulfur-containing hetero-
molecules.5 Thiols and thioethers have traditionally been used as cycles via two reaction modes: [5+m, path a], with pyridine as a
the sulfur-containing synthons, and sulfur powder, inorganic metal reactive moiety, and [3+m, path b], with pyridine as a leaving group
sulfides and sulfur-containing small organic molecules have also (Scheme 1). Thus, we embarked on a program to explore and
been developed as sulfuration agents. However, the use of these understand their properties and reactivities comprehensively.
synthons to incorporate sulfur into organic molecules does have
some drawbacks, such as the unpleasant odor of thiols and
thioethers, and the need to involve transition-metal catalysts.1c,6
Thus, developing air-stable, odorless, easy- to -handle, and
readily available sulfur-containing synthons is highly desired.
Pyridinium zwitterions have been long used as a class of
powerful and flexible organic synthons, and great advances in this
field have been made during the past decades by organic chemists.7
a Institute of Marine Biomedicine, Shenzhen Polytechnic, Shenzhen 518055, China.
E-mail: chengbin@szpt.edu.cn
b State Key Laboratory of Applied Organic Chemistry, College of Chemistry and
Chemical Engineering, Lanzhou University, Lanzhou 730000, China
c State Key Laboratory of Chemical Oncogenomics, Shenzhen Engineering Laboratory
of Nano Drug Slow-Release, Peking University Shenzhen Graduate School,
Shenzhen 518055, China. E-mail: zhaihb@pkusz.edu.cn
† Electronic supplementary information (ESI) available: Experimental procedures,
NMR spectra and HRMS data. CCDC 1885455 (3a) and 1887981 (4l). For ESI and
Scheme 1 Commonly used pyridinium zwitterions and our design of
crystallographic data in CIF or other electronic format see DOI: 10.1039/c9cc08326j
pyridinium 1,4-zwitterionic thiolates.
‡ These authors contributed equally to this work.
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Table 2 [4+3] cascade cyclization reactiona
Here, we describe our preliminary results on their cascade cycliza-
tion reactions with azoalkenes to access 2,5-dihydro-1,4,5-thia-
diazepines via path b. In addition, libraries of highly functionalized
sulfoxide and sulfone analogues of 2,5-dihydro-1,4,5-thiadiazepines
were obtained via selective oxidation with m-CPBA.
According to the literature,10 azoalkenes could be readily
prepared in situ from a-halo hydrazones. Thus, a-bromo N-Ac
hydrazone 1a and pyridinium 1,4-zwitterionic thiolate 2a were
adopted as the model substrates to probe the cyclization
reaction. To our delight, the reaction proceeded cleanly with Na2CO3
as the base in dichloromethane (DCM) at room temperature under
air, affording 2,5-dihydro-1,4,5-thiadiazepine 3a, an intriguing
seven-membered sulfur-containing diazaheterocycle, in 79% yield
(Table 1, entry 1).11 The exact structure of 3a was unambiguously
established using X-ray diffraction analysis.12 It was evident that 3a
was generated along the [4+3] pathway (Scheme 1, path b) with 2a as
a three-atom reactant. It should be pointed out that there have been
no reports on the reactions of pyridiniums A1–A3 with azoalkenes
in the literature, although some other 1,3-dipoles (e.g., nitrones,
azomethines) could react with azoalkenes to form seven-membered
Yield (%)
R2 = Ac
Entry
R1
R3
X
R2 = Boc
1
2
3
4
5
6
7
8
9
10
C6H5
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Br
Br
Br
Br
Br
Cl
Br
Cl
Br
Br
3a, 98 (91)b
3b, 89
3c, 86
3d, 81
3e, 91
3f, 92
3g, 55
3h, 91
3i, 64
3k, 93
3l, 62
3m, 83
3n, 97
3o, 95
3p, 92
3q, 84
3r, 51
3s, 52
3t, 92
4-MeO-C6H4
4-Me-C6H4
4-NO2-C6H4
4-CF3-C6H4
4-F-C6H4
2-Furyl
t-Bu
(E)-Styrenyl
C6H5
3j, 89
a
Reaction conditions: 1 (0.3 mmol), 2 (0.45 mmol, 1.5 equiv.), Na2CO3
(0.6 mmol, 2.0 equiv.), solvent (3 mL), 25 1C, in air. Isolated yield. The
b
reaction was conducted on the gram scale.
heterocycles.10a–f Encouraged by this initial success, we then ester-derived 1,4-zwitterionic thiolate was equally efficient and
screened a series of reaction conditions including the equivalents delivered 3j in 89% yield. The reaction of a-bromo N-Boc
of the reactants (entries 1–4), bases (entries 5 and 6), and solvents hydrazones showed a similar situation as the a-bromo N-Ac
(entries 7–9), and a 98% yield of 3a was obtained under the optimal ones and gave a library of analogues of seven-membered sulfur-
reaction conditions (1a : 2a : Na2CO3 = 1 : 1.5 : 2, DCM, room containing heterocycles (3k–t). As exemplified by 3f, 3h, 3p and
temperature, under air, Table 1, entry 2).
3r, a-chloro hydrazones were amenable to this cascade trans-
With the optimal reaction conditions in hand, we started to formation. Interestingly, N-Ac hydrazones showed higher yields
scrutinize the generality and scope of this [4+3] cascade cyclization than did N-Boc hydrazones for some substrates (e.g., 3h vs. 3r)
reaction. As shown in Table 2, we first studied the aryl-substituted and lower yields for other substrates (e.g., 3g vs. 3q). In addition,
N-Ac hydrazones. The electronic properties of the substituents on this [4+3] cascade cyclization reaction could be performed on
the phenyl group had no obvious influence on the cyclization the gram scale with only a slight decrease in yield (see, 3a).
efficiency, as all of them worked well and afforded an array of
With the library of seven-membered sulfur-containing hetero-
seven-membered S/N-heterocycles (3a–i) in 81% to 98% yields. The cycles established above, we next turned our attention to acces-
2-furyl-substituted substrate was also tolerated and gave the sing their sulfone and sulfoxide analogues via selective oxidation.
corresponding product (3g) in 55% yield. Then, alkyl and Thioethers can be transformed to and from sulfoxides or
alkenyl-substituted N-Ac hydrazones were examined, and found sulfones. More importantly, their different oxidative states
to be suitable substrates as well, furnishing the cyclization could exhibit diverse bioactivities.13 Fortunately, when m-CPBA
products (3h and 3i) in 91% and 64% yields, respectively. Ethyl (1.0 equiv.) was adopted as the oxidant, sulfoxides (4a–j, Table 3)
were obtained as the major products with satisfying yields.
Moreover, when 3 equiv. of m-CPBA was used, representative
sulfone analogues (4k–o) comprising phenyl, 2-furyl, t-butyl,
Table 1 Optimization of the reaction conditionsa
and (E)-styrenyl groups were smoothly produced as the sole
products.12 Of note, both of the N-Ac and N-Boc substrates and
various functional groups were compatible with these selective
oxidation conditions. Thus, a library of seven-membered sulfur-
containing diazaheterocycles with three distinct oxidation states
(thioether, sulfoxide and sulfone) was successfully established,
and is expected to have great potential and value for structure–
activity relationship (SAR) studies.
Entry
1a : 2a
Base (equiv.)
Solvent
Yield (%)
1
2
3
4
5
6
7
8
9
1 : 1.5
1 : 1.5
1 : 2.0
1 : 1.1
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.5
1 : 1.5
Na2CO3 (1.5)
Na2CO3 (2.0)
Na2CO3 (2.0)
Na2CO3 (2.0)
K2CO3 (2.0)
Cs2CO3 (2.0)
Na2CO3 (2.0)
Na2CO3 (2.0)
Na2CO3 (2.0)
DCM
DCM
DCM
DCM
DCM
DCM
THF
79
98
93
81
78
97
41
90
78
Based on the previous reports,14 we proposed a plausible
reaction mechanism for the [4+3] cascade cyclization reaction
(Scheme 2). Here azoalkenes, formed in situ from a-halo
hydrazones under basic conditions, react with 1,4-zwitterionic
thiolates via a cascade process including S-Michael addition,
N-Michael addition and retro-Michael addition/Py extrusion to
afford 2,5-dihydro-1,4,5-thiadiazepines. An alternative pathway
MeCN
DCE
a
Reaction conditions: 1a (0.3 mmol), 2a, base, solvent (3 mL), r.t.
(25 1C), under air. Isolated yield.
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Table 3 Oxidation of 3 to sulfoxides or sulfones with m-CPBAa
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Yield (%)
Entry
1
R1
R3
Sulfoxide
Sulfone
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4c, 69
4d, 62
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4j, 69
4k, 70
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4o, 71
a
For sulfoxides, reaction conditions: 3 (0.3 mmol), m-CPBA (1.0 equiv.),
CH2Cl2 (3 mL), 25 1C, R2 = Boc unless otherwise noted. For sulfones,
reaction conditions: 3 (0.3 mmol), m-CPBA (3.0 equiv.), CH2Cl2 (3 mL),
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Scheme 2 Proposed mechanism for the [4+3] cascade cyclization reac-
tion of a-halo hydrazones and pyridinium 1,4-zwitterionic thiolates.
involving S-nucleophilic substitution reaction of halides fol-
lowed by N-Michael addition and retro-Michael addition/Py
extrusion could not be excluded.15
In summary, a new reaction mode of pyridinium 1,4-zwitterionic
thiolates has been developed, and was found to allow expedient
access to 2,5-dihydro-1,4,5-thiadiazepines via a [4+3] cascade
cyclization reaction under mild conditions. Selective oxidations
of 2,5-dihydro-1,4,5-thiadiazepines with m-CPBA were success-
fully achieved, affording libraries of highly functionalized sulf-
oxide and sulfone analogues. The other performances and
reaction modes of pyridinium 1,4-zwitterionic thiolates will be
reported in due course.
We thank the NSFC (21971092, 21472072, 21871018, 21732001,
and 2167201), Program for Changjiang Scholars and Innovative
Research Team in University (PCSIRT: IRT_15R28) and FRFCU
(lzujbky-2019-50, lzujbky-2017-90). We also thank Dr Hanwei Hu
for assistance in polishing the manuscript.
Conflicts of interest
There are no conflicts to declare.
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14608 | Chem. Commun., 2019, 55, 14606--14608
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