Regiospecific Bi-Catalysed Domino C-N/C-S Bonds Formation: Synthesis of 1,4-Thiazines/1,4-Thiomorpholines

Article abstract of DOI:10.1002/adsc.201800511

A domino Bi-catalysed C?N/C?S bond formation of N-sulfonylaziridines is developed with 1,4-dithiane-2,5-diol to give 3,4-dihydro-1,4-thiazines at room temperature. The use of Bi(OTf)₃ as a catalyst, atom economy and regioselectivity are the important practical features. (Figure presented.).

Full text of DOI:10.1002/adsc.201800511

Title: Regiospecific Bi-Catalysed Domino C-N/C-S Bonds Formation:
Synthesis of 1,4-Thiazines/1,4-Thiomorpholines
Authors: Tharmalingam Punniyamurthy, Murugan Vijay, Vanaparthi
Satheesh, and Sundaravel Vivek Kumar
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800511
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10.1002/adsc.201800511
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Regiospecific Bi-Catalysed Domino C-N/C-S Bonds Formation:
Synthesis of 1,4-Thiazines/1,4-Thiomorpholines
Murugan Vijay, Vanaparthi Satheesh, Sundaravel Vivek Kumar and Tharmalingam
Punniyamurthy *
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781039, India.
E-mail: tpunni@iitg.ernet.in.
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######.
Abstract. A domino Bi-catalysed C-N/C-S bond formation of N-sulfonylaziridines is developed with 1,4-dithiane-2,5-
diol to give 3,4-dihydro-1,4-thiazines at room temperature. The use of Bi(OTf)3 as a catalyst, atom economy and
regioselectivity are the important practical features.
Keywords: 1,4-thiazine; 1,4-thiomorpholine; domino; Bi-catalysis; regioselectivity
N,S-Heterocycles are privileged structural scaffolds
due to their interesting medicinal and agrochemical
properties.[1] Among them, the structural frameworks
bearing 3,4-dihydro-1,4-thiazine motifs are attractive,
because of their important antibacterial,[2] antibiotic,[3]
5-lipoxygenase inhibitor[4] properties, and the use in
flavor (Figure 1).[5] In addition, the compounds
having 1,4-thiomorpholine structural units show anti-
inflammatory,[6] antimycobacterial,[7] hypolipidemic[8]
and DPP-IV inhibitor properties.[9] Development of
effective synthetic routes for their construction is thus
important in synthetic chemistry.[10-11] Recently, Wan
the former furnished the best result (entries 1-6).
CH2Cl2 was found to be the solvent of choice,
whereas toluene, (CH2Cl)2 and THF produced 3j in
<62% yield (entries 7-9). At 0 °C, 1,4-thiomorpholin-
3-ol 4a was formed in 45% yield (entry 10), which
led to dehydration to give 3j at room temperature.
Control experiment confirmed that 3j was not formed
in the absence of the Lewis acid.
and co-workers demonstrated
a
Cu-catalysed
coupling of enaminones with -aminoethanethiol to
produce 1,4-thiazines (Scheme 1a),[10k] while Cossy
and co-workers reported a Fe-catalysed cyclization of
sulfonamides to give 1,4-thiomorpholines (Scheme
1b).[11] Aziridines are versatile building blocks and
several excellent examples are available for the
selective nucleophilic ring opening.[12,13] Similarly,
1,4-dithiane-2,5-diol is a versatile synthon for the
synthesis of S-containing heterocycle motifs.[14]
Herein we report a Bi-catalysed[15] domino[16] C-N/C-
S bonds formation of N-sulfonylaziridines with 1,4-
dithiane-2,5-diol to provide 3,4-dihydro-1,4-thiazines
at room temperature (Scheme 1c). At 0 °C produces
1,4-thiomorpolin-3-ol, which leads to dehydration to
yield 3,4-dihydro-1,4-thiazines that can be oxidized
to 1,4-thiazine-1,1-dioxides.
First, we commenced the optimization using 2-(p-
toluyl)aziridine 1j as a model substrate with 1,4-
dithiane-2,5-diol 2 in the presence of different Lewis
acids (Table 1). Gratifyingly, the reaction occurred to
give 2-phenyl-4-tosyl-3,4-dihydro-2H-1,4-thiazine 3j
in 68% yield when 1j and 2 were stirred employing
10 mol% Bi(OTf)3 in CH2Cl2 at room temperature
(entry 1). In a set of Lewis acids screened, Bi(OTf)3,
Sc(OTf)3, Yb(OTf)3, Cu(OTf)2, Zn(OTf)2 and AgOTf,
Figure 1. Examples of biologically important 3,4-dihydro-
1,4-thiazine derivatives.
Having optimized the reaction, the substrate scope
was studied (Scheme 2). 2-Phenylaziridine 1a reacted
to give 3,4-dihydro-1,4-thiazine 3a in 62% yield. The
reaction of aziridines bearing at the 2-position of the
aryl ring with chloro 1b and fluoro 1c groups gave 3b
and 3c in 54 and 56% yield, respectively. Aziridines
containing substitution at the 3-position of the aryl
ring with bromo 1d, methyl 1e and nitro 1f functional
groups provided 3d-f in 64-68% yields. The reaction
of aziridines having substitution at the 4-position with
bromo 1g, chloro 1h, fluoro 1i, chloromethyl 1k and
acetate 1l groups afforded thiazines 3g-l in 56-64%
yields. Similar result observed with aziridine 1m
1
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10.1002/adsc.201800511
Advanced Synthesis & Catalysis
having 2,4,6-trimethyl group, producing 3m in 57%
yield. In addition, 2-naphthylaziridine can be reacted
to give 3n in 55% yield.
reaction was further studied for the coupling of N-
acetyl and N-Boc aziridines. The reaction of N-acetyl
aziridine produced an inseparable complex mixture,
while N-Boc aziridine 1s underwent reaction to give
oxazolidinone 4 in 74% yield (Scheme 4).[17]
Scheme 1. Recent approaches for the syntheses of 3,4-
dihydro-1,4-thiazines and 1,4-thiomorpholines.
Table 1. Optimization of the reaction conditionsa,b
Scheme 2. Reaction of different 2-arylaziridines with 2. a,b
[a] Aziridine 1a-l, 1k-n (0.5 mmol), 2 (0.3 mmol), Bi(OTf)3
[c]
(10 mol %), CH2Cl2 (1 mL), rt. [b]Isolated yield.
Reaction time 1 h.
Entry Catalyst
Solvent
Time Yield (%)b
3j
4a
1
2
3
4
5
6
7
8
Bi(OTf)3
Sc(OTf)3
Yb(OTf)3
Cu(OTf)2
Zn(OTf)2
AgOTf
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PhCH3
0.5
3
3
3
3
68
30
n.d
60
10
n.d
20
62
n.d
n.d
n.d
n.d
trace
n.d
n.d
n.d
3
3
Bi(OTf)3
Bi(OTf)3
(CH2Cl)2 0.5
9
10c
Bi(OTf)3
Bi(OTf)3
THF
3
3
32
n.d
45
CH2Cl2
trace
[a]
Aziridine 1j (0.5 mmol), 1,4-dithiane-2,5-diol 2 (0.3
mmol), catalyst (10 mol %), solvent (1 mL). [b]Isolated
yield. [c] Reaction temperature 0 °C. n.d = Not detected.
Scheme 3. Reaction of different N-sulfonyl aziridines with
2. a,b [a] Aziridine 1o-r (0.5 mmol), 2 (0.3 mmol), Bi(OTf)3
(10 mol %), CH2Cl2 (1 mL), rt. [b]Isolated yield.
The utility of the protocol was extended to the
coupling of aziridines with different N-substituents
(Scheme
3).
1-(Phenylsulfonyl)aziridine
1o
underwent reaction to furnish 3o in 66% yield.
Similar result observed with 1p having 1-(4-
nitrophenyl)sulfonyl group, affording 3p in 58%
yield, whereas 1q with 1-(4-tert-butylphenyl)sulfonyl
substituent afforded 3q in 64% yield. In contrast, 1-
alkylaziridine 1r was an unsuccessful substrate and
the starting material was recovered intact. The
2
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10.1002/adsc.201800511
Advanced Synthesis & Catalysis
Scheme 4. Reaction of aziridine 1s with 2.
Next, we explored the scope of the reaction with 2-
alkylaziridines (Scheme 5). 2-Benzylaziridine 1t
underwent reaction to give 3t in 72% yield. The
reaction of 1u-v bearing 2-hexyl and 2-heptyl groups
afforded 3u and 3v in 75 and 80% yields,
respectively. Similar result observed with 2-
(cycloxhexylmethyl)-aziridine 1w giving 3w in 75%
yield. Further, meso-cyclohexylaziridine 1x reacted to
afford 3x in 61% yield.
a,b [a]
Scheme 7. Reaction of aziridines with 2 at 0 °C.
Aziridine (0.5 mmol), 2 (0.3 mmol), Bi(OTf)3 (10 mol %),
CH2Cl2 (1 mL), rt. [b]Isolated yield.
Scheme 5. Reaction of different 2-alkyl-N-tosylaziridines
[a]
with 2.a,b
Aziridine 1t-x (0.5 mmol), 2 (0.3 mmol),
Bi(OTf)3 (10 mol %), CH2Cl2 (1 mL), rt. [b]Isolated yield.
Scheme 8. Reaction of chiral aziridine (S)-1a with 2.
Scheme 6. Reaction of aziridine 1y with 2.
Finally, the reaction of 2-methyl-3-phenylaziridine
1y was studied (Scheme 6). The reaction occurred to
produce 3y in 80% yield as a 13:1 (syn:anti) mixture
of diastereomers. Syn isomer was crystallized in ethyl
acetate and hexane mixture whose structure was
determined using a single crystal X-ray analysis (see
SI). The reaction is temperature dependant. At 0 °C,
the reaction can be stopped to give 1,4-
thiomorpholin-3-ol (Scheme 7). For examples, the
reaction of 2-(4-bromophenyl)aziridine gave 4b in
53% yield. Similar result observed with 2-(4-
flurophenyl)aziridine to give thiomorpholin-3-ol 4c in
56% yield. In addition, 2-phenylaziridine bearing
arylsulfonyl with electron withdrawing 4-nitro group
underwent reaction to give 4d in 58% yield, whereas
1e containing N-(4-methylpyridinyl)-2-sulfonyl group
furnished 4e in 60% yield. Recrystallization of 4d in
CDCl3 afforded single crystals whose structure was
determined using X-ray analysis (See SI). The
reaction conditions was further investigated for the
coupling of aziridine 1a with 2,5-dimethyl-1,4-
dithiane-2,5-diol in place of 1,4-dithiane-2,5-diol.
However, the substrate was failed to react and no
annulation product was observed.
Scheme 9. Proposed catalytic cycle.
To get into the reaction pathway, the reaction of
enantiopure aziridine (S)-1a (99% ee) was studied
(Scheme 8). The annulation occurred to furnish 3a in
64% yield with 52:48 er, which suggests that the
1
reaction involves a SN pathway. Thus, chelation of
Bi(OTf)3 with 2-arylaziridine can lead to ring
opening to give the benzyl carbocation A, which can
react with 2 to yield B. Intramolecular cyclization of
3
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10.1002/adsc.201800511
Advanced Synthesis & Catalysis
the reaction mixture was quenched with water and the
aqueous layer was extracted using CH2Cl2 (3 x 10 mL).
Drying (Na2SO4) and evaporation of the solvent gave a
residue, which was purified on a silica gel column
chromatography using ethyl acetate and hexane (4:6) as an
eluent.
B can furnish C that can provide 1,4-thiomorpholin-
o
3-ol by aqueous workup (0 C). Alternatively, C can
undergo dehydration at room temperature to furnish
3,4-dihydro-1,4-thiazines 3 to complete the catalytic
cycle. The formation of a single diastereomer of 4
suggests that a chair like transition state B is favoured,
in which, the carbonyl and sulfonyl groups are trans
to each other due to steric and electronic repulsion (pl
see the crystal structure of 4d), whereas the transition
state B' is disfavoured due to unfavourable
interaction between the -C=O and -SO2 groups
(Scheme 9). These results suggest that the ring
opening takes place in 2-arylaziridines at the benzylic
carbon due to an electronic effect, while steric effect
favours in 2-alkylaziridines to occur the ring opening
at the less hindered CH2 carbon.[18]
General Procedure for the Synthesis of 3,4-Dihydro-
1,4-Thiazine-1,1-dioxide.
1,4-Thiazines (0.2 mmol) and oxone (0.6 mmol) were
stirred in THF and H2O (1:1, 1 mL) at room temperature.
The progress of the reaction was monitored by TLC using
ethyl acetate and hexane as an eluent. After completion,
the solvent was evaporated and aqueous layer was
extracted with CH2Cl2 (3 x 10 mL). Drying (Na2SO4) and
evaporation of the solvent gave a residue, which was
purified on a silica gel column chromatography using ethyl
acetate and hexane as eluent.
Acknowledgements
The product can be oxidized using oxone in THF-
water (Scheme 10).[11] For examples, the oxidation of
3b, 3o, 3t and 3x was performed as the representative
examples. The reaction took place to produce 6a-d in
quantitative yields.
We thank Science and Engineering Research Board (SERB)
(EMR/2015/43) and Council of Scientific and Industrial Research
(CSIR) (02(0255)/16/EMR-II) for the financial support. M. V and
V.S thanks MHRD and CSIR respectively for SRF Fellowship.
S.V.K. thanks SERB for National Postdoctoral Fellowship
(PDF/2016/001460). We also thank Central Instrumental Facility,
IIT Guwahati for the NMR and Single Crystal XRD facilities.
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4
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10.1002/adsc.201800511
Advanced Synthesis & Catalysis
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5
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10.1002/adsc.201800511
Advanced Synthesis & Catalysis
COMMUNICATION
Regiospecific Bi-Catalyzed Domino C-N/C-S
Bonds Formation: Synthesis of 3,4-Dihydro-1,4-
Thiazines/Thiomorpholines
Adv. Synth. Catal. Year, Volume, Page – Page
Murugan Vijay, Vanaparthi Satheesh, Sundaravel
Vivek Kumar and Tharmalingam Punniyamurthy *
6
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