Synthesis of 1,3-benzothiazines by intramolecular dehydrogenative C–S cross-coupling in a flow electrolysis cell

Article abstract of DOI:10.1007/s11426-019-9554-1

Dehydrogenative cyclization of thioamides is an attractive approach for the synthesis of S-heterocycles. Reported herein is an electrochemical dehydrogenative cyclization reaction of N-benzyl thioamides in a flow electrolysis cell. The continuous-flow electrosynthesis has addressed the limitations associated with previously reported methods for the cyclization of alkylthioamides and provide a transition metal- and oxidizing reagent-free access to various functionalized 1,3-benzothiazines in good yields.

Full text of DOI:10.1007/s11426-019-9554-1

SCIENCE CHINA
Chemistry
•COMMUNICATIONS•
SPECIAL ISSUE: Organic Free Radical Chemistry
https://doi.org/10.1007/s11426-019-9554-1
Synthesis of 1,3-benzothiazines by intramolecular dehydrogenative
C–S cross-coupling in a flow electrolysis cell
Chong Huang & Hai-Chao Xu*
State Key Laboratory of Physical Chemistry of Solid Surfaces, Innovative Collaboration Center of Chemistry for Energy Materials, Key Laboratory
of Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China
Received June 6, 2019; accepted August 4, 2019; published online September 27, 2019;
Dehydrogenative cyclization of thioamides is an attractive approach for the synthesis of S-heterocycles. Reported herein is an
electrochemical dehydrogenative cyclization reaction of N-benzyl thioamides in a flow electrolysis cell. The continuous-flow
electrosynthesis has addressed the limitations associated with previously reported methods for the cyclization of alkylthioamides
and provide a transition metal- and oxidizing reagent-free access to various functionalized 1,3-benzothiazines in good yields.
C-H functionalization, electrochemistry, flow chemistry, heterocycles,
Citation:
Huang C, Xu HC. Synthesis of 1,3-benzothiazines by intramolecular dehydrogenative C–S cross-coupling in a flow electrolysis cell. Sci China Chem,
2019, 62, https://doi.org/10.1007/s11426-019-9554-1
Dehydrogenative C–S cross-coupling is an attractive ap-
proach for the construction of S-containing organic mole-
cules because of its step and atom economic features [1–6].
Ideally, these reactions should proceed through H2 evolution
and avoid the use of stoichiometric chemical oxidants [7].
Organic electrochemistry has been demonstrated to be an
enabling tool to achieve dehydrogenative cross-coupling
through H2 evolution [8–17]. In this context, inter- and intra-
molecular dehydrogenative C–S cross-coupling has been
reported using batch reactors [18–24]. We have been inter-
ested in the synthesis of heterocycles through electro-
chemical dehydrogenative cyclization and annulation
reactions [25–31] and recently shown that dehydrogenative
cyclization of thioamides proceeds more efficiently in a
microflow electrochemical reactor than that in a batch re-
actor (Scheme 1(a)) [32]. We wonder if the continuous-flow
electrosynthesis can be applied to the preparation of 1,3-
benzothiazines through dehydrogenative cyclization of N-
benzyl thioamides. Such cyclization reactions have been
previously achieved chemically by employing hypervalent
iodine as the chemical oxidant (Scheme 1(b)) [33] and
electrochemically using a batch reactor (Scheme 1(c)) [34].
Under these established conditions, alkylthioamides remain
to be difficult substrates probably because of competitive
desulfurization, a common side reaction for the oxidation of
thioamides. Herein, we report a continuous-flow electro-
synthesis of 1,3-benzothiazines that is applicable to aryl- and
alkyl-thioamides (Scheme 1(d)).
The dehydrogenative cyclization of thioamide 1 was
chosen as a model reaction to search for optimal reaction
conditions (Table 1). The electrolysis was conducted at
r.t. using a flow cell equipped with a Pt cathode and a
carbon filled with polyvinylidene fluoride (C/PVDF) anode
[32]. After a screening of reaction parameters such as flow
rate, solvent, additives and current, the optimal conditions
were found to be passing a solution of 1 (0.03 M) and tri-
fluoromethanesulfonic acid (TfOH, 0.06 M) in MeCN
through the cell with a flow rate of 0.3 mL min−1 and a
constant current of 42 mA. No supporting salt was needed
because the addition of TfOH increased the conductivity of
*Corresponding author (email: haichao.xu@xmu.edu.cn)
© Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature 2019
chem.scichina.com link.springer.com

2
Huang et al. Sci China Chem
Table 2 Substrate scope
a)
a) Reaction condition: flow rate=0.3 mL min−1, r.t., TfOH (2.0 equiv.),
MeCN, thioamide (0.3 mmol, 0.03 M); b) r.r.=regioisomeric ratio.
Scheme 1 Dehydrogenative cyclization of thioamides (color online).
a)
presence of TfOH also prevented desulfurization. In the
absence of TfOH, the yield of 2 was reduced to 50% with
concomitant formation of amide 3 in 40% (entry 2). The
reduction of TfOH to 1 equiv. (entry 3) or the use of other
acidic additives such as trifluoroacetic acid (TFA) (entry 4)
or AcOH (entry 5) all led to a decrease in the yield of 2.
Other cathode materials such as Ni (entry 6) and stainless
steel (entry 7) and anode materials such as graphite (entry 8)
were less efficient in promoting the formation of 2.
The scope of the dehydrogenative cyclization reaction was
investigated by varying the substituents of the N-benzyl
thioamide substrate (Table 2). The R1 substituent tolerated
primary (4 and 5), secondary (6) and tertiary (7) alkyl groups
as well as a phenyl (8) group. Thioamides bearing at the
benzylic position one (9) or two (10) methyl groups were
also suitable substrates. The N-benzyl group tolerated sub-
stituents at various positions such as Me (11), Br (12) and
CF3 (13) at the para position, Me at the meta or ortho posi-
tions (14, 15). Meta-, para-dichloro-substituted thioamide
cyclized to give a mixture of regioisomers (16). The elec-
trochemical dehydrogenative cyclization reaction was also
applicable to seven-membered ring formation (17).
Table 1 Optimization of reaction conditions
b)
Deviation from
standard condi-
tions
Yield (%)
Entry
2
3
Trace
40
c)
1
2
3
None
83
No TfOH
50(3)
71
1.0 equiv. TfOH
4
TFA instead of
TfOH
4
26(10)
55
AcOH instead of
TfOH
5
6
7
8
25(31)
77
23
12
25
14
Ni cathode
Stainless steel
cathode
65
Graphite anode
74
a) Electrolysis conditions: C/PVDF anode, Pt cathode, electrode area=
10 cm2, I=42 mA, flow rate=0.3 mL min−1, r.t., 1 (0.03 M, 0.3 mmol),
TfOH (2.0 equiv.), MeCN, 2.9 F mol−1. b) Determined by 1H NMR analysis
using 1,3,5-trimethoxybenzene as internal standard. Recovered 1 is given in
brackets. c) Isolated yield. Cy, cyclohexyl.
In continuous-flow electrosynthesis, reaction scale up can
be achieved by passing more material through the very same
reactor [35–38]. To increase the productivity, the substrate
concentration and electric current was increased to 0.05 M
and 75 mA, respectively. Under these conditions, the passing
the reaction solution. Under these conditions, the reaction of
1 afforded the desired product 2 in 83% yield and only trace
amount of desulfurized compound 3 (entry 1, Table 1). The

3
Huang et al. Sci China Chem
http://chem.scichina.com and http://link.springer.com/journal/11426. The
supporting materials are published as submitted, without typesetting or
editing. The responsibility for scientific accuracy and content remains en-
tirely with the authors.
1
2
Yan H, Xu HC. Synthesis of heterocycles from thioamides. In: Murai
T, Ed. Chemistry of Thioamides. Singapore: Springer, 2019
Hosseinian A, Ahmadi S, Nasab FAH, Mohammadi R, Vessally E. Top
Curr Chem, 2018, 376: 39
3
4
5
Lee CF, Liu YC, Badsara SS. Chem Asian J, 2014, 9: 706–722
Cheng Y, Yang J, Qu Y, Li P. Org Lett, 2012, 14: 98–101
Wang H, Wang L, Shang J, Li X, Wang H, Gui J, Lei A. Chem
Commun, 2012, 48: 76–78
6
7
Song S, Zhang Y, Yeerlan A, Zhu B, Liu J, Jiao N. Angew Chem Int
Ed, 2017, 56: 2487–2491
Wang H, Gao X, Lv Z, Abdelilah T, Lei A. Chem Rev, 2019, 119:
6769–6787
8
9
Yan M, Kawamata Y, Baran PS. Chem Rev, 2017, 117: 13230–13319
Moeller KD. Chem Rev, 2018, 118: 4817–4833
Scheme 2 A proposed mechanism (color online).
10 Jiang Y, Xu K, Zeng C. Chem Rev, 2018, 118: 4485–4540
11 Tang S, Liu Y, Lei A. Chem, 2018, 4: 27–45
12 Wiebe A, Gieshoff T, Möhle S, Rodrigo E, Zirbes M, Waldvogel SR.
Angew Chem Int Ed, 2018, 57: 5594–5619
of 10.1 g of 1 through the flow electrolysis cell afforded
6.5 g of 2 (65% yield) in 48 h (Reaction (1)).
13 Yang QL, Fang P, Mei TS. Chin J Chem, 2018, 36: 338–352
14 Francke R, Little RD. Chem Soc Rev, 2014, 43: 2492
15 Sauermann N, Meyer TH, Qiu Y, Ackermann L. ACS Catal, 2018, 8:
7086–7103
16 Yoshida JI, Shimizu A, Hayashi R. Chem Rev, 2018, 118: 4702–4730
17 Yuan Y, Cao Y, Qiao J, Lin Y, Jiang X, Weng Y, Tang S, Lei A. Chin
J Chem, 2019, 37: 49–52
18 Li D, Li S, Peng C, Lu L, Wang S, Wang P, Chen YH, Cong H, Lei A.
Chem Sci, 2019, 10: 2791–2795
19 He TJ, Ye Z, Ke Z, Huang JM. Nat Commun, 2019, 10: 833
20 Lu F, Yang Z, Wang T, Wang T, Zhang Y, Yuan Y, Lei A. Chin J
Chem, 2019, 37: 547–551
21 Wang P, Tang S, Lei A. Green Chem, 2017, 19: 2092–2095
22 Wang P, Tang S, Huang P, Lei A. Angew Chem Int Ed, 2017, 56:
3009–3013
23 Qian XY, Li SQ, Song J, Xu HC. ACS Catal, 2017, 7: 2730–2734
24 Folgueiras-Amador AA, Qian XY, Xu HC, Wirth T. Chem Eur J,
2018, 24: 487–491
25 Xiong P, Xu HH, Xu HC. J Am Chem Soc, 2017, 139: 2956–2959
26 Xu HH, Song J, Xu HC. ChemSusChem, 2019, 12: 3060–3063
27 Cai CY, Xu HC. Nat Commun, 2018, 9: 3551
28 Hou ZW, Yan H, Song JS, Xu HC. Chin J Chem, 2018, 36: 909–915
29 Wu ZJ, Li SR, Xu HC. Angew Chem Int Ed, 2018, 57: 14070–14074
30 Zhao HB, Xu P, Song J, Xu HC. Angew Chem Int Ed, 2018, 57:
15153–15156
31 Xu F, Long H, Song J, Xu HC. Angew Chem Int Ed, 2019, 58: 9017–
9021
32 Huang C, Qian XY, Xu HC. Angew Chem Int Ed, 2019, 58: 6650–
6653
33 Wen LR, Zhou CC, Zhu MZ, Xie SG, Guo WS, Li M. Org Biomol
Chem, 2019, 17: 3356–3360
34 Yu H, Jiao M, Huang R, Fang X. Eur J Org Chem, 2019: 2004–2009
35 Watts K, Baker A, Wirth T. J Flow Chem, 2014, 4: 2–11
36 Pletcher D, Green RA, Brown RCD. Chem Rev, 2018, 118: 4573–
4591
37 Atobe M, Tateno H, Matsumura Y. Chem Rev, 2018, 118: 4541–4572
38 Laudadio G, de Smet W, Struik L, Cao Y, Noël T. J Flow Chem, 2018,
8: 157–165
39 Lo WS, Hu WP, Lo HP, Chen CY, Kao CL, Vandavasi JK, Wang JJ.
Org Lett, 2010, 12: 5570–5572
A possible mechanism was proposed based on the results
of this work and our previous report (Scheme 2) [32]. The
thioamide I is oxidized through single electron transfer
(SET) at the anode to afford radical cation II, which un-
dergoes cyclization and oxidative aromatization to afford the
final heterocycle V. The intermediate II can lose a proton to
give III, which is less reactive than II to undergo cyclization.
The radical III can dimerize to give VI [39], which then
undergo hydrolysis to furnish desulfurized material such as
3. The added TfOH ensures a more favorable equilibrium to
the side of II to reduce desulfurization.
In summary, we have developed a continuous-flow elec-
trosynthesis of 1,3-benzothiazines through dehydrogenative
cyclization of easily available thioamides. A variety of alkyl
and arylthioamides undergo efficient intramolecular dehy-
drogenative C–S cross-coupling without the need for che-
mical oxidants and transition metal catalysts, providing clean
access to S-heterocycles. The electrochemical protocol can
be expanded to 7-membered ring formation.
Acknowledgements This work was supported by the National Natural
Science Foundation of China (21672178) and Fundamental Research Funds
for the Central Universities.
Conflict of interest The authors declare that they have no conflict of
interest.
Supporting information The supporting information is available online at