TEMPO-Catalyzed Electrochemical C-H Thiolation: Synthesis of Benzothiazoles and Thiazolopyridines from Thioamides

Article abstract of DOI:10.1021/acscatal.7b00426

Benzothiazoles and thiazolopyridines are widely prevalent in pharmaceuticals and organic materials. Herein, we report a metal- and reagent-free method for the uniform synthesis of benzothiazoles and thiazolopyridines through 2,2,6,6-tetramethylpiperidine-N-oxyl radical (TEMPO)-catalyzed electrolytic C-H thiolation. This dehydrogenative coupling process provides access to a host of benzothiazoles and thiazolopyridines from N-(hetero)arylthioamides. Mechanistic studies suggested that the thioamide substrate was oxidized with the electrochemically generated TEMPO⁺ through an inner-sphere electron transfer to afford a thioamidyl radical, which undergoes homolytic aromatic substitution to form the key C-S bond.

Full text of DOI:10.1021/acscatal.7b00426

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Letter
TEMPO-Catalyzed Electrochemical C–H Thiolation: Synthesis
of Benzothiazoles and Thiazolopyridines from Thioamides
Xiang-Yang Qian, Shu-Qi Li, Jinshuai Song, and Hai-Chao Xu
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b00426 • Publication Date (Web): 16 Mar 2017
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ACS Catalysis
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TEMPO-Catalyzed Electrochemical C–H Thiolation: Synthesis of
Benzothiazoles and Thiazolopyridines from Thioamides
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XiangꢀYang Qian,† ShuꢀQi Li,† Jinshuai Song,*,‡ and HaiꢀChao Xu*,†
† iChEM, State Key Laboratory of Physical Chemistry of Solid Surfaces, and College of Chemistry and Chemical Engineerꢀ
ing, Xiamen University, Xiamen 361005 (P. R. China)
‡ Fujian Institute of Research on Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002 (P. R. China)
ABSTRACT: Benzothiazoles and thiazolopyridines are widely prevalent in pharmaceuticals and organic materials. Herein, we
report a metalꢀ and reagentꢀfree method for the uniform synthesis of benzothiazoles and thiazolopyridines through 2,2,6,6ꢀ
tetramethylpiperidineꢀNꢀoxyl radical (TEMPO) catalyzed electrolytic C–H thiolation. This dehydrogenative coupling process proꢀ
vides access to a host of benzothiazoles and thiazolopyridines from Nꢀ(hetero)arylthioamides. Mechanistic studies suggested that
the thioamide substrate was oxidized with the electrochemically generated TEMPO+ through an innerꢀsphere electron transfer to
afford a thioamidyl radical, which undergoes homolytic aromatic substitution to form the key C–S bond. KEYWORDS: electro-
chemistry, radicals, benzothiazole, TEMPO, cyclization
Crossꢀcoupling of C–H and X–H (X = C or heteroatom) bonds
is a powerful approach for the construction of carbon–carbon
as well as carbon–heteroatom bonds because it offers several
advantages including the use of simple and easily available
starting materials and the elimination of substrate prefunctionꢀ
alization.1 Nonetheless, these methods frequently require the
use of metal or organic stoichiometric oxidants, which create
potential safety hazards for largeꢀscale synthesis and frequentꢀ
ly impose considerable amount of waste on the environment.2
Hence, the development of more environmentꢀfriendly cross
dehydrogenativeꢀcoupling reactions entails the reduction in
use or complete elimination of oxidizing reagents.3
cyclization of Nꢀarylthioamides through direct electrolysis was
reported in 1979 but received little attention.10 Although this
process required the use of a divided cell and high potential
(1.5–1.8 V vs SCE) and a full scope was not available, it did
show promising results on the synthesis of benzothiazoles
bearing 2ꢀalkyl substituents. Indirect electrolysis, in which a
redox catalyst is employed as the electron shuttle, is advantaꢀ
geous in its avoidance of electrode passivation and kinetic
inhibition, as well as achievement of better (or different) selecꢀ
tivity and energy efficiency.8b We have recently developed
electrochemical cross coupling reactions of N–H/C–H centers
to synthesize Nꢀheterocycles.11a,b Herein, we report a metalꢀ
and reagentꢀfree method for the uniform synthesis of diversiꢀ
fied benzothiazoles and thiazolopyridines via 2,2,6,6ꢀ
tetramethylpiperidineꢀNꢀoxyl radical (TEMPO) catalyzed elecꢀ
trochemical C–H thiolation of Nꢀ(hetero)arylthioamides
(Scheme 1).12,13
The oxidative cyclization of the easily available Nꢀ
arylthioamides is an attractive method for the construction of
the ubiquitous benzothiazole scaffold (Scheme 1).4 Often, the
reported reaction system comprises an oxidant of choice and
optionally a transition metal catalyst.4 The use of oxidants in
these reactions cause, in addition to the aboveꢀmentioned
problems, formation of undesirable side products such as amꢀ
ides as a result of desulfurization of the thioamides.4aꢀc To this
end, Wu and Lei recently developed a novel Ru/Coꢀ
cocatalyzed photoredox process that obviates the need for
oxidants by reducing the protons released to form H2.5 Despite
these substantial advances, the construction of 2ꢀalkyl substiꢀ
tuted benzothiazoles and of the challenging thiazolopyridines
remains difficult with the known C–H thiolation methods.4–6
This is likely because alkylthioamides have strong propensity
toward desulfurization,4a,b,5 while the azaꢀarenes are electronꢀ
deficient and coordinating. In addition, the use of transitionꢀ
metals in many of the reported methods entails additional proꢀ
cedures and cost to reduce the residual metals to ppm levels in
order for the end products to qualify as pharmaceutical ingreꢀ
dients.7
Scheme 1. Aromatic C–H Thiolation
We began our investigation with optimizing the reaction
conditions for the cyclization of thioacetanilide (1), which
failed under the chemical and photochemical conditions.4a,b,5
Our previous work showed that TEMPO11c and ferrocene11d
Organic electrosynthesis, which accomplishes redox proꢀ
cesses by employing electrons as “reagents”, is accepted to be
an environmentꢀfriendly and enabling synthetic tool.8,9 The
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were competent mediators for electrochemical activation of
1
S
RVC
TEMPO (5 mol %)
Pt
X
H
X
1
2
3
4
5
6
7
8
Y
Z
S
Y
amidyl N–H bonds to generate nitrogenꢀcentered radicals.
After some screening with these redox catalysts, the optimal
conditions were defined as running the electrolysis with 5 mol
% of TEMPO as the redoxꢀmediator and an electrolyte soluꢀ
tion of nBu4NBF4 (0.2 equiv) in 1:1 MeCN/MeOH (Table 1).
Under these conditions, the desired 2ꢀmethylbenzothiazole (2)
was isolated in 68% yield without detection of acetanilide, a
common type side product under oxidative conditions (entry
1).4aꢀc Running the electrolysis without TEMPO (entry 2) or
the use of other redox mediators such as ferrocene (entry 3) or
(4ꢀBrPh)3N (entry 4) all led to inferior results. The mixed solꢀ
vent of MeOH and MeCN was important for reaction efficienꢀ
cy as the use of either MeOH (entry 5) or MeCN (entry 6)
alone resulted in lower yield. Other anode materials such as
platinum (entry 7) or graphite (entry 8) were found to be less
efficient than RVC. The reaction could be conducted under
atmospheric conditions, albeit with a slightly deceased yield
(entry 9).
R
+
H2
5 Z
N
3
N
H
R
nBu4NBF4 (20 mol %, 0.018 M)
Yielda
MeOH/MeCN (1:1), RT
5
6
7
8
9
, R = OH, 48%
R
S
N
S
, R = OTBDPS, 80%
R
S
N
8
, R = OCO Bu, 92%
, R = OCONHBn, 93%
, R = NTsBoc, 56%
t
N
3
4
n
, R = Pr, 76%
10, 64%
, R = Bu, 86%
n
AcO
H
Ts
S
N
OMe
S
N
9
H
H
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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43
44
45
46
47
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51
52
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13, 70%
H
OP
(from cholic acid)
11
S
H
AcO
S
N
b
, P = MeCO, 72%
N
b
12
, P = H, 69%
14
15
19
, 94%
, 82%
S
S
N
S
S
N
N
N
OTBS
OH
NHTs
NHCbz
16
20
17
18
, 95%
, 88%
, 91%
, 78%
S
S
S
N
S
N
N
N
Table 1. Optimization of Reaction Conditions
N
N
c
d
21
22
, 95%
23
, 80%
, 83%
, 60%
HO
S
N
R2
MeS
S
N
S
S
nPr
nPr
nPr
R1
Ph
N
N
R1 = Ph
b,c
24
, 68%
35
36,
70%
, 64%
, R2 = OMe, 90%c,e
, R2 = OCF3, 92%c
, R2 = Br, 82%c
25
MeO
Me
26
27
28
S
N
S
N
S
nPr
nPr
, R2 = NO2, 0%c
F
MeO
N
R1 = nPr
38,
r.r.
39,
37
, 85% (
r.r.
68% (
= 9:1)
82% ( = 7:1)
r.r.
= 2:1)
, R2 = OMe, 60%b
, R2 = Me, 73%
, R2 = F, 84%e
32, R2 = Br, 70%e
33, R2 = CF3, 89%
34, R2 = CN, 75%e
29
F
30
F
S
MeO
S
N
S
N
31
nPr
nPr
nPr
N
F
40
41
45
42
r.r.
, 90%
, 82%
, 88% ( > 20:1)
S
N
S
S
N
S
N
N
N
nPr
nPr
n
Pr
nPr
N
N
N
43
, 73%
44, 77%b
46
r.r.
, 80%
, 77% (
N
= 7:1)
aReticulated vitreous carbon (RVC) anode (100 PPI, 1 cm x 1 cm
x 1.2 cm), Pt plate cathode (1 cm × 1 cm), undivided cell, conꢀ
stant current = 10 mA (janode ≅ 0.13 mA cm−2), 1 (0.53 mmol),
solvent (6 mL), argon, RT, 5.5 h (3.9 F). bDetermined by 1H NMR
analysis using 1,3,5ꢀtrimethoxybenzene as the internal standard.
Recovered 1 is given in brackets. cIsolated yield.
N
Cl
S
N
S
N
F
N
N
S
S
N
nPr
nPr
nPr
nPr
N
47
, 95% (r.r. = 5:1)
48
, 90% (r.r. > 20:1)
49
50
, 67%
, 97%
Scheme 2. Substrate Scope. Reaction conditions: Table 1, entry
1 (2.8–5.7 F). aYield of isolated product. bReaction run with
We next explored the substrate scope of the C–H thiolation
reaction using a wide range of Nꢀarylthioamides (Scheme 2).
First, a series of primary (3–13) and secondary (14–19) alkyl
thioamides underwent smooth cyclization. Many common
functionalities such as free alcohol (5, 12, 17, 35), silyl ether
(6, 16), ester (7, 11), carbamate (8, 9 and 19), alkyne (10),
electronꢀrich arene (13), and sulfonamide (18) were tolerated.
The retention of the hydroxyl group is particularly noteworthy
because TEMPO is a wellꢀknown redox catalyst for the chemꢀ
ical and electrochemical oxidation of alcohols.12a,b,f,14 The elecꢀ
trochemical reaction was also suitable for the synthesis of
benzothiazoles bearing other 2ꢀsubstituents such as tertꢀbutyl
(20), alkenyl (21), aryl (22, 24–27) and heteroaryl (23) groups.
The addition of small amount of water to the reaction mixture
facilitated the formation of 2ꢀarylbenzothiazoles (22, 25–27).15
c
TEMPO (10 mol %) and nBu4NBF4 (50 mol %). 0.2 mL of H2O
were added. dCF3CH2OH/MeCN (1:1) were used as solvent. eReꢀ
action run with substrate (0.35 mmol), MeCN (5 mL), MeOH (5
mL), TEMPO (5 mol %), and nBu4NBF4 (50 mol %). TBDPS =
tertꢀbutyldiphenylsilyl, Ts = 4ꢀtoluenesulfonyl, Boc = tertꢀ
butoxycarbonyl, TBS = tertꢀbutyldimethylsilyl, Cbz = benꢀ
zyloxycarbonyl.
The electronic and steric effects of the Nꢀaryl group on the
cyclization reaction was also probed. Electronꢀdonating (SMe,
OMe, Me) and ꢀwithdrawing (CN) substituents, halogens (F,
Br) and fluorineꢀcontaining functionalities (OCF3, CF3) were
all tolerated at the para position (Scheme 2, 24–27, 29–34).
The highly electronꢀwithdrawing nitro group, however, led to
substrate decomposition and no benzothiazole formation (28).
The selective oxidation of the thioamide group in the presence
of a thioether further highlighted the mildness of the reaction
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conditions.16 Both orthoꢀ (36) and metaꢀsubstituted (37) thioꢀ
amides were viable substrates, although two regioisomers
were obtained when the latter were used. In particular, the
employment of thioamides bearing a multisubstituted Nꢀaryl
ring led to the production of highly functionalized benzothiaꢀ
zoles (38–41).17 2ꢀAminonapthaleneꢀderived substrate reacted
regioselectively to give naphtho[2,1ꢀd]thiazole 42.
A)
1
2
3
4
5
6
B
)
N
O
S
TEMPO
(1 equiv)
S
PhHN
a: TEMPO
54
PhN
55,
b: TEMPO + 46s
30% yield
7
8
9
In addition to the production of benzothiazoles, the electroꢀ
lytic C–H thiolation reaction could also be applied to the prepꢀ
aration of thiazolopyridines, which are synthetically more
challenging.6 Gratifyingly, thiazolopyridines (43–50) could be
accessed without difficulty by employing aminopyridineꢀ
derived thioamides (Scheme 2). Notably, the 3ꢀaminopyridineꢀ
based substrates reacted regioselectively at the αꢀposition of
the pyridyl ring to afford thiazolo[5,4,b]pyridines (46–48).
C
)
e
N
S
e
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
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60
H2
N
n
Pr
H
N
O
46s, Ep/2 = 1.2 V
2H+
H+
N
O
N
N
O
G = 1.8
S
E
p/2 = 0.62 V
BDE (SꢀO) = 12.5
a
nPr
N
N
2
S
I
b
N
II
nPr
H
4
X
X
S
S
N
e
nPr
nPr
path a: G‡ = 7.7, G = 3.8
path b: G‡ = 10.1, G = 7.2
Y
H+
Y
N
III and III'
46
46'
(X = N, Y = CH)
(X = CH, Y = N)
Scheme 4. Mechanistic Investigation and Proposed Mechaꢀ
nism. A) cyclic voltammograms of TEMPO (0.003 M) in the
absence (a) or presence (b) of thioamide 46s (0.018 M). Condiꢀ
tions: glassy carbon working electrode, Pt wire counter electrode,
SCE reference electrode, MeOH/MeCN (1:1), nBu4NBF4 (0.1 M),
scan rate = 10 mV s−1. B) radical clock experiment. C) Proposed
mechanism. DFTꢀderived energetics (kcal mol−1) were obtained at
the level of B3LYP/6ꢀ31G*.
Scheme 3. Synthetic Application
To demonstrate its synthetic potential, the electrosynthetic
method was incorporated as a key step for the synthesis of
thiazolo[4,5ꢀc]quinoline 53 (Scheme 3), which is an intermeꢀ
diate for the preparation of CL075, a tollꢀlike receptor 8
(TRL8) agonist.6a A previously reported synthetic route to 53
required 5 steps from 2ꢀaminobenzoic acid.6a In comparison,
we accomplished the same synthesis in 3 steps from commerꢀ
cially available 3ꢀquinolinamine (51) involving acylation,
thiolation, and electrochemical cyclization. Unlike the 3ꢀ
aminopyridineꢀderived substrates that cyclized at the αꢀ
position of the pyridyl ring, quinoline 52 reacted at the γꢀ
position to furnish 53 in 92% yield.18 Note that the electrolysis
reaction could be scaled up by 20ꢀfold to 2.3 g with even betꢀ
ter current efficiency. The gramꢀscale reaction was conducted
in a beakerꢀtype cell with larger electrodes, allowing the use of
higher current of 90 mA (see the Supporting Information, page
S2).
Based on the observations above, a possible mechanism for
the C–H thiolation reaction was proposed. As illustrated in
Scheme 4C, TEMPO first gets oxidized at the anode to give
TEMPO+, which then reacts with thioamide 46s to give interꢀ
mediate I20 after a proton loss. The weak S–O bond (BDE =
12.5 kcal mol−1) in I subsequently undergoes homolytic cleavꢀ
age to furnish thioamidyl radical II and concomitantly regenꢀ
erate TEMPO.21 The oxidation through innerꢀsphere electron
transfer allows Nꢀarylthioamides with diverse electronic propꢀ
erties to participate efficiently in the electrochemical reaction.
In addition, the formation of I reduces the concentration of
thioamidyl radical and thus the chance of radical dimerizaꢀ
tion.22 In the following step, radical cyclization of II at αꢀ
(path a) or γꢀposition (path b) of the pyridyl ring then produces
the azacyclohexadienyl radicals III and IIIʹ, both of which can
then rearomatize through electron and proton loss to give the
corresponding thiazolopyrdines 46 and 46ʹ. Density functional
theory (DFT)ꢀbased calculations suggested that formation of
III was both kinetically and thermodynamically favored comꢀ
pared to that of IIIʹ, a possible explanation for the experiꢀ
mental observation that 46 was the predominant product.
Similar computational investigation on the cyclization of 52ꢀ
derived radical showed that the opposite was true (see the
Supporting Information, page S36).
To elucidate the mechanism of the electrochemical C–H
thiolation reaction, the voltammograms of TEMPO (Scheme
4A) were recorded in the absence and presence of thioamide
46s (Scheme 4C). The inclusion of thioamide 46s (Ep/2 = 1.2 V
vs SCE) resulted in the disappearance of the reduction wave in
the voltammogram but without detection of a catalytic current.
These data implied that the electrochemically generated
TEMPO+ reacted with 46s but was not immediately reduced to
TEMPO as a result. Next, thioamide 54 bearing a cyclopropyl
group as the radical probe19 was electrolyzed in the presence
of 1 equiv of TEMPO (Scheme 4B). The ringꢀopening product
55 was obtained in 30% yield, suggesting that a thioamidyl
radical was involved. Taken together, these mechanistic data
indicated that the reaction of anode generated TEMPO+ and
the thioamide afforded an intermediate that could decompose
into a thioamidyl radical and TEMPO.
In summary, we have developed a TEMPOꢀcatalyzed elecꢀ
trochemical C–H thiolation reaction for the synthesis of benꢀ
zothiazoles and thiazolopyridines. The use of TEMPO as a
mild redoxꢀmediator along with the metalꢀ and reagentꢀfree
conditions allows a variety of Nꢀ(hetero)arylthioamides to
participate in the reaction. Application of the electrochemical
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(9) Selected recent examples of electrochemical C–H functionaliꢀ
C–H thiolation strategy in the synthesis of other Sꢀ
zation: (a) Hayashi, R.; Shimizu, A.; Yoshida, J.ꢀi. J. Am. Chem. Soc.
2016, 138, 8400–8403. (b) Morofuji, T.; Shimizu, A.; Yoshida, J.ꢀi. J.
Am. Chem. Soc. 2015, 137, 9816–9819. (c) Kang, L.ꢀS.; Luo, M.ꢀH.;
Lam, C. M.; Hu, L.ꢀM.; Little, R. D.; Zeng, C.ꢀC. Green Chem. 2016,
18, 3767–3774. (d) Yoo, S. J.; Li, L.ꢀJ.; Zeng, C.ꢀC.; Little, R. D.
Angew. Chem., Int. Ed. 2015, 54, 3744–3747. (e) Wiebe, A.;
Schollmeyer, D.; Dyballa, K. M.; Franke, R.; Waldvogel, S. R. An-
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DeRoy, P. L.; Perreault, C.; Larivée, A.; Siddiqui, A.; Caldwell, C. G.;
Harran, S.; Harran, P. G. Angew. Chem., Int. Ed. 2015, 54, 4818–
4822. (h) Broese, T.; Francke, R. Org. Lett. 2016, 18, 5896–5899.
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X.; Song, J.; Xu, H.ꢀC. Angew. Chem., Int. Ed. 2016, 55, 9168–9172.
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genꢀcentered radicals as redox catalysts: (a) Badalyan, A.; Stahl, S. S.
Nature 2016, 535, 406–410. (b) Rafiee, M.; Miles, K. C.; Stahl, S. S.
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(14) (a) Inokuchi, T.; Matsumoto, S.; Torii, S. J. Org. Chem. 1991,
56, 2416–2421. (b) Tebben, L.; Studer, A. Angew. Chem., Int. Ed.
2011, 50, 5034–5048.
(15) The addition of water reduced the formation of unidentifiable
side products. But its role remained unclear to us.
(16) (a) Examples of TEMPOꢀcatalyzed oxidation of thioethers:
Lang, X.; Zhao, J.; Chen, X. Angew. Chem., Int. Ed. 2016, 55, 4697–
4700. (b) Chinnusamy, T.; Reiser, O. ChemSusChem 2010, 3, 1040–
1042.
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heterocycles is underway in our laboratory.
AUTHOR INFORMATION
Corresponding Author
*haichao.xu@xmu.edu.cn
*jssong@fjirsm@ac.cn
Author Contributions
9
X.ꢀY.Q. and S.ꢀQ.L. contributed equally to this work.
Notes
The authors declare no competing financial interest.
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ASSOCIATED CONTENT
Supporting Information. The experimental procedure, characterꢀ
ization data, computational studies and copies of 1H and 13C NMR
spectra. The Supporting Information is available free of charge
via the Internet at http://pubs.acs.org.
ACKNOWLEDGMENT
We are grateful for financial support from MOST
(2016YFA0204100), NSFC (No. 21402164, 21672178,
21603227), the “Thousand Youth Talents Plan” and XMU.
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