Regioselective C-H dithiocarbamation of indolizines with tetraalkylthiuram disulfide under metal-free conditions

Article abstract of DOI:10.1039/d1ob00701g

An efficient and straightforward metal-free regioselective C-H dithiocarbamation of indolizines with tetraalkylthiuram disulfide has been described. A series of indolizine-dithiocarbamate derivatives were easily accessed in moderate to good yields with a broad scope. In addition, imidazo[1,2-a]pyridines were also well tolerated to afford diverse imidazoheterocycle-dithiocarbamate products, which are expected to be utilized for drug discovery. Of note, the reaction could be readily scaled up, and shows its practical value in organic synthesis.

Full text of DOI:10.1039/d1ob00701g

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Regioselective C–H dithiocarbamation of
indolizines with tetraalkylthiuram disulfide under
metal-free conditions†
Cite this: Org. Biomol. Chem., 2021,
19, 5284
Received 10th April 2021,
Accepted 19th May 2021
Xiang Liu, Dan Song, Zemin Zhang, Jiatong Lin, Canzhan Zhuang, Haiying Zhan* and
DOI: 10.1039/d1ob00701g
Hua Cao
*
rsc.li/obc
An efficient and straightforward metal-free regioselective C–H
C–H bond functionalization of indolizines was considered
dithiocarbamation of indolizines with tetraalkylthiuram disulfide as one of the most powerful and useful tools to construct a
has been described. A series of indolizine-dithiocarbamate deriva- C(sp2)–S bond owing to some attractive advantages such as no
tives were easily accessed in moderate to good yields with a broad need for pre-functionalization, high atom economy, and so
scope. In addition, imidazo[1,2-a]pyridines were also well tolerated on.10 In 2018, our group11 described for the first time a H2O2-
to afford diverse imidazoheterocycle-dithiocarbamate products, mediated C–H thiolation of indolizines with thiols, in which
which are expected to be utilized for drug discovery. Of note, the dithiolation of indolizines could be obtained in the presence
reaction could be readily scaled up, and shows its practical value in of TBHP and catalytic KI (Scheme 1a). Although a few C–H
organic synthesis.
thiolation of indolizines have been disclosed later,10 regio-
selective C–H dithiocarbamation of indolizines with tetra-
methylthiuram disulfide (TMTD) has not been well developed.
As a continuation of our efforts on the functionalization of
indolizines,12 herein we describe a Lewis acid-induced dithio-
carbamation of indolizines with TMTD to give indolizine-
dithiocarbamate derivatives under metal-free conditions
(Scheme 1b).
The novel reactivity of regioselective C–H dithiocarbamation
of indolizines with tetramethylthiuram disulfide under metal-
free conditions was studied (Table 1). Reaction conditions
were screened by varying the additives, reaction temperature,
and solvents. Upon addition of 10 mol% AgOAc, the target
product 3a was detected in 35% yield at 80 °C (entry 1). Cu
(OAc)2 and CuI were similarly effective to silver salts, though
Organic dithiocarbamates are significant building blocks in
synthesis chemistry, functional materials, pesticide industry,
and pharmaceutical industry and have attracted extensive
attention.1–3 In particular, these compounds have proven to
possess outstanding biological activities such as antifungal,
anticancer, and antibacterial activities.4,5 Consequently,
numerous efforts have been devoted to introduce a dithiocar-
bamate group into the parent molecules.6 Among them, the
incorporation of a dithiocarbamate group into heterocycles
received increasing interest.7 In 2006, Tang and co-workers dis-
closed a C–H thiolation strategy for the introduction of dithio-
carbamates into imidazoheterocycles in the presence of I2 and
FeF3.7a Recently, they reported KI/K2S2O8-promoted selective
C–H dithiocarbamation of N-heterocycles.7f However, to the
best of our knowledge, the strategies for the introduction of
dithiocarbamates into indolizines have not been reported until
now. The indolizine core, a privileged N-heterocycle, has
emerged as a promising class of bioactive compounds.8
Moreover, indolizines have also been shown to be of great
value in fluorescent materials.9 Therefore, the development of
efficient and straightforward approaches for the synthesis of
indolizine-dithiocarbamate derivatives is highly desirable
(Fig. 1).
School of Chemistry and Chemical Engineering and Guangdong Cosmetics
Engineering & Technology Research Center, Guangdong Pharmaceutical University,
Zhongshan 528458, China. E-mail: nancyzhy@foxmail.com, caohua@gdpu.edu.cn
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
d1ob00701g
Fig. 1 Biologically active molecules and the fluorescent core skeleton.
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A range of indolizines were treated with tetramethylthiuram
disulfides 2a under the optimized reaction conditions
(Scheme 2). Different substituted indolizines were tested. The
methyl, ethyl, methoxy, and halogen substituents on the pyri-
dine ring of indolizines were all well tolerated, affording C–H
dithiocarbamation products in generally good yields (65%–
80%) (3b–3h). The presence of halogen atoms reduces the elec-
tron cloud density of the aromatic ring, resulting in a slight
decrease in the yield of product 3g. In addition, various aryl
substituted indolizines were also good candidates for the syn-
Scheme 1 Regioselective C–H carboxamidation of indolizines.
Table 1 Optimization of the reaction conditionsa
Entry
Additive
Solvent
T (°C)
Yieldb (%)
1c
2c
3c
4c
5
6
7
8
9
10
11
12
13
14
15
16
17
AgOAc
Cu(OAc)2
CuI
AlCl3
Cs2CO3
K2CO3
AcOH
PivOH
TFA
TFA
AcOH
TFA
TFA
TFA
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
Toluene
80
80
80
80
80
80
80
80
35
37
40
20
15
39
42
35
44
55
65
88
Trace
54
85
81
48
80
100
120
120
120
120
120
120
120
DCM
THF
MeCN
1,4-Dioxane
TFA
TFA
—
a Standard conditions: 1a (0.2 mmol), 2a (0.3 mmol), additive
(0.45 mmol), solvents (2 mL), 15 h. b Determined by NMR analysis.
c Additive (0.02 mmol).
AlCl3 was slightly less active (entries 2–4). Adding 1.5 equiva-
lents of Cs2CO3 also resulted in a decreased yield (entry 5).
The use of K2CO3, AcOH, PivOH, and TFA promoted the con-
version, although further increases were disadvantageous
(entries 6–9). To our delight, switching to higher temperatures
in the presence of acids enabled the formation of the desired
products in higher yields (entries 10–12, 55%, 65%, and 88%).
Next, the solvent was evaluated. Only trace amounts of indoli-
zine-dithiocarbamate 3a were detected by switching to a less
polar solvent at the same temperature (entry 13). After screen-
ing of different solvents, the results indicated that no other
solvent was better than 1,4-dioxane (entries 14–16 vs. entry 12).
Only 48% yield was obtained without additives (entry 17).
Thus, indolizines 1a and thiuram reagent 2a could react in the
presence of TFA at 120 °C to yield 3a in 88% yield, which were
selected as the optimal reaction conditions.
Scheme 2 Substrate scope for the reaction of indolizines and tetra-
methylthiuram disulfide. Reaction conditions:
1 (0.3 mmol), 2a
(0.45 mmol), TFA (0.45 mmol), 1,4-dioxane = 2 mL, 120 °C, 15 h.
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thesis of indolizine-dithiocarbamate derivatives, providing the different substituents nor the position of the functional
corresponding products 3i–3u in a range of yields of 70–83%. groups on the parent compound had small impact.
a
It was gratifying to note that functional groups such as –F, –Cl, Subsequently, indolizines with two substituents were investi-
–Br, –OMe, –OBn, –CF3 and –CN had good compatibility in the gated. The results showed that they participated in the reaction
metal-free regioselective C–H dithiocarbamation of indolizines with good tolerance, but the yield of the required products
with tetraalkylthiuram disulfide. The scope of this catalytic decreased to 62% and 61%, respectively (5l and 5m).
system was also extended to indolizines with substituents on
Importantly, this transformation is not limited to indoli-
both the pyridine ring and the aryl ring. The reaction pro- zines. Treatment of imidazo[1,2-a]pyridines with tetraalk-
ceeded smoothly and the desired products were obtained (3v– ylthiuram disulfide 2a under the standard reaction conditions
3x). Heterocycle-containing indolazines and 2-methyl indola- furnished imidazoheterocycle-dithiocarbamate 7a in 78% yield
zines were also obtained in good yields of the corresponding (Scheme 4). Of note, a good yield could be achieved in the case
products (3y–3aa). But 2ab and 2ac could not convert to the of the phenyl and pyridine rings of imidazo[1,2-a]pyridines
target dithiocarbamate derivatives. We also tried to extend the carrying methyl, methoxy, and halogen (7b–7d). Herein, the
scope, but failed to synthesize substrates indolizine and 2-(4- protocol provided a convenient and efficient approach for the
nitrophenyl)indolizine. Therefore, this method provides an introduction of dithiocarbamates into N-heterocycle molecules
effective way for the preparation of various substituted indoli- under metal-free conditions.
zine-dithiocarbamate derivatives.
In order to verify the efficiency and expansibility of this
Encouraged by the above results, the scope of tetramethyl- metal-free C–H dithiocarbamylation reaction, we carried out a
thiuram disulfide was subsequently investigated. As shown in large-scale reaction using 2-phenylindolizine 1a (6.0 mmol)
Scheme 3, tetraethylthiuram disulfides could participate in and tetramethylthiuram disulfide 2a (9.0 mmol) as substrates.
this transformation to form the desired products in moderate To our satisfaction, the indolizine-dithiocarbamate derivative
to good yields. Indolizines with methyl, halogen, trifluoro- could still be obtained in 82% yield (Scheme 5).
methyl, and cyano groups on the para-position of the aryl ring
Control experiments were conducted to gain mechanism
reacted well with 2b, giving the corresponding products in sat- insight for the synthesis of indolizine-dithiocarbamates under
isfactory yields (5b–5k). Neither electronic effects induced by transition-metal-free conditions. When the radical scavengers
BHT, hydroquinone, and TEMPO were added under the stan-
dard conditions, the corresponding products were generated
in 82%, 72%, and 22% yields, respectively (Scheme 6). This
result indicates that the free radical process might not be
involved in the transformation. Thus, a possible reaction
Scheme 4 Substrate scope for the reaction of imidazo[1,2-a]pyridines
and tetramethylthiuram disulfide. Reaction conditions: 6 (0.3 mmol), 2a
(0.45 mmol), TFA (0.45 mmol), 1,4-dioxane = 2 mL, 120 °C, 15 h.
Scheme 3 Substrate scope for the reaction of indolizines and tetra-
ethylthiuram disulfide. Reaction conditions:
(0.45 mmol), TFA (0.45 mmol), 1,4-dioxane = 2 mL, 120 °C, 15 h.
4
(0.3 mmol), 2b
Scheme 5 Scale-up experiment. Reaction conditions: 1a (6.0 mmol),
2a (9.0 mmol), TFA (9.0 mmol), 1,4-dioxane = 15 mL, 120 °C, 15 h.
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Distinguished Young Scholars for GuangDong Province
(2020B1515020026), the Scientific Research Projects for Key
Disciplines of Guangdong Province (2019-GDXK-0009), the
Innovation and Strong School Project of Guangdong
Pharmaceutical University (2019KQNCX061), the Guangdong
Cosmetics Engineering & Technology Research Center, the
Provincial Experimental Teaching Demonstration Center of
Chemistry & Chemical Engineering, and the Special funds of
key disciplines construction from Guangdong and Zhongshan
cooperating.
Scheme 6 Control experiments.
Notes and references
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Firstly, 2-phenylindolizine 1a reacts with tetraalkylthiuram di-
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desired product 3a is produced after a proton is released
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In summary, we have developed a simple and direct protocol
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This work was supported by the National Natural Science
Foundation of China (22001045), the Science Foundation for
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