Iron-catalyzed tandem oxidative coupling and acetal hydrolysis reaction to prepare formylated benzothiazoles and isoquinolines

Article abstract of DOI:10.1039/d1cc00621e

The aldehyde group is one of the most versatile intermediates in synthetic chemistry, and the introduction of an aldehyde group into heteroarenes is important for the transformation of molecular structure. Herein, we achieved the direct formylation of benzothiazo/les and isoquinolines. The reaction features a novel iron-catalyzed Minisci-type oxidative coupling process using commercially available 1,3-dioxolane as a formylated reagent followed by acetal hydrolysis without a separation process. The reaction can be performed under exceedingly mild reaction conditions and exhibits broad functional group tolerance.

Full text of DOI:10.1039/d1cc00621e

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Iron-catalyzed tandem oxidative coupling and
acetal hydrolysis reaction to prepare formylated
benzothiazoles and isoquinolines†
Cite this: Chem. Commun., 2021,
57, 3271
Received 3rd February 2021,
Accepted 16th February 2021
Yue Wu,‡a Peng Guo,‡a Long Chen,a Weijie Duan,a Zengzhuan Yang,b
ab
ab
Tao Wang,
*
Ting Chena and Fei Xiong
*
DOI: 10.1039/d1cc00621e
rsc.li/chemcomm
The aldehyde group is one of the most versatile intermediates in aldehyde derivatives. However, this type of reaction always
synthetic chemistry, and the introduction of an aldehyde group into involves rigorous reaction conditions, such as high tempera-
heteroarenes is important for the transformation of molecular ture and pressure, and the requirement of a pre-functionalized
structure. Herein, we achieved the direct formylation of benzothiazo/ aryl halide (Scheme 1, eqn (1)).6 Hence, the development of
les and isoquinolines. The reaction features a novel iron-catalyzed novel access to the formylation of heteroarenes under mild
Minisci-type oxidative coupling process using commercially available conditions is still of much significance.
1,3-dioxolane as a formylated reagent followed by acetal hydrolysis
In recent years, new reagents, such as formaldehyde,7 alcohols,8
without a separation process. The reaction can be performed under formic acid,9 glyoxylic acetal,10 and glyoxylic acid,11 have been
exceedingly mild reaction conditions and exhibits broad functional developed as formylated surrogates for olefins and arenes.
group tolerance.
Benzothiazole has been used as a crucial heterocyclic skeleton,
although the direct formylation has rarely been reported. In
Nitrogen-containing heterocycles are prevalent key motifs in a addition to classical Vilsmeier–Haack and Duff reactions, the
myriad of biologically active compounds, agrochemicals, and oxidization of methyl or hydroxymethyl groups using a stoichio-
organic functional materials, such as liquid crystals and fluo- metric oxidant is a method currently used to obtain benzothiazole-
rescent dyes.1 Because functionalized heteroarenes are ubiqui- 2-carboxaldehydes (Scheme 1, eqn (2 and 3)).12 The acetal group
tously present in natural and pharmaceutical products, there is
a continuous need for efficient synthetic methods to produce
them.2 Accordingly, introducing a formyl group into an aro-
matic heterocycle is important because the aldehyde group is
widely used as a valuable and powerful synthon in the synthesis
of drugs and industrial products.3,4 Although aromatic alde-
hydes are widely applied in synthetic chemistry, their synthetic
routes are rather limited. Some classical methods, such as
Vilsmeier–Haack and Duff reactions, are suboptimal due to
their relatively poor regioselectivity and harsh work-up.5
Palladium-catalyzed reductive carbonylation of aryl halides is
an effective route to obtain various formylated a,b-unsaturated
a College of Chemistry and Chemical Engineering, Jiangxi Normal University,
Nanchang, Jiangxi 330022, P. R. China. E-mail: xiongfei@jxnu.edu.cn,
wangtao@jxnu.edu.cn
b National Research Center for Carbohydrate Synthesis and Key Laboratory of
Chemical Biology, Jiangxi Normal University, Nanchang, Jiangxi 330022,
P. R. China
† Electronic supplementary information (ESI) available: Experimental proce-
dures, characterization data, Copies of 1H and 13C NMR spectra for all com-
pounds. See DOI: 10.1039/d1cc00621e
Scheme 1 Strategies for the formylation.
‡ Yue Wu and Peng Guo contributed equally to this work.
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Table 1 Optimization of the reaction conditionsa
can be used as an aldehyde precursor and be introduced into a
molecular skeleton by oxidative cross-coupling, and then sub-
sequently hydrolyzed to aldehyde compounds.13
In 2018, Xia’s group reported the formylation of heteroarenes in
moderate yields using 2,2-diethoxyacetic acid (acyclic acetal form)
as a formylation mask reagent under visible light irradiation.13a In
2018, Yeung and co-workers designed an approach that harnesses
the direct activation of weak C–H bonds in acetals (trioxane) and
achieved the partial formylation of N-heterocycles with a Minisci-
type reaction (Scheme 1, eqn (4)).13b,14 In 2020, Wang’s group
reported a protocol for a photoredox-catalyzed redox-neutral
Minisci C–H formylation reaction of N-heteroarenes (Scheme 1,
eqn (5)).13c,14 In addition, 1,3-dioxolane (cyclic acetal form) as a
formylation mask reagent was also applied to the introduction of
the formyl group. In 2017, Doyle’s group described a protocol for
direct formylation of aryl halide with 1,3-dioxolane through a
photoredox-catalyzed mode, where pre-functionalized aryl halide
was used in this reaction.13d
Although some works reported Minisci-type reactions with
heteroarene (arene) and cyclic ether (including cyclic acetal,
such as 1,3-dioxolane), in most of them, the substrate’s scope
or yields were unsatisfactory, and systematic hydrolysis pro-
ducts (cyclic acetal) were surprisingly scarce.15 Inspired by
these reports on various acetals as formyl radical equivalents,
here, we report a new iron-catalyzed cascading Minisci and
hydrolysis reaction of benzothiazoles and isoquinolines with
1,3-dioxolane as a formyl equivalent under exceedingly mild
reaction conditions that affords the corresponding formylated
products in moderate to good yields (Scheme 1, eqn (6)). This
tandem oxidative coupling-hydrolysis procedure features green
and efficient C–C building from C–H/C–H and avoids the use of
pre-functionalized substrates.16
Entry
Catalyst
Oxidant
T (1C)
Yieldb (%)
1
2
3
4
5
6
7
8
—
CuBr
CuBr2
Cu(OTf)2
Cu(acac)2
Cu(OAc)2
CoCl2
FeCl2
FeCl3
Fe(OTf)2
Fe(OTf)2
Fe(OTf)2
Fe(OTf)2
Fe(OTf)2
Fe(OTf)2
Fe(OTf)2
Fe(OTf)2
Fe(OTf)2
Fe(OTf)2
Fe(OTf)2
Fe(OTf)2
Fe(OTf)2
Fe(OTf)2
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
Na2S2O8
K2S2O8
DTBP
TBHP
TBHP
TBHP
TBHP
TBHP
35
35
35
35
35
35
35
35
35
35
35
35
35
35
35
35
35
35
35
35
35
25
50
NR
NR
Trace
Trace
15%
32%
Trace
NR
Trace
Trace
84
58
74
57
64
Trace
Trace
NR
62
67
52
43
76
9
10
11
12c
13d
14e
15f
16
17
18
19g
20h
21i
22
23
a
Reaction conditions: 1a (0.15 mmol), 1,3-dioxolane (1.0 mL), DCE (1.0 mL),
metal salt (10 mmol%), and oxidant (2.5 equiv.) at 35 1C for 24 h under
b
c
d
air. Isolated yield. Fe(OTf)2 (8 mmol%). Fe(OTf)2 (12 mmol%).
e
f
g
TBHP (2 equiv.). TBHP (3 equiv.). 1,3-Dioxolane/DCE (1.5 : 0.5, 2 mL).
1,3-Dioxolane/DCE (0.5 : 1.5, 2 mL). 1,3Dioxolane (2 mL). TBHP = tert-
h
i
butyl hydroperoxide (5.0–6.0 M in decane).
reaction temperature also resulted in lower yields (Table 1,
In our initial study, benzothiazole 1a and 1,3-dioxolane were entries 22 and 23).
selected as model substrates to test our designed methodology.
For the synthesis of heteroarene aldehyde, 1,3-dioxolane as
First, we carried out the reaction in DCE/1,3-dioxolane (v/v = 1 : 1) an aldehyde precursor is currently underutilized. The sub-
at 35 1C in the presence of TBHP (2.5 equiv.) as oxidant, and sequent hydrolysis of 2a was attempted to afford aldehyde
product 2a was not observed (Table 1, entry 1). We speculated derivative 3a in the presence of 6 M HCl (in acetone) at room
that the catalytic nature of transition metals would have a temperature for 6–8 h, and compound 3a was conveniently
profound impact on reactivity, and thus, the combination of prepared from benzothiazole 1a and 1,3-dioxane via a two-step
transition metal catalysts (10 mol%) and TBHP was examined. It process in 79% total yields (Table 2, entry 3ac). Otherwise, the
was observed that Fe(OTf)2 exhibited higher catalytic activity byproduct 2a0 was not transferred to the hydrolysis product in
than other metal catalysts, and afforded product 2a in 84% yield the presence of protons or Lewis acids. Compared with a two-
as the main regioisomer (C2 isomer at 1,3-dioxolane; Table 1, step procedure, a one-pot synthetic strategy for 3a was also
entries 2–11), and byproduct 2a0 (C4 isomer at 1,3-dioxolane) was carried out, and afforded product 3a in good yield (82% yield
isolated in 7% yield (see ESI,† S2). By respectively varying the based on 1a, Table 2, 3ab).
amount of Fe(OTf)2 as well as TBHP, the target product was
Based on the above experimental results, we explored the
produced with inferior yield (Table 1, entries 12–15). Other substrate scope via a one-pot strategy. Various substituted ben-
oxidants, such as Na2S2O8, DTBP, and K2S2O8, were not satisfac- zothiazoles 1 were employed to react with 1,3-dioxolane (shown in
tory for the reaction because either lower yield or no expected Table 2). First, 6-substituted benzothiazoles 1 containing electron-
product was observed (Table 1, entries 16–18). Furthermore, donating groups, such as –Me, –OMe, and –tBu, reacted smoothly
variations of the ratio of DCE and 1,3-dioxolane produced the to generate the corresponding products (Table 2, 3b-3d) in mod-
product 2a in lower yields (Table 1, entries 19–21), and incre- erate to good yields (54–82%). Second, 6-substituted benzothia-
mentally decreasing amounts of 1,3-dioxolane resulted in lower zoles 1 attached by an electron-withdrawing group, including
yields. Instead of DCE, other solvents, such as DCM, CH3CN, –OCF3, –COOEt, and –CF3, also proceeded to deliver the corres-
DMF, and NMP, afforded inferior yields, although these results ponding products (Table 2, 3h-3j) in moderate yields (43–60%).
are not shown in Table 1. Finally, increasing or lowering the Additionally, 6-substituted benzothiazoles with halogen (F, Cl, Br)
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Table 2 Substrate scope of benzothiazolesab
Table 3 Substrate scope of isoquinolines and quinolinesab
a
Reaction conditions: 4 (0.15 mmol), 1,3-dioxolane (1.0 mL), DCE
(1 mL), Fe(OTf)2 (10 mol%), and TBHP (2.5 equiv.) at 35 1C for 36 h
under air. TBHP = tert-butyl hydroperoxide (5.0–6.0 M in decane).
b
c
Isolated yield. 48 h.
a
Reaction conditions: 1 (0.15 mmol), 1,3-dioxolane (1.0 mL), DCE
(1.0 mL), Fe(OTf)2 (10 mol%), and TBHP (2.5 equiv.) at 35 1C for 24 h
under air. TBHP = tert-butyl hydroperoxide (5.0–6.0 M in decane).
under the optimized conditions (Table 3). Fortunately, most of
the available substrates smoothly completed to the desired
products in moderate to good yields (Table 3, 47–70%) via a
slightly modified hydrolysis procedure (1 M BCl3/CH2Cl2 as the
Lewis acid catalyst instead of 6 M HCl). The desired product was
not obtained with 8-chloroisoquinoline (Table 3, 6j), which
implies that a heterocyclic skeleton may impart a steric hindrance
effect.
To gain further insight to the reaction mechanism, TEMPO
(2,2,6,6-tetramethylpiperidine-N-oxyl), as a classical radical
trapping reagent, was added to the reaction under optimized
conditions. The desired oxidative cross-product 2a was not
found upon addition of TEMPO, and dioxolane-TEMPO
coupled species were detected by GC–MS. The reaction was
entirely suppressed, which indicated that radicals may be
involved in the reaction (Scheme 2). In the reaction, the
homolytic cleavage of TBHP to form the hydroxide and tert-
butoxy radical species might be accelerated in the presence of
reductive ferric salt at low temperature. A significant kinetic
isotopic effect (kH/kD = 3.18) in ref. 17a suggested that the
C(sp3)–H bond cleavage with concomitant formation of an
a-oxyalkyl radical is likely the rate-determining step. In addi-
tion, it was proposed that benzothiazole was easily attacked by
a radical.15c
b
d
c
Isolated yield. Isolated yield based on 1 via two-step procedure.
e
f
36 h. 48 h. Aldehyde does not form under hydrolysis conditions.
substituents (Table 2, 3e-3g) were also well tolerated with moderate
yields (52–64%). However, 6-substituted benzothiazoles with –NO2
and –SO2CH3 groups (Table 2, 3k-3l) proved to be unsuitable for
the reaction, and no desired products were detected or isolated.
Third, the substituents on different positions of the benzothiazole
core structure also worked well to generate the corresponding
products in 42–74% yield under standard conditions (Table 2,
3m-3s). Fourth, non-benzo-fused thiazole also afforded the desired
product in 76% yield (Table 2, 3r). Fifth, benzimidazole only
afforded the oxidative crossing product under the optimized
conditions.
The desired formylated product was not detected, although
we also used other protons and Lewis acids (In(OTf)3 and BCl3,
etc.) to catalyze the acetal hydrolysis reaction, but these catalysts
were ineffective for the reaction (Table 2, 3s). In addition,
benzoxazole as a substrate was only transferred to the oxidative
crossing product, and a hydrolysis product was not detected by
GC–MS. Further investigations of benzimidazoles and benzox-
azoles were not performed. Sixth, reactions with benzothiazoles
and 2-methyl-1,3-dioxolane were carried out under standard
conditions, hydrolysis products (ketone derivatives) were
obtained in moderate yields (Table 2, entries 3t-3v, 55–63%
yields), and evident steric effects were not observed in these
reactions. Finally, the model reaction on a 1 mmol scale was also
carried out under the optimized conditions, and 71% isolated
yield (3a) was obtained. However, partial substrates could not
completely transfer to oxidative coupling products, even with an
increase in the reaction time to 36 h or 48 h. Hydrolysis
processes were always thoroughly completed in the presence of
protons or Lewis acids.
Based on our experimental results and analyses in previous
publications,15b,15c,17 a plausible catalytic mechanism is presented
in Scheme 3. Initially, single-electron transfer (SET) reduction of
TBHP along with oxidation of Fe(OTf)2 to Fe(OTf)2OH produced
the tert-butyl oxygen radical (t-BuOꢀ), and the radical can pro-
duce the alkyl radical B via abstracting hydrogen atoms from the
To further extend the substrate scope of the above synthetic
strategy, isoquinoline and quinoline substrates were explored
Scheme 2 Control experiment.
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Scheme 3 Proposed mechanism.
1,3-dioxolane. Subsequently, radical B would attack benzothiazole-
generated intermediate C, which can be oxidized to cation inter-
mediate D, followed by proton release and re-aromatization to
yield product 2a. Finally, 2a can be absolutely transformed into
the desired product 3a by an acid hydrolytic procedure. In
addition, we assumed that Fe(OTf)2 completed the catalytic cycle
in assisting both the homolytic cleavage of TBHP and the oxida-
tion of carbon radical C to cation D.
In conclusion, we report herein a new formylated procedure
via iron catalytic oxidative coupling between heteroarenes and
1,3-dioxolane under mild reaction conditions, followed by the
acid hydrolytic process. Under our optimized reaction condi-
tions, benzothiazoles and isoquinolines were easily transformed
to their corresponding aldehyde derivatives by a one-pot proce-
dure. The reaction has the major characteristic advantages of a
broad substrate scope and satisfactory functional group tolerance.
The synthetic strategy provides a simple and efficient means of
formylation of heteroarenes and their derivatives.
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We gratefully acknowledge the National Natural Science Founda-
tion of China (21762025, 21562026) and the Key Projects of Natural
Science Foundation of Jiangxi Province (20192ACBL200 26) for
financial support.
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