Catalytic Aerobic Photo-oxidation of a Methyl Group on a Heterocycle to Produce an Aldehyde via Homolytic C-I Bond Cleavage caused by Irradiation with Visible Light

Article abstract of DOI:10.1002/adsc.201500811

A new catalytic method was developed for photo-oxidizing the methyl group on aromatic heterocycles such as benzothiazole, benzoxazole, and quinoline to produce the corresponding aldehyde. This is the first report of the metal-free catalytic synthesis of benzothiazole-2-carboxaldehydes using molecular oxygen as the terminal oxidant.

Full text of DOI:10.1002/adsc.201500811

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DOI: 10.1002/adsc.201500811
Catalytic Aerobic Photo-oxidation of a Methyl Group on a
À
Heterocycle to Produce an Aldehyde via Homolytic C I Bond
Cleavage caused by Irradiation with Visible Light
Y. Nagasawa,a Y. Tachikawa,a E. Yamaguchi,a N. Tada,a T. Miura,b,* and A. Itoha,*
a
Gifu Pharmaceutical University 1-25-4, Daigaku-nishi, Gifu 501-1196, Japan
Fax: (+81)-058-230-8108; phone: (+81)-058-230-8100; e-mail: itoha@gifu-pu.ac.jp
Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
b
Fax: (+81)-042-676-4469; phone: (+81)-042-676-4469; e-mail: tmiura@toyaku.ac.jp
Received: August 30, 2015; Revised: October 29, 2015; Published online: January 12, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500811.
Abstract: A new catalytic method was developed
for photo-oxidizing the methyl group on aromatic
heterocycles such as benzothiazole, benzoxazole,
and quinoline to produce the corresponding alde-
hyde. This is the first report of the metal-free cata-
lytic synthesis of benzothiazole-2-carboxaldehydes
using molecular oxygen as the terminal oxidant.
activated with a Brønsted acid. However, this reaction
required two equivalents of 2-methylbenzothiazole,
a high temperature, and the use of transition metals.
More economical methods for achieving this type of
oxidation reaction are, therefore, still required. To the
best of our knowledge, no other methods for oxidizing
2-methylbenzazoles to form aldehydes have been de-
veloped, and this is probably because of the difficul-
ties involved in oxidizing a stable methyl group with-
out oxidizing other groups on the heterocycle and oxi-
dizing the target aldehyde that is generated in situ.
We have previously described oxidation reactions
using catalytic amounts of iodine and irradiation with
visible light. These reactions have included the
Keywords: aldehydes; halogenation; heterocycles;
photo-oxidation
The oxidation of a methyl group on an aromatic het- tandem oxidation and rearrangement of b-keto esters
erocycle to form an aldehyde is an important subject to form a-hydroxymalonic esters,[4a] the oxidative de-
because aldehydes have been used as helpful inter- carboxylation of 1,3-diketones,[4b] and the oxidative
mediates in the synthesis of drugs and industrial prod- cleavage of olefins.[4c] We assumed that the homolytic
ucts because of their electrophilicity.[1] In particular,
substituted benzazoles are crucial reagents in pharma-
ceutical chemistry.[2] However, reports on the synthe-
sis of benzazole-2-carboxaldehydes are surprisingly
rare. Such a synthesis has been achieved by perform-
ing a formylation reaction using an alkyllithium re-
agent, giving the product in good yield, but ketones
and bromine were generally not tolerated under the
strongly basic reaction conditions that were used
[Scheme 1, Eq. (1)].[3a] A method was developed for
oxidizing the inexpensive and easily accessible 2-
methylbenzazoles using a stoichiometric amount of
selenium dioxide (which is toxic), but this reaction re-
quired harsh conditions [Scheme 1, Eq. (2)].[2a,3b]
A
method for the copper-catalyzed aerobic oxidative
3
À
amination of sp C H bonds, including those in 2-
methylbenzothiazole, was recently developed by Han
and co-workers [Scheme 1, Eq. (3)].[3c] This reaction
does not produce the aldehydes but is noteworthy in
that the methyl group on a heterocycle can be easily Scheme 1. Previous work.
178
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Catalytic Aerobic Photo-oxidation of a Methyl Group on a Heterocycle
Table 1. Optimization of the reaction conditions.[a]
Entry
Acid
Equiv.
Iodine source
Yield[b] [%]
1
–
I2
0
2
3
4
5
6
7
8
9
AlCl3
TfOAg
Yb(OTf)3
AcOH
HCl
TFA
TFA
TFA
TFA
0.1
0.1
0.1
0.1
0.1
0.1
0.2
0.5
1.0
1.0
1.0
1.0
I2
I2
I2
I2
I2
I2
I2
I2
trace
trace
trace
0
6
13
21
49
80 (78)
0
15
Scheme 2. This work.
À
cleavage and oxidation of the C I bond, promoted by
irradiation with visible light, allowed the reactions to
proceed. From this perspective, we hypothesized that
the acid-mediated tautomerization of the 2-methyl-
benzazole to the enamine would be activated by an
10
11
12
I2
TFA
TFA
TFA
MgI2
NIS
I2
acid catalyst. The enamine tautomer produced would 13[c]
80 (81)
be a good nucleophile, allowing it to attack the iodine
[a]
Reaction conditions: A mixture of 2-methylbenzothiazole
(1a) (0.3 mmol), the acid, the iodine source (0.06 mmol),
and EtOAc (5 mL) was heated and irradiated using a flu-
orescent lamp for 20 h under an oxygen atmosphere.
Yields were determined by H NMR using 1,1,2,2-tetra-
chloroethane as an internal standard. The numbers in pa-
rentheses are the isolated yields.
atom, leading to the production of an iodinated inter-
mediate. The subsequent oxidation of the iodinated
intermediate could occur through the homolytic
[b]
1
À
cleavage of the C I bond caused by irradiation with
visible light under an oxygen atmosphere, giving the
desired aldehyde (Scheme 2). Here, we report a novel
method for the transition metal-free, catalytic direct
[c]
The reaction temperature was 708C.
photo-oxidation of a methyl group on a heteroaromat-
ic compound to form the corresponding aldehyde.
The reaction presented gave the desired aldehydes in
Table 2. Aldehyde synthesis from various benzothiazoles.[a]
good yields with a high degree of selectivity.
First, we explored the reactions of 2-methylbenzo-
thiazole under
a variety of reaction conditions
(Table 1). No reaction occurred when a promoter was
not present or when a promoter such as a Lewis acid
or acetic acid was used (entries 1–5). In contrast,
strong Brønsted acids, such as hydrochloric acid and
trifluoroacetic acid, did promote the reaction (en-
tries 6 and 7). The yields increased as the amount of
acid used was increased (entries 7–10). The yield was
zero or poor when magnesium iodide (MgI2) or N-io-
dosuccinimide (NIS) was used as the iodine source
even though MgI2 was found to be a good source of
iodide ions in our previous work[5] and NIS is a well-
known electrophilic iodine source (entries 11 and
12).[6] The reaction gave the best result when it was
performed at 708C (entry 13).
The range of substrates that could be used in this
newly developed oxidation reaction was evaluated
(Table 2). The electron-rich substrates 1e, 1f, and 1g
and the electron-neutral substrates 1b, 1c, and 1d re-
acted well under the optimized reaction conditions,
whereas the strongly electron-deficient substrates 1h,
1i and 1j (which have an ester group, a cyano group
and a nitro group, respectively) required longer reac-
tion times. The reaction could accommodate sub-
strates containing a chloro or bromo substituent,
[a]
Reaction conditions: a mixture of substrate 1 (0.3 mmol),
TFA (1.0 equiv.), I2 (0.06 mmol), and EtOAc (5 mL) was
stirred for the indicated reaction time at 708C under an
oxygen atmosphere, and the mixture was irradiated using
a fluorescent lamp.
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Y. Nagasawa et al.
Table 3. Aldehyde synthesis from various methylheteroaro-
matic compounds.[a]
[a]
Reaction
conditions:
A
mixture
of
substrate
1 (0.3 mmol), TFA (1.0 equiv.), I2 (0.06 mmol), and
EtOAc (5 mL) was stirred for the indicated reaction
timeat 708C and irradiated with fluorescent lamp under
an oxygen atmosphere.
Solvent was PhMe (5 mL) and the mixture was heated to
1008C.
[b]
which can later be applied to various cross-coupling
reactions with metal catalysts.[7] It should be noted
that the oxidation reaction was strongly site-selective
when a substrate with one or more other methyl
groups (1f and 1g) was used, and no site other than
the 2-Me group was found to be oxidized. Further-
more, 2-ethylbenzothiazole (1l) and 2-benzylbenzo-
thiazole (1m) were oxidized to form the correspond-
ing ketones using these reaction conditions.
The scope and limitations of the reaction for other
heteroaromatic compounds are shown in Table 3. In-
triguingly, the oxidation of 2- or 4-methylquinoline
proceeded smoothly to give the desired products in
moderate to good yields but no reaction occurred
with 3-methylquinoline (1n, 1o, and 1p). These results
suggest that the formation of the enamine form is
probably crucial to the subsequent iodination that
occurs at the methyl group of the heteroarene. Al-
though 2-methylbenzoxazole reacted to give the cor-
responding aldehyde in moderate yield under modi-
Scheme 3. Control experiments: The yields were determined
by 1H NMR analysis using 1,1,2,2-tetrachloroethane as an
internal standard.
fied conditions, 2-methylbenzoimidazole and deriva- a TEMPO substituent (4a), which suggests that the
tives of toluene did not give the corresponding oxida- reaction followed pathway involving radicals
tion products (2q, 2r, and 2s). [Scheme 3, Eq. (7)]. These results indicate that the re-
a
Some control experiments were performed to ex- action required irradiation with visible light and the
amine the mechanism involved in the reaction in presence of molecular oxygen and it also indicates
detail (Scheme 3). The reaction was suppressed dra- that it proceeded through a radical pathway. Using 2-
matically in the dark or under an argon atmosphere, benzothiazolemethanol (5a) as the substrate gave 2a
and iodo-2-methylbenzothiazole (3a) was found when in 66% yield, but unreacted 5a remained in 15%
the reaction products were analyzed by NMR spec- yield [Scheme 3, Eq. (8)]. Aldehydes 2a and 2t were
troscopy [Scheme 3, Eqs. (4) and (5)]. The iodinated obtained from each of iodo-2-methylbenzothiazole
intermediate 3a was rapidly reconverted into 1a when (3a) and benzyl iodide (3t) irradiated using a fluores-
aqueous HI was added [Scheme 3, Eq. (6)]. The reac- cent lamp under an oxygen atmosphere [Scheme 3,
tion of 1a with TEMPO gave a product with Eqs. (9) and (10)]. These observations suggest that 5a
180
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Adv. Synth. Catal. 2016, 358, 178 – 182

COMMUNICATIONS
Catalytic Aerobic Photo-oxidation of a Methyl Group on a Heterocycle
selectively oxidize the 2-methyl group in benzothia-
zoles. The reaction is an economical and practical
method for achieving oxidation because it uses a cata-
lytic amount of iodine, molecular oxygen as the termi-
nal oxidant, and visible light produced by a general
purpose fluorescent lamp.
Experimental Section
Typical Procedure
A solution of 2-methylbenzothiazole (1a, 0.3 mmol), iodine
(0.06 mmol), and TFA (0.3 mmol) in EtOAc (5 mL) was
stirred, heated at 708C, and irradiated using a fluorescent
lamp under an O2 atmosphere for 20 h. The reaction mixture
was treated with saturated aqueous Na2S2O3 (30 mL) and
the aqueous layer was extracted three times with EtOAc
(10 mL). Then, the organic layer was dried over magnesium
sulfate and filtered. The solvent was removed by rotary
evaporation and the residue purified by PTLC to furnish
benzothiazole-2-carboxaldehyde (2a).
Scheme 4. Proposed mechanism.
was not an intermediate and that 3a was an inter-
mediate in the reaction. When methylene blue,
known as a producer of singlet oxygen, was employed
instead of molecular iodine, aldehyde 2a could not be
obtained and substrate 1a was recovered quantitative-
ly [Scheme 3, Eq. (11)].[8] Probably, singlet oxygen is
not involved in the reaction mechanism. We could not
follow the detailed reason why the oxidation stopped
at the aldehyde, however, no reaction occurred when
the aldehyde 2a was irradiated with a fluorescent
lamp under an oxygen atmosphere [Scheme 3, Eq.
(12)]. It seems that the aldehyde is stable even under
an oxygen atmosphere. We searched for several meth-
ods to calculate the quantum yield of the photo pro-
cess, however, the determination of the quantum
yield was difficult for us because molecular iodine,
Acknowledgements
We would like to thank Elemental Analysis center of Gifu
Pharmaceutical University for the elemental analysis and
Enago (www.enago.jp) for the English language review.
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