Article
DOI: 10.1002/bkcs.12199
BULLETIN OF THE
H. K. Sung et al.
KOREAN CHEMICAL SOCIETY
C3-Formylation of Indoles in Continuous Flow
*
Ha Kyoung Sung, Dong Hyun Kim, Joon Seok Kim, and Chan Pil Park
Graduate School of Analytical Science and Technology (GRAST), Chungnam National University,
Received November 17, 2020, Accepted December 15, 2020, Published online December 28, 2020
We have developed a continuous flow C3-formylation technique for indoles using hexamethylenetetramine
(
HMTA) and iodine. A mixed solvent system of DMF–H O (1:1, vol/vol) completely dissolves reagents
2
and prevents clogging of microchannels during fluid flow. The continuous flow technique provides maxi-
mized mixing and excellent heat transfer efficiency. Thus, flow chemistry accelerates the rate of
C3-formylation of indoles in the absence of a strong acid, base, or metal catalyst. We show that high yields
ꢀ
of C3-formylated indoles (up to 83%) can be obtained at 150 C when the residence time is as low as 8 min.
Keywords: Continuous flow synthesis, Indoles, Formylation, Solid clogging
17–25
Introduction
methods.
First, the batch process was used to determine
the flow-compatible conditions for the C3-formylation of
indoles (Table 1). Insoluble reactants in the form of slurry
clog the microchannel and disturb the continuous flow reac-
tion (See Supporting Information section 2 for details).
Hence, studies were conducted using the batch technique to
identify the solvent system that can form a homogeneous
reaction medium. Hexamethylenetetramine (HMTA) formed
the slurry in DMF (Table 1, entries 1 and 2), which can
potentially clog the channels in the continuous flow reaction
The indole ring is an important scaffold present in biologi-
cally active molecules. It is widely used for manufacturing
dyes, dietary supplements, flavor enhancers, and perfumes.
The introduction of a carbonyl group at the C3 position of
indoles is one of the most effective ways of utilizing and
functionalizing this valuable structural framework.
1–4
3-Formylindoles obtained through C3-formylation of indoles
are important building blocks of biologically active molecules
such as indole-3-carbinol, bis(indolyl)methanes, tris
system. A mixed solvent system (DMF:H O = 1:1) was used
2
(
indolyl)methanes, coscinamides A and B, camalexin,
to completely dissolve HMTA. A solution of iodine and
indole in DMF was mixed with an aqueous solution of
HMTA (Table 1, entry 3). The product yield increased (from
α-methyltryptamine, brassinin, cyclobrassinin, chondramides
A and C, cryptosanguinolentine, aplysinopsin, isocryptolepine,
5–8
and caulilexin A.
However, traditional C3-formylation
6
2% to 74%) when reactions were carried out in this mixed
solvent system. When the reaction time was increased from
0 h to 23 h, there was little or no improvement in yield
Table 1, entries 3 and 4). No progress in the reaction was
reactions like the Vilsmeier-Haack, Reimer–Tiemann, Rieche,
Gattermann–Koch, and Duff require the use of a strong acid,
strong base, or metal catalyst. Moreover, the reactions have
low selectivity and lack functional group tolerance.
1
(
observed, and a large amount of insoluble solid remained in
the reaction mixture when methyl isobutyl ketone (MIBK)
Tetrabutylammonium iodide (Bu NI), potassium iodide (KI),
4
and iodine (I ) have been used as catalysts to address these
2
and toluene–H O (1:1, vol/vol) were used as the solvent sys-
2
shortcomings, but short reaction time could not be
9–15
tems (Table 1, entries 5 and 6). It has been reported that the
addition of activated carbon shortens the reaction time and
achieved.
Recently, an electrochemical C3-formylation
method based on a two-step transformation via a Mannich-
18
16
improves the yield. However, we could not validate the
additive effect of activated carbon (Table 1, entries 7 and 8).
We think that the presence of activated carbon in the slurry
may clog the microchannels of the continuous flow reactor.
Hence, we used graphene oxide as the additive as it gets dis-
type reaction and C N bond cleavage has been reported,
but a long reaction time of over 12 h is required to obtain
good yields.
Results and Discussion
26,27
persed easily in an aqueous solution
; however, the prod-
uct yield did not improve (Table 1, entry 9). When the
We attempted to find an efficient and safe method that could
overcome the problems mentioned above. We used continu-
ous flow chemistry techniques to carry out the
C3-formylations reported by Zhang et al and Wang
volume ratios of DMF and H O were 2:3 and 3:2, the prod-
2
uct yields were 60% and 58%, respectively (Table 1, entries
10 and 11). Though a similar product yield was obtained in
the DMSO–H O (1:1, vol/vol) solvent system (Table 1,
2
17,18
et al.
We expected the continuous flow method to pro-
vide a solution for the poor functional group tolerance and
long reaction times seen in the conventional batch reaction
entry 12), it is better to use DMF as the organic counterpart
as it is cost-effective. Therefore, the subsequent continuous
Bull. Korean Chem. Soc. 2021, Vol. 42, 388–392
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