Tetrahydrocarbazoles by mechanochemical Fischer indolisation

Article abstract of DOI:10.1016/j.tetlet.2021.153068

The Fischer indolisation (FI) typically proceeds in the presence of a Br?nsted or Lewis acid in an organic solvent at elevated temperatures. Herein, we report that tetrahydrocarbazoles (THCs) are accessible by mechanochemical FI at ambient temperature. Using phenylhydrazine hydrochlorides in the presence of silica is critical for this solid-state variant of the FI.

Full text of DOI:10.1016/j.tetlet.2021.153068

Tetrahedron Letters 72 (2021) 153068
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Tetrahedron Letters
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Tetrahydrocarbazoles by mechanochemical Fischer indolisation
⇑
Yichen Qiu, Kararaina Te Puni, Clotilde C. Duplan, Ashley C. Lindsay, Jonathan Sperry
Centre for Green Chemical Science, University of Auckland, 23 Symonds Street, Auckland, New Zealand
a r t i c l e i n f o
a b s t r a c t
Article history:
The Fischer indolisation (FI) typically proceeds in the presence of a Brønsted or Lewis acid in an organic
solvent at elevated temperatures. Herein, we report that tetrahydrocarbazoles (THCs) are accessible by
mechanochemical FI at ambient temperature. Using phenylhydrazine hydrochlorides in the presence of
silica is critical for this solid-state variant of the FI.
Received 8 March 2021
Revised 29 March 2021
Accepted 6 April 2021
Available online 9 April 2021
Ó 2021 Elsevier Ltd. All rights reserved.
Keywords:
mechanochemistry
heterocycles
Fischer indole synthesis
Introduction
istry principles [16–18]. Accordingly, we instigated a programme
to examine if the FI was compatible with mechanochemistry,
Tetrahydrocarbazoles (THCs) are privileged heteroaromatic
scaffolds present in a variety of compounds with a range of biolog-
ical properties [1] (Fig. 1). For example, THCs are present in the
anti-emetic ondansetron, [2] the migraine treatment frovatriptan
[3] and experimental therapeutics in advanced stages of clinical
trials, including the BTK inhibitor BMS-986142 [4] and the PET tra-
cer flutriciclamide F18 [5]. A large number of natural products also
contain the THC scaffold [6–9].
A reliable and very commonly employed method for the synthe-
sis of THCs is the Fischer indolisation (FI), a timeless reaction with
an array of applications in industry and academia (Scheme 1). [10]
Despite being an exemplar method for constructing indoles, the FI
typically requires a Brønsted acid (e.g., HCl, H2SO4, TFA, p-toluene-
sulfonic acid) [11] or Lewis acid (e.g., BF3, ZnCl2, AlCl3) [12] in
organic solvents at elevated temperatures. As a result, the FI is
energy-intensive and generates large amounts of waste.
specifically targeting the THC scaffold. Phenylhydrazine hydrochlo-
ride (1) and cyclohexanone (2) were ball-milled at 400 rpm, but no
THC (3) was observed (Table 1, Entry 1). Several different grinding
auxiliaries [19] were screened; addition of sodium chloride,
sodium sulfate and alumina (basic and neutral) all resulted in no
reaction (Entries 2–5). Pleasingly, upon addition of silica, THC (3)
was obtained in a respectable yield (Entry 6). Reducing the amount
of silica by half (0.5g) led to a noticeable reduction in yield (Entry
7), while doubling the mass added (2.0 g) had little effect (Entry 8).
The addition of acidic silica was vital, as both neutral (Entry 9) and
pyrogenic silica [20] (Entry 10) did not promote the reaction. Inter-
estingly, when phenylhydrazine free base was used as the sub-
strate, the reaction failed (Entry 11). Clearly, the presence of both
the HCl and silica is vital to the solid-state FI’s success – if either
is absent, the reaction fails. The exact mechanism of this process
is not clear, but it is possible that the HCl adsorbs onto the silica,
generating acidic surfaces that promote the FI. Investigations into
this process are ongoing.
Results and discussion
Next, an optimisation study focusing on reaction time and
milling speed was undertaken (Table 2; entry 1 represents the
best conditions discovered during the auxiliary screen). Reducing
the milling speed to 300 rpm led to no reaction (entry 2). Short-
ening the reaction time at 400 rpm significantly decreased the
yield (entry 3), while increasing the reaction time led to a signif-
icant increase (entries 4 and 5). Attempts to replicate the high
yields under shorter reaction times by increasing the milling
speed were partially successful (entries 6–13); at 600–
The development of greener FIs has focused on heterogeneous
and recyclable acid catalysts (zeolites, montmorillonite clays,
etc.) [13], environmentally friendly solvents [14], and flow chem-
istry methods [15]. To the best of our knowledge, there are no
reports of the FI being conducted using mechanochemistry, an
emerging synthesis technique that adheres to many green chem-
⇑
Corresponding author.
E-mail address: j.sperry@auckland.ac.nz (J. Sperry).
https://doi.org/10.1016/j.tetlet.2021.153068
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

Y. Qiu, Kararaina Te Puni, C.C. Duplan et al.
Tetrahedron Letters 72 (2021) 153068
Figure 1. THCs present in approved therapeutics, investigational medicines, and natural products.
Scheme 1. Synthesis of tetrahydrocarbazoles (THCs) by Fischer indolisation (FI).
650 rpm, degradation occurred at reaction times longer than
those stated in Table 2.
6) were readily accessible, demonstrating that halogenated
phenylhydrazines are compatible with this process. 6-Methylte-
trahydrocarbazole (7), 8-ethyltetrahydrocarbazole (8) and 5,7-
dimethyltetrahydrocarbazole (9) were accessible, showing that
para-, ortho- and meta-alkylphenylhydrazines are viable reactants.
Alkylcyclohexanones are compatible with this process, as exempli-
fied by the synthesis of THCs 10–13. The fluorinated THCs 14/15
The solid-state FI scope was investigated using a series of com-
mercially available phenylhydrazine hydrochlorides and cyclohex-
anones (Scheme 2). All the reactions were performed at 600 rpm as
the optimisation study indicated this resulted in shorter reaction
times. 6-Fluoro-, 6-bromo- and 6-chlorotetrahydrocarbazoles (4–
2

Y. Qiu, Kararaina Te Puni, C.C. Duplan et al.
Tetrahedron Letters 72 (2021) 153068
Table 1
Effect of auxiliaries on the solid-state FI.a,b
Entry
Auxiliary (g)
Time (h)
rpm
outcome
1
2
3
4
5
6
none
NaCl (1)
Na2SO4 (1)
neutral alumina (1)
basic alumina (1)
silica (1)
1
200–600
200–600
200–600
200–600
200–600
400
no reaction
no reaction
no reaction
no reaction
no reaction
58%
0.5
0.5
0.5
2
4
7
silica (0.5)
4
400
28%
8
silica (2.0)
4
400
54%
9
neutral silica (1)
pyrogenic silica (1)
silica (1)
4
4
1–10
400–500
400–500
200–600
no reaction
no reaction
no reaction
10
11c
a
Auxiliary was added to phenylhydrazine.HCl (1.38 mmol) and cyclohexanone (1.38 mmol) in a 12 mL stainless steel jar filled to 1/3 capacity with 5 mm stainless steel
balls. bAll reactions conducted in a Retsch PM 100 planetary ball-mill. cPhNHNH2 used instead of PhNHNH2.HCl. rpm = revolutions per minute.
Table 2
Effect of milling speed and reaction time and on the solid-state FI synthesis of tetrahydrocarbazole (3)
Entry
Time (h)
rpm
Yield 3 (%)
1
2
3
4
5
6
7
8
4
2
3
8
10
1
2
3
5
2
3
4
3
400
300
400
400
400
500
500
500
500
600
600
600
650
58
no reaction
28
88
95
28
30
42
64
68
80
70
56
9
10
11
12
13
Phenylhydrazine.HCl and cyclohexanone were added in equimolar amounts (1.38 mmol) to silica (1 g) in a 12 mL stainless steel jar filled to 1/3 capacity with 5 mm stainless
steel balls. All reactions were conducted in a Retsch PM 100 planetary ball-mill. rpm = revolutions per minute.
were readily accessible, important examples given the utility of
fluorine in medicinal chemistry settings. [21] Several THCs (16–
19) were formed in low yield (<20%), while other FIs failed alto-
gether (20–24).
ascertained upon milling a small sample with silica, a practice we
now routinely employ in our laboratory.
In the examples where yields were low (<20%) or the reaction
failed altogether, there does not appear to be a clear steric or elec-
tronic reason to support these outcomes. However, in the lower
yielding reactions, competing degradation pathways are clearly
apparent (TLC and 1H NMR analysis of the crude reaction mixture).
Thus, it appears the success of the solid-state FI is reliant on the
stability of the reaction components during ball-milling. This is
unsurprising as ball-milling has emerged as an effective technol-
ogy for the destruction of environmentally-persistent organic pol-
lutants [22]. To determine if a specific FI is compatible with a solid-
state process, the stability of the individual reactants can be readily
Conclusions
In summary,
a solid-state FI between phenylhydrazine
hydrochlorides and cyclohexanones occurs in the presence of silica
at ambient temperature to give THCs in variable yields. The success
of this reaction is reliant on both silica and HCl (from the phenyl-
hydrazine salt) being present, inferring the reaction may be pro-
moted by acidic surfaces resulting from adsorption of HCl onto
the silica. This clean process provides an alternative to a widely
employed heteroannulation reaction typically reliant on
Brønsted/Lewis acids, organic solvents and elevated temperatures.
3

Y. Qiu, Kararaina Te Puni, C.C. Duplan et al.
Tetrahedron Letters 72 (2021) 153068
Scheme 2. Solid-state synthesis of THCs. aPhenylhydrazine.HCl and cyclohexanone were added in equimolar amounts (1.38 mmol) to silica (1 g) in a 12 mL stainless steel jar
filled to 1/3 capacity with stainless steel balls (5 mm; 14.6 g total). All reactions conducted in a Retsch PM 100 planetary ball-mill.
313. (b) D.P. Chakraborty. In Alkaloids; G.A. Cordell, Ed.; Academic Press: New
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Chemistry, 3rd Ed.; Chapman and Hall: London, 1995; p. 330; (d) F. Tan, H-G.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Cheng. Chem. Commun. 2019; 55: 6151–6164.
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Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.153068.
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