One-pot, three-component Fischer indolisation-N-alkylation for rapid synthesis of 1,2,3-trisubstituted indoles

Article abstract of DOI:10.1039/d0ob02185g

A one-pot, three-component protocol for the synthesis of 1,2,3-trisubstituted indoles has been developed, based upon a Fischer indolisation-indoleN-alkylation sequence. This procedure is very rapid (total reaction time under 30 minutes), operationally straightforward, generally high yielding and draws upon readily available building blocks (aryl hydrazines, ketones, alkyl halides) to generate densely substituted indole products. We have demonstrated the utility of this process in the synthesis of 23 indoles, benzoindoles and tetrahydrocarbazoles bearing varied and useful functionality.

Full text of DOI:10.1039/d0ob02185g

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One-pot, three-component Fischer indolisation–N-alkylation for rapid synthesis of 1,2D,3O-I: 10.1039/D0OB02185G
trisubstituted indoles
Christopher A. Hughes-Whiffinga and Alexis Perrya*
a – Biosciences, University of Exeter, Stocker Road, Exeter EX4 4QD, UK.
* – A.Perry@Exeter.ac.uk
Abstract
A one-pot, three-component protocol for the synthesis of 1,2,3-trisubstituted indoles has been
developed, based upon a Fischer indolisation–indole N-alkylation sequence. This procedure is very
rapid (total reaction time under 30 minutes), operationally straightforward, generally high yielding
and draws upon readily available building blocks (aryl hydrazines, ketones, alkyl halides) to generate
densely substituted indole products. We have demonstrated the utility of this process in the
synthesis of 23 indoles, benzoindoles and tetrahydrocarbazoles bearing varied and useful
functionality.
Introduction
Indoles are prominent in natural and non-natural products of biological and pharmaceutical
importance, and are often considered as a “privileged scaffold” within the drug discovery arena.1,2
Furthermore, they are versatile building blocks in synthesis, providing access to diverse heterocycles
(e.g. tryptolines,3 spiropyrans,4 indolines,5 oxindoles6 and spirocycles7), substrates for asymmetric
dearomatisation,8,9 and polymers and composite materials with energy storage and biomedical
applications.10-12 Accordingly, indole synthesis has a long and distinguished history, and the many
published protocols for generating and elaborating the indole core ensure that few indole structures
are beyond the reach of the present-day synthetic chemist.13-17 Our recent studies into structurally-
diverse spiropyrans4,18 required a broad range of 1,2,3-trisubstituted indole building blocks and, to
meet this demand, we have developed a rapid, cheap and concise one-pot, three-component
sequence for their synthesis, based upon Fischer indolisation–N-alkylation, and the evolution of this
process is described herein.19 One-pot, multistep regimens can provide efficiency in terms of time,
cost, yield, labour, energy and consumables,20-22 and the combination of Fischer indole synthesis and
indole N-alkylation is inherently geared towards successful application as a rapid one-pot process for
two principal reasons: (i) Fischer indolisation and indole N-alkylation are robust, clean, high-yielding
processes which generate minimal quantities of by-products or leftovers, hence are ideal within one-
pot, multicomponent reaction cascades; (ii) indole N-alkylation is rapid (commonly <1 hour) and
whilst Fischer indolisation displays more varied reaction rate, use of microwave irradiation often
leads to short reaction times (<10 minutes).23 A further benefit to this Fischer indolisation–N-
alkylation approach is that a broad range of structurally-diverse starting materials are commercially
available for each of the aryl hydrazine, ketone and alkyl halide components, hence the process is
amenable to rapid generation of trisubstituted indole libraries.
There is considerable precedence for the use of multicomponent reaction cascades in indole
synthesis, often combining aryl hydrazone formation with Fischer indolisation (e.g. via addition of
metalloimines to aryl hydrazines,24 via addition of diazonium salts to acid chlorides25 or via Heck
26
isomerisation (see Scheme 1, a-c respectively)), although non-hydrazone-based methodologies –
e.g. Sonagashira coupling preceding intramolecular hydroamination27 (Scheme 1d) – have also
proved successful. Generally, simple 1,2,3-trisubstituted indoles have been obtained by stepwise

Organic & Biomolecular Chemistry
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Fischer indolisation–N-alkylation,18 whilst modern techniques have accessed related indDoOleI:s10b.1e0a39ri/nD0gOB02185G
more complex functionality (e.g. via rhodium carbene insertions,28 transition metal catalysed C-H/N-
H functionalisation,29 Cu(I)-catalysed imine cyclisations30 and on a solid support).31,32
Recent examples of one-pot, multicomponent indole synthesis:
(a) Ganem
R1
R3
R1
R2CN
1. Et2O
R2
NH
3 Cl
N
R3CH2Li
2. AcOH
N
H
H
(b) El Kaïm:
R1
R2XH
Ar(R3)N2+BF4
O
R3
1. Pyridine
2. AcOH
O
-
R1
Cl
XR2
N
H
(c) Müller:
R3
Ar
R1
1. [Pd], Cy2NMe
70 C (MW)
Br Ar
R3
NH
3 Cl
OH
N
R2
2. 220 C (MW)
N
R2
R1
(d) Ackermann:
R1
R1
Cl
[Pd], [Cu], base
R2
H
R2
N
R3
H2NR3
I
This work:
R1
R2
R1
R2
R4X, base
R3
NH
3 Cl
N
R4
N
O
R3
H
Scheme 1 – Precedence for multicomponent reactions in indole synthesis (a-d; references 19-22
respectively), and (lower) the methodology described in this publication.
Despite the congested nature of this field of research, we consider that the one-pot Fischer
indolisation–N-alkylation process documented herein is complementary to current methods,
especially given its speed and simplicity, and the commercial availability of diverse substrates. This is
fundamentally useful, robust methodology and we envisage that it will be adopted for rapid,
straightforward access to a broad range of 1,2,3-trisubstituted indole structures.
Results and Discussion
Our strategy to identify optimal conditions for Fischer indolisation–indole N-alkylation was based on
the premise that N-alkylation would present limited tolerance for varied reaction conditions, hence
the more adaptable conditions for Fischer indolisation should be directed to accommodate the
subsequent alkylation as much as possible. Classical conditions for indole N-alkylation employ indole,
sodium hydride and alkyl halide in DMF or THF, and often proceed in excellent yield and with high
selectivity for N- over C-alkylation, though with caveats around reagent toxicity, limitations in
substrate scope through use of strong base, and the sometimes unpredictable behaviour of hydride
in DMF on a large scale.33 Whilst various alternative N-alkylation processes have been documented
(e.g. alkylation with alcohols via Mitsunobu conditions34 or transition metal catalysis;35 Brønsted acid
catalysed aza-Michael addition;36 transition metal catalysed allylation37) all have their strengths and
weaknesses, and the simplicity and off-the-shelf nature of the classical method was more consistent

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DOI: 10.1039/D0OB02185G
with our approach, hence we considered this as the optimum alkylation to explore within this one-
pot sequence.
In adopting alkylation methodology based around generation of a sodium indole salt using sodium
hydride, we necessarily constrained conditions for the preceding Fischer indolisation – i.e. a
minimum of acid should be employed and only sodium hydride-tolerant solvents would be
appropriate – without compromising reaction rate, yield or practical convenience. To achieve this,
we employed microwave-promoted Fischer indole synthesis (several studies have documented
considerable rate acceleration over standard thermal heating for this process)23,38,39, using 1
equivalent of acid (most conveniently through use of hydrazine hydrochloride salts) and proceeding
in ethereal solvents (DMF is unstable under microwave heating)40. Our initial investigations briefly
explored the influence of solvent on the reaction between phenylhydrazine hydrochloride (1) (1 eq.)
and butanone (2) (1.05 eq.), to give 2,3-dimethylindole (3), at 150 °C for 15 minutes (max 300 W)
(see Table 1). In THF, 2-MeTHF and cyclopentyl methyl ether (CPME) (0.63 M), Fischer indolisation
was clean and high-yielding (Table 1, entries 1-3), whereas reaction in the absence of solvent41 was
less effective (entry 4). To reduce solvent usage, the reaction could be performed with equal success
at concentrations of up to 2.1 M in THF; further increase in concentration caused erosion of yield
(entries 5 and 6). Subsequently, we optimised reaction time and temperature in THF: (i) reaction at
100 °C proved ineffective (entry 7), whereas reaction at 125 °C took only marginally more time to
reach completion than at 150 °C (conversion 97% vs >99% after 15 mins); (ii) At 125 °C or above, the
reaction reached 95% conversion within 5 minutes (entries 9 and 10); (iii) at 150 °C, the reaction was
complete after 10 minutes (entry 11). Given that we were identifying conditions for the first step of
a one-pot, two-step sequence, our main priority was that the reaction should reach completion to
avoid unreacted starting materials interfering with subsequent N-alkylation. Correspondingly, we
adopted 10 minutes at 150 °C in THF as our optimal conditions, whilst acknowledging that, for given
specific substrates, milder conditions may be attainable. Finally, in order to explore the effect of
microwave irradiation in promoting this reaction, a control experiment was performed using
standard thermal heating at 125 °C in a sealed tube for 15 minutes. In this case, we observed
conversion of 64%, whilst the corresponding microwave-irradiated replicate reached 97% (entry 8),
thus it seems likely that microwave irradiation has a role in rate acceleration for this reaction beyond
a straightforward thermal effect.
O
2
NH3Cl
Conditions:
See Table 1
N
H
1
N
H
3
Entrya
1
2
3
4
5
6
7
8
9
10
11
T / °C
150
150
150
150
150
150
100
125
125
150
150
t / mins
15
15
15
15
15
15
15
15
5
Solvent
THF
2-MeTHF
CPME
None
THF
THF
THF
THF
THF
Conc / M
0.63
0.63
0.63
-
2.1
6.3
2.1
2.1
Conv. / %b
>99
94
93
71
>99
75
42
97
95
Yield / %c
96
92
92
64
-
-
-
-
-
2.1
2.1
2.1
5
10
THF
THF
98
>99
-
96

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12d
125
15
THF
2.1
64
-
a – Reactions were conducted using phenylhydrazine·HCl (1) (99 mg, 0.682 mmol, 1 eq.), butanone
(2) (64 µL, 0.716 mmol, 1.05 eq) and solvent in thick-walled microwave vials sealed with septa, and
heated to the specified temperature using microwave irradiation (maximum of 300 W). Reactions
were then held at the specified temperature for the specified time; b – Based on ratio of
phenylhydrazine·HCl : dimethylindole, estimated by analysis of crude reaction mixtures using 1H
NMR; c – Isolated yield; d – heated using an oil bath, all other parameters as previously described.
We then explored conditions for the indole N-alkylation step of this two-step process. 2,3-Dimethyl
indole was generated using the optimum conditions as described above, then deprotonation (with
sodium hydride) and alkylation (with benzyl bromide) were investigated directly on this crude
reaction mixture (which we assumed to consist of 2,3-dimethylindole (1 eq.), water (1 eq.),
ammonium chloride (1 eq.) and THF (300 µL)). Our previous experience of indole N-alkylation (as an
isolated reaction) identified DMF as a superior solvent to THF and 2-MeTHF,18 hence we were keen
to employ DMF to promote the alkylation step in this one-pot sequence. Furthermore, in our hands,
N-alkylation performs similarly in anhydrous or non-dried DMF, thereby enabling development of an
operationally straightforward process without requirement for rigorously anhydrous reaction
conditions. The instability of DMF towards aqueous acid defined the order of addition of reagents in
this process: sodium hydride was added first (to quench the ammonium chloride and water, and
deprotonate the indole), then DMF was added, then benzyl bromide. Our initial foray employed 3
eq. NaH then 1 mL of DMF, then allowed 5 minutes for deprotonation prior to introduction of benzyl
bromide. After 1 h, the quenched reaction mixture contained a 20:48:32 mixture of unalkylated 2,3-
dimethylindole (3), the desired 1-benzyl-2,3-dimethylindole (4a) and 2,3-dimethyl-3-
benzylindolenine (5) (i.e. the product of competing C-3 alkylation)(Table 2, entry 1), and this ratio
remained unchanged with longer reaction times or an increase in benzyl bromide quantity (entry 2).
Complete consumption of dimethylindole 3 was achieved through use of 4 eq. of sodium hydride,
however, this did not suppress reaction through C-3 (entry 3). Use of ethereal solvents THF, CPME
and 2-MeTHF in place of DMF resulted in poorer regioselectivity and precipitation of (presumably)
the indole sodium salt; in each case, 2,3-dimethylindole was the predominant product within
complex product mixtures (entries 4, 5 and 6). With respect to competing C-3 alkylation, our
suspicion was that incomplete deprotonation was allowing direct reaction of 2,3-dimethylindole
with benzyl bromide (via C-3), and this was due to poor solubility of hydride and the indole anion in
solvent mixtures containing THF. This hypothesis was supported by the observation that alkylation in
media containing an increased proportion of DMF displayed a slight but significant shift towards
reaction through nitrogen (compare entries 3 and 7). It is also plausible that reaction of the indole
anion itself through C-3 was further compromising regioselectivity, despite the kinetic and
thermodynamic favourability of N-alkylation.42,43 In either case, there is an argument to suggest that
higher reaction temperatures should favour alkylation through nitrogen; accordingly, we repeated
our protocol (hydride addition, DMF addition, stir 5 minutes then BnBr addition) with heating
applied to the reaction vessel following DMF addition. Whilst reactions at 50 °C and 65 °C offered
modest improvements in regioselectivity, we were delighted to observe complete N-alkylation at 80
°C, and this corresponded to 91% isolated yield (96% per step) of the desired 1,2,3-trisubstituted
indole 4a. Further development of this process identified that the DMF volume could be halved
without detriment at this elevated temperature (entry 11) (further reduction resulted in reduced
regioselectivity) and that alkylation was complete in under 15 minutes (entries 12 and 13).

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DOI: 10.1039/D0OB02185G
O
2
Bn
NaH, BnBr
NH3Cl
+
Conditions:
See Table 1,
entry 11
Conditions:
See Table 2
N
N
N
N
H
H
Bn
1
3
4a
5
Entrya
NaH /
BnBr / Solventc
eqb
Volume Td / °C
/ mL
te / mins 3:4a:5f
Yieldg 4a
/ %
eqb
3
1
2
3
4
5
6
7
8
1.05
2.1
DMF
DMF
DMF
THF
1
22
22
22
22
22
22
22
50
65
80
80
80
80
60
60
60
60
60
60
60
60
60
60
60
30
15
20:48:32 42
3
4
4
4
4
4
4
4
4
4
4
4
1
1
1
1
20:48:32
0:63:37
52:17:31
56:14:30
55:22:23
0:72:28
0:78:22
0:80:20
0:100:0
0:100:0
0:100:0
0:100:0
-
59
-
-
-
66
74
75
91
90
91
89
1.05
1.05
1.05
1.05
1.05
1.05
1.05
1.05
1.05
1.05
1.05
2-MeTHF
CPME
DMF
DMF
DMF
DMF
DMF
DMF
DMF
1
2
1
1
9
10
11
12
13
1
0.5
0.5
0.5
a – Benzylations were performed directly on the crude reaction mixture of Fischer indolisation,
derived using the conditions defined by Table 1, entry 11 (i.e. microwave promoted reaction of
phenylhydrazine·HCl (99 mg, 0.682 mmol, 1 eq.) and butanone (64 µL, 0.716 mmol, 1.05 eq) in THF
(0.3 mL) at 150 °C for 10 minutes). After cooling to room temperature, NaH was added to this crude
mixture, then solvent, and the mixture was stirred for 5 minutes before addition of BnBr; b – Molar
equivalents based upon phenylhydrazine·HCl (0.682 mmol, 1 eq.); c – Standard “bench” non-
anhydrous solvents were used; d – Heating commenced following solvent addition; e – Reaction time
following addition of BnBr; f – ratio estimated by analysis of crude reaction mixtures using 1H NMR; g
– Isolated yield from phenylhydrazine·HCl.
In order to validate this one-pot approach, we performed a control experiment evaluating the
analogous stepwise pathway as a point of comparison for our optimum conditions (defined in Table
2, entry 13), in terms of yield, time, material and energy costs (a full breakdown of which is available
in the supporting information). For Fischer indolisation, we employed our microwave promoted
conditions (Table 1, entry 11) followed by standard aqueous work-up/organic extraction and
purification using silica gel chromatography, whilst N-alkylation was performed using standard
published conditions (1.0 eq. indole, 1.2 eq. NaH, 1.1 eq. BnBr, DMF (0.4 M), RT, 1 hour), followed by
a methanol quench and direct silica gel chromatography. In terms of yield, the one-pot approach
offered a modest advantage over its stepwise analogue (one-pot, 91%; stepwise, 84%), however,
more stark contrasts were evident in terms of time and consumable consumption. The total time,
from empty reaction vessel to pure indole product, for the one-pot method was 103 minutes,
whereas the stepwise approach required 268 minutes. Whilst it is harder to quantify working hours
(given the variable efficiencies of laboratory workers and differing intensities of laboratory tasks),
the extra chromatography, aqueous work-up and washing up in the stepwise protocol contribute to
a more labour intensive process. These same additional processes were also instrumental in the use
of an extra 971 mL of organic solvent over the one-pot route (one-pot: 723 mL total, 1.16 L solvent /
mmol product; stepwise: 1694 mL total, 2.96 L solvent / mmol product), and silica and TLC plate
usage doubled. On the other hand, the one-pot route carries two disadvantages: (i) a requirement

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DOI: 10.1039/D0OB02185G
for 3.3x more sodium hydride; (ii) 15 minutes of heating at 80 °C is necessary, corresponding to an
extra 0.02 kWh over the stepwise protocol.
We then investigated the substrate scope of this one-pot, two-step process in terms of its hydrazine,
ketone and alkyl halide components, using the optimised conditions identified above (see Table 2,
entry 12). In general, a wide variety of functionality could be tolerated – derived from each of these
three components – rapidly generating 1,2,3-trisubstituted indoles in high yield. We successfully
incorporated useful functional groups for further elaboration, including alkenes, alkynes,
heteroaromatics, carboxylates and halides, and we were able to access related heterocyclic
structures such as tetrahydrocarbazoles, tetrahydrocyclopentaindoles and benzoindoles, and
hindered indoles such as 4i and 4k. Carboxylic acid 4n was derived from in-situ basic hydrolysis of
the corresponding ester (the reaction sequence generates 1 eq. of hydroxide) and we suspect that
the modest yield of 4n can be attributed to partial decarboxylation: indole 2-carboxylic acids are
susceptible to acidic, basic, thermal and microwave-promoted decarboxylation (all evident
conditions in this reaction sequence),44-46 and 1H NMR analysis of the crude reaction mixture
revealed the presence of decarboxylated indole. The reaction sequence was unsuccessful with
nitrophenylhydrazine (electron poor hydrazones are often unwilling substrates in Fischer
indolisation),47,48 with enolisable ester-based alkylating agents, or with unactivated secondary
alkylating agents (see products 4x-z respectively). Given that hindered, secondary electrophiles are
documented as challenging substrates for indole alkylation,37 it is encouraging that a secondary
benzyl halide was tolerated in this study, to give indole 4v, albeit in somewhat modest yield.
Somewhat surprisingly, iodomethane was a less effective substrate in this reaction cascade and 2.5
eq were required to achieve satisfactory yields. Presumably this can be attributed to the volatility of
this reagent at 80 °C, despite the reaction occurring in a sealed tube.

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R2
R1
R1
THF, MW, 150 o
C
O
Cl
R3
R2
NH3
R3
then NaH, DMF,
R4-X, 80 o
N
N
R4
H
C
R
N
N
N
Bn
F
4b, R=H, 89%
4c, R=Me, 98%
4d, R=Br, 75%
4e, R=OMe, 72%
4f, 80%
4g, 78%
R
n
R3
N
R
N
N
R4
4h, R=Et, 97%
4i, R=iPr, 95%
4j, R=Bn, 91%
4k, R=C6H4Br, 67%
4o, n=1, R=Me, 74%
4p, n=2, R=Me, 85%
4q, n=2, R=Bn, 72%
4r, n=3, R=Me, 80%
4l, R3=Et, R4=Me, 92%
4m, R3=Ph, R4=Bn, 85%
4n, R3=CO2H, R4=Bn, 57%
4s, R= nHexyl, 93%
4t, R=
, 63%
4v, R=
4w, R=
Ph
, 92%
, 70%
N
R
4u, R=
, 87%
N
N
O2N
N
N
4x
4y
4z
EtO
O
Table 3 – Scope of one-pot Fischer indolisation–N-alkylation. Reactions were conducted using
conditions defined in Table 2, entry 12, using varied hydrazine hydrochloride (0.682 mmol), ketone
(0.716 mmol, 1.05 eq.) and alkyl halide (0.716 mmol, 1.05 eq.) components. N-Methylated products
4b-f, 4h-l, 4o-p, and 4r were synthesised using iodomethane (1.71 mmol, 2.5 eq.). Yields refer to
isolated compounds. Attempted synthesis of 4x-4z was unsuccessful using this procedure.
Conclusions
In summary, we have developed methodology that enables rapid, straightforward and generally high
yielding synthesis of 1,2,3-trisubstituted indoles via one-pot, three-component Fischer indolisation–
indole N-alkylation, in a process that requires neither anhydrous nor inert reaction conditions. The
reaction sequence draws upon cheap, widely available substrates to incorporate diverse and useful
functionality onto the indole nucleus and provides a fundamentally practical and robust approach to
these valued heterocycles. Finally, we have attempted to quantify the benefits of our one-pot, two-
reaction approach over its stepwise counterpart in terms of economy and efficiency, and this has
provided concrete evidence for the effectiveness of this one-pot strategy.
Experimental
General Experimental Information

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Solvents and reagents were used as commercially supplied and no anhydrous solvents were
employed. Analytical thin layer chromatography was carried out using Merck Kieselgel 60 F254,
coated on aluminium plates, with visualisation of spots where necessary by quenching of UV(254
nm) fluorescence. Silica gel with particle size 40–63 mm was used for flash chromatography.
Microwave reactions were performed in a CEM Discover microwave in 10 mL, thick-walled
microwave tubes, sealed with septum caps and were magnetically stirred. Infrared spectra were
recorded as thin films using attenuated total reflectance with a Nicolet iS5 FTIR spectrometer. Mass
spectra were recorded on a QToF 6520 mass spectrometer (Agilent Technologies, Palo Alto, USA). 1H
NMR and 13C NMR spectra were recorded at 400 MHz and 100 MHz respectively, using a Bruker
Avance III HD400 spectrometer. Chemical shifts are quoted in ppm relative to tetramethylsilane, the
residual solvent peak being used for referencing purposes. Coupling constants are quoted to the
nearest 0.1 Hz with peak multiplicities for single resonances being labelled as: s, singlet; d, doublet;
t, triplet; q, quartet; m, unresolved multiplet. Complete and unambiguous assignment of 1H and 13
NMR spectra was achieved through use of COSY, NOESY, HSQC and HMBC experiments.
C
Synthetic Methods and Characterisation Data
General Procedure, illustrated by the synthesis of 1-benzyl-2,3-dimethylindole 4a
Butanone (64 µL, 0.716 mmol, 1.05 eq.) was added to a stirred suspension of phenylhydrazine
hydrochloride (99 mg, 0.682 mmol, 1 eq.) in THF (300 µL) in a thick-walled microwave tube. The tube
was capped with a septum and heated to 150 °C using microwave irradiation (maximum power =
300 W; time to reach 150 °C = 3.5 minutes), then held at this temperature for 10 minutes. After
cooling to room temperature, sodium hydride (110 mg of a 60% dispersion in mineral oil, 2.51 mmol,
4 eq.) then DMF (500 µL) were cautiously added in small portions to the stirred reaction mixture,
which was then recapped and heated to 80 °C using an oil bath. After 5 minutes, benzyl bromide (85
µL, 0.716 mmol, 1.05 eq.) was carefully added, and the resulting mixture was capped and stirred at
80 °C for 30 minutes, then quenched by dropwise addition of methanol and concentrated under
reduced pressure. The crude indole was purified by flash chromatography, eluting with 3% ethyl
acetate in hexane, to give 1-benzyl-2,3-dimethylindole 4a (146 mg, 91%) as a yellow oil,
spectroscopically identical to that previously reported.18
1,2,3-Trimethylindole 4b
By the same general method, butanone (64 µL, 0.716 mmol, 1.05 eq.), phenylhydrazine
hydrochloride (99 mg, 0.682 mmol, 1 eq.) and iodomethane (106 µL, 1.71 mmol, 2.5 eq.) gave 1,2,3-
trimethylindole 4b (97 mg, 89%) as a yellow oil, spectroscopically identical to that previously
reported.18
1,2,3,5-Tetramethylindole 4c
By the same general method, butanone (64 µL, 0.716 mmol, 1.05 eq.), p-tolylhydrazine
hydrochloride (108 mg, 0.682 mmol, 1 eq.) and iodomethane (106 µL, 1.71 mmol, 2.5 eq.) gave
1,2,3,5-tetramethylindole 4c (116 mg, 98%) as a red oil, spectroscopically identical to that previously
reported.4
5-Bromo-1,2,3-trimethylindole 4d
By the same general method, butanone (64 µL, 0.716 mmol, 1.05 eq.), 4-bromophenylhydrazine
hydrochloride (152 mg, 0.682 mmol, 1 eq.) and iodomethane (106 µL, 1.71 mmol, 2.5 eq.) gave 5-
bromo-1,2,3-trimethylindole 4d (112 mg, 75%) as an amorphous orange solid, spectroscopically
identical to that previously reported.4
5-Methoxy-1,2,3-trimethylindole 4e

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By the same general method, butanone (64 µL, 0.716 mmol, 1.05 eq.), 4-methoxyphenyDlhOyI:d1r0a.1z0i3n9e/D0OB02185G
hydrochloride (119 mg, 0.682 mmol, 1 eq.) and iodomethane (106 µL, 1.71 mmol, 2.5 eq.) gave 5-
methoxy-1,2,3-trimethylindole 4e (94 mg, 72%) as an amorphous blue solid, spectroscopically
identical to that previously reported.49
7-Fluoro-1,2,3-trimethylindole 4f
By the same general method, butanone (64 µL, 0.716 mmol, 1.05 eq.), 2-fluorophenylhydrazine
hydrochloride (111 mg, 0.682 mmol, 1 eq.) and iodomethane (106 µL, 1.71 mmol, 2.5 eq.) gave 2-
fluoro-1,2,3-trimethylindole 4f (97 mg, 80%) as a yellow oil, spectroscopically identical to that
previously reported.50
1-Benzyl-2,3-dimethylbenzo[g]indole 4g
By the same general method, butanone (64 µL, 0.716 mmol, 1.05 eq.), 1-naphthylhydrazine
hydrochloride (133 mg, 0.682 mmol, 1 eq.) and benzyl bromide (85 µL, 0.716 mmol, 1.05 eq.) gave 1-
benzyl-2,3-dimethylbenzo[g]indole 4g (140 mg, 78%) as an amorphous yellow solid,
spectroscopically identical to that previously reported.51
3-Ethyl-1,2-dimethylindole 4h
By the same general method, 2-pentanone (76 µL, 0.716 mmol, 1.05 eq.), phenylhydrazine
hydrochloride (99 mg, 0.682 mmol, 1 eq.) and iodomethane (106 µL, 1.71 mmol, 2.5 eq.) gave 3-
ethyl-1,2-dimethylindole 4h (115 mg, 97%) as an brown oil, spectroscopically identical to that
previously reported.18
3-Isopropyl-1,2-dimethylindole 4i
By the same general method, 4-methylpentan-2-one (90 µL, 0.716 mmol, 1.05 eq.), phenylhydrazine
hydrochloride (99 mg, 0.682 mmol, 1 eq.) and iodomethane (106 µL, 1.71 mmol, 2.5 eq.) gave 3-
isopropyl-1,2-dimethylindole 4i (121 mg, 95%) as an amorphous brown solid, spectroscopically
identical to that previously reported.4
3-Benzyl-1,2-dimethylindole 4j
By the same general method, 4-phenylbutan-2-one (107 µL, 0.716 mmol, 1.05 eq.), phenylhydrazine
hydrochloride (99 mg, 0.682 mmol, 1 eq.) and iodomethane (106 µL, 1.71 mmol, 2.5 eq.) gave 3-
benzyl-1,2-dimethylindole 4j (144 mg, 91%) as an orange oil, spectroscopically identical to that
previously reported.4
3-(4-Bromophenyl)-1,2-dimethylindole 4k
By the same general method, 4-bromophenylacetone (107 µL, 0.716 mmol, 1.05 eq.),
phenylhydrazine hydrochloride (99 mg, 0.682 mmol, 1 eq.) and iodomethane (106 µL, 1.71 mmol,
2.5 eq.) gave 3-(4-bromophenyl)-1,2-dimethylindole 4k (145 mg, 67%) as an amorphous yellow solid,
spectroscopically identical to that previously reported.4
2-Ethyl-1,3-dimethylindole 4l
By the same general method, 3-pentanone (76 µL, 0.716 mmol, 1.05 eq.), phenylhydrazine
hydrochloride (99 mg, 0.682 mmol, 1 eq.) and iodomethane (106 µL, 1.71 mmol, 2.5 eq.) gave 2,3-
diethyl-1-methylindole 4l (109 mg, 92%) as an orange oil, spectroscopically identical to that previous
reported.52
1-Benzyl-3-methyl-2-phenylindole 4m
By the same general method, propiophenone (95 µL, 0.716 mmol, 1.05 eq.), phenylhydrazine
hydrochloride (99 mg, 0.682 mmol, 1 eq.) and benzyl bromide (85 µL, 0.716 mmol, 1.05 eq.) gave 1-

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DOI: 10.1039/D0OB02185G
benzyl-3-methyl-2-phenylindole 4m (172 mg, 85%) as an amorphous colourless solid,
spectroscopically identical to that previously reported.53
1-Benzyl-3-methylindole-2-carboxylic acid 4n
By the same general method, methyl 2-oxobutanoate (78 µL, 0.716 mmol, 1.05 eq.),
phenylhydrazine hydrochloride (99 mg, 0.682 mmol, 1 eq.) and benzyl bromide (85 µL, 0.716 mmol,
1.05 eq.) gave 1-benzyl-3-methylindole-2-carboxylic acid 4n (103 mg, 57%) as a colourless
amorphous solid, Rf 0.2 (5% ethyl acetate in hexane); νmax = 3335, 3060, 3033, 2928, 1680, 1546,
1334, 1243, 1190, 1098 and 742 cm–1; δH(400 MHz, CDCl3) 8.59 (1 H, br s, OH), 7.59 (1 H, d, J 8.0, 4-
H), 7.40 (2 H, d, J 7.0, Bn 2- and 6-H), 7.34 (2 H, t, J 7.0, Bn 3- and 5-H), 7.32–7.26 (2 H, m, Bn 4- and
7-H), 7.25 (1 H, t, J 8.0, 6-H), 7.07 (1 H, t, J 8.0, 5-H), 5.34 (2 H, s, CH2) and 2.58 (3 H, s, CH3); δC(100
MHz, CDCl3) 162.3 (C=O), 135.9 (7a), 135.9 (2), 128.7 (Bn3,5), 128.5 (Bn1), 128.4 (Bn4), 128.3 (Bn2,6),
128.3 (3), 125.8 (6), 123.0 (3a), 120.8 (4), 120.0 (5), 111.6 (7), 66.4 (CH2) and 10.1 (CH3); ES (m/z):
288 (55%, MNa+). This compound has been synthesised previously, but without publication of
characterisation data.54,55
4-Methyl-1,2,3,4-tetrahydrocyclopenta[b]indole 4o
By the same general method, cyclopentanone (63 µL, 0.716 mmol, 1.05 eq.), phenylhydrazine
hydrochloride (99 mg, 0.682 mmol, 1 eq.) and iodomethane (106 µL, 1.71 mmol, 2.5 eq.) gave 4-
methyl-1,2,3,4-tetrahydrocyclopenta[b]indole 4o (87 mg, 74%) as a brown oil, spectroscopically
identical to that previously reported.56
9-Methyl-2,3,4,9-tetrahydrocarbazole 4p
By the same general method, cyclohexanone (74 µL, 0.716 mmol, 1.05 eq.), phenylhydrazine
hydrochloride (99 mg, 0.682 mmol, 1 eq.) and iodomethane (106 µL, 1.71 mmol, 2.5 eq.) gave 9-
methyl-2,3,4,9-tetrahydrocarbazole 4p (108 mg, 85%) as an amorphous brown solid,
spectroscopically identical to that previously reported.56
9-Benzyl-2,3,4,9-tetrahydrocarbazole 4q
By the same general method, cyclohexanone (74 µL, 0.716 mmol, 1.05 eq.), phenylhydrazine
hydrochloride (99 mg, 0.682 mmol, 1 eq.) and benzyl bromide (85 µL, 0.716 mmol, 1.05 eq.) gave 9-
benzyl-2,3,4,9-tetrahydrocarbazole 4q (128 mg, 72%) as an orange oil, spectroscopically identical to
that previously reported.57
5-Methyl-5,6,7,8,9,10-hexahydrocyclohepta[b]indole 4r
By the same general method, cycloheptanone (85 µL, 0.716 mmol, 1.05 eq.), phenylhydrazine
hydrochloride (99 mg, 0.682 mmol, 1 eq.) and iodomethane (106 µL, 1.71 mmol, 2.5 eq.) gave 5-
methyl-5,6,7,8,9,10-hexahydrocyclohepta[b]indole 4r (119 mg, 80%) as an amorphous brown solid,
spectroscopically identical to that previously reported.58
1-Hexyl-2,3-dimethylindole 4s
By the same general method, butanone (64 µL, 0.716 mmol, 1.05 eq.), phenylhydrazine
hydrochloride (99 mg, 0.682 mmol, 1 eq.) and 1-bromohexane (100 µL, 0.716 mmol, 1.05 eq.) gave
1-hexyl-2,3-dimethylindole 4s (146 mg, 93%) as a red oil, Rf 0.3 (hexane); νmax = 2916, 2860, 1614,
1569, 1469, 1417, 1357, 1230, 1217, 1013 and 735 cm–1; δH(400 MHz, CDCl3) 7.40 (1 H, d, J 7.5, 4-H),
7.15 (1 H, d, J 7.5, 7-H), 7.05 (1 H, t, J 7.5, 6-H), 6.88 (1 H, t, J 7.5, 5-H), 3.95 (2 H, t, J 7.5, 1’-CH2), 2.26
(3 H, s, 2-CH3), 2.17 (3 H, s, 3-CH3), 1.68–1.56 (2 H, m, 2’-CH2), 1.33–1.17 (6 H, m, 3’-, 4’- and 5’-CH2)
and 0.80 (3 H, t, J 7.1, 6’-CH3); δC(100 MHz, CDCl3) 135.8 (7a), 132.1 (2), 128.5 (3a), 120.3 (6), 118.4
(5), 117.9 (4), 108.6 (7), 106.3 (3), 43.3 (1’), 31.6 (3’), 30.4 (2’), 26.8 (4’), 22.6 (5’), 14.1 (6’), 10.2 (2-
CH3) and 8.8 (3-CH3); HRMS-ES (m/z): Found: 230.1908 (MH+, C16H24N requires: 230.1908).

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2,3-Dimethyl-1-(pent-4-en-1-yl)indole 4t
By the same general method, butanone (64 µL, 0.716 mmol, 1.05 eq.), phenylhydrazineDOI: 10.1039/D0OB02185G
hydrochloride (99 mg, 0.682 mmol, 1 eq.) and 5-bromo-1-pentene (85 µL, 0.716 mmol, 1.05 eq.)
gave 2,3-dimethyl-1-(pent-4-en-1-yl)indole 4t (135 mg, 92%) as a red oil, Rf 0.2 (hexane); νmax = 3052,
2915, 2858, 1640, 1469, 1415, 1354, 1333, 1242, 1181, 1013, 992, 910 and 733 cm–1; δH(400 MHz,
CDCl3) 7.39 (1 H, d, J 7.1, 4-H), 7.13 (1 H, d, J 7.1, 7-H), 7.04 (1 H, t, J 7.1, 6-H), 6.97 (1 H, t, J 7.1, 5-H),
5.72 (1 H, ddt, J 16.3, 10.1, 7.0, 4’-H), 4.96 (1 H, dd, J 16.3, 1.6, 5’-H), 4.92 (1 H, dd, J 10.1, 1.6, 5’-H),
3.92 (2 H, t, J 7.0, 1’-CH2), 2.23 (3 H, s, 2-CH3), 2.16 (3 H, s, 3-CH3), 2.00 (2 H, q, J 7.0, 3’-CH2) and 1.70
(2 H, pentet, J 7.0, 2’-CH2); δC(100 MHz, CDCl3) 137.7 (4’), 135.9 (7a), 132.2 (2), 128.8 (3a), 120.5 (6),
118.8 (5), 118.1 (4), 115.5 (5’), 108.7 (7), 106.5 (3), 42.7 (1’), 31.3 (3’), 29.4 (2’), 10.3 (2-CH3) and 9.0
(3-CH3); HRMS-ES (m/z): Found: 214.1590 (MH+, C15H20N requires: 214.1595).
1-(Hex-5-yn-1-yl)-2,3-dimethylindole 4u
By the same general method, butanone (64 µL, 0.716 mmol, 1.05 eq.), phenylhydrazine
hydrochloride (99 mg, 0.682 mmol, 1 eq.) and 6-iodo-1-hexyne (94 µL, 0.716 mmol, 1.05 eq.) gave 1-
(hex-5-yn-1-yl)-2,3-dimethylindole 4u (134 mg, 87%) as a purple oil, Rf 0.2 (2% ethyl acetate in
hexane); νmax = 3056, 2917, 2860, 2587, 1469, 1357, 1230, 1242, 1217, 1013 and 734 cm–1; δH(400
MHz, CDCl3) 7.39 (1 H, d, J 7.5, 4-H), 7.14 (1 H, d, J 7.5, 7-H), 7.04 (1 H, t, J 7.5, 6-H), 6.98 (1 H, t, J 7.5,
5-H), 3.95 (2 H, t, J 7.3, 1’-CH2), 2.24 (3 H, s, 2-CH3), 2.16 (3 H, s, 3-CH3), 2.10 (2 H, dt, J 7.0, 2.6, 4’-
CH2), 1.86 (1 H, t, J 2.6, 6’-H), 1.79–1.70 (2 H, m, 2’-CH2) and 1.50–1.41 (2 H, m, 3’-CH2); δC(100 MHz,
CDCl3) 135.9 (7a), 132.1 (2), 128.6 (3a), 120.5 (6), 118.6 (5), 118.0 (4), 108.7 (7), 106.6 (3), 83.9 (5’),
69.0 (6’), 42.8 (1’), 29.5 (2’), 25.9 (3’), 18.3 (4’), 10.3 (2-CH3) and 9.0 (3-CH3); HRMS-ES (m/z): Found:
226.1583 (MH+, C16H20N requires: 226.1595).
2,3-Dimethyl-1-(1-phenylethyl)indole 4v
By the same general method, butanone (64 µL, 0.716 mmol, 1.05 eq.), phenylhydrazine
hydrochloride (99 mg, 0.682 mmol, 1 eq.) and (1-bromoethyl)benzene (98 µL, 0.716 mmol, 1.05 eq.)
gave 2,3-dimethyl-1-(1-phenylethyl)indole 4v (98 mg, 63%) as an amorphous yellow solid,
Rf 0.1 (hexane); νmax = 3016, 2970, 2946, 1441, 1365, 1229, 1217, 1091 and 747 cm–1; δH(400 MHz,
CDCl3) 7.41 (1 H, d, J 7.7, 4-H), 7.23–7.11 (3 H, m, Bn 3-, 4- and 5-H), 7.08 (2 H, d, J 7.8, Bn 2- and 6-
H), 6.96–6.85 (3 H, m, 5-, 6- and 7-H), 5.65 (1 H, q, J 7.1, CHCH3), 2.18 (6 H, s, 2- and 3-CH3) and 1.82
(3 H, d, J 7.1, CHCH3); δC(100 MHz, CDCl3) 140.8 (Bn1), 134.1 (7a), 131.3 (2), 128.1 (3a), 127.4
(Bn3,5), 125.9 (Bn4), 125.2 (Bn2,6), 119.2 (6), 117.4 (5), 116.9 (4), 109.5 (7), 106.2 (3), 51.2 (CHCH3),
17.6 (CHCH3), 10.1 (2-CH3) and 7.9 (3-CH3); HRMS-ES (m/z): Found: 250.1595 (MH+, C18H20N requires:
250.1595).
2,3-Dimethyl-1-((6-methylpyridin-2-yl)methyl)indole 4w
By the same general method, butanone (64 µL, 0.716 mmol, 1.05 eq.), phenylhydrazine
hydrochloride (99 mg, 0.682 mmol, 1 eq.) and 2-(bromomethyl)-6-methylpyridine (133 mg, 0.716
mmol, 1.05 eq.) gave 2,3-dimethyl-1-((6-methylpyridin-2-yl)methyl)indole 4w (120 mg, 70%) as an
amorphous yellow solid, Rf 0.3 (20% ethyl acetate in hexane); νmax = 3054, 2916, 2859, 1593, 1576,
1469, 1459, 1366, 1332, 1183 and 738 cm–1; δH(400 MHz, CDCl3) 7.46–7.41 (1 H, m, 4-H), 7.21 (1 H,
t, J 7.7, pyr 4-H), 7.09–7.04 (1 H, m, 7-H), 7.02–6.97 (2 H, m, 5- and 6-H), 6.87 (1 H, d, J 7.7, pyr 5-H),
6.08 (1 H, d, J 7.7, pyr 3-H), 5.28 (2 H, s, CH2), 2.49 (3 H, s, pyr CH3), 2.21 (3 H, s, 3-CH3) and 2.19 (3 H,
s, 3-CH3); δC(100 MHz, CDCl3) 157.0 (pyr 6), 156.5 (pyr 2), 136.3 (pyr 4), 135.2 (7a), 131.3 (2), 127.7
(3a), 120.7 (pyr 5), 119.8 (6), 118.0 (5), 117.0 (4), 115.8 (pyr 3), 107.7 (7), 106.2 (3), 47.5 (CH2), 23.3
(pyr CH3), 9.0 (2-CH3) and 7.9 (3-CH3); HRMS-ES (m/z): Found: 251.1544 (MH+, C17H19N2 requires:
251.1548).
Conflicts of Interest

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DOI: 10.1039/D0OB02185G
There are no conflicts to declare
Acknowledgements
We would like to thank Dr Debbie Salmon (Mass Spectrometry, University of Exeter) for recording of
mass spectra of novel compounds presented in this work.
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Electronic supplementary information (ESI) available: 1H NMR spectra for 4a-4w and 13C NMR
spectra for 4n and 4s-4w. Full details of time, energy and consumables analysis for one-pot and
stepwise syntheses of 4a.