Synthesis of substituted indoles using continuous flow micro reactors

Full text of DOI:10.1016/j.tet.2010.03.005

Tetrahedron 66 (2010) 3861–3865
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of substituted indoles using continuous flow micro reactors
,
Ben Wahab a, George Ellames b, Stephen Passey b, Paul Watts a
*
a Department of Chemistry, University of Hull, Cottingham Road, Hull, HU6 7RX, UK
b Isotope Chemistry and Metabolite Synthesis, sanofi-aventis, Alnwick Research Centre, Willowburn Avenue, Alnwick, Northumberland, NE66 2JH, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Continuous flow micro fluidic devices for organic synthesis (‘micro reactors’) are becoming established in
a number of facets of modern applied chemistry. As part of a concurrent research project with a pharma-
ceutical company for generation of materials of pharmaceutical interest within continuous flow environ-
ments, we present here, for the first time a series of indoles that have been produced within micro reactor
systems. We have developed three different approaches to the synthesis, which are compared with tradi-
tional batch synthesis as well as each other in terms of ease of optimization, chemical suitability and ver-
satility, and implications as to throughput. Typical throughputs of approach 1 (simulated classical synthesis)
were in the region of 2 mghꢀ1 of indoles such as tetrahydrocarbazole and cyclopentaindole. The second
approach (based on Elk’s modification of Fischer indole synthesis) gave throughputs of 5.7–8.9 mghꢀ1 and
the final approach (using heterocatalytic flow reactors) gave the highest throughputs of 12.7–20.1 mghꢀ1. All
throughputs are per single channel reactor system (i.e., one single reactor set up), and the latter two ap-
proaches produce viable output quantities for the syntheses of radiolabelled materials (where typically
minute amounts of high purity materials are required from a rapid and safe production environment).
Ó 2010 Elsevier Ltd. All rights reserved.
Received 29 November 2009
Received in revised form 7 February 2010
Accepted 1 March 2010
Available online 17 March 2010
1. Introduction
are looking towards micro reactors as a possible platform onwhich to
perform radiolabelled synthesis, where typically small amounts of
Micro reactors are comprised of a series of channels etched into
a solid substrate through which fluids are manipulated so as to
create a continuous flow reaction environment. In recent years
there has been much development in technologies used within
micro reactor groups, from the construction materials, to novel
pumping systems and elaborate micro- and nano-architecture. In
the work outlined in this paper, glass micro reactors are used due to
their chemical inertness and robust physical strength. These re-
actors are typically etched using HF to give channels of the di-
high purity materials are required rapidly with low human exposure.
mensions in the range of 50–200 mm wide by 50–75 mm deep and
are prepared as per the method outlined by McCreedy.1 Typical
channel shape and dimensions are shown in Figure 1.
Using micro reactors for synthesis offers a number of advantages
over conventional batch procedures, such as lower reagent con-
sumption (and thus lower waste generation), faster mixing times due
to minute diffusion distances, better thermal control brought about
by very large surface area to volume ratios of the reactor, and the fact
that the reactor array is a sealed system where there is no risk of
losses to the environment, and minimal human exposure to haz-
ardous reagents (being that the micro reactor itself acts as a primary
engineering control).2,3 For these reasons pharmaceutical companies
Figure 1. Micro reactor cross section demonstrating shape and typical dimensions.
In-line with a parallel investigation on the above topic of radio
synthesis, we have developed three methods for the synthesis of the
indole core. The indole unit is a well established pharmacophore due
to the fact that many biological species include the indole nucleus,
including serotonin (‘5-HT’, a neurotransmitter 1) and melatonin
(a master regulatory hormone 2) and as such the indole unit is
realised in many classes of pharmaceuticals from beta blockers (e.g.,
Pindolol 3), anti-inflammatory drugs (e.g., Indomethacin 4) and
migraine management (e.g., Zolmitriptan and Almotriptan) as well
* Corresponding author. E-mail address: p.watts@hull.ac.uk (P. Watts).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.03.005

3862
B. Wahab et al. / Tetrahedron 66 (2010) 3861–3865
as their use in anti-depressives and treatments for schizophrenia and
other psychological conditions.4–8
Gas tight syringes are loaded with the reagents, which are
pumped using a syringe pump (a simple motorized worm drive,
which provides a continuous, relatively pulse free driving force). The
syringes are linked to microbore tubing via low dead-volume luer
assemblies, which provide the step down in diameter from the sy-
ringe luer to the tubing diameter. The tubing then led directly into
the micro reactors via the ports drilled in the top plate of the reactor.
The tubing is supported in place using an epoxy based adhesive.
The first and simplest of the three approaches discussed in this
report is the direct conversion of the commonly used classical batch
methodology to a homogenous continuous flow system. Figure 5
demonstrates the micro reactor set up used to indolise the ketone
series 10–13 (Table 1).
Substituted indoles (such as those shown in Fig. 2) have been
a topic of interest for over a century since Fischer’s first report some
120 years ago.9 Today, there are a number of routes to the indole unit
but the most commercially used is still the Fischer method Fig. 3 as its
versatility, availability of the starting reagents and the range of suit-
able catalysts and solvents make it viable on an industrial scale. The
development of continuous flow systems for the synthesis of indoles
has been briefly touched upon in the innovative works of Bagley et al.
whodevelopedanovelmicrowave-irradiatedcontinuousflowsystem
for the synthesis of 1,2,3,4-tetrahydro-1H-carbazole 5,10 and also the
works of Kappe et al., who utilised high temperature and high pres-
sure to produce 5 using custom pressurised continuous flow reactors
to allow solvent temperatures to exceed their normal boiling points.11
We have focused our efforts on the development of the Fischer
indole synthesis for continuous flow micro reactor environments
using conventional heating and simpler, more available devices and
we now present our results.
NH2
O
HN
HO
O
N
H
1
2
N
H
Figure 5. Schematic of micro reactor set up for homogeneous indolisation (approach 1).
O
O
The reactor allowed for a mixing period in which the ketone and
phenylhydrazine could react in order to form the phenylhydrazone
in situ, and then mixed methanesulfonic acid (MSA) as a catalyst,
which on heating rendered the indole at the channel output. This
system gave reasonable first results (e.g., 98% conversion from cycꢀlo1-
HN
OH
N
O
O
N
hexanone to 1,2,3,4-tetrahydro-1H-carbazole at 160 ꢁC, 2.3 mgh
)
H
OH
Cl
but there were problems associated with high backpressures and
insolubility at high concentrations, which led to channel blocking
and seal breaches at the luer and syringe plunger. Protic solvents
such as alcohols make good reaction solvents for indolisation;
however the low boiling points of short chain alcohols (Cꢂ4) lim-
ited the temperature of the system. Larger alcohols have issues
solubilising the intermediates. High boiling solvents tend to have
higher viscosities (e.g., DMSO vs ethanol, n20¼2.14 and 1.20 mPa,
respectively), which did not alleviate the pressure problems. A
compromise of DMSO doped with 10% EtOH allowed for solubility
and the required protic nature of the solvent to be fulfilled. Reagent
concentration was limited to 0.1 M as solubility of the phenyl-
hydrazone species was restrictive. In the case of cyclohexanone and
cyclopentanone (ketones 11 and 12, respectively) temperatures
were capped at 175 ꢁC, and discolouration of the solution stream
was seen. Throughputs were limited by the back-pressures gener-
ated within the system, but high conversions of the simpler ketones
such as butan-2-one 10 were as high as 98%, offering throughputs
of 2.0 mghꢀ1). Both the cyclic ketones cyclised efficiently (cyclo-
pentanone gave 86% conversion to the cyclopentaindole 15, and
cyclohexanone gave 98% conversion to the tetrahydrocarbazole 5
(giving throughputs of 2.3 and 1.9 mghꢀ1, respectively). However
ethyl pyruvate would not cyclise. In the application for which these
reactors were developed, the throughputs produced by this
method were considered non-viable.
3
4
Figure 2. Selected pharmaceutically important indoles.
R'
R'
NH2
O
N
R
H
H+
heat
7
R
R
N
N
R'
N
H
6
H
8
9
Figure 3. Fischer indole synthesis where the ketone (6), is reacted with phenyl-
hydrazine (7) to form the phenylhydrazone (8), which is cyclised via a [3,3]-sigmatropic
rearrangement to form the substituted indole (9).
2. Results and discussion
In the course of our investigation into the adaptation of Fischer
indole synthesis for micro reactor environments we undertook
three separate approaches.
For this piece of work, a reasonably simple reaction system was
set up using a syringe pump (so as to drive the system hydrody-
namically, as at the low pH involved in the use of strong acids, electro
kinetic methods such as electro osmotic flow become ineffective).
A schematic of the set up is shown in Figure 4.
With the problems associated with the first method, a second
approach was devised, using harsher chemical conditions so that
milder environmental conditions could be employed – allowing the
reduction of the backpressures, which would increase system
throughput by allowing faster flow rates. This approach, adapted
from Elk et al.,12 used neat glacial acetic acid as a highly protic solvent,
and 10% (v/v) sulfuric acid as the catalyst. This strategy is not
Figure 4. Schematic of syringe pump.

B. Wahab et al. / Tetrahedron 66 (2010) 3861–3865
3863
Table 1
Comparison of micro fluidic indolisation versus classical synthesis
Ketone
Indole
Batch (%)a
Homogeneous approach (1) (%)b
Elks’ approach (2) (%)b
Heterogeneous approach (3) (%)b
O
10
11
12
13
14
5
88
98
96
98
98
74
56
N
H
O
O
O
O
O
68
69
76
98
86
0
88
68
52
N
H
OEt
15
16
N
H
O
N
H
a
Isolated yield.
Conversion (chromatographic yield).
b
commonly used industrially due to the hazardous nature of the
strong acids, however within sealed glass micro reactors, the risks of
exposure to such solvents was minimal, and no damage to the re-
action vessels are observed. The micro reactor set up can be seen in
Figure 6.
solvent stream using a specialised in-line phase separation system
(whereby the product is flowed into laminar flowing streams of
dichloromethane and water, so as to perform an organic extraction)
were unsuccessful as glacial acetic acid will persist in the organic
layer for several washes.
The third and final approach investigated the use of heteroge-
neous catalysis. Although Fischer indole synthesis employs the use of
an acid ‘catalyst’ it has been a point of debate that the acid is in fact
not regenerated as a true catalyst would.14 Traditionally the indoli-
sation would be performed in excesses of acids, even with hetero-
geneous acids, a large excess is usually used. In a study to assess acid
suitability, the nature of this untrue catalysis was conducted with the
use of Amberlyst A-15, whereby the acid efficacy reduced rapidly
over time in the generation of indole 16 (Fig. 7).
Normalised Catalysis Decay
100.00
90.00
80.00
70.00
60.00
50.00
40.00
30.00
20.00
10.00
0.00
Figure 6. Schematic of set up for approach 2.
Using an acid as the solvent meant that the cyclisation from the
phenylhydrazone to the indole was faster than the first method,
allowing the shortening of the reactor length. This therefore reduced
the back pressure of the system and allowed slightly improved flow
rates (and hence throughputs) of the system. Lower temperatures
were required (experiments were conducted at 105 ꢁC, just under the
boiling point of acetic acid). It must be noted that the phenyl-
hydrazone had to be pre-synthesised and purified to use as the
starting material; it was no longer a ‘1-pot’ synthesis. Phenyl-
hydrazones are often unstable in air and autooxidise (even more so if
they are impure), which made this approach less than satisfactory.13
In the case of ethyl pyruvate 13, a number of side products were
produced, which thus reduced the maximum yield. Typical
throughputs were much improved over the firstmethod (forexample
2,3-dimethylindole 14 was synthesised at 8.3 mghꢀ1, and ethyl py-
ruvate 13, which failed to cyclise to ethyl indole-2-carboxylate 16 in
the previous method converted at 5.7 mghꢀ1). The strongly acidic
solvent stream had an extensive work-up. This method was not
suitable for sequential (‘in-line’) reactions as glacial acetic acid is not
a suitable solvent for many other reactions. Attempts to clean the
0
10
20
30
Time (min)
40
50
60
Figure 7. Catalytic decay of Amberlyst A-15 during indolisation in ethanol.
It is documented that Amberlite IR-120 is replenishable in situ as
is routinely performed in the purification of water on an industrial
scale. This inexpensive and easy to handle solid supported acid
catalyst did not exhibit the same loss of activity in ethanol and as
such was packed into a flow reactor and used as in the set up shown
in Figure 8.

3864
B. Wahab et al. / Tetrahedron 66 (2010) 3861–3865
Synthesis of various indoles with throughputs of up to 20.1 mghꢀ1
per single channel reactor array (running from a single pump) was
possible. This is a viable level of production for the application for
which these systems were developed (rapid and safe synthesis of
radiolabelled materials).
4. Experimental procedures
4.1. General experimental procedures
All materials were obtained from commercial sources and used
without further purification. Column chromatography was per-
formed using Kieselgel 60 (Fluka) and the components were eluted
from ethyl acetate/hexane mixtures. Thin layer chromatography was
conducted using Kieselgel 60, HF254 aluminium backed TLC plates
(Merck) and ethyl acetate/hexane mixtures as mobile phase. Sepa-
ration was visualised by irradiating with 254 nm ultra violet light.
Nuclear magnetic resonance (NMR) spectra were recorded at
room temperature in deuterated DMSO-d6 using tetramethylsilane
(TMS) as an internal standard. All spectra were recorded on a Jeol
GX400 spectrometer (with the chemical shifts given in parts per
million (ppm) and coupling constants in Hertz (Hz)), 1H spectra
were taken at 400 MHz, and 13C taken at 100 MHz. Melting points
were determined using a Stuart SMP10 melting point apparatus
and were uncorrected. Mass spectrometry was performed using
a Varian 2100 T GC–MS. High performance liquid chromatography
(HPLC) was performed with a Shimadzu LC-6A single solvent pump
and an Applied Biosystems 759A UV detector on a Phenomenex
Figure 8. Schematic of micro reactor set up for heterogeneous indolisation (approach 3).
By utilising a flow reactor packed with a solid supported acid, it
was possible to greatly reduce backpressures, and thus increase the
flow rate by 10-fold. The output solution stream was acid free and
required little or no work-up. In practice the product was collected
into ice water, in which the product precipitated. Temperatures
afforded by heating ethanol were suitable for indolisation (which in
the first approach, were not enough) due to the greatly increased
physical exposure to the aciddexperiments in all cases were con-
ducted at 70 ꢁC.
Of the three approaches considered, it is clear that the use of the
heterogeneous acid system was the most beneficial in synthetic
terms. As the system output is free of acid and is low boiling (eth-
anol, bp 78 ꢁC) compared with glacial acetic acid (bp 118 ꢁC) and
DMSO (bp 189 ꢁC), using a heterogeneous catalyst rendered the
system more amenable for sequential reactions such as further
functionalisation of the indole structure. The reduced backpressures
of the capillary based heterogeneous catalysis allowed greater flow
rates to be applied and thus the throughput was significantly in-
creased over the other methods. Typical throughputs of this method
were nearly an order of magnitude greater than the first method,
due to increased flow rates (e.g., 2,3-dimethylindole 14 was pro-
duced at a rate of 17.1 mghꢀ1 compared with just 2.0 mghꢀ1 in the
Luna column (5
Datalys Azur 4.0.2.0 software.
m
m, 100 Å, 4.60ꢃ250 mm C18), and integrated with
4.2. General micro reactor procedures
Technical data for the micro reactor arrays are presented in the
Electronic Supplementary data.
4.2.1. Approach 1: homogenous catalysis. Separate solutions of the
ketones and phenylhydrazine were made to 0.1 M, and the MSA
solution was made to 0.05 M in the solvent mixture of DMSO/
ethanol (9:1) and sonicated for 10 min to remove gases then taken
up into luer-lock syringes (Hamilton). The micro reactor array used
was a mixing ‘double T’ chip, and a long wide-bore serpentine,
joined by suitable PEEKÔ (DuPont) microbore tubing. The total
first method, tetrahydrocarbazole 5 was produced at 20.1 mghꢀ1
,
compared with 2.3 mghꢀ1, and ethyl pyruvate 13, which would not
cyclise in the first method, converted to ethyl indole-2-carboxylate
16 at 12.7 mghꢀ1). The comparison of throughputs is shown in
Table 2.
length of the channel array was 1.06 m, with a volume of 19.60
giving a residence time in the system of 19.60 min at the bulk op-
erational flow rate of 1
L minꢀ1. The reactors were primed by
mL
Table 2
Throughputs comparison of micro reactor approaches
m
Indole
Throughput (mghꢀ1
)
pumping the solvent mixture through for 20 min, to ensure all
channel surfaces were wetted. The reagents were then connected
to the reactors via low dead-volume luers and flow was provided by
a syringe drive (BASi Bee, MD1001, controlled with the BASi Bee
Homogenous
approach (1)
Elks’ approach (2)
Heterogeneous
approach (3)
13
14
15
16
2.0
2.3
1.9
d
8.3
8.9
6.3
5.7
17.1
20.1
14.0
12.7
Hive, MD1020). The flow was set to 1 m
L minꢀ1 and the output
stream was collected for a set period. The solution collected was
then diluted with ethanol for quantitative HPLC analysis (products
and intermediates calibrated versus starting materials, mobile
phase 65% acetonitrile in water).
3. Conclusions
4.2.2. Approach 2: neat acid catalysis. The relevant phenylhydrazone
was solubilised in glacial acetic acid to 0.1 M, sonicated for 10 min to
remove gases, and then taken up in a luer-lock syringe. The sulfuric
acid was made up to 10% (v/v) in glacial acetic acid, sonicated and
taken up into a separate syringe. The reactor array used for this ap-
proach was a mixing T-chip and a wide-bore serpentine with a total
Micro reactors can be used for the cyclisation of ketones to in-
doles via Fischer indole synthesis. The different approaches
employed demonstrate the versatility of the micro reactor platform
for synthesis. The problems of back pressure associated with high
throughput synthesis have been considered as well as the adapt-
ability for further sequential reactions.
To this end, the heterogeneous approach using Amberlite IR-120
was deemed the most useful of the three methods as minimal
work-up of the product and higher throughputs were possible.
reaction length of 0.74 m, and a volume of 12.47
time of 6.24 min at the bulk operational flow rate of 2
m
L giving a residence
m
L minꢀ1. The
micro reactors were joined with acid impervious fused silica. The
array was held in a custom built aluminium cradle to prevent

B. Wahab et al. / Tetrahedron 66 (2010) 3861–3865
3865
the reactors moving and stressing the relatively inflexible fused silica,
and thus reduce risk of mechanical damage to the tubing. The reactors
were primed with glacial acetic acid for 10 min and the reagents were
introduced to the array using low dead-volume luers. The flow was
(CH2), 108.6 (C0), 111.1 (C0), 117.6 (CH), 118.5 (CH), 120.5 (CH), 127.9
(C0), 134.9 (C0), 136.2 (C0); 172 (Mþþ1, 13), 171 (Mþ, 64), 143 (100).
4.3.4. 1,2,3,4-Tetrahydrocyclopenta[b]indole (15)17. The reaction
was carried out in accordance with general procedure for batch
synthesis (4.3) using cyclopentanone 12 and phenylhydrazine 7
to give the title compound 15 as a white solid, mp 104–105 ꢁC
(lit.,16 107 ꢁC); dH 2.43 (2H, p, J¼7.0 Hz, CH2), 2.70 (2H, t,
J¼7.0 Hz, CH2), 2.79 (2H, t, J¼7.1 Hz, CH2), 6.89 (1H, t, J¼7.3 Hz,
ArH), 6.94 (1H, t, J¼7.4 Hz, ArH), 7.24 (1H, d, J¼7.1 Hz, ArH), 7.27
(1H, d, J¼7.1 Hz, ArH), 10.76 (1H, br s, NH); dC 24.59 (CH2), 25.83
(CH2), 28.85 (CH2), 112.11 (CH), 118.04 (C0) 118.34 (CH), 118.97
(CH), 120.10 (CH), 124.72 (C0), 141.55 (C0), 144.73 (C0); 157
(Mþ, 74), 156 (100), 130 (41), 77 (36).
set to 2 m
L minꢀ1 and the output stream was collected for a set period.
The produced solution was then diluted with ethanol for quantitative
HPLC analysis.
4.2.3. Approach 3: heterogeneous catalysis. Separate solutions of
the ketones and phenylhydrazine were made to 0.1 M in ethanol
and sonicated for 10 min to remove gases then taken up into luer-
lock syringes. The micro reactor array comprised of a T-chip and
a capillary, which was packed with Amberlite IR 120H (60 mg,
265
connected by low dead-volume luers and unions. The total reaction
length was 0.38 m, with a volume of 69.43 L giving a residence
time of 3.47 min at the bulk operational flow rate of 20
L minꢀ1
mmol), joined with suitable PEEKÔ microbore tubing and
m
4.3.5. Ethyl 1H-indole-2-carboxylate (16)18. The reaction was car-
ried out in accordance with general procedure for batch synthesis
(4.3) using ethyl pyruvate 13 and phenylhydrazine 7 to give the title
compound 16 as a cream coloured solid, mp 122–123 ꢁC (lit.,19
125 ꢁC); dH 1.34 (3H, t, J¼7.1 Hz, CH3), 4.33 (2H, q, J¼7.1 Hz, CH2),
7.07 (1H, t, J¼8.0 Hz, ArH), 7.13–7.14 (1H, m, ArH), 7.25 (1H, t,
J¼8.3 Hz, ArH), 7.45 (1H, d, J¼8.2 Hz, ArH), 7.65 (1H, d, J¼8.0 Hz,
ArH),11.87 (1H br s, NH); dC 14.87 (CH3), 60.98 (O–CH2),108.23 (CH),
113.14 (CH),120.72 (CH),122.62 (CH),125.18 (CH),127.29 (C0),127.91
(C0), 137.93 (C0) 161.89 (C0); 190 (Mþþ1, 9), 189 (Mþ, 68), 143 (100),
115 (33).
m
.
The system was primed with ethanol for 5 min and then connected
to the reagents via luers. The reagents were pumped through the
system at up to 20 m
L minꢀ1 (bulk), and the output stream was
collected for a set period. The solution collected was then diluted
with ethanol for quantitative HPLC analysis.
4.3. Batch reactions
4.3.1. General procedure for batch synthesis of indoles 8, 9 and
10. Ketone (2.5 mmol) was added to a solution of phenylhydrazine
(1 equiv) in ethanol, and stirred for 10 min at room temperature. p-
TSA (1 equiv) was added and the solution was heated to reflux for
4 h. The solution was then allowed to cool, and concentrated in
vacuo to remove the solvent, before diluting in water (50 mL) and
extracting into dichloromethane (50 mL). The organic layer was
washed with water (50 mL), ammonium chloride solution (0.1 M,
50 mL) and then sodium hydrogen carbonate solution (saturated,
50 mL). The organic layer was then dried over magnesium sulfate
and concentrated in vacuo to render the crude indole product. The
indole was purified by either recrystallisation (ethanol/water) or by
flash chromatography on silica gel.
Acknowledgements
The authors thank the EPSRC and sanofi-aventis (B.W.) for fi-
nancial support. We are grateful to Dr. Steve Clark (University of
Hull) for help in fabricating the micro reactor devices.
Supplementary data
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.03.005.
References and notes
4.3.2. 2,3-Dimethyl-1H-indole (14)15. The reaction was carried out
in accordance with general procedure for batch synthesis (4.3)
using butan-2-one 10 and phenylhydrazine 7 to give the title
compound 14 as a white solid, mp 105–106 ꢁC (lit.,16 106 ꢁC); dH 2.13
(3H, s, CH3), 2.29 (3H, s, CH3), 6.90 (1H, t, J¼7.04 Hz, ArH), 6.95
(1H, t, J¼7.75 Hz, ArH), 7.19 (1H, d, J¼7.96 Hz, ArH), 7.33 (1H, d, ArH,
1. McCreedy, T. Anal. Chim. Acta 2001, 427, 39–43.
2. Fletcher, P. D. I.; Haswell, S. J.; Pombo-Villar, E.; Warrington, B. H.; Watts, P.;
Wong, S. Y. F.; Zhang, X. Tetrahedron 2002, 58, 4735–4757.
3. Watts, P.; Haswell, S. J. Drug Discov. Today 2003, 8, 586–593.
4. Marzabadi, M. R.; Jones, C.; Rydstro¨m, J. Mech. Ageing Dev. 1995, 80, 189–197.
5. Singh, R. K.; Lange, T. S.; Kim, K. K.; Shaw, S. K.; Brard, L. Gynecol. Oncol. 2008,
109, 240–249.
6. Weng, J.-R.; Tsai, C.-H.; Kulp, S. K.; Chen, C. S. Cancer Lett. 2008, 262, 153–163.
7. Jenck, F.; Boes, M.; Martin, J. R.; Sleight, A.; Moreau, J. L. Biol. Psychiat. 1997, 42,
30S.
8. Frederich, M.; Tits, M.; Angenot, L. T. Roy. Soc. Trop. Med. H. 2008, 102, 11–19.
9. Fischer, E.; Jourdan, F. Chem. Ber. 1883, 16, 2241–2245.
10. Bagley, M. C.; Jenkins, R. L.; Lubinu, M. C.; Mason, C.; Wood, R. J. Org. Chem.
2005, 70, 7003–7006.
11. Kappe, C. O.; Razzaq, T.; Glasnov, T. Eur. J. Chem. 2009, 1321–1325.
12. Elks, J.; Elliott, D. F.; Hems, B. A. J. Chem. Soc. 1944, 629–632.
13. Pausacker, K. H. J. Chem. Soc. 1950, 3478–3481.
14. Pausacker, K. H.; Schubert, C. J. Chem. Soc. 1950, 1814–1816.
15. Furstner, A.; Jumbam, D. N. Tetrahedron 1992, 48, 5991–6010.
16. Kanaoka, Y.; Ban, Y.; Miyashita, K.; Irie, K.; Yonemitsu, O. Chem. Pharm. Bull.
1966, 14, 934–939.
17. Wender, P. A.; Cooper, C. B. Tetrahedron 1986, 42, 2985–2991.
18. Mali, R. S.; Yadav, V. J. Synthesis 1984, 10, 862–865.
19. Millich, F.; Becker, E. I. J. Org. Chem. 1958, 23, 1099–1102.
J¼7.55 Hz, ArH), 10.61 (1H, br s, NH); 13C (
d, DMSO-d6): 8.9 (CH3),
11.8 (CH3), 105.5 (C0), 110.7 (CH), 117.8 (CH), 118.5 (CH), 120 (CH),
129.5 (C0), 131.8 (C0), 135.7 (C0).146 (Mþþ1, 11), 145 (Mþ, 100), 130
(38), 144 (22).
4.3.3. 1,2,3,4-Tetrahydro-1H-carbazole (5)17. The reaction was car-
ried out in accordance with general procedure for batch synthesis
(4.3) using cyclohexanone 11 and phenylhydrazine 7 to give the
title compound 5 as an off-white solid, mp 118–119 ꢁC (lit.,16
116–118 ꢁC); dH 1.70–1.81 (4H, m, 2ꢃCH2). 2.55 (2H, t, J¼5.6 Hz,
CH2), 2.63 (2H, t, J¼2.6 Hz, CH2), 6.85 (1H, t, J¼7.3 Hz, ArH), 6.91
(1H, t, J¼7.5 Hz), 7.17 (1H, d, J¼7.1 Hz, ArH), 7.26 (1H, d, J¼7.1 Hz,
ArH), 10.56 (1H, br s, NH); dC 21.2 (CH2), 23.3 (CH2), 23.5 (CH2), 23.6