Three-component, four-centered, one-pot synthesis of 1-(arylethynyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole derivatives

Article abstract of DOI:10.1016/j.tetlet.2017.04.008

An efficient three component, four-centered A3 coupling strategy has been developed for the synthesis of a novel series of 1-arylethynyl-tetrahydro-β-carboline derivatives in good yields with high selectivity. This method is also useful for the preparation of 1-arylethynyl tetrahydroisoquinolines, which can be used for the synthesis of biologically active molecules such as homolaudanosine, dysoxyline, methopoline and almorexant. The use of a readily available ZnCl₂/Et₃N reagent system makes this method simple, convenient and practical.

Full text of DOI:10.1016/j.tetlet.2017.04.008

Accepted Manuscript
Three-component, four-centered, one-pot synthesis of 1-(arylethynyl)-2,3,4,9-
tetrahydro-1H-pyrido[3,4-b]indole derivatives
B.V. Subba Reddy, Kavya Kota, R. Anji Babu, P. Rasvan Khan, K. Mukkanti
PII:
S0040-4039(17)30428-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.04.008
TETL 48800
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
12 December 2016
28 March 2017
2 April 2017
Please cite this article as: Subba Reddy, B.V., Kota, K., Anji Babu, R., Rasvan Khan, P., Mukkanti, K., Three-
component, four-centered, one-pot synthesis of 1-(arylethynyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
derivatives, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.04.008
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Graphical Abstract
Three-component, four-centered, one-pot
synthesis of 1-(arylethynyl)-2,3,4,9-
tetrahydro-1H-pyrido[3,4-b]indole
derivatives
Leave this area blank for abstract info.
B. V. Subba Reddy,* Kavya Kota, R. Anji Babu, P.
Rasvan Khan, K. Mukkanti*

1
Tetrahedron Letters
Three-component, four-centered, one-pot synthesis of 1-(arylethynyl)-2,3,4,9-
tetrahydro-1H-pyrido[3,4-b]indole derivatives
B. V. Subba Reddy,*a Kavya Kota,a,b R. Anji Babu,a P. Rasvan Khan,a K. Mukkanti*b
aCentre for Semiochemicals, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, India. E-mail: basireddy@iict.res.in
bDepartment of Chemistry, JNTU, Hyderabad, 500085, India.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient three component, four-centered A3 coupling strategy has been
developed for the synthesis of a novel series of 1-arylethynyl-tetrahydro--
carboline derivatives in good yields with high selectivity. This method is also
useful for the preparation of 1-arylethynyl tetrahydroisoquinolines, which can be
used for the synthesis of biologically active molecules such as homolaudanosine,
dysoxyline, methopoline and almorexant. The use of a readily available
ZnCl2/Et3N reagent system makes this method simple, convenient and practical.
Available online
Keywords:
Three component reaction
Halocyclization
Cyclic iminium Ion
Alkyne addition
Tetrahydrocarbolines
2009 Elsevier Ltd. All rights reserved.
Introduction
The classical route for the synthesis of THBCs is the
Pictet−Spengler reaction, which involves the condensation of
-Carboline alkaloids are widely distributed in nature and
possess a broad spectrum of biological activity.1 They are
known to intercalate into DNA to inhibit CDK topoisomerase,
and monoamine oxidase, and to interact with benzodiazepine
receptors and 5-hydroxy serotonin receptors.2 In particular,
tetrahydro--carboline alkaloids are potential neuroactive
alkaloids found in Chocolate and Cocoa.3 They occur in foods
such as wine, spices, vinegar and fruit products and act as
good radical scavengers (Figure 1).4 Furthermore, 1-
substituted tetrahydroisoquinolines are structural components
of several natural products.5
tryptamines with aldehydes in the presence of protic or Lewis
acids.6 Another useful method for the synthesis of tetrahydro-
β-carbolines is the Bischler-Napieralski reaction, which
proceeds in three steps through N-acylation, cyclization and
reduction.7
On the other hand, multi-component reactions (MCRs) are
important synthetic tools to generate combinatorial libraries of
highly functionalized heterocycles for drug discovery.8 They
are extremely convergent and highly efficient for producing
molecular complexity and diversity in a single step.9 A post-
modification of MCRs provides a direct access to fused
heterocycles.10 In particular, three-component four-centered
reactions are very useful to produce diversified scaffolds,
which play a key role in drug discovery.11-13 Furthermore,
haloamine cyclization has become one of the most prominent
strategies for the synthesis of nitrogen containing
heterocycles.14
Results and Discussion
Following our interest on multi-component reactions,15 we
herein report a novel and efficient three component four-
centered A3 coupling strategy for the synthesis of
Figure 1. Examples of THBCs and THIQs

2
Tetrahedron
obtained in good to excellent yields with high purity without
2-aryl-1-(arylethynyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-
any side products. On the other hand, N-methyl- and N-benzyl
chloroaldehydes participated well in this reaction (entries a-q,
s, Table 2). Finally, we examined the reactivity of 2-(2-
b]indole derivatives from chloroaldehyde, aryl amine and aryl
alkyne. The requisite chloroaldehyde was prepared from
indole-3-acetic acid (Scheme 1).16
bromoethyl)benzaldehyde
and
2-(2-chloroethyl)-4,5-
dimethoxybenzaldehyde. Interestingly, the corresponding 2-
phenyl-1-(phenylethynyl)-1,2,3,4-tetrahydroisoquinolines
were obtained in good yields under similar conditions (entries
t, u, Table 2). Therefore, this method is useful not only for the
synthesis of THBCs but also for THIQs. In particular, 1-
arylethynyl THIQs can be used for the synthesis of
isoquinoline alkaloids like homolaudanosine, dysoxyline,
methopoline and a commercially available drug, almorexant.
To our surprise, the reaction didn't proceed with aliphatic
alkyne like 1-pentyne because of its low reactivity over
aromatic alkyne.
Scheme 1. Reagents and conditions: a) benzyl bromide, or
CH3I, NaH, DMF; b) LAH, THF, 0 oC; c) DMF, POCl3, 60
oC, 12h.
Preliminary experiment was performed between 3-(2-
chloroethyl)-1-methyl-1H-indole-2-carbaldehyde (1), aniline
(2) and phenyl acetylene (3) in different solvents and
temperatures (Table 1). Initially, the efficacy of copper and
silver salts such as CuI, CuBr and AgOTf was tested for this
reaction (entries a-e, Table 1). The reaction was found to be
sluggish at room temperature (entry f, Table 1). The product
was obtained in low yield in THF (entries a, c, h, Table 1).
The reaction was also successful with a catalytic amount of
ZrCl4 (entry i, Table 1). Among Ag, Cu, Zn and Zr salts, the
use of 10 mol% ZnCl2.and 1.5 equiv of Et3N in toluene at
reflux temperature (entry g, Table 1) was found to be optimal.
Table 2. A3 coupling for THBCs and THIQs
Table 1. Optimization of the reaction conditions for 4a
Encouraged by these initial findings, we extended this method
to other substrates and the results are summarized in Table 2.
A wide range of functional groups are well tolerated under
these reaction conditions (Table 2). This reaction works well
with a diverse range of aromatic amines including electron-
rich and electron-deficient anilines. The substituent present on
aromatic ring had shown a modest effect on the conversion. It
was observed that p-nitroaniline gave the product relatively in
lower yield than halide or methyl substituted one (entry d,
Table 2). To further illustrate the power of this process, we
performed the reaction using substituted anilines and alkynes
(entries a-q, Table 2). Interestingly, the reaction was
successful not only with anilines but also with benzyl amine
(entry r, Table 2). In most of the cases, the products were

3
Scheme 2. A plausible reaction mechanism
Based on previous reports,17 we propose an alternate
mechanism as shown in Scheme 3. The reaction likely
proceeds through the formation of either intermediate C or D.
A subsequent cyclization led to the formation of the desired
product.
Scheme 3. A plausible reaction mechanism
In conclusion, we have developed a novel multi-component
approach for the synthesis of 1-susbstituted tetrahydro--
carboline derivatives. It works with a diverse range of
substrates through a four-centered three-component A3
coupling reaction. This method is operationally simple and
more convenient to produce the biologically more relevant
scaffolds, which may find application in drug discovery.
The reaction is expected to proceed through the formation of
iminium ion (B) from chloro aldehyde (1) and aryl amine (2)
en route to imine (A). A subsequent addition of zinc acetylide
(formed in situ from aryl acetylene and zinc chloride in the
presence of triethyl amine) on iminium ion (B) would give the
required product 4 as depicted in Scheme 2. The formation of
intermediate B was observed by heating the reactant A in
toluene at 110 C. A subsequent experiment was carried out
using intermediate B and preformed zinc acetylide. In fact,
there was no considerable improvement in yield. To avoid
metal contaminations, further reaction was performed in a
new apparatuses along with the new magnetic needle without
any metals like zinc. However, no desired product was
formed.
Experimental
General
All solvents were dried according to standard literature
procedures. The reactions were performed in oven-dried
round bottom flasks and the flasks were fitted with rubber
septa and the reactions were conducted under a nitrogen
atmosphere. Glass syringes were used to transfer solvents.
Crude products were purified by column chromatography on
silica gel of 60–120 or 100-200 mesh. Thin layer
chromatography plates were visualized by exposure to
ultraviolet light and/or by exposure to iodine vapors and/or by
exposure to methanolic acidic solution of p-anisaldehyde
followed by heating (<1 min) on a hot plate (~250 °C).
Organic solutions were concentrated on rotary evaporator at
35–40 °C. IR spectra were recorded on FT-IR spectrometer.
1H and 13C NMR (proton-decoupled) spectra were recorded in
CDCl3 solvent on 200, 300, 400 or 500 MHz NMR

4
Tetrahedron
spectrometer. Chemical shifts (δ) were reported in parts per
(b) Awuah, E.; Capretta, A. J. Org. Chem., 2010, 75, 5627;
(c) Czarnocli, Z.; Sowocka, A; Szawkalo, J. Curr. Org.
Synth., 2005, 2, 301; (d) Lorenz, M.; Linn, M. L. V.; Cook,
J. M. Curr. Org. Synth., 2010, 7, 189; (e) da Silva, W. A.;
Jr. Rodrigues, M. T.; Shankaraiah, N.; Ferreira, R. B.;
Andrade, C. K. Z.; Pilli, R. A.; Santos, L. S. Org. Lett.,
2009, 11, 3238; (f) Gremmen, C.; Willemse, B.; Wanner,
M. J.; Koomen, G.-J. Org. Lett., 2000, 2, 1955; (g) Amat,
M.; Subrizi, F.; Elias, V.; Llor, N.; Molins, E.; Bosch, J.
Eur. J. Org. Chem., 2012, 1835.
million (ppm) with respect to TMS as an internal standard.
Coupling constants (J) are quoted in hertz (Hz). Mass spectra
were recorded on mass spectrometer by Electrospray
ionization (ESI).
Typical procedure
To a solution chloroaldehyde 1 (0.5 mmol) in anhydrous
toluene (4 mL) were added aniline 2 (0.5 mmol) and alkyne 3
(0.5 mmol), followed by triethylamine (1.5 mmol) and
anhydrous ZnCl2 (0.5 mmol). The resulting mixture was
stirred at 110 °C for 2-3 h. After completion, as indicated by
TLC, the mixture was cooled to room temperature and the
solvent was removed under reduced pressure. Purification on
silica gel column chromatography using hexane/EtOAc (95:5)
afforded the product 4 in pure form.
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Acknowledgements
K.K. thanks UGC, New Delhi for the award of a fellowship.
Supplementary Information
Experimental details, characterization data, copies of H and 13C
NMR spectrum of products can be found, in the online version, at
http://dx.doi.org/
1
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Entry
Catalyst a
mol%
Solvent
THF
Temp.
oC
70
Time
(h)
8
Yield
(%)b
25
a
b
c
d
e
f
CuI
10
10
10
10
10
10
10
10
10
CuI
Toluene 110
THF 70
Toluene 110
Toluene 110
Toluene 25
Toluene 110
5
8
2
5
12
2
8
60
20
60
58
50
85
30
53
CuBr
CuBr
AgOTf
ZnCl2
ZnCl2
ZnCl2
ZrCl2
g
h
i
THF
70
Toluene 110
8

Entry
Chloroaldehyde (1) Amine (2)
Product (4)a
Alkyne
(3)
Time Yield
(h)
(%)b
a
2
85
b
2
76
c
2
78
70
d
3
e
2
2
83
75
f

g
h
i
2
2
2
2
82
79
76
75
j
k
2
2
2
79
80
79
l
m

n
o
2
3
82
76
p
2
75
q
3
76
r
2
76
s
2
80

t
2
3
84
78
u
v
8
0
aAll products were characterized by NMR, IR and mass spectrometry.
bYield refers to pure products after chromatography. cReaction conditions: chloroaldehyde 1 (0.5 mmol),
toluene (4 mL), aniline 2 (0.5 mmol) and alkyne 3 (0.5 mmol), triethylamine (1.5 mmol) and anhyd.ZnCl2
(0.5 mmol). The resulting mixture was stirred at 110 °C for 2-3 h.

5
Highlights
 It describes one-pot synthesis of 1-
(arylethynyl)-2,3,4,9-tetrahydro-1H-
pyrido[3,4-b]indoles
 This method is effective and operationally
simple.
 It is a highly convergent process.
 This method works with a diverse range of
substrates
 It is a three-component, four-centered
reaction