Copper-catalyzed protodecarboxylation and aromatization of tetrahydro-β-carboline-3-carboxylic acids

Article abstract of DOI:10.1055/s-0033-1340053

An efficient synthetic methodology has been developed to construct aromatic β-carbolines from tetrahydro-β-carboline-3-carboxylic acids by copper-promoted sequential decarboxylation and oxidative aromatization. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1340053

120▌
LETTER
lCettoerpper-Catalyzed Protodecarboxylation and Aromatization of Tetrahydro-
β-Carboline-3-Carboxylic Acids
Copper-Catalyzed Protodecarboxylation
Ramu Meesala, Mohd Nizam Mordi,* Sharif Mahsufi Mansor
Centre For Drug Research, Universiti Sains Malaysia, Minden, 11800 USM, Penang, Malaysia
Fax +60(4)6568669; E-mail: mnizam@usm.my
Received: 03.09.2013; Accepted after revision: 30.09.2013
action of tetrahydro-β-carboline-3-carboxylic acid in the
Abstract: An efficient synthetic methodology has been developed
presence of a catalytic amount (10 mol%) of copper salts,
to construct aromatic β-carbolines from tetrahydro-β-carboline-
without any ligand, in DMF at 130 °C as shown in Table
3-carboxylic acids by copper-promoted sequential decarboxylation
1. After examining various copper salts, the best outcome
was obtained by using 10 mol% of CuCl2 (Table 1, entry
4). Cu(OAc)2 also catalyzed the reaction similarly (Table
1, entry 5). Copper(I) salts can also perform the reaction
but with less efficiency (Table 1, entry 1–3).
and oxidative aromatization.
Key words: tetrahydro-β-carboline-3-carboxylic acids, decarboxy-
lation, aromatization, copper, aromatic β-carboline
The aromatic β-carboline moiety is found in a wide vari-
ety of natural products and synthetic congeners.1 Com-
pounds containing this fragment display a wide range of
biological properties including antimalarial,2 antitumor,3
and anti-HIV activities.4 β-Carbolines also exhibit potent
binding affinities toward benzodiazepine receptors in the
central nervous system, thereby acting as diazepam antag-
onists.5 As a result of their significant potential as thera-
peutics, interest has grown in the development of methods
for the efficient and rapid synthesis of β-carboline deriva-
tives. A general synthetic method for its preparation is the
dehydrogenation of a suitable tetrahydro-β-carboline pre-
cursor. Typical reported methods6 involve heating the
Table 1 Screening of Reaction Conditions
COOH
Cu salt, DMF
N
NH
+ CO2
130 °C
N
H
N
H
Entry
Cu salt (mol%)
Time (h)
Yield (%)a
1
2
3
4
5
CuI (10)
6
6
6
1
3
76
72
74
81
75
CuBr (10)
CuCl (10)
CuCl2 (10)
Cu(OAc)2 (10)
8
substrate with palladium on carbon,6a–c sulfur,7 and SeO2
for extended reaction times.
Decarboxylation of aromatic carboxylic acids by copper
has been widely investigated since the 1960s by Shep-
pard,9 Cohen,10 Nilsson,11 and others.12 Sheppard et al. re-
a Isolated yields.
After having optimized reaction conditions, we attempted
the decarboxylation–aromatization of various tetrahydro-
β-carboline-3-carboxylic acid derivatives, obtained by
Pictet–Spengler condensation of L-tryptophan with the
appropriate aldehyde,16 to explore the scope and generali-
ty of the reaction. The outcomes of the reactions17 are pre-
sented in Table 2. Yields were generally good and were
observed to be dependent on the electronic characteristics
of the substituent at C(1); substrates containing electron-
donating groups (Table 2, entries 2 and 4) affording high-
er yields than those with electron-withdrawing groups
(Table 2, entry 5). Finally, the conditions proved to be tol-
erant of aromatic functional groups.
Based on previous reports,18 a possible mechanism is out-
lined in Scheme 1. Initially, the copper catalyst inserts
into the carboxylate bond to give intermediate 4 which un-
dergoes oxidative addition to provide intermediate 5.
Finally, a rapid reductive elimination provides the decar-
boxylation to produce intermediate 6. On protonolysis,
the intermediate 6 is converted into tetrahydro-β-carbo-
ported
that
cuprous
arylcarboxylates
readily
decarboxylate on heating. Myers developed a palladium-
catalyzed decarboxylative Heck-type reaction in 2002.13
Gooßen reported a practical and an efficient large-scale
synthesis of biaryls by using decarboxylative coupling.14
Carboxylic acids have many advantages as surrogates of
organometallic nucleophiles. They are stable, easy to
make and store, and readily available. In addition, they
generate carbon dioxide as a byproduct in the decarboxyl-
ation process instead of producing metal waste. A variety
of decarboxylative coupling reactions of carboxylic acids
have been developed over the past few decades.15
In this Letter, we describe a simple method for the synthe-
sis of aromatic β-carbolines by sequential decarboxy-
lation and aromatization of tetrahydro-β-carboline-3-
carboxylic acids by employing 10 mol% of CuCl2 without
any ligand. We initiated our studies by examining the re-
SYNLETT 2014, 25, 0120–0122
Advanced online publication: 12.11.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340053; Art ID: ST-2013-D0848-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Copper-Catalyzed Protodecarboxylation
121
Table 2 Cu-Mediated Decarboxylation and Aromatization of Tetra-
hydro-β-Carboline-3-Carboxylic Acids
N
N
H
2a
Entry Substrate
Product
Yield
(%)a
oxidative
aromatization
COOH
NH
O
N
HO
1
81
84
N
H
N
H
HN
HN
N
H
[Cu]
2a
2b
1a
N
H
3
7
COOH
NH
Me
N
protonolysis
2
N
H
O
N
Me
H
[Cu]
O
[Cu]
N
1b
HN
COOH
NH
H
N
N
H
H
N
4
6
N
H
N
H
3
4
5
77
87
63
CO2
O
decarboxylation
O
2c
[Cu]
HN
1c
N
H
5
COOH
NH
N
N
H
N
H
Scheme 1 Proposed mechanism for copper-mediated decarboxy-
lation and aromatization of tetrahydro-β-carboline-3-carboxylic acids
OMe
OMe
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
2d
1d
r
t
iornat
COOH
N
References and Notes
NH
N
H
NO2
N
H
NO2
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a Isolated yields.
line 7 which then transforms into the aromatic β-carboline
by oxidative aromatization.
In summary, we have developed a convenient protocol for
the synthesis of aromatic β-carbolines via copper(II)-
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of tetrahydro-β-carboline-3-carboxylic acid precursors in
the absence of a ligand.
Acknowledgement
Financial support of this research provided by the Research Univer-
sity Grant Scheme of Universiti Sains Malaysia (RUT-USM) is gra-
tefully acknowledged by the authors.
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Synlett 2014, 25, 120–122

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R. Meesala et al.
LETTER
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(17) General Procedure
To 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic
acid (1 mmol) in DMF (10 mL) was added CuCl2 (10 mol%)
and stirred for 1 h at 130 °C. On completion of the reaction
(TLC), H2O (5 mL) was added to the reaction, and the
mixture was basified to pH 9 with 1 M NaOH. The aqueous
layer was extracted with CH2Cl2 (3 × 20 mL), and the
combined organic layers were dried over anhydrous Na2SO4.
The CH2Cl2 was evaporated, and the residue was purified by
chromatography which afforded pure 9H-pyrido[3,4-b]indole
(2a) as a white solid. 1H NMR (500 MHz, DMSO-d6): δ =
11.63 (1 H, s), 8.89 (d, J = 0.5 Hz, 1 H), 8.31 (d, J = 5.5 Hz,
1 H), 8.2 (d, J = 7.0 Hz, 1 H), 8.09 (dd, J1 = 0.5 Hz, J2 = 1.0
Hz, 1 H), 7.60 (d, J = 10.0 Hz, 1 H), 7.55–7.53 (m, 1 H),
7.24–7.21 (m, 1 H). 13C NMR (125 MHz, DMSO-d6): δ =
140.5, 137.9, 135.9, 133.7, 128.5, 127.6, 121.7, 120.4,
119.4, 114.7, 112.1. GC–MS: 168 [M+].
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Synlett 2014, 25, 120–122
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