PhI(OAc)2-mediated one-pot oxidative decarboxylation and aromatization of tetrahydro-β-carbolines: Synthesis of norharmane, harmane, eudistomin U and eudistomin i

Article abstract of DOI:10.1039/c5ob00871a

Iodobenzene diacetate was employed as a mild and efficient reagent for one-pot oxidative decarboxylation of tetrahydro-β-carboline acids and dehydrogenation of tetrahydro-β-carbolines to access the corresponding aromatic β-carbolines. To the best of our knowledge this is the first synthesis of β-carbolines via a one-pot oxidative decarboxylation at ambient temperature. The utility of this protocol has been demonstrated in the synthesis of β-carboline alkaloids norharmane (2o), harmane (2p), eudistomin U (9) and eudistomin I (12).

Full text of DOI:10.1039/c5ob00871a

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PhI(OAc)2-Mediated one-pot oxidative decarboxylation and
aromatization of tetrahydro-β-carbolines: synthesis of
norharmane, harmane, eudistomin U and eudistomin I
Received 00th January 20xx,
Accepted 00th January 20xx
Ahmed Kamal*a,b,c, YellaiahTangellaa, Kesari Lakshmi Manasac, Manda Sathisha,
DOI: 10.1039/x0xx00000x
Vunnam Srinivasulua, Jadala Chetnac and Abdullah Alarifib
www.rsc.org/
Iodobenzene diacetate was employed as a mild and efficient reagent for one-pot oxidative decarboxylation
of tetrahydro-β-carboline acids and dehydrogenation of tetrahydro-β-carbolines to access the corresponding
aromatic β-carbolines. To the best of our knowledge this is the first synthesis of β-carbolines via a one-pot
oxidative decarboxylation at ambeint temperature. The utility of this protocol has been demonstrated in the
synthesis of β-carboline alkaloids norharmane (2o), harmane (2p), eudistomin U (9) and eudistomin I (12).
carboline carboxylate genrally requires exposure to large excess of
oxidants like SeO214, MnO215, sulfur3d,16, palladium on carbon17 for
long periods of time. Other reagents like chloranil18 and DDQ19 are
Introduction
Natural products constitute an important source of chemical leads
in the drug discovery program worldwide. Majority of the drugs
that are presently in clinical use are derived from natural product
scaffolds.1 The aromatic β-carboline skeleton is
also effective in the dehydrogenation reaction, but the yields are
often very low. Recently, gold (III)-catalyzed cycloisomerisation,
palladium catalyzed cross-coupling and iminoannulation reactions
have been reported for the construction of β-carbolines.20 However,
most of the methods discussed above require expensive and toxic
transition metal reagents and harsh reaction conditions. They
cannot be deemed as environment-friendly and therefore
development of ecofriendly and cost effective protocols under
milder conditions assumes importance.
a common
structural motif found in a wide variety of biologically active natural
and synthetic compounds.2 β-Carboline derivatives are known to
exhibit diverse biological properties such as antitumor,3
antimalarial,4 anti-HIV5 and antibacterial6 activities. Additionally,
detailed investigations on certain β-carboline derivatives have
revealed thier excellent binding affinities towards 5-hydroxy
serotonin receptors,7 monoamine oxidase8 and benzodiazepine
receptors9 in the central nervous system. Moreover, compounds
bearing this ring system have also been used as versatile synthetic
intermediates in the construction of pharmaceutically important
molecules.10
In recent years, the use of hypervalent iodine based reagents as
alternative to toxic heavy metal oxidants has gained popularity.21
Reagents such as Dess-Martin periodinane (DMP) and 2-
iodoxybenzoic acid (IBX) have been used for the dehydrogenation
of tetrahydro-β-carbolines.22 Based on these observations and in
continuation our efforts to develop greener and practical synthetic
routes for compounds of pharmaceutical relevance, we attempted
the synthesis of β-carbolines using iodobenzene diacetate under
mild reaction conditions. In the following passages, we disclose a
one-pot oxidative decarboxylation and aromatization of tetrahydro-
β-carbolines mediated by the hypervalent iodine reagent,
iodobenzene diacetate. Additionally, this method has been
employed for the synthesis of β-carboline alkaloids such as
norharmane (2o), harmane (2p) eudistomin U (9) and eudistomin I
(12) in high yields.
In view of their biological importance, development of newer
practical methods for the synthesis of this scaffold is of
considerable interest. In general, Pictet–Spengler reaction followed
by oxidative decarboxylation and dehydrogenation reactions are
the most widely followed methods to access β-carbolines. Oxidative
decarboxylation reactions are genrally sluggish and are typically
carried out at high temperatures using reagents such as K2Cr2O711 in
acetic acid, persulfate in the presence of catalytic silver12 or copper
salts.13 On the other hand, dehydrogenation of the tetrahydro-β-
Address here.
Address here.
Address here.
Results and discussion
Initially, as
a test reaction, we investigated the effect of
† Footnotes relaꢀng to the ꢀtle and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
iodobenzene diacetate on the tetrahydro β-carboline acid 1a in
various solvents at ambient temperature. The β-carboline
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derivative 2a was readily fomed in all the conditions explored. The substrates bearing electron-rich groups (entries 2-5, Table 2)
use of equimolar amounts of iodobenzene diacetate in acetonitrile afforded products in higher yields than those bearing electron-
afforded 32% yield of 2a (entry 1, Table 1). Increasing the amount deficient groups (entries 6 and 7, Table 2). Importantly, two
of iodobenzene diacetate to 2 mmol led to a huge improvement of naturally occurring β-carbolines, norharmane (2o) and harmane
the yield as well as reduction of the reaction time (68%, entry 2, (2p), were synthesized using this protocol in good yields (entries 15
Table 1). Further increase in the stoichiometric ratio of the reagent and 16, Table 2).
showed no effect on the yield as well as time (entry 3, Table 1).
Table 2. Synthesis of β-carbolines (2a-p) from tetrahydro-β-
Screening of various solvents such as DMF, DMSO, DCM and 1,4-
carboline acids (1a-p) by using iodobenzene diacatatea
dioxane (entries 4-7, Table 1) revealed that the use of DMF afforded
the best yield (82%, entry 7, Table 1) for the reaction. Additionally,
carrying out the reaction under oxygen atmosphere with varying
mmols of the reagent led to similar results with respect to the
reaction times and yields (entries 8-9, Table 1). Based on these
Entry Substrate
R
product
Yield
(%)b
82
observations it can be concluded that oxygen has no effect on
oxidative decarboxylation process. Thus, the optimal reaction
conditions involved the use of iodobenzene diaceate (2 mmol) in
DMF at ambient temperature for 1h (entry 7, Table 1). It was
evident that a facile and convenient method for one-pot oxidative
decarboxylation of tetrahydro-β-carboline acids leading to the
formation of β-carbolines at room temperature was developed and
to the best of our knowledge this was the first successful case of
this transformation being carried out under such mild conditions.
1
2
1a
1b
1c
1d
1e
1f
C6H5
4-OMe-C6H4
3,4,5-(OMe)3-C6H3
2-OMe-C6H4
4-Me-C6H4
4-O2N-C6H4
4-CN-C6H4
4-F-C6H4
2a
2b
2c
2d
2e
2f
88
3
90
4
81
5
85
6
76
7
1g
1h
1i
2g
2h
2i
78
8
79
9
3-F-C6H4
80
Table 1. Optimization studies of the iodobenzene diacetate
10
11
12
1j
4-OH-3-OMe-C6H3
3-OH-C6H4
3,4-methylenedioxy-
C6H3
2j
80
mediated one-pot oxidative decarboxylation on tetrahydro-β-
1k
1l
2k
2l
76
carboline acidsa
89
O
OH
13
14
15
1m
1n
1o
3-pyridyl
2m
2n
90
80
77
N
NH
(conditions)
N
N
H
H
1-naphthyl
H
norharman
e(2o)
1a
2a
PhI(OAc)2
(mmol)
Yield
(%)b
32c
68
16
1p
CH3
harmane(2
p)
76
Entry
Solvent
Time (h)
aReactions were performed using tetrahydro-β-carboline acid (1
mmol) and iodobenzene diacetate (2 mmol) for 1 h at rt in DMF.
bIsolated yield.
1
2
3
4
5
6
7
8
9
1
2
3
2
2
2
2
2
1
acetonitrile
acetonitrile
acetonitrile
DMSO
12
3
3
68
2
74
DCM
8
71
The facile nature of the decarboxylative oxidation prompted us to
examine the effect of iodobenzene diacetate on the related acid
derivatives, viz. the tetrahydro-β-carboline esters (3a-p).
Interestingly, the reaction resulted in the formation of the
corresponding aromatic β-carbolines in very good yields, with the
ester functionality intact (Table 3).
1,4-dioxane
DMF
4
73
1
82
DMF
1
82d
44d
DMF
1
aReactions were performed using 1a (1 mmol) and iodobenzene
diacetate (1-3 mmol)
at rt. bIsolated yields. cProduct
accompanied by 40% of starting material. dIsolated yield in
presence of oxygen.
Table 3. Synthesis of aromatized β-carboline methyl esters (4a-
p) from tetrahydro-β-carboline methyl ester (3a-p) by using
iodobenzene diacetatea
With the optimal reaction conditions in hand, the scope and
generality of oxidative decarboxylation were examined by
employing various substituted tetrahydro-β-carboline acids as
reaction substrates and the results are depicted in Table 2. A wide
array of aliphatic, aromatic and heteroaromatic substituents at
position-1 of tetrahydro-β-carboline acids are tolerated in the
reaction. Interestingly, better yields of the products were obtained
from substrates possessing aromatic and heteroaromatic
substituents compared to those with aliphatic substituents (entries
15 and 16, Table 2). It was also apparent that the electronic nature
of the substituents has some effect on the product yields. The
Entry Substrate
R
product
Yield
(%)b
88
1
2
3
4
5
6
3a
3b
3c
3d
3e
3f
C6H5
4a
4b
4c
4d
4e
4f
4-OMe-C6H4
3,4,5-(OMe)3-C6H3
2-OMe-C6H4
4-Me-C6H4
93
95
88
90
4-O2N-C6H4
80
2 | J. Name., 2012, 00, 1-3
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7
8
3g
3h
3i
4-CN-C6H4
4-CF3-C6H4
4-F-C6H4
3-F-C6H4
3-OH-C6H4
3,4-
4g
4h
4i
83
85
86
87
83
92
Eudistomin I (12), on the other hand, was isolated from Caribbean
tunicate Eudistoma olivaceum and showed strong antiviral and
antimicrobial activities.24 Eudistomin U (9) has been synthesised six
times22,25 and eudistomin I (12) thrice.26 However, most of these
syntheses employed expensive metal catalysts, drastic conditions or
required prolonged reaction times to construct the core skeleton. In
view of these issues, we attempted the syntheses of these natural
products from commercially available starting materials in three
linear steps. In the event, too shorter and more efficient syntheses
of these natural products were developed and the details are
described in the following passages.
9
10
11
12
3j
4j
3k
3l
4k
4l
methylenedioxy-
C6H3
13
14
15
16
3m
3n
3o
3p
3-pyridyl
N-acetyl-3-indolyl
H
4m
4n
4o
4p
90
85
82
80
CH3
aReactions were performed using tetrahydro-β-carboline ester (1
mmol) and iodobenzene diacetate (2 mmol) for 1 h at rt in DMF.
bIsolated yield.
The synthesis of eudistomin U (9) started with tryptophan methyl
ester (6), which underwent a Pictet-Spengler condensation with N-
acetyl indole-3-carboxaldehyde to provide the corresponding
tetrahydro-β-carboline ester 7 as diastereomeric mixture (86%
yield). Saponification of ester 7 was accompanied by the loss of N-
acetyl group to provide the carboxylic acid 8. The latter, on
exposure to iodobenzene diacetate, underwent ready oxidative
decarboxylation to afford eudistomin U (9) in 66% yield.
A series of substituents were found to be well tolerated and the
yields were generally excellent for β-carboline esters with electron-
donating groups (entries 2-5, Table 3) than the ones with electron-
withdrawing groups (entries 6-8, Table 3). Moreover, heteroaryl
(entries 13 and 14, Table 3) and aliphatic (entries 15 and 16, Table
3) substrates also reacted well to furnish the corresponding
products.
This protocol is applicable for the dehydrogenation of tetrahydro-β-
carbolines without any functionality at position-3. Here, the
corresponding β-carbolines are formed in excellent yields as evident
from the entries 1-4, Table 4. It is important to note that previously
this transformation has been achieved using DDQ in very low yields.
19c
Table 4. Synthesis of β-carbolines from tetrahydro-β-carbolines
(5a-d) by using iodobenzene diacetatea
Scheme 1. Total synthesis of eudistomin U (9) via iodobenzene
diacetate-mediated oxidative decarboxylation.
Entry Substrate
R
product
Yield
(%)b
85
Synthesis of eudistomin I (12) began with the acid catalyzed Pictet-
Spengler condensation of tryptophan methyl ester 6 with tert-butyl
2-formyl pyrrolidine-1-carboxylate to give the corresponding
tetrahydro-β-carboline 10 as a diastereomeric mixture (88% yield).
Further, saponification of 10 followed by deprotection of the Boc
group with 2N HCl in dioxane, afforded the corresponding
hydrochloride salt, which under the optimized conditions of
oxidative decarboxylation, furnished eudistomin I 12 in 63% yield
(Scheme 3). Here, it is important to note that iodobenzene
diacetate mediates three distinct chemical transformations
(decarboxylation, aromatization and dehydrogenation of the
pyrrolidine ring) in a single, one-pot operation.
1
2
3
4
5a
5b
5c
5d
C6H4
4-OMe-C6H4
4-O2N-C6H4
CH3
2a
2b
2f
90
80
harmane (2p)
84
aReactions were performed using tetrahydro-β-carboline (1
mmol) and iodobenzenediacetate (2 mmol) for 1 h at rt in DMF.
bIsolated yield.
In view of the above findings, this method appeared suitable for the
total syntheses of marine β-carboline alkaloids eudistomin U (9) and
eudistominI (12). Eudistomin U (9) was isolated from the marine
ascidian lissoclinum fragile and is reported to possess antimicrobial
and anticancer activities with strong DNA binding ability.23
Scheme 2. Total synthesis of eudistomin I (12) via iodobenzene diacetate-mediated oxidative decarboxylation.
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General experimental procedure for the synthesis of β-
carbolines (2a-p) via one-pot oxidative decarboxylation of
tetrahydro-β-carboline acids (1a-p)
Conclusions
In summary, we have developed a practical and highly efficient
protocol for the synthesis of aromatic β-carbolines through a
one-pot oxidative decarboxylation of the corresponding
tetrahydro-β-carboline precursors at ambient temperature. The
To a stirred solution of tetrahydro-β-carboline acids 1a-p (1
mmol) in DMF was added iodobenzene diacetate (2 mmol) and
the resulting mixture was stirred for 1h at room temperature.
After completion of the reaction (monitored by TLC), the
reaction mixture was quenched with saturated NaHCO3 solution
and extracted with ethyl acetate. The combined organic layers
were washed with brine, dried over anhydrous magnesium
sulfate, filtered and concentrated under reduced pressure. The
residue obtained was purified by silica-gel column
chromatography using ethyl acetate-hexane as eluent in
increasing polarity to afford the desired β-carbolines 2a-p.
method employs
a mild oxidant, iodobenzene diacetate,
providing high yields of the desired products and could serve as
an alternative to the traditional methods employing harsh
metal-based reagents. In addition, this protocol could be useful
in instances when forcing conditions must be avoided. The
method provides easy access to biologically active β-carboline
derivatives like norharmane (2o) and harmane (2p). Moreover,
efficient total syntheses of marine β-carboline alkaloids
eudistomin U (9) and eudistomin I (12) from commercially
available starting materials were carried out by employing this
protocol in just three linear steps. In view of its efficiency and
operational simplicity, this method may be expected to find
commercial applications in the synthesis of β-carboline
derivatives of pharmaceutical as well as industrial importance.
1-Phenyl-9H-pyrido[3,4-b]indole (2a):
Yellow solid: 68 mg (82% yield); Rf = 0.51 (ethyl acetate/n-
hexane, 3:7), mp: 242–244 °C (Ref28: 241‒242 °C); IR (KBr): 3448,
3057, 2954, 2874, 1621, 1559, 1495, 1447, 1414, 1319, 1232,
1
1061, 736, 696, 615 cm–1; H NMR (300 MHz, DMSO−d6) δ:
11.52 (s, 1H), 8.46 (d,
8.12 (d, = 5.3 Hz, 1H), 8.04 (d,
5H), 7.27 (t,
= 7.5 Hz, 1H); 13C NMR (75 MHz, DMSO−d6) δ:
J
= 5.3 Hz, 1H), 8.27 (d,
J = 7.7 Hz, 1H),
J
J
= 7.0 Hz, 2H), 7.68−7.49 (m,
J
Acknowledgements
142.1, 141.0, 138.4, 138.3, 132.9, 129.1, 128.7, 128.4, 128.3,
128.1, 121.5, 120.7, 119.4, 113.8, 112.4; MS (ESI): m/z 245 [M +
H]+; HRMS (ESI): m/z: calcd for C17H13N2: 245.10732; found:
245.10627 [M + H]+.
The authors, Y.T, M.S and V.S acknowledge the Council of
Scientific and Industrial Research (CSIR), New Delhi (India) for
the financial support under the 12th Five Year Plan project
“Affordable Cancer Therapeutics (ACT)” (CSC0301). This project
was also supported by King Saud University, Deanship of
Scientific Research, Research Chair.
1-(4-Methoxyphenyl)-9H-pyrido[3,4-b]indole (2b):
White solid: 75 mg (88% yield); Rf = 0.55 (ethyl acetate/n-
hexane, 1:1), mp: 156–159 °C (Ref28: 156‒159 °C); IR (KBr): 3053,
2952, 2850, 1735, 1608, 1563, 1512, 1496, 1465, 1321, 1248,
1
1174, 1039, 821, 752 cm–1; H NMR (500 MHz, CDCl3) δ: 8.57 (s,
Experimental Section
1H), 8.54 (d,
(m, 3H), 7.55 (t,
7.0 Hz, 1H), 7.10 (d,
J
= 5.2 Hz, 1H), 8.16 (d,
= 7.1Hz, 1H), 7.50 (t,
= 8.7 Hz, 2H), 3.89 (s, 3H); 13C NMR (75
J
= 7.9 Hz, 1H), 7.94‒7.88
General Information
J
J
= 8.1 Hz, 1H), 7.31 (t, J =
J
The reagent, chemicals and solvents were either purchased from
commercial Suppliers or prepared and purified by standard
techniques. Thin layer chromatography (TLC) was performed
using pre-coated silica gel 60 F254 MERCK. TLC plates were
visualized by exposure to UV light or iodine vapors and aqueous
solution of ninhydrin. Column chromatography was performed
using indicated solvent system on Merck flash silica gel with 60–
120 mesh size. 1H and 13C NMR spectra were recorded with 300
and 500 MHz NMR instruments with tertramethylsilane (TMS) as
an internal standard. Infrared spectra were recorded using a FT-
IR spectrophotometer and values reported in cm-1. Mass spectra
were recorded by 45 electro spray ionization mass spectrometry
(ESI-MS). High-resolution mass spectra (ESI-HRMS) were
recorded on ESI-QTOF mass spectrometer. Melting points were
determined on an Electro thermal melting point apparatus and
are uncorrected.
MHz, CDCl3 + DMSO−d6) δ: 158.7, 141.6, 140.5, 137.2, 132.2,
130.2, 128.7, 128.3, 126.8, 120.2, 118.4, 113.0, 112.0, 111.3,
54.2; MS (ESI): m/z 275 [M + H]+; HRMS (ESI): m/z: calcd for
C18H15ON2: 275.11789; found: 275.11665 [M + H]+.
1-(3,4,5-Trimethoxyphenyl)-9H-pyrido[3,4-b]indole (2c):
White solid: 78 mg (90% yield); Rf = 0.36 (ethyl acetate/n-
hexane, 4:6), mp: 168–171 °C (Ref29: 241‒242 °C); IR (KBr): 3310,
3058, 2937, 1624, 1584, 1503, 1455, 1404, 1346, 1232, 1127,
1
1004, 747 cm–1; H NMR (500 MHz, CDCl3) δ: 8.77 (s, 1H), 8.54
(d,
J
= 5.2 Hz, 1H), 8.17 (d,
J
= 7.9 Hz, 1H), 7.94 (d,
J = 5.2 Hz,
1H), 7.59‒7.52 (m, 2H), 7.32 (t,
J
= 7.5 Hz, 1H), 7.13 (s, 2H), 3.92
(s, 9H); 13C NMR (75 MHz, CDCl3) δ: 153.5, 143.1, 140.5, 139.0,
138.3, 134.1, 133.5, 129.8, 128.4, 121.7, 121.8, 120.1, 113.7,
111.7, 105.7, 60.8, 56.1; MS (ESI): m/z 335 [M + H]+; HRMS (ESI):
This journal is © The Royal Society of Chemistry 20xx
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m/z: calcd for C20H19O3N2: 335.13902; found: 335.13750 [M +
H]+.
7.63 (d,
J
= 8.1 Hz, 1H), 7.52 (t,
J
= 7.5 Hz, 1H), 7.33−7.22 (m, 3H);
13C NMR (75 MHz, CDCl3 + DMSO−d6) δ: 163.2 and 160.0 (d,
J
=
1-(2-Methoxyphenyl)-9
H
-pyrido[3,4-
b]indole (2d):
247.6 Hz), 140.4 (d,
J
= 21.4 Hz), 137.3, 133.9 (d, J = 2.2Hz),
White solid: 69 mg (81% yield); Rf = 0.42 (ethyl acetate/n-
hexane, 4:6), mp: 172‒174 °C; IR (KBr): 3424, 3058, 2934, 1625,
132.3, 129.4, 129.3, 128.6, 127.0, 120.2, 122.1, 118.5, 114.4 (d, J
= 21.0 Hz), 112.5, 111.3; MS (ESI): m/z 263 [M + H]+; HRMS (ESI):
m/z: calcd for C17H12N2F: 263.09790; found: 263.09668 [M + H]+.
1
1496, 1456, 1421, 1320, 1240, 1023, 745 cm–1; H NMR (500
MHz, CDCl3) δ: 8.59 (d,
7.9 Hz, 1H), 7.97 (d, = 5.2 Hz, 1H), 7.77 (d,
= 7.6 Hz, 1H), 7.51−7.46 (m, 2H), 7.29 (t,
= 7.5 Hz, 1H), 7.14 (d,
J
= 5.2 Hz, 1H), 8.51 (s, 1H), 8.16 (d,
J
=
1-(3-Fluorophenyl)-9H-pyrido[3,4-b]indole (2i):
J
J
J
= 7.5 Hz, 1H),7.54
= 7.6 Hz, 1H), 7.19
White solid: 67 mg (80% yield); Rf = 0.51 (ethyl acetate/n-
hexane, 3:7), mp: 183–184 °C; IR (KBr): 3132, 3065, 1868, 1726,
1619, 1588, 1494, 1448, 1411, 1318, 1231, 1200, 1066, 881, 790,
(t,
(t,
J
J
J
= 8.2 Hz, 1H), 3.86 (s, 3H); 13C NMR
1
(75 MHz, CDCl3) δ: 156.5, 141.1, 140.4, 139.2, 134.8, 132.4,
130.3, 129.3, 128.2, 127.7, 121.9, 121.8, 121.7, 119.9, 113.7,
737, 617, 555 cm–1; H NMR (300 MHz, CDCl3 + DMSO−d6) δ:
11.35 (s, 1H), 8.41 (d,
(t, = 4.7 Hz, 1H), 7.83 (d,
7.60 (d, = 8.3 Hz, 1H), 7.54 (d,
1H), 7.19 (dd,
= 7.5, 14.7 Hz, 2H); 13C NMR (75 MHz, DMSO−d6
δ: 163.8 and 160.6 (d, = 244.8 Hz), 140.9, 140.4, 137.8, 132.8,
= 8.2 Hz), 129.3, 127.7, 123.8, 120.8, 120.5, 119.1,
J
= 5.1 Hz, 1H), 8.11 (d,
= 7.7 Hz, 1H),7.73 (d,
= 6.2 Hz, 1H), 7.48 (d,
J
= 7.9Hz, 1H), 7.96
= 10.0 Hz, 1H),
= 7.9 Hz,
112.2, 111.5, 56.4; MS (ESI): m/z 275 [M + H]+; HRMS (ESI): m/z
:
J
J
J
calcd for C18H15ON2: 275.11789; found: 275.11679 [M + H]+.
J
J
J
1-(p-Tolyl)-9
H
-pyrido[3,4-
b]indole (2e):
J
)
White solid: 71 mg (85% yield); Rf = 0.45 (ethyl acetate/n-
hexane, 3:7), mp: 191–193 °C (Ref30: 190.3‒191.6 °C); IR (KBr):
3643, 3057, 2975, 2875, 1623, 1562, 1495, 1423, 1319, 1069,
820, 740 cm–1; 1H NMR (300 MHz, CDCl3 + DMSO−d6) δ: 11.24 (s,
J
129.8 (d,
114.9 (d,
J
J
= 14.3 Hz), 114.6 (d,
J = 13.2 Hz), 113.6, 111.9; MS
(ESI): m/z 263 [M + H]+; HRMS (ESI): m/z: calcd for C17H12N2F:
1H), 8.38 (d,
5.5 Hz, 3H), 7.59 (d,
(d, = 7.9 Hz, 2H), 7.18 (t,
J
= 5.2 Hz, 1H), 8.10 (d,
= 8.2 Hz, 1H),7.45 (t,
= 7.3 Hz, 1H), 2.42 (s, 3H); 13C NMR
J
= 7.9 Hz, 1H), 7.90 (t,
J
=
263.09790; found: 263.09777 [M + H]+.
J
J
= 7.3 Hz, 1H), 7.34
2-Methoxy-4-(9H-pyrido[3,4-b]indol-1-yl)phenol (2j):
J
J
White solid: 68 mg (80% yield); Rf = 0.46 (ethyl acetate/n-
hexane, 4:6), mp: 261–264 °C (Ref32: 260‒262 °C); IR (KBr): 3357,
3059, 2928, 1626, 1523, 1446, 1325, 12233, 1027, 743 cm–1; H
(75 MHz, CDCl3 + DMSO−d6) δ: 142.2, 140.8, 137.8, 135.4, 135.4,
132.9, 128.9, 128.0, 127.5, 120.8, 120.6, 119.0, 112.9, 112.0,
20.8; MS (ESI): m/z 259 [M + H]+; HRMS (ESI): m/z: calcd for
C18H15N2: 259.12298; found: 259.12192 [M + H]+.
1
NMR (300 MHz, CDCl3 + DMSO−d6) δ: 11.24 (s, 1H), 9.05 (s, 1H),
8.41 (d,
J
= 5.1 Hz, 1H), 8.13 (d,
J
= 7.9 Hz, 1H), 7.90 (d,
= 8.1 Hz, 1H),7.57 (d, = 1.7 Hz, 1H), 7.53−7.46 (m,
= 7.7 Hz, 1H), 7.04 (d, = 8.1 Hz, 1H), 3.99 (s, 3H),
J = 5.3 Hz,
1-(4-Nitrophenyl)-9
H
-pyrido[3,4-
b]indole (2f):
1H), 7.64 (d,
2H), 7.23 (d,
J
J
Yellow solid: 65 mg (76% yield); Rf = 0.49 (ethyl acetate/n-
hexane, 3:7), mp: 244–246 °C (Ref31: 241‒242 °C); IR (KBr): 3367,
3055, 1623, 1597, 1506, 1346, 1316, 1223, 1100, 854, 784, 553
cm–1; 1H NMR (300 MHz, CDCl3 + DMSO−d6) δ: 11.07 (s, 1H), 8.56
J
J
peaks at 11.35, 9.29, 7.97, 7.60 and 4.02 are due to rotamours;
13C NMR (75 MHz, CDCl3 + DMSO−d6) δ: 147.4, 147.0, 142.2,
140.8, 137.7, 132.6, 129.5, 128.6, 127.4, 121.3, 120.9, 120.7,
119.0, 115.2, 112.6, 112.1, 111.9, 55.3, small peaks at 140.9,
127.6, 113.1, 110.2 and 55.8 are due to rotamers; MS (ESI): m/z
291 [M + H]+; HRMS (ESI): m/z: calcd for C18H15O2N2: 291.11280;
found: 291.11153 [M + H]+.
(d,
8.17 (d,
Hz, 1H), 7.56 (t,
J
= 5.3 Hz, 1H), 8.42 (d,
= 7.9 Hz, 1H), 8.03 (d,
= 7.7 Hz, 1H), 7.30 (t,
J
= 8.9 Hz, 2H), 8.30 (d,
= 5.1 Hz, 1H), 7.64 (d,
= 7.0 Hz, 1H); 13C NMR
J
= 8.9 Hz, 2H),
J
J
J
= 8.1
J
J
(75 MHz, CDCl3 + DMSO–d6) δ: 146.5, 144.2, 140.7, 138.9, 137,9,
133.0, 129.6, 128.7, 127.7, 122.9, 120.6, 120.2, 119.1, 114.1,
111.6; MS (ESI): m/z 290 [M + H]+; HRMS (ESI): m/z: calcd for
C17H12O2N3: 290.09240; found: 290.09110 [M + H]+.
3-(9H-Pyrido[3,4-b]indol-1-yl)phenol (2k):
Pale yellow solid: 64 mg (76% yield); Rf = 0.52 (ethyl acetate/n-
hexane, 7:3), mp: 215–216 °C; IR (KBr): 3260, 3055, 2600, 1711,
1624, 1597, 1455, 1427, 1322, 1244, 853, 745 cm–1; H NMR
1
4-(9H
-Pyrido[3,4-
b]indol-1-yl)benzonitrile (2g):
White solid: 66 mg (78% yield); Rf = 0.42 (ethyl acetate/n-
hexane, 3:7), mp: 230–232 °C; IR (KBr): 3404, 3058, 2220, 1624,
(300 MHz, CDCl3 + DMSO−d6) δ: 10.88 (s, 1H), 9.21 (bs, 1H), 8.47
(d,
J
= 5.1 Hz, 1H), 8.13 (d,
J
= 7.7 Hz, 1H), 7.93 (d,
= 3.0 Hz, 1H), 7.55−7.44 (m, 3H), 7.39 (t,
= 7.4 Hz, 1H), 6.95 (d,
J
J
= 5.1 Hz, 1H),
= 7.7 Hz, 1H),
1
1602, 1563, 1454, 1399, 1322, 1225, 1138, 833, 744 cm–1; H
7.61 (d,
7.25 (d,
J
J
NMR (300 MHz, CDCl3 + DMSO−d6) δ: 11.12 (s, 1H), 8.53 (d,
5.3 Hz, 1H), 8.24 (d, = 8.1 Hz, 2H), 8.16 (d, = 7.7 Hz, 1H), 8.02
(d, = 5.3 Hz, 1H), 7.88 (d, = 8.1 Hz, 2H), 7.64 (d, = 7.9 Hz, 1H),
7.58 (t, = 5.5 Hz, 1H), 7.29 (t,
= 7.7 Hz, 1H); 13C NMR (75 MHz,
J
=
J
= 7.2 Hz, 1H); 13C NMR (75 MHz,
J
J
DMSO−d6) δ: 157.0, 142.1, 140.4, 139.0, 137.4, 132.7, 129.0,
128.6, 127.2, 120.4, 120.3, 118.6, 115.0, 114.8, 112.7, 111.5; MS
(ESI): m/z 261 [M + H]+; HRMS (ESI): m/z: calcd for C17H13ON2:
261.10224; found: 261.10197 [M + H]+.
J
J
J
J
J
CDCl3 + DMSO−d6) δ: 142.5, 140.7, 139.5, 138.0, 133.0, 131.6,
129.6, 128.6, 127.8, 120.7, 120.4, 119.2, 118.1, 113.9, 111.6,
110.7; MS (ESI): m/z 270 [M + H]+; HRMS (ESI): m/z: calcd for
C18H12N3: 270.10257; found: 270.10141 [M + H]+.
1-(Benzo[d][1,3]dioxol-5-yl)-9H-pyrido[3,4-b]indole (2l):
White solid: 76 mg (89% yield); Rf = 0.40 (ethyl acetate/n-
hexane, 3:7), mp: 169–170 °C (Ref28: 171‒172 °C); IR (KBr): 3113,
3054, 2956, 2883, 1625, 1563, 1501, 1471, 1244, 1038, 934, 810,
745 cm–1; 1H NMR (500 MHz, CDCl3 + DMSO−d6) δ: 11.14 (s, 1H),
1-(4-Fluorophenyl)-9H-pyrido[3,4-b]indole (2h):
White solid: 66 mg (79% yield); Rf = 0.53 (ethyl acetate/n-
hexane, 3:7), mp: 206–207 °C (Ref30: 203‒205 °C); IR (KBr): 3447,
3122, 3062, 2874, 1623, 1605, 1507, 1461, 1425, 1319, 1234,
8.43 (d,
J
= 5.1 Hz, 1H), 8.13 (d,
J
= 7.9 Hz, 1H), 7.92 (d,
J
J
= 5.1 Hz,
= 7.2 Hz,
1H), 7.65 (d,
1H), 7.03 (d,
J
J
= 8.1 Hz, 1H), 7.61−7.47 (m, 3H), 7.24 (t,
= 7.9 Hz, 1H), 6.09 (s, 2H); 13C NMR (75 MHz, CDCl3
1153, 1066, 854, 735 cm–1; 1H NMR (300 MHz, CDCl3
DMSO−d6) δ: 11.11 (s, 1H), 8.47 (d, = 5.3 Hz, 1H), 8.14 (d,
7.7 Hz, 1H), 8.06 (dd, = 5.5, 8.5 Hz, 2H), 7.95 (d,
+
=
J
J
+ DMSO−d6) δ: 146.6, 146.5, 141.0, 140.0, 136.9, 131.9, 131.5,
128.1, 126.7, 121.1, 120.0, 119.8, 118.2, 112.0, 111.1, 107.6,
J
J
= 5.1 Hz, 1H),
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107.1, 99.9; MS (ESI): m/z 289 [M + H]+; HRMS (ESI): m/z: calcd
reaction mixture was quenched with saturated NaHCO3 and
extracted with ethyl acetate. The combined organic layers were
washed with brine, dried over anhydrous magnesium sulfate,
filtered and concentrated. The residue obtained was purified by
silica-gel column chromatography using ethyl acetate-hexane as
eluent in increasing polarity to afford the desired β-carbolines
esters 4a-p.
for C18H13O2N2: 289.09715; found: 289.09561 [M + H]+.
1-(Pyridin-3-yl)-9H-pyrido[3,4-b]indole (2m):
White solid: 75 mg (90% yield); Rf = 0.48 (ethyl acetate), mp:
205–208 °C; IR (KBr): 3207, 3154, 3055, 2980, 2891, 1624, 1567,
1
1428, 1405, 1320, 1229, 1139, 1025, 823, 727 cm–1; H NMR
(300 MHz, CDCl3 + DMSO−d6) δ: 11.08 (s, 1H), 9.32 (s, 1H), 8.69
(dd,
1H), 8.16 (d,
8.1 Hz, 1H), 7.58−7.49 (m, 2H), 7.29 (t,
J
= 1.1, 4.5 Hz, 1H), 8.55(d,
J
= 5.3 Hz, 1H), 8.38 (d,
= 5.1 Hz, 1H), 7.63 (d,
= 7.2 Hz, 1H); 13C NMR
J
= 7.9 Hz,
Methyl 1-phenyl-9H-pyrido [3, 4-b] indole-3-carboxylate (4a):
J
= 7.9 Hz, 1H), 8.00 (d,
J
J
=
White solid: 87 mg (88% yield); Rf = 0.50 (ethyl acetate/n-
hexane, 4:6), mp: 257–259 °C (Ref28: 256‒257 °C); IR (KBr): 3315,
3002, 2947, 1720, 1622, 1350, 1251, 1214, 1098, 739, 542 cm–1;
J
(75 MHz, DMSO−d6) δ: 149.3, 148.9, 141.1, 139.3, 138.5, 135.8,
134.0, 133.2, 129.3, 128.3, 123.8, 121.6, 120.6, 119.6, 114.4,
112.3; MS (ESI): m/z 246 [M + H]+; HRMS (ESI): m/z: calcd for
C16H12N3: 246.10257; found: 246.10124 [M+H]+.
1HNMR (300 MHz, DMSO−d6) δ: 8.92 (s, 1H), 8.42 (d,
1H), 8.02 (d, = 7.0 Hz, 2H), 7.73−7.54 (m, 5H), 7.33 (t,
J
= 7.9 Hz,
J
J = 7.7 Hz,
1H), 3.93 (s, 3H); 13C NMR (75 MHz, CDCl3 + DMSO−d6) δ: 165.8,
141.9, 141.3, 137.4, 136.4, 134.4, 128.9, 128.5, 128.4, 128.2,
121.4, 121.3, 120.9, 120.0, 116.3, 112.5, 51.7; MS (ESI): m/z 303
[M + H]+; HRMS (ESI): m/z: calcd for C19H15O2N2: 303.11280;
found: 303.11159 [M + H]+.
1-(Naphthalen-1-yl)-9H-pyrido[3,4-b]indole (2n):
Off white solid: 69 mg (80% yield); Rf = 0.50 (ethyl acetate/n-
hexane, 3:7), mp: 178–180 °C; IR (KBr): 3448, 3052, 2940, 2654,
2759, 2675, 1623, 1562, 1502, 1453, 1421, 1322, 1239, 1067,
1
777, 749, 622 cm–1; H NMR (300 MHz, CDCl3 + DMSO−d6) δ:
Methyl 1-(4-methoxyphenyl)-9
carboxylate (4b):
H-pyrido[3,4-b]indole-3-
10.79 (s, 1H),8.47 (d,
(d, = 5.5 Hz, 1H), 7.95 (d,
7.72‒7.67 (m, 2H), 7.63 (d,
1H), 7.45−7.40 (m, 2H), 7.34 (t,
J
= 5.3 Hz, 1H), 8.12 (d,
= 5.5 Hz, 1H), 7.85‒7.76 (m, 1H),
= 7.5 Hz, 1H), 7.48 (d, = 7.7 Hz,
= 8.1 Hz, 1H), 7.21−7.14 (m,
J = 7.9 Hz, 1H), 8.00
J
J
White solid: 92 mg (93% yield); Rf = 0.49 (ethyl acetate/n-
hexane, 4:6), mp: 228–231 °C (Ref28: 228‒230 °C); IR (KBr): 3249,
2946, 2833, 1712, 1610, 1508, 1431, 1351, 1248, 1106, 1029,
J
J
J
1H); 13C NMR (75 MHz, CDCl3 + DMSO−d6) δ: 142.4, 140.8, 137.6,
135.4, 134.6, 133.4, 131.1, 128.5, 128.3, 127.8, 127.6, 127.1,
125.9, 125.6, 125.4, 125.2, 121.0, 120.7, 119.0, 113.4, 111.9; MS
(ESI): m/z 295 [M + H]+. HRMS (ESI): m/z: calcd for C21H14N2: 295.
12298; found: 295.12249 [M + H]+.
833, 744, 577 cm–1; 1H NMR (300 MHz, CDCl3 + DMSO−d6
δ:11.65 (s, 1H), 8.79 (s, 1H), 8.22 (d, = 7.9 Hz, 1H), 8.00 (d,
8.7 Hz, 2H), 7.69 (d, = 8.3 Hz, 1H), 7.55 (t, = 7.1 Hz, 1H),7.31 (t,
= 7.2 Hz, 1H), 7.11 (d, = 8.7 Hz, 2H), 3.99 (s, 3H), 3.90 (s, 3H);
13C NMR (75 MHz, CDCl3 + DMSO−d6) δ: 164.9, 158.5, 140.1,
135.2, 133.3, 128.8, 128.5, 127.6, 126.8, 119.9, 119.8, 118.8,
114.6, 112.5, 111.3, 53.7, 50.6; MS (ESI): m/z 333 [M + H]+;
HRMS (ESI): m/z: calcd for C20H17O3N2: 333.12337; found:
333.12194 [M + H]+.
)
J
J =
J
J
J
J
Norharmane (2o):
Yellow solid: 60 mg (77% yield); Rf = 0.43 (ethyl acetate),
mp:193–196 °C (Ref32: 196 °C); IR (KBr): 3450, 3045, 2931, 2853,
1
2736, 2655, 1626, 1447, 1327, 1241, 737 cm–1; H NMR (500
MHz, DMSO−d6) δ: 11.63 (s, 1H), 8.91 (s, 1H), 8.34 (d,
1H), 8.24 (d, = 7.9 Hz, 1H), 8.10 (d, = 5.0 Hz, 1H), 7.60 (d,
9.0 Hz, 1H), 7.54 (t, = 7.6 Hz, 1H), 7.24 (t,
= 7.9 Hz, 1H); 13C
J
= 5.2Hz,
Methyl 1-(3,4,5-trimethoxyphenyl)-9
carboxylate (4c):
H-pyrido[3,4-b]indole-3-
J
J
J =
J
J
Off white solid: 94 mg (95% yield); Rf = 0.47 (ethyl acetate/n-
hexane, 1:1), mp: 227–229 °C (Ref28: 228‒230 °C); IR (KBr): 3605,
3262, 2963, 2942, 2830, 1710, 1625, 1588, 1502, 1461, 1431,
1394, 1358, 1330, 1253, 1129, 1008, 842, 745, 631 cm–1; H
NMR (125 MHz, DMSO−d6) δ; 140.4, 138.0, 135.9, 133.9, 128.0,
127.3, 121.7, 120.5, 119.1, 114.6, 111.8; MS (ESI): m/z 169 [M +
H]+; HRMS (ESI): m/z: calcd for C11H9N2: 169.07602; found:
169.07576 [M + H]+.
1
NMR(300 MHz, CDCl3 + DMSO−d6) δ: 11.52 (s, 1H), 8.75 (s, 1H),
Harmane (2p):
8.12 (d,
J
= 7.7 Hz, 1H), 7.62 (d,
J = 8.1 Hz, 1H), 7.48 (t, J = 8.1 Hz,
Off white solid: 60 mg (76% yield); Rf = 0.51 (ethyl acetate), mp:
229–231 °C (Ref28: 235‒236 °C); IR (KBr): 3129, 3065, 2957,
2884, 2783, 1626, 1565, 1505, 1449, 1324, 1255, 819, 741 cm–1;
1H), 7.25 (t,
J
= 7.1 Hz, 1H), 7.15 (s, 2H), 3.95 (s, 3H), 3.90 (s, 6H),
3.81 (s, 3H); 13C NMR (75 MHz, CDCl3 + DMSO−d6) δ: 165.8,
152.7, 142.2, 141.2, 137.8, 136.2, 134.5, 132.9, 128.7, 128.0,
121.1, 120.9, 119.9, 116.1, 112.4, 105.5, 59.9, 55.5, 51.7; MS
(ESI): m/z 393 [M + H]+; HRMS (ESI): m/z: calcd for C22H21O5N2:
393.14450; found: 393.14320 [M + H]+.
1H NMR (300 MHz, CDCl3 + DMSO−d6) δ: 10.78 (s, 1H), 8.29 (d,
= 4.7 Hz, 1H), 8.10 (d, = 7.5 Hz, 1H), 7.81 (d, = 4.7 Hz, 1H),
7.63–7.47 (m, 2H), 7.24 (t,
= 7.0 Hz, 1H), 2.86 (s, 3H); 13C NMR
J
J
J
J
(75 MHz, CDCl3 + DMSO–d6) δ: 141.7, 140.3, 136.8, 134.3, 127.4,
126.9, 121.1, 120.8, 118.2, 112.2, 111.6, 20.0; MS (ESI): m/z 183
[M + H]+; HRMS (ESI): m/z: calcd for C12H11N2: 183.09167; found:
183.09165 [M + H]+.
methyl 1-(2-methoxyphenyl)-9
carboxylate (4d):
H-pyrido[3,4-b]indole-3-
White solid: 87 mg (88% yield); Rf = 0.42 (ethyl acetate/n-
hexane, 4:6), mp: 208–210 °C; IR (KBr): 3251, 3056, 2947, 2837,
General experimental procedure for the synthesis of β-
carboline esters (4a-p) via dehydrogenation of tetrahydro-β-
carboline esters (3a-p)
1730, 1711, 1624, 1459, 1434, 1239, 1222, 1120, 1027, 741 cm–
1
1; H NMR (500 MHz, CDCl3) δ: 8.91 (d,
J
= 0.4 Hz, 1H), 8.75 (bs,
= 7.9 Hz, 1H), 7.79 (dd, = 1.8, 7.6 Hz, 1H),
7.60−7.56 (m, 1H), 7.53 (d, = 8.1 Hz, 1H), 7.50−7.46 (m, 1H),
7.37−7.34 (m, 1H), 7.20−7.17 (m, 1H), 7.12 (d, = 7.6 Hz, 1H),
1H), 8.22 (d,
J
J
To a stirred solution of tetrahydro-β-carboline esters 3a-p in
DMF was added iodobenzene diacetate (2 equiv) and the
resulting solution was stirred at room temperature for 1h. After
consumption of starting material (monitored by TLC), the
J
J
4.05 (s, 3H), 3.84 (s, 3H); 13C NMR (75 MHz, CDCl3) δ: 166.9,
156.6, 141.0, 140.5, 137.6, 136.3, 132.6, 130.5, 128.9, 128.6,
6 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C5OB00871A
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127.0, 121.8, 121.7, 120.6, 116.8, 112.0, 111.8, 56.3, 52.5; MS
(ESI): m/z 333 [M + H]+; HRMS (ESI): m/z: calcd for C20H17O3N2:
333.12337; found: 333.12278 [M + H]+.
1045, 847, 750, 541 cm–1; 1H NMR (500 MHz, CDCl3 + DMSO−d6
δ: 8.87 (s, 1H), 8.83 (s, 1H), 8.22 (d, = 7.8 Hz, 1H), 7.92 (dd,
5.3, 8.7 Hz, 2H), 7.61 (t, = 8.1 Hz, 1H), 7.56 (d, = 8.1 Hz, 1H),
7.39 (t, = 7.9 Hz, 1H), 7.22 (t,
= 8.7 Hz, 2H), 4.06 (s, 3H); 13C
NMR (75 MHz, CDCl3 + DMSO−d6) δ: 165.7, 164.0 and 160.7 (d,
= 247.0 Hz), 141.3, 140.8, 136.4, 134.3, 133.7 (d, = 2.7 Hz),
130.5, (d, = 8.2 Hz), 129.0, 128.2, 121.4, 120.9, 120.0, 116.3,
115.4 and 115.1 (d,
)
J
J =
J
J
Methyl 1-(p-tolyl)-9
H
-pyrido[3,4-b]indole-3-carboxylate (4e):
J
J
Yellow solid: 89 mg (90% yield); Rf = 0.51 (ethyl acetate/n-
hexane, 3:7), mp: 192–194 °C; IR (KBr): 3640, 3325, 3028, 2946,
J
J
1716, 1621, 1457, 1433, 1350, 1258, 1218, 1109, 1047, 819, 750
J
1
cm–1; H NMR (500 MHz, DMSO−d6) δ: 8.90 (s, 1H), 8.42 (d,
J
=
J = 21.4 Hz), 112.4, 51.7; MS (ESI): m/z 321
[M + H]+; HRMS (ESI): m/z: calcd for C19H14O2N2F: 321.10338;
7.8 Hz, 1H), 7.93 (d,
J
= 9.1 Hz, 2H), 7.70 (d,
J
= 8.2 Hz, 1H), 7.60
= 7.9 Hz, 1H),
(t, J = 8.2 Hz, 1H), 7.45 (d,
J
= 7.9 Hz, 2H), 7.32 (t,
J
found: 321.10298 [M + H]+.
3.93 (s, 3H), 2.45 (s, 3H); 13C NMR (75 MHz, DMSO−d6) δ: 166.0,
142.1, 141.4, 138.4, 136.5, 134.6, 134.4, 129.3,129.0, 128.5,
128.4, 121.9, 121.1, 120.3, 116.4, 112.7, 52.0, 20.9; MS (ESI):
m/z 317 [M + H]+; HRMS (ESI): m/z: calcd for C20H17O2N2:
317.12845; found: 317.12788 [M + H]+.
Methyl 1-(3-fluorophenyl)-9
carboxylate (4j):
H-pyrido[3,4-b]indole-3-
White solid: 86 mg (87% yield); Rf = 0.52 (ethyl acetate/n-
hexane, 3:7), mp: 255–257 °C; IR (KBr): 3316, 3213, 3063, 1723,
1453, 1351, 1289, 1252, 1225, 1104, 746, 543 cm–1; H NMR
1
Methyl 1-(4-nitrophenyl)-9
H
-pyrido[3,4-
b
]indole-3-carboxylate
(300 MHz, DMSO−d6) δ: 11.15 (s, 1H), 8.96 (s, 0.6H), 8.44 (d,
7.9 Hz, 0.7H), 7.87 (t, = 7.4 Hz, 1H), 7.80 (d, = 10.2 Hz, 1H),
7.74−7.67 (m, 2H), 7.66−7.59 (m, 1H), 7.46−7.31 (m, 2H), 3.94 (s,
3H); 13C NMR (75 MHz, DMSO‒d6) δ: 165.8, 163.8 and 160.6 (d,
= 243.7 Hz), 149.8, 141.4, 136.5, 134.4, 130.7(d, = 8.2
Hz),129.4, 128.8, 124.8, 124.7 (d, = 2.2 Hz), 122.0, 121.7, 121.0,
J =
(4f):
J
J
Yellow solid: 79 mg (83% yield); Rf = 0.33 (ethyl acetate/n-
hexane, 3:7), mp: 265−266 °C (Ref22: 260 °C); IR (KBr): 3262,
2952, 1733, 1519, 1433, 1350, 1246, 1109, 1046, 854,741 cm–1;
J
J
1H NMR (300 MHz, DMSO−d6) δ: 9.00 (s, 1H), 8.47 (d,
3H), 8.29 (d, = 8.9 Hz, 2H), 7.70 (d, = 8.1 Hz, 1H), 7.64 (t,
7.5 Hz, 1H), 7.36 (t,
= 7.7 Hz, 1H), 3.94 (s, 3H); 13C NMR (75
J
= 8.7 Hz,
J
J
J
J
=
117.0, 115.7 (d, J = 20.9 Hz),115.2(d, J = 22.2 Hz), 112.7, 52.0;
J
MS (ESI): m/z 321 [M + H]+; HRMS (ESI): m/z: calcd for
MHz, DMSO−d6) δ: 165.7, 147.4, 143.5, 141.5, 139.3, 139.8,
1345.7, 129.8, 129.0, 123.8, 122.1, 120.9, 120.6, 117.5, 112.6,
52.1; MS (ESI): m/z 348 [M + H]+; HRMS (ESI): m/z: calcd for
C19H14O4N3: 348.09788; found: 348.09769 [M + H]+.
C19H14O2N2F: 321.10338; found: 321.10298 [M + H]+.
Methyl 1-(3-hydroxyphenyl)-9
carboxylate (4k):
H-pyrido[3,4-b]indole-3-
Off white solid: 82 mg (83% yield); Rf = 0.32 (ethyl acetate/n-
hexane, 1:1), mp: 234–235 °C; IR (KBr): 3448, 3289, 2953, 1690,
Methyl 1-(4-cyanophenyl)-9
carboxylate (4g):
H-pyrido[3,4-b]indole-3-
1
1599, 1563, 1440, 1356, 1329, 1264, 1113, 1047, 745 cm–1; H
White solid: 82 mg (85% yield); Rf = 0.55 (ethyl acetate/n-
hexane, 3:7), mp: 324–327 °C; IR (KBr): 3250, 2952, 2227, 1726,
1500, 1386, 1253, 1104, 1045, 846, 754, 550 cm–1; 1H NMR (300
NMR (300 MHz, CDCl3 + DMSO−d6) δ : 8.54 (bs, 1H), 8.81 (s, 1H),
8.24 (d,
J
= 7.9 Hz, 1H), 7.67 (d,
J
= 8.1 Hz, 1H), 7.52 (t,
= 7.5 Hz, 1H), 6.92 (d,
J
J
= 7.7 Hz,
= 7.4 Hz,
1H), 7.46−7.32 (m, 3H), 7.27 (t,
J
MHz, DMSO−d6) δ: 8.98 (s, 1H), 8.45 (d,
= 8.3 Hz, 2H), 8.11 (d, = 8.1 Hz, 2H), 7.70 (d,
(t, = 7.0 Hz, 1H), 7.35 (t,
= 7.2 Hz, 1H), 3.94 (s, 3H); 13C NMR
J
= 7.9 Hz, 1H), 8.21 (d,
J
1H), 3.93 (s, 3H); 13C NMR (75 MHz, DMSO−d6) δ; 165.7, 157.4,
142.2, 141.2, 138.5, 136.1, 134.4, 129.5, 128.9, 128.0, 121.1,
121.0, 120.0, 119.0, 116.1, 115.7, 115.3, 112.5, 51.6; MS (ESI):
m/z 319 [M + H]+; HRMS (ESI): m/z: calcd for C19H15O3N2:
319.10772; found: 319.10674[M + H]+.
J
J
= 8.1 Hz, 1H), 7.63
J
J
(75 MHz, DMSO−d6) δ: 165.8, 141.7, 141.5, 139.8, 136.7, 134.6,
132.6, 129.7, 129.4, 128.9, 122.1, 120.9, 120.6, 118.7, 117.4,
112.7, 111.3, 52.1; MS (ESI): m/z 328 [M + H]+; HRMS (ESI): m/z
calcd for C20H14O2N3: 328.10805; found: 328.10760 [M + H]+.
:
Methyl 1-(benzo[d][1,3]dioxol-5-yl)-9H-pyrido[3,4-b]indole-3-
carboxylate (4l):
Methyl 1-(4-(trifluoromethyl)phenyl)-9
carboxylate (4h):
H
-pyrido[3,4-
b
]indole-3-
White solid: 91 mg (92% yield); Rf = 0.48 (ethyl acetate/n-
hexane, 4:6), mp: 294–296 °C (Ref28: 292‒293 °C); IR (KBr): 3337,
2988, 2947, 2903, 1712, 1623, 1499, 1446, 1353, 1283, 1251,
1176, 1039, 747, 529 cm–1; 1H NMR (300 MHz, DMSO−d6) δ: 8.89
White solid: 84 mg (85% yield); Rf = 0.55 (ethyl acetate/n-
hexane, 3:7), mp: 306–310°C; IR (KBr): 3258, 2951, 1707, 1623,
1565, 1499, 1436, 1354, 1322, 1253, 1173, 1117, 1066, 846, 738,
(s, 1H), 8.42 (d,
7.1 Hz, .0.9H), 7.58‒7.51 (m, 2H), 7.32 (t,
J = 8.3 Hz, 0.9H), 6.17 (s, 1.8H), 3.93 (s, 3H) peaks at 7.45, 7.10,
J
= 7.9 Hz, 1H), 7.70 (d,
J
= 8.3 Hz, 1H), 7.61 (d,
J =
575 cm–1; 1H NMR (300 MHz, DMSO−d6) δ: 8.80 (s, 1H), 8.13 (t,
= 7.4 Hz, 3H), 7.75 (d, = 8.3 Hz, 2H), 7.60 (d, = 8.1 Hz, 1H), 7.50
(t, = 7.7 Hz, 1H), 7.26 (t,
= 7.5 Hz, 1H), 3.95 (s, 3H); 13C NMR
(75 MHz, DMSO−d6) δ: 165.8, 141.5, 141.3, 140.3, 136.7, 134.7,
129.4 (q, = 8.8, 17.6 Hz), 128.9, 128.8, 125.6, 125.5, 122.4,
J
J
= 7.1 Hz, 1H), 7.18 (d,
J
J
J
J
6.14 are due to 10% minor rotamer; 13C NMR (75 MHz,
DMSO−d6) δ: 165.9, 147.9, 147.5, 141.6, 141.3, 136.4, 134.2,
131.5, 129.0, 128.5, 122.7, 121.9, 121.1, 120.3, 116.3, 112.7,
108.7, 108.5, 101.4, 52.0; MS (ESI): m/z 347 [M + H]+; HRMS
(ESI): m/z: calcd for C20H15O4N2: 347.10263; found: 347.10194
[M + H]+.
J
122.1, 121.0, 120.5, 117.3, 112.6, 52.0; MS (ESI): m/z 371 [M +
H]+; HRMS (ESI): m/z: calcd for C20H14O2N2F3: 371.10019; found:
371.09935 [M + H]+.
Methyl 1-(4-fluorophenyl)-9
H
-pyrido[3,4-
b]indole-3-
Methyl 1-(pyridin-3-yl)-9
(4m):
H-pyrido [3, 4-b] indole-3-carboxylate
carboxylate (4i):
White solid: 85 mg (86% yield); Rf = 0.54 (ethyl acetate/n-
hexane, 3:7), mp: 275–278 °C (Ref34: 203‒205 °C); IR (KBr): 3314,
2955, 1719, 1623, 1509, 1435, 1387, 1351, 1252, 1221, 1101,
White solid: 88 mg (90% yield); Rf = 0.32 (ethyl acetate), mp:
233–236 °C (Ref22: 234‒236 °C); IR (KBr): 3207, 3097, 3062,
2946, 2839, 1728, 1710, 1626, 1565, 1500, 1433, 1356, 1262,
This journal is © The Royal Society of Chemistry 20xx
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ARTICLE
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1218, 1107, 1032, 741, 712, 620 cm–1; 1H NMR (300 MHz,
DMSO−d6) δ: 9.21 (s, 1H), 8.98 (s, 1H), 8.77 (d, = 3.8 Hz, 1H),
= 7.9 Hz, 1H), 8.42−8.36 (m, 1H), 7.73−7.60 (m, 3H),
= 7.7 Hz, 1H), 3.94 (s, 3H); 13C NMR (75 MHz, CDCl3 +
CDCl3) δ: 8.44 (d,
J
= 8.1 Hz, 1H), 8.00 (s, 0.2H), 7.65 (s, 0.7H),
J
7.61−7.54 (m, 1H), 7.52 (s, 1H), 7.40−7.33 (m, 2H), 7.24−7.18 (m,
2H), 7.18−7.11 (m, 2H), 7.56 (s, 0.2H), 5.58 (t, = 1.8 Hz, 0.8H),
8.46 (d,
7.35 (t,
J
J
J
4.07−4.00 (m, 1H), 3.82 (s, 2.4H), 3.72 (s, 0.6H), 3.32−3.26 (m,
1H), 3.10−3.01 (m, 1H), 2.50 (s, 2.4H), 2.41 (s, 0.6H); 13C NMR
(125 MHz, CDCl3) δ: 174.1, 173.1, 168.7, 168.6, 136.3, 136.2,
136.0, 133.6, 132.4, 128.9, 128.7, 127.0, 126.9, 125.8, 125.7,
124.3, 124.1, 123.0, 122.5, 122.0, 121.7, 120.2, 119.7, 119.5,
118.3, 118.2, 116.8, 111.1, 108.3, 108.0, 56.9, 53.2, 52.3, 52.1,
50.5, 46.9, 29.7, 25.6, 24.5, 23.7; MS (ESI): m/z 388 [M + H]+;
HRMS (ESI): m/z: calcd for C23H22O3N3: 388.16557; found:
388.16572 [M + H]+.
DMSO−d6) δ: 165.6, 149.4, 149.0, 141.4, 139.0, 136.6, 135.9,
134.6, 133.2, 129.2, 128.4, 123.5, 121.5, 120.8, 120.2, 116.8,
112.5, 51.8; MS (ESI): m/z 304 [M + H]+; HRMS (ESI): m/z: calcd
for C18H14O2N3: 304.10805; found: 304.10700 [M + H]+.
Methyl 1-(1-acetyl-1
carboxylate (4n):
H-indol-3-yl)-9H-pyrido[3,4-b]indole-3-
Yellow solid: 84 mg (85% yield); Rf = 0.36 (ethyl acetate/n-
hexane, 4:6), mp: 199–201 °C (Ref22: 192‒194 °C); IR (KBr): 3281,
2949, 1711, 1624, 1569, 1451, 1333, 1302, 1251, 1218, 1108,
1-(1
H-Indol-3-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-
1
1002, 744, 620 cm–1; H NMR (300 MHz, CDCl3 + DMSO−d6) δ:
carboxylic acid (8):
11.64 (s, 1H), 8.83 (s, 1H), 8.60 (dd,
J
= 3.0, 6.6 Hz, 1H), 8.52 (dd,
= 2.1, 6.2, Hz, 1H), 8.40 (s, 1H), 8.25 (d, = 7.9 Hz, 1H), 7.72 (d,
= 7.9 Hz, 1H), 7.46‒7.33 (m, 3H), 4.05 (s,
A stirred mixture of tetrahydro-β-carboline 12 (500mg, 1.29
mmol) and 2M LiOH•H2O (5 ml) in THF (5ml) was heated at
reflux for 12 h. The reaction mixture was cooled to rt, THF was
removed under reduced pressure and the reaction mixture was
acidified (pH 7) by drop wise addition of 5N HCl. The resultant
precipitate was collected by filtration, washed with ice cold
water and dried well to provide pure carboxylic acid 8 (384 mg,
J
J
J
= 8.1 Hz, 1H), 7.60 (t,
J
3H), 2.89 (s, 3H); 13C NMR (75 MHz, DMSO−d6) δ: 169.9, 165.9,
141.1, 137.0, 136.2, 135.2, 134.3, 128.9, 128.8, 128.6, 127.1,
125.3, 123.9, 122.7, 121.9, 121.3, 120.5, 117.6, 116.0, 115.7,
112.6, 52.1, 24.1; MS (ESI): m/z 384 [M + H]+; HRMS (ESI): m/z
calcd for C23H18O3N3: 384.13427; found: 384.13417 [M + H] +.
:
90%
yield)
as
a
yellow
solid:
Rf
=
0.39
Methyl 9
H
-pyrido [3, 4-
b
] indole-3-carboxylate (4o):
(methanol/dichloromethane, 4:6), mp: 250–253 °C; IR (KBr):
3176, 2475, 1628, 1453, 1382, 1310, 1236, 1155, 1099, 738, 693
White solid: 80 mg (82% yield); Rf = 0.41 (ethyl acetate), mp:
247–249 °C (Ref22: 242‒244 °C) ; IR (KBr): 3245, 2944, 1716,
1501, 1434, 1343, 1301, 1248, 1101, 729 cm–1; H NMR (300
1
cm–1; H NMR (300 MHz, DMSO−d6) δ: 11.35 (s, 0.2H), 10.82 (s,
1
1H), 10.51 (s, 0.1H), 7.52 (d,
1H), 7.29 (d, = 2.1 Hz, 1H), 7.23 (d,
7.7 Hz, 1H), 7.11−6.97 (m, 3H), 6.89 (t,
0.8H), 5.80 (s, 0.2H),3.73 (q, = 5.5, 7.5 Hz, 1H), 3.21 (dd,
15.7 Hz, 1H), 3.05 (dd,
= 7.9, 15.3 Hz, 1H); 13C NMR (75 MHz,
J
= 7.4 Hz, 1H), 7.40 (d,
= 7.9 Hz, 1H), 7.16 (d,
= 7.7 Hz, 1H), 5.99 (s,
= 5.3,
J = 8.1 Hz,
MHz, DMSO−d6) δ: 8.95 (d,
J
= 10.2 Hz, 2H), 8.41 (d,
J
= 7.9Hz,
J
J
J =
1H), 7.69 (d,
J
= 8.3 Hz, 1H), 7.60 (d,
J
= 7.7 Hz, 1H), 7.32 (d,
J
=
J
7.7Hz, 1H), 3.91 (s, 3H); 13C NMR (75 MHz, DMSO−d6) δ: 165.9,
J
J
140.9, 137.3, 136.3, 133.7, 128.6, 127.4, 122.2, 120.8, 120.1,
J
117.6, 112.3, 51.9; MS (ESI): m/z 227 [M + H]+. HRMS (ESI): m/z
:
DMSO−d6) δ: 171.2, 170.7, 136.4, 136.3, 136.2, 131.0, 127.2,
126.2, 126.1, 121.3, 121.2, 121.0, 119.1, 118.7, 118.6, 118.0,
117.8, 111.8, 111.2, 110.2, 110.0, 107.4, 106.8, 57.7, 53.4,, 50.2,
calcd for C13H11N2O2: 227.08260; found: 227.08124 [M + H]+.
Methyl 1-methyl-9H-pyrido[3,4-b]indole-3-carboxylate (4p):
White solid: 78 mg (80% yield); Rf = 0.42 (ethyl acetate/n-
hexane, 9:1), mp: 243–244 °C (Ref28: 242‒243 °C); IR (KBr): 3329,
47.7, 23.7, 23.1; MS (ESI): m/z 332 [M + H]+; HRMS (ESI): m/z
calcd for C20H18O2N3: 332.13935; found: 332.13866 [M + H]+.
Eudistomin U (9):
:
1
3041, 2948, 1716, 1500, 1434, 1256, 1010, 784, 743 cm–1; H
NMR (300 MHz, CDCl3) δ: 8.23 (s, 1H), 8.80 (s, 1H), 8.17 (d,
J
=
To a stirred solution of acid 8 (100mg, 0. 30 mmol) in DMF was
added iodobenzene diacetate (195 mg 0.60 mmol) and the
resulting mixture was stirred at room temperature for 1h. After
completion of the reaction (monitored by TLC), the reaction
mixture was quenched with saturated NaHCO3 solution and
extracted with ethyl acetate. The combined organic layers were
washed with brine and dried over anhydrous magnesium
sulfate, filtered and concentrated. The residue obtained was
7.5 Hz, 1H), 7.57 (s, 2H),7.41–7.30 (m, 1H), 4.03 (s, 3H), 2.84 (s,
3H); 13C NMR (75 MHz, DMSO−d6) δ: 166.1, 142.1, 140.6, 136.1,
135.8, 128.3, 126.7, 122.0, 121.2, 120.1, 115.9, 112.2, 51.8, 20.3;
MS (ESI): m/z 241 [M + H]+; HRMS (ESI): m/z: calcd for
C14H13O2N2: 241.09715; found: 241.09615 [M + H]+.
Synthesis of Eudistomin U:
Methyl 1-(1-acetyl-1
pyrido[3,4- ]indole-3-carboxylate (7):
A stirred solution of L-tryptophan methyl ester hydrochloride 6
(1g, 3.93 mmol) and -acetyl indole-3-carboxaldehyde (736 mg,
3.93 mmol) in ethanol was refluxed for 12 h. Ethanol was
removed, basified with saturated NaHCO3 solution and
H-indol-3-yl)-2,3,4,9-tetrahydro-1H-
b
purified by silica gel chromatography
(9:1 ethyl
acetate/methanol) to afford the eudistomin U (3, 56 mg, 66%
yield) as a pale yellow solid: Rf = 0.51 (ethyl acetate/n-hexane,
9:1), mp: 232–234 °C (Ref25d: 235‒236 °C); IR (KBr): 3433, 3058,
2922, 1625, 1567, 1453, 1325, 1237, 743 cm–1; 1HNMR (500
N
extracted with ethyl acetate. The combined organic layer was
washed with brine, dried over MgSO4 and concentrated in
vacuo. The residue was purified by column chromatography (4:6
ethyl acetate/n-hexane) to afford diastereomeric mixture
tetrahydro-β-carboline 7 (1.3g, 86% yield) as a yellow solid; Rf =
0.50 (ethyl acetate/n-hexane, 7:3), mp: 237–239 °C; IR (KBr):
3394, 3214, 3088, 2906, 2552, 2462, 1748, 1704, 1455, 1375,
1328, 1224, 1135, 1002, 743, 620 cm–1; 1H NMR (400 MHz,
MHz, DMSO−d6) δ: 11.72 (s, 1H), 11.31 (s, 1H), 8.56 (d,
1H), 8.45 (d, = 5.2Hz, 1H), 8.30 (d, = 2.7 Hz, 1H), 8.24 (d,
7.9 Hz, 1H), 7.96 (d, = 5.2 Hz, 1H), 7.70 (d, = 7.2 Hz, 1H), 7.55
(d, = 7.7 Hz, 1H), 7.52 (d, = 8.1 Hz, 1H), 7.26 (t, = 7.3 Hz, 1H),
7.22 (t, = 7.9 Hz, 1H), 7.14 (t,
= 7.9 Hz, 1H); 13C NMR (125
J = 7.9 Hz,
J
J
J =
J
J
J
J
J
J
J
MHz, DMSO−d6) δ: 159.5, 159.2, 156.7, 155.3, 150.3, 146.9,
146.5, 145.0, 144.8, 141.1, 140.8, 140.1, 140.0, 138.6, 138.2,
132.0, 131.2, 130.4, 130.3; MS (ESI): m/z 284 [M + H]+; HRMS
8 | J. Name., 2012, 00, 1-3
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(ESI): m/z: calcd for C19 H14 N3: 284.11822; found: 284.11692 [M
+ H]+.
(monitored by TLC), the reaction mixture was concentrated
under reduced pressure. The residue obtained was washed with
diethylether, dried anddissolved in DMF was added iodobenzene
diacetate (166mg, 0.51mmol) and the resulting mixture was
stirred for 1h at room temperature. After completion of the
reaction (monitored by TLC), the reaction mixture was quenched
with saturated NaHCO3 solution and extracted with ethyl
acetate. The combined organic layers were washed with brine,
dried over anhydrous magnesium sulfate, filtered and
concentrated under reduced pressure. The residue obtained was
purified by silica gel chromatography (2:8 ethylactate/n-hexane)
to afford the eudistomin I (12, 38 mg, 63% yield) as a pale yellow
solid: Rf = 0.43 (ethyl acetate/n-hexane, 3:7), mp: 153–155 °C
(Ref26a: 153‒155 °C); IR (KBr): 3355, 3047, 2918, 2855, 1627,
1608, 1490, 1452, 1430, 1345, 1319, 1285, 1256, 1135, 1034,
Synthesis of Eudistomin I:
Methyl 1-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-2,3,4,9-
tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate (10):
A stirred solution of L-tryptophan methyl ester hydrochloride
salt 6 (1g, 3.93 mmol) and (S)-tert-butyl-2-formylpyrrolidine-1-
carboxylate (783 mg, 3.93 mmol) in ethanol was heated at reflux
for 12 h. After cooling to rt, the ethanol was removed and
basified with saturated NaHCO3 solution. The aqueous layer was
extracted with ethyl acetate. The combined organic layer was
washed with brine, dried over MgSO4 and concentrated in
vacuo. The residue was purified by column chromatography (3:7
ethyl acetate/n-hexane) to afford the tetrahydro-β-carboline 10
(1.33 mg, 88% yield) as a diastereomeric mixture, Pale yellow
solid; Rf = 0.48 (ethyl acetate/n-hexane, 1:1), mp: 100–102 °C; IR
(KBr): 3345, 2971, 1738, 1675, 1453, 1398, 1165, 1116, 1012,
741 cm–1; 1H NMR (500 MHz, CDCl3) δ: 7.97 (m, 0.5H), 7.52−7.47
(m, 1H), 7.36−7.29 (m, 1H), 7.19−7.13 (m, 1H), 7.13−7.08 (m,
1H), 4.93 (s, 0.6H), 4.88 (s, 0.4H), 4.07−3.97 (s, 1H), 3.82 (s,
1.3H), 3.76−3.72 (s, 0.5H), 3.68 (s, 1.7H), 3.66−3.58 (m, 0.5H),
3.48−3.39 (m, 0.5H), 3.27−3.19 (m, 0.5H), 3.18−3.04 (m, 1.6H),
2.87−2.76 (m, 0.4H), 2.08−1.96 (m, 1H), 1.74−1.58 (m, 4H), 1.54
(s, 4.7H), 1.53 (s, 1.3H), 1.50 (bs, 3H); 13C NMR (125 MHz, CDCl3)
δ: 174.3, 155.8, 155.7, 136.4, 136.1, 131.6, 126.9, 126.6, 121.7,
119.5, 119.3, 117.8, 117.8, 110.8, 110.4, 108.9, 80.4, 79.9, 79.6,
62.7, 61.4, 60.8, 56.2, 55.8, 54.2, 53.9, 53.5, 52.2, 52.1, 52.0,
51.9, 51.2, 48.4, 47.9, 28.5, 28.4, 27.5, 25.5, 24.6, 23.8; MS (ESI):
m/z 400 [M + H]+. HRMS (ESI): m/z: calcd for C22 H30 O4 N3:
400.22308; found: 400.22348 [M + H]+.
1
977, 751, 603, 551 cm–1; H NMR (500 MHz, CDCl3) δ: 10.85 (s,
1H), 8.51 (d, J = 5.0 Hz, 1H), 8.16 (d, J = 7.9 Hz, 1H), 8.01 (d, J =
5.2 Hz, 1H), 7.60−7.55 (m, 2H), 7.33−7.28 (m, 1H), 4.31−4.26 (m,
2H), 3.36−3.31 (m, 2H), 2.13−2.06 (m, 2H); 13C NMR (125 MHz,
CDCl3) δ: 176.8, 140.7, 138.1, 135.8, 135.3, 129.5, 128.5, 121.8,
121.8, 120.0, 116.1, 111.9, 62.2, 34.9, 21.8; MS (ESI): m/z 236 [M
+ H]+. HRMS (ESI): m/z: calcd for C15H14N3: 236.11822 found:
236.11774 [M + H]+.
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