A Unified Approach to the Isomeric α-, β-, γ-, and δ-Carbolines via their 6,7,8,9-Tetrahydro Counterparts

Article abstract of DOI:10.1021/acs.joc.7b00323

A cross-coupling/reductive cyclization protocol has been employed in a unified approach to all four carbolines. So, for example, the 2-nitropyridine 8, which is readily prepared through an efficient palladium-catalyzed Ullmann cross-coupling reaction, is reductively cyclized under conventional conditions to give 6,7,8,9-tetrahydro-α-carboline that is itself readily aromatized to give α-carboline (1).

Full text of DOI:10.1021/acs.joc.7b00323

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Article
A Unified Approach to the Isomeric #-,#-,#- and #-
Carbolines via their 6,7,8,9-Tetrahydro-counterparts
Qiao Yan, Emma Gin, Martin G Banwell, Anthony C Willis, and Paul D Carr
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00323 • Publication Date (Web): 17 Mar 2017
Downloaded from http://pubs.acs.org on March 17, 2017
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A Unified Approach to the Isomeric α-,β-,γ- and δ-Carbolines via their
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6,7,8,9-Tetrahydro-counterparts
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Qiao Yan, Emma Gin, Martin G. Banwell,* Anthony C. Willis and Paul D. Carr
Research School of Chemistry, Institute of Advanced Studies,
The Australian National University, Canberra, ACT 2601, Australia
Email: Martin.Banwell@anu.edu.au
_____________________________________________________________________________________
palladiumꢀcatalyzed
Ullmann crossꢀcoupling
H2
10 wt. % Pd/C
10 wt. % Pd/C
MeOH, 22 °C
16 h, 75%
O
O2N
Ph2O, 210 °C
0.66 h, 97%
N
N
N
H
8
1
A crossꢀcoupling/reductive cyclisation protocol has been employed in a unified approach to all four
carbolines. So, for example, the 2ꢀnitropyridine 8, which is readily prepared through an efficient palladiumꢀ
catalyzed Ullmann crossꢀcoupling reaction, is reductively cyclized under conventional conditions to give
6,7,8,9ꢀtetrahydroꢀαꢀcarboline that is itself readily aromatized to give αꢀcarboline (1).
INTRODUCTION
The isomeric αꢀ,βꢀ,γꢀ and δꢀcarbolines (1ꢀ4, respectively in Figure 1) are important
heterocyclic rings systems.1 All are encountered, albeit to varying extents, as key
structural motifs in natural products. They also feature in a wide range of medicinally
relevant compounds. The utility of various of their derivatives in materials science is a
further focus of current studies.2 The αꢀcarboline framework (1) is encountered in a
limited number of naturally occurring antiꢀcancer agents and in the neuroꢀprotective
alkaloid mescengricin.3 On the other hand, synthetically derived αꢀcarbolines have
shown anxiolytic, antiꢀinflammatory, CNSꢀstimulating and kinase inhibitory properties.4
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βꢀCarboline (2), itself a natural product isolated from both plants and microꢀorganisms, is
the most well known of the four systems and represents a key substructure associated
with, for example, the eudistomine and manzamine classes of biologically active marine
alkaloid.5 Many medicinal agents embodying this heterocyclic framework have been
identified.5,6 Derivatives of γꢀcarboline (3) have been explored extensively as antiꢀcancer
and antiꢀAlzheimer agents7 while those associated with δꢀcarboline (4) have been studied,
inter alia, for their antiꢀbacterial and antiꢀtumor properties.1b,8 δꢀCarbolineꢀcontaining
alkaloids have been isolated from, for example, various West and Central African plants
that are prized as sources of traditional medicines for treating malaria and certain
infectious diseases.1b
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N
N
N
N
H
N
H
N
H
N
H
N
1
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Figure 1: The Isomeric αꢀ,βꢀ,γꢀ and δꢀCarbolines (1ꢀ4)
A multitude of methods has been established for the synthesis of the carbolines, including
classical ones involving GraebeꢀUllmann, Fischer indolization, BischlerꢀNapieralski and
PictetꢀSpengler reactions.9,10 Variations on the Cadogan syntheses of carbazoles are also
known,11 as are routes involving the annulation of pyridines onto indoles,9,10,12 including
through DielsꢀAlder and electrocyclization processes. Generally speaking, though,
“customized” approaches are required for the assembly of each of the αꢀ,βꢀ,γꢀ and δꢀ
carboline frameworks and thus prompting the search for more general routes to them.13
There has been modest success in this regard with the most effective route involving the
cyclization of anilinoꢀpyridines.13gꢀj Recently, Driver13i and Ray13j have each reported
variations on such methods that allow access to three of the four frameworks. It is
against this background that we now detail a distinct, operationally simple and likely
flexible route to all four of the isomeric carbolines and highlight the utility of this through
the synthesis of the simple natural product harman (5, Figure 2), a compound that
displays antiꢀHIV and antiꢀbacterial properties.14
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Figure 2: The βꢀCarboline Alkaloid Harman (5)
RESULTS AND DISCUSSION
The pivotal steps associated with the unified approach to the carbolines reported here are
the palladiumꢀcatalyzed Ullmann crossꢀcoupling15 of 2ꢀiodocyclohexꢀ2ꢀenꢀ1ꢀone16 with
the relevant halogenated nitropyridine and the reductive cyclization of the ensuing 2ꢀ
pyridylꢀcyclohexꢀ2ꢀenꢀ1ꢀone to give the corresponding 6,7,8,9ꢀtetrahydrocarboline.
Oxidation of these tetrahydroꢀcompounds to their fully aromatic counterparts (viz. the
carbolines) was readily accomplished using 10 wt % palladium on carbon. This sequence
mirrors that used in in our recently reported syntheses of various carbazoleꢀbased natural
products including glycoborine, glycozoline, clausazoline K, mukonine and
karapinchamine A.17
The synthesis of αꢀcarboline (1), as shown in Scheme 1, is illustrative and starts with the
palladiumꢀcatalyzed Ullmann crossꢀcoupling of the readily prepared17 2ꢀiodocyclohexꢀ2ꢀ
enꢀ1ꢀone (6) with commercially available 3ꢀbromoꢀ2ꢀnitropyridine (7) and thus affording
the 2ꢀpyridylꢀcyclohexꢀ2ꢀenꢀ1ꢀone 8 in 82% yield. In order to reduce the extent of homoꢀ
coupling of the pyridine in this reaction, the iodoꢀenone 6 was treated with a combination
of copper metal, copper(I) iodide and Pd(dppf)Cl2ꢀCH2Cl2 in DMSO at 50 °C for 0.75 h
prior the addition of compound 7. Presumably this allows cupration of compound 6 to
take place prior to a palladiumꢀcatalyzed crossꢀcoupling reaction with halide 7 and so
increasing the yields of product 8. The reductive cyclization of compound 8 was effected
using hydrogen in the presence of catalytic amounts of 10 wt. % palladium on carbon
(Pd/C) in methanol at room temperature for 16 h and this produced the 6,7,8,9ꢀ
tetrahydrocarboline 918 in 75% yield. In our hands, the oxidation19 of compound 9 to αꢀ
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carboline (1)4a was best carried out by exposing the former system to an equivalent mass
of 10 wt % palladium on carbon in diphenyl ether at 210 °C for 0.66 h. By such means
target 1 was obtained in 97% yield and all of the spectral data acquired on this material
were in complete accord with the assigned structure and matched those reported in the
literature. A singleꢀcrystal Xꢀray analysis was carried out on compound 1 and details are
provided in the Experimental Section and the Supporting Information (SI).
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Scheme 1: The Synthesis of αꢀCarboline (1)
Cu, CuI
Pd(dppf)Cl2•CH2Cl2
Br
+
I
DMSO, 50 °C
6.25 h, 82%
O2N
N
O
O2N
O
N
7
6
8
H2, 10 wt % Pd/C
MeOH, 22 °C
16 h, 75%
10 wt % Pd/C
Ph2O, 210 °C
0.66 h, 97%
N
N
H
N
N
H
9
1
Given the use of 10 wt % palladium on carbon in both the second and third steps of the
reaction sequence these could, in principle, be “telescoped” so establish a oneꢀpot
process. To date, however, we have not been able to identify conditions that allow for this
to be conducted in both an operationally superior way and with better outcomes.
The synthesis of βꢀcarboline (2) (Scheme 2) required 4ꢀiodoꢀ3ꢀnitropyridine (10)20 as a
coupling partner and this was readily obtained by reacting the commercially available
chloroꢀanalogue with sodium iodide in acetonitrile (see Experimental Section for details).
Crossꢀcoupling of compounds 6 and 10 proceeded smoothly under essentially the same
conditions as employed for the conversion 6 + 7 → 8 and provided the anticipated
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coupling product 11 in 86% yield. Reductive cyclization of compound 11 proceeded
uneventfully under the previously established conditions and product 1221 (88%) was
readily oxidized to target 2 (94%) on brief exposure to an equal mass of 10 wt %
palladium on carbon in hot diphenyl ether. Once again, all the spectral data acquired on
βꢀcarboline (2) matched those reported22 previously. The structure of compound 2 was
also confirmed by single crystal Xꢀray analysis.
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Scheme 2: The Synthesis of βꢀCarboline (2)
Cu, CuI
I
Pd(dppf)Cl2•CH2Cl2
+
N
DMSO, 50 °C
2.5 h, 86%
I
O2N
O
O2N
N
O
10
6
11
H2, 10 wt % Pd/C
MeOH, 22 °C
16 h, 88%
10 wt % Pd/C
N
N
Ph2O, 210 °C
0.66 h, 94%
N
N
H
H
12
2
The analogous synthesis of γꢀcarboline (3) is shown in Scheme 3 and in this instance the
required pyridine, 13, was a commercially available material. Reductive cyclization of
the crossꢀcoupling product 14 (89%) produced from compound 6 and 13 proceeded as
anticipated to give the tetrahydrocarboline 15,23 albeit in just 66% yield. Similarly, the
oxidation of this last compound under the previously employed conditions was less
efficient than observed in the two previous cases with compound 324 being obtained in
77% yield. Once again, full characterization of this product was undertaken including
through a singleꢀcrystal Xꢀray analysis.
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Scheme 3: The Synthesis of γꢀCarboline (3)
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9
Cu, CuI
Pd(dppf)Cl2•CH2Cl2
Br
N
+
N
DMSO, 50 °C
6.25 h, 89%
I
O2N
O
O
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O2N
13
14
6
H2, 10 wt % Pd/C
MeOH, 22 °C
16 h, 66%
10 wt % Pd/C
N
N
Ph2O, 210 °C
0.66 h, 77%
N
H
N
H
15
3
The establishment of a unified approach to all the carbolines followed from the
successful synthesis of δꢀcarboline (4) by the pathway shown in Scheme 4.
Scheme 4: The Synthesis of δꢀCarboline (4)
Cu, CuI
Br
N
Pd(dppf)Cl2•CH2Cl2
+
N
DMSO, 50 °C
3.75 h, 75%
I
O2N
O
O2N
O
16
6
17
H2, 10 wt % Pd/C
MeOH, 22 °C
16 h, 65%
N
N
10 wt % Pd/C
Ph2O, 210 °C
0.66 h, 92%
N
N
H
H
18
4
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So, as before, the palladiumꢀcatalyzed Ullmann crossꢀcoupling of iodoꢀenone 6 with the
required and commercially available pyridine 16 proceeded uneventfully to give product
17 (75%) that was reductively cyclized in the usual manner to afford the
tetrahydrocarboline 1825 (65%). Oxidation of this last compound using an equal mass of
10 wt % palladium on carbon in hot diphenyl ether then gave δꢀcarboline (4)26 (92%) that
was subject to the usual range of spectroscopic analyses, including a singleꢀcrystal Xꢀray
study.
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In order to test the capacities of the abovementioned protocols to deliver substituted
carbolines, the βꢀcarbolineꢀbased natural product harman (5, Figure 2) was targeted for
synthesis. The required pyridine was prepared by the route shown in Scheme 5. Thus,
commercially available 2ꢀmethylpyridinꢀ4ꢀamine (19) was subjected to a Sandmeyer
reaction using water as the nucleophile and so providing the previously reported nitric
acid salt27 20 of 2ꢀmethylpyridinꢀ4ꢀol.
Scheme 5: Route to the Triꢀsubstituted Pyridine 24 Required for the
S
the βꢀCarboline Alkaloid
(5)
HO
H2N
HNO3, NaNO2
HNO3
•
N
N
H2O, 0 to 22 o
14.5 h, 82%
C
19
20
H2SO4, HNO3
0 to 130 oC
6.2 h, 70%
NO2
NO2
HO
O2N
Br
Br
HO
POBr3
+
+
N
N
N
N
O2N
toluene, reflux
10 h, 92%
23
24
21
22
Aromatic nitration of this last compound could only be achieved under rather forcing
conditions and so providing a 1:3 and inseparable mixture of pyridines 21 and 22 (70%
combined yield). Accordingly, this mixture was treated with POBr3 in refluxing toluene
and thereby affording what is presumed to be the corresponding mixture of bromides 23
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and 24 (92% combined yield). These regioisomers could only be separated by HPLC
techniques but sufficient quantities of the pure form of the latter could be accumulated by
such means. The former product (presumed to be compound 23) was not purified or
subject to any spectroscopic characterization.
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With compound 24 in hand, the synthesis of harman (5) was completed by the now
standard pathway shown in Scheme 6. Thus, palladiumꢀcatalyzed Ullmann crossꢀ
coupling of iodoꢀenone 6 with pyridine 24 delivered the required product 25 in 84%
yield. Reductive cyclization of the last compound under the usual conditions gave the
tetrahydroharman 2628 (83%) that could be oxidized to the natural product 514,29 (91%) on
treatment with an equal mass of 10 wt % palladium on carbon in hot diphenyl ether. Once
again, all the spectral data, including a singleꢀcrystal Xꢀray analysis, acquired on
compound 5 confirmed the assigned structure and appropriate comparisons with those
reported14 for the natural product were entirely favorable.
Scheme 6: Completion of the Synthesis of H
man (5)
Cu, CuI
Br
O2N
Pd(dppf)Cl2•CH2Cl2
+
N
DMSO, 50 °C
7.4 h, 84%
I
O
O2N
N
O
24
6
25
H2, 10 wt % Pd/C
MeOH, 22 °C
16 h, 83%
10 wt % Pd/C
N
N
Ph2O, 210 °C
0.66 h, 91%
N
N
H
H
26
5
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CONCLUSIONS
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The reaction sequences reported here should allow for the rational/logical design of
pathways to a wide range of αꢀ,βꢀ,γꢀ and δꢀcarbolines. This is all the more so given the
increasingly ready availability of a wide range of polyꢀsubstituted pyridines30 and 2ꢀ
iodocyclohexꢀ2ꢀenꢀ1ꢀones. For similar reasons, the protocols defined here should allow
for ready access to a wide range of azaindoles, compounds of considerable interest from a
medicinal chemistry perspective.31 Studies exploiting such possibilities will be reported
in due course.
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EXPERIMENTAL SECTION
General Experimental Procedures
Unless otherwise specified, proton (1H) and carbon (13C) NMR spectra were recorded at
18 °C in baseꢀfiltered CDCl3 on a spectrometer operating at 400 MHz for proton and 100
1
MHz for carbon nuclei. H NMR data are recorded as follows: chemical shift (δ)
[multiplicity, coupling constant(s) J (Hz), relative integral] where multiplicity is defined
as s = singlet; d = doublet; t = triplet; q = quartet; m = multiplet or combinations of the
above. In relevant cases, the signal due to residual CHCl3 appearing at δH 7.26 and the
1
central resonance of the CDCl3 “triplet” appearing at δC 77.0 were used to reference H
and 13C NMR spectra, respectively. Samples were analyzed by infrared spectroscopy
(νmax) as thin films on KBr plates. Lowꢀ and highꢀresolution electron impact (EI) mass
spectra were recorded on a double focusing, triple sector machine. Lowꢀ and highꢀ
resolution ESI mass spectra were recorded on a tripleꢀquadrupole mass spectrometer
operating in positive ion mode. Melting points are uncorrected. Analytical thin layer
chromatography (TLC) was performed on aluminumꢀbacked 0.2 mm thick silica gel 60
F254 plates. Eluted plates were visualized using a 254 nm UV lamp and/or by treatment
with a suitable dip followed by heating. These dips included phosphomolybdic acid/ceric
sulfate/sulfuric acid (conc.)/water (37.5 g : 7.5 g : 37.5 g : 720 mL), potassium
permanganate/potassium carbonate/5% sodium hydroxide aqueous solution/water (3 g :
20 g : 5 mL : 300 mL), and pꢀanisaldehyde or vanillin/sulfuric acid (conc.)/ethanol (15 g :
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2.5 mL : 250 mL). Flash chromatographic separations were carried out following
protocols defined by Still et al.32 with silica gel 60 (40ꢀ63 ꢁm) as the stationary phase and
using the ARꢀ or HPLCꢀgrade solvents indicated. The melting points of solids purified by
such means were recorded directly (ie after they had crystallized from the concentrated
chromatographic fractions). Starting materials, reagents, drying agents, and other
inorganic salts were generally commercially available and were used as supplied. The
copper powder used in the palladiumꢀcatalyzed Ullmann crossꢀcoupling reactions had a
particle size of <75 ꢀm. Tetrahydrofuran (THF), methanol and dichloromethane were
dried using a solvent purification system that is based upon a technology originally
described by Grubbs et al.33 Where necessary, reactions were performed under a nitrogen
atmosphere by subjecting the relevant solution to reduced pressure for several minutes
and then admitting nitrogen. This process was repeated three times.
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Specific Chemical Transformations
2-(2-Nitropyridin-3-yl)cyclohex-2-en-1-one (8). A magnetically stirred mixture of 2ꢀ
iodocyclohexꢀ2ꢀenꢀ1ꢀone (6)16 (2.63 g, 11.82 mmol), copper powder (1.50 g, 23.65
mmol), CuI (1.69 g, 8.87 mmol) and Pd(dppf)Cl2ꢀCH2Cl2 (483 mg, 0.59 mmol) in
degassed DMSO (118 mL) was heated at 50 °C under a nitrogen atmosphere for 0.75 h.
After this time a solution of commercially available 3ꢀbromoꢀ2ꢀnitropyridine (7) (1.20 g,
5.91 mmol) in degassed DMSO (30 mL) was added to the reaction mixture over 1.5 h.
After a further 4 h the reaction mixture was cooled, quenched with water (30 mL) then
diluted with ethyl acetate (50 mL). The ensuing mixture was filtered through a pad
comprised of a mixture of diatomaceous earth and silica gel. The solids thus retained
were rinsed with ethyl acetate (2 × 50 mL) and the separated organic phase associated
with the combined filtrates washed with water (2 × 100 mL) then brine (2 × 100 mL)
before being dried (Na2SO4), filtered and concentrated under reduced pressure to give a
brown oil. Subjection of this material to flash column chromatography (silica, 1:3:11
v/v/v acetone/dichloromethane/40ꢀ60 petroleum ether elution) gave, after concentration
of the appropriate fractions (Rf = 0.2 in 1:1 v/v ethyl acetate/40ꢀ60 petroleum ether),
compound 8 (1.06 g, 82%) as a lightꢀbrown solid, mp = 115ꢀ116 °C. 1H NMR (400 MHz,
CDCl3) δ 8.52 (dd, J = 4.7 and 1.7 Hz, 1H), 7.74 (dd, J = 7.6 and 1.7 Hz, 1H), 7.60 (dd, J
13
= 7.6 and 4.7 Hz, 1H), 7.08 (t, J = 4.2 Hz, 1H), 2.60 (m, 4H), 2.15 (m, 2H); C NMR
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(100 MHz, CDCl3) δ 196.0, 157.0, 148.5, 147.8, 141.7, 137.2, 128.1, 126.7, 38.2, 26.5,
22.6; IR νmax 2950, 1679, 1540, 1405, 1366, 975, 864, 810, 707 cm–1; MS (ESI, +ve) m/z
241 [(M+Na)+, 100%]; HRMS m/z (M+Na)+ calcd for C11H10N2NaO3 241.0589, found
241.0591.
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6,7,8,9-Tetrahydro-5H-pyrido[2,3-b]indole (9). A magnetically stirred mixture of
compound 8 (30 mg, 0.14 mmol) and 10 wt % Pd/C (12 mg) in degassed methanol (7
mL) was maintained under an atmosphere of hydrogen for 16 h at 22 °C then filtered and
the solids thus retained washed with methanol (20 mL). The combined filtrates were
concentrated under reduced pressure and the white solid thus obtained was subjected to
flash column chromatography (silica, 1:4 v/v ethyl acetate/40ꢀ60 petroleum ether
elution). Concentration of the appropriate fractions (Rf = 0.7 in ethyl acetate) then gave
compound 918 (18 mg, 75%) as a white, crystalline solid, mp = 155ꢀ156 °C (lit.18 mp =
155ꢀ156 °C). 1H NMR (400 MHz, CDCl3) δ 10.65 (m, 1H), 8.19 (d, J = 4.3 Hz, 1H), 7.75
(dd, J = 7.7 and 1.3 Hz, 1H), 7.01 (dd, J = 7.7 and 4.3 Hz, 1H), 2.84 (t, J = 6.0 Hz, 2H),
13
2.70 (m, 2H), 1.98ꢀ1.86 (complex m, 4H); C NMR (100 MHz, CDCl3) δ 148.9, 140.8,
135.4, 125.7, 120.8, 115.1, 108.4, 23.3(4), 23.2(8), 23.1, 20.8; IR νmax 3149, 3075, 2921,
2846, 1587, 1418, 1289, 786, 765, 677 cm–1; MS (ESI, +ve) m/z 173 [(M+H)+, 100%];
HRMS m/z (M+H)+ calcd for C11H13N2 173.1079, found 173.1078.
9H-Pyrido[2,3-b]indole (α-carboline, 1). A magnetically stirred mixture of compound 9
(20 mg, 0.12 mmol) and 10 wt % Pd/C (20 mg) in diphenyl ether (15 mL) maintained
under a nitrogen atmosphere was heated at 210 °C for 0.66 h. The reaction mixture was
then cooled to room temperature, filtered (through filter paper) and the solids so retained
washed with ethyl acetate (2 × 15 mL). The combined filtrates were concentrated under
reduced pressure and the residue thus obtained subjected to flash column chromatography
(silica, 0:1 → 1:4 v/v ethyl acetate/40ꢀ60 petroleum ether gradient elution).
Concentration of the appropriate fractions (Rf = 0.2 in 1:1 v/v ethyl acetate/40ꢀ60
petroleum ether) gave compound 14a (19 mg, 97%) as a white, crystalline solid, mp =
1
200ꢀ202 °C (lit.4a mp = 215ꢀ217 °C). H NMR (400 MHz, CD3OD) δ 8.44 (dd, J = 7.7
and 1.5 Hz, 1H), 8.34 (dd, J = 4.9 and 1.2 Hz, 1H), 8.09 (d, J = 7.9 Hz, 1H), 7.52 (d, J =
8.1 Hz, 1H), 7.48ꢀ7.44 (complex m, 1H), 7.26ꢀ7.19 (complex m, 2H) (signal due to NꢀH
13
group proton not observed); C NMR (100 MHz, CD3OD) δ 152.9, 146.1, 140.6, 129.9,
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128.0, 122.0, 121.9, 121.0, 118.0, 116.1, 112.3; IR νmax 3048, 2984, 2906, 1600, 1587,
1572, 1455, 1411, 1274, 998, 767, 736 cm–1; MS (ESI, +ve) m/z 169 [(M+H)+, 100%];
HRMS m/z (M+H)+ calcd for C11H9N2 169.0766, found 169.0768.
4-Iodo-3-nitropyridine (10). A magnetically stirred solution of commercially available
4ꢀchloroꢀ3ꢀnitropyridine (1.00 g, 6.31 mmol) in acetonitrile (126 mL) maintained at
ambient temperatures was treated with sodium iodide (17.02 g, 113.55 mmol). The
ensuing mixture was heated under reflux for 2 h then cooled to 22 °C and diluted with
ethyl acetate (200 mL). The resulting solution was washed with Na2CO3 (1 × 100 mL of a
saturated aqueous solution), Na2SO3 (1 × 50 mL of a saturated solution), water (1 × 200
mL) and brine (1 × 100 mL) before being dried (Na2SO4,), filtered then concentrated
under reduced pressure. The residue thus obtained was subjected to flash column
chromatography (silica, 1:19 v/v ethyl acetate/40ꢀ60 petroleum ether elution) to give,
after concentration of the appropriate fractions (Rf = 0.5 twice in 1:5 v/v ethyl acetate/40ꢀ
60 petroleum ether), 4ꢀiodoꢀ3ꢀnitropyridine 1020 (1.46 g, 92%) as a lightꢀyellow solid, mp
9
10
11
12
13
14
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= 80ꢀ82 °C. H NMR (400 MHz, CDCl3) δ 9.04 (broad s, 1H), 8.35 (d, J = 5.1 Hz, 1H),
8.03 (d, J = 5.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 152.5, 149.6, 145.9, 136.5, 98.5;
IR νmax 1572, 1540, 1521, 1357, 1223, 1058, 835, 657 cm–1; MS (EI, 70 ev) m/z 250 (M+•,
100%), 204 (70), 177 (60); HRMS m/z M+• calcd for C5H3127IN2O2 249.9239, found
249.9236.
2-(3-Nitropyridin-4-yl)cyclohex-2-en-1-one (11). A magnetically stirred mixture of 2ꢀ
iodocyclohexꢀ2ꢀenꢀ1ꢀone (6) (888 mg, 4.00 mmol), copper powder (508 mg, 8.00 mmol),
CuI (571 mg, 3.00 mmol) and Pd(dppf)Cl2ꢀCH2Cl2 (163 mg, 0.20 mmol) in degassed
DMSO (40 mL) was heated at 50 °C under a nitrogen atmosphere for 0.75 h. After this
time a solution of compound 10 (500 mg, 2.00 mmol) in degassed DMSO (10 mL) was
added to the reaction mixture over 1 h. After a further 0.75 h the reaction mixture was
cooled, quenched with water (10 mL) then diluted with ethyl acetate (15 mL). The
ensuing mixture was filtered through a pad comprised of a mixture of diatomaceous earth
and silica gel. The solids thus retained were rinsed with ethyl acetate (2 × 15 mL) and the
separated organic phase associated with the combined filtrates washed with water (2 × 30
mL) then brine (2 × 30 mL) before being dried (Na2SO4), filtered and concentrated under
reduced pressure to give a brown oil. This was subjected to flash column chromatography
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(silica, 1:3:10 v/v/v acetone/dichloromethane/40ꢀ60 petroleum ether elution) and gave,
after concentration of the appropriate fractions [Rf = 0.1(5) in 1:1 v/v ethyl acetate/40ꢀ60
petroleum ether], compound 11 (374 mg, 86%) as a lightꢀyellow solid, mp = 105ꢀ107 °C.
1H NMR (400 MHz, CDCl3) δ 9.18 (s, 1H), 8.78 (d, J = 4.9 Hz, 1H), 7.22 (d, J = 4.9 Hz,
1H), 7.13 (t, J = 4.2 Hz, 1H), 2.63ꢀ2.57 (complex m, 4H), 2.19ꢀ2.13 (complex m, 2H);
13C NMR (100 MHz, CDCl3) δ 195.5, 153.9, 148.7, 145.3, 145.0, 140.0, 137.5, 125.6,
38.2, 26.5, 22.5; IR νmax 2948, 1679, 1600, 1542, 1523, 1357, 1217, 1159, 1121, 851, 716
cm–1; MS (ESI, +ve) m/z 219 [(M+H)+, 100%]; HRMS m/z (M+H)+ calcd for C11H11N2O3
219.0770, found 219.0768.
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6,7,8,9-Tetrahydro-5H-pyrido[3,4-b]indole (12). A magnetically stirred mixture of
compound 11 (190 mg, 0.87 mmol) and 10 wt % Pd/C (76 mg) in degassed methanol (44
mL) was maintained under an atmosphere of hydrogen for 16 h at 22 °C then filtered and
the solids thus retained washed with methanol (100 mL). The combined filtrates were
concentrated under reduced pressure and the white solid thus obtained subjected to flash
column chromatography (silica, 1:4 v/v methanol/dichloromethane elution) to give, after
concentration of the appropriate fractions [Rf
=
0.3(5) in 1:1 v/v
methanol/dichloromethane], compound 1221 (132 mg, 88%) as a white, crystalline solid,
mp = 163ꢀ164 °C (lit.21 mp = 199ꢀ200 °C). 1H NMR (700 MHz, CD3OD) δ 8.49 (broad s,
1H), 7.97 (broad s, 1H), 7.36 (d, J = 4.9 Hz, 1H), 2.77 (t, J = 6.0 Hz, 2H), 2.65 (t, J = 6.0
13
Hz, 2H), 1.92ꢀ1.83 (complex m, 4H) (signal due to NꢀH group proton not observed); C
NMR (175 MHz, CD3OD) δ 142.2, 136.9, 134.5, 134.2, 132.6, 113.7, 110.4, 24.2(2),
24.2(0), 24.0, 21.6; IR νmax 3143, 3040, 2926, 2850, 2839, 1569, 1471, 1442, 1359, 1142,
1030, 808 cm–1; MS (ESI, +ve) m/z 173 [(M+H)+, 100%]; HRMS m/z (M+H)+ calcd for
C11H13N2 173.1079, found 173.1078.
9H-Pyrido[3,4-b]indole (β-carboline, 2). A magnetically stirred mixture of compound
12 (20 mg, 0.12 mmol) and 10 wt % Pd/C (20 mg) in diphenyl ether (15 mL) maintained
under a nitrogen atmosphere was heated at 210 °C for 0.66 h. The reaction mixture was
then cooled to room temperature, filtered (through filter paper) and the solids so retained
washed with ethyl acetate (2 × 15 mL). The combined filtrates were concentrated under
reduced pressure and the residue thus obtained subjected to flash column chromatography
(silica, 0:1 → 1:1 v/v ethyl acetate/40ꢀ60 petroleum ether gradient elution) to give, after
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concentration of the appropriate fractions (Rf = 0.5 in 1:2 v/v methanol/dichloromethane),
compound 222 (18 mg, 94%) as a white, crystalline solid, mp = 210ꢀ211 °C (lit.22 mp =
199ꢀ201 °C). 1H NMR (400 MHz, CD3OD) δ 8.79 (s, 1H), 8.27 (d, J = 5.3 Hz, 1H), 8.18
(d, J = 8.0 Hz, 1H), 8.08 (d, J = 5.3 Hz, 1H), 7.56 (m, 2H), 7.29ꢀ7.23 (complex m, 1H)
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13
(signal due to NꢀH group proton not observed); C NMR (100 MHz, CD3OD) δ 142.7,
138.4, 137.8, 134.1, 130.4, 129.7, 122.7, 122.2, 120.8, 116.1, 112.8; IR νmax 3134, 3052,
2963, 2754, 1628, 1449, 1331, 1245, 746, 732 cm–1; MS (ESI, +ve) m/z 191 [(M+Na)+,
70%], 169 [(M+H)+, 100]; HRMS m/z (M+H)+ calcd for C11H9N2: 169.0766, found:
169.0766.
2-(4-Nitropyridin-3-yl)cyclohex-2-en-1-one (14). A magnetically stirred mixture of 2ꢀ
iodocyclohexꢀ2ꢀenꢀ1ꢀone (6) (2.19 g, 9.85 mmol), copper powder (1.26 g, 19.70 mmol),
CuI (1.41 g, 7.39 mmol) and Pd(dppf)Cl2ꢀCH2Cl2 (400 mg, 0.49 mmol) in degassed
DMSO (98 mL) was heated at 50 °C under a nitrogen atmosphere for 0.75 h. After this
time a solution of compound 13 (1.00 g, 4.93 mmol) in degassed DMSO (25 mL) was
added to the reaction mixture over 1.5 h. After a further 4 h the reaction mixture was
cooled, quenched with water (20 mL) then diluted with ethyl acetate (1 × 30 mL). The
ensuing mixture was filtered through a pad comprised of a mixture of diatomaceous earth
and silica gel. The solids thus retained were rinsed with ethyl acetate (2 × 30 mL) and the
separated organic phase associated with the combined filtrates washed with water (2 × 60
mL) then brine (2 × 60 mL) before being dried (Na2SO4), filtered and concentrated under
reduced pressure to give a brown oil. Subjection of this material to flash column
chromatography (silica, 1:3:11 v/v/v acetone/dichloromethane/40ꢀ60 petroleum ether
elution) gave, after concentration of the appropriate fractions (Rf = 0.2 in 1:3:6 v/v/v
acetone/dichloromethane/40ꢀ60 petroleum ether), compound 14 (956 mg, 89%) as a lightꢀ
brown solid, mp = 94ꢀ95 °C. 1H NMR (400 MHz, CDCl3) δ 8.82 (d, J = 5.3 Hz, 1H), 8.61
(s, 1H), 7.81 (d, J = 5.3 Hz, 1H), 7.17 (t, J = 4.2 Hz, 1H), 2.66ꢀ2.58 (complex m, 4H),
13
2.18 (m, 2H); C NMR (100 MHz, CDCl3) δ 196.1, 154.1, 152.8, 151.4, 148.6, 136.0,
125.4, 116.6, 38.2, 26.5, 22.6; IR νmax 2945, 1677, 1557, 1529, 1401, 1358, 1222, 1159,
839, 705, 675 cm–1; MS (ESI, +ve) m/z 241 [(M+Na)+, 100%], 219 [(M+H)+, 15]; HRMS
m/z (M+Na)+ calcd for C11H10N2NaO3 241.0589, found 241.0589.
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6,7,8,9-Tetrahydro-5H-pyrido[4,3-b]indole (15). A magnetically stirred mixture of
compound 14 (50 mg, 0.23 mmol) and 10 wt % Pd/C (20 mg) in degassed methanol (12
mL) was maintained under an atmosphere of hydrogen at 22 °C for 16 h then filtered and
the solids so retained washed with methanol (25 mL). The combined filtrates were
concentrated under reduced pressure and the white solid thus obtained was subjected to
flash column chromatography (silica, 1:4 v/v methanol/dichloromethane elution) to give,
after concentration of the appropriate fractions [Rf = 0.3(5) in 1:1 v/v
methanol/dichloromethane], compound 1523 (26 mg, 66%) as a white, crystalline solid,
mp = 223ꢀ224 °C (lit.23 mp = 269ꢀ271 °C). 1H NMR (700 MHz, CD3OD) δ 8.58 (broad s,
1H), 8.05 (broad s, 1H), 7.28 (d, J = 5.3 Hz, 1H), 2.74 (m, 4H), 1.95ꢀ1.87 (complex m,
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13
4H) (signal due to NꢀH group proton not observed); C NMR (175 MHz, CD3OD) δ
141.6, 139.9, 139.1, 138.1, 126.2, 110.3, 107.5, 24.2, 24.1, 23.9, 21.6; IR νmax 2926,
2839, 2693, 1625, 1466, 1294, 1169, 1142, 989, 802, 684 cm–1; MS (ESI, +ve) m/z 173
[(M+H)+, 100%]; HRMS m/z (M+H)+ calcd for C11H13N2 173.1079, found 173.1078.
5H-Pyrido[4,3-b]indole (γ-carboline, 3). A magnetically stirred mixture of compound
15 (20 mg, 0.12 mmol) and 10 wt % Pd/C (20 mg) in diphenyl ether (15 mL) maintained
under a nitrogen atmosphere was heated at 210 °C for 0.66 h. The reaction mixture was
then cooled to room temperature, filtered (through filter paper) and the solids thus
retained washed with ethyl acetate (2 × 15 mL). The combined filtrates were concentrated
under reduced pressure and the residue thus obtained subjected to flash column
chromatography (silica,
40ꢀ60
petroleum
ether
elution
→
1:3
v/v
methanol/dichloromethane gradient elution) to give, after concentration of the appropriate
fractions [Rf = 0.2(5) in 1:3 v/v methanol/dichloromethane], compound 324 (15 mg, 77%)
1
as a white, crystalline solid, mp = 223ꢀ225 °C (lit.24 mp = 225ꢀ227 °C). H NMR [700
MHz, (CD3)2SO] δ 11.69 (s, 1H), 9.33 (s, 1H), 8.43 (s, 1H), 8.22 (d, J = 7.8 Hz, 1H),
13
7.56 (m, 1H), 7.47 (m, 2H), 7.26 (t, J = 7.4 Hz, 1H); C NMR [175 MHz, (CD3)2SO] δ
144.5, 143.5, 142.7, 139.5, 126.5, 120.7, 120.6, 119.9, 119.4, 111.4, 106.4; 1H NMR (700
MHz, CD3OD) δ 9.20 (s, 1H), 8.36 (s, 1H), 8.16 (d, J = 7.8 Hz, 1H), 7.53 (d, J = 8.1 Hz,
1H), 7.49ꢀ7.46 (m, 2H), 7.28 (t, J = 7.4 Hz, 1H) (signal due to NꢀH group proton not
13
observed); C NMR (175 MHz, CD3OD) δ 145.8, 144.4, 142.7, 141.5, 128.2, 122.4,
121.6(4), 121.6(0), 121.5, 112.4, 107.6; IR νmax 3062, 2956, 2806, 2679, 1607, 1582,
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1467, 1239, 999, 744 cm–1; MS (ESI, +ve) m/z 169 [(M+H)+, 100%]; HRMS m/z (M+H)+
calcd for C11H9N2 169.0766, found 169.0766.
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4
5
6
7
8
9
2-(3-Nitropyridin-2-yl)cyclohex-2-en-1-one (17). A magnetically stirred mixture of 2ꢀ
iodocyclohexꢀ2ꢀenꢀ1ꢀone (6) (1.09 g, 4.93 mmol), copper powder (630 mg, 9.85 mmol),
CuI (704 mg, 3.69 mmol) and Pd(dppf)Cl2ꢀCH2Cl2 (200 mg, 0.25 mmol) in degassed
DMSO (50 mL) was heated at 50 °C under a nitrogen atmosphere for 0.75 h. After this
time a solution of compound 16 (500 mg, 4.93 mmol) in degassed DMSO (12 mL) was
added to the reaction mixture over 1 h. After a further 2 h the reaction mixture was
cooled, quenched with water (10 mL), diluted with ethyl acetate (15 mL) then filtered
through a pad comprised of a mixture of diatomaceous earth and silica gel. The solids
thus retained were rinsed with ethyl acetate (2 × 15 mL) and the separated organic phase
associated with the combined filtrates washed with water (2 × 30 mL) then brine (2 × 30
mL) before being dried (Na2SO4), filtered and concentrated under reduced pressure to
give a brown oil. Subjection of this material to flash column chromatography (silica,
1:3:12 v/v/v acetone/dichloromethane/40ꢀ60 petroleum ether elution) gave, after
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concentration of the appropriate fractions [Rf
=
0.1(5) in 1:3:6 v/v/v
acetone/dichloromethane/40ꢀ60 petroleum ether], compound 17 (403 mg, 75%) as a lightꢀ
1
brown solid, mp = 104ꢀ106 °C. H NMR (400 MHz, CDCl3) δ 8.79 (dd, J = 4.7 and 1.3
Hz, 1H), 8.29 (dd, J = 8.2 and 1.3 Hz, 1H), 7.49ꢀ7.43 (complex m, 2H), 2.65 (m, 2H),
13
2.58 (m, 2H), 2.20ꢀ2.13 (complex m, 2H); C NMR (100 MHz, CDCl3) δ 196.2, 152.9,
151.0, 149.4, 146.1, 139.2, 132.2, 123.4, 38.3, 26.6, 22.5; IR νmax 2947, 1677, 1593,
1561, 1526, 1451, 1357, 765 cm–1; MS (ESI, +ve) m/z 241 [(M+Na)+, 100%], 219
[(M+H)+, 15]; HRMS m/z (M+Na)+ calcd for C11H10N2NaO3 241.0589, found 241.0589.
6,7,8,9-Tetrahydro-5H-pyrido[3,2-b]indole (18). A magnetically stirred mixture of
compound 17 (213 mg, 0.98 mmol) and 10 wt % Pd/C (86 mg) in degassed methanol (49
mL) was maintained under an atmosphere of hydrogen for 16 h at 22 °C then filtered and
the solids so retained washed with methanol (100 mL). The combined filtrates were
concentrated under reduced pressure and the white solid thus obtained subjected to flash
column chromatography (silica, 1:1 v/v ethyl acetate/40ꢀ60 petroleum ether elution) to
give, after concentration of the appropriate fractions (Rf = 0.2 in 1:1 v/v ethyl acetate/40ꢀ
60 petroleum ether), compound 1825 (109 mg, 65%) as a white, crystalline solid, mp =
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183ꢀ185 °C (lit.25 mp = 200ꢀ202 °C). H NMR (400 MHz, CDCl3) δ 8.86 (broad s, 1H),
5
6
7
8
8.38 (d, J = 4.3 Hz, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.00 (m, 1H), 2.84 (m, 2H), 2.76 (m,
13
2H), 1.95ꢀ1.84 (complex m, 4H); C NMR (100 MHz, CDCl3) δ 145.6, 141.9, 139.2,
129.1, 117.4, 115.8, 110.8, 23.8, 23.2, 23.1, 20.1; IR νmax 3136, 3083, 3053, 2929, 2847,
1483, 1414, 1362, 1286, 1144, 904, 767, 729 cm–1; MS (ESI, +ve) m/z 173 [(M+H)+,
100%]; HRMS m/z (M+H)+ calcd for C11H13N2 173.1079, found 173.1080.
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60
5H-Pyrido[3,2-b]indole (δ-carboline, 4). A magnetically stirred mixture of compound
18 (20 mg, 0.12 mmol) and 10 wt % Pd/C (20 mg) in diphenyl ether (15 mL) maintained
under a nitrogen atmosphere was heated at 210 °C for 0.66 h. The reaction mixture was
then cooled to room temperature, filtered (through filter paper) and the solids thus
retained washed with ethyl acetate (2 × 15 mL). The combined filtrates were concentrated
under reduced pressure and the residue thus obtained subjected to flash column
chromatography (silica, 0:1 → 1:4 v/v ethyl acetate/40ꢀ60 petroleum ether gradient
elution) to give, after concentration of the appropriate fractions [Rf = 0.2(5) in 1:1 v/v
ethyl acetate/40ꢀ60 petroleum ether], compound 426 (18 mg, 92%) as a white, crystalline
1
solid, mp = 211ꢀ212 °C (lit.26 mp = 206ꢀ207 °C). H NMR (400 MHz, CD3OD) δ 8.39
(dd, J = 4.8 and 1.4 Hz, 1H), 8.28 (d, J = 7.9 Hz, 1H), 7.88 (d, J = 8.2 Hz, 1H), 7.52 (m,
13
2H), 7.40 (m, 1H), 7.26 (m, 1H) (signal due to NꢀH group proton not observed); C
NMR (100 MHz, CD3OD) δ 142.4, 142.3, 141.5, 135.1, 129.0, 122.4, 121.4, 121.3,
120.8, 119.9, 112.6; IR νmax 3057, 2979, 2919, 2848, 2760, 1629, 1460, 1396, 1320,
1223, 741, 724 cm–1; MS (ESI, +ve) m/z 169 [(M+H)+, 100%]; HRMS m/z (M+H)+ calcd
for C11H9N2 169.0766, found 169.0766.
2-Methylpyridin-4-ol Nitrate (20). Commercially available 2ꢀmethylpyridinꢀ4ꢀamine
(8.00 g, 73.98 mmol) was dissolved in a mixture of concentrated HNO3 (44.1 mL) and
H2O (59.4 mL) and the resulting solution was cooled, with vigorous magnetic stirring, to
0 °C. A chilled solution of NaNO2 (7.40 g, 107.25 mmol) in water (21.7 mL) was then
added dropwise over 0.5 h and the mixture thus formed stirred at 0 °C for 4 h before
being allowed to warm to 22 °C and then stirred at this temperature for another 10 h then
reꢀcooled to 0 °C. The resulting solid was removed by filtration, the filtrate concentrated
to about oneꢀthird of its original volume then cooled to 0 °C and a second crop of solid
removed by filtration. The combined solids were then airꢀdried to give the nitric acid
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salt27 of compound 20 (10.49 g, 82%) as a white, crystalline solid, mp = 162ꢀ164 °C
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(lit.27 mp = 164ꢀ165 °C). H NMR (400 MHz, CD3OD) δ 8.34 (d, J = 6.5 Hz, 1H), 7.11ꢀ
5
6
7
8
9
7.09 (complex m, 2H), 2.62 (s, 3H) (signals due to OꢀH and NꢀH group protons not
13
observed); C NMR (100 MHz, CD3OD) δ 173.4, 156.0, 143.2, 114.7, 113.0, 19.3; IR
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νmax 3098, 2919, 2617, 1627, 1501, 1305, 1216, 830 cm–1; MS (ESI, +ve) m/z 110
[(M+H)+, 100%]; HRMS m/z (M+H)+ calcd for C6H8NO 110.0606, found 110.0608.
2-Methyl-4-nitropyridin-3-ol (21) and 2-Methyl-3-nitropyridin-4-ol (22). A
magnetically stirred solution of salt 20 (3.00 g, 17.43 mmol) in concentrated H2SO4 (6.9
mL) was cooled to 0 °C then treated, dropwise, with fuming HNO3 (6.9 mL). The
ensuing mixture reaction was stirred at 0 °C for 0.17 h, heated at 130 °C for 20 h then
cooled to 0 °C and carefully neutralized with NaOH (25 mL of a 10 M aqueous solution).
FCꢀgrade silica gel (20 g) was added to the ensuing mixture and this was then
concentrated under reduced pressure. The freeꢀflowing solid thus obtained was subjected
to flash column chromatography (silica, 1:19 v/v methanol/dichloromethane elution) to
give, after concentration of the appropriate fractions (Rf = 0.6 in 1:1 v/v
methanol/dichloromethane), a 1:3 mixture of 2ꢀmethylꢀ5ꢀnitropyridinꢀ4ꢀol (21) and 2ꢀ
methylꢀ3ꢀnitropyridinꢀ4ꢀol (22) (1.88 g, 70% combined yield) as a white crystalline solid,
mp = 148ꢀ150 °C. 1H NMR [400 MHz, (CD3)2SO] δ (major product) 12.17 (broad s, 1H),
7.72 (d, J = 7.5 Hz, 1H), 6.33 (d, J = 7.5 Hz, 1H), 2.29 (s, 3H); 13C NMR [100 MHz,
(CD3)2SO] δ (for mixture) 168.2, 151.2, 148.1, 143.5, 142.2, 139.4, 137.8, 137.3, 120.7,
118.0, 18.2, 15.3; IR νmax 3037, 2796, 1612, 1557, 1502, 1356, 1222, 836, 768 cm–1; MS
(ESI, +ve) m/z 331 (42%), 177 [(M+Na)+, 100], 155 [(M+H)+, 10]; HRMS (ESI) m/z
(M+Na)+ calcd for C6H6N2NaO3 177.0276, found 177.0278.
4-Bromo-2-methyl-3-nitropyridine (24). A magnetically stirred 1:3 mixture of 2ꢀ
methylꢀ5ꢀnitropyridinꢀ4ꢀol (21) and 2ꢀmethylꢀ3ꢀnitropyridinꢀ4ꢀol (22) (1.12 g, 7.27
mmol), obtained as described immediately above, in toluene (8.0 mL) and maintained
under a nitrogen atmosphere was treated with POBr3 (2.19 g, 7.63 mmol). The ensuing
mixture was heated under reflux for 10 h then cooled to 0 °C before being quenched with
NaOH (30 mL of a 1 M aqueous solution). The ensuing mixture was extracted with ethyl
acetate (1 × 150 mL) and washed with H2O (2 × 150 mL). The separated organic phase
was then dried (Na2SO4), filtered and concentrated under reduced pressure. The solid so
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obtained was subjected to flash column chromatography (silica, 1:3:20 v/v/v
acetone/dichloromethane/40ꢀ60 petroleum ether elution) to give, after concentration of
the appropriate fractions (Rf = 0.4 in 1:3:6 v/v/v acetone/dichloromethane/40ꢀ60
petroleum ether), a 1:3 mixture of what is presumed to be 4ꢀbromoꢀ2ꢀmethylꢀ5ꢀ
nitropyridine (23) and 4ꢀbromoꢀ2ꢀmethylꢀ3ꢀnitropyridine (24) (1.46 g, 92% combined) as
a white solid. A ca. 800 mg portion of this material was subjected to semiꢀpreparative
HPLC (silica, normal phase, 17:83 v/v ethyl acetate/nꢀhexane elution, 600 mL/h) to
afford, after concentration of the relevant fractions (Rt = 0.45 h), a pure sample of 4ꢀ
bromoꢀ2ꢀmethylꢀ3ꢀnitropyridine (24) (ca. 350 mg) as a white, crystalline solid, mp = 78ꢀ
79 °C. 1H NMR (400 MHz, CDCl3) δ 8.40 (d, J = 5.3 Hz, 1H), 7.50 (d, J = 5.3 Hz, 1H),
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2.60 (s, 3H); C NMR (100 MHz, CDCl3) δ 151.8, 150.5, 148.5, 126.3, 123.7, 20.9; IR
νmax 3072, 1575, 1534, 1365, 1266, 846, 837, 714 cm–1; MS (EI, 70 eV) m/z 218 and 216
(M+•, both 90%), 201 and 199 (both 70), 172 and 170 (both 95), 93 and 91 (both 83), 62
79
(100%); HRMS m/z M+• calcd for C6H5 BrN2O2 215.9534, found. 215.9533.
2-(2-Methyl-3-nitropyridin-4-yl)cyclohex-2-en-1-one (25). A magnetically stirred
mixture of 2ꢀiodocyclohexꢀ2ꢀenꢀ1ꢀone (6) (205 mg, 0.92 mmol), copper powder (117 mg,
1.84 mmol), CuI (132 mg, 0.69 mmol) and Pd(dppf)Cl2ꢀCH2Cl2 (38 mg, 0.05 mmol) in
degassed DMSO (9 mL) was heated at 50 °C under a nitrogen atmosphere for 0.75 h.
After this time a solution of compound 24 (100 mg, 0.46 mmol) in degassed DMSO (3
mL) was added to the reaction mixture over 0.66 h. After a further 6 h the reaction
mixture was cooled, quenched with water (3 mL) then diluted with ethyl acetate (5 mL).
The ensuing mixture was filtered through a pad comprised of a mixture of diatomaceous
earth and silica gel and the solids so retained were rinsed with ethyl acetate (2 × 5 mL).
The separated organic phase associated with the combined filtrates was washed with
water (2 × 10 mL) then brine (2 × 10 mL) before being dried (Na2SO4), filtered and
concentrated under reduced pressure to give a brown oil. Subjection of this material to
flash column chromatography (silica, 3:9:40 v/v/v acetone/dichloromethane/40ꢀ60
petroleum ether elution) gave, after concentration of the appropriate fractions [Rf = 0.1(5)
in 1:3:6 v/v/v acetone/dichloromethane/40ꢀ60 petroleum ether], compound 25 (90 mg,
1
84%) as a lightꢀbrown, crystalline solid, mp = 80ꢀ81 °C. H NMR (400 MHz, CDCl3) δ
8.59 (d, J = 5.0 Hz, 1H), 7.09ꢀ7.05 (complex m, 2H), 2.66 (s, 3H), 2.58ꢀ2.54 (complex m,
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4H), 2.12 (m, 2H); C NMR (100 MHz, CDCl3) δ 195.6, 151.4, 150.8, 150.1, 146.6,
139.0, 136.3, 123.4, 38.2, 26.5, 22.5, 22.0; IR νmax 2939, 1681, 1594, 1528, 1359, 1229,
860 cm–1; MS (ESI, +ve) m/z 255 [(M+Na)+, 100%], 233 [(M+H)+, 10]; HRMS m/z
(M+Na)+ calcd for C12H12N2NaO3 255.0746, found 255.0734.
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1-Methyl-6,7,8,9-tetrahydro-5H-pyrido[3,4-b]indole (26). A magnetically stirred
mixture of compound 25 (103 mg, 0.44 mmol) and 10 wt % Pd/C (42 mg) in degassed
methanol (22 mL) was maintained under an atmosphere of hydrogen at 22 °C for 16 h
then filtered and the solids thus retained washed with methanol (50 mL). The combined
filtrates were concentrated under reduced pressure and the white solid thus obtained was
subjected to flash column chromatography (silica, 1:4 v/v methanol/dichloromethane
elution) to give, after concentration of the appropriate fractions (Rf = 0.2 in 1:1 v/v
methanol/dichloromethane), compound 2628 (69 mg, 83%) as a white, crystalline solid,
1
mp = 187ꢀ189 °C (lit.28 mp = 184ꢀ188 °C). H NMR (400 MHz, CD3OD) δ 7.84 (d, J =
5.4 Hz, 1H), 7.19 (d, J = 5.4 Hz, 1H), 2.78 (broad s, 2H), 2.63 (broad s, 5H), 1.91ꢀ1.84
13
(complex m, 4H) (signal due to NꢀH group proton not observed); C NMR (100 MHz,
CD3OD) δ 141.6, 141.2, 136.7, 133.7, 132.9, 111.9, 110.6, 24.3, 24.2, 24.1, 21.7, 19.1; IR
νmax 3045, 2930, 2846, 1563, 1498, 1308, 1226, 809 cm–1; MS (ESI, +ve) m/z 187
[(M+H)+, 100%]; HRMS m/z (M+H)+ calcd for C12H15N2 187.1235, found 187.1232.
1-Methyl-9H-pyrido[3,4-b]indole (harman, 5). A magnetically stirred mixture of
compound 26 (36 mg, 0.19 mmol) and 10 wt % Pd/C (36 mg) in diphenyl ether (15 mL)
maintained under a nitrogen atmosphere was heated at 210 °C for 0.66 h. The reaction
mixture was then cooled to room temperature, filtered (through filter paper) and the
solids so retained washed with ethyl acetate (2 × 7 mL). The combined filtrates were
concentrated under reduced pressure and the residue thus obtained subjected to flash
column chromatography (silica, 40ꢀ60 petroleum ether elution →1:9 v/v
methanol/dichloromethane elution) to give, after concentration of the appropriate
fractions (Rf = 0.5 in 1:3 v/v methanol/dichloromethane), compound 529 (32 mg, 91%) as
a white, crystalline solid, mp = 233ꢀ235 °C (lit.29 mp = 235ꢀ238 °C). 1H NMR (400 MHz,
CDCl3) δ 8.91 (broad s, 1H), 8.38 (d, J = 5.4 Hz, 1H), 8.12 (d, J = 7.9 Hz, 1H), 7.84 (d, J
13
= 5.4 Hz, 1H), 7.56ꢀ7.51 (complex m, 2H), 7.29 (m, 1H), 2.84 (s, 3H); C NMR (100
MHz, CDCl3) δ 141.9, 140.3, 138.7, 134.8, 128.5, 128.4, 122.2, 122.0, 120.2, 113.1,
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111.7, 20.5; IR νmax 3135, 3068, 2925, 1626, 1568, 1504, 1450, 1323, 1251, 1237, 742
cm–1; MS (ESI, +ve) m/z 183 [(M+H)+, 100%]; HRMS (ESI) m/z (M+H)+ calcd for
C12H11N2 183.0922, found 183.0922.
X-ray Crystallographic Studies
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Crystallographic Data
Compound 1. C11H8N2, M = 168.20, T = 150 K, monoclinic, space group P21/n, Z = 4, a
= 11.1814(2) Å, b = 5.53776(8) Å, c = 13.4546(2) Å; β = 96.2939(15) °; V = 828.09(2)
Å3, Dx = 1.349 g cm–3, 1673 unique data (2
θmax = 147.6°), R = 0.035 [for 1520 reflections
with I > 2.0σ(I)]; Rw = 0.089 (all data), S = 1.00.
Compound 2. C11H8N2, M = 168.20, T = 150 K, orthorhombic, space group P212121, Z =
4, a = 5.8440(1) Å, b = 9.8140(1) Å, c = 14.4195(1) Å; V = 827.00(2) Å3, Dx = 1.351 g
cm–3, 1004 unique data (2
θmax = 147.8°), R = 0.027 [for 998 reflections with I > 2.0σ(I)];
Rw = 0.073 (all data), S = 1.00.
Compound 3. C11H8N2, M = 168.20, T = 150 K, orthorhombic, space group Pna21, Z = 4,
a = 17.1576(6) Å, b = 12.2955(6) Å, c = 3.8213(2) Å; V = 806.15(6) Å3, Dx = 1.386 g
cm–3, 944 unique data (2θmax = 147.8°), R = 0.032 [for 906 reflections with I > 2.0σ(I)];
Rw = 0.062 (all data), S = 1.00.
Compound 4. C11H8N2, M = 168.20, T = 150 K, monoclinic, space group
12.1155(7) Å, b = 3.9036(2) Å, c = 18.1199(13) Å; β = 107.250(7) °; V = 818.42(9) Å3,
Dx = 1.365 g cm–3, 820 unique data (2
max = 146.6°), R = 0.042 [for 807 reflections with I
Ιa, Z = 4, a =
θ
> 2.0σ(I)]; Rw = 0.107 (all data), S = 1.05.
Compound 5. C12H10N2, M = 182.23, T = 150 K, orthorhombic, space group P212121, Z =
8, a = 9.5865(2) Å, b = 13.2423(4) Å, c = 15.1680(4) Å; V = 1925.54(9) Å3, Dx = 1.257 g
cm–3, 1994 unique data (2
θmax = 52.0°), R = 0.032 [for 1805 reflections with I > 2.0σ(I)];
Rw = 0.073 (all data), S = 1.00.
Structure Determination
The image for compound 5 was measured on a diffractometer (Mo Kα, graphite
monochromator, λ = 0.71073 Å) fitted with an area detector and the data extracted using
CrysAlis PRO.34 Images for compounds 1, 2, 3 and 4 were measured on a diffractometer
(Cu Kα, mirror monochromator, λ = 1.54184 Å) fitted with an area detector and the data
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extracted using the CrysAlis.34 The structure solutions for all eleven compounds were
solved by direct methods (SIR92)35 then refined using the CRYSTALS program
package.36Atomic coordinates, bond lengths and angles, and displacement parameters
have been deposited at the Cambridge Crystallographic Data Centre (CCDC nos.
1530002, 1530003, 1530004, 1530005, 1530006). These data can be obtained freeꢀofꢀ
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charge
via
www.ccdc.cam.ac.uk/data_request/cif,
by
emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
ASSOCIATED CONTENT
Supporting Information
Crystallographic data (CIFs); ORTEPs derived from the singleꢀcrystal Xꢀray analyses of
compounds 1ꢀ5; and 1H and 13C NMR spectra of compounds 1ꢀ5, 8, 9, 10, 11, 12, 14, 15,
17, 18, 20, 21/22 and 24-26 This material is available free of charge via the internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Email: Martin.Banwell@anu.edu.au
Notes
The authors declare no competing financial interest
ACKNOWLEDGEMENTS
We thank the Australian Research Council and the Institute of Advanced Studies for
financial support. QY is the grateful recipient of a PhD Scholarship provided by the
China Scholarship Council of the People’s Republic of China.
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REFERENCES
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1.
For useful pointsꢀofꢀentry into the substantial body of literature on these
compounds see (a) Smirnova, O. B.; Golovko, T. V.; Granik, V. G. Pharm. Chem. J.,
2011, 44, 654; (b) Hung, T. Q.; Dang, T. T.; Janke, J.; Villinger, A. Langer, P. Org.
Biomol. Chem., 2015, 13, 1375 and references cited therein.
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2.
3.
See, for example, Lee, C. W.; Lee, J. Y. Adv. Mater., 2013, 25, 5450.
Basavaiah, D.; Reddy, D. M. Org. Biomol. Chem. 2012, 10, 8774 and references
cited therein.
4.
(a) Laha, J. K.; Petrou, P.; Cuny, G. D. J. Org. Chem., 2009, 74, 3152; (b)
Ghahremanzadeh, R.; Ahadi, S.; Bazgir, A. Tetrahedron Lett., 2009, 50, 7379; (c)
Mineno, M.; Sera, M.; Ueda, T.; Mizuno, M.; Yamano, M.; Mizufune, H.; Zanka, A.
Tetrahedron, 2014, 70, 5550; (d) Mineno, M.; Sera, M.; Ueda, T.; Mizufune, H.;
Zanka, A.; O’Bryan, C.; Brown, J.; Scorah, N. J. Org. Chem., 2015, 80, 1564 and
references cited therein.
5.
(a) Zhu, Y.ꢀP.; Liu, M.ꢀC.; Cai, Q.; Jia, F.ꢀC.; Wu, A.ꢀX. Chem. Eur. J., 2013, 19,
10132; (b) Dhiman, S.; Mishra, U. K.; Ramasastry, S. S. V. Angew. Chem. Int. Ed.,
2016, 55, 7737; (c) Dighe, S. U.; Yadav, V. D.; Mahar, R.; Shukla, S. K.; Batra, S. Org.
Lett., 2016, 18, 6010 and references cited therein.
6.
7.
See, for example, (a) Kamlah, A.; Lirk, F.; Bracher, F. Tetrahedron, 2016, 72,
837; (b) Du, H.; Gu, H.; Li, N.; Wang, J. Med. Chem. Commun., 2016, 7, 636.
See, for example, (a) Otto, R.; Penzis, R.; Gaube, F.; Winckler, T.; Appenroth, D.;
Fleck, C.; Tränke, C.; Lehmann, J.; Enzensperger, C. Eur. J. Med. Chem., 2014, 87, 63;
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(b) Ran, X.; Zhao, Y.; Liu, L.; Bai, L.; Yang, C.ꢀY.; Zhou, B.; Meagher, J. L.;
Chinnaswamy, K.; Stuckey, J. A.; Wang, S. J. Med. Chem., 2015, 58, 4927.
Cao, J.; Xu, Y.; Kong, Y.; Cui, Y.; Hu, Z.; Wang, G.; Deng, Y.; Lai, G. Org.
Lett., 2012, 14, 38.
8.
9.
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For some useful reviews see (a) Wadsworth, A. D.; Naysmith, B. J.; Brimble, M.
A. Eur. J. Med. Chem., 2015, 97, 816; (b) Alekseyev, R. S.; Kurkin, A. V.;
Yurovskaya, M. A. Chem. Heterocyclic Comp., 2009, 45, 889; (c) Alekseyev, R. S.;
Kurkin, A. V.; Yurovskaya, M. A. Chem. Heterocyclic Comp., 2010, 46, 777.
10.
See also, (a) Ishiyama, H.; Ohshita, K.; Abe, T.; Nakata, H.; Kobayashi, J.
Bioorg. Med. Chem., 2008, 16, 3825; (b) Butin, A. V.; Pilipenko, A. S.; Milich, A. A.;
Finko, A. V. Chem. Heterocyclic Compd, 2009, 45, 613; (c) Dagar, A.; Biswas, S.;
Samanta, S. RSC Adv., 2015, 5, 52497; (d) Li, J.; Tang, Y.; Jin, H.ꢀJ.; Cui, Y.ꢀD.;
Zhang, L.ꢀJ.; Jiang, T. J. Asian. Nat. Prod., 2015, 17, 299; (e) Wang, G.; You, X.; Gan,
Y.; Liu, Y. Org. Lett., 2017, 19, 110.
11.
5725.
12.
Peng, H.; Chen, X.; Chen, Y.; He, Q.; Xie, Y.; Yang, C. Tetrahedron, 2011, 67,
(a) Zhang, H.; Larock, R. C. J. Org. Chem., 2002, 67, 9318; (b) Hostyn, S.; Van
Baelen, G.; Lemiere, G. L. F.; Maes, B. U. W. Adv. Synth. Catal., 2008, 350, 2653; (c)
Gupta, S.; Kumar, B.; Kundu, B. J. Org. Chem., 2011, 76, 10154; (d) Dassonneville,
B.; Witulski, B.; Detert, H. Eur. J. Org. Chem., 2011, 2836; (e) Ma, Z.; Ni, F.; Woo, G.
H. C.; Lo, S.ꢀM.; Roveto, P. M.; Schaus, S. E.; Snyder, J. K. Beilstein J. Org. Chem.,
2012, 8, 829; (f) Markey, S. J.; Lewis, W.; Moody, C. J. Org. Lett., 2013, 15, 6306; (g)
Mineno, M.; Sera, M.; Ueda, T.; Mizuno, M.; Yamano, M.; Mizufune, H.; Zanka, A.
ACS Paragon Plus Environment

Page 25 of 27
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Tetrahedron, 2014, 70, 5550; (h) Pilipenko, A. S.; Uchuskin, M. G.; Trushkov, I. V.;
Butin, A. V. Tetrahedron, 2015, 71, 8786; (i) Dondas, H. A.; Hempshall, A.;
Narramore, S.; Kilner, C.; Fishwick, C. W. G.; Grigg, R. Tetrahedron, 2016, 72, 1316;
(j) Hingane, D. G.; Parekh, N. P.; Khan, A.; Kusurkar, R. S. Synth. Commun., 2016, 46,
160; (k) He, L.; Allwein, S. P.; Dugan, B. J.; Knouse, K. W.; Ott, G. R.; Zificsak, C. A.
Org. Synth., 2016, 93, 272.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13.
(a) Clark, V. M.; Cox, A.; Herbert, E. J. J. Chem. Soc. (C), 1968, 831; (b) Rocca,
P.; Marsais, F.; Godard, A.; Queguiner, G. Tetrahedron, 1993, 49, 49; (c) Rocca, P.;
Cochennec, C.; Marsais, F.; ThomasꢀditꢀDumont, L.; Mallet, M.; Godard, A.;
Quéguiner, G. J. Org. Chem., 1993, 58, 7832; (d) Rocca, P.; Marsais, F.; Godard, A.;
Queguiner, G. Tetrahedron, 1993, 49, 3325; (e) Rocca, P.; Marsais, F.; Godard, A.;
Quéguiner, G. Tetrahedron Lett., 1993, 34, 7917; (f) Rocca, P.; Marsais, F.; Godard,
A.; Quéguiner, G. J. Heterocyclic Chem., 1995, 32, 1171; (g) Iwaki, T.; Yasuhara, A.;
Sakamoto, T. J. Chem. Soc., Perkin Trans. 1, 1999, 1505; (h) Laha, J. K.; Barolo, S.
M.; Rossi, R. A.; Cuny, G. D. J. Org. Chem., 2011, 76, 6421; (i) Pumphrey, A. L.;
Dong, H.; Driver, T. G. Angew. Chem. Int. Ed., 2012, 51, 5920; (j) Dhara, S.; Singha,
R.; Ahmed, A.; Mandal, H.; Ghosh, M.; Nuree, Y.; Ray, J. K. RSC Adv., 2014, 4,
45163.
14.
(a) Ishiad, J.; Wang, H.ꢀK.; Oyama, M.; Cosentino, M. L.; Hu, C.ꢀQ.;Lee, K.ꢀL. J.
Nat. Prod., 2001, 64, 958; (b) Aassila, H.; BourguetꢀKondracki, M. L.; Rifai, S.;
Fassouane, A.; Guyot, M. Mar. Biotechnol., 2003, 5, 163; (c) Kusurkar, R. S.;
Goswami, S. K.; Vyas, S. M. Tetrahedron Lett., 2003, 44, 4761.
15.
Banwell, M. G.; Jones, M. T.; Reekie, T. A. Chem. New Zealand, 2011, 75, 122.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 27
1
2
3
4
5
6
16.
17.
Pandey, G.; Balakrishnan, M. J. Org. Chem. 2008, 73, 8128.
Yan, Q.; Gin, E.; WasinskaꢀKalwa, M.; Banwell, M. G.; Carr, P. D. J Org. Chem.
7
8
9
accepted for publication (DOI: 10.1021/acs.joc.7b00044).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
18.
19.
Okuda, S.; Robison, M. M. J. Am. Chem. Soc. 1959, 81, 740.
Various methods are available for the oxidation of tetrahydrocarbolines to their
fully aromatic counterparts: (a) Panarese, J. D.; Waters, S. P. Org. Lett., 2010, 12,
4086; (b) Kamal, A.; Tangella, Y.; Manasa, K. L.; Sathish, M.; Srinivasulu, V.; Chetna,
J.; Alarifi, A. Org. Biomol. Chem., 2015, 13, 8652; (c) Pakhare, D. S.; Kusurkar, R. S.
Tetrahedron Lett., 2015, 56, 6012; (d) Hati, S.; Sen, S. Tetrahedron Lett., 2016, 57,
1040.
20.
Burger, M.; Ding, Y.; Han, W.; Lindvall, M.; Nishiguchi, G. A.; Rico, A.; Smith,
A.; Tanner, H.; Wan, L. PCT WO 2012/004217 A1, 2012.
21.
Abramovitch, R. A.; Adams, K. A. H. Can. J. Chem. 1962, 40, 864.
Snyder, H. R.; Werber, F. X. J. Am. Chem. Soc. 1950, 72, 2962.
Mann, F. G.; Prior, A. F.; Willcox, T. J. J. Chem. Soc. 1959, 3830.
Smith, P. A. S.; Boyer, J. H. J. Am. Chem. Soc. 1951, 73, 2626.
Fontan, R.; Galvez, C.; Viladoms, P. Heterocycles 1981, 16, 1473.
Mazu, T. K.; Etukala, J. R.; Jacob, M. R.; Khan, S. I.; Walker, L. A.;
22.
23.
24.
25.
26.
Ablordeppey, S. Y. Eur. J. Med. Chem. 2011, 46, 2378.
27. Reich, M. F.; Fabio, P. F.; Lee, V. J.; Kuck, N. A.; Testa, R. T. J. Med. Chem.
1989, 32, 2474.
28. Remers, W. A.; Greenblatt, E. N.; Ellenbogen, L.; Weiss, M. J. J. Med. Chem.
1971, 14, 331.
ACS Paragon Plus Environment

Page 27 of 27
The Journal of Organic Chemistry
1
2
3
4
5
6
29.
30.
Kusurkar, R. S.; Goswami, S. K. Tetrahedron 2004, 60, 5315.
See, for example, (a) Hardegger, L. A.; Habegger, J.; Donohoe, T. J. Org. Lett.,
7
8
9
2015, 17, 3222; (b) Sasaki, I. Synthesis, 2016, 48, 1974.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
31.
See, for example, (a) Lachance, N.; April, M.; Joly, M.ꢀC. Synthesis, 2005, 2571;
(b) Spergel, S. H.; Okoro, D. R.; Pitts, W. J. Org. Chem., 2010, 75, 5316.
32.
33.
Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.
Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J.
Organometallics 1996, 15, 1518.
34.
CrysAlis PRO Version 1.171.37.35h (released 09ꢀ02ꢀ2015 CrysAlis171.NET)
(compiled Feb 9 2015,16:26:32) Agilent Technologies: Oxfordshire, UK.
35.
SIR92. Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A.; Burla, M.
C.; Polidori, G.; Camalli, M. J. Appl. Crystallogr. 1994, 27, 435.
36.
Betteridge, P. W.; Carruthers, J. R.; Cooper, R. I.; Prout, K.; Watkin, D. J. J.
Appl. Crystallogr. 2003, 36, 1487.
ACS Paragon Plus Environment