A Palladium-Catalyzed Ullmann Cross-Coupling/Reductive Cyclization Route to the Carbazole Natural Products 3-Methyl-9H-carbazole, Glycoborine, Glycozoline, Clauszoline K, Mukonine, and Karapinchamine A

Article abstract of DOI:10.1021/acs.joc.7b00044

The title natural products 2-7 have been prepared by reductive cyclization of the relevant 2-arylcyclohex-2-en-1-one (e.g. 20) to the corresponding tetrahydrocarbazole and dehydrogenation (aromatization) of this to give the target carbazole (e.g. 4). Compounds such as 20 were prepared using a palladium-catalyzed Ullmann cross-coupling reaction between the appropriate 2-iodocyclohex-2-en-1-one and o-halonitrobenzene.

Full text of DOI:10.1021/acs.joc.7b00044

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Article
A Palladium-catalyzed Ullmann Cross-coupling/Reductive Cyclisation
Route to the Carbazole Natural Products 3-Methyl-9H-carbazole,
Glycoborine, Glycozoline, Clauszoline K, Mukonine and Karapinchamine A
Qiao Yan, Emma Gin, Malgorzata Wasinska-Kalwa, Martin Gerhardt Banwell, and Paul D Carr
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00044 • Publication Date (Web): 22 Feb 2017
Downloaded from http://pubs.acs.org on February 23, 2017
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Page 1 of 30
The Journal of Organic Chemistry
A Palladium-catalyzed Ullmann Cross-coupling/Reductive Cyclisation Route to the Carbazole
Natural Products 3-Methyl-9H-carbazole, Glycoborine, Glycozoline, Clauszoline K, Mukonine
and Karapinchamine A
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Qiao Yan, Emma Gin, Malgorzata WasinskaꢀKalwa, Martin G. Banwell* and Paul D. Carr
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Research School of Chemistry, Institute of Advanced Studies, The Australian National University,
Canberra, ACT 2601, Australia
___________________________________________________________________________________
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Pd[0]ꢀcatalyzed
Ullmann crossꢀcoupling
(i) reductive
cyclization
OMe
OMe
(ii) aromatization
O
O2N
N
H
glycozoline (4)
20
Abstract: The title natural products 2ꢀ7 have been prepared by reductive cyclisation of the relevant 2ꢀ
arylcyclohexꢀ2ꢀenꢀ1ꢀone (e.g. 20) to the corresponding tetrahydrocarbazole and dehydrogenation
(aromatization) of this to give the target carbazole (e.g. 4). Compounds such as 20 were prepared using
a palladiumꢀcatalyzed Ullmann crossꢀcoupling reaction between the appropriate 2ꢀiodocyclohexꢀ2ꢀenꢀ1ꢀ
one and oꢀhalonitrobenzene.
___________________________________________________________________________________
INTRODUCTION
9HꢀCarbazole (1) (Figure 1) was first isolated from coal tar more than one hundred years ago1
and since that time this aromatic heterocycle and its various derivatives have fascinated organic
chemists because of their value in both medicine and materials science.2 Many biologically active
natural products embodying this framework have also been isolated, particularly from higher
plants.2d,2e,3 As such, the development of methods for the synthesis of the carbazoles has been an
ongoing field of research. A suite of approaches to these compounds has been reported, ranging from the
classical FischerꢀBorsche4 and GraebeꢀUllmann5 routes to more contemporary ones such as the
cyclization of biarylnitrenes (Cadogan synthesis)6 or variants thereof and the annulation of indoles,7
including through electrocyclization processes. Despite the demonstrated utility of these and other
approaches,8 perhaps the most effective route to carbazoles involves the cyclization of diarylamines,
especially under oxidative conditions.9 Variations on this last approach have been used to great effect in
developing total syntheses of a plethora of carbazoleꢀcontaining natural products with particularly
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notable contributions having being made, especially in recent times, by the Knölker
group.2,9e,9f,9g,9h,9i,9k,9m
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7
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5
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2
4b
8a
A
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7
C
B
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9a
9
N
H
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Figure 1: Structure of parent 9Hꢀcarbazole (1) and the associated ringꢀlabeling and atomꢀnumbering
Sometime ago we reported10 that 1,2,3,4ꢀtetrahydroꢀ9Hꢀcarbazoles (formally 2,3,4,9ꢀtetrahydroꢀ1Hꢀ
carbazoles) can be formed by a twoꢀstep process involving an initial the palladiumꢀcatalysed Ullmann
crossꢀcoupling of 2ꢀhalocyclohexꢀ2ꢀenꢀ1ꢀones with oꢀhalonitrobenzenes and then subjecting the
resulting 2ꢀarylcyclohexꢀ2ꢀenꢀ1ꢀones to a reductive cyclisation reaction.11 Since various methods are
available for or could be applied to the oxidation of tetrahydrocarbazoles to carbazoles12 we sought to
establish if the reaction sequence just mentioned could provide a useful means for obtaining natural
products embodying the latter ring system. Herein we report the outcomes of such studies and by which
means we have been able to realize syntheses of the parent carbazole (1) as well as the natural products
3ꢀmethylꢀ9Hꢀcarbazole (2),13 glycoborine (3, a.k.a. glycrophylamine),3a,14 glycozoline (4),3a,15
clauszoline K (5),16 mukonine (6)17 and karapinchamine A (7)18 together with their monoꢀmethoxylated
congener 8 (Figure 2).
OMe
OMe
N
H
N
H
N
H
3
4
2
(glycoborine)
(glycozoline)
(3ꢀmethylꢀ9Hꢀcarbazole)
OHC
N
CO2Me
OH
N
N
N
OMe
OMe
H
H
H
OMe
5
6
7
8
(2ꢀmethoxyꢀ9Hꢀcarbazole)
(clauszoline K)
(mukonine)
(karapinchamine A)
Figure 2: Structures of natural products 2ꢀ7 and the monoꢀsubstituted congener 8.
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The Journal of Organic Chemistry
RESULTS AND DISCUSSION
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Our initial studies focused on the acquiring targets 1 and 2 and this involved (Scheme 1) the
palladiumꢀcatalysed Ullmann crossꢀcoupling of 2ꢀiodocyclohexꢀ2ꢀenꢀ1ꢀone (9)19 or its C4ꢀmethylayed
counterpart 1011 with commercially available oꢀbromonitrobenzene (11) under conditions defined
earlier10 and thereby affording the anticipated and previously reported 2ꢀarylcyclohexꢀ2ꢀenꢀ1ꢀones
1210,11 (85%) and 1311 (86%), respectively. A methanolic solution of each of compounds 12 and 13 was
subjected to reaction with hydrogen in the presence of commercially available Wꢀ2 Raneyꢀnickel at
room temperature and so affording the tetrahydrocarbazoles 1410,11,12b (64%) and 1511,12b (58%),
respectively. Various attempts to modify these reductive cyclisation conditions in an effort to obtain
dihydrocarbazoles (or perhaps even the carbazoles themselves as a result of conducting the workꢀup
under aerobic conditions) were unsuccessful. In the final step of the reaction sequence, then, mesitylene
solutions of compounds 14 and 15 were each heated at 150 °C with an equal weight of 10% palladium
on carbon and thus affording carbazoles 1 (55%) and 212b (57%), respectively. All of the spectroscopic
and physical data acquired on these reaction products were in complete accord with assigned structures
and matched those derived from a commercially available sample (in the former case) or reported6h,12b
in the literature (in the latter case). Furthermore, each was subjected to singleꢀcrystal Xꢀray analysis.20
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Scheme 1: Reaction Sequences Leading to Carbazoles 1 and 2
R
R
Cu, CuI
Pd(dppf)Cl2•CH2Cl2
Br
+
DMSO, 50 °C
8 ꢀ 10 h
I
O2N
O
O2N
O
9 (R=H)
11
12 (R=H) 85%
10 (R=Me)
13 (R=Me) 86%
H2, RaneyꢀNickel
MeOH, 22 °C
18 h
R
R
10 wt. % Pd/C
mesitylene, 150 °C
24 h
N
H
N
H
14 (R=H) 64%
1 (R=H) 55%
15 (R=Me) 58%
2 (R=Me) 57%
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The preparation of glycoborine (3), a synthetic target pursued by others,6e,6g,6k,9h,9k,14 was readily
accomplished as shown in Scheme 2 by coupling 2ꢀiodoꢀ4ꢀmethylcyclohexꢀ2ꢀenꢀ1ꢀone (10)11 with
nitroarene 1621 and thereby producing the arylated cyclohexenone 17 (88%), the structure of which was
secured by a singleꢀcrystal Xꢀray analysis.20 The appearance of twentyꢀeight signals in the 13C NMR
spectrum of this C14ꢀcompound suggested that it existed as diastereoisomeric atropisomers under
ambient conditions. Reductive cyclisation of compound 17 using hydrogen in the presence of Wꢀ2
Raneyꢀnickel gave the tetrahydrocarbazole 1811a (72%) and dehydrogenation of this under the same
conditions as employed before then afforded the target natural product 3 that was obtained in 75% yield.
Once again, all the appropriate spectral comparisons left no doubt the glycoborine had been obtained but
final confirmation of this followed from a singleꢀcrystal Xꢀray analysis.20
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Scheme 2: The Synthesis of Glycoborine (3)
OMe
Cu, CuI
OMe
I
Pd(dppf)Cl2•CH2Cl2
+
DMSO, 50 °C
4 h, 88%
I
O2N
O
O2N
O
17
16
10
H2, RaneyꢀNickel
MeOH, 22 °C
10 h, 72%
OMe
OMe
10 wt. % Pd/C
mesitylene, 150 °C
24 h, 75%
N
N
H
H
3
18
An essentially analogous reaction sequence to that described above was used to synthesize
glycozoline (4), a compound that has also been the target of previous studies.3c,4c,6i,12b,22 Thus, as shown
in Scheme 3, reaction of 2ꢀiodoꢀ4ꢀmethylcyclohexꢀ2ꢀenꢀ1ꢀone (10) with commercially available
nitroarene 19 under the by now standard palladiumꢀcatalysed Ullmann crossꢀcoupling conditions gave
the anticipated product 20 (87%) that was reductively cyclized with hydrogen in the presence of Wꢀ2
Raneyꢀnickel and so providing the tetrahydrocarbazole 2112b,12d,22b in 72% yield. Dehydrogenation of
compound 21 through brief treatment with 10% Pd on C in diphenyl ether at 210 °C then gave
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The Journal of Organic Chemistry
glycozoline (4) in 89% yield and the structure of which was confirmed by singleꢀcrystal Xꢀray
analysis.20
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3
4
5
6
Scheme 3: The Synthesis of Glycozoline (4)
7
8
9
Cu, CuI
10
11
12
13
14
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16
17
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20
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Pd(dppf)Cl2•CH2Cl2
I
OMe
+
OMe
DMSO, 50 °C
4 h, 87%
I
O2N
O
O2N
O
20
19
10
H2, RaneyꢀNickel
MeOH, 22 °C
16 h, 72%
10 wt. % Pd/C
OMe
OMe
Ph2O, 210 °C
0.33 h, 89%
N
N
H
H
4
21
The reaction sequence leading to clauszoline K (5) (Scheme 4), another popular target,22d,23
provided some insights into the propensity of 2,3,4,9ꢀtetrahydroꢀ1Hꢀcarbazoles to engage in alternate
oxidation reactions.12a Thus, the palladiumꢀcatalysed Ullmann crossꢀcoupling of the iodinated
cyclohexenone 10 with the commercially available 2ꢀiodonitroarene 22 proceeded as anticipated to give
the required arylated cyclohexenone 23 (80%) and this, in turn, engaged in the same type of reductive
cyclisation reaction as seen before to give tetrahydrocarbazole 2411a,14 (65%). However, compound 24
proved rather prone to oxidation with the hydroperoxide 25 being formed in increasing quantities when
its precursor was allow to stand at 22 °C as a solution (in various solvents) left open to the atmosphere.
Compound 25, the structure of which was established by singleꢀcrystal Xꢀray analysis,20 may arise
through a facially selective eneꢀreaction between indole 24 and singlet oxygen, the latter reactant (most
likely) being produced through the other (24) serving as a sensitizer. Despite the ease of the conversion
24 → 25, the tetrahydrocarbazole was readily dehydrogenated in the same manner as described in the
other instances reported herein and so producing carbazole 269c,9h,22d,23a,23b in 88% yield. Unlike isomer
4, compound 26 is not a naturally occurring material but is readily converted into one, namely aldehyde
5 (clauszoline K) (66%), on treatment with DDQ in aqueous methanol9h,23a,23b at ambient temperatures
for 4 h. The structure of compound 5 was confirmed by singleꢀcrystal Xꢀray analysis.20
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Scheme 4: The Synthesis of Clauszoline K (5)
1
2
3
4
5
6
7
Cu, CuI
Pd(dppf)Cl2•CH2Cl2
I
+
I
O2N
OMe
O
O2N
DMSO, 50 °C
6 h, 80%
O
OMe
8
23
9
22
10
10
11
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H2, RaneyꢀNickel
MeOH, 22 °C
16 h, 65%
OHC
DDQ
10 wt. % Pd/C
MeOH:H2O 10:1, 22 °C
4 h, 66%
Ph2O, 210 °C
0.5 h, 88%
N
N
N
H
OMe
OMe
OMe
H
H
5
26
24
air
various solvent mixtures
22 oC, variable yields
OOH
N
OMe
25
The carbazole natural product mukonine (6), another popular target compound,9a,12d,17a,24 carries
both the methoxy and carbomethoxy substituents in the same ring and so requiring, as the first step in
the present synthesis, the palladiumꢀcatalysed Ullmann crossꢀcoupling of the “parent” 2ꢀ
iodocyclohexeneone 9 with the readily obtained (see below) tetraꢀsubstituted arene 27 (Scheme 5) and
so affording the required 2ꢀarylatedcyclohexenone 28, albeit in just 39% yield. Reductive cyclisation of
compound 28 under standard conditions gave tetrahydrocarbazole 29 (79%) that upon dehydrogenation
under the usual conditions afforded mukonine (6) (66%) as a white, crystalline solid. Once again all the
derived spectral data were fully consistent with the assigned structure as well as those reported for the
natural product but final confirmation of this followed from a singleꢀcrystal Xꢀray analysis.20 The arene
27 used in this sequence was prepared by first brominating commercially available methyl 4ꢀaminoꢀ3ꢀ
methoxybenzoate with Nꢀbromosuccinimide (NBS) and then oxidizing the previously reported25
bromide to the corresponding nitroꢀcompound (viz. 27) using mꢀchloroperbenzoic acid (mCPBA) (see
Experimental Section for details).
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The Journal of Organic Chemistry
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2
3
Scheme 5: The Synthesis of Mukonine (6)
4
5
6
7
8
Cu, CuI
Br
CO2Me
Pd(dppf)Cl2•CH2Cl2
+
CO2Me
I
O2N
DMSO, 50 °C
28 h, 39%
O
O2N
O
OMe
9
OMe
10
11
12
13
14
15
16
17
18
19
20
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28
27
9
H2, RaneyꢀNickel
MeOH, 22 °C
16 h, 79%
10 wt. % Pd/C
CO2Me
CO2Me
mesitylene, 150 °C
24 h, 66%
N
N
H
H
OMe
OMe
6
29
The triꢀsubstituted carbazole natural product karapinchamine A (7), the subject of just one
previous synthetic study,7e was readily obtained (Scheme 6) by treating compound 26 with boron
tribromide so as to effect cleavage of the methyl ether moiety and then treating the product
hydroxycarbazole 309h (84%), as a solution in THF, with an excess of nꢀbutyllithium and then ca. 1.5
equivalents of geranyl bromide.
Scheme 6: The Synthesis of Karapinchamine A (7)
nꢀBuLi
geranyl bromide
BBr3
N
OH
THF, 0 to 22 °C
2.2 h, 50%
N
N
CH2Cl2, −78 to 22 °C
OH
OMe
H
H
15 h, 84%
7
26
30
By such means karapinchamine A (7) was obtained in 50% yield after column chromatography.
Interestingly, there was no evidence for the formation of the isomeric Oꢀgeranylated product during the
course of this reaction. All of the spectral data acquired on product 7 matched those recorded for the
natural product (see SI for relevant spectral comparisons).
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Monoꢀsubstituted carbazoles wherein the single substituent derives from the arene coupling
partner are also readily available by the procedures reported here. Thus, as shown in Scheme 7, crossꢀ
coupling of compounds 9 and 22 under the usual conditions afforded enone 3110,11b (91%) that on
subjection to reductive cyclisation using hydrogen in the presence of Raneyꢀnickel afforded the
tetrahydrocarazole 3210,11b,26 (76%). Dehydrogenation of compound 32 using 10% Pd on C in hot
mesitylene then afforded carbazole 86f,6k,6l,9j (64%), the spectral data for which matched those reported
previously.
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Scheme 7: The Synthesis of 2-Methoxy-9H-carbazole (8)
Cu, CuI
Pd(dppf)Cl2•CH2Cl2
I
+
I
DMSO, 50 °C
10 h, 91%
O2N
OMe
O
O2N
O
OMe
31
22
9
H2, RaneyꢀNickel
MeOH, 22 °C
16 h, 76%
10 wt. % Pd/C
N
N
H
OMe
OMe
mesitylene, 150 °C
24 h, 64%
H
8
32
CONCLUSIONS
The procedures detailed here allow for the straightforward preparation, in a fully regiocontrolled
manner, of a range of carbazoles carrying various combinations of substituents in both the Aꢀ and the Cꢀ
rings as well as on the nitrogen of the Bꢀring. Substitution patterns encountered in naturally occurring
and biologically active carbazoles appear to be completely accessible using the methods described here.
As a further indication of the utility of the title protocol, it is worth noting that carbazole 30 is an
established precursor to the pyrano[3,2ꢀa]carbazole alkaloids isogirinimbine and mahanimbicine.9h In a
related vein, clauszoline K (5) is an established synthetic precursor to the alkaloids clauszoline M and N
(the corresponding methyl ester and acid, respectively).22d,23a The present study also serves to highlight
the continued utility of the palladiumꢀcatalyzed Ullmann crossꢀcoupling reaction,27 especially when
used in combination with reductive cyclization protocols.28
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The Journal of Organic Chemistry
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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 baseꢀ
6
7
8
1
filtered CDCl3 on a spectrometer operating at 400 MHz for proton and 100 MHz for carbon nuclei. H
9
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 central resonance of the CDCl3 “triplet” appearing at δC 77.0 were used to reference 1H 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 highꢀresolution ESI mass spectra were recorded on a tripleꢀquadrupole
mass spectrometer operating in either positive or negative 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 : 2.5 mL : 250 mL). Flash chromatographic separations were
carried out following protocols defined by Still et al.29 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.30 Where necessary, reactions were performed under a nitrogen
atmosphere.
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Specific Chemical Transformations.
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2-Iodocyclohex-2-en-1-one (9). Following a procedure reported by Johnson et al,31 a magnetically
stirred solution of cyclohexꢀ2ꢀenꢀ1ꢀone (2.00 g, 20.8 mmol) in chloroform/pyridine (80 mL of a 1:1 v/v
mixture) maintained at 0 °C under a nitrogen atmosphere was treated, dropwise over 2 h, with a solution
of molecular iodine (18.5 g, 72.8 mmol) in chloroform/pyridine (80 mL of a 1:1 v/v mixture). The
ensuing mixture was warmed to 22 °C, stirred at this temperature for 16 h then diluted with diethyl ether
(200 mL), washed with water (1 × 100 mL), Na2S2O3 (2 × 100 mL of a 20% w/v aqueous solution), HCl
(2 × 100 mL of a 1 M aqueous solution), water (2 × 100 mL) and brine (1 × 100 mL) before being dried
(MgSO4), filtered and concentrated under reduced pressure to give a yellow oil. This was subjected to
flash column chromatography (silica, 2:5:70 v/v/v ethyl acetate/dichloromethane/40ꢀ60 petroleum ether
elution) to give, after concentration of the appropriate fractions (Rf = 0.6 in 2:5:11 v/v/v ethyl
acetate/dichloromethane/40ꢀ60 petroleum ether), 2ꢀiodocyclohexꢀ2ꢀenꢀ1ꢀone 919 (3.85 g, 83%) as a
lightꢀyellow solid, mp = 47ꢀ50 °C (lit.19 mp = 47ꢀ49 °C). 1H NMR (400 MHz, CDCl3) δ 7.77 (t, J = 4.4
Hz, 1H), 2.67 (m, 2H), 2.44 (m, 2H), 2.09 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 192.3, 159.6, 104.0,
37.4, 30.1, 23.0; IR νmax 2949, 2939, 1675, 1585, 1421, 1314, 1120, 966, 914, 803, 703 cm–1; MS (EI,
70 eV) m/z 222 (M+•, 100%), 194 (75), 67 (40); HRMS M+• calcd for C6H7127IO 221.9542, found
221.9540.
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2-Iodo-4-methylcyclohex-2-en-1-one (10). A magnetically stirred solution of 4ꢀmethylcyclohexꢀ2ꢀenꢀ
1ꢀone32 (2.29 g, 20.8 mmol) in chloroform/pyridine (80 mL of a 1:1 v/v mixture) maintained at 0 °C
under a nitrogen atmosphere was treated, dropwise over 2 h, with a solution of molecular iodine (18.5 g,
72.8 mmol) in chloroform/pyridine (80 mL of a 1:1 v/v mixture). The ensuing mixture was warmed to
22 °C, stirred at this temperature for 16 h then diluted with diethyl ether (200 mL), washed with water
(1 × 100 mL), Na2S2O3 (2 × 100 mL of a 20% w/v aqueous solution), HCl (2 × 100 mL of a 1 M
aqueous solution), water (2 × 100 mL) and brine (1 × 100 mL) before being dried (MgSO4), filtered and
concentrated under reduced pressure to give a yellow oil. Subjection of this material to flash column
chromatography (silica, 1:19 v/v ethyl acetate/40ꢀ60 petroleum ether elution) gave, after concentration
of the appropriate fractions (Rf = 0.5 in 1:5 v/v ethyl acetate/40ꢀ60 petroleum ether), compound 1011b
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(3.98 g, 81%) as a lightꢀyellow oil. H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 2.6 Hz, 1H), 2.66ꢀ2.56
(complex m, 2H), 2.48ꢀ2.39 (complex m, 1H), 2.07 (m, 1H), 1.64 (m, 1H), 1.08 (d, J = 7.2 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 191.8, 164.7, 102.9, 35.6, 35.5, 30.6, 19.7; IR νmax 2959, 2930, 2870, 1686,
1585, 1454, 1318, 1109, 790 cm–1; MS (EI, 70 eV) m/z 236 (M+•, 100%), 208 (25), 109 (75), 81 (50), 53
(60); HRMS M+• calcd for C7H9127IO 235.9698, found 235.9691.
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The Journal of Organic Chemistry
2'-Nitro-4,5-dihydro-[1,1'-biphenyl]-2(3H)-one (12). A magnetically stirred mixture of oꢀbromonitroꢀ
benzene (11) (941 mg, 4.7 mmol), 2ꢀiodocyclohexꢀ2ꢀenꢀ1ꢀone (9) (470 mg, 2.1 mmol), copper powder
(673 mg, 10.6 g.atom), CuI (605 mg, 3.2 mmol) and Pd(dppf)Cl2ꢀCH2Cl2 (87 mg, 0.1 mmol) in
deoxygenated DMSO (21 mL) maintained under nitrogen was heated at 50 °C for 10 h. The reaction
mixture was then cooled to room temperature, quenched with water (1 × 20 mL), diluted with ethyl
acetate (1 × 40 mL) and filtered through a pad of diatomaceous earth and silica gel. The pad and the
solids thus retained were washed with ethyl acetate (2 × 50 mL) and the filtrate washed with water (2 ×
100 mL) and then brine (2 × 100 mL). The separated organic phase was dried (Na2SO4), filtered and
concentrated under reduced pressure to give a brown oil and subjection of this material to flash
chromatography (silica, 1:9 v/v ethyl acetate/40ꢀ60 petroleum ether elution) gave, after concentration of
the appropriate fractions (Rf = 0.4 in 1:1 v/v ethyl acetate/40ꢀ60 petroleum ether), compound 1210,11 (390
mg, 85%) as a lightꢀyellow crystal, mp = 96ꢀ99 °C (lit.10 mp = 92ꢀ95 °C). 1H NMR (400 MHz, CDCl3) δ
7.99 (m, 1H), 7.58 (m, 1H), 7.46 (m, 1H), 7.25 (m, 1H), 7.00 (t, J = 4.2 Hz, 1H), 2.56 (m, 4H), 2.13 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 196.6, 148.7, 146.8, 139.4, 133.4, 132.2, 131.8, 128.8, 124.2, 38.4,
26.4, 22.7; IR νmax 2949, 2868, 1679, 1523, 1353, 1158, 859, 788, 751, 709 cm–1; MS (ESI, +ve) m/z
240 [(M+Na)+, 100%], 218 [(M+H)+, 10]; HRMS (M+H)+ calcd for C12H12NO3 218.0817, found
218.0825.
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5-Methyl-2'-nitro-4,5-dihydro-[1,1'-biphenyl]-2(3H)-one (13). A magnetically stirred mixture of oꢀ
bromonitrobenzene (11) (960 mg, 4.75 mmol), 2ꢀiodoꢀ4ꢀmethylcyclohexꢀ2ꢀenꢀ1ꢀone (10) (510 mg, 2.16
mmol), copper powder (687 mg, 10.80 g.atom), CuI (617 mg, 3.24 mmol) and Pd(dppf)Cl2ꢀCH2Cl2 (88
mg, 0.11 mmol) in deoxygenated DMSO (22 mL) was heated at 50 °C under a nitrogen atmosphere for
8 h. The reaction mixture was then cooled to room temperature, quenched with water (20 mL), diluted
with ethyl acetate (40 mL) then filtered through a pad of diatomaceous earth and silica gel. The pad and
the solids thus retained were washed with ethyl acetate (2 × 50 mL) and the organic phase associated
with the filtrate then washed with water (2 × 100 mL) and 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 chromatography (silica, 1:9 v/v ethyl acetate/40ꢀ60 petroleum ether elution) gave, after
concentration of the appropriate fractions (Rf = 0.5 in 1:1 v/v ethyl acetate/40ꢀ60 petroleum ether),
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compound 1311 (430 mg, 86%) as a lightꢀyellow oil. H NMR (400 MHz, CDCl3) δ 7.99 (m, 1H), 7.58
(m, 1H), 7.45 (m, 1H), 7.40 (d, J = 7.6 Hz, 1H), 6.80 (d, J = 1.6 Hz, 1H), 2.79 (broad s, 1H), 2.65ꢀ2.47
(complex m, 2H), 2.20 (m, 1H), 1.86ꢀ1.76 (complex m, 1H), 1.24 (m, 3H); 13C NMR (100 MHz,
CDCl3) δ 196.6, 152.3, 148.7, 138.4, 133.4, 132.1, 131.8, 128.9, 124.3, 37.2, 31.8, 30.7, 20.4; IR νmax
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2960, 2872, 1681, 1525, 1354, 1159, 788, 750 cm–1; MS (ESI, +ve) m/z 254 [(M+Na)+, 100%], 232
[(M+H)+, 10]; HRMS (M+Na)+ calcd for C13H13NNaO3 254.0793, found 254.0799.
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2,3,4,9-Tetrahydro-1H-carbazole (14). A magnetically stirred mixture of compound 12 (100 mg, 0.46
mmol) and commercially available Wꢀ2 Raneyꢀnickel (200 mg, washed twice with absolute ethanol) in
methanol (23 mL) was deoxygenated and then stirred under an atmosphere of hydrogen at 22 °C for 18
h. After this time and using an externally applied magnet to hold the solid associated with the reaction
mixture within the flask, the supernatant liquid was decanted and the retained solid washed with
methanol (2 × 30 mL) (Caution: after these washings water should be added to the residual solid so as
to prevent a fire). The methanolic solutions were combined then concentrated under reduced pressure to
give a white solid. Subjection of this material to flash column chromatography (silica, 1:9 v/v ethyl
acetate/40ꢀ60 petroleum ether elution) gave, after concentration of the appropriate fractions (Rf = 0.6 in
1:5 v/v ethyl acetate/40ꢀ60 petroleum ether), compound 1410,11,12b (50 mg, 64%) as a white solid, mp =
104ꢀ106 °C (lit.12b mp = 104ꢀ106 °C). 1H NMR [400 MHz, (CD3)2CO] δ 9.70 (broad s, 1H), 7.36 (d, J =
7.8 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 7.02ꢀ6.92 (complex m, 2H), 2.73 (t, J = 5.9 Hz, 2H), 2.68ꢀ2.65
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(complex m, 2H), 1.92ꢀ1.81 (complex m, 4H); C NMR [100 MHz, (CD3)2CO] δ 137.1, 135.1, 128.8,
121.1, 119.1, 118.0, 111.3, 109.7, 24.2, 24.0, 23.8, 21.7; IR νmax 3396, 2926, 2849, 1467, 1450, 1439,
1325, 1304, 1233, 736, 635 cm–1; MS (ESI, +ve) m/z 226 [(M+MeOH+Na)+, 100%], 188 (56), 172
[(M+H)+, 70]; HRMS (M+H)+ calcd for C12H14N 172.1126, found: 172.1121.
3-Methyl-2,3,4,9-tetrahydro-1H-carbazole (15). A magnetically stirred mixture of compound 13 (320
mg, 1.38 mmol) and commercially available Wꢀ2 Raneyꢀnickel (640 mg, washed twice with absolute
ethanol) in methanol (69 mL) was deoxygenated and then stirred under an atmosphere of hydrogen at 22
°C for 18 h. After this time and using an externally applied magnet to hold the solid associated with the
reaction mixture within the flask, the supernatant liquid was decanted and the retained solid washed
with methanol (2 × 30 mL) (Caution: after these washings water should be added to the residual solid
so as to prevent a fire). The methanolic solutions were combined then concentrated under reduced
pressure to give a white solid. Subjection of this material to flash column chromatography (silica, 1:9
v/v ethyl acetate/40ꢀ60 petroleum ether elution) to give, after concentration of the appropriate fractions
(Rf = 0.6 in 1:5 v/v ethyl acetate/40ꢀ60 petroleum ether), compound 1511,12b (148 mg, 58%) as a white
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solid, mp = 98ꢀ100 °C (lit.12b mp = 98ꢀ100 °C). H NMR [400 MHz, (CD3)2CO] δ 9.70 (broad s, 1H),
7.36 (d, J = 7.6 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 7.02ꢀ6.92 (complex m, 2H), 2.83ꢀ2.75 (complex m,
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3H), 2.24 (m, 1H), 1.98ꢀ1.86 (complex m, 2H), 1.53 (m, 1H), 1.13 (d, J = 6.6 Hz, 3H); C NMR [100
MHz, (CD3)2CO] δ 137.4, 134.9, 128.7, 121.1, 119.1, 118.0, 111.3, 109.7, 32.3, 30.6, 30.2, 23.4, 22.1;
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IR νmax 3405, 2949, 2923, 1620, 1467, 1326, 1232, 1009, 740 cm–1; MS (ESI, +ve) m/z 240
[(M+MeOH+Na)+, 100%], 202 (45), 186 [(M+H)+, 30]; HRMS (M+H)+ calcd for C13H16N 186.1283,
found 186.1286.
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9H-Carbazole (1). A magnetically stirred mixture of compound 14 (46 mg, 0.27 mmol) and 10 wt. %
Pd/C (46 mg) in mesitylene (5 mL) was stirred at 150 °C under an atmosphere of nitrogen for 24 h. The
cooled reaction mixture was filtered through filter paper and the solids thus retained washed with ethyl
acetate (2 x 15 mL). The filtrate was concentrated under reduced pressure and the ensuing mixture of
product 1 and mesitylene then subjected to flash column chromatography (silica, 1:19 v/v ethyl
acetate/40ꢀ60 petroleum ether elution). Concentration of the appropriate fractions (Rf = 0.6 in 1:5 v/v
ethyl acetate/40ꢀ60 petroleum ether) then gave compound 1 (25 mg, 55%) as a white, crystalline solid,
mp = 237ꢀ238 °C (lit.33 mp = 245 °C). 1H NMR [400 MHz, (CD3)2CO] δ 10.32 (broad s, 1H), 8.11 (d, J
= 7.8 Hz, 2H), 7.51 (d, J = 8.1 Hz, 2H), 7.39 (m, 2H), 7.18 (m, 2H); 13C NMR [100 MHz, (CD3)2CO] δ
141.0, 126.4, 124.0, 120.9, 119.6, 111.7; IR νmax 3416, 3049, 1597, 1449, 1233, 928, 745, 722 cm–1; MS
(ESI, −ve) m/z 166 [(M−H)–, 100%]; HRMS (M−H)– calcd for C12H8N 166.0657, found 166.0656.
3-Methyl-9H-carbazole (2). A magnetically stirred mixture of compound 15 (145 mg, 0.78 mmol) and
10 wt. % Pd/C (145 mg) in mesitylene (15 mL) was stirred at 150 °C under an atmosphere of nitrogen
for 24 h. The cooled reaction mixture was filtered through filter paper and the solids thus retained
washed with ethyl acetate (2 x 15 mL). The filtrate was concentrated under reduced pressure and the
ensuing mixture of product 2 and mesitylene then 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 = 0.6 in 1:3 v/v ethyl acetate/40ꢀ60 petroleum ether), compound 212b (80 mg, 57%) as a
white solid, mp = 200ꢀ202 °C (lit.12b mp = 205ꢀ210 °C). 1H NMR [400 MHz, (CD3)2CO] δ 10.17 (broad
s, 1H), 8.07 (d, J = 7.8 Hz, 1H), 7.90 (s, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.37ꢀ
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7.33 (complex m, 1H), 7.22 (dd, J = 8.2 and 1.2 Hz, 1H), 7.15 (m, 1H), 2.48 (s, 3H); C NMR [100
MHz, (CD3)2CO] δ 141.3, 139.2, 128.6, 127.7, 126.2, 124.2, 123.8, 120.8, 120.7, 119.4, 111.6, 111.4,
21.5; IR νmax 3403, 3050, 2914, 2853, 1605, 1459, 1333, 1238, 805, 746, 726 cm–1; MS (ESI, −ve) m/z
180 [(M−H)–, 100%]; HRMS (M−H)– calcd for C13H10N 180.0813, found 180.0804.
2'-Methoxy-5-methyl-6'-nitro-4,5-dihydro-[1,1'-biphenyl]-2(3H)-one (17). A magnetically stirred
mixture of 2ꢀiodoꢀ1ꢀmethoxyꢀ3ꢀnitrobenzene (16)21 (341 mg, 1.22 mmol), 2ꢀiodoꢀ4ꢀmethylcyclohexꢀ2ꢀ
enꢀ1ꢀone (10) (519 mg, 2.20 mmol), copper powder (311 mg, 4.89 g.atom), CuI (349 mg, 1.83 mmol)
and Pd(dppf)Cl2ꢀCH2Cl2 (100 mg, 0.12 mmol) in deoxygenated DMSO (24 mL) was heated at 50 °C
under a nitrogen atmosphere for 4 h. The reaction mixture was then cooled to room temperature,
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quenched with water (10 mL), diluted with ethyl acetate (20 mL) then filtered through a pad of
diatomaceous earth and silica gel. The pad and the solids thus retained were washed with ethyl acetate
(2 × 25 mL) and the organic phase associated with the filtrate then washed with water (2 × 50 mL) and
brine (2 × 50 mL) before being dried (Na2SO4), filtered and concentrated under reduced pressure to give
a brown oil. Subjection of this material to flash chromatography (silica, 2:5:40 v/v/v ethyl
acetate/dichloromethane/40ꢀ60 petroleum ether elution) gave, after concentration of the appropriate
fractions (Rf = 0.3 in 2:5:11 v/v/v ethyl acetate/dichloromethane/40ꢀ60 petroleum ether), compound 17
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(281 mg, 88%) as a lightꢀyellow solid, mp = 94ꢀ96 °C. H NMR (400 MHz, CDCl3) δ 7.53 (m, 1H),
7.40ꢀ7.10 (complex m, 2H), 6.63 (m, 1H), 3.78 (m, 3H), 2.76ꢀ2.48 (complex m, 3H), 2.24ꢀ2.14
(complex m, 1H), 1.90ꢀ1.76 (complex m, 1H), 1.20 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 196.9,
196.7, 158.1, 158.0, 153.7, 153.5, 150.3, 150.0, 133.0, 132.6, 129.1, 129.2, 121.5, 121.4, 116.1, 116.0,
115.6, 115.4, 56.7, 56.6, 37.3, 37.1, 32.0, 31.6, 30.9, 30.5, 20.4, 20.1; IR νmax 2959, 1674, 1524, 1461,
1351, 1263, 1052, 794, 736 cm–1; MS (ESI, +ve) m/z 284 [(M+Na)+, 100%], 262 [(M+H)+, 15]; HRMS
(M+Na)+ calcd for C14H15NNaO4 284.0899, found 284.0896.
5-Methoxy-3-methyl-2,3,4,9-tetrahydro-1H-carbazole (18). A magnetically stirred mixture of
compound 17 (211 mg, 0.81 mmol) and commercially available Wꢀ2 Raneyꢀnickel (422 mg, washed
twice with absolute ethanol) in methanol (40 mL) was deoxygenated and then stirred under an
atmosphere of hydrogen at 22 °C for 10 h. After this time and using an externally applied magnet to
hold the solid associated with the reaction mixture within the flask, the supernatant liquid was decanted
and the retained solid washed with methanol (2 × 15 mL) (Caution: after these washings water should
be added to the residual solid so as to prevent a fire). The methanolic solutions were combined then
concentrated under reduced pressure to give a white solid. Subjection of this material to flash column
chromatography flash column chromatography (silica, 1:3:30 v/v/v acetone/dichloromethane/40ꢀ60
petroleum ether elution) gave, after concentration of the appropriate fractions (Rf = 0.5 in 1:3:6 v/v/v
acetone/dichloromethane/40ꢀ60 petroleum ether), compound 1811a (125 mg, 72%) as a white solid, mp =
126ꢀ128 °C. 1H NMR [400 MHz, (CD3)2CO] δ 9.63 (broad s, 1H), 6.91ꢀ6.85 (complex m, 2H), 6.41 (dd,
J = 6.5 and 1.9 Hz, 1H), 3.84 (s, 3H), 3.11 (dd, J = 16.0 and 4.7 Hz, 1H), 2.72 (m, 2H), 2.41 (m, 1H),
1.92ꢀ1.79 (complex m, 2H), 1.48 (m, 1H), 1.10 (d, J = 6.6 Hz, 3H); 13C NMR [100 MHz, (CD3)2CO] δ
155.1, 138.8, 132.8, 121.8, 118.6, 109.6, 105.1, 99.7, 55.3, 32.7, 32.1, 30.8, 23.4, 22.2; IR νmax 3397,
2948, 2923, 2836, 1565, 1505, 1349, 1253, 1244, 1104, 775, 729 cm–1; MS (ESI, +ve) m/z 232 (100%),
216 [(M+H)+, 90]; HRMS (M+H)+ calcd for C14H18NO 216.1388, found: 216.1393.
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Glycoborine (3). A magnetically stirred mixture of compound 18 (50 mg, 0.23 mmol) and 10 wt. %
Pd/C (50 mg) in mesitylene (5 mL) was stirred at 150 °C under an atmosphere of nitrogen for 24 h. The
cooled reaction mixture was filtered through filter paper and the solids thus retained washed with ethyl
acetate (2 x 10 mL). The combined filtrates were concentrated under reduced pressure and the ensuing
mixture of product 3 and mesitylene then subjected to flash column chromatography (silica, 2:5:62 v/v/v
ethyl acetate/dichloromethane/40ꢀ60 petroleum ether elution) to give, after concentration of the
appropriate fractions (Rf = 0.4(5) in 2:5:11 v/v/v ethyl acetate/dichloromethane/40ꢀ60 petroleum ether),
compound 33a (35 mg, 75%) as a white solid, mp = 130ꢀ132 °C (lit.3a mp = 132.0ꢀ134.6). 1H NMR [400
MHz, (CD3)2CO] δ 10.17 (broad s, 1H), 8.07 (s, 1H), 7.36 (d, J = 8.2 Hz, 1H), 7.28 (t, J = 8.0 Hz, 1H),
7.17 (dd, J = 8.2 and 1.2 Hz, 1H), 7.08 (d, J = 8.2 Hz, 1H), 6.68 (d, J = 8.0 Hz, 1H), 4.06 (s, 3H), 2.48
(s, 3H); 13C NMR [100 MHz, (CD3)2CO] δ 157.1, 142.7, 138.4, 128.5, 127.2, 126.7, 123.6, 123.5,
113.0, 110.8, 104.7, 100.5, 55.6, 21.6; IR νmax 3402, 2917, 2838, 1608, 1585, 1506, 1459, 1347, 1260,
1098, 750, 723 cm–1; MS (ESI, +ve) m/z 234 [(M+Na)+, 10%], 212 [(M+H)+, 100]; HRMS (M+H)+
calcd for C14H14NO 212.1075, found 212.1078.
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5'-Methoxy-5-methyl-2'-nitro-4,5-dihydro-[1,1'-biphenyl]-2(3H)-one (20). A magnetically stirred
mixture of commercially available 2ꢀiodoꢀ4ꢀmethoxynitrobenzene (19) (150 mg, 0.54 mmol), 2ꢀiodoꢀ4ꢀ
methylcyclohexꢀ2ꢀenꢀ1ꢀone (10) (229 mg, 0.97 mmol), copper powder (137 mg, 2.15 g.atom), CuI (154
mg, 0.81 mmol) and Pd(dppf)Cl2ꢀCH2Cl2 (44 mg, 0.05 mmol) in deoxygenated DMSO (12 mL) was
heated at 50 °C under a nitrogen atmosphere for 4 h. The reaction mixture was then cooled to room
temperature, quenched with water (5 mL), diluted with ethyl acetate (10 mL) then filtered through a pad
of diatomaceous earth and silica gel. The pad and the solids thus retained were washed with ethyl
acetate (2 × 15 mL) and the separated organic phase associated with the filtrate then washed with water
(2 × 25 mL) and brine (2 × 25 mL) before being dried (Na2SO4), filtered and concentrated under
reduced pressure to give a brown oil. Subjection of this material to flash chromatography (silica, 1:3:25
v/v/v acetone/dichloromethane/40ꢀ60 petroleum ether elution) gave, after concentration of the
appropriate fractions [Rf = 0.5(5) in 1:3:6 v/v/v acetone/dichloromethane/40ꢀ60 petroleum ether],
1
compound 20 (125 mg, 87%) as a lightꢀyellow oil. H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 9.1 Hz,
1H), 6.90 (dd, J = 9.1 and 2.6 Hz, 1H), 6.70 (m, 2H), 3.88 (s, 3H), 2.76ꢀ2.51 (complex m, 3H), 2.21 (m,
1H), 1.84 (m, 1H), 1.25 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 196.8, 163.4, 151.2, 141.7,
139.1, 135.2, 127.2, 117.2, 113.2, 56.1, 37.3, 31.8, 30.8, 20.5; IR νmax 2953, 1681, 1578, 1512, 1340,
1298, 1238, 1026, 844 cm–1; MS (ESI, +ve) m/z 284 [(M+Na)+, 100%], 262 [(M+H)+, 10]; HRMS
(M+Na)+ calcd for C14H15NNaO4 284.0899, found 284.0890.
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6-Methoxy-3-methyl-2,3,4,9-tetrahydro-1H-carbazole (21). A magnetically stirred mixture of
compound 20 (100 mg, 0.38 mmol) and commercially available Wꢀ2 Raneyꢀnickel (200 mg, washed
twice with absolute ethanol) in methanol (19 mL) was deoxygenated and then stirred under an
atmosphere of hydrogen at 22 °C for 16 h. After this time and using an externally applied magnet to
hold the solid associated with the reaction mixture within the flask, the supernatant liquid was decanted
and the retained solid washed with methanol (2 × 10 mL) (Caution: after these washings water should
be added to the residual solid so as to prevent a fire). The methanolic solutions were combined then
concentrated under reduced pressure to give a white solid. Subjection of this material to flash column
chromatography (silica, 1:3:20 v/v/v acetone/dichloromethane/40ꢀ60 petroleum ether elution) gave,
after concentration of the appropriate fractions (Rf = 0.6 in 1:3:6 v/v/v acetone/dichloromethane/40ꢀ60
petroleum ether), compound 2112b,12d,22b (50 mg, 61%) as a white solid, mp = 108ꢀ109 °C. 1H NMR [400
MHz, (CD3)2CO] δ 9.52 (broad s, 1H), 7.14 (d, J = 8.6 Hz, 1H), 6.88 (s, 1H), 6.65 (d, J = 8.6 Hz, 1H),
3.78 (s, 3H), 2.80ꢀ2.73 (complex m, 3H), 2.20 (m, 1H), 1.95ꢀ1.85 (complex m, 2H), 1.52 (m, 1H), 1.12
(d, J = 6.5 Hz, 3H); 13C NMR [100 MHz, (CD3)2CO] δ 154.6, 135.7, 132.5, 129.1, 111.8, 110.7, 109.6,
100.6, 55.8, 32.4, 30.6, 30.4, 23.6, 22.1; IR νmax 3401, 2947, 2909, 2830, 1591, 1481, 1454, 1431, 1210,
1137, 1030, 831, 796 cm–1; MS (ESI, −ve) m/z 214 [(M−H)–, 100%]; HRMS (M−H)– calcd for
C14H16NO 214.1232, found 214.1235.
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Glycozoline (4). A magnetically stirred mixture of compound 21 (44 mg, 0.20 mmol) and 10 wt. %
Pd/C (44 mg) in diphenyl ether (5 mL) was stirred at 210 °C under an atmosphere of nitrogen for 0.33 h.
The cooled reaction mixture was filtered through filter paper and the solids thus retained washed with
ethyl acetate (2 x 5 mL). The combined filtrates were concentrated under reduced pressure and the
ensuing mixture of product 4 and diphenyl ether then subjected to flash column chromatography (silica,
1:9 v/v ethyl acetate/40ꢀ60 petroleum ether elution) to give, after concentration of the appropriate
fractions (Rf = 0.4 in 3:7 v/v ethyl acetate/40ꢀ60 petroleum ether), compound 43a,15 (39 mg, 89%) as a
white, crystalline solid, mp = 180ꢀ181 °C (lit.22b mp. = 177ꢀ178 °C). 1H NMR [400 MHz, (CD3)2CO] δ
9.96 (broad s, 1H), 7.87 (s, 1H), 7.63 (d, J = 2.2 Hz, 1H), 7.36 (t, J = 8.5 Hz, 2H), 7.18 (d, J = 8.2 Hz,
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1H), 7.00 (dd, J = 8.5 and 2.2 Hz, 1H), 3.88 (s, 3H), 2.47 (s, 3H); C NMR [100 MHz, (CD3)2CO] δ
154.5, 140.0, 136.1, 128.1, 127.7, 124.2(2), 124.2(0), 120.8, 115.6, 112.3, 111.5, 103.5, 56.1, 21.5; IR
νmax 3398, 2928, 1493, 1470, 1457, 1208, 1148, 1033, 806 cm–1; MS (ESI, −ve) m/z 210 [(M−H)–, 60%],
195 (100); HRMS (M−H)– calcd for C14H12NO 210.0919, found 210.0912.
4'-Methoxy-5-methyl-2'-nitro-4,5-dihydro-[1,1'-biphenyl]-2(3H)-one (23). A magnetically stirred
mixture of commercially available 1ꢀiodoꢀ4ꢀmethoxyꢀ2ꢀnitrobenzene (22) (341 mg, 1.22 mmol), 2ꢀiodoꢀ
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4ꢀmethylcyclohexꢀ2ꢀenꢀ1ꢀone (10) (519 mg, 2.20 mmol), copper powder (311 mg, 4.89 g.atom), CuI
(349 mg, 1.83 mmol) and Pd(dppf)Cl2ꢀCH2Cl2 (100 mg, 0.12 mmol) in deoxygenated DMSO (24 mL)
was heated at 50 °C under a nitrogen atmosphere for 6 h. The ensuing mixture was cooled to room
temperature, quenched with water (10 mL), diluted with ethyl acetate (20 mL) and then filtered through
a pad of diatomaceous earth and silica gel. The pad and the solids thus retained were washed with ethyl
acetate (2 × 30 mL) and the separated organic phase associated with the filtrate washed with water (2 ×
50 mL) and brine (2 × 50 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, 2:5:64
v/v/v ethyl acetate/dichloromethane/40ꢀ60 petroleum ether elution) gave, after concentration of the
appropriate fractions (Rf = 0.4 in 2:5:11 v/v/v ethyl acetate/dichloromethane/40ꢀ60 petroleum ether),
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compound 23 (256 mg, 80%) as a lightꢀyellow oil. H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 2.3 Hz,
1H), 7.15ꢀ7.09 (complex m, 2H), 6.75 (dd, J = 2.7 and 1.1 Hz, 1H), 3.85 (s, 3H), 2.75 (m, 1H), 2.65ꢀ
2.40 (complex m, 2H), 2.19 (m, 1H), 1.80 (m, 1H), 1.24 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 196.9, 159.7, 151.8, 149.2, 138.1, 132.7, 124.2, 119.7, 109.3, 56.0, 37.3, 31.8, 30.8, 20.5; IR
νmax 2960, 1681, 1529, 1353, 1302, 1266, 1236, 1032, 800 cm–1; MS (ESI, +ve) m/z 284 [(M+Na)+,
100%], 262 [(M+H)+, 15]; HRMS (M+Na)+ calcd for C14H15NNaO4 284.0899, found 284.0901.
7-Methoxy-3-methyl-2,3,4,9-tetrahydro-1H-carbazole (24) and trans-4a-Hydroperoxy-7-methoxy-
3-methyl-2,3,4,4a-tetrahydro-1H-carbazole (25). A magnetically stirred mixture of compound 23
(202 mg, 0.77 mmol) and commercially available Wꢀ2 Raneyꢀnickel (404 mg, washed twice with
absolute ethanol) in methanol (38 mL) was deoxygenated and then stirred under an atmosphere of
hydrogen at 22 °C for 16 h. After this time and using an externally applied magnet to hold the solid
associated with the reaction mixture within the flask, the supernatant liquid was decanted and the
retained solid washed with methanol (2 × 20 mL) (Caution: after these washings water should be added
to the residual solid so as to prevent a fire). The methanolic solutions were combined then concentrated
under reduced pressure to give a white solid. Subjection of this material to flash column
chromatography (silica, 1:3:20 v/v/v acetone/dichloromethane/40ꢀ60 petroleum ether elution) gave two
fractions, A and B.
Concentration of fraction A (Rf = 0.5 in 1:3:6 v/v/v acetone/dichloromethane/40ꢀ60 petroleum ether)
1
afforded compound 2411a,14 (109 mg, 65%) as a white, crystalline solid, mp = 130ꢀ132 °C. H NMR
[400 MHz, (CD3)2CO] δ 9.50 (broad s, 1H), 7.22 (d, J = 8.5 Hz, 1H), 6.83 (d, J = 2.2 Hz, 1H), 6.63 (dd,
J = 8.5 and 2.2 Hz, 1H), 3.76 (s, 3H), 2.83ꢀ2.71 (complex m, 3H), 2.19 (m, 1H), 1.90 (m, 2H), 1.50 (m,
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1H), 1.11 (d, J = 6.5 Hz, 3H); C NMR [100 MHz, (CD3)2CO] δ 156.6, 138.2, 133.4, 123.2, 118.5,
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109.5, 108.6, 95.4, 55.7, 32.3, 30.6, 30.3, 23.5, 22.1; IR νmax 3390, 2909, 2835, 1630, 1570, 1496, 1459,
1335, 1291, 1203, 1157, 1029, 826, 805 cm–1; MS (ESI, +ve) m/z 238 [(M+Na)+, 20%], 218 (100), 216
[(M+H)+, 90]; HRMS (M+H)+ calcd for C14H18NO 216.1388, found 216.1386.
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Concentration of fraction B (Rf = 0.1 in 1:3:6 v/v/v acetone/dichloromethane/40ꢀ60 petroleum ether)
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afforded hydroperoxide 25 (15 mg, 8%) as a white, crystalline solid, mp = 106ꢀ108 °C. H NMR [700
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MHz, (CD3)2CO] δ δ 10.81 (s, 1H), 7.26 (d, J = 8.0 Hz, 1H), 6.97 (d, J = 2.3 Hz, 1H), 6.71 (dd, J = 8.0
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and 2.3 Hz, 1H), 3.82 (s, 3H), 2.82ꢀ2.76 (complex m, 1H), 2.68 (m, 1H), 2.43 (m, 1H), 2.14 (m, 2H),
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1.13 (m, 1H), 0.95 (m, 1H), 0.92 (d, J = 6.6 Hz, 3H); C NMR [175 MHz, (CD3)2CO] δ 186.1, 162.2,
157.4, 131.5, 123.8, 110.8, 107.4, 92.3, 55.8, 44.4, 37.4, 30.3, 28.1, 21.0; IR νmax 3100, 2954, 2836,
1607, 1484, 1347, 1276, 1144, 1130, 1028, 845, 815 cm–1; MS (ESI, +ve) m/z 270 [(M+Na)+, 100%],
248 [(M+H)+, 10]; HRMS (ESI) (M+Na)+ calcd for C14H17NNaO3 270.1106, found 270.1107.
2-Methoxy-6-methyl-9H-carbazole (26). A magnetically stirred mixture of compound 24 (100 mg,
0.46 mmol) and 10 wt. % Pd/C (100 mg) in diphenyl ether (10 mL) was stirred at 210 °C under an
atmosphere of nitrogen for 0.5 h. The cooled reaction mixture was filtered through filter paper and the
solids thus retained washed with ethyl acetate (2 x 10 mL). The combined filtrates were concentrated
under reduced pressure and the ensuing mixture of product 269c,9h,22d,23a,23b and diphenyl ether then
subjected to flash column chromatography (silica, 2:5:60 v/v/v ethyl acetate/dichloromethane/40ꢀ60
petroleum ether elution) to give, after concentration of the appropriate fractions (Rf = 0.4 in 2:5:11 v/v/v
ethyl acetate/dichloromethane/40ꢀ60 petroleum ether), compound 26 (87 mg, 88%) as a white solid, mp
= 229ꢀ231 °C. (lit.9c mp = 228ꢀ229 °C). 1H NMR [400 MHz, (CD3)2CO] δ 10.03 (braod s, 1H), 7.92 (d,
J = 8.6 Hz, 1H), 7.78 (s, 1H), 7.32 (d, J = 8.2 Hz, 1H), 7.11 (d, J = 8.2 Hz, 1H), 6.99 (d, J = 2.2 Hz,
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1H), 6.77 (dd, J = 8.6 and 2.2 Hz, 1H), 3.85 (s, 3H), 2.46 (s, 3H); C NMR [100 MHz, (CD3)2CO] δ
160.0, 142.7, 139.3, 128.6, 126.3, 124.4, 121.5, 120.0, 117.6, 111.1, 108.6, 95.3, 55.7, 21.5; IR νmax
3391, 2962, 1615, 1460, 1310, 1261, 1164, 1035, 811 cm–1; MS (ESI, +ve) m/z 212 [(M+H)+, 100%];
HRMS (M+H)+ calcd for C14H14NO 212.1075, found 212.1077.
Clauszoline K (5). A magnetically stirred solution of 2ꢀmethoxyꢀ6ꢀmethylꢀ9Hꢀcarbazole (26) (50 mg,
0.24 mmol) in methanol/water (16 mL of 10:1 v/v mixture) was treated with DDQ (226 mg, 0.99
mmol). The ensuring mixture was stirred at room temperature for 4 h then diluted with ethyl acetate (30
mL). The separated organic phase was washed with NaHCO3 (2 × 15 mL of a saturated aqueous
solution), water (1 × 30 mL), and brine (1 × 30 mL) before being dried (Na2SO4), filtered and
concentrated under reduced pressure. The residue thus obtained was subjected to flash chromatography
(silica, 1:3 v/v ethyl acetate/40ꢀ60 petroleum ether elution) to give, after concentration of the
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appropriate fractions (Rf = 0.5 in 1:1 v/v ethyl acetate/40ꢀ60 petroleum ether), compound 5 (35 mg,
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66%) as a yellow solid, mp = 170ꢀ171 °C (lit.22d mp = 184ꢀ185 °C). H NMR [400 MHz, (CD3)2CO] δ
10.72 (broad s, 1H), 10.07 (s, 1H), 8.58 (s, 1H), 8.12 (d, J = 8.6 Hz, 1H), 7.88 (broadened d, J = 8.4 Hz,
1H), 7.59 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 2.3 Hz, 1H), 6.91 (dd, J = 8.6 and 2.3 Hz, 1H), 3.89 (s, 3H);
13C NMR [100 MHz, (CD3)2CO] δ 192.0, 160.8, 144.8, 143.1, 130.1, 126.3, 124.4, 123.5, 122.2, 117.6,
111.8, 110.1, 96.0, 55.8; IR νmax 3306, 2923, 2849, 1667, 1604, 1569, 1456, 1317, 1159, 817, 807 cm–1;
MS (ESI, −ve) m/z 224 [(M−H)–, 100%], 209 (54); HRMS (M−H)– calcd for C14H10NO2 224.0712,
found 224.0705.
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Methyl 3-Bromo-5-methoxy-4-nitrobenzoate (27). Step i: A magnetically stirred and iceꢀcold solution
of methyl 4ꢀaminoꢀ3ꢀmethoxybenzoate (3.00 mg, 16.56 mmol) in chloroform (33 mL) was treated, in
portions over 1 h, with Nꢀbromosuccinimide (NBS) (2.95, 16.6 mmol). The ensuing mixture was stirred
at 5ꢀ10 °C for 2 h before being diluted with dichloromethane (1 × 200 mL) then washed with Na2S2O3
(2 × 100 mL of a 20% w/v aqueous solution), water (2 × 100 mL) and brine (1 × 100 mL). The
separated organic phase was then dried (Na2SO4), filtered and concentrated under reduced pressure. The
residue thus obtained was subjected to flash column chromatography (silica, 3:17 v/v ethyl acetate/40ꢀ
60 petroleum ether elution) to give, after concentration of the appropriate fractions (Rf = 0.6 in 1:3 v/v
ethyl acetate/40ꢀ60 petroleum ether), methyl 4ꢀaminoꢀ3ꢀbromoꢀ5ꢀmethoxybenzoate25 (3.70 g, 86%) as a
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yellow solid, mp = 90ꢀ91 °C. H NMR (CDCl3, 400 MHz) δ 7.81 (s, 1H), 7.38 (s, 1H), 4.65 (broad s,
2H), 3.91 (s, 3H), 3.87 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.5, 146.3, 139.4, 127.1, 119.5, 109.9,
106.8, 56.2, 52.1; IR νmax 3503, 3399, 1692, 1603, 1566, 1502, 1435, 1270, 1209, 1041, 995, 759 cm–1;
MS (EI, 70 eV) m/z 261 and 259 (M+•, 98 and 100%, respectively), 246 and 244 (both 65 and 63,
respectively), 230 and 228 (both 54); HRMS M+• calcd for C9H1079BrNO3 258.9844, found 258.9846.
Step ii: A magnetically stirred solution of methyl 4ꢀaminoꢀ3ꢀbromoꢀ5ꢀmethoxybenzoate (4.24 g, 16.31
mmol), obtained as described immediately above, in 1,2ꢀdichloroethane (163 mL) was treated with mꢀ
chloroperbenzoic acid (mCPBA) (11.26 g of ca. 77% technical grade material, 65.3 mmol). The
resulting mixture was heated at 70 °C for 14 h before being cooled, diluted with dichloromethane (150
mL), washed with NaOH (2 × 150 ml of a 1 M aqueous solution) followed by brine (1 x 100 mL) then
dried (MgSO4), filtered and concentrated under reduced pressure. The residue thus obtained was
subjected to flash column chromatography (silica, 1:8 v/v ethyl acetate/40ꢀ60 petroleum ether elution) to
give, after concentration of the appropriate fractions (Rf = 0.5 in 1:2 v/v ethyl acetate/40ꢀ60 petroleum
ether), methyl 3ꢀbromoꢀ5ꢀmethoxyꢀ4ꢀnitrobenzoate (27) (4.13 g, 87%) as a yellow solid, mp = 103ꢀ104
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°C. H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 1.4 Hz, 1H), 7.65 (d, J = 1.4 Hz, 1H), 3.95(9) (s, 3H),
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13
3.95(6) (s, 3H); C NMR (100 MHz, CDCl3) δ 164.4, 151.8, 144.7, 133.1, 126.2, 113.8, 112.8, 57.1,
53.2; IR νmax 3097, 1730, 1540, 1406, 1289, 1248, 1037, 984, 822, 764 cm–1; MS (EI, 70 eV) m/z 291
and 289 (M+•, 98 and 100%, respectively) 259 and 257 (40 and 35, respectively) 199 and 197 (60 and
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50, respectively); HRMS M+• calcd for C9H8 BrNO5 288.9586, found 288.9587.
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Methyl 5-Methoxy-6-nitro-2'-oxo-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-3-carboxylate (28).
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magnetically stirred mixture of methyl 3ꢀbromoꢀ5ꢀmethoxyꢀ4ꢀnitrobenzoate (28) (2.56 g, 8.82 mmol),
2ꢀiodocyclohexꢀ2ꢀenꢀ1ꢀone (9) (890 mg, 4.01 mmol), copper powder (1.27 g, 20.04 g.atom), CuI (1.15
g, 6.01 mmol) and Pd(dppf)Cl2ꢀCH2Cl2 (164 mg, 0.20 mmol) in deoxygenated DMSO (17 mL) was
heated at 50 °C under a nitrogen atmosphere for 28 h. The reaction mixture was then cooled to room
temperature, quenched with water (20 mL), diluted with ethyl acetate (40 mL) and then filtered through
a pad of diatomaceous earth and silica gel. The pad and the solids thus retained were washed with ethyl
acetate (2 × 60 mL) and the organic phase associated with the filtrate 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, 1:9 v/v ethyl
acetate/40ꢀ60 petroleum ether elution) gave, after concentration of the appropriate fractions (Rf = 0.5 in
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1:1 v/v ethyl acetate/40ꢀ60 petroleum ether), compound 28 (478 mg, 39%) as a yellow oil. H NMR
(400 MHz, CDCl3) δ 7.67 (d, J = 1.3 Hz, 1H), 7.51 (d, J = 1.3 Hz, 1H), 7.05 (t, J = 4.2 Hz, 1H), 3.96 (s,
3H), 3.94 (s, 3H), 2.58ꢀ2.50 (complex m, 4H), 2.10 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 196.1,
165.4, 151.2, 150.2, 143.3, 136.3, 132.4, 131.6, 124.2, 113.3, 57.0, 52.9, 38.3, 26.5, 22.7; IR νmax 2956,
2924, 1716, 1683, 1535, 1360, 1245, 1022, 838, 766 cm–1; MS (ESI, +ve) m/z 328 [(M+Na)+, 100%];
HRMS (M+Na)+ calcd for C15H15NNaO6 328.0797, found 328.0793.
Methyl 8-Methoxy-2,3,4,9-tetrahydro-1H-carbazole-6-carboxylate (29). A magnetically stirred
mixture of compound 28 (400 mg, 1.31 mmol) and commercially available Wꢀ2 Raneyꢀnickel (800 mg,
washed twice with absolute ethanol) in methanol (65 mL) was deoxygenated and then stirred under an
atmosphere of hydrogen at 22 °C for 16 h. After this time and using an externally applied magnet to
hold the solid associated with the reaction mixture within the flask, the supernatant liquid was decanted
and the retained solid washed with methanol (2 × 40 mL) (Caution: after these washings water should
be added to the residual solid so as to prevent a fire). The methanolic solutions were combined then
concentrated under reduced pressure to give a white solid. Subjection of this material to flash column
chromatography (silica, 3:17 v/v ethyl acetate/40ꢀ60 petroleum ether elution) gave, after concentration
of the appropriate fractions (Rf = 0.6 in 1:2 v/v ethyl acetate/40ꢀ60 petroleum ether), compound 29 (268
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mg, 79%) as a white solid, mp = 181ꢀ182 °C. H NMR [400 MHz, (CD3)2CO] δ 10.15 (broad s, 1H),
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7.81 (s, 1H), 7.25 (s, 1H), 3.96 (s, 3H), 3.86 (s, 3H), 2.77 (m, 2H), 2.70 (m, 2H), 1.92ꢀ1.82 (complex m,
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4H); C NMR [100 MHz, (CD3)2CO] δ 168.5, 146.2, 136.6, 129.7, 129.4, 122.1, 114.8, 111.7, 102.5,
55.7, 51.8, 24.0, 23.9, 23.7, 21.6; IR νmax 3339, 2928, 2836, 1696, 1628, 1366, 1326, 1231, 1188, 993,
765 cm–1; MS (ESI, +ve) m/z 541 (65%), 282 [(M+Na)+, 100]; HRMS (M+Na)+ calcd for C15H17NNaO3
282.1106, found 282.1105.
4
5
6
7
8
9
Mukonine (6). A magnetically stirred mixture of compound 29 (264 mg, 1.02 mmol) and 10 wt. %
Pd/C (264 mg) in mesitylene (20 mL) was stirred at 150 °C under an atmosphere of nitrogen for 24 h.
The cooled reaction mixture was filtered through filter paper and the solids thus retained washed with
ethyl acetate (2 x 20 mL). The filtrate was concentrated under reduced pressure and the ensuing mixture
of product 6 and mesitylene then 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
in 1:3 v/v ethyl acetate/40ꢀ60 petroleum ether), compound 617 (171 mg, 66%) as a white solid, mp =
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196ꢀ198 °C (lit.17a mp = 193ꢀ195 °C). H NMR (400 MHz, CDCl3) δ 8.52 (broad s, 1H), 8.48 (s, 1H),
8.10 (d, J = 7.8 Hz, 1H), 7.60 (s, 1H), 7.49ꢀ7.43 (complex m, 2H), 7.28 (m, 1H), 4.05 (s, 3H), 3.98 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 168.1, 145.2, 139.6, 133.0, 126.5, 123.9, 123.7, 122.0, 120.9,
120.4, 116.4, 111.4, 106.8, 55.9, 52.2; IR νmax 3350, 2941, 1689, 1608, 1585, 1433, 1338, 1255, 758,
732 cm–1; MS (ESI, +ve) m/z 533 (28%), 278 [(M+Na)+, 100]; HRMS (M+Na)+ calcd for C15H13NNaO3
278.0793, found 278.0792.
6-Methyl-9H-carbazol-2-ol (30). A magnetically stirred solution of compound 26 (50 mg, 0.24 mmol)
in dichloromethane (15 mL) maintained at –78 ºC under an atmosphere of nitrogen was treated,
dropwise, with BBr3 (470 ꢀL of a 1 M solution in dichloromethane, 0.47 mmol). The resulting mixture
was stirred at –78 ºC for another 2 h and then warmed to –40 ºC. After 2 h the reaction mixture was reꢀ
cooled to –78 °C and a further portion of BBr3 (520 ꢀL of a 1 M solution in dichloromethane, 0.52
mmol) added dropwise. The reaction mixture was then warmed to 22 °C, stirred at this temperature for
11 h, cooled to 0 °C and then quenched by the slow addition of NaHCO3 (30 mL of a saturated aqueous
solution). The resulting mixture was extracted with dichloromethane (1 × 20 mL) and the combined
organic phases washed with water (1 × 20 mL) and brine (1 × 20 mL) before being dried (Na2SO4),
filtered and concentrated under reduced pressure. The residue thus obtained was subjected to flash
chromatography (silica, 3:17 v/v ethyl acetate/40ꢀ60 petroleum ether elution) to give, after concentration
of the appropriate fractions [Rf = 0.2(5) in 3:7 v/v ethyl acetate/40ꢀ60 petroleum ether], compound 309h
1
(39 mg, 84%) as a white, crystalline solid, mp = 259ꢀ261 °C (lit.9h mp = 230ꢀ233 °C). H NMR [400
MHz, (CD3)2CO] δ 9.91 (broad s, 1H), 8.25 (s, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.74 (s, 1H), 7.28 (d, J =
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8.2 Hz, 1H), 7.08 (d, J = 8.2 Hz, 1H), 6.90 (d, J = 2.1 Hz, 1H), 6.71 (dd, J = 8.4 and 2.1 Hz, 1H), 2.45
(s, 3H); 13C NMR (100 MHz, (CD3)2CO) δ 157.4, 143.0, 139.2, 128.4, 126.0, 124.7, 121.5, 119.8,
117.1, 110.9, 109.1, 97.4, 21.5; IR νmax 3403, 2922, 2853, 1633, 1616, 1490, 1459, 1296, 1026, 804 cm–
1; MS (ESI, −ve) m/z 196 [(M−H)–, 100%]; HRMS (M−H)– calcd for C13H10NO 196.0762, found
196.0767.
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9
Karapinchamine A (7). A magnetically stirring solution of compound 30 (27 mg, 0.14 mmol) in
anhydrous THF (7 mL) maintained at 0 °C under a nitrogen atmosphere was treated, dropwise, with nꢀ
BuLi (340 µL of a 1.6 M solution in nꢀhexane, 0.55 mmol). After 0.17 h, a solution of geranyl bromide
(51 mg, 0.21 mmol) in THF (7 mL) was added dropwise over 0.5 h. The resulting mixture was warmed
to 22 °C, stirred at this temperature for 1.5 h then cooled to 0 °C and quenched with NH4Cl (15 mL of a
saturated aqueous solution). The resulting mixture was extracted with ethyl acetate (2 × 30 mL) and the
combined organic phases washed with water (1 × 20 mL) and brine (1 × 20 mL) before being dried
(Na2SO4), filtered and concentrated under the reduced pressure. The residue thus obtained was subjected
to flash chromatography (silica, 1:9 v/v ethyl acetate/40ꢀ60 petroleum ether elution) to give, after
concentration of the appropriate fractions (Rf = 0.6 in 3:7 v/v ethyl acetate/40ꢀ60 petroleum ether),
compound 77e,18 (23 mg, 50%) as a white solid, mp = 118ꢀ119 °C (lit.7e mp = 124.3ꢀ125.6 °C). 1H NMR
(400 MHz, CDCl3) δ 7.87 (d, J = 8.3 Hz, 1H), 7.78 (s, 1H), 7.23ꢀ7.18 (complex m, 2H), 6.78 (d, J = 1.9
Hz, 1H), 6.70 (dd, J = 8.3 and 2.0 Hz, 1H), 5.24 (m, 1H), 5.02 (m, 1H), 4.88 (s, 1H), 4.79 (d, J = 6.1 Hz,
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2H), 2.52 (s, 3H), 2.09ꢀ1.98 (complex m, 4H), 1.90 (s, 3H), 1.62 (s, 3H), 1.55 (s, 3H); C NMR (100
MHz, CDCl3) δ 154.6, 142.2, 138.9, 138.7, 131.9, 128.4, 125.8, 123.9, 123.4, 121.2, 120.0, 119.6,
117.1, 108.4, 107.7, 95.2, 41.3, 39.5, 26.4, 25.8, 21.5, 17.8, 16.8; IR νmax 3278, 2922, 2855, 1635, 1610,
1487, 1471, 1348, 1171, 801 cm–1; MS (ESI, +ve) m/z 356 [(M+Na)+, 100%], 334 [(M+H)+, 20]; HRMS
(M+Na)+ calcd for C23H27NNaO 356.1990, found 356.1994.
4'-Methoxy-2'-nitro-4,5-dihydro-[1,1'-biphenyl]-2(3H)-one (31). A magnetically stirred mixture of 1ꢀ
iodoꢀ4ꢀmethoxyꢀ2ꢀnitrobenzene (22) (912 mg, 3.27 mmol), 2ꢀiodocyclohexꢀ2ꢀenꢀ1ꢀone (9) (330 mg,
1.49 mmol), copper powder (472 mg, 7.43 g.atom), CuI (425 mg, 2.23 mmol) and Pd(dppf)Cl2ꢀCH2Cl2
(61 mg, 0.07 mmol) in deoxygenated DMSO (15 mL) was heated at 50 °C under a nitrogen atmosphere
for 10 h. The reaction mixture was then cooled to room temperature, quenched with water (15 mL),
diluted with ethyl acetate 30 mL) then filtered through a pad of diatomaceous earth and silica gel. The
pad and the solids thus retained were washed with ethyl acetate (2 × 40 mL) and the separated organic
phase associated with the filtrate washed with water (2 × 80 mL) and brine (2 × 80 mL) before being
dried (Na2SO4), filtered and concentrated under reduced pressure to give a brown oil. Subjection of this
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material to flash column chromatography (silica, 2:5:44 v/v/v ethyl acetate/dichloromethane/40ꢀ60
petroleum ether elution) gave, after concentration of the appropriate fractions (Rf = 0.3 in 2:5:11 v/v/v
ethyl acetate/dichloromethane/40ꢀ60 petroleum ether), compound 3110,11b (334 mg, 91%) as a lightꢀ
yellow oil. 1H NMR [400 MHz, (CD3)2CO] δ 7.51 (d, J = 2.2 Hz, 1H), 7.28 (m, 2H), 7.10 (m, 1H), 3.92
(s, 3H), 2.58 (m, 2H), 2.46 (m, 2H), 2.09 (m, 2H); 13C NMR [100 MHz, (CD3)2CO] δ 196.5, 160.5,
150.4, 147.5, 139.5, 133.6, 125.1, 120.0, 109.9, 56.4, 39.0, 27.0, 23.5; IR νmax 2945, 1678, 1525, 1496,
1353, 1232, 1035, 913, 830, 798 cm–1; MS (ESI, +ve) m/z 270 [(M+Na)+, 100%], 248 [(M+H)+, 10];
HRMS (M+Na)+ calcd for C13H13NNaO4 270.0742, found 270.0739.
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7-Methoxy-2,3,4,9-tetrahydro-1H-carbazole (32). A magnetically stirred mixture of compound 31
(100 mg, 0.40 mmol) and commercially available Wꢀ2 Raneyꢀnickel (200 mg, washed twice with
absolute ethanol) in methanol (23 mL) was deoxygenated and then stirred under an atmosphere of
hydrogen at 22 °C for 16 h. After this time and using an externally applied magnet to hold the solid
associated with the reaction mixture within the flask, the supernatant liquid was decanted and the
retained solid washed with methanol (2 × 20 mL) (Caution: after these washings water should be added
to the residual solid so as to prevent a fire). The methanolic solutions were combined then concentrated
under reduced pressure to give a white solid. Subjection of this material to flash column
chromatography (silica, 1:3:20 v/v/v acetone/dichloromethane/40ꢀ60 petroleum ether elution) gave,
after concentration of the appropriate fractions (Rf = 0.4(5) in 1:3:6 v/v/v acetone/dichloromethane/40ꢀ
60 petroleum ether), compound 3210,11b,26 (62 mg, 76%) as a white, crystalline solid, mp = 138ꢀ139 °C
1
(lit.10 mp = 136ꢀ142 °C). H NMR (400 MHz, CDCl3) δ 7.54 (broad s, 1H), 7.33 (d, J = 8.5 Hz, 1H),
6.80 (d, J = 2.2 Hz, 1H), 6.75 (dd, J = 8.5 and 2.2 Hz, 1H), 3.84 (s, 3H), 2.69 (m, 4H), 1.88 (m, 4H); 13C
NMR (100 MHz, CDCl3) δ 155.9, 136.5, 132.9, 122.5, 118.3, 110.1, 108.4, 95.0, 56.0, 23.4, 23.3(5),
23.3(4), 21.1; IR νmax 3405, 2919, 2842, 1628, 1464, 1307, 1213, 1156, 1029, 826, 803 cm–1; MS (ESI,
+ve) m/z 202 [(M+H)+, 100%]; HRMS (M+H)+ calcd for C13H16NO 202.1232, found 202.1230.
2-Methoxy-9H-carbazole (8). A magnetically stirred mixture of compound 32 (40 mg, 0.20 mmol) and
10 wt. % Pd/C (40 mg) in mesitylene (5 mL) was stirred at 150 °C under an atmosphere of nitrogen for
24 h. The cooled reaction mixture was filtered through filter paper and the solids thus retained washed
with ethyl acetate (2 x 10 mL). The combined filtrates were concentrated under reduced pressure and
the ensuing mixture of product 6 and mesitylene then 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 = 0.3 in 1:5 v/v ethyl acetate/40ꢀ60 petroleum ether), compound 86f,6k,6l,9j (25 mg, 64%) as a
1
white, crystalline solid, mp = 227ꢀ228 °C (lit.6f mp = 233ꢀ235 °C). H NMR [400 MHz, (CD3)2CO] δ
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10.18 (broad s, 1H), 7.97 (m, 2H), 7.44 (d, J = 8.1 Hz, 1H), 7.28 (t, J = 7.9 Hz, 1H), 7.13 (m, 1H), 7.03
(broad s, 1H), 6.80 (m, 1H), 3.86 (s, 3H); 13C NMR [100 MHz, (CD3)2CO] δ 160.1, 142.4, 141.0, 125.0,
124.2, 121.6, 120.0, 119.7, 117.7, 111.4, 108.8, 95.4, 55.7; IR νmax 3391, 2929, 1608, 1463, 1444, 1308,
1196, 1163, 1033, 818, 727 cm–1; MS (ESI, −ve) m/z 196 [(M−H)–, 100%]; HRMS (M−H)– calcd for
C13H10NO 196.0762, found 196.0753.
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X-ray Crystallographic Studies
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Crystallographic Data.
Compound 1. C12H9N, M = 167.21, T = 150 K, orthorhombic, space group Pnma, Z = 4, a = 7.6589(2)
Å, b = 19.0353(5) Å, c = 5.6814(1) Å; V = 828.29(3) Å3, Dx = 1.341 g cm–3, 864 unique data (2θmax
=
147.4°), R = 0.035 [for 795 reflections with I > 2.0σ(I)]; Rw = 0.058 (all data), S = 1.00.
Compound 2. C13H11N, M = 181.24, T = 150 K, monoclinic, space group P21/c, Z = 4, a = 20.3990(8)
Å, b = 5.7846(2) Å, c = 7.8899(3) Å; β = 98.458(4)°; V = 920.88(6) Å3, Dx = 1.307 g cm–3, 1858 unique
data (2θmax = 147.8°), R = 0.057 [for 1748 reflections with I > 2.0σ(I)]; Rw = 0.096 (all data), S = 1.00.
Compound 3. C14H13NO, M = 211.26, T = 150 K, monoclinic, space group P21/n, Z = 4, a =
11.4714(17) Å, b = 5.6130(6) Å, c = 16.915(2) Å; β = 95.648(12)°; V = 1083.9(2) Å3, Dx = 1.295 g cm–
3, 2160 unique data (2
θmax = 151.8°), R = 0.058 [for 1763 reflections with I > 2.0σ(I)]; Rw = 0.164 (all
data), S = 1.00.
Compound 4. C14H13NO, M = 211.26, T = 150 K, orthorhombic, space group P212121, Z = 4, a =
6.4420(1) Å, b = 7.5921(1) Å, c = 21.9422(3) Å; V = 1073.16(3) Å3, Dx = 1.308 g cm–3, 2166 unique
data (2θmax = 147.8°), R = 0.035 [for 2114 reflections with I > 2.0σ(I)]; Rw = 0.064 (all data), S = 1.00.
Compound 5. C14H11NO2, M = 225.25, T = 150 K, orthorhombic, space group Pbca, Z = 8, a =
7.1367(1) Å, b = 13.2390(1) Å, c = 22.5108(2) Å; V = 2126.88(4) Å3, Dx = 1.407 g cm–3, 2152 unique
data (2θmax = 147.8°), R = 0.033 [for 2089 reflections with I > 2.0σ(I)]; Rw = 0.058 (all data), S = 1.00.
Compound 6. C15H13NO3, M = 255.27, T = 150 K, monoclinic, space group C2/c, Z = 8, a = 15.7767(2)
Å, b = 9.4629(1) Å, c = 16.1402(2) Å; β = 91.7342(13)°; V = 2408.52(5) Å3, Dx = 1.408 g cm–3, 3284
unique data (2
1.00.
θmax = 59.6°), R = 0.039 [for 2869 reflections with I > 2.0σ(I)]; Rw = 0.077 (all data), S =
Compound 17. C14H15NO4, M = 261.27, T = 150 K, monoclinic, space group P21/c, Z = 8, a =
21.5986(4) Å, b = 6.89910(11) Å, c = 17.6362(3) Å; β = 104.596(2)°; V = 2543.16(8) Å3, Dx = 1.365 g
cm–3, 5147 unique data (2
θ
max = 147.6°), R = 0.084 [for 4826 reflections with I > 2.0σ(I)]; Rw = 0.214
(all data), S = 1.12.
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Compound 25. C14H17NO3, M = 247.29, T = 150 K, monoclinic, space group P21/c, Z = 4, a =
14.6135(2) Å, b = 5.8504(1) Å, c = 14.6942 (2) Å; β = 96.2796(15)°; V = 1248.74(3) Å3, Dx = 1.315 g
cm–3, 2542 unique data (2
θmax = 147.6°), R = 0.036 [for 2433 reflections with I > 2.0σ(I)]; Rw = 0.098
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(all data), S = 1.00.
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Structure Determination. The image for compound 6 was measured on a diffractometer (Mo Kα,
graphite monochromator, λ = 0.71073 Å) fitted with an area detector and the data extracted using the
DENZO/Scalepack package.34 Images for compounds 1, 2, 3, 4, 5, 17 and 25 were measured on a
diffractometer (Cu Kα, mirror monochromator, λ = 1.54184 Å) fitted with an area detector and the data
extracted using the CrysAlis package.35 The structure solutions for all eight compounds were solved by
direct methods (SIR92)36 then refined using the CRYSTALS program package.37 Atomic coordinates,
bond lengths and angles, and displacement parameters have been deposited at the Cambridge
Crystallographic Data Centre (CCDC nos. 1525166, 1525163, 1525164, 1525162, 1525167, 1525160,
1525161, 1525165 for compounds 1, 2, 3, 4, 5, 6, 17 and 25, respectively). These data can be obtained
freeꢀofꢀcharge 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. Singleꢀcrystal Xꢀray analyses of compound 1 have been reported previously.38
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ASSOCIATED CONTENT
Supporting Information
Crystallographic data (including CIFs) and anisotropic displacement ellipsoid plots derived from the
1
singleꢀcrystal Xꢀray analyses of compounds 1, 2, 3, 4, 5, 6, 17 and 25. H and 13C NMR spectra of
compounds 1ꢀ15, 17, 18, 20, 21, 23ꢀ32 and methyl 4ꢀaminoꢀ3ꢀbromoꢀ5ꢀmethoxybenzoate (precursor to
compound 27). This material is available free of charge via the internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* Eꢀmail: Martin.Banwell@anu.edu.au
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
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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 China Scholarship Council of the
People’s Republic of China. EG acknowledges scholarship support from the ANU. MWꢀK thanks the
Department of Organic Chemistry, Faculty of Chemistry, Wroclaw University of Technology, Poland
for giving her leave to undertake research at the ANU.
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REFERENCES
1.
2.
Graebe, C.; Glaser, C. Ber. Dtsch. Chem. Ges. 1872, 5, 12.
For useful pointsꢀofꢀentry into the relevant literature see: (a) Thevissen, K.; Marchand, A.;
Chatlin, P.; Meert, E. M.; Cammue, B. P. Curr. Med. Chem. 2009, 16, 2205ꢀ2211; (b) Yaqub, G.;
Huissain, E. A.; Rehman, M. A.; Mateen, B. Asian J. Chem. 2009, 21, 2485ꢀ2520; (c) Roy, J.;
Jana, A. K.; Mal, D. Tetrahedron, 2012, 68, 6099ꢀ6121; (d) Schmidt, A. W.; Reddy, K. R.;
Knölker, H.ꢀJ. Chem. Rev. 2012, 112, 3193ꢀ3328; (e) Gluszynska, A. Eur. J. Med. Chem. 2015,
94, 405ꢀ426; (f) Bashir, M.; Bano, A.; Ijaz, A. S.; Chaudhary, B. A. Molecules, 2015, 20, 13496ꢀ
13517; (g) Sathiyan, G.; Sivakumar, E. K. T.; Ganesamoorthy, R.; Thangamuthu, R.; Sakthivel, P.
Tetrahedron Lett., 2016, 57, 243ꢀ252.
3.
See, for example, (a) Cheenpracha, S.; Laphookhieo, S. Phytochem. Lett. 2011, 4, 187ꢀ189; (b)
Miller, C. M.; McCarthy, F. O. RSC Advances, 2012, 2, 8883ꢀ8918; (c) Pieroni, M.; Girmay, S.;
Sun, D.; Sahu, R.; Tekwani, B. L.; Tan, G. T. Chem. Med. Chem. 2012, 7, 1895ꢀ1900; (d) Russell,
F.; Harmody, D.; McCarthy, P. J.; Pomponi, S. A.; Wright, A. E. J. Nat. Prod. 2013, 76, 1989ꢀ
1992; (e) Kim, S.ꢀH.; Ha, T.ꢀK.ꢀQ.; Oh, W. K.; Shin, J.; Oh, D.ꢀC. J. Nat. Prod. 2016, 79, 51ꢀ58;
(f) Patel, O. P. S.; Mishra, A.; Maurya, R.; Saini, D.; Pandey, J.; Taneja, I.; Raju, K. S. R.;
Kanojiya, S.; Shukla, S. K.; Srivastava, M. N.; Wahajuddin, M.; Tamrakar, A. K.; Srivastava, A.
K.; Yadav, P. P. J. Nat. Prod. 2016, 79, 1276ꢀ1284.
4.
(a) Fischer, E.; Jourdan, F. Ber. Dtsch. Chem. Ges. 1883, 16, 2241ꢀ2245; (b) Borsche, W.; Witte,
A.; Bothe, W. Liebigs Ann. Chem. 1908, 359, 49ꢀ80. For related and recent approaches see (c)
Chakraborty, S.; Chattopadhyay, G.; Saha, C. J. Heterocyclic Chem. 2013, 50, 91ꢀ98; (d) Wu, J.;
Xie, Y.; Chen, X.; Deng, G.ꢀJ. Adv. Synth. Catal. 2016, 358, 3206ꢀ3211.
5.
6.
Graebe, C.; Ullmann, F. Liebigs Ann. Chem. 1896, 291, 16ꢀ17.
(a) Cadogan, J. I. G.; CameronꢀWood, M.; Mackie, R. K.; Searle, R. J. G. J. Chem. Soc. 1965,
4831ꢀ4837. For related and recent variants see: (b) Smitrovich, J. H.; Davies, I. W. Org. Lett.
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