Novel methodology for the synthesis of the benzo[b]phenanthridine and 6H-dibenzo[c,h]chromen-6-one skeletons. Reactions of 2-naphthylbenzylamines and 2-naphthylbenzyl alcohols

Article abstract of DOI:10.1016/j.tet.2016.10.071

Novel syntheses of both the benzo[b]phenanthridine and the 6H-dibenzo[c,h]chromen-6-one motif are described. Reaction of (2-(3-bromo-1,4-dimethoxynaphthalen-2-yl)phenyl)methanamine with PIFA afforded benzo[b]phenanthridine-7,12-dione, while the related nonbrominated precursor, (2-(1,4,5-trimethoxynaphthalen-2-yl)phenyl)methanamine on treatment with PIFA, furnished the ortho-quinone 1-methoxybenzo[c]phenanthridine-11,12-dione. Unexpectedly, treatment of related oxygen analogs such as (2-(1,4-dimethoxynaphthalen-2-yl)phenyl)methanol with NBS under an O₂atmosphere, afforded a chromenone, 12-methoxy-6H-dibenzo[c,h]chromen-6-one.

Full text of DOI:10.1016/j.tet.2016.10.071

Accepted Manuscript
Novel methodology for the synthesis of the benzo[b]phenanthridine and
6H-dibenzo[c,h]chromen-6-one skeletons. Reactions of 2-naphthylbenzylamines and
2-naphthylbenzyl alcohols
Priyamvada Pradeep, Kennedy J. Ngwira, Chevonne Reynolds, Amanda L.
Rousseau, Andreas Lemmerer, Manuel A. Fernandes, Myron M. Johnson, Charles B.
de Koning
PII:
S0040-4020(16)31130-9
10.1016/j.tet.2016.10.071
TET 28212
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 2 August 2016
Revised Date: 20 October 2016
Accepted Date: 31 October 2016
Please cite this article as: Pradeep P, Ngwira KJ, Reynolds C, Rousseau AL, Lemmerer A, Fernandes
MA, Johnson MM, de Koning CB, Novel methodology for the synthesis of the benzo[b]phenanthridine
and 6H-dibenzo[c,h]chromen-6-one skeletons. Reactions of 2-naphthylbenzylamines and 2-
naphthylbenzyl alcohols, Tetrahedron (2016), doi: 10.1016/j.tet.2016.10.071.
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ACCEPTED MANUSCRIPT
Graphical Abstract
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Novel methodology for the synthesis of the
benzo[b]phenanthridine and 6H-
Leave this area blank for abstract info.
dibenzo[c,h]chromen-6-one skeletons.
Reactions of 2-naphthylbenzylamines and 2-
naphthylbenzyl alcohols
Priyamvada Pradeep, Kennedy J. Ngwira, Chevonne Reynolds, Amanda L. Rousseau, Andreas Lemmerer,
Manuel A. Fernandes, Myron M. Johnson and Charles B. de Koning*
Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, PO Wits 2050,
Johannesburg, South Africa.
N
X= NH2; Y=H; Z=OMe, PIFA, 63%
O
O
OMe
O
OMe
OMe
PIFA, 56%
O
X= NH2; Y=Br; Z=H
N
O
Y
X
O
Z
X= OH; Y=H; Z=H, NBS, 42%
OMe

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Novel methodology for the synthesis of the benzo[b]phenanthridine and 6H-
dibenzo[c,h]chromen-6-one skeletons. Reactions of 2-naphthylbenzylamines and 2-
naphthylbenzyl alcohols
Priyamvada Pradeep, Kennedy J. Ngwira, Chevonne Reynolds, Amanda L. Rousseau, Andreas Lemmerer,†
Manuel A. Fernandes,† Myron M. Johnson and Charles B. de Koning*
Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, PO Wits 2050, Johannesburg, South Africa.
† For correspondence regarding X-ray crystallography
ARTICLE INFO
ABSTRACT
Article history:
Received
Novel syntheses of both the benzo[b]phenanthridine and the 6H-dibenzo[c,h]chromen-6-one
motif are described. Reaction of (2-(3-bromo-1,4-dimethoxynaphthalen-2-
Received in revised form
Accepted
Available online
yl)phenyl)methanamine with PIFA afforded benzo[b]phenanthridine-7,12-dione, while the
related nonbrominated precursor, (2-(1,4,5-trimethoxynaphthalen-2-yl)phenyl)methanamine on
treatment with PIFA, furnished the ortho-quinone 1-methoxybenzo[c]phenanthridine-11,12-
dione. Unexpectedly, treatment of related oxygen analogs such as (2-(1,4-dimethoxynaphthalen-
2-yl)phenyl)methanol with NBS under an O2 atmosphere, afforded a chromenone, 12-methoxy-
6H-dibenzo[c,h]chromen-6-one.
Keywords:
Keyword_1 benzo[b]phenanthridines
Keyword_2 dibenzo[c,h]chromen-6-ones
Keyword_3 benzo[c]phenanthridines
Keyword_4 Suzuki-Miyaura reaction
Keyword_5 N-bromosuccinimide (NBS)
2016 Elsevier Ltd. All rights reserved
.
1. Introduction
HO
Me
O
O
HO
Me
The 6H-dibenzo[c,h]chromen-6-one skeleton is embedded in
many natural products such as gilvocarcin V 1a1 and related
compounds, such as ravidomycin 1b2 and arnottin 23 (Figure 1).
Many of these compounds are known to display antibiotic and
O
O
H
H
N
O
N
O
antitumor
activities.
The
biosynthetically
related
O
benzo[b]phenanthridine skeleton4 is found in the natural product
phenanthroviridone 3, with the more complex natural products
jadomycin A 4 and jadomycin Y 5 also falling into this
category.5-9 This class of natural products also exhibits interesting
biological properties, such as aurora -B kinase inhibitory activity.
OH
OH
O
O
O
HO
Me
Me
Jadomycin A 4
Jadomycin Y 5
OH
Figure 1. Naturally occurring 6H-dibenzo[c,h]chromen-6-ones and
benzo[b]phenanthridines
As a result of their biological activity and interesting structures,
many methods have been developed for their synthesis.10,11 One
reported approach to the synthesis of the phenanthroviridone
skeleton10a is by the palladium catalyzed coupling of
a
naphthoquinone, such as 6, with the protected benzaldehyde 7 to
afford 8 (Figure 2). Under suitable conditions and in the presence
of an ammonia source, presumably by way of intermediate 9, a 6-
exo-trig cyclisation reaction results in the formation of the
phenanthroviridone skeleton 10. However, it was noted that from
the corresponding benzaldehyde 11, the intermediate imine 12
forms and this results in the formation of an undesired
benzo[c]phenanthridine 13 by means of 1,2-addition, rather than

2
Tetrahedron
the desired product 10. Similar observations were noted by
the desired product 17. As benzylamine 17 was sticky and
ACCEPTED MANUSCRIPT
O'Doherty.10b
resinous in nature, it was treated as an intermediate. By FTIR it
was clear that the nitrile functionality of 14 was no longer present
and a characteristic amine broad band at 3400-3300 cm-1 was
evident. The HRMS showed a molecular ion at [M+H]+ of
294.1480 for the molecular formula C19H20NO2.
Figure 2.
Scheme 1. Reagents and Conditions: (a) 2-cyanophenylboronic acid, cat.
Pd(PPh3)4, CsF, DME, microwave irradiation, 150 °C, 150 W, 30 min, 76%;
(b) LiAlH4, dry THF, reflux, 6 h, 63%; (c) CAN, CH3CN:H2O (1:1), 4 h, rt,
atmospheric conditions, 19, 12%, 20, 41%.
As part of our programme on the synthesis of aromatic and
heteroaromatic compounds,12 we report here our results leading
to the synthesis of both the benzo[b]phenanthridine and the 6H-
dibenzo[c,h]chromen-6-one
framework.
These
naturally
Unfortunately, exposure of 17 to CAN resulted in the formation
of two undesired products formed by way of a cyclization,
presumably from a 1,2-addition to the 1,4-naphthoquinone
formed from the CAN reaction to initially afford 19 while further
oxidation yielded 20. The first, formed in only a yield of 12%,
was obtained as yellow crystals suitable for X-ray
crystallographic analysis. Similar to that reported by
Echavarren,10a (Figure 2) the structure was elucidated to be that
of the undesired heterocycle 19 (Scheme 1).15 The major product
from the reaction, which was formed in 41% yield, showed a
molecular ion of [M+H]+ 260.0699 by HRMS. Two characteristic
quinone carbonyls were observed in the 13C NMR spectrum at δ
182.8 and 179.8. While this information would not exclude the
formation of the desired para-quinone 18, HMBC spectral data
allowed for the identification of the ortho quinone 20.16
occurring frameworks were synthesized from related 2-
naphthylbenzylamines and naphthylbenzyl alcohols respectively,
which were synthesized utilizing the Suzuki-Miyaura reaction as
a key step.
2. Results and discussion
Synthesis of Benzo[b]phenanthridines
In our synthetic approach, we initially prepared the substituted
naphthalene 14 containing a nitrile substituent (Scheme 1). This
was achieved utilizing the Suzuki-Miyaura coupling reaction
from commercially available (2-cyanophenyl)boronic acid 15 and
readily prepared 2-bromo-1,4-dimethoxynaphthalene 16.13
At this point we realized that if we were able to reduce the
nitrile of 14 to the corresponding benzylamine 17, we would be
able to attempt ring closure reactions allowing for the formation
of the benzo[b]phenanthridine 18 by oxidation of 17 to the
corresponding 1,4-naphthoquinone followed by
addition reaction.
Disappointed by these results, we investigated if it was possible
to force the reaction to allow for the formation of the desired
para-quinone. Exposure of 14 to NBS as expected resulted in the
formation of the 3-bromonaphthalene 21 in good yield (Scheme
2). Reduction of the nitrile functional group of 21 under the
LiAlH4 conditions developed for the previous reaction, resulted
in the formation of the desired product 22, albeit in a poor yield
(34%). Gratifyingly, exposure of 22 to an alternative oxidizing
agent, phenyliodine bis(trifluoroacetate (PIFA), which worked
a Michael
Surprisingly, reduction of the nitrile of 14 to the corresponding
benzylamine 17 proved to be challenging. Numerous methods
were unsuccessful14 and only heating 14 in THF with ten mole
14e
equivalents of LiAlH4 resulted in a reasonable yield (63%) of

3
better than CAN in this case, resulted in the formation of the
desired para-quinone 18 in a fair yield of 56%. The identity of
the product 18 was confirmed by X-ray crystallographic analysis.
acid 34 afforded 35 in excellent yield. Reduction of the
ACCEPTED MANUSCRIPT
aldehyde to the benzyl alcohol proceeded smoothly to afford 36
in very good yield.
As a result of this, we wished to extend this methodology to the
synthesis of related juglone analogs bearing an additional oxygen
substituent on the aromatic ring. Although the selective
bromination of juglone has been reported,17a we chose to
synthesize 2-bromo-1,4,5-trimethoxynaphthalene according to a
procedure developed by Jung.17b Exposure of 1,5-
dihydroxynaphthalene 23 to acetic anhydride and pyridine
resulted in the formation of 24 (Scheme 3). This was then treated
with NBS in acetic acid to give the quinone 25 in 79% yield. The
acetate 25 was then treated with sulfuric acid to furnish the
naphthol 26. Reduction of the quinone 26 and methylation
resulted in the formation of the desired naphthalene 27 ready for
the next Suzuki-Miyaura coupling reaction. Treatment of 27 with
(2-cyanophenyl)boronic acid 15 under palladium catalysis
conditions afforded the desired naphthalene 28 in good yield.
At this point we thought it would be best to attempt the
aromatic bromination of 36 to afford 31 before oxidation to the
quinone. However, treatment of 36 with NBS resulted in the
formation of an unexpected product, the lactone 37, containing
the 6H-dibenzo[c,h]benzo[c]chromen-6-one skeleton, found
embedded in, for example, the gilvocarcins. The identity of the
product was confirmed by X-ray crystallography (Scheme 4).
The lactone 37 was formed in poor yield along with other
uncharacterizable products as evidenced by thin layer
chromatography
.
Scheme 2. Reagents and Conditions: (a) NBS, NaOAc, acetic acid, rt, 4 h,
83%; (b) LiAlH4, dry THF, reflux, 5 h, 34%; (c) PIFA, CH3CN:H2O (1:1), rt,
2 h, 56%.
All attempts to facilitate selective bromination at the 3-position
of the naphthalene nucleus of 28 met with failure, with mixtures
of product isolated. Presumably this is due to the naphthalene
being more electron rich than the previous naphthalene 14, hence
not allowing for regioselective control. However, treatment of 28
with LiAlH4 under reflux afforded intermediate benzylamine 29,
lacking the desired bromine atom at C-3 in 58% yield. Hence, we
decided to test the cyclisation with PIFA on this substrate.
Unfortunately, exposure of 29 to PIFA again resulted in the
formation of the undesired ortho-quinone 30. The identity of the
product 30 was again determined by X-ray crystallography
(Scheme 3). Thus it is clear that without a bromine atom in place
the undesired 1,2-addition occurs readily.
Scheme 3. Reagents and Conditions: (a) Ac2O, pyridine, rt, 98%; (b) NBS,
AcOH/H2O, 65 °C, 45 min, 79%; (c) 3 N H2SO4, EtOH, reflux, 2 h, 98%; (d)
Ag2O, MeI, CH2Cl2, rt, 24 h, 96%; Or Na2S2O4, TBAI, KOH, Me2SO4, THF-
H2O, rt, 18 h, 79% (e) 2-cyanophenylboronic acid, cat. Pd(PPh3)4, CsF, DME,
microwave irradiations, 150 °C, 150 W, 30 min, 85%; (f) LiAlH4, dry THF,
reflux, 6 h, 58%; (g) PIFA, CH3CN:H2O (1:1), rt, 4 h, 63%.
Synthesis of 6H-Dibenzo[c,h]chromen-6-ones
We were interested to see whether oxygen analogs such as 31
(Figure 3) would react in a similar manner to the nitrogen-
containing compounds we had prepared to afford 32, the
backbone of natural products such as naphthgeranine E 3318.
Hence we set about synthesizing the related alcohol 31. The
Suzuki-Miyaura coupling reaction between 16 and the boronic

4
Tetrahedron
Figure 3.
57% and 26% respectively (Scheme 6). This result seemed to
ACCEPTED MANUSCRIPT
indicate that the reaction did not proceed via the acid bromide 44
or the aldehyde 35.
Initial attempts to repeat the reaction were met with frustration
until it was ascertained that the reaction vessel had to be left open
to the atmosphere indicating that oxygen in the atmosphere was a
requirement for the reaction to proceed. In order to obtain
reproducible yields, the reaction was best conducted under an
oxygen atmosphere. Further careful experimentation of the
unexpected reaction on substrate 36 allowed for the isolation of
both the lactone 37 as well as the related benzaldehyde
containing quinone 38 where C-3 bromination had taken place,
but in addition, oxidation of both the dimethoxynaphthalene and
of the benzylic alcohol had also occurred.
A second possibility was that the reaction was proceeding via the
benzyl bromide 46 which would be oxidized under the reaction
conditions in oxygen to 44. To investigate this option, the benzyl
bromide 46 had to be prepared. Exposure of 36 to
triphenylphosphine and CBr4 in CH2Cl2 resulted in the formation
of the desired product 46 in 67% yield (Scheme 6). However, all
attempts to convert this to lactone 37 failed, suggesting that the
reaction did not proceed in this manner.
OMe
OMe
B(OH)2
Br
OMe
(b)
OMe
34
B(OH)2
CHO
Br
CHO
CHO
34
(a)
CHO
R
39a, R = OMe
39b, R = H
40a, R = OMe
40b, R = H
(a)
R
16
35
OMe
OMe
O
O
OMe
OMe
OMe
OMe
OMe
O
O
(b)
(c)
(c)
CHO
OH
+
Br
OH
36
R
37
OMe
43
R
41a, R = OMe
42a, R = OMe
42b, R =H
41b, R = H
O
CHO
Br
O
38
Scheme 4. Reagents and conditions: (a) 2-formylphenyl boronic acid, cat.
Pd(PPh3)4, CsF, DME, microwave irradiation, 76%; (b) LiAlH4, dry THF,
96%; (c) NBS, CH2Cl2, O2, 18 h, 37 42% and 38 36%.
At this stage we decided to investigate if this reaction would
proceed on the related dimethoxybenzene and anisole-containing
substrates. Reaction of 2-bromo-1,4-dimethoxybenzene 39a or 2-
bromoanisole 39b with 2-formylphenyl boronic acid 34 under
Suzuki-Miyaura reaction conditions smoothly afforded both 40a
and 40b (Scheme 5). The biaryl compounds (40a and 40b) were
easily reduced to the corresponding benzyl alcohols 41a and 41b.
Treatment of 41a with NBS under an oxygen atmosphere as
described before again afforded the aromatic lactone 42a in a
44% yield, together with the brominated biaryl compound 43
where the benzyl alcohol had again been oxidized to a
benzaldehyde. The identity of the lactone 42 was confirmed by
X-ray crystallography. In a similar manner and under the same
NBS reaction conditions 41b resulted in the formation of lactone
42b, but in an improved yield of 70%, together with small
amounts of 40b.
Scheme 5. Reagents and conditions: (a) 2-formylphenyl boronic acid, cat.
Pd(PPh3)4, CsF, DME, microwave irradiation, 150 ºC, 150 W, 30 mins, 40a,
88% 40b, 87%; (b) LiAlH4, dry THF, 0 ºC,-rt, 1 h, 41a, 99% 41b, 92%; (c)
NBS, CH2Cl2, O2, 8 h, 42a 42% and 43 36%; 42b, 70%.
OMe
OMe
37
Br
O
H
O
OMe
44
OMe
35
OMe
O
(a)
+
CHO
CHO
Br
Br
OMe 45
O 38
Examination of the literature19 led us to initially speculate that,
in the presence of oxygen, NBS may be able to oxidize the
alcohol 36 back to the aldehyde 35. Then following literature
precedent,19 the aldehyde 35 would be converted to the
intermediate acid bromide 44 (Scheme 6). Ring closure, would
result in the formation of the unexpected lactone 37 by
nucleophilic acyl substitution, as a result of the aromatic methoxy
reacting with the acid bromide of 44 followed by demethylation.
To test this theory, we took previously synthesized aldehyde, 35
and treated this with NBS in CH2Cl2 to afford two products, the
brominated 1,4-dimethoxynaphthalene 45 and the brominated
quinone 38, (afforded from the NBS reaction of 36) in yields of
OMe
OMe
OMe
OMe
(b)
37
X
Br
OH
46
36
Scheme 6. Reagents and conditions: (a) NBS, CH2Cl2, O2, reflux,
atmospheric conditions, 18 h, 45 57% and 38 26%; (b) PPh3, CBr4, CH2Cl2,
67%
Further examination of the literature revealed that another
possibility for the transformation of alcohol 36 to the lactone 37

5
Nuclear magnetic resonance (NMR) spectra were recorded on
ACCEPTED MANUSCRIPT
existed. Benzylic bromination of 36 could allow for the
formation of intermediate 47 (Figure 4). The existence and
isolation of these types of compounds has been reported in the
literature,20 as long ago as 1905.21 The formation of intermediates
such as 47 in this reaction may then result in the formation of
lactol 48. Under these reaction conditions, 47 could undergo
expulsion of the bromide to afford the protonated aldehyde,
which would serve as the electrophile allowing for the addition of
the nucleophilic aromatic methoxy substituent to afford 48,
which in the presence of oxygen would be oxidized to the lactone
37.
either a Bruker AVANCE 300 MHz or a Bruker AVANCE III
500 MHz spectrometer. All spectra were recorded in chloroform-
d or dimethylsulfoxide-d6. All chemical shift values are reported
in parts per million referenced against trimethylsilane which is
given an assignment of zero parts per million. Coupling constants
(J-values) are given in Hertz (Hz).
The infra-red spectra were recorded on a Bruker Tensor 27
standard system spectrometer. Measurements were made by
loading the sample directly onto
a diamond cell. The
measurements are reported on the wavenumber scale (cm-1).
Preliminary evidence for this reaction proceeding in this
manner was obtained in one attempt of conducting the reaction
under atmospheric conditions when the lactol 48 was isolated, as
shown by 1H NMR and 13C NMR spectroscopy.
Melting points were determined on a Reichert hot-stage
microscope, and remain uncorrected. All crystalline compounds
were recrystallized in the appropriate solvents prior to melting
point determination. Microwave reactions were conducted in a
CEM Discover microwave.
High resolution mass spectra were obtained with a Waters-
LCT-Premier mass spectrometer. The sample was dissolved in
methanol to a concentration of 2 ng/ꢀl and introduced by direct
infusion. The ionization mode was electrospray positive with a
capillary voltage of 2500 V and a desolvation temperature of 250
°C using nitrogen gas at 250 L/hr.
O
O
O
O
Br
OH
O
OH
47
36
The intensity data was recorded on a Bruker APEX II CCD
area detector diffractometer with graphite monochromated Mo
K3 radiation (50 kV, 30 mA) with temperature of measurement
at 173(2) K, using the APEX 2 data collection software. The
collection method involved 4-scans of width 0.5 and 512×512 bit
data frames. The data reduction was achieved by means of the
program SAINT+ and face indexed absorption corrections were
made using XPRE.
OH
O
O
O
O
37
48
Figure 4.
Crystal structures were solved employing direct methods using
SHELXTL. Nonhydrogen atoms were first refined isotropically
followed by anisotropic refinement by full matrix least-squares
calculations based on F2 using SHELXTL. The hydrogen atoms
were first located in the difference map then positioned
geometrically and allowed to ride on their respective precursor
atoms. Diagrams and publication material were generated using
SHELXTL, PLATON151 and ORTEP-3.
3. Conclusions
Novel syntheses of both the benzo[b]phenanthridine and the
6H-dibenzo[c,h]chromen-6-one motif have been discovered.
Reactions of the brominated 2-naphthylbenzylamine 22 with
PIFA afforded the desired benzo[b]phenanthridine 18, while the
related nonbrominated 2-naphthylbenzylamine, i.e. 29, on
treatment with PIFA, furnished the undesired ortho-quinone 30.
Unexpectedly, treatment of the related oxygen analogs with NBS,
such as 36, afforded compounds that contained a chromenone
nucleus, e.g. 37. Oxygen is necessary for the transformation and
it would appear that bromo(phenyl)methanol equivalents, such as
47, are possible intermediates in the transformation.
2-(1,4-Dimethoxynaphthalen-2-yl)benzonitrile 14
2-Bromo-1,4-dimethoxynaphthalene13 16 (250 mg, 0.939 mmol),
2-cyanophenylboronic acid 15 (207 mg, 1.41 mmol),
tetrakis(triphenylphosphine)palladium(0) (217 mg, 0.188 mmol)
and cesium fluoride (356 mg, 2.35 mmol) were transferred to a
microwave reactor vial. Dimethoxyethane (2.0 mL) which was
previously degassed for 10 mins was added to the reaction. The
reaction mixture was placed in a microwave reactor at 150 °C
and 150 W for 30 mins. After that time the reaction mixture was
filtered to get rid of the solid palladium and then purified by
column chromatography (5% EtOAc/Hexane) to obtain product
14 as a yellow solid (207 mg, 0.716 mmol, 76%). Mp 166-168
°C, (C2H5)2O; FTIR (ν/cm-1) 2967, 2934, 2843, 2225, 1625,
4. Experimental section
Solvents utilized for chromatographic techniques (ethyl acetate
and n-hexane) were distilled preceding use by means of
conventional distillation processes. The solvents employed in
reactions were first dried over the suitable drying agent, followed
by distillation under an inert atmosphere (argon or nitrogen gas).
Acetonitrile and dichloromethane were distilled over calcium
hydride, whereas tetrahydrofuran was distilled over sodium with
benzophenone as an indicator. All the required chemicals or
reagents were obtained from FLUKA, SIGMA ALDRICH or
MERCK and were used without further purification.
1
1591, 1266, 1227; H NMR (300 MHz, CDCl3) δ 8.29 (1H, d, J
= 9.2 Hz, ArH), 8.17 (1H, d, J = 9.2 Hz, ArH), 7.82 (1H, d, J =
7.7 Hz, ArH), 7.68 (2H, d, J = 3.9 Hz, ArH), 7.63-7.45 (3H, m,
ArH), 6.73 (1H, s, ArH-3′), 4.01 (3H, s, OMe), 3.53 (3H, s,
OMe); 13C NMR (75 MHz, CDCl3) δ 151.8, 147.3, 142.9, 133.2,
132.4, 131.4, 128.8, 127.7, 127.0, 126.9, 126.3, 126.2, 122.5,
122.4, 118.5, 113.0, 105.4, 61.9, 55.8; HRMS (ESI+): Found
[M+H]+ 290.1168, C19H16NO2 [M+H]+ requires 290.1181, m/z
290.1168 [M+H]+, 100%), 289.1086 (50%).
Normal chromatography was performed with silica gel 60
(Macherey-Nagel, particle size 0.063-0.200 mm) adsorbent, with
both isocratic and gradient eluent systems being employed. Thin
layer chromatography (TLC) of the compounds was executed on
Macherey-Nagel Alugram Sil G/UV254 plates pre-coated with
0.25 mm silica gel 60. The TLC plates were viewed under UV
light (254 nm and 366 nm).
(2-(1,4-Dimethoxynaphthalen-2-yl)phenyl)methanamine
17

6
Tetrahedron
ACCEPTED MANUSCRIPT
2-(1,4-Dimethoxynaphthalen-2-yl)benzonitrile 14 (276 mg,
conditions for 4 h. On completion, an aq. saturated solution of
0.957 mmol) was dissolved in freshly distilled THF (25 mL) in a
50 mL round bottom flask and the temperature of the solution
was maintained at 0 °C. LiAlH4 (361 mg, 9.57 mmol) was added
in portions under inert conditions at 0 °C. Slowly the temperature
of the reaction was allowed to rise to rt and followed by heating
the reaction under reflux and inert conditions for 12 h after which
the reaction was allowed to cool down to rt. The temperature of
the reaction mass was reduced to 0 °C and a 4% aq. NaOH was
added dropwise to quench the unreacted LiAlH4. After the
bubbling stopped, ice cold water was added and the crude
mixture was transferred to a separating funnel where organic
material was extracted into Et2O (20 mL × 3). The organic phases
were then combined and washed with brine (30 mL), dried over
anhydrous MgSO4, filtered and then the solvent was removed in
vacuo. The crude product was purified by column
chromatography (98% EtOAc and 2% Et3N) to afford the product
17 as a brown sticky resin (177 mg, 0.606 mmol, 63%). Mp 73-
75 °C, (C2H5)2O; FTIR (ν/cm-1): 3331, 3059, 2928, 2849, 1626,
1592, 1269, 1225; HRMS (ESI+): Found [M+H]+ 294.1480,
C19H20NO2 [M+H]+ requires 294.1495, m/z 294.1480 (M+H+,
40%), 295.1517 (10%).
sodium sulfite (20 mL) was added and the solution was
transferred to a separating funnel and then washed with CH2Cl2
(20 mL × 3). The organic phases were collected, washed with
brine (50 mL), dried over anhydrous MgSO4, and then the
solvent was removed in vacuo. The crude product obtained was
purified by column chromatography (10% EtOAc/Hexane) to
yield the product 21 as an off-white solid (206 mg, 0.568 mmol,
83%). Mp 184-186 °C, CH2Cl2; FTIR (ν/cm-1) 2967, 2935, 2841,
1
2229, 1626, 1602, 1594, 1570, 1285, 1264, 1252, 679, 655; H
NMR (300 MHz, CDCl3) δ 8.21-8.14 (2H, m, ArH), 7.81 (1H,
dd, J = 7.9, 1.4 Hz, ArH), 7.70-7.64 (1H, m, ArH), 7.63-7.48
(4H, m, ArH), 3.99 (3H, s, OMe), 3.58 (3H, s, OMe); 13C NMR
(75 MHz, CDCl3) δ 150.6, 143.9, 137.6, 137.4, 132.6, 132.3,
131.8, 129.4, 128.3, 127.4, 127.2, 126.5, 123.3, 123.0, 122.4,
117.9, 114.3, 62.1, 62.1.
(2-(3-Bromo-1,4-dimethoxynaphthalen-2-
yl)phenyl)methanamine 22
2-(3-Bromo-1,4-dimethoxynaphthalen-2-yl)benzonitrile 21 (172
mg, 0.466 mmol) was dissolved in 10 mL dry THF and LiAlH4
(176 mg, 4.66 mmol) was added. The reaction was heated under
reflux for 5 h. On completion, the reaction was cooled down to 0
°C and a 2% aq. NaOH solution (10 mL) was added dropwise to
quench the reaction. The solution was transferred to a separating
funnel and washed with CH2Cl2 (20 mL × 3). The combined
organic phases were washed with brine (20 mL), dried over
anhydrous MgSO4 and then the solvent was removed under
reduced pressure and the residue purified by flash
chromatography (20% MeOH/CH2Cl2) to obtain the intermediate
22 as a brown resinous solid (59.1 mg, 0.159 mmol, 34%). Mp.
102-104 °C, CH2Cl2; FTIR (ν/cm-1) 3521, 2935, 2841, 1609,
1580, 1571, 1541, 1270, 1257, 682, 658.
12-Methoxybenzo[c]phenanthridine
Benzo[c]phenanthridine-11,12-dione 20
19
and
(2-(1,4-Dimethoxynaphthalen-2-yl)phenyl)methanamine 17 (164
mg, 0.559 mmol) was added to acetonitrile (2 mL) at rt and was
allowed to dissolve completely under atmospheric conditions.
CAN (920 mg, 1.68 mmol) was dissolved in water (2 mL) and
added dropwise to the stirring mixture. The reaction immediately
turned orange in color. The reaction was allowed to stir under the
same conditions for a further 4 h. Water (5 mL) was added and
the mixture was transferred to a separating funnel, washed with
CH2Cl2 (10 mL × 3). The combined organic phases were washed
with brine (20 mL), dried over anhydrous MgSO4, filtered and
the solvent was removed in vacuo to obtain the crude product
which was purified by column chromatography (20%
EtOAc/Hexane) to yield 20 (59.5 mg, 0.227 mmol, 41%) and 19
(17.4 mg, 0.066 mmol, 12%). Compound 19 was produced as a
yellow solid. Mp 132-134 °C, CHCl3; FTIR (ν/cm-1): 2850,
1707, 1253; 1H NMR (300 MHz, CDCl3) δ 9.34 (1H, J = 8.3 Hz,
ArH), 9.31 (1H, s, ArH-6), 8.52 (1H, d, J = 8.3 Hz, ArH), 8.37
(1H, d, J = 8.0 Hz, ArH), 8.07 (1H, d, J = 7.8 Hz, ArH), 7.80
(2H, dt, J = 13.4, 7.6 Hz, ArH), 7.74-7.67 (2H, m, ArH), 7.64
(1H, s, ArH-11), 4.17 (3H, s, OMe); 13C NMR (75 MHz, CDCl3)
δ 154.7, 149.3, 137.1, 132.8, 132.3, 130.3, 128.7, 127.6, 127.1,
127.0, 127.0, 126.8, 124.6, 122.1, 121.9, 121.9, 95.8, 55.6;
HRMS (ESI+): Found (M+H)+ 260.1071, C18H14NO (M+H)+
requires 260.1076, m/z 260.1071 (M++H, 100%), 261.1104
(20%). Compound 20 was obtained as a bright orange solid. Mp
Benzo[b]phenanthridine-7,12-dione 18
(2-(3-Bromo-1,4-dimethoxynaphthalen-2-
yl)phenyl)methanamine 22 (59.4 mg, 0.158 mmol, 1 eq.) was
dissolved in MeCN (2 mL) and phenyliodine bis(trifluoroacetate
(PIFA) (137 mg, 0.318 mmol, 2 eq.) already dissolved in water
(2 mL) was added. The solution changed its color from light
yellow to red immediately. The reaction was stirred at rt, under
atmospheric conditions for 2 h before it was quenched by adding
an aq. saturated solution of sodium bicarbonate (10 mL) and then
the organic material was extracted into EtOAc (15 mL × 3). The
organic phases were combined and washed with brine (20 mL),
dried over anhydrous MgSO4, filtered and organic solvent was
removed in vacuo. The crude residue was purified by column
chromatography
(20%
EtOAc/Hexane)
to
afford
benzo[b]phenanthridine-7,12-dione 18 as a bright yellow solid
(23.0 mg, 0.089 mmol, 56%). Mp 167-170 °C CHCl3; FTIR
101-103 °C, CHCl3; FTIR (ν/cm-1) 2922, 1662, 1637, 1333; H
1
(ν/cm-1) 2923, 1667, 1676, 1660, 1589, 1588; H NMR (300
1
NMR (300 MHz, CDCl3) δ 9.36 (1H, s, ArH-6), 9.34 (1H, J =
7.9 Hz, ArH), 8.75 (1H, d, J = 7.9 Hz, ArH), 8.12 (1H, d, J = 7.5
Hz, ArH), 7.98 (1H, d, J = 8.1 Hz, ArH), 7.88 (1H, t, J = 7.8 Hz,
ArH), 7.75 (1H, t, J = 7.6 Hz, ArH), 7.66 (1H, t, J = 7.5 Hz,
ArH), 7.52 (1H, t, J = 7.5 Hz, ArH); 13C NMR (75 MHz, CDCl3)
δ 182.8, 179.8, 158.9, 151.3, 137.4, 136.2, 134.7, 134.0, 130.8,
130.5, 129.5, 128.8, 128.6 (×2), 127.6, 126.3, 119.4; HRMS
(ESI+): Found [M+H]+ 260.0699, C17H10NO2 [M+H]+ requires
260.0712, m/z 260.0699 (M++H, 100%), 262.0875 (30%).
MHz, CDCl3) δ 9.67 (1H, d, J = 8.7 Hz, ArH), 9.58 (1H, s, ArH-
5), 8.37-8.34 (1H, m, ArH), 8.31-8.27 (1H, m, ArH), 8.11 (1H, d,
J = 8.1 Hz, ArH), 7.98 (1H, ddd, J = 8.6, 7.0, 1.4 Hz, ArH), 7.87-
7.79 (3H, m, ArH); 13C NMR (75 MHz, CDCl3) δ 186.2, 182.3,
158.4, 145.5, 134.4, 134.1, 134.1, 134.0, 132.8, 132.2, 130.6,
130.2, 128.7, 127.9, 127.2, 127.1, 124.5; HRMS (ESI+): Found
[M+H]+ 260.0713, C17H10NO2 [M+H]+ requires 260.0712, m/z
260.0703 (M+H+, 100%), 261.0744 (20%).
2-(3-Bromo-1,4-dimethoxynaphthalen-2-yl)benzonitrile 21
1,5-Diacetoxynaphthalene 24
2-(1,4-Dimethoxynaphthalen-2-yl)benzonitrile 14 (195 mg, 0.675
mmol) was dissolved in acetic acid (20 mL). NaOAc (67.2 mg,
0.896 mmol) was added followed by NBS (144 mg, 0.896
mmol). The reaction was allowed to stir at rt under inert
Commercially available 1,5-dihydroxynaphthalene 23 (10.00 g,
62.40 mmol), Ac2O (57.36 g, 53 mL, 56.19 mmol) and pyridine
(49.35 g, 50.4 mL, 62.40 mmol) were stirred at rt under argon for

7
12 h. On completion, water (1 L) was added to the reaction to
quench unreacted Ac2O and reaction was cooled down to 0 °C,
by doing so the product precipitated out of solution which was
then filtered and dried to obtain 1,5-diacetoxynaphthalene 24 as a
To a clear solution of 2-bromo-5-methoxy-1,4-naphthoquinone
ACCEPTED MANUSCRIPT
(6.10 g, 22.85 mmol) in THF (380 mL) was added Na2S2O4 (19.9
g, 114.30 mmol) in H2O (100 mL) and TBAI (0.84 g, 2.28
mmol). The reaction was stirred at rt under argon for 30 mins
followed by the addition of KOH (12.8 g, 0.23 mol) in H2O (300
mL). The reaction was stirred for 1 h and Me2SO4 (28.8 g, 21.6
mL, 0.23 mol) was added. The reaction mixture was then stirred
for 18 h before being quenched with 25% aqueous NH4OH (150
mL) and the organic material extracted into EtOAc (3 x 200 mL).
The combined organic extracts were washed sequentially with
distilled water (200 mL), 10% HCl (200 mL) and brine (200
mL). The organic extract was dried over MgSO4, filtered through
celite and concentrated under reduced pressure. The crude
product was purified by silica gel column chromatography to
give 2-bromo-1,4,5-trimethoxynaphthalene 27 as a yellowish-
1
light brown powder (14.98 g, 61.33 mmol, 98%). H NMR (300
MHz, CDCl3) δ 7.77 (2H, d, J = 8.5 Hz, ArH), 7.49 (2H, t, J =
8.0 Hz, ArH), 7.28 (2H, d, J = 7.5 Hz, ArH), 2.44 (6H, s, CH3 ×
2); 13C NMR (75 MHz, CDCl3) δ 169.3 (×2), 146.7 (×2), 128.1,
126.0, 119.3, 118.8, 21.0 (×2).18
5-Acetoxy-2-bromo-1,4-naphthoquinone 25
1,5-Diacetoxynaphthalene 24 (2.40 g, 10.00 mmol) was
dissolved in 100mL of warm AcOH and to the stirring solution
was added dropwise a solution of NBS (7.20 g, 40.00 mmol) in
200 mL AcOH and 100 mL water maintained at a temperature of
65 °C. This reaction was then stirred under inert conditions and a
temperature of 65 °C for 45 mins. After which time, the reaction
was allowed to warm up to rt and then 200 mL of water was
added and transferred to a separating funnel where it was
extracted with CHCl3 (250 mL × 3). The organic phases were
combined and washed with brine (500 mL), dried over anhydrous
MgSO4, filtered through a pad of celite and then the CHCl3 was
removed in vacuo to provide the crude product which was further
recrystallized from EtOH to obtain pure 5-acetoxy-2-bromo-1,4-
naphthoquinone 25 as a bright orange powder (2.30 g, 77.70
1
brown solid (5.43 g, 18.27 mmol, 79%). H NMR (500 MHz,
CDCl3) δ 7.68 (1H, dd, J = 8.4, 1.0 Hz, ArH), 7.43 (1H, t, J = 8.5
ArH), 6.90 (1H, s, ArH-3), 6.88 (1H, dd, J = 7.8, 1.0 Hz, ArH),
3.95 (3H, s, OMe), 3.93 (3H, s, OMe), 3.92 (3H, s, OMe). 13C
NMR (126 MHz, CDCl3) δ 157.5, 153.9, 146.7, 131.7, 127.5,
117.6, 114.6, 112.6, 109.8, 106.9, 61.2, 56.8, 56.4.22
2-(1,4,5-Trimethoxynaphthalen-2-yl)benzonitrile 28
2-Bromo-1,4,5-trimethoxynaphthalene 27 (200 mg, 0.673 mmol),
(2-cyanophenyl)boronic acid 15 (148 mg, 1.00 mmol),
tetrakis(triphenylphosphine)palladium(0) (155 mg, 0.135 mmol)
and CsF (255 mg, 1.68 mmol) were added to a microwave vial
together with dimethoxy ethane (2 mL). The reaction was set in
the microwave reactor under conditions of vigorous stirring, 150
°C and 150 W. On completion the reaction mixture was filtered,
washed with EtOAc and the residue obtained after evaporation of
the organic solvent was adsorbed onto silica and subjected to
column chromatography (15% EtOAc/Hexane) to procure the
pure product 28 as a yellow solid (182 mg, 0.570 mmol, 85%).
1
mmol, 79%). H NMR (300 MHz, CDCl3) δ 8.09 (1H, dd, J =
7.6, 1.6 Hz, ArH), 7.96 (1H, s, ArH-3), 7.62 (1H, d, J = 7.6 Hz,
ArH), 7.57 (1H, dd, J = 7.6, 1.6 Hz, ArH), 2.52 (3H, s, CH3); 13
C
NMR (75 MHz, CDCl3) δ 174.9, 167.9, 148.8, 148.7, 134.1,
131.0, 130.0, 126.8, 124.9, 120.0, 41.8, 21.6.18
2-Bromo-5-hydroxynaphthoquinone 26
5-Acetoxy-2-bromo-1,4-naphthoquinone 25 (2.00 g, 6.70
mmol, 1 eq.) was stirred with 75 mL of EtOH. To this stirring
solution, 22.5 mL of 3 N H2SO4 was added dropwise and the
reaction mixture was stirred under reflux for 2 h. After which, the
reaction was allowed to cool down to rt and solvent was removed
in vacuo. The residue left was dissolved in water (50 mL) and
extracted with CHCl3 (25 mL × 3). The combined organic phases
were washed with brine (100 mL), dried over anhydrous MgSO4,
filtered and then concentrated in vacuo to obtain crude product
which was later purified by column chromatography to furnish
pure product 26 as a bright orange solid (1.66 g, 6.53 mmol,
1
Mp 95-97 °C, CH2Cl2; H NMR (300 MHz, CDCl3) δ 7.81 (2H,
dd, J = 8.5, 1.0 Hz, ArH), 7.72-7.64 (2H, m, ArH), 7-51-7.45
(2H, m, ArH), 6.95 (1H, d, J = 7.7 Hz, ArH), 6.79 (1H, s, ArH-
3′), 4.00 (3H, s, OMe), 3.99 (3H, s, OMe), 3.50 (3H, s, OMe).
13C NMR (75 MHz, CDCl3) δ 157.5, 153.4, 147.2, 142.5, 133.2,
132.4, 131.6, 131.3, 127.7, 127.2, 126.8, 118.8, 118.4, 115.3,
112.9, 107.9, 107.6, 61.6, 57.0, 56.6; HRMS (ESI+): Found
(M+H)+ 320.1281, C20H18NO3 [M+H]+ requires 320.1287, m/z
320.1281 [M+H+, 100%), 321.1312 (20%).
1
98%). H NMR (300 MHz, CDCl3) δ 11.81 (1H, s, OH), 7.73
(2-(1,4,5-Trimethoxynaphthalen-2-yl)phenyl)methanamine 29
(1H, d, J = 8.2 Hz, ArH), 7.67 (1H, t, J = 8.2 Hz, ArH), 7.32 (1H,
d, J = 8.2 Hz, ArH), 7.20 (1H, s, ArH-3); 13C NMR (75 MHz,
CDCl3) δ 187.9, 161.7, 147.1, 136.5, 135.8, 131.1, 125.3, 120.7,
114.6.18
2-(1,4,5-Trimethoxynaphthalen-2-yl)benzonitrile 28 (100 mg,
0.313 mmol) in freshly distilled dry THF (10 mL) and the
temperature of the solution was maintained at 0 °C. LiAlH4 (119
mg, 3.15 mmol) was added carefully and in portions at the same
temperature. The temperature of the reaction mixture was
allowed to rise to rt slowly and then stirred under reflux for 6 h.
On completion the reaction mixture was allowed to cool down to
rt and the temperature was further maintained at 0 °C. An aq. 2%
NaOH was added dropwise until all of unreacted LiAlH4 was
quenched. Ice cold water (20 mL) was added and the solution
was extracted in Et2O (25mL × 3). The organic phases were
collected and washed with brine (30 mL) and then dried over
anhydrous MgSO4, filtered and concentrated in vacuo to obtain a
residue which was subjected to column chromatography (10%
MeOH/CH2Cl2) to afford (2-(1,4,5-trimethoxynaphthalen-2-
yl)phenyl)methanamine 29 (59.0 mg, 0.182 mmol, 58%) as a
brown resinous solid. Due to solubility and polarities issues the
product was considered as an intermediate as was used as such in
the next step without characterization.
2-Bromo-5-methoxy-1,4-naphthoquinone
In a 100 mL round bottom flask equipped with a magnetic
stirring bar was placed 2-bromo-5-hydroxy-1,4-naphthalenedione
(4.70 g, 18.60 mmol) dissolved in CH2Cl2 (60 mL) followed by
Ag2O (10.80 g, 46.63 mmol). To this suspension, MeI (7.92 g,
3.6 mL, 55.81 mmol) was added and the reaction mixture was
stirred at rt for 24 h under argon. The suspension was filtered
through a pad of celite and the solvent removed in vacuo. The
crude product was purified by column chromatography on silica
gel to give 2-bromo-5-methoxy-1,4-naphthoquinone as a yellow
solid (5.90 g, 96%). 1H NMR (300 MHz, CDCl3) δ 7.81 (1H, dd,
J = 7.7, 1.2 Hz, ArH), 7.69 (1H, t, J = 8.1 Hz ArH), 7.39 (1H, s,
ArH-3), 7.35 (1H, dd, J = 8.5, 1.2 Hz, ArH), 4.02 (3H, s, OMe).
13C NMR (75 MHz, CDCl3) δ 181.4, 178.2, 159.9, 142.3, 136.8,
135.1, 133.0, 120.6, 119.3, 118.5, 56.6.
1-Methoxybenzo[c]phenanthridine-11,12-dione 30
2-Bromo-1,4,5-trimethoxynaphthalene 27

8
Tetrahedron
ACCEPTED MANUSCRIP
(2-(1,4,5-Trimethoxynaphthalen-2-yl)phenyl)methanamine 29
Hz, one of CH2OH), 4.37 (1H, d, J = 11.1 Hz, one of CH2OH),
T
(50.0 mg, 0.154 mmol) was transferred to a flask containing
MeCN (2 mL) which was stirred at rt and under atmospheric
conditions. Phenyliodine bis(trifluoroacetate (232 mg, 0.539
mmol) dissolved in water (2 mL) was added drop wise to the
stirring mixture. The reaction was allowed to stir under the same
conditions for 4 h. Water (5 mL) was added and the mixture was
transferred to a separating funnel where the organic material was
extracted into CH2Cl2 (10 mL × 3). The combined organic phases
were washed with brine (20 mL), dried over anhydrous MgSO4,
filtered and then the solvent was removed under vacuo to obtain
the crude product which was purified using column
chromatography (15% EtOAc/Hexane) to obtain the product 30
as a bright red solid (28.2 mg, 0.096 mmol, 63%). Mp 114-116
3.93 (3H, s, OMe), 3.61 (1H, s, OH), 3.47 (3H, s, OMe); 13C
NMR (75 MHz, CDCl3) δ 152.0, 146.2, 139.5, 137.9, 130.1,
129.9, 129.1, 128.4, 128.3, 127.8, 127.1, 126.2, 125.8, 122.4,
122.1, 106.4, 64.1, 61.6, 55.7; HRMS (ESI+): Found M+
294.1244, C19H18O3 M+ requires 294.1256, m/z 277.1240 (100%),
294.1244 (30%).
12-Methoxy-6H-dibenzo[c,h]chromen-6-one23 37 and 2-(3-
bromo-1,4-naphthoquinone)benzaldehyde 38
A solution of (2-(1,4-dimethoxynaphthalen-2-yl)phenyl)methanol
36 (900 mg, 3.06 mmol) in CH2Cl2 (30 mL) was oxygenated and
to this solution, NBS (1090 mg, 6.12 mmol) was slowly added
under oxygen atmosphere and the reaction mixture was allowed
to stir under oxygen at rt for 8 h. On completion, the reaction was
quenched with saturated solution of aq. sodium sulfite (30 mL).
The organic layer was collected and washed with water (50 mL)
and brine (50 mL), dried over anhydrous MgSO4, filtered and the
organic solvent was removed under reduced pressure. The crude
product was purified by column chromatography (10%
EtOAc/Hexane) to isolate 12-methoxy-6H-dibenzo[c,h]chromen-
6-one 37 as light tan solid (356 mg, 1.29 mmol, 42%) and 2-(3-
bromo-1,4-naphthoquinone)benzaldehyde as a yellow solid (324
mg, 0.949 mmol 36%). The spectroscopic data for 37 was found
to be in agreement with that of Jones and Qabaja.23 Mp 228-230
1
°C, CHCl3; H NMR (500 MHz, CDCl3+drop DMSO) δ 9.44
(1H, s, ArH-6), 9.34 (1H, d, J = 8.5 Hz, ArH), 8.52 (1H, d, J =
7.6 Hz, ArH), 8.05 (1H, d, J = 7.9 Hz, ArH), 7.91 (1H, t, J = 7.4
Hz, ArH), 7.78-7.65 (2H, m, ArH), 7.15 (1H, d, J = 8.3 Hz,
ArH), 4.04 (3H, s, OMe); 13C NMR (126 MHz, CDCl3) δ 184.1,
179.7, 162.3, 158.5, 151.2, 139.2, 137.2, 134.4, 133.6, 128.7,
128.6, 128.5, 126.1, 120.4, 119.2, 118.9, 114.6, 56.4; HRMS
(ESI+): Found [M+H]+ 290.0807, C18H12NO3 [M+H]+ requires
290.0818, m/z 290.0807 [M+H]+, 100%), 290.2681 (30%).
2-(1,4-Dimethoxynaphthalen-2-yl)benzaldehyde 35
2-Bromo-1,4-dimethoxynaphthalene 1613 (200 mg, 0.751 mmol),
2-formylphenylboronic acid 34 (169 mg, 1.13 mmol),
tetrakis(triphenylphosphine)palladium(0) (47.0 mg, 0.302 mmol)
and CsF (285 mg, 1.877 mmol) were added to a microwave vial
and freshly degassed dimethoxy ethane (2 mL) was added to the
mixture. The reaction was set up in a microwave reactor at 150
°C and 150 W power with high stirring for 30 mins. On
completion, the reaction mass was filtered off, adsorbed on silica
and subjected to column chromatography (5% EtOAc/Hexane) to
obtain the product 35 as an off-white solid (166 mg, 0.572 mmol,
76%). Mp 190-192 °C, (C2H5)2O; FTIR (ν/cm-1): 2935, 1723,
1625, 1591, 1506, 1464, 1263, 1223; 1H NMR (500 MHz,
CDCl3) δ 9.90 (1H, s, CHO), 8.30 (1H, dd, J = 8.0, 1.5 Hz, ArH),
8.17-8.11 (1H, m, ArH), 8.08 (1H, dd, J = 8.1, 1.5 Hz, ArH),
7.71 (1H, td, J = 7.5, 1.5 Hz, ArH), 7.64-7.50 (4H, m, ArH), 6.74
(1H, s, ArH-3′), 4.01 (3H, s, OMe), 3.40 (3H, s, OMe); 13C NMR
(75 MHz, CDCl3) δ 192.4, 152.0, 147.0, 141.9, 133.8, 133.5,
131.0, 128.4, 127.9, 127.2, 127.1, 126.6, 126.2, 125.4, 122.4,
122.3, 105.9, 60.9, 55.8; HRMS (ESI+): Found [M+H]+
293.1169, C19H17O3 [M+H]+ requires 293.1178, m/z 293.1169
(100%), 292.1092 (50%).
°C, (C2H5)2O; H NMR (300 MHz, CDCl3) δ 8.58-8.43 (2H, m,
1
ArH), 8.26 (1H, d, J = 7.7 Hz, ArH), 8.12 (1H, d, J = 8.1 Hz,
ArH), 7.95-7.82 (1H, m, ArH), 7.69-7.55 (3H, m, ArH), 7.24
(1H, s, ArH-11), 4.12 (3H, s, OMe); 13C NMR (75 MHz, CDCl3)
δ 161.4, 152.4, 141.8, 135.5, 134.7, 130.7, 128.4, 127.7, 127.3,
126.8, 124.8, 122.1, 122.1, 121.8, 121.4, 112.6, 95.7, 55.8;
HRMS (ESI+): Found [M+H]+ 277.0865, C18,H12,O3 [M+H]+
requires 277.0865, m/z 277.0865 (100%), 278.0694 (20%).
Compound 38 Mp 114-116 °C, (C2H5)2O; FTIR (ν/cm-1) 3069,
2759, 1693, 1667, 1591, 1578, 1268, 1246, 1129, 759; 1H NMR
(500 MHz, CDCl3) δ 9.94 (1H, d, J = 0.7 Hz, CHO), 8.26-8.24
(1H, m, ArH), 8.12-8.10 (1H, m, ArH), 7.97 (1H, dd, J = 8.4, 1.3
Hz, ArH), 7.80-7.78 (2H, m, ArH), 7.75 (1H, td, J = 7.5, 1.4 Hz,
ArH), 7.70 (1H, td, J = 7.6, 1.3 Hz, ArH), 7.38 (1H, dd, J = 8.4,
1.4 Hz, ArH); 13C NMR (126 MHz, CDCl3) δ 191.3, 180.9,
177.8, 150.9, 136.8, 135.1, 134.3, 134.1, 134.0, 133.9, 133.6,
131.9, 131.3, 130.2, 129.8, 127.7, 127.3.; HRMS (ESI+): Found
[M+H]+ 340.9799, C17H10O3Br [M+H]+ requires 340.9813.
2',5'-Dimethoxybiphenyl-2-carbaldehyde 40a
2-Bromo-1,4-dimethoxybenzene 39a24 (250 mg, 1.15 mmol), 2-
formylphenylboronic acid 34 (207 mg, 1.38 mmol),
tetrakis(triphenylphosphine)palladium(0) (133 mg, 0.29 mmol)
and CsF (437 mg, 2.88 mmol) were added to a microwave vial in
dimethoxy ethane (2 mL) as solvent and the solution was
degassed for 2 mins. The reaction mixture was transferred to a
microwave reactor at 150 °C and 150 W power with vigorous
stirring for 30 mins. On completion, the reaction mass was
filtered off, adsorbed on silica and subjected to column
chromatography (5% EtOAc/Hexane) to yield the product 40a as
[2-(1,4-Dimethoxynaphthalen-2-yl)phenyl]methanol 36
2-(1,4-Dimethoxynaphthalen-2-yl)benzaldehyde 35 (657 mg,
2.25 mmol) was dissolved in 10 mL of freshly distilled dry THF
under inert conditions. LiAlH4 (255 mg, 6.75 mmol) was added
to the mixture carefully. The reaction was allowed to stir at rt
under inert conditions for 2 h. When completed, the reaction was
cooled down to 0 °C and a 2% aq. NaOH (10 mL) solution was
added dropwise to quench the unreacted LiAlH4 and then the
mixture diluted with ice-cold water (25 mL). The organic
material was the extracted into EtOAc (20 mL × 3) and combined
organic phases were washed with brine (50 mL), dried over
anhydrous MgSO4, filtered and the solvent was removed under
vacuum to obtain the crude product which was then subjected to
column chromatography (40% EtOAc/Hexane) to obtain the
product 36 as a white solid (638 mg, 2.17 mmol, 96%). Mp 114-
115 °C, (C2H5)2O; FTIR (ν/cm-1): 3442, 2931, 1626, 1593, 1505,
1
white low melting solid (246 mg, 1.0 2mmol, 88%). H NMR
(500 MHz, CDCl3) δ 9.79 (1H, s, CHO), 8.01-7.97 (1H, m, ArH),
7.64 (1H, td, J = 7.5, 1.2 Hz, ArH), 7.48 (1H, t, J = 7.6 Hz, ArH),
7.38-7.34 (1H, m, ArH), 6.94 (1H, dd, J = 8.9, 3.0 Hz, ArH),
6.90 (1H, d, J = 8.9 Hz, ArH), 6.87 (1H, d, J = 3.0 Hz, ArH),
3.81 (3H, s, OMe), 3.67 (3H, s, OMe); 13C NMR (126 MHz,
CDCl3) δ 192.5, 153.8, 150.7, 141.6, 134.0, 133.7, 131.0, 127.8,
127.7, 126.6, 117.3, 114.4, 111.8, 55.9, 55.8.25
1
1491, 1455, 1274, 1230; H NMR (300 MHz, CDCl3) δ 8.28
2',5'-Dimethoxybiphenyl-2-carbaldehyde 40b
(1H, d, J = 7.8 Hz, ArH), 8.10 (1H, d, J = 7.8 Hz, ArH), 7.65-
7.32 (6H, m, ArH), 6.62 (1H, s, ArH-3′′), 4.44 (1H, d, J = 11.1

9
To a deoxygenated solution of 2-bromoanisole (4.00 g, 21.34
7.4, 1.6 Hz, ArH), 7.11 (1H, dd, J = 7.4, 1.8 Hz, ArH), 6.98
ACCEPTED MANUSCRIPT
mmol) and 2-formylphenylboronic acid (4.80 g, 32.09 mmol) in
DME (160 mL) was added Pd(PPh3)4 (2.46 g, 2.13 mmol) under
argon atmosphere with stirring. To this mixture was added a
deoxygenated aq. Na2CO3 (2M, 42.7 mL, 85.36 mmol). The
mixture was then heated at reflux for 18 h. After this time, the
mixture was cooled to rt and reaction quenched with H2O (100
mL). The organic material was extracted into EtOAc (3 × 100
mL), the combined extract dried with MgSO4, and the solvent
removed in vacuo. The crude product was purified by column
chromatography on silica gel (5-10% EtOAc/hexane) to afford
product 40b as an off-white solid (3.95 g, 18.63 mmol, 87%). 1H
NMR (500 MHz, CDCl3) δ 9.78 (1H, d, J = 0.9 Hz, CHO),
7.98 (1H, dd, J = 7.8, 1.5 Hz, ArH), 7.60 (1H, td, J = 7.5, 1.5
Hz, ArH), 7.44 (1H, t, J = 7.6 Hz, ArH), 7.39 (1H, td, J = 7.5,
1.8 Hz, ArH), 7.33 (1H, dd, J = 7.7, 1.2 Hz, ArH), 7.26 (1H,
dd, J = 7.5, 1.8 Hz, ArH), 7.06 (1H, td, J = 7.5, 1.1 Hz, ArH),
6.95 (1H, dd, J = 8.3, 1.0 Hz, ArH), 3.70 (3H, s, OMe); 13C
NMR (126 MHz, CDCl3) δ 192.5, 156.5, 141.8, 134.0, 133.6,
131.4, 131.2, 130.0, 127.7, 126.8, 126.5, 121.0, 110.6, 55.3.26
(1H, td, J = 7.5, 1.1 Hz, ArH), 6.92 (1H, dd, J = 8.4, 1.0 Hz,
ArH), 4.40-4.27 (2H, bm, CH2OH), 3.64 (3H, s, OMe), 2.66 (1H,
s, OH); 13C NMR (126 MHz, CDCl3) δ 156.3, 139.3, 137.3,
131.2, 130.2, 129.0, 128.0, 127.8, 127.4, 126.8, 120.9, 111.0,
63.3, 55.6.27
2-Methoxy-6H-benzo[c]chromen-6-one 42a and (4'-Bromo-
2',5'-dimethoxybiphenyl-2-yl)benzaldehyde 43
NBS (1280 mg, 7.21 mmol) was slowly added under an oxygen
atmosphere
to
an
oxygenated
solution
of
(2',5'-
dimethoxybiphenyl-2-yl)methanol 41a (880 mg, 3.60 mmol) in
CH2Cl2 (40 mL). The reaction mixture was allowed to stir under
oxygen at rt for 8 h. On completion, the reaction was quenched
with saturated solution of aq. sodium sulfite (30 mL). The
aqueous layer was extracted with CH2Cl2 (3 × 50 mL) and the
combined organic phases were washed with water (50 mL) and
brine (50 mL), dried over anhydrous MgSO4, filtered and the
organic solvent was removed under reduced pressure. The crude
product was purified by column chromatography (5%
EtOAc/Hexane) to afford 2-methoxy-6H-benzo[c]chromen-6-one
42a as a white solid (358 mg, 1.58 mmol, 44%) and (4’-bromo-
2',5'-dimethoxybiphenyl-2-yl)benzaldehyde 43 (382 mg, 1.18
[2',5'-Dimethoxy-(1,1'-biphenyl)-2-yl]methanol 41a
1
mmol 33%). 42a: Mp 117-119 °C CH2Cl2; H NMR (300 MHz,
2',5'-dimethoxybiphenyl-2-carbaldehyde 40a (200 mg, 0.826
mmol) was taken up in THF (20mL) and LiAlH4 (63.0 mg, 1.65
mmol) was added to it at 0 °C under inert conditions. The
reaction mixture was allowed to warm up to rt and reaction was
stirred for 1 h. On completion the temperature was again reduced
to 0 °C and an ice cold aq. 2 M NaOH solution (10mL) was
added dropwise to quench the unreacted LiAlH4. The mixture
was then transferred to a separating funnel and washed repeatedly
with Et2O (30 mL × 3). The combined organic phases were
washed with water (20 mL) and brine (20 mL), dried over
anhydrous MgSO4, filtered and solvent was removed in vacuum
to isolate crude product which was purified using column
chromatography (20% EtOAc/Hexane) to isolate the product 41a
as a clear oil (244 mg, 0.821 mmol, 100%). FTIR (ν/cm-1): 3422,
2999, 2836, 1600, 1499, 1483, 1460, 1447, 1440, 1274, 1211; 1H
NMR (300 MHz, CDCl3) δ 7.55 (1H, d, J = 7.5 Hz, ArH), 7.44-
7.34 (2H, m, ArH), 7.25-7.20 (1H, m, ArH), 6.95-6.87 (2H, m,
ArH), 6.76 (1H, d, J = 2.9 Hz, ArH-2), 4.44 (1H, d, J = 6.6 Hz,
one of CH2OH), 4.40 (1H, d, J = 6.6 Hz, one of CH2OH), 3.79
(3H, s, OMe), 3.68 (3H, s, OMe), 2.42 (1H, s, OH); 13C NMR
(75 MHz, CDCl3) δ 153.9, 150.6, 139.3, 137.4, 131.1, 130.1,
128.8, 128.1, 127.7, 117.0, 113.6, 112.8, 63.8, 56.7, 55.7; HRMS
(ESI+): Found M+ 244.1091 C15H16O3 M+ requires 244.1099, m/z
244.1091 (15%), 227.1065 (100%).
CDCl3) δ 8.41 (1H, dd, J = 7.9, 1.0 Hz, ArH), 8.07 (1H, d, J =
8.1 Hz, ArH), 7.83 (1H, td, J = 7.8, 1.4 Hz, ArH), 7.64-7.55 (1H,
m, ArH), 7.50 (1H, d, J = 2.9 Hz, ArH), 7.31 (1H, d, J = 9.0 Hz,
ArH), 7.05 (1H, dd, J = 9.0, 2.9 Hz, ArH), 3.91 (3H, s, OMe);
13C NMR (75 MHz, CDCl3) δ 161.3, 156.4, 145.7, 134.7, 134.7,
130.7, 129.0, 121.7, 121.4, 118.7, 118.6, 117.1, 106.4, 55.9;
HRMS (ESI+): Found [M+H]+ 227.0701, C14H11O3 [M+H]+
requires 227.0709, m/z 227.0701 (100%), 226.0625 (30%).
1
Bromo-2',5'-dimethoxybiphenyl-2-yl)benzaldehyde 43: H NMR
(500 MHz, CHCl3) δ 9.78 (1H, s, CHO), 8.02-7.97 (1H, m, ArH),
7.65 (1H, d, J = 1.2 Hz, ArH), 7.51 (1H, s, ArH), 7.34 (1H, d, J =
7.6 Hz, ArH), 7.18 (1H, s, ArH), 6.86 (1H, s, ArH), 3.88 (3H, s,
OMe), 3.69 (3H, s, OMe); 13C NMR (126 MHz, CHCl3) δ 192.1,
150.8, 150.4, 140.7, 134.0, 133.7, 130.9, 128.2, 126.9, 126.7,
116.3, 115.2, 112.1, 57.0, 56.2; HRMS (ESI+): Found [M+H]+
321.0120, C15H14BrO3 [M+H]+ requires 321.0127, m/z 320.0043
(100%), 322.0043 (97%).
6H-benzo[c]chromen-6-one 42b
NBS (1.10 g, 6.17 mmol) was slowly added under an oxygen
atmosphere to an oxygenated solution of (2'-methoxybiphenyl-2-
yl)methanol 41b (880 mg, 4.11 mmol) in CH2Cl2 (100 mL). The
reaction mixture was allowed to stir under reflux for 18 h. On
completion, the reaction was quenched with saturated solution of
aq. sodium sulfite (50 mL). The aqueous layer was extracted with
CH2Cl2 (3 × 50 mL) and the combined organic phases were
washed with water (100 mL) and brine (100 mL), dried over
anhydrous MgSO4, filtered and the organic solvent was removed
under reduced pressure. The crude product was purified by
column chromatography (5-10% EtOAc/Hexane) to isolate the
product 42b as a white crystalline solid (0.57 g, 2.91 mmol,
[2'-Methoxy-(1,1'-biphenyl)-2-yl]methanol 41b
2'-Methoxybiphenyl-2-carbaldehyde 40b (3.20 g, 15.09 mmol)
was dissolved in 140 mL of freshly distilled dry THF under inert
conditions. LiAlH4 (1.71 g, 45.28 mmol) was added to the
mixture carefully at 0 °C. The reaction was warmed up to room
temperature and allowed to stir at rt under inert conditions for 2
h. When completed, the reaction was cooled down to 0 °C and a
2% aq. NaOH (50 mL) solution was added dropwise to quench
the unreacted LiAlH4 and then the mixture diluted with ice-cold
water (100 mL). The organic material was then extracted into
EtOAc (100 mL × 3) and combined organic phases were washed
with brine (100 mL), dried over anhydrous MgSO4, filtered and
the solvent was removed under reduced pressure. The crude
product was then subjected to column chromatography (20%
EtOAc/Hexane) to obtain the product 41b as a clear oil (2.97 g,
13.87 mmol, 92%); 1H NMR (500 MHz, CDCl3) δ 7.49 (1H, dd,
J = 7.4, 1.6 Hz, ArH), 7.35-7.27 (3H, m, ArH), 7.16 (1H, dd, J =
1
70%); H NMR (300 MHz, CDCl3) δ 8.39 (1H, d, J = 8.1 Hz,
ArH), 8.10 (1H, d, J = 8.1 Hz, ArH), 8.04 (1H, d, J = 7.9 Hz,
ArH), 7.81 (1H, t, J = 8.7, ArH), 7.57 (1H, t, J = 7.1, ArH), 7.42-
7.51 (1H, m, ArH), 7.39-7.28 (2H, m, ArH); 13C NMR (75 MHz,
CDCl3) δ 161.1, 151.3, 134.8, 134.7, 130.6, 130.4, 128.9, 124.5,
122.8, 121.7, 121.3, 118.0, 117.8.28
2-(3-Bromo-1,4-dimethoxynaphthalen-2-yl)benzaldehyde 45
and 2-(3-Bromo-1,4-naphthoquinone)benzaldehyde 38
A solution of 2-(1,4-dimethoxynaphthalen-2-yl)benzaldehyde 35
(410 mg, 1.42 mmol) in CH2Cl2 (10 mL) was oxygenated and to

10
Tetrahedron
ACCEPTED MANUSCRIPT
this solution, NBS (504 mg, 2.83 mmol) was slowly added
Hz, ArH), 7.31 (1H, td, J = 7.6, 1.3 Hz, ArH), 7.12 (1H, s, ArH),
under oxygen atmosphere and the reaction mixture was allowed
to stir under oxygen over 18 h at rt. On completion, the reaction
was quenched with saturated solution of aq. sodium sulfite (15
mL). The organic layer was collected and washed with water (30
mL) and brine (30 mL), dried over anhydrous MgSO4, filtered
and the organic solvent was removed under reduced pressure.
The crude product was purified by column chromatography (15%
7.08 (1H, s, CH(OH)), 7.01 (1H, td, J = 7.5, 7.5, 1.1 Hz, ArH),
6.70 (1H, d, J = 7.6 Hz, ArH), 4.04 (3H, s, OMe), 1.54 (1H, s,
CH(OH)); 13C NMR (126 MHz, CDCl3) δ 150.9, 139.5, 129.4,
129.3, 128.9, 127.5, 127.0, 126.8, 126.7, 126.5, 126.1, 122.3,
121.7, 121.5, 115.4, 98.3, 92.8, 55.8.
Acknowledgments
EtOAc/Hexane)
to
isolate
2-(3-bromo-1,4-
naphthoquinone)benzaldehyde 38 as a yellow solid (276 mg,
0.809 mmol, 57 %) and 2-(3-bromo-1,4-dimethoxynaphthalen-2-
yl)benzaldehyde 45 (137 mg, 0.369 mmol 26%). Naphthalene 45
Mp 89-91 °C CH2Cl2; FTIR (ν/cm-1) 3070, 2933, 2844, 2745,
This work was supported by SABINA (Southern African
Biochemistry and Informatics for Natural Products Network), the
SPARC Foundation, the National Research Foundation (NRF)
Pretoria, South Africa, and the University of the Witwatersrand
(Science Faculty Research Council). The University of
Stellenbosch is thanked for providing the HRMS spectroscopy
service.
1
1694, 1596, 1576, 1491, 1351, 1146, 1080, 1040; H NMR (500
MHz, CDCl3) δ 9.82 (1H, d, J = 0.6 Hz), 8.20-8.17 (1H, m, ArH),
8.13-8.11 (1H, m, ArH), 8.10 (1H, dd, J = 7.8, 1.4 Hz), 7.72 (1H,
td, J = 7.5, 1.4 Hz), 7.61 (3H, m, ArH), 7.42 (1H, dd, J = 7.7, 1.7
Hz), 4.03 (3H, s, OMe), 3.48 (3H, s, OMe).; 13C NMR (126
MHz, CDCl3) δ 191.6, 150.8, 150.4, 140.4, 134.1, 133.5, 132.0,
129.2, 128.7, 128.2, 128.0, 127.7, 127.6, 127.2, 123.1, 122.6,
114.7, 61.6, 61.5.; HRMS (ESI+): Found [M+H]+ 371.0267,
C19H16O3Br [M+H]+ requires 371.0283. Quinone 38 was identical
to that described above.
References and notes
1. (a) Nakano, H.; Matsuda, Y.; Ito, K.; Ohkubo, S.; Morimoto, M.;
Tomita, F. J. Antibiot. 1981, 34, 266–270; (b) Takahashi, K.;
Yoshida, M.; Tomita, F.; Shirahata, K. J. Antibiot. 1981, 34, 271–
275; (c) Hosoya, T.; Takashiro, E.; Matsumoto, T.; Suzuki, K. J.
Am. Chem. Soc. 1994, 116, 1004–1015.
2. (a) Futagami, S.; Ohashi, Y.; Imura, K.; Hosoya, T.; Ohmori, K.;
Matsumoto, T.; Suzuki, K. Tetrahedron Lett. 2000, 41, 1063–
1067; (b) Findlay, J. A.; Daljeet, A.; Murray, P. J.; Rej, R. N.;
Can. J. Chem. 1987, 65, 427–431.
3. (a) Ishii, H.; Ishikawa, T.; Haginiwa, J. Yakugaku Zasshi 1977, 97,
890–900; (b) Ishikawa, T.; Murota, M.; Watanabe, T.; Harayama,
T.; Ishii, H. Tetrahedron Lett. 1995, 36, 4269–4272.
4. Kharel, M. K.; Zhu, L.; Liu, T.; Rohr, J. J. Am. Chem. Soc. 2007,
129, 3780–3781.
5. Akagi, Y.; Yamada, S.-n; Etomi, N.; Kumamoto, T.; Nakanishi,
W. Ishikawa, T. Tetrahedron Lett. 2010, 51, 1338–1340.
6. Monro, S. M. A.; Cottreau, K. M.; Spencer, C.; Wentzell, J. R.;
Graham, C. L.; Borissow, C. N.; Jakeman, D. L.; McFarland, S.
A.; Bioorg. Med. Chem. 2011, 19, 3357–3360.
7. Jakeman, D. L.; Bandi, S.; Graham, C. L.; Reid, T. R.; Wentzell,
J. R.; Douglas, S. E.; Antimicrob. Agents Chemother. 2009, 53,
1245–1247.
8. Yang, X.; Yu, B. Chem. Eur. J. 2013, 19, 8431–8434.
9. Martinez-Farina, C. F.; McCormick, N.; Robertson, A. W.;
Clement, H.; Jee, A.; Ampaw, A.; Chan, N.-L.; Syvitski, R. T.;
Jakeman, D. L. Org. Biomol. Chem., 2015, 13, 10324–10327.
10. (a) de Frutos, Ó.; Atienza, C.; Echavarren, A. M. Eur. J. Org.
Chem. 2001, 163–171; (b) Shan, M.; Sharif, E. U.; O'Doherty, G.
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2-[2-(Bromomethyl)phenyl]-1,4-dimethoxynaphthalene 46
[2-(1,4-Dimethoxynaphthalen-2-yl]phenyl)methanol 36 (100 mg,
0.340 mmol) was dissolved in dry CH2Cl2 (10 mL). PPh3 (446
mg, 1.70 mmol) and CBr4 (563 mg, 1.70 mmol) were added to it
and the reaction was allowed to stir at rt under an Ar atmosphere
for 3 h after which time the reaction mixture goes from clear to
bright orange in color. On completion of the reaction the CH2Cl2
was removed under vacuum and the resulting orange residue was
subjected to column chromatography (10% EtOAc/Hexane) to
obtain product 46 as a yellow oil (85.0 mg, 0.237 mmol, 67%).
1
FTIR (ν/cm-1) 3056, 1591, 1365, 690; H NMR (300 MHz,
CDCl3) δ 8.29 (1H, d, J = 7.7 Hz, ArH), 8.13 (1H, d, J = 8.3 Hz,
ArH), 7.62-7.50 (3H, m, ArH), 7.39 (3H, s, ArH), 6.76 (1H, s,
ArH-3), 4.55 (1H, d, J = 10.2 Hz, one of CH2Br), 4.47 (1H, d, J =
10.2 Hz, one of CH2Br), 3.99 (3H, s, OMe), 3.49 (3H, s, OMe);
13C NMR (75 MHz, CDCl3) δ 151.5, 146.5, 138.6, 136.2, 130.9,
130.7, 128.7, 128.3, 128.2, 127.9, 126.9, 126.3, 125.8, 122.3,
122.2, 106.3, 61.5, 55.8, 32.5; HRMS (ESI+): Found M+ for
C19H17O279Br: 356.03912 and C19H17O281Br: 358.03737;
C19H17O2Br M+ requires 357.24108.
11. (a) For synthesis of 6H-dibenzo[c,h]chromen-6-one skeleton and
arnottin see (a) (i) Jung, M. E.; Jung, Y. H. Tetrahedron Lett.
1988, 29, 2517–2520; (ii) Hart, D. J.; Merriman, Tetrahedron Lett.
G. H. 1989, 30, 5093–5096; (iii) Deshpande, P. P.; Martin, O. R.
Tetrahedron Lett. 1990, 31, 6313–6316; (iv) James, C. A.;
Snieckus, V. J. Org. Chem. 2009, 74, 4080–4093; (v) Patra, A.;
Pahari, P.; Ray, S.; Mal, D. J. Org. Chem. 2005, 70, 9017–9020;
(vi) Cortezano-Arellano, O.; Cordero-Vargas, Tetrahedron Lett.
A. 2010, 51, 602–604; (vii) Konno, F.; Ishikawa, T.; Kawahata,
M.; Yamaguchi, K. J. Org. Chem. 2006, 71, 9818–9823; (viii)
Moschitto, M. J.; Anthony, D. R.; Lewis, C. A. J. Org. Chem.
2015, 80, 3339–3342; (ix) Jangir, R. Argade, N. P. RSC Adv.
2014, 4, 5531–5535. (b) For synthesis of phenanthrovirdin
aglycon see (i) Gore, M. P.; Gould, S. J.; Weller, D. D. J. Org.
Chem. 1991, 56, 2289–2291; (ii) Valderrama, J. A.; Spate, A.;
González, M. F. Heterocycl. Commun. 1997, 3, 23–28; (iii)
Valderrama, J. A.; González, M. F.; Valderrama, C. Tetrahedron
1999, 55, 6039–6050; (iv) Mohri, S.-i; Stefinovic, M.; Snieckus,
V. J. Org. Chem. 1997, 62, 7072–7073. (c) For synthesis of
jadomycins see (i) Akagi, Y.; Yamada, S.-i; Etomi, N.:
Kumamoto, T.; Nakanishi, W.; Ishikawa, T. Tetrahedron Lett.
2010, 51, 1338–1340.
12-Methoxy-6H-dibenzo[c,h]chromen-6-one 37 and 12-
Methoxy-6H-dibenzo[c,h]chromen-6-ol 48
In one experiment that was not readily reproducible [2-(1,4-
dimethoxynaphthalen-2-yl)phenyl]methanol 31 (720 mg, 2.45
mmol) was dissolved in CH2Cl2 (25 mL) and to this stirring
solution, NBS (850 mg, 4.78 mmol) was slowly added and the
reaction mixture was allowed to stir at rt and under atmospheric
conditions for 8 h. On completion, the reaction was quenched
with saturated solution of aq. sodium sulfite (30 mL). The
organic layer was collected and washed with water (30 mL) and
brine (30 mL), dried over anhydrous MgSO4, filtered and the
organic solvent was removed under reduced pressure. The crude
product was purified by column chromatography (10%
EtOAc/Hexane) to isolate 12-methoxy-6H-dibenzo[c,h]chromen-
6-one 37 as light tan solid (290 mg, 1.05 mmoles, 43%) and 12-
methoxy-6H-dibenzo[c,h]chromen-6-ol 48 (245 mg, 0.882
mmoles 36%). The spectroscopic data for 37 was found to be in
agreement with that of Jones and Qabaja.23 and that described
above. Compound 48 was partially characterized. 1H NMR (500
MHz, CDCl3) δ 8.59 (1H, d, J = 8.3 Hz, ArH), 8.30 (1H, d, J =
8.4 Hz, ArH), 7.72-7.68 (2H, m, ArH), 7.60 (1H, d, J = 6.9, 7.0
12. (a) Pathak, R.; Vandayar, K.; van Otterlo, W. A. L.; Michael, J. P.;
Fernandes, M. A.; de Koning, C. B. Org. Biomol. Chem. 2004, 2,
3504–3509; (b) de Koning, C. B.; Michael, J. P.; Pathak, R.; van
Otterlo, W. A. L. Tetrahedron Lett. 2004, 45, 1117–1119; (c)
Pathak, R.; Nhlapo, J. M.; Govender, S.; Michael, J. P.; van

11
Otterlo, W. A. L.; de Koning, C. B. Tetrahedron 2006, 62, 2820–
2830; (d) Moleele, S. S.; Michael, J. P.; de Koning, C. B.
Tetrahedron 2006, 62, 2831–2844; (e) Lötter, A. N. C.; Pathak,
R.; Sello, T. S.; Fernandes, M. A.; van Otterlo, W. A. L.; de
Koning, C. B. Tetrahedron 2007, 63, 2263–2274; (f) Pelly, S. C.;
Govender, S.; Fernandes, M. A.; Schmalz, H.-G.; de Koning, C.
B. J. Org. Chem. 2007, 72, 2857–2864; (g) Govender, S.;
Mmutlane, E. M.; van Otterlo, W. A. L.; de Koning, C. B. Org.
Biomol. Chem. 2007, 5, 2433–2440; (h) Leboho, T. C.; Michael, J.
P.; van Otterlo, W. A. L.; van Vuuren, S. F.; de Koning, C. B.
Bioorg. Med. Chem. Lett. 2009, 19, 4948–4951; (i) Leboho, T. C.;
van Vuuren, S. F.; Michael, J. P.; de Koning, C. B. Org. Biomol.
Chem. 2014, 12, 307–315; (j) Leboho, T. C.; Giri, S.; Popova, I.;
Cock, I.; Michael, J. P.; de Koning, C. B. Bioorg. Med. Chem.
2015, 23, 4943–4951.
V = 2319.5(2) Å3, no. of formula units in the unit cell Z = 8;
ACCEPTED MANUSCRIPT
calculated density rcalcd 1.485 Mg/m3; linear absorption coefficient,
m 0.099 mm-1; radiation and wavelength, MoKα = 0.71073 Å;
temperature of measurement, 173(2) K, 2 Qmax 25.50°; no of
measured and independent reflections, 8630 and 2020; Rint
=
0.0264; R [I > 2.0σ (I)] = 0.0485, wR = 0.1212, GoF = 1.072,
refined on F; residual electron density, 0.247 and -0.152 eÅ-3.
Crystal data for 30, CCDC 1479577, C18H11NO3: Mr 289.28 g.mol-
1; crystal dimensions (mm) 0.36 x 0.26 x 0.16; crystal system,
monoclinic; space group, C2/c; unit cell dimensions and volume, a
= 17.5504(8) Å, b = 7.1638(3) Å, c = 20.5142(9) Å, α= 90°, β=
96.459(2)°, γ = 90°, V = 2562.83(19) Å3, no. of formula units in
the unit cell Z = 8; calculated density rcalcd 1.499 Mg/m3; linear
absorption coefficient, m 0.103 mm-1; radiation and wavelength,
MoKα = 0.71073 Å; temperature of measurement, 173(2) K, 2
Qmax 28.00°; no of measured and independent reflections, 17130
and 3089; Rint = 0.0296; R [I > 2.0σ(I)] = 0.0487, wR = 0.1356,
GoF = 1.040, refined on F; residual electron density, 0.568 and -
0.523 eÅ-3. Crystal data for 37, CCDC 1479574, C18H12O3: Mr
276.28 g.mol-1; crystal dimensions (mm) 0.62 x 0.14 x 0.04;
crystal system, triclinic; space group, P-1; unit cell dimensions
and volume, a = 7.1970(7) Å, b = 9.0700(9) Å, c = 10.8400(11)
Å, α= 103.237(3)°, β= 105.722(3)°, γ = 104.026(3)°, V =
627.07(11) Å3, no. of formula units in the unit cell Z = 2;
calculated density rcalcd 1.463 Mg/m3; linear absorption coefficient,
m 0.100 mm-1; radiation and wavelength, MoKα = 0.71073 Å;
temperature of measurement, 173(2) K, 2 Qmax 27.00°; no of
13. Johnson, M. M.; Naidoo, J. M.; Mmutlane, E. M.; Fernandes, M.
A.; van Otterlo, W. A. L.; de Koning, C. B. J. Org. Chem. 2010,
75, 8701-8704.
14. (a) Brown, H. C.; Choi, Y. M.; Narasimhan, S. J. Org Chem.
1982, 47, 3153–3163 (borane tetrahydrofuran complex); (b)
Mebane, R. C.; Jensen, D. R.; Rickerd, K. R; Gross, B. H. Syn.
Comm. 2006, 33, 3373–3379 (Raney nickel); (c) Vilches-Herrera,
M.; Werkmeister, S.; Junge, K.; Börner, A.; Beller, M. Catal. Sci.
Technol. 2014, 4, 629–632. (Pd/C); (d) Caddick, S.; Judd, D. B.;
Lewis, A. K. de K.; Reich, M. T.; Williams, M. R. V. Tetrahedron
2003, 59, 5417–5423 (NiBH4); (e) Gaylord, N. G. J. Chem. Ed.
1957, 34, 367–374 (LiAlH4).
15. Maestri, G.; Larraufie, M.-H.; Derat, É.; Ollivier, C.; Fensterbank,
L.; Lacôte, E.; Malacria, M. Org. Lett. 2010, 12, 5692–5695.
16. Watanabe, T.; Ohashi, Y.; Yoshino, R.; Komano, N.; Eguchi, M.;
Maruyama, S.; Ishikawa, T. Org. Biomol. Chem. 2003, 1, 3024–
3032.
17. (a) Brimble, M. A.; Brenstrum, T. J. J. Chem. Soc., Perkin Trans.
1 2001, 1612–1623; (b) Jung, M. E.; Hagenah, J. A. J. Org. Chem.
1987, 52, 1889–1902.
18. Wessels, P.; Göhrt, A.; Zeeck, A. J. Antibiot. 1991, 44, 1013–
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7240.
measured and independent reflections, 6387 and 2743; Rint =
0.0758; R [I > 2.0 σ (I)] = 0.0479, wR = 0.1016, GoF = 0.874,
refined on F; residual electron density, 0.229 and -0.271 eÅ-3.
Crystal data for 42, CCDC 1479573, C14H10O3: Mr 226.22 g.mol-1;
crystal dimensions (mm) 0.50 x 0.16 x 0.06; crystal system,
triclinic; space group, P-1; unit cell dimensions and volume, a =
7.4581(8) Å, b = 10.7427(12) Å, c = 13.7087(15) Å, α=
83.115(4)°, β= 83.963(4)°, γ = 73.844(4)°, V = 1044.4(2) Å3, no.
of formula units in the unit cell Z = 4; calculated density rcalcd
1.439 Mg/m3; linear absorption coefficient, m 0.101 mm-1;
radiation and wavelength, MoKα = 0.71073 Å; temperature of
measurement, 173(2) K, 2 Qmax 28.00°; no of measured and
independent reflections, 44613 and 5037; Rint = 0.0294; R [I >
2.0σ (I)] = 0.0381, wR = 0.1033, GoF = 1.017, refined on F;
residual electron density, 0.328 and -0.227 eÅ-3.
20. Zhou, Z.; Bian, Y. Heteroatom Chem. 2008, 19, 682–687.
21. Vorländer, D.; Siebert, C.; Weissheimer, P.; Rolle, O. Justus
Liebigs Ann. Chem, 1905, 341, 1–80.
22. (a) Zhang, Y.; Wang, X.; Sunkara, M.; Ye, Q.; Ponomereva, L. V.;
She, Q.-B.; Morris, A. J.; Thorson, J. S. Org. Lett. 2013, 15,
5566–5569; (b) Fernandes, R. A.; Brückner, R. Synlett 2005, 8,
1281. (c) Eid, C. N.; Shim, J.; Bikker, J.; Lin, M. J. Org. Chem.
2009, 74, 423–426.
23. Qabaja, G.; Jones, G. B. J. Org. Chem. 2000, 65, 7187–7194.
24. Mulay, S. V.; Bhowmik, A.; Fernandes, R. A. Eur. J. Org. Chem.
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H. Org. Biomol. Chem. 2003, 1, 1643–1646.
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27. Rashkin, M. J.; Hughes, R. M.; Calloway, N. T.; Waters, M. L. J.
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28. Nealmongkol, P.; Tangdenpaisal, K.; Sitthimonchai, S.;
Ruchirawat, S.; Thasana, N. Tetrahedron 2013, 69, 9277–9283.
29. X-ray crystallography data: The five data sets were collected
using ω-scans on a APEX II CCD area detector diffractometer.
The crystals for compound 19, 18, 30, 37 and 42 were prepared by
dissolving the samples in CH2Cl2 in a vial. These vials were put
into bigger vials filled with hexane and the whole system was
sealed. Cotton wool was used to keep the inner and outer vials
apart. Crystal data for 19, CCDC 1479576, C18H13NO: Mr 259.29
g.mol-1; crystal dimensions (mm) 0.22 x 0.17 x 0.16; crystal
system, Orthorhombic; space group, P2(1); unit cell dimensions
and volume, a = 18.0958(19) Å, b = 8.9270(11) Å, c =
15.7941(19) Å, α= 90°, β= 90°, γ = 90°, V = 2551.4(5) Å3, no. of
formula units in the unit cell Z = 8; calculated density rcalcd 1.350
Mg/m3; linear absorption coefficient, m 0.084 mm-1; radiation and
wavelength, MoKα = 0.71073 Å; temperature of measurement,
173(2) K, 2 Qmax 27.99°; no of measured and independent
reflections, 18478 and 3176; Rint = 0.0333; R [I > 2.0σ(I)] =
0.0389, wR = 0.0967, GoF = 1.031, refined on F; residual electron
density, 0.247 and -0.142eÅ-3. Crystal data for 18, CCDC
1479575, C17H9NO2: Mr 259.25 g.mol-1; crystal dimensions (mm)
0.40 x 0.38 x 0.31; crystal system, monoclinic; space group, C2/c;
unit cell dimensions and volume, a = 10.5737(6) Å, b =
11.0912(6) Å, c = 20.0250(11) Å, α= 90°, β= 98.998(2)°, γ = 90°,