Synthesis of murrayaquinone A and analogues via ring-closing C-H arylation

Article abstract of DOI:10.1016/j.tet.2013.02.055

A compact synthesis of Murrayaquinone A is reported, based on sequential Buchwald-Hartwig amination/annulative C-H activation followed by oxidation of the intermediate carbazole. The methodology can be readily extended to other analogues with electron-rich quinone rings.

Full text of DOI:10.1016/j.tet.2013.02.055

Tetrahedron 69 (2013) 4389e4394
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of murrayaquinone A and analogues via ring-closing CeH
arylation
*
Robin B. Bedford , John G. Bowen, Amanda L. Weeks
School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A compact synthesis of Murrayaquinone A is reported, based on sequential BuchwaldeHartwig amina-
tion/annulative CeH activation followed by oxidation of the intermediate carbazole. The methodology
can be readily extended to other analogues with electron-rich quinone rings.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 29 November 2012
Received in revised form 12 February 2013
Accepted 18 February 2013
Available online 13 March 2013
Keywords:
CeH activation
Palladium
Carbazoles
Murrayaquinone A
BuchwaldeHartwig amination
1. Introduction
intermediates, such as 2, to the desired carbazole 1,4-qui-
none.4a,d,e,f,h,j,k,m,p,q
Murrayaquinone A, 1a, is one of a class of carbazole 1,4-quinone
alkaloids isolated from the root bark of Murraya euchrestifolia
Hayata, a plant used in folk medicine as an analgesic, local an-
aesthetic and for the treatment of eczema, rheumatism and
dropsy.1 Murrayaquinone has been shown to have a mild cardio-
tonic effect on heart muscle2 as well as possessing cytotoxic
properties.3
Annulation by intramolecular CeH activation (Scheme 1) is
a versatile method for the synthesis of a range of heterocycles, and
has been used in the synthesis of a variety of natural products,
including carbazoles.5
Scheme 1. Annulation by intramolecular direct arylation.
We previously developed a method for the synthesis of carba-
zoles based on sequential BuchwaldeHartwig amination then an-
nulation by CeH arylation, starting from 2-chloroanilines and aryl
bromides (Scheme 2) in either a two pot or a one-pot tandem
process. This methodology allowed us to synthesize a range of
carbazoles, including the simple carbazole alkaloids Clausine P,
glycozolidine and a precursor in the synthesis of Clausines H, K, O,
and 7-methoxy-O-methylmukonal6 as well as a range of fluorinated
carbazoles.7
There have been several syntheses of murrayaquinone A,
14 many of these involve oxidation of appropriate carbazole
* Corresponding author. Tel.: þ44 117 331 7538; e-mail address: r.bedford@
bristol.ac.uk (R.B. Bedford).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.02.055

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R.B. Bedford et al. / Tetrahedron 69 (2013) 4389e4394
the molecule, potentially allowing facile access to a range of syn-
thetic analogues of murrayaquinone A.
The aryl bromide 4a was prepared in two steps from 2,5-
dimethoxybenzaldehyde by bromination followed by reduction
of the aldehyde, as outlined in Scheme 4.8 Gratifyingly, the
one-pot reaction of 4a with 2-chloroaniline, 3a, in toluene
using sodium tert-butoxide as base under microwave heating led
to tandem BuchwaldeHartwig/CeH arylation-ring-closing re-
actions, furnishing the intermediate carbazole 5a in reasonably
good yield.
Scheme 2. The formation of carbazoles by BuchwaldeHartwig amination of
2-chloroanilines with aryl bromides followed by annulation via CeH activation.
Key to the success of the reaction is the markedly different rates
of oxidative addition of the aryl bromide versus the 2-chloroaniline,
this allows for strict ordering of the reaction, without competitive
self-amination of the 2-haloaniline. A consequence of this is that
the highly electronically deactivated 2-chloroaniline substrates
require a very electron-rich palladium-based catalyst to facilitate
oxidative addition, using tri-tert-butylphosphine as the supporting
ligand.
We were interested to see whether this methodology could be
exploited to enable a compact synthesis of murrayaquinone A that
could be readily extended to synthetic analogues. This indeed
proves to be the case, and the results from this study are presented
below.
Scheme 4. Synthesis of murrayaquinone A. Conditions: (i) bromine (44 mmol) added
dropwise to 2,5-dimethoxybenzaldehyde (40 mmol), (SnCl4 (44 mmol) in DCM and
heated at reflux temperature for 2 h. (ii) Borane dimethylsulfide (6 mmol) added
dropwise to 4-bromo-2,5-dimethoxybenzaldehyde (2 mmol) in chlorobenzene at 0 ꢀC,
130 ꢀC 18 h. (iii) 2-Chloroaniline (0.5 mmol), aryl bromide (0.5 mmol), palladium ac-
etate (1 mol %), sodium tert-butoxide (2.5 mmol), tri-tert-butylphosphonium tetra-
fluoroborate (15 mol %) and toluene (3 ml) heated to 160 ꢀC, 3 h, microwave conditions
(iv) boron tribromide (1 M, 0.46 mmol) in DCM was added dropwise to carbazole
(0.2 mmol) in DCM at ꢁ78 ꢀC.
Initial attempts at oxidizing 5a to the desired carbazole 1,4-
dione with cerium ammonium nitrate failed; 1H NMR spectros-
copy showed not only no product, but also revealed that 5a had
undergone extensive decomposition. The use of silver nitrate as an
oxidizing agent also proved unsuccessful, however employing
boron tribromide under air, as described by Moody and co-
workers,4a furnished murrayaquinone A, in excellent yield. In an
attempt to shorten the procedure still further, we investigated the
possibility of directly oxidizing the crude carbazole in the product
mixture, however while partially successful, this led to no more
than 21% isolated yield of the desired product 1a after several
attempts.
2. Results and discussion
Scheme 3 outlines the compact synthetic strategy we envisaged
for the synthesis of 1a in two steps from 2-chloroaniline, 3a, and
the appropriate aryl bromide 4a. While simpler syntheses can be
performed, such as McErlean’s recently reported two-step syn-
thesis from aniline and toluhydroquinone via an oxidative Heck
reaction,4t the strength of the proposed approach lies in the ability
to vary substitution patterns in both left and right hand portions of
Having successfully synthesized murrayaquinone A, we were
next interested to see whether the methodology could be ex-
tended to other synthetic analogues. Table 1 shows both the for-
mation of the intermediate carbazoles 5 and their subsequent
oxidation to the desired carbazole 1,4-quinones, 1. The carbazoles
5 were generally isolated in reasonable yield, while the BBr3-
mediated oxidative demethylation reaction proceeded well, pro-
vided there were one or two methyl groups on the dimethox-
ybenzene fragment.
By contrast intermediates 5k and 5l proved to be too electron-
deficient for this protocol to be effective. In order to see whether
the desired quinones could be produced using an alternative oxi-
dant, we next examined the oxidations of these substrates with
phenyl iodine (bis)trifluoroacetate, PIFA, Scheme 5, however this
also proved unsuccessful, leading to extensive decomposition of the
carbazole starting material. Furthermore, the attempted oxidation
of the unsubstituted analogue, 5m under a range of conditions also
proved unsuccessful (Scheme 5).
Scheme 3. Proposed synthesis of murrayaquinone A.

R.B. Bedford et al. / Tetrahedron 69 (2013) 4389e4394
4391
Table 1
Synthesis of carbazole-1,4-quinone analogues of murrayaquinone Aa
Entry
Chloroaniline
Aryl bromide
Carbazole, 5 (yield, %)
Carbazole 1,4-quinone, 1 (yield, %)
1
2
3
4
4a
4a
4a
5
6
7
3b
4b
4b
3c
8
9
3d
3e
4b
4b
No reaction
10
3b
(continued on next page)

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R.B. Bedford et al. / Tetrahedron 69 (2013) 4389e4394
Table 1 (continued )
Entry
Chloroaniline
Aryl bromide
Carbazole, 5 (yield, %)
Carbazole 1,4-quinone, 1 (yield, %)
11
3e
4c
No reaction
a
Conditions: synthesis of carbazole, 5, chloroaniline, 3, (0.5 mmol), aryl bromide, 4, (0.5 mmol), palladium acetate (1 mol %), sodium tert-butoxide (2.5 mmol), tri-tert-
butylphosphonium tetrafluoroborate (15 mol %) and toluene (3 ml) were sealed in a microwave reaction vial and heated under microwave conditions to 160 ꢀC for 3 h.
Carbazole, 1: boron tribromide (1 M, 0.46 mmol) in DCM was added dropwise to carbazole (0.2 mmol) in DCM at ꢁ78 ꢀC.
10.40 (s, 1H, ArH), 7.34 (s, 1H, ArH), 7.25 (s, 1H, ArH), 3.90 (s, 3H,
OCH3), 3.89 (s, 3H, OCH3).
3.2.2. 1-Bromo-2,5-dimethoxy-4-methylbenzene, 4a. 4-Bromo-2,5-
dimethoxybenzaldehyde (0.50 g, 2 mmol) was suspended in chlo-
robenzene (4 ml) and cooled to 0 ꢀC. Borane dimethylsulfide
(0.60 ml, 6 mmol) was added with vigorous stirring, when effer-
vescence ceased reaction mixture was heated for 3 h at 80 ꢀC and
then for a further 18 h at 130 ꢀC. The reaction mixture was then
quenched with sodium carbonate. The crude product was extracted
into CH2Cl2, dried with magnesium sulfate and solvent removed in
vacuo. This gave the product as a white solid: 1.03 g (35%); mp
88e90 ꢀC; 1H NMR (400 MHz, CDCl3)
d ppm 6.98 (s, 1H, ArH), 6.73
(s, 1H, ArH), 3.82 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 2.17 (s, 3H, CH3).
Scheme 5. Attempted oxidative demethylation of less electron-rich carbazoles. Con-
ditions: (a) PIFA (4 equiv) in 3% MeOH/H2O v/v %. (b) HNO3 acidified MnO2 (12 equiv)
in DCM. (c) 2-(4-Iodophenoxy)acetic acid (5 mol %), oxone (4 equiv) in 30% CF3CH2OH/
H2O v/v %.
3.2.3. 1,4-Dimethoxy-2,3-dimethylbenzene. To potassium hydroxide
(16.2 g, 288 mmol) in DMSO (75 ml) was added 2,3-
dimethylhydroquinone (5.00 g, 36.1 mmol) and iodomethane
(9.0 ml, 74.4 mmol). The reaction mixture was stirred for 1 h at
room temperature and then quenched with water. The product was
then extracted into CH2Cl2 (3ꢂ30 ml) and dried over magnesium
sulfate. The product was then filtered and dried under reduced
pressure. This gave the product as a pink/brown solid: 5.54 g (93%);
Rf 0.28 (hexane/Et2O: 95/5); mp 70e72 ꢀC; 1H NMR (300 MHz,
In summary we have demonstrated a simple two step meth-
odology for the synthesis of murrayaquinone A and related carba-
zole 1,4-quinones from 2-chloroanilines and 2,5-dimethoxy aryl
bromides. This entails a tandem BuchwaldeHartwig amination/
CeH activation annulation followed by oxidative demethylation
with BBr3 under air. Attempts to oxidize analogues that lack methyl
groups on the dimethoxybenzene ring proved unsuccessful.
CDCl3)
d
2.08 (s, 6H, CH3), 3.69 (s, 6H, OCH3), 6.57 (s, 2H, ArH); 13
12.1, 56.1, 107.9, 126.7, 152.0.
C
NMR (75 MHz, CDCl3)
d
3.2.4. 1-Bromo-2,5-dimethoxy-3,4-dimethylbenzene, 4b. To a solu-
tion of 1,4-dimethoxy-2,3-dimethylbenzene (5 g, 30 mmol) in
acetic acid (350 ml) was added bromine (1.54 ml, 30 mmol). After
stirring for 10 min the mixture was quenched with aqueous
bisulphate and extracted into ether (3ꢂ50 ml). The organic layer
was dried with magnesium sulfate and then the solvent removed
under reduced pressure.
3. Experimental
3.1. General experimental conditions
All reactions and preparations were carried out under a dry
nitrogen atmosphere, either in a glove box or using standard
Schlenk techniques with anhydrous solvents unless otherwise de-
scribed. Microwave reactions were performed using a Biotage AB
Initiator (300 W; software version 1.1) with autochanger (8 posi-
tions) using Biotage 5 ml sealed vials.
The product was purified by silica column chromatography.
Gave product as a colourless oil Rf 0.31 (hexane/Et2O: 98/2); 1H
NMR (300 MHz, CDCl3)
d 2.10 (s, 3H, CH3), 2.25 (s, 3H, CH3), 3.75
(s, 3H, OCH3), 3.77 (s, 3H, OCH3), 6.88 (s, 1H, ArH).
3.2. Preparation of aryl bromides
3.3. General method for the synthesis of carbazoles, 5
3.2.1. 4-Bromo-2,5-dimethoxybenzaldehyde. SnCl4 (11.5 g, 44 mmol)
was added to a solution of the 2,5-dimethoxybenzaldehyde (6.65 g,
40 mmol) in anhydrous CH2Cl2, followed by bromine (2.1 ml,
44 mmol) dropwise over 20 min. The reaction mixture was heated to
reflux for 2 h and then left stirring overnight at room temperature.
The orange black suspension was poured onto ice and the layers
separated. The organic layer was washed with a saturated sodium
hydrogen carbonate solution, then dried with sodium sulfate and the
solvent removed in vacuo to give a brown solid. The product was re-
precipitated from methanol/water to give a yellow/cream powder:
NaOt-Bu (0.240 g, 2.5 mmol), Pd(OAc)2 (0.006 g, 0.025 mmol)
and [HPt-Bu3][BF4] (0.010 g, 0.035 mmol) were suspended in
toluene (3 ml) in
a 5 ml microwave vial. The appropriate
2-chloroaniline (0.50 mmol) and aryl bromide (0.50 mmol) were
then added and the vial sealed. The reaction was then heated in the
microwave reactor at 160 ꢀC for 3 h, allowed to cool, and then
quenched by addition of aqueous HCl (2 M, 3 ml). The organic phase
was extracted with CH2Cl2 (2ꢂ20 ml), dried (MgSO4), then filtered
and the solvent removed under reduced pressure. The crude
product mixture was then subjected to column chromatography
(SiO2).
4.31 g (44% yield); mp 132e134 ꢀC; 1H NMR (400 MHz, CDCl3)
d ppm

R.B. Bedford et al. / Tetrahedron 69 (2013) 4389e4394
4393
3.3.1. 1,4-Dimethoxy-3-methyl-9H-carbazole, 5a. 2-Chloroaniline,
3a and 1-bromo-2,5-dimethoxy-4-methylbenzene, 4a gave the
product as a white crystalline solid: 0.083 g (69%); Rf 0.88 (CH2Cl2);
132.4, 138.6, 139.8, 149.7; HRMS (EI) calcd for C17H19NO2 [Mþ]
270.1494, found, 270.1488.
mp 98e100 ꢀC; 1H NMR (400 MHz, CDCl3)
d
2.53 (s, 3H, CH3), 3.99
3.3.8. 1-Fluoro-5,8-dimethoxy-6,7-dimethyl-9H-carbazole,
5h. 2-
(s, 3H, OCH3), 4.05 (s, 3H, OCH3), 6.75 (s, 1H, ArH), 7.31 (ddd, 1H,
J1þ2¼7.9, J3¼2.8 Hz, ArH), 7.45 (m, 2H, ArH), 8.33 (ddd, 1H, J¼8.6,
2.6, 1.0 Hz, ArH), 8.42 (br s, NH); 13C NMR (125 MHz, DMSO-d6)
Chloro-6-fluoroaniline, 3c and 1-bromo-2,5-dimethoxy-3,4-
dimethylbenzene, 4b (0.12 g, 0.5 mmol) gave the product as beige
crystals: 0.085 g (62%); Rf 0.80 (CH2Cl2); mp 156e158 ꢀC; 1H NMR
d
15.4, 55.8, 60.2, 108.8, 110.6, 117.3, 119.5, 120.2, 122.0, 122.6, 125.3,
(400 MHz, CDCl3) d 2.33 (s, 3H, CH3), 2.36 (s, 3H, CH3), 3.90 (s, 3H,
129.3, 139.0, 141.7, 147.1; HRMS (EI) calcd for C15H15NO2 [Mþ]
241.1103, found, 241.1100. Anal. Calcd for C15H15NO2: C, 74.67; H,
6.27; N, 5.80. Found: C, 74.69; H, 6.26; N, 5.85.
OCH3), 3.92 (s, 3H, OCH3), 7.12 (m, 2H, ArH), 7.94 (ddd, 1H, J¼7.9,
5.3, 1.2 Hz, ArH), 8.38 (br s, 1H, NH); 13C NMR (75 MHz, DMSO-d6)
d
12.1, 12.9, 60.4, 60.9, 110.4, 115.9, 118.1, 120.0 (d, J¼10.1 Hz, CH),
121.6, 126.0 (d, J¼7.5 Hz, C), 127.2 (d, J¼21.4 Hz, C), 128.5, 132.6,
139.9, 148.5 (d, J¼236.3 Hz, CF), 150.7; HRMS (EI) calcd for
C16H16FNO2 [Mþ] 274.1243, found, 274.1242.
3.3.2. 1,4-Dimethoxy-3,8-dimethyl-9H-carbazole, 5b. 2-Chloro-6-
methylaniline, 3b and 1-bromo-2,5-dimethoxy-4-methylbenzene,
4a, gave the product as a brown/yellow gum: 0.110 g (86%); Rf 0.86
(CH2Cl2); 1H NMR (400 MHz, CDCl3)
d
2.48 (s, 3H, CH3), 2.57 (s, 3H,
3.3.9. 2-Fluoro-5,8-dimethoxy-6,7-dimethyl-9H-carbazole,
5i. 2-
CH3), 3.98 (s, 3H, OCH3), 4.01 (s, 3H, OCH3), 6.71 (s, 1H, ArH), 7.23
Chloro-5-fluoroaniline, 3d and 1-bromo-2,5-dimethoxy-3,4-
dimethylbenzene 4b gave the product as red/brown crystals:
0.087 g (64%); Rf 0.69 (CH2Cl2); mp 139e141 ꢀC; 1H NMR (300 MHz,
(m, 2H, ArH), 8.11 (ddd, 1H, J1¼7.1, J2þ3¼0.9 Hz, ArH), 8.15 (br s, 1H,
NH); 13C NMR (125 MHz, DMSO-d6)
d 15.4, 16.9, 55.8, 60.2, 108.6,
117.8, 119.7, 119.8, 120.2, 121.3, 125.9, 129.2, 138.4, 141.7, 147.1; HRMS
CDCl3) d 2.34 (s, 3H, CH3), 2.36 (s, 3H, CH3), 3.90 (s, 3H, OCH3), 3.93
(EI) calcd for C16H17NO2 [Mþ] 255.1259, found, 255.1264.
(s, 3H, OCH3), 6.97 (ddd, J¼9.6, 8.6, 2.3 Hz, 1H, ArH), 7.07 (dd, J¼9.6,
2.3 Hz, 1H, ArH), 8.09 (dd, J¼8.6, 5.7 Hz, 1H, ArH), 8.28 (br s, 1H,
3.3.3. 1-Fluoro-5,8-dimethoxy-6-methyl-9H-carbazole, 5c. 2-Chloro-
6-fluoroaniline, 3c and 1-bromo-2,5-dimethoxy-4-methylbenzene,
4a gave the product as a brown/yellow gum: 0.060 g (46%); Rf 0.86
NH); 13C NMR (75 MHz, DMSO-d6)
d 12.1, 12.9, 60.3, 60.9, 97.4 (d,
J¼26.4 Hz, CH), 107.8 (d, J¼23.4 Hz, CH), 115.4, 119.0, 121.4, 123.2 (d,
J¼10.6 Hz, CH), 127.4, 132.8 (d, J¼2.3 Hz, C), 139.6 (d, J¼10.6 Hz, C),
139.9, 149.2 (d, J¼1.5 Hz, C), 161.6 (d, J¼241.1 Hz, CF); HRMS (EI)
calcd for C16H16FNO2 [Mþ] 274.1243, found, 274.1233.
(CH2Cl2); 1H NMR (400 MHz, CDCl3)
d 2.44 (s, 3H, CH3), 3.94 (s, 3H,
OCH3), 3.96 (s, 3H, OCH3), 6.71 (s, 1H, ArH), 7.12 (ddd, 1H, J¼6.4, 3.0,
1.1 Hz, ArH), 7.15 (dd, 1H, J¼6.3, 3.1 Hz, ArH), 7.97 (ddd, 1H, J¼6.3, 3.0,
1.1 Hz, ArH).
3.3.10. 3-Fluoro-5,8-dimethoxy-6,7-dimethyl-9H-carbazole,
5j. 2-Chloro-4-fluoroaniline, 3e and 1-bromo-2,5-dimethoxy-3,4-
dim-ethylbenzene, 4b, gave the product as white crystals: 0.081 g
(59%); Rf 0.73 (CH2Cl2); mp 124e126 ꢀC; 1H NMR (300 MHz, CDCl3)
3.3.4. 2-Fluoro-5,8-dimethoxy-6-methyl-9H-carbazole, 5d. 2-Chloro-
5-fluoroaniline, 3d and 1-bromo-2,5-dimethoxy-4-methylbenzene,
4a gave the product as a grey solid: 0.060 g (46%); Rf 0.83 (CH2Cl2);
d
2.33 (s, 3H, CH3), 2.36 (s, 3H, CH3), 3.90 (s, 3H, OCH3), 3.93 (s, 3H,
mp 124e126 ꢀC; 1H NMR (400 MHz, CDCl3)
d
2.45 (s, 3H, CH3), 3.94
OCH3), 7.12 (ddd, J¼9.0, 2.6 Hz, 1H, ArH), 7.31 (dd, J¼8.8, 4.2 Hz, 1H,
(s, 3H, OCH3), 3.96 (s, 3H, OCH3), 6.67 (s, 1H, ArH), 6.97 (ddd, 1H,
J¼9.5, 8.6, 2.3 Hz, ArH), 7.08 (dd, 1H, J¼9.6, 2.3 Hz, ArH), 8.13 (dd, 1H,
J¼8.7, 5.6 Hz, ArH), 8.24 (br s, 1H, NH); MS (EI) 259.3 [Mþ]; Anal.
Calcd for C15H14FNO2: C, 69.49; H, 5.44; N, 5.40. Found: C, 68.98; H,
5.06; N, 5.59.
ArH), 7.85 (dd, J¼9.4, 2.6 Hz, 1H, ArH), 8.19 (br s, 1H, NH); 13C NMR
(75 MHz, DMSO-d6)
d
12.0, 12.9, 60.5, 60.8, 108.0 (d, J¼24.9 Hz, CH),
110.9 (d, J¼9.8 Hz, CH), 112.9 (d, J¼25.7 Hz, CH), 115.7, 120.9, 123.0 (d,
J¼9.8 Hz, C), 128.3, 133.5,135.5,139.7, 149.5,157.6 (d, J¼234.3 Hz, CF).
3.3.11. 1,4-Dimethoxy-8-methyl-9H-carbazole, 5k. 2-Chloro-6-me-
thylaniline, 3b and 1-bromo-2,5-dimethoxybenzene, 4c, gave the
product as a green/grey powder: 0.050 mg (41%); mp 130e132 ꢀC; 1H
3.3.5. 3-Fluoro-5,8-dimethoxy-6-methyl-9H-carbazole, 5e. 2-Chloro-
4-fluoroaniline, 3e and 1-bromo-2,5-dimethoxy-4-methylbenzene,
4a gave the product as a brown oil: 0.070 g (54%); Rf 0.86 (CH2Cl2);
NMR (300 MHz, CDCl3) d 2.61 (s, 3H, CH3), 4.03 (s, 3H, OCH3), 4.07 (s,
1H NMR (400 MHz, CDCl3)
d
2.44 (s, 3H, CH3), 3.94 (s, 3H, OCH3), 3.96
3H, OCH3), 6.59 (d, J¼7.6 Hz,1H, ArH), 8.82 (d, J¼7.6 Hz, 1H, ArH), 7.24
(m, 2H, ArH), 8.23 (d, J¼6.49 Hz, 1H, ArH), 8.25 (br s,1H, NH); MS (EI)
241.2 [Mþ].
(s, 3H, OCH3), 6.69 (s, 1H, ArH), 7.14 (ddd, 1H, J1þ2¼9.0, J3¼2.6, ArH),
7.33 (ddd, 1H, J¼9.0, 2.6, 1.0 Hz, ArH), 7.87 (dd, 1H, J1¼9.4, 2.6 Hz,
ArH), 8.18 (br s, 1H, NH); MS (EI) 259.3 [Mþ].
3.3.12. 3-Fluoro-5,8-dimethoxy-9H-carbazole, 5l. 2-Chloro-4-flu-
oroaniline, 3e and 1-bromo-2,5-dimethoxybenzene, 4c, gave the
product as a brown/green oil: 0.040 g (33%); 1H NMR (300 MHz,
3.3.6. 1,4-Dimethoxy-2,3-dimethyl-9H-carbazole, 5f. 2-Chloroaniline,
3a and 1-bromo-2,5-dimethoxy-3,4-dimethylbenzene, 4b gave the
product as a brown crystalline solid: 0.042 g (33%); Rf 0.76 (CH2Cl2);
CDCl3)
d
3.96 (s, 3H, OCH3), 4.02 (s, 3H, OCH3), 6.51 (d, J¼8.4 Hz, 1H,
mp 96e98 ꢀC; 1H NMR (300 MHz, CDCl3)
d
2.37 (s, 3H, CH3), 2.40 (s,
ArH), 6.79 (d, J¼8.4 Hz, 1H, ArH), 7.12 (ddd, J1þ2¼9.2 Hz, J3¼2.6 Hz,
1H, ArH), 7.32 (dd, J¼8.7, 4.3 Hz,1H, ArH), 7.97 (dd, J¼9.4, 2.6 Hz,1H,
ArH), 8.24 (br s, 1H, ArH); MS (EI) 245.2 Mþ.
3H, CH3), 3.92(s, 3H, OCH3),3.98(s,3H, OCH3),7.26(ddd,J¼8.0,2.2Hz,
1H, ArH), 7.37e7.46 (m, 2H, ArH), 8.23 (dd, J¼8.0,0.6 Hz,1H, ArH), 8.29
(br s, 1H, NH); 13C NMR (75 MHz, DMSO-d6)
d 12.0, 12.9, 60.4, 60.8,
110.5, 115.8, 119.7, 120.9, 122.5, 125.2, 127.6, 132.4, 139.2, 139.6, 149.6;
3.4. General method oxidative demethylation to carbazole
1,4-quinones, 1
HRMS (EI) calcd for C16H17NO2 [Mþ] 256.1338, found, 256.1343.
3.3.7. 1,4-Dimethoxy-2,3,8-trimethyl-9H-carbazole, 5g. 2-Chloro-6-
methylaniline, 3b and 1-bromo-2,5-dimethoxy-3,4-dimethylben-
zene, 4b gave the product as peach coloured crystals: 0.091 g
(67%); Rf 0.82 (CH2Cl2); mp 159e160 ꢀC; 1H NMR (400 MHz, CDCl3)
To the appropriate carbazole (0.2 mmol) in CH2Cl2 (1 ml) cooled
to ꢁ78 ꢀC, was added boron tribromide in CH2Cl2 (1 M; 0.46 ml,
0.46 mmol) and the mixture was stirred for 18 h at room temper-
ature under air. The reaction mixture was then poured in to ice
water (2 ml) and the product extracted into ether (3ꢂ3 ml). The
organic phase was dried with MgSO4, filtered and the solvent re-
moved under reduced pressure. The crude product mixture was
then subjected to column chromatography (SiO2).
d
2.41 (s, 3H, CH3), 2.44 (s, 3H, CH3), 2.62 (s, 3H, CH3), 3.99 (s, 3H,
OCH3), 4.01 (s, 3H, O CH3), 7.24 (m, 2H, ArH), 8.12 (dd, J¼7.3, 1.7 Hz,
1H, ArH), 8.26 (br s, 1H, NH); 13C NMR (75 MHz, DMSO-d6)
12.1,
13.0,17.1, 60.4, 61.0,116.3,119.8,120.0,120.2,121.0,122.0,125.9,127.4,
d

4394
R.B. Bedford et al. / Tetrahedron 69 (2013) 4389e4394
3.4.1. Murrayaquinone A (3-methyl-1H-carbazole-1,4 (9H)-dione),
1a. 1,4-Dimethoxy-3-methyl-9H-carbazole, 5a, gave the product as
a red/orange gum: 0.040 g (95%); Rf 0.33 (CH2Cl2); 1H NMR
ArH), 12.64 (br s, 1H, NH); 13C NMR (125 MHz, DMSO-d6)
d 12.2,
12.6, 17.4, 115.9, 116.7, 119.5, 121.4, 124.1, 126.9, 129.1, 136.0, 139.0,
142.2, 180.2, 182.2; HRMS (EI) calcd for C15H13NO2 [Mþ] 240.1024,
(400 MHz, acetone-d6)
d
2.12 (d, J¼1.7 Hz, 3H, CH3), 6.57 (d,
found, 240.1026; IR, neat (n
cmꢁ1): 1544.3 (m), 1609.2 (m), 1638.0
J¼1.7 Hz, 1H, ArH), 7.30e7.45 (m, 2H, ArH), 7.64 (dd, J¼8.3, 0.9 Hz,
1H, ArH), 8.16 (dd, J¼7.9, 0.9, 1H, ArH), 11.73 (br s, 1H, NH); HRMS
(EI) calcd for C13H9NO2 [Mþ] 212.0712, found 212.0719. Anal. Calcd
for C13H9NO2: C, 73.9; H, 4.3; N, 6.6. Found: C, 74.2; H, 4.4; N, 6.4.
(s), 2921.7 (w), 3288.0 (m); Anal. Calcd for C15H13NO2.H2O: C, 65.4;
H, 6.2; N, 5.1. Found C, 64.4; H, 6.8; N, 4.7.
3.4.8. 1-Fluoro-6,7-dimethyl-9H-carbazole-5,8-dione, 1h. 1-Fluoro-
5,8-dimethoxy-6,7-dimethyl-9H-carbazole, 5h, gave the product as
a red/orange gum: 0.032 g (82%); Rf 0.54 (CH2Cl2); 1H NMR
3.4.2. 3,8-Dimethyl-9H-carbazole-1,4-dione,
3,8-dimethyl-9H-carbazole, 5b, gave product as a red/orange gum:
0.041 g (91%); Rf 0.60 (CH2Cl2); 1H NMR (400 MHz, CDCl3)
2.20 (d,
1b. 1,4-Dimethoxy-
(400 MHz, CDCl3)
1H, ArH), 7.24 (ddd, J¼8.0, 4.8 Hz, 1H, ArH), 7.95 (dd, J¼8.1, 0.9 Hz,
1H, ArH), 9.48 (br s, 1H, NH); 13C NMR (125 MHz, DMSO-d6)
12.2,
d
1.54 (s, 6H, CH3), 7.11 (ddd, J¼11.0, 7.9, 0.9 Hz,
d
J¼1.7 Hz, 3H, CH3), 2.57 (s, 3H, CH3), 6.53 (d, J¼1.7 Hz, ArH),
7.19e7.35 (m, 2H, ArH), 8.10 (dd, J¼8.1, 0.5 Hz, 1H, ArH), 9.20 (br s,
1H, NH); HRMS (EI) calcd for C14H11NO2 [Mþ] 226.0868, found
d
12.6, 111.1 (d, J¼16 Hz, CH), 116.0, 118.2 (d, J¼3.7 Hz, CH), 124.6 (d,
J¼6 Hz, C), 126.3 (d, J¼13 Hz, C), 127.3 (d, J¼5.7 Hz, CH), 136.9, 139.3,
142.3, 150.3 (d, J¼248.9 Hz, CF), 180.1, 183.1; HRMS (EI) calcd for
226.0862; IR, neat (n
cmꢁ1): 1642.3 (m), 2936.0 (w), 3279.5 (s).
C14H10FNO2 [Mþ] 244.0774, found, 244.0772. IR, neat ( cmꢁ1):
n
3.4.3. 1-Fluoro-6-methyl-9H-carbazole-5,8-dione, 1c. 1-Fluoro-5,8-
dimethoxy-6-methyl-9H-carbazole, 5c, gave the product as a red/
orange gum: 41 mg (90%); Rf 0.44 (CH2Cl2); 1H NMR (400 MHz,
1504.1 (m), 1547.9 (m), 1637.0 (s), 2920.3 (w), 3251.8 (s); Anal. Calcd
for C14H10N02: C, 69.1; H, 4.1; N, 5.8. Found: C, 68.9; H, 3.8; N, 5.45.
CDCl3)
d
2.22 (d, J¼1.7 Hz, 3H, CH3), 6.58 (d, J¼1.7 Hz, ArH), 7.15
3.4.9. 2-Fluoro-6,7-dimethyl-9H-carbazole-5,8-dione, 1i. 2-Fluoro-
5,8-dimethoxy-6,7-dimethyl-9H-carbazole, 5i, gave the product as
a red/orange gum: 0.031 g (85%); Rf 0.48 (CH2Cl2); 1H NMR
(ddd, J¼10.7, 7.8, 0.7 Hz, 1H, ArH), 7.30 (ddd, J¼8.0, 4.6 Hz, 1H, ArH),
8.04 (dd, J¼8.0, 0.7 Hz,1H, ArH), 9.37 (br s,1H, NH); HRMS (EI) calcd
for C13H8FNO2 [Mþ] 230.0617, found 230.0619; IR, neat (
n
cmꢁ1):
(300 MHz, DMSO-d6) d 2.00 (s, 3H, CH3), 2.02 (s, 3H, CH3), 7.18 (ddd,
1508.1 (w), 1541.0 (m), 1608.0 (s), 1635.9 (s), 1664.4 (w), 2962.1 (w),
3238.2 (m); Anal. Calcd for C13H8FNO2: C, 68.1; H, 3.5; N, 6.1. Found:
C, 68.4; H, 3.8; N, 5.8.
J¼11.2, 9.0, 2.4 Hz, 1H, ArH), 7.24 (dd, J¼9.5, 2.3 Hz, 1H, ArH), 8.01
(dd, J¼8.8, 5.5 Hz, 1H, ArH), 12.86 (br s, 1H, NH); 13C NMR (125 MHz,
DMSO-d6)
d
12.2, 12.6, 99.9 (d, J¼25.0 Hz, CH), 113.1 (d, J¼25.0 Hz,
CH), 115.6, 120.7, 123.8 (d, J¼11.0 Hz, CH), 136.8 (d, J¼3.7 Hz, C),
138.3, 139.0, 142.1, 161.4 (d, J¼242.1 Hz, CF), 179.9, 183.2; HRMS (EI)
3.4.4. 2-Fluoro-6-methyl-9H-carbazole-5,8-dione, 1d. 2-Fluoro-5,8-
dimethoxy-6-methyl-9H-carbazole, 5d, gave the product as a red/
orange gum: 0.085 g (48%); Rf 0.36 (CH2Cl2); 1H NMR (300 MHz,
calcd for C14H10FNO2 [Mþ] 244.0774, found, 244.0773; IR, neat (
n
cmꢁ1): 1512.5 (m), 1603.1 (m), 1625.7 (s), 1654.6 (m), 2924.8 (w),
3192.7 (m); Anal. Calcd for C14H10N02: C, 69.1; H, 4.1; N, 5.8. Found:
C, 68.6; H, 4.2; N, 4.9.
DMSO-d6)
d
2.01 (d, J¼4.0 Hz, 6H, CH3), 7.18 (ddd, J¼11.2, 9.0, 2.4 Hz,
1H, ArH), 7.24 (dd, J¼9.5, 2.3 Hz, 1H, ArH), 8.01 (dd, J¼8.8, 5.5 Hz, 1H,
ArH), 12.86 (br s, 1H, NH); HRMS (EI) calcd for C13H8NO2 [Mþ]
230.0617, found 230.0614; IR, neat (
n
cmꢁ1): 1510.3 (s), 1529.4 (s),
3.4.10. 3-Fluoro-6,7-dimethyl-9H-carbazole-5,8-dione, 1j. 3- Flu-
oro-5,8-dimethoxy-6,7-dimethyl-9H-carbazole, 5j, gave the prod-
uct as a red/orange gum: 0.007 g (19%); Rf 0.57 (CH2Cl2); 1H NMR
1582.1 (m), 1607.5 (s), 1624.6 (s), 2924.7 (w), 3242.3 (m); Anal. Calcd
for C13H8FNO2: C, 68.1; H, 3.5; N, 6.1. Found: C, 67.05; H, 3.7; N, 6.25.
(300 MHz, DMSO-d6)
d
2.09 (s, 6H, CH3), 7.25 (ddd, J¼9.3, 9.0,
3.4.5. 3-Fluoro-6-methyl-9H-carbazole-5,8-dione,
1e. 3-Fluoro-
2.6 Hz, 1H, ArH), 7.55 (ddd, J¼9.0, 4.6, 0.6 Hz, 1H, ArH), 7.68 (ddd,
J¼9.2, 2.6, 0.6 Hz, 1H, ArH); MS 244.1 [Mþ]. Anal. Calcd for
C14H10N02: C, 69.1; H, 4.7; N, 5.8. Found: C, 68.6; H, 5.2; N, 5.8.
5,8,dimethoxy-6-methyl-9H-carbazole, 5e, gave the product as
a red/orange gum: 0.041 g (90%); Rf 0.33 (CH2Cl2); 1H NMR
(400 MHz, acetone-d6)
d
2.12 (d, J¼1.7 Hz, 3H, CH3), 6.59 (d,
J¼1.7 Hz, 1H, ArH), 7.24 (ddd, J¼9.4, 2.6 Hz, 1H, ArH), 7.67 (ddd,
References and notes
J¼9.0, 4.4, 0.6 Hz, 1H, ArH), 7.78 (ddd, J¼9.1, 2.8, 0.5 Hz, 1H, ArH),
11.73 (br s, 1H, NH); 13C NMR (125 MHz, DMSO-d6)
d 16.0, 99.9,
1. Furukawa, H.; Wu, T.-S.; Ohita, T.; Kuoh, C.-S. Chem. Pharm. Bull. 1985, 33, 4132.
2. Takeya, K.; Itoigawa, M.; Furukawa, H. Eur. J. Pharmacol. 1989, 169, 137.
3. Itoigawa, M.; Kashiwada, Y.; Ito, C.; Furukawa, H.; Tachibana, Y.; Bastow, K.; Lee,
K.-H. J. Nat. Prod. 2000, 63, 893.
106.4 (d, J¼23.9 Hz, CH), 115.5 (d, J¼26.3 Hz, CH), 115.9 (s, C), 116.0
(d, J¼10.1 Hz, CH), 124.3 (d, J¼10.1 Hz, C), 132.2, 134.6, 148.5, 159.9
(d, J¼238.3 Hz, CF), 180.3, 183.2; MS (EI) 229.4 [Mþ]; Anal. Calcd for
C13H8FNO2: C, 68.1; H, 3.5; N, 6.1. Found: C, 67.7; H, 3.9; N, 6.1.
4. (a) Martin, T.; Moody, C. J. Chem. Soc., Perkin Trans. 1 1988, 235; (b) Ito, M.;
Furukawa, H. Chem. Pharm. Bull. 1991, 39, 328; (c) Miki, Y.; Hachiken, H. Synlett
€
1993, 333; (d) Knolker, H.-J.; Bauermeister, M. Tetrahedron 1993, 49, 11221; (e)
Wada, A.; Hirai, S.; Hanaoka, M. Chem. Pharm. Bull. 1994, 42, 416; (f) Matsuo, K.;
Ishida, S. Chem. Pharm. Bull. 1994, 42, 1325; (g) Akermark, B.; Oslob, J.; Heuschert,
3.4.6. 2,3-Dimethyl-9H-carbazole-1,4-dione, 1f. 1,4-Dimethoxy-2,3-
dimethyl-9H-carbazole, 5f, gave the product as a red/orange gum:
ꢀ
U. Tetrahedron Lett. 1995, 36, 1325; (h) Bringmann, G.; Ledermann, A.; Stahl, M.;
Gulden, K.-P. Tetrahedron 1995, 51, 9353; (i) Murphy, W.; Bertrand, M. J. Chem.
Soc., Perkin Trans. 1 1998, 4115; (j) Hagiwara, H.; Choshi, T.; Fujimoto, H.; Sugino,
E.; Hibino, S. Chem. Pharm. Bull. 1998, 46, 1948; (k) Murakami, Y.; Yokoo, H.;
0.021 g (86%); Rf 0.52 (CH2Cl2); 1H NMR (300 MHz, DMSO-d6)
d 2.02
(s, 6H, CH3), 7.29 (ddd, J¼7.9 0.7 Hz, 1H, ArH), 7.37 (ddd, J¼7.6,
1.0 Hz, 1H, ArH), 7.53 (d, J¼8.1 Hz, 1H, ArH), 8.03 (dd, J¼7.9, 0.6 Hz,
ꢀ
Watanabe, T. Heterocycles 1998, 49, 127; (l) Hagelin, H.; Oslob, J.; Akermark, B.
1H, ArH), 12.78 (br s, 1H, NH); 13C NMR (125 MHz, DMSO-d6)
d 12.2,
Chem.dEur. J. 1999, 5, 2413; (m) Chowdhury, B. K.; Shailendra, J.; Bibek, K.;
€
Ranjan; Saha, C. Indian J. Chem. 1999, 38B, 1106; (n) Knolker, H.-J.; Reddy, K.
12.7, 114.1, 115.5, 122.1, 124.0, 124.0, 126.5, 136.0, 138.0, 139.0, 142.4,
€
Heterocycles 2003, 60, 1049; (o) Scott, T.; Soderberg, B. Tetrahedron 2003, 59,
180.3, 183.2; IR, neat (n
cmꢁ1): 1543.7 (m), 1637.2 (s), 2921.8 (w),
6323; (p) Bernardo, P.; Chai, C.; Guen, M.; Smith, G.; Waring, P. Bioorg. Med.
Chem. Lett. 2007, 17, 82; (q) Mal, D.; Senapati, B. ,; Pahari, P. Tetrahedron 2007, 63,
3768; (r) Chakraborty, S.; Chattopadhyay, G.; Sahaa, C. J. Heterocyclic Chem. 2011,
48, 331; (s) Nishiyama, T.; Choshi, T.; Kitano, K.; Hibino, S. Tetrahedron Lett. 2011,
52, 3876; (t) Norcott, T.; Spielman, C.; McErlean, C. Green Chem. 2012, 14, 605.
3286.9 (m); MS (EI) 225.3 [Mþ]; Anal. Calcd for C14H11NO2: C, 74.65;
H, 4.9; N, 6.2. Found: C, 70.1; H, 4.8; N, 6.3.
3.4.7. 2,3,8-Trimethyl-1H-carbazole-1,4
(9H)-dione,
1g. 1,4-
€
5. For an overview see: Schmidt, A.; Reddy, K.; Knolker, H.-J. Chem. Rev. 2012, 112,
3193.
Dimethoxy-2,3,8-trimethyl-9H-carbazole, 5g, gave the product as
a red/orange gum: 0.044 g (93%); Rf 0.57 (CH2Cl2); 1H NMR
6. Bedford, R.; Betham, M. J. Org. Chem. 2006, 25, 9403.
7. Bedford, R.; Betham, M.; Charmant, J.; Weeks, A. Tetrahedron 2008, 64, 6038.
8. Wan, J.; Feng, J.; Wen, G.; Wang, H.; Fan, Q.; Wei, W.; Huang, C.; Huang, W.
Tetrahedron Lett. 2006, 47, 2829.
(300 MHz, DMSO-d6)
J¼6.4 Hz, 1H, ArH), 7.16 (dd, J¼7.3 Hz, 1H, ArH), 7.84 (d, J¼7.3 Hz, 1H,
d 1.98 (s, 3H, CH3), 2.00 (s, 6H, CH3), 7.13 (d,