Carbazomycin G: Method Development and Total Synthesis

Article abstract of DOI:10.1002/ejoc.201800359

A novel total synthesis leading to the carbazole alkaloid carbazomycin G was designed and developed. The outlined synthetic route is composed of twelve synthetic steps including the transformations of the initial simple substrate and intermediates. To rea

Full text of DOI:10.1002/ejoc.201800359

A Journal of
Accepted Article
Title: Carbazomycin G: Method development and total synthesis
Authors: Vijayaragavan Elumalai, Cristian Gambarotti, and Hans-René
Bjørsvik
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10.1002/ejoc.201800359
European Journal of Organic Chemistry
Accepted Article
European Journal of Organic Chemistry - ejoc.201800359
1
Carbazomycin G: Method Development and Total Synthesis
Vijayaragavan Elumalai,a Cristian Gambarotti,b and Hans-René Bjørsvika,*
aDepartment of Chemistry, University of Bergen, Allégaten 41, N-5007 Bergen, Norway
bDepartment of Chemistry, Materials, and Chemical Engineering, Politecnico di Milano, Piazza Leonardo da Vinci 32,
I-20133 Milan, Italy
eMail: hans.bjorsvik@kj.uib.no, telephone: +47 55 58 34 52, web: http://folk.uib.no/nkjhn/
Graphical abstract
O
OCH3
Carbazomycin G
12 steps whereof six involves new methods
mean step yield of 83.4%
overall yield 8.3%
CH3
N
H
CH3
HO
Text for the table of content
The carbazole alkaloid carbazomycin G was synthesised via a novel synthetic route composed of twelve synthetic steps
whereof six new synthetic methods that including two various oxidation methods, a reduction method, Suzuki cross-
coupling, and a Pd catalysed tandem C–H activation and C–N bond formation for making the carbazole scaffold.
Key Topic
Total synthesis
Abstract
A novel total synthesis leading to the carbazole alkaloid carbazomycin G was designed and developed. The outlined
synthetic route is composed of twelve synthetic steps including the transformations of the very first simple substrate and
intermediates. In order to realize the designed synthesis, in total six new synthetic methods were developed and
implemented in the new total synthesis, which afforded target molecule in an overall yield of 8.3%.
Introduction
For almost four decades ago, a distinct class of carbazole alkaloids named carbazomycin A–H were
discovered, isolated, and structure elucidated,[1] Scheme 1. These carbazole alkaloids are
characterized by an unusual unsymmetrical substitution pattern, which consists in the fact that one of
the two carbocycles moieties that make up integral parts of the carbazole scaffold is completely naked
and the other one is highly crowded as it carries substituents in all the positions that are not occupied
by the bonds that make up the carbazole framework.
Investigations of the biological activity of the carbazomycins A-H, revealed anticancer,[2]
antibacterial,[3] and antifungal[4] activities. Their biological activities and challenging molecular
structure made the carbazomycins to be an interesting target scaffold for the synthetic organic
chemist, which has resulted in a series of distinct synthetic routes.[5]
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Scheme 1. Structure of the carbazomycins A-H
RO
RO
OCH3
OCH3
H3CO
CH3
CH3
N
N
CH3
CH3
H
H
Carbazomycin C (R=H)
Carbazomycin D (R=CH3)
Carbazomycin A (R=CH3)
Carbazomycin B (R=H)
O
HO
OCH3
CH3
R
OCH3
CH3
R
N
N
CH3
CHO
Carbazomycin E (R=H)
H
Carbazomycin G (R=H)
H
HO
Carbazomycin F (R=OCH3)
Carbazomycin H (R=OCH3)
The carbazomycins as synthetic targets attracted us as we recognized several synthetic challenges,
especially for the synthesis of the carbazomycin G and H. Synthetic routes leading to carbazomycin G
have previously been reported.[5] In particular, approaches involving consecutive transition metal-
mediated C–C bond and C–N bond formations are crucial in the total syntheses of the carbazomycins
A,[6] B,[6] C,[7] D,[7] and E,[8] but also for a few other important carbazole alkaloids.[9] Knölker and
collaborators[10] developed initially an iron-mediated total synthesis of carbazomycin G and H
(pathway a of Scheme 2), but in addition a pathway (b) involving Pd-catalyzed oxidative cyclization
of arylamino-1,4-benzoquinone for the synthesis of both of the carbazomycin G and H scaffolds. [11]
Hibino and collaborators[12] disclosed a carbazomycin G synthesis that involved an allene mediated
electrocyclic reaction (pathway (c) of Scheme 2). Recently, Hu and collaborators[13] disclosed a
carbazomycin G synthesis that involved a method comprising a thermal ring expansion and self-redox
cascade reaction, see pathway (d) of Scheme 2. Chakraborty and Saha[14] disclosed a carbazomycin
G total synthesis based on a method utilizing the Fischer indole cyclization, outlined in pathway (e)
of Scheme 2.
Our approach disclosed herein, pathway (f) Scheme 2, is based on two distinct Pd-catalysed reactions,
first a Suzuki cross-coupling to obtain a 2-nitro-1,1’-biphenyl intermediate that is reduced and
protected and then submitted for a concomitant intramolecular C–H activation that is followed by a
C–N bond formation to obtain the congested carbazole intermediate.[15]
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Scheme 2. Previously described synthetic methods leading to carbazomycin G
Previous work
OCH3
AcO
R
AcO
H2N
OCH3
CH3
OCH3
(a)
R
OCH3
CH3
2 steps
7 steps
CH3
v. a. MnO2
CH2Cl2, 25oC, 2 h
oy =7%
N
H
OCH3
R= H (72%)
R= OMe (34%)
(OC)3Fe
OCH3
O
(b)
O
OCH3
R
OCH3
CH3
0.1 eq Pd(OAc)2
2.5 eq Cu(OAc)2
R
OCH3
CH3
5 steps
CH3
1 step
CH3COOH,
117oC, 19 h
R= H (71%)
R= OMe (73%)
N
H
oy =28%
N
H
OCH3
O
O
OCH3
OCH3
CH3
(c)
3 steps
5 steps
O
tBuOK,tBuOH, THF
90oC, 12 h
(85%)
O
R
OCH3
oy =17%
N
H
N
N
H
OMOM
OMOM
CH3
CH3
SO2Ph
N
CH3
O
H
OH
O
OCH3
R=H:
Carbazomycin G
R=OMe: Carbazomycin H
(d)
1 step
4 steps
2 steps
DMF, reflux, 2 h
OCH3
OH
CH3
O
(66%)
oy =26%
N
H
N
N
H
Ts
(e)
H3C
O
5 steps
H3C
O
CH3COOH, Conc.HCl
HN
N
H3C
oy =7%
(84%)
N
H
O
This work
(f)
R
AcO
OCH3
OCH3
CH3
AcO
Pd(OAc)2 (5 mol%)
IMes.HCl (5 mol%)
R
OCH3
8 steps
3 steps
CH3
OCH3
H2O2, AcOH
CH3
oy >8%
µW, 120oC, 5 h
N
HN
OCH3
OCH3
R= H (70%)
R= OCH3 (30%, mix.)
Ac
Ac
Methods and results
Retrosynthetic analysis. Our retrosynthetic analysis of carbazomycin G is shown in Scheme 3. We
envisioned two Pd-catalysed key steps that together might provide the carbazole framework; (1) a
Suzuki cross-coupling that produce the 2-N-substituted-1,1’-biphenylic moiety, and (2) a
simultaneous C–H activation and C–N formation that ultimately afford the carbazole scaffold
embedded with requested functionality.
The outlined retrosynthetic analysis looked alluring to us, but after we had started to implement our
synthetic plan, twelve steps in total, it turned out to be requirement for several new synthetic methods
that we developed during the course of the elaboration of the total synthesis presented herein.
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Scheme 3. Retrosynthetic analysis of carbazomycin G. The natural product TM was envisioned to arise through two key
disconnections that would enable the generation of the most of the molecular complexity. Two key steps: a Suzuki cross-
coupling that afford a biphenyl core moiety and a concomitant C–H activation and C–N bond formation, which
ultimately afford the carbazole framework that subsequently, by means of a handful of transformations, afford the
natural product carbazomycin G TM.
(1) C-C: Suzuki cross-coupling
O
OH
O
H3CO
H3C
H3CO
H3C
H3CO
H3CO
H3C
OH
C-C
FGI
C-N
H3C
H3C
Oxidation
Methylation
Tandem C-H
activation and
C-N bond
N
H
N
N
H
O
(2) C-N: C-H activation & C-N bond formation
H3CO
OH
H
H3CO
NH2
FGI
formation
TM
Carbazomycin G
H3CO
H3C
H3CO
Reduction
O
O
O
H3C
H3C
H3CO
H3CO
H3C
OH
H3CO
H3C
H3CO
O
H3CO
OH
H3CO
H3C
OH
FGI
C-O
C-N
C-C
H3C
H3C
H3CO
X
Halogen
-ation
NO2
Suzuki
cross-
coupling
Hydroxy-
lation
Nitration
H3CO
H3CO
NO2
H3CO
NO2
Realization of the total synthesis. With the basis in our retrosynthetic analysis, Scheme 3, we
commenced the design of a total synthesis (Scheme 4) using the commercially available 2,6-
dimethoxytoluene 1 as the very first starting material. Originally, we planned to utilize a three steps
sequence previously described by Knölker and collaborators [16] for the production of the phenol 2.
This pathway is composed by a Friedel-Crafts acylation, step (a’), that produce the acetophenone 1a.
In the following step (a’’), the compound 1a is submitted for a Baeyer-Villiger oxidation that gives
the phenyl acetate 3, which in the ultimate step (a’’’) is hydrolysed to obtain the anticipated phenol
2. For this sequence, we undertook a modification of the Baeyer-Villiger oxidation step (a’’) by
replacing meta-chloroperbenzoic acid (mCPBA) as the oxidation reagent with a more environmental
benign procedure composed of hydrogen peroxide in acetic acid with trifluoroacetic acid as reaction
medium. During this oxidation, a by-product 3b was formed in small quantities (≈7%) along with the
target oxidation product 5-hydroxy-2,4-dimethoxy-3-methylphenyl acetate 3. The by-product
hydroxyphenyl acetate 3b, materialized to be produced as a result of direct hydroxylation of the
aromatic kernel. This observation prompted us to undertake a thoroughly investigation of the by-
product formation,[17] from which a high yielding direct hydroxylation method for methyl and
methoxy substituted benzenes, step (a) Scheme 4, was established using H2O2 in acetic acid with the
presence of trifluoroacetic acid as oxidizing system. The organic peracid oxidation mechanisms that
clearly can follow either the Baeyer-Villiger oxidation mechanism or the direct aromatic ring
hydroxylation was later explored in-depth by means of multivariate modelling of designed multi-
response experiments.[18]
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In order to be able to perform nitration of the phenol 2, it was necessary to protect the free hydroxy
group. Treatment with acetyl chloride, step (b), afforded the O-acetyl intermediate 3, which allowed
nitration of the aromatic kernel using standard conditions using nitric acid (65%) in a mixture of
acetic acid and acetic anhydride.
Iodination of intermediate 4, step (e’) was initially performed according to a protocol using I2 in the
presence of n-butylamine,[19] a reaction that afforded target iodinated intermediate 6’, although in low
yield (32%) only. Along with the challenging iodination, we designed and developed a well operating
Suzuki cross-coupling reaction allowing producing 2-nitro-1,1’-biphenyl. This method as well with
our the congested iodoarene 6’ to produce 7.
Nevertheless, it turned out that the iodination step (e’) became impossible to reproduce. We believe
this relied on the inferior iodine quality we gradually needed to use (new supplies) compared to the
superior iodine quality we used at the outset when the method was developed.
Additional iodination trials were conducted by using the well-established ICl as iodination reagent,
step (e’’) of Scheme 4. Surprisingly, the chlorinated product 6 was produced in the place of the
expected iodinated product 6’, although in low yield only (35%). Unfortunately, we were not able to
acquire further supplies of the initial iodine quality, which forced us to abandon this methodology,
that is the iodination step (e’), which thus appeared to be a “dead-end” for our overall strategy.
In spite of this, the steps (a–d) were further developed to approach a telescoped synthesis, that is,
without purification of the intermediates to obtain the Criphol 5 in a good overall yield of »64%.
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Scheme 4. Synthesis of the key intermediates Criphol 5 and 2-nitro-1,1’-biphenyl 7 for the total synthesis of
Carbazomycin G.
CH3
CH3
CH3
OCH3
O
H3CO
OCH3
O
H3CO
H3CO
HO
OCH3
O
(a'')
+
Baeyer-Villiger
Oxidation
O
O
CH3
CH3
1a
3
3b
CH3
by-productª 7%
Friedel-Craft
Acylation
(a''')
Hydrolysis
(a')
CH3
CH3
CH3
CH3
(c)
(a)
H2O2 (35%)
TFA, 75 oC, 2 h
Direct ring
hydroxylation
(b)
H3CO
OCH3
H3CO
OCH3
OH
H3CO
OCH3
H3CO
O2N
OCH3
O
HNO3 (65%)
AcCl
CHCl3 (dry)
reflux, 2 h
AcOH/Ac2O
0-5 oC
O
1
2 (85%)
3 (94%)
O
4 (77%)
CH3
O
CH3
CH3
(d)
MeOH, conc. HCl
H3CO
O2N
OCH3
OH
Reflux, 1h
Telescoped steps: (a)-(d), overall yield 64%
5 Criphol (>99%)
CH3
(f ')
B(OH)2
(e')
O2N
OCH3
CH3
OCH3
H3CO
O2N
OCH3
OH
NaI / I2 , H2O
O
H3C
NH2
Pd(PPh3)4, MeOH, H2O
TBAB, K2CO3,100 o
C
HO
I
6' (32%)
H3C
N
CH3
H
7 (<30%)
CH3
(e'')
ICl
H3CO
O2N
OCH3
OH
6 (35%)
Cl
Long time after the effort developing the pathways outlined in Scheme 4, a new method for fast
halogenation of heterocycles using N,N′-dihalo-5,5-dimethylhydantoin was developed by our
group.[20] The excellent result we achieved with this method propelled us to attempt the method for
the purpose to iodinate the intermediates 4 and 5, trials that unfortunately failed. Subsequently, we
attempted to perform bromination of the Criphol 5 using N,N′-dibromo-5,5-dimethylhydantoin
(DBH) as brominating agent and N,N′-dichloro-5,5-dimethylhydantoin (DCH) as chlorination agent,
respectively. The bromination failed, but the chlorination was highly successfully resulting in a
quantitative yield of 6, Scheme 5.
With compound 6 in hand, we needed a new Suzuki cross-coupling protocol for coupling with
phenylboronic acid as the coupling partner. We set-out to utilize our previous disclosed Suzuki cross-
coupling method (involving iodoarene 6’),[21] but we achieved only low yield (29%) of the bi-phenyl
7, which called for a further development of the method. Thus, our previously disclosed method
(involving iodoarene) was tailored to operate with chloroarenes for the synthesis of our congested 2-
nitrobiphenyl 7,[22] to achieve a yield of 50%.
With access to the nitro-biphenyl 7, we could proceed further with our synthesis to Carbazomycin G.
For the next step (g), we needed access to a nitro-reduction method to obtain 2-amino-1,1’-biphenyl
8. For this purpose, we developed a new improved indium in ammonium chloride based reduction
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protocol [23] that furthermore showed up a high functional group tolerance and allowed for a very
simple work-up.
Scheme 5. Synthesis of the carbazole alkaloid Carbazomycin G
O
Cl
N
(e)
R R
H
OCH3
H3C
H3C
(f)
(g)
CH3
CH3
R
HO
OCH3
CH3
O
H3CO
N
In (3 equiv)
NH4Cl
B(OH)2
H3CO
O2N
OCH3
OH
OCH3
OH
(a)-(d)
Cl
Na2CO3, Pd(PPh3)4
TBAB, MeOH/H2O
120 oC, 30 min, µW
H2SO4, EtOH
rt,
EtOH, H2O
120 oC, 3 h
sealed tube
Overall yield
64%
O2N
O2N
OCH3
(50%)
7a R= OCH3 (50%)
5
Cl
6 (>99%)
7
R= H
(i)
AcO
R
AcO
OCH3
R
HO
OCH3
CH3
R1
OCH3
CH3
(h)
Ac2O (2.1 equiv)
Pd(OAc)2 (5 mol%)
IMes. HCl (5 mol%)
CH3
H2O2, AcOH
µW, 120 oC, 5 h
Et3N, CH2Cl2
rt, 1 h
N
R2
H N
OCH3
CH3
H2N
OCH3
R= H (96%)
8a R= OCH3 (98%)
OCH3
CH3
8
O
R1
H
OCH3
R2
O
R= H
9 (94%)
9a R= OCH3 (92%)
10
10a
H
94%, GC, 71% isol.
30% mix. isom.
H
OCH3
10b H
O
(k)
HNO3 (90%)
AcOH
0-20 oC
30 min.
(l)
CH3Li (1.6M)
THF
-78 oC, 30 min.
OCH3
CH3
O
HO
OCH3
(j)
MeOH
conc. HCl
Reflux, 1h
OCH3
CH3
CH3
N
H
OH
H3C
N
N
H
12 (83%)
O
H
11 (94%)
OCH3
13 (51%) Carbazomycin G
The 2-nitro-1,1’-biphenyl intermediate 7 and 7a (Scheme 5) was achieved in yields of 50% (R=H)
and 50% (R=OCH3). Reduction of nitro group yielded 8 and 8a. Several synthetic methods were
available for nitro group reduction. [24] However, we screened the reaction with various experimental
conditions using indium powder based on a method reported by Moody et al.[25] We initially tested
the method with two different indium powders (Purchased from Aldrich and Alfa Aesar). Both
methods afforded only 3% yield at 100 oC. An increased reaction time (3 h) and temperature (120 oC)
afforded a quantitative yield of target amine 8.
Both nitro compounds 7 and 7a were successfully converted into their corresponding amines using
indium mediated reduction method. Amine 8 underwent direct cyclization using our new method
involves intramolecular C-H activation and C-N bond formation.[15] However, this method was not
successful to compounds bearing oxidizible functional groups such as methoxy and hydroxyl groups.
The hydroxyl groups of compounds (8) was protected with tert-butyl dimethylsilylchloride (TBS-Cl)
operated well (98% yield), however, the subsequent ring closure failed resulting in only
decomposition of products.
Since the direct ring closing failed, we attempted to perform the ring closing step when the 2-amino
group was acetylated.[15] The acetylation procedure, step (h) was conducted by using acetic anhydride
that afforded 9 (both hydroxyl and amine was acetylated) in a yield of 94%. The ring closing step (i)
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proceeded successfully to obtain 10 in a medium yield (37 %). Prolonged reaction time up to 5 h
afforded a yield of 71% isolated yield. In the case of the intermediate 9a (intermediate for
Carbazomycin H), the ring closing took place, although in a poor selectivity producing the two
isomers 10a,b, which were difficult to separate. Therefore, we abandoned the further pathway
designed for the synthesis of Carbazomycin H.
Thus, we focused to complete the synthesis of Carbazomycin G, which implied removal of the acetyl
groups step (j) that involved an acidic hydrolysis in methanol to achieve compound 11 in a yield of
94%. The last two steps involve oxidation of 11 and a regio selective methylation, respectively. The
oxidation step (k) was performed by using nitric acid. This method was developed by our group on
an early stage of this project.[17] The oxidation product 1,4-quinone 12 was successfully obtained in
a yield of 83%. The final step (l)[5c] comprising a regio-selective methylation of 12 that afforded the
ultimate target molecule Carbazomycin G (13) in a yield of 51% and a not structure elucidated side
product (15-20%, MW 225).
Conclusion
We have developed a total synthesis leading to the carbazole alkaloid carbazomycin G. The synthesis
is composed of in total twelve steps, whereof each step afford medium to excellent yields, which
resulting in an overall yield of 8.3%. This total synthesis is associated with a couple of fascinating
organic reactions including Suzuki cross-coupling of congested chloroarenes and intramolecular C–
H activation followed by C–N bond formation for the synthesis of novel congested intermediates.
Experimental section
Experimental Details. All reagents and solvents were purchased from commercial sources and used
as received. Melting points were determined in open capillaries. Reagent grade chemicals were
purchased from commercial sources and used without further purification. All reaction mixtures and
column eluents were monitored by means of TLC (TLC plates Merck Kieselgel 60 F254). The TLC
plates were observed under UV light at λ = 254 nm and λ = 365 nm. IR spectra were recorded as KBr
1
discs with a Shimadzu FTIR-8300 spectrophotometer, and H and 13C NMR spectra were recorded
with the Brüker instruments AC-200F (compounds 6 and 6’), DMX 400WB, DPX 400, AV
500, and Biospin 850SB. High-resolution mass spectra (HRMS) were performed with a Q-TOF
Micro YA263 instrument.
General Methods. GC analyses were performed with a capillary gas chromatograph equipped with
a fused silica column (l25 m, 0.20 mm i.d., 0.33 mm film thickness) at a helium pressure of 200 kPa,
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split less/split injector and flame ionization detector. Mass spectra were obtained with a GC–MS
instrument, with a gas chromatograph equipped with a fused silica column (l30 m, 0.25 mm i.d., 0.25
mm film thickness) and helium as the carrier gas. DART mass spectra were obtained by using PEG
1
13
as an internal standard in positive ionization mode with a TOF mass analyzer. H and C NMR
spectra were recorded at ambient temperature at a frequency of 400, 500, and 850 MHz and 100, 125,
212.5 MHz respectively. The chemical shifts are reported in ppm relative to residual CDCl3 for proton
(δ = 7.26 ppm), CDCl3 for carbon (δ = 77.0 ppm), DMSO-d6 for proton (δ = 2.50 ppm), and DMSO-
d6 for carbon (δ = 39.51 ppm) with tetramethylsilane as an external reference. Flash chromatography
was performed by using the indicated solvent system and silica gel (230–400 mesh). All reagents
used were commercially available from Aldrich Chemical Co. For intermediates and new compounds,
HRMS data were also recorded.
The microwave-assisted experiments were performed by means of a Biotage Initiator Sixty EXP
Microwave System, that operates at 0–400 W at 2.45 GHz, in the temperature range of 40–250 °C, a
pressure range of 0–20 bar (2 MPa, 290 psi), and with reactor vial volumes of 0.2–20 mL.
2,4-Dimethoxy-3-methyl phenol (2) [19676-67-6]. To a solution of 2, 6-dimethoxy toluene 1 (3 g,
19.7 mmol) in acetonitrile (25 mL), was added trifluoroacetic acid (1.3 mL, 19.7 mmol ) and hydrogen
peroxide (35%, 3.5 mL, 39.4 mmol). The reaction mixture was stirred for 2 h at 75 oC. The reaction
mixture was cooled to room temperature and the solvent acetonitrile was removed under reduced
pressure. The crude mixture was diluted with water (30 mL) and extracted with EtOAc (2 ´ 40 mL).
The organic layers were combined and dried over Na2SO4. The solvent was evaporated under reduced
pressure. The title compound was isolated by silica gel column chromatography [(EtOAc:Hx, 20:80)]
1
as orange liquid (2.85 g, 85%); Rf = 0.49 [(EtOAc:Hx, 20:80)]; H-NMR (500 MHz, CDCl3): δ =
6.67 (d, J= 9 Hz, 1H), 6.46 (d, J= 9 Hz, 1H), 5.10 (s, br, 1H), 3.69 (s, 6H), 2.09 (s, 3H); 13C-NMR
(125 MHz, CDCl3,): δ =151.9, 145.9, 142.8, 120.1, 111.8, 106.9, 60.9, 56.1, 9.3; MS (EI): m/z (%);
168 (100, M+), 153 (61), 125 (49), 107 (23), 93 (9), 79 (11), 65 (21), 53 (12); IR (cm-1): 3406, 2996,
2940, 2834, 1486, 1259, 1098, 730.
2,4-Dimethoxy-3-methylphenyl acetate (3) [96502-90-8]. To a solution of 2, 4-Dimethoxy-3-
methyl phenol 2 (1.5 g, 8.9 mmol) in CHCl3 (15 mL), was added acetyl chloride (1.3 mL, 17.8 mmol).
The reaction mixture was heated for 2 h under reflux. The reaction mixture was cooled to ambient
temperature and the solvent was removed under reduced pressure to afford the title compound as a
dark orange liquid (1.75 g, 94%); Rf = 0.78 [(EtOAc:Hx, 40:60)]; 1H-NMR (500 MHz, CDCl3): δ =
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European Journal of Organic Chemistry - ejoc.201800359
10
6.86 (d, J= 8.5 Hz, 1H ), 6.60 (d, J= 8.5 Hz, 1H), 3.80 ( s, 3H), 3.75 ( s, 3H), 2.32 (s, 3H), 2.17 (s,
13
3H); C-NMR (125 MHz, CDCl3): δ = 169.7, 156.4, 150.5, 137.6, 121.2, 119.7, 105.6, 60.8, 55.7,
20.7, 9.2; MS (EI): m/z (%): 210 (9, M+), 168 (100), 153 (53), 139 (4), 125 (19), 107 (12), 79 (6),
65 (8), 53 (7); IR (cm-1): 2940, 2838, 1759, 1484, 1199, 1106, 728.
2,4-Dimethoxy-3-methyl-5-nitrophenyl
acetate
(4)
[192188-84-4].
2,4-Dimethoxy-3-
methylphenyl acetate 3 (1.6 g, 7.6 mmol) was dissolved in a solution of AcOH/Ac2O (1:3 ratio, 12
o
mL) at 0-5 C. A solution of HNO3 (65 %, 1.0 mL, 14.5 mmol) in AcOH/Ac2O (1:3 ratio, 12 mL)
was added dropwise to the reaction mixture under vigorous stirring at 0-5 oC. When the addition was
completed, the reaction mixture was stirred for 30 minutes at ambient temperature. The reaction
mixture was poured into water (100 mL) and extracted with CH2Cl2 (3 ´ 30 mL). The organic layers
were combined and washed with NaHCO3 (2 ´ 50 mL) and dried over Na2SO4. The solvent was
evaporated under reduced pressure to afford the title compound as a yellow liquid (1.49 g, 77 %); Rf
= 0.70 [(EtOAc:Hx, 40:60)]; 1H-NMR (500 MHz, CDCl3): δ = 7.54 (s, 1H), 3.87 ( s, 3H, ), 3.83 ( s,
3H ), 2.33 (s, 3H), 2.26 (s, 3H); 13C-NMR (125 MHz, CDCl3): δ= 168.7, 155.2, 151.3, 139.1, 138.8,
129, 118, 62.1, 60.9, 20.6, 10; MS (EI): m/z (%): 255 (4, M+), 213 (100), 166 (26), 152 (8), 137 (8),
123 (11), 107 (10), 77 (14), 53 (14); IR (cm-1): 2946,1770, 1522, 1343, 1187, 988, 729.
2,4-Dimethoxy-3-methyl-5-nitrophenol (5) [136763-93-3]. A solution of conc. HCl (12 mL) in
MeOH (25 mL) was added dropwise to 2,4-dimethoxy-3-methyl-5-nitrophenyl acetate 4 (1.5 g, 5.9
mmol) at 0 oC . The reaction mixture was stirred for 1 h at 70 oC under reflux. The reaction mixture
was cooled to ambient temperature and the solvent was removed under reduced pressure. The crude
product was diluted with water (40 mL) and extracted with EtOAc (2 ´ 40 mL). The organic layers
were combined and dried over Na2SO4 to afford the Criphol 5 as an orange colored solid (1.25 g, 99
%); Rf = 0.34 [(EtOAc:Hx, 20:80)]; mp 53-55 oC; 1H NMR (500 MHz, CDCl3): δ = 7.26 (s, 1H), 3.78
( s, 6H), 2.21 (s, 3H); 13CNMR (125 MHz, CDCl3): δ = 150.2, 146.3, 145.1, 140.0, 127.5, 109.4, 62.1,
61.0, 10; MS (EI): m/z (%): 213 (100, M+), 166 (59), 152 (21), 137 (36), 125 (43), 122 (28), 91(23),
83(40), 77 (32), 53 (49); IR (cm-1): 3418, 2944, 1519, 1338, 1245, 1102, 988, 733.
®
Telescoped procedure 1 5 [2,4-Dimethoxy-3-methyl-5-nitrophenol (5)]. 2,6-dimethoxy-toluene
1 (6.02 g, 40 mmol) was dissolved in glacial acetic acid (40 mL) that were added CF3COOH (1.33
mL) and H2O2 (35%, 80 mmol) under vigorous stirring. The reaction mixture was continuously stirred
for 2 h at 75 °C. After that, the post-reaction mixture was concentrated under reduced pressure. The
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isolated product was added to water (100 mL), whereupon the resulting suspension was extracted
with dichloromethane (3 ´ 50 mL). The combined organic extracts were dried over anhydrous Na2SO4
and filtered. The solvent was removed under reduced pressure, whereupon the residue was dissolved
in CHCl3 (70 mL) and AcCl (8 mL) was slowly added under vigorous stirring. The resulting mixture
was stirred at reflux for 2 hours. Thereafter, the mixture was cooled at ambient temperature and the
solvent removed under vacuum. The new crude product, containing 3 and unreacted 1, was then
dissolved in a solution of glacial acetic acid (12 mL) in acetic anhydride (36 mL) and the resulting
mixture was cooled at ≈5°C in a ice-water bath. The mixture of HNO3 (65 %, 2.27 mL) in AcOH (3
mL) and Ac2O (12 mL) was then added drop-wise to the previous cooled mixture over a period of 2
h “in the dark”; at the end of this period all the solvents were removed under reduced pressure. The
residue was dissolved in EtOH (80 mL) and a aqueous solution of NaOH (30%, 12 mL) was slowly
added under vigorous stirring. The resulting mixture was stirred at ambient temperature for 2 h. The
solvent was removed under reduced pressure, whereupon water (100 mL) was added and the resulting
aqueous mixture was washed with CH2Cl2 (2 ´ 50 mL). The aqueous layer was acidified (pH ≈ 2)
by adding conc. HCl under vigorous stirring and then extracted with CH2Cl2 (3 ´ 50 mL). The
combined organic layers were dried over Na2SO4, filtered and the solvent was removed under reduced
pressure, to obtain 3.8 g of Criphol 5 (45% yield) as dark solid product.
2-Iodo-4, 6-dimethoxy-5-methyl-3-nitrophenol (6’) [1872386-67-8].[26] A solution of KI (0.332 g,
2 mmol) and iodine (0.295 g, 1.16 mmol) in H2O (1 mL) was drop-wise added to a aqueous solution
of BuNH2 (20 %, 1.5 mL) and acetic acid 2,4-dimethoxy-3-methyl-5-nitrophenyl 4 (0.170 g, 0.67
mmol), for 1-2 min. at room temperature. The resulting dark mixture was stirred for 30 min. at room
temperature, and then poured into CH2Cl2 (50 mL). The organic layer was washed with aqueous
sodium thiosulfate (10 % , 30 mL), dried over anhydrous Na2SO4 and filtrated. After removal of the
solvent under reduced pressure, the final crude (0.100 g) contained Criphol 5 as major product in a
yield of 32 % (with a purity of 81 %), and 2,4-dimethoxy-3-methyl-5-nitrophenol as a major impurity.
C9H10NO5I MW 339.09. 1H NMR (200 MHz, CDCl3, ppm): d = 3.85 (s, 3H, -Ome), 3.79 (s, 3H, -
13
Ome), 2.26 (s, 3H, -Me). C NMR (200 MHz, CDCl3, ppm): d =146.7, 146.0, 144.3, 127.0, 71.1,
62.9, 61.1, 10.1. MS m/z (%): 339 (100), 324 (3), 278 (14), 263 (19), 248 (6), 235 (6), 207 (8), 179
(14), 167 (19), 151 (13), 136 (22), 123 (15), 108 (39), 93 (13), 79 (38), 67 (47), 53 (40), 43 (16).
2-Chloro-4, 6-dimethoxy-5-methyl-3-nitrophenol (6) [1872386-65-6]. To a solution of 2,4-
dimethoxy-3-methyl-5-nitrophenol 5 (0.311 g, 0.145 mmol) in EtOH (15 mL), DCH (146 mg, 0.074
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mmol) was added followed by drop-wise addition of conc. H2SO4 (≈ 24 drops) under good stirring.
After the addition was completed, the reaction mixture was quenched with NaOH (4.1 M, 5 mL). A
heavy red precipitation was observed during the addition of NaOH, which was neutralized with acetic
acid (pH ≈ 4), and the resulting mixture was diluted with water (25 mL) and extracted with diethyl
ether (3 × 40 mL). The organic layers were combined and dried with Na2SO4. The crude product was
isolated by silica gel column chromatography (CH2Cl2/hexane, 40:60) to afford the title compound
1
as pale yellow crystals (0.34 g, 95 %), m.p. 118.5 °C. Rf = 0.29 (CH2Cl2/hexane, 60:40). H-NMR
(400 MHz, CDCl3): δ = 5.91 (s, 1 H), 3.87 (s, 3 H), 3.80 (s, 3 H), 2.26 (s, 3 H) ppm. 13C-NMR (100
MHz, CDCl3): δ = 147.5, 144.0, 142.7, 125.6, 109.3, 62.9, 61.0, 9.9 ppm. MS (EI): m/z (%) = 247
(100, M+), 217 (5), 213 (16), 186 (25), 171 (27), 138 (26), 108 (20), 83 (22), 77 (48), 67 (32). HRMS
(EI): Calcd. for C9H10ClNO5 247.0248; Found 247.0248. IR (cm-1) = 3406, 3083, 2970, 2929, 2846,
1500, 1108.
3,5-Dimethoxy-4-methyl-6-nitrobiphenyl-2-ol (7) [1872386-66-7].
In a microwave tube, 2-
chloro4,6-dimethoxy-5-methyl-3-nitrophenol 6 (0.21 g, 0.85 mmol), phenylboronic acid (0.155 g,
1.27 mmol), Na2CO3 (0.10 g, 0.97 mmol), TBAB (0.021 g, 0.065 mmol) and Pd(PPh3)4 (0.025 g,
0.022 mmol) were added. The reaction mixture was carefully flushed with argon before adding a
mixture of MeOH (4 mL) and water (1 mL), The tube was sealed and placed in the microwave cavity
for 30 min. at 120 oC. The reaction mixture was diluted with water (40 mL) and extracted with diethyl
ether (2 ´ 30 mL). The organic layers were combined and dried over Na2SO4. The crude product was
isolated by silica gel column chromatography [(DCM:Hx, 40:60)] eluent to afford the title compound
as yellow solid (0.122 g, 50 %); Rf =0.1 (CH2Cl2/hexane, 40:60); mp: 102.7oC; 1H-NMR (500 MHz,
CDCl3): δ = 7.46-7.40 (m, 3H), 7.37-7.35 (m, 2H), 5.55 (s, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 2.33 (s,
3H); 13C-NMR (125 MHz, CDCl3): δ = 147.2, 143.2, 142.9, 142.6, 130.8, 129.4, 128.9, 128.8, 125.6,
119.4, 62.8, 61.0, 10; MS (EI): m/z (%): 289 (100, M+), 272 (7), 246 (20), 207 (24), 199 (13), 169
(13), 141 (20), 129 (40), 115 (33), 102 (12), 83 (23), 77 (20); HR-MS (EI): (M+Na)+: Calcd for
C15H15NNaO5 312.0848; Found 312.0846);: IR (cm-1) = 3413, 2937, 2929, 2849, 1528, 1101, 991,
748.
3,3',5-trimethoxy-4-methyl-6-nitro-[1,1'-biphenyl]-2-ol (7a) [NEW]. In a microwave reactor tube,
2-chloro-4,6-dimethoxy-5-methyl-3-nitrophenol 6 (0.168 g, 0.68 mmol), 3-methoxy phenylboronic
acid (0.155 g, 1.02 mmol), Na2CO3 (0.079 g, 0.75 mmol), TBAB (0.019 g, 0.05 mmol) and Pd(PPh3)4
(0.020 g, 0.018 mmol) were added. The reaction mixture was carefully flushed with argon before
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adding a mixture of MeOH (4 mL) and water (1 mL), The tube was sealed and submerged in the
o
microwave cavity for 30 min at 120 C. The reaction mixture was diluted with water (40 mL) and
extracted with diethyl ether (2 ´ 30 mL). The organic layers were combined and dried over Na2SO4.
The crude product was isolated by silica gel column chromatography [(DCM:Hx, 40:60)] eluent to
afford the title compound as yellow oil (0.109 g, 50 %); Rf =0.1 (CH2Cl2/hexane, 40:60); 1H- NMR
(500 MHz, CDCl3): δ = 7.28 (t, J= 8Hz, 1H), 6.88-6.85 (m, 2H), 6.82 (s, 1H), 5.48 (s, 1H), 3.80 (s,
3H), 3.76 (s, 3H), 3.73 (s, 3H), 2.25 (s, 3H); 13C-NMR (125 MHz, CDCl3): δ = 159.8, 147.2, 143.2,
142.8, 142.4, 131.9, 130, 125.7, 121.6, 119.2, 114.9, 114.8, 62.8, 60.9, 10; MS (EI): m/z (%): 320
(17), 319 (100, M+), 276 (33), 257 (15), 244 (22), 159 (32), 128 (35), 115 (45), 83 (38), 55 (22); HR-
MS (DART): (M+H)+: Calcd for C16H18NO6 320.1134; Found 320.1136); IR (cm-1) = 3450, 2942,
2837, 1530, 1238, 1103, 997, 765.
6-amino-3,5-dimethoxy-4-methyl-[1,1'-biphenyl]-2-ol (8) [NEW]. 3,5-Dimethoxy-4-methyl-6-
nitro-[1,1'-biphenyl]-2-ol 7 (0.20 g, 0.69 mmol) was dissolved in EtOH (4 mL) and transferred to a
tube reactor. Then, a mixture of NH4Cl (0.073 g, 1.38 mmol) in H2O (1.2 mL) and indium powder
(0. 238 g, 2.01 mmol) were added whereupon a magnetic stirrer bar was transferred to the tube. The
tube was then sealed and the reaction mixture was stirred and heated at 120 °C for 3 h. The reaction
mixture was cooled to room temperature and diluted with ethyl acetate (30 mL) and filtered through
a pad of celite. Another portion (20 mL) of ethyl acetate was used to wash through the filter pad. The
resulting organic phase was dried over Na2SO4, filtered and the solvent was removed under reduced
pressure to obtain compound 8 as a purple oil (0.175 g, 98%).; Rf = 0.44 [(EtOAc:Hx, 30:70)]; 1H-
NMR (500 MHz, CDCl3): δ= 7.50-7.47 (m, 3H), 7.43-7.40 (m, 2H), 5.30 (s, 1H), 3.76 (s, 3H), 3.74
13
(s, 3H), 2.27 (s, 3H); C-NMR (125 MHz, CDCl3): δ= 142.8, 138.5, 137.2, 134.4, 134.0, 130.5,
129.1, 127.7, 123.3, 113.0, 61.1, 59.5, 9.5; MS (EI): m/z (%): 260 (9), 259 (58, M+), 244 (100), 229
(9), 216 (22), 201 (36), 184 (11), 144 (14), 128(11), 89 (8), 77(9); HR-MS (DART): (M+H)+: Calcd
for C15H18NO3 260.1287; Found 260.1287); IR (cm-1): 3458, 3334, 3057, 2933, 2849, 1580, 1460,
994, 727.
6-amino-3,3',5-trimethoxy-4-methyl-[1,1'-biphenyl]-2-ol (8a) [NEW]. 3,3',5-trimethoxy-4-
methyl-6-nitro-(1,1'-biphenyl)-2-ol (7a) (0.08 g, 0.25 mmol) was dissolved in EtOH (4 mL) and
transferred to a tube reactor. Then, a slurry of NH4Cl (0.027 g, 0.50 mmol) in H2O (1.2 mL) and
indium powder (0. 086 g, 0.75 mmol, 99.99% 100 mesh), use preferably a freshly opened bottle or
stored under Ar) were added whereupon a magnetic stirrer bar was transferred to the tube. The tube
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was then sealed and the reaction mixture was stirred and heated at 120 °C for 3 h. The reaction
mixture was cooled to room temperature and diluted with ethyl acetate (20 mL) and filtered through
a pad of celite. Another portion (20 mL) of ethyl acetate was used to wash through the filter pad. The
resulting organic phase was dried over Na2SO4, filtered and the solvent was removed under reduced
pressure using a rotary evaporator to obtain the compound 8a in purple oil (0.071 g, 98%).; Rf = 0.36
1
[(EtOAc:Hx, 30:70)]; H-NMR (500 MHz, CDCl3): δ= 7.40 (t, J = 8 Hz, 1H), 6.99-6.97 (m, 1H),
6.95-6.94 (m, 1H), 6.93-6.91 (m, 1H), 5.29 (s, 1H), 3.82 (s, 3H), 3.76 (s, 3H), 3.74 (s, 3H), 2.27 (s,
3H),; 13C-NMR (125 MHz, CDCl3): δ= 160.1, 142.8, 138.5, 137.1, 135.3, 134.4, 130.2, 123.4, 122.7,
115.8, 113.6, 112.8, 61.0, 59.5, 55.3, 9.5; MS (EI): m/z (%): 290 (12), 289 (74, M+), 274 (100), 259
(12), 246 (26), 231 (25), 137 (14), 130 (32), 115 (15), 83 (14), 77(10);HR-MS (DART): (M+H)+:
Calcd for C16H20NO4 290.1392; Found 290.1395); IR (cm-1): 3458, 3341, 3057, 2933, 2849, 1580,
1360, 994, 727.
6-acetamido-3,5-dimethoxy-4-methyl-(1,1'-biphenyl)-2-yl acetate (9) [2041574-03-0]. In a round
bottom flask (50 mL), 6-amino-3,5-dimethoxy-4-methyl-(1,1'-biphenyl)-2-ol 8 (0.12 g, 0.46 mmol)
was dissolved in dry CH2Cl2 (10 mL) under inert atmosphere. To the stirred solution added
triethylamine (0.14 mL, 0.97 mmol). The solution was cooled under ice bath and added acetic
anhydride (0.09 mL, 1.01 mmol) dropwise to the reaction mixture. The reaction mixture was stirred
at room temperature for 1 hour. The residue was diluted in EtOAc (50 mL) and washed with water
(40 mL). The organic layer was washed with NaHCO3 (30 mL) and finally dried over Na2SO4. The
solvent was evaporated under reduced pressure to obtain the acetylated product 9 (0.148 g, purple
liquid) in 94 % crude yield. Rf = 0.74 [(EtOAc:Hx, 50:50)]; 1H-NMR (500 MHz, CDCl3): δ = 7.34
(m, 3H), 7.20 (m, 2H), 6.50 (s, br, 1H), 3.76 (d, J=8.5Hz, 6H), 2.29 (s, 3H), 2.17 (s, 3H), 1.99 (s, 3H);
MS (EI): m/z (%): 343 (11, M+), 301 (46), 270 (24), 244 (100), 201 (24), 144 (51), 128 (39), 115
(60), 89 (72), 83(94), 77(47), 55(43); HR-MS (DART): (M+H)+: Calcd for C19H22NO5 344.14980;
Found 344.14999; IR (cm-1): 2928, 2552, 1669, 1603, 1451, 1422, 1290, 1205, 707.
6-acetamido-3,3',5-trimethoxy-4-methyl-(1,1'-biphenyl)-2-yl acetate (9a) [NEW]. In a round
bottom flask (50 mL), 6-amino-3,3',5-trimethoxy-4-methyl-(1,1'-biphenyl)-2-ol 8a (0.13 g, 0.45
mmol) was dissolved in dry CH2Cl2 (10 mL) under inert atmosphere. Triethylamine (0.13 mL, 0.97
mmol) was then added to the stirred mixture. The solution was cooled under ice bath and added acetic
anhydride (0.09 mL, 1.01 mmol) drop-wise to the reaction mixture. The reaction mixture was stirred
at room temperature for 1 hour. The residue was diluted in EtOAc (50 mL) and washed with water
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(40 mL). The organic layer was washed with NaHCO3 (30 mL) and finally dried over Na2SO4. The
solvent was evaporated under reduced pressure to obtain the acetylated product 9a (0.131 g, purple
liquid) in 92% crude yield. Rf = 0.67 [(EtOAc:Hx, 50:50)]; MS (EI): m/z (%): 373 (16, M+), 332 (12),
331 (68), 316(7), 300 (26), 274 (100), 256 (11), 242 (13), 231 (11), 174 (12), 115 (9), 83 (15). The
acetylated product 9a was used in the next step without further purification.
9-acetyl-1,3-dimethoxy-2-methyl-9H-carbazol-4-yl acetate (10) [2041574-04-1]. 6-Acetamido-
3,5-dimethoxy-4-methyl-(1,1'-biphenyl)-2-yl acetate 9 (0.063 g, 0.183 mmol) was dissolved in
glacial acetic acid (5 mL), Pd(OAc)2 (2.1 mg, 0.009 mmol), IMes × HCl (3.2 mg, 0.009 mmol), and
H2O2 (35%, 0.05 mL, 0.53 mmol) were added. The vial was sealed whereupon a magnetic stirrer bar
was transferred to the tube. The tube was submerged in the microwave cavity at 120 oC for 5 h. The
reaction mixture was monitored by means of GC (94% yield). The crude product was dissolved in
EtOAc (20 mL) and washed with water (25 mL). The water phase was extracted with EtOAc (2 × 15
mL). The combined layer was washed with aq. NaHCO3 (20 mL). The organic layer was dried over
Na2SO4 and filtered off. The solvent was evaporated under reduced pressure. The crude product was
purified by using silica gel column chromatography (20:80, EtOAc:Hx) to obtain the N-acetyl
1
Carbazole compound 10 (0.043 g, brown liquid) in 71% yield. Rf = 0.33 [(EtOAc:Hx, 20:80)]; H-
NMR (500 MHz, CDCl3): δ = 8.26 (d, J= 8.5 Hz, 1H), 7.83 (d, J= 7.5 Hz, 1H), 7.45 (t, J= 7.5 Hz,
1H), 7.33 (t, J= 7.5 Hz, 1H), 3.85 (s, 3H), 3.73 (s, 3H), 2.62 (s, 3H), 2.54 (s, 3H), 2.39 (s, 3H); 13C-
NMR (125 MHz, CDCl3): δ = 172.8, 168.6, 147.4, 144.0, 140.4, 134.8, 128.5, 127.7, 124.9, 123.7,
123.6, 121.1, 119.7, 115.1, 61.1, 60.0, 26.8, 20.8, 10.2; MS (EI): m/z (%): 341 (11, M+), 299 (19),
257 (46), 242 (100), 226 (11), 196 (12), 168 (22), 154 (23), 127 (22), 115 (27), 89(12), 77(12),
55(12);HR-MS (DART): (M+H)+: Calcd for C19H20NO5 342.1341; Found 342.1343); IR (cm-1):
2935, 1766, 1702, 1445, 1398, 1367, 1269, 1254, 1183, 1082, 1002, 749.
9-acetyl-1,3,6-trimethoxy-2-methyl-9H-carbazol-4-yl acetate (10a)
&
9-acetyl-1,3,8-
trimethoxy-2-methyl-9H-carbazol-4-yl acetate (10b) (mixture of isomers). 6-Acetamido-3,3',5-
trimethoxy-4-methyl-[1,1'-biphenyl]-2-yl acetate 9a (0.130 g, 0.348 mmol) was dissolved in glacial
acetic acid (5 mL), Pd(OAc)2 (8 mg, 0.024 mmol), IMes × HCl (12 mg, 0.024 mmol) and H2O2 (35%,
0.09 mL, 1.0 mmol) were added. The vial was sealed whereupon a magnetic stirrer bar was transferred
to the tube. The tube was submerged in the microwave cavity at 120 oC for 5 hours. The reaction
mixture was monitored by means of GC (50% yield). Acetic acid was removed under reduced
pressure. The crude product was dissolved in EtOAc (40 mL) and washed with water (25 mL). The
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water phase was extracted with EtOAc (2 × 40mL). The combined organic layer was washed with
aq. NaHCO3 (30 mL). The organic layer was dried over Na2SO4 and filtered off. The solvent was
evaporated under reduced pressure. The crude product was purified by using silica gel column
chromatography (20:80, EtOAc:Hx) afforded a mixture of the isomers 10a and 10b in a yield of 30%.
1H-NMR (500 MHz, CDCl3): δ = 8.13 (d, J= 9 Hz, 1H), 7.64 (d, J= 7.5 Hz, 1H), 7.54-7.55 (m, 1H),
7.32 (t, J= 8 Hz, 1H), 7.25 (m, 1H), 6.96-6.98 (dd, J= 2.5, 9 Hz, 1H), 3.82 (s, 1H), 3.79 (s, 3H), 3.77
(s, 1H), 3.65 (s, 3H), 2.54 (s, 3H), 2.47 (s, 3H), 2.31 (s, 3H),; 13C-NMR (125 MHz, CDCl3): δ = 172.5,
168.6, 159.6, 156.3, 147.4, 144.2, 135.1, 134.7, 130.5, 129.5, 129.1, 125.1, 124.6, 122.6, 120.4, 119.7,
116.2, 114.4, 114.3, 105.5, 61.1, 59.9, 55.8, 55.5, 26.6, 20.8, 10.2; MS (EI): m/z (%): 371 (7, M+),
331 (11), 287 (28), 272 (62), 207 (69), 115 (34), 96 (38), 83 (42), 77(76).
1,3-dimethoxy-2-methyl-9H-carbazol-4-ol (11) [NEW]. To a stirred solution of 9-acetyl-1,3-
dimethoxy-2-methyl-9H-carbazol-4-yl acetate 10 (0.023 g, 0.07 mmol) in methanol (10 mL) at 0 oC
, was added a solution of Conc.HCl (2 mL) in MeOH (5 mL) dropwise. The reaction mixture was
stirred for 1 h at 70 oC. The reaction mixture was cooled to room temperature. The reaction mixture
was diluted with water (40 mL) and extracted with EtOAc (2 ´ 20 mL). The combined organic layer
was dried over Na2SO4. The solvent was filtered off to obtain the compound 11 as a brown solid
(0.017 g, 94%). Rf = 0.42[(EtOAc:Hx, 20:80)]; 1H-NMR (500 MHz, CDCl3): δ = 8.24 (d, J= 8 Hz,
1H), 8.10 (s, br, 1H), 7.41 (m, 1H), 7.39-7.35 (td, J= 1.0 Hz, 6.5 Hz, 1H), 7.24-7.20 (m, 1H), 6.03 (s,
1H), 3.90 (s, 3H), 3.85 (s, 3H), 2.42 (s, 3H),; 13C-NMR (125 MHz, CDCl3): δ = 140.7, 139.1, 137.6,
135.8, 130.7, 125.0, 123.2, 122.6, 121.0, 119.5, 110.6, 110.2, 61.3, 60.8, 9.8; HR-MS (DART):
(M+H)+: Calcd for C15H16NO3 258.1130; Found 258.1133); IR (cm-1): 3309, 3244, 2973, 2924, 2896,
1624, 1321, 1087, 1046, 879.
3-methoxy-2-methyl-1-carbazole-1,4 (9H)-dione (12) [192188-88-8]. To a solution of 1,3-
dimethoxy-2-methyl-9H-carbazol-4-ol (11) (40 mg, 0.155 mmol) in glacial acetic acid (3 mL), HNO3
o
(90%, 0.01 mL, 0.186 mmol) was added slowly at 0-5 C. Then, the reaction mixture was stirred at
ambient temperature for 15 min. After the reaction time, H2O (20 mL) was added to the solution and
extracted with EtOAc (3 ´ 30 mL). The combined organic extracts were washed with H2O (2 ´ 40
mL) and dried over MgSO4 and filtered. The solvent was evaporated under reduced pressure. The
crude product was purified by using silica gel column chromatography (50:50, DCM:Hx) to obtain
the compound 12 as a pale-green solid (36 mg, 0.124 mmol) Rf = 0.86[(EtOAc:Hx, 50:50)]; 1H-NMR
(500 MHz, DMSO-d6): δ = 12.85 (s, br, 1H), 8.01 (d, J= 8 Hz, 1H), 7.53 (m, , 1H), 7.35-7.38 (td, J=
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10.1002/ejoc.201800359
European Journal of Organic Chemistry
Accepted Article
European Journal of Organic Chemistry - ejoc.201800359
17
13
1.0, 8.0 Hz, 1H), 7.29-7.32 (td, J= 1.0 Hz, 8.0 Hz, 1H), 4.03 (s, 3H), 1.92 (s, 3H); C-NMR (125
MHz, DMSO-d6): δ = 180.5, 178.7, 157.8, 137.6, 136.4, 129.3, 128.4, 126.6, 126.0, 123.8, 121.4,
113.7, 61.2, 8.4; HR-MS (ESI-): (M-H)+: Calcd for C14H10NO3 240.06606; Found 240.06632); IR
(cm-1): 3257, 2958, 2923, 2853, 1639, 1258, 1094, 1022, 794.
Carbazomycin G (1-hydroxy-3-methoxy-1,2-dimethyl-1,9-dihydro-4H-carbazol-4-one) (13)
[115920-44-0]. To a vacuum dried Schlenk tube, the solution of compound 12 (0.022 g, 0.091 mmol)
dissolved in THF (10 mL) was added under Ar atmosphere. The solution was cooled at –78 oC (using
a dry ice and acetone mixture). A solution of methyllithium (1.6 M in Et2O, 0.26 mL, 0.42 mmol)
o
was added dropwise at –78 C. The reaction mixture was left (»30 min.) to approach room
temperature. Then NH4Cl (10%, 10 mL) was added to quenched the reaction, whereupon the post-
reaction mixture was extracted with EtOAc (2 × 50 mL). The organic extracts were combined and
dried over Na2SO4. The solvent was removed under reduced pressure. The crude product was purified
by using silica gel column chromatography (50:50, EtOAc:Hx) to obtain the compound 13 as a pale-
yellow solid (51%, 12 mg, 0.047 mmol) Rf = 0.41[(EtOAc:Hx, 50:50)]; 1H-NMR (850 MHz, DMSO-
d6): δ = 12.19 (s, br, 1H), 8.01 (d, J= 7.7 Hz, 1H), 7.44 (d, J= 7.7 Hz, 1H), 7.22 (t, J= 7.7 Hz, 1H),
7.17 (t, J= 7.7 Hz, 1H), 5.92 (s, 1H), 3.69 (s, 3H), 1.98 (s, 3H), 1.57 (s, 3H); 13C-NMR and DEPT
(212.5 MHz, DMSO-d6): δ = 177.6 (C=O), 154.4 (C), 147.7 (C), 140.8 (C), 136.5 (C), 123.9 (C),
122.9 (CH), 121.4 (CH), 120.5 (CH), 112.0 (CH), 108.4 (C), 67.4 (C), 59.2 (CH3), 27.9 (CH3), 10.1
(CH3); HR-MS (ESI-): (M-H)+: Calcd for C15H14NO3 256.09737; Found 256.09799); IR (cm-1): 3255
br, 2924, 2853, 1719, 1643, 1618, 1468, 1375, 1289, 1138, 1092, 1011, 961, 804, 748.
Acknowledgments
V. E. gratefully acknowledges Department of Chemistry at the University of Bergen for his research
fellowship. C. G. acknowledges financial support from Department of Chemistry at University of
Bergen in connection with several research stays. Dr. Bjarte Holmelid is acknowledged for excellent
technical support with the HRMS analyses.
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