Total Synthesis of Marine Alkaloid Hyellazole and its Derivatives

Article abstract of DOI:10.1002/ejoc.201800187

The total synthesis of the naturally occurring marine alkaloids hyellazole and chlorohyellazole was attempted from the corresponding easily accessible 2-methyl-1-ketotetrahydrocarbazoles obtained through the Japp–Klingemann reaction, followed by Fischer indole cyclization and subsequent Grignard coupling with phenylmagnesium bromide. Grignard coupling with 2-methyl-1-ketotetrahydrocarbazole unfortunately led directly to 2-methyl-1-phenylcarbazole through dehydration followed by aromatization through aerial oxidation, but application of the same reaction conditions to 6-chloro-2-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one, with careful treatment, led to the isolation of 6-chloro-2-methyl-1-phenyl-4,9-dihydro-3H-carbazole. However, selenium dioxide oxidation of this dihydrochloro derivative led to the formation of 6-chloro-2-methyl-1-phenyl-9H-carbazole. A different route was then adopted: a suitably substituted aromatic amine was used to establish the substitution pattern of the required carbazole derivative with a bromo group at C-1, and the required phenyl group at the 1-postion was then attached through Suzuki–Miyaura cross-coupling to furnish hyellazole.

Full text of DOI:10.1002/ejoc.201800187

A Journal of
Accepted Article
Title: Total Synthesis of Marine Alkaloid Hyellazole and Its Derivatives
Authors: Suchandra Chakraborty and Chandan Saha
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800187
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800187
Supported by

10.1002/ejoc.201800187
European Journal of Organic Chemistry
FULL PAPER
Total Synthesis of Marine Alkaloid Hyellazole and Its Derivatives
Suchandra Chakraborty*[a] and Chandan Saha[b]
Abstract: Total syntheses of naturally occurring marine alkaloids
Hyellazole and chlorohyellazole is attempted from easily accessible
corresponding 2-methyl-1-ketotetrahydrocarbazoles incurred through
Japp-Klingeman reaction followed by Fischer indole cyclization and
then Grignard reaction using phenyl magnesium bromide in
yielded hyellazole. Moddy et al.[11] have subsequently published
a versatile route to polysubstituted carbazoles based on Diels-
Alder reaction on pyrano[3,4-b]indol-3-ones with alkynes and
this concept was utilized to obtain hyellazole in a short route.
Knoelkar
et
al.
developed
a
highly
sequence.
Although
Grignard
reaction
on
2-methyl-1-
convergent scheme to 3-oxygenated carbazole alkaloids, in
which heterocyclic framework was constructed by a successive
iron-mediated C—C and C—N bonds formation and this method
was established to be useful for the synthesis of hyellazole[14]
and 6-chlorohyellazole.[18] In 1996 Hibino et al.[15] have
ketotetrahydrocarbazole leads directly to furnish 1-phenyl-2-
methylcarbazole through dehydration followed by aromatization
through aerial oxidation, the same reaction on 6-chloro-2-methyl-
2,3,4,9-tetrahydro-1H-carbazol-1-one through careful treatment
leads to the isolation of 6-chloro-2-methyl-1-phenyl-4,9-dihydro-3H-
carbazole. However selenium dioxide oxidation of this
dihydrochloroderivative leads to the formation of 6-chloro-2-methyl-
1-phenyl-9H-carbazole. A different route is then adopted using
suitably substituted aromatic amine to arrive at the substitution
pattern of required carbazole derivative with a bromo group at C-1
and the required phenyl group at 1-postion is then fabricated through
Suzuki-Miyaura cross-coupling to furnish Hyellazole.
synthesized hyellazole by
a new type allene mediated
electrocyclic ring closure with the participation of indole 2,3-
double bond. Here we have developed a very simple strategy to
synthesis the marine alkaloid, hyellazole in which heterocyclic
framework is constructed via consecutive Fischer indole
cyclization and aromatization and required phenyl group is
fabricated at the 1-position through Suzuki-Miyaura cross-
coupling.[19]
Introduction
Over past 40 years[1-6] a vast number of carbazole alkaloids
have mostly been isolated from terrestrial plants. Other than this,
a large number of carbazole alkaloids have been encountered in
different algae and streptomycillin species.[2] In 1979 Hyellazole
and 6-chlorohyellazole (Figure 1) were the first carbazole
alkaloids isolated from the blue-green alga Hyella caespitosa, a
marine sources by Moore.[7] Although these two alkaloids have
different in origin, yet these are structurally unique having a
methoxy group at 3-position like some other carbazole alkaloids
along with a phenyl group at 1-position. Interesting structural
features of these alkaloids allured several research groups to
spring up different route for their total synthesis.
Since the isolation of these alkaloids more than fifteen different
methods of total syntheses[8-18] were originated for them till date.
Kano et al. in 1981 have synthesized[8] both hyellazole and 6-
chlorohyellazole from the correspondding 2,3-divinylindoles
Figure 1. Naturally occurring marine alkaloids.
As an extension of this Suzuki-Miyaura cross-coupling reaction
is utilized to afford 4-deoxycarbazomycin B (1A).[20a]
Results and Discussion
Initial Synthetic Plan for Hyellazole and 6-Chlorohyellazole
Our laboratory is well conversant about the chemistry of 1-
ketotetrahydrocarbazole derivatives which are easily procurable
through Japp-Klingeman reaction between diazonium chloride
and 2-formylcyclohexanone derivatives followed by Fischer
indole cyclization.[20] As a result we are interested to synthesize
hyellazole (1) and 6-chlorohyellazole (2) through the treatment
through
thermal
electrocylic
ring
closure
followed
dehydrogenation with palladised charcoal in situ. Later on in
1989 Kawasaki et al.[10] have utilized unique electrocylic ring
closure procedure on properly substituted 3-butadienylindoles to
obtain carbazole moiety which on subsequent desilylation
of
phenyl
magnesium
bromide
on
2-methyl-1-
ketotetrahydrocarbazoles (3a and 3b) followed by dehydration to
yield 2-methyl-1-phenyl-3,4-dihydrocarbazoles (4a and 4b)
which on allylic oxidation and functional group interconversion
may lead to the target molecules (Scheme 1).
[a]
[b]
Dr. Suchandra Chakraborty
Department of Chemistry
The Bhawanipur Education Society College
5, LLR Sarani, Kolkata - 700020
E-mail: suchandra82@gmail.com
Dr. Chandan Saha
Department of Clinical and Experimental Pharmacology
School of Tropical Medicine
108, C. R. Avenue, Kolkata – 700073
E-mail: cskatichandan@gmail.com
Supporting information for this article is available.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800187
European Journal of Organic Chemistry
FULL PAPER
with Pd-C aromatized[20a] the ring to the corresponding
chlorohyellazole derivative 10b (Scheme 3).
Scheme
3.
Grignard
Reaction
on
2-methyl-6-choloro-1-
Scheme 1. Proposed plan to synthesize Hyellazole (1) and 6-Chlorohyellazole
(2).
ketotetrahydrocarbazoles (3b) under inert atmosphere
Actual Observation
Now according the proposed Scheme 1, as it was possible
to synthesis 9b, it is then allowed to meet with selenium dioxide
to execute the allylic oxidation[21] followed by O-methylation to
furnish 6-chlorohyellazole. However, selenium dioxide oxidation
of 9b surprisingly turned back to the starting material 2-methyl-6-
choloro-1-ketotetrahydrocarbazoles (3b) with the expulsion of
phenyl motif as a major product along with minor amount of
aromatized demethoxychlorohyellazole 10b (Scheme 4)
To
accomplish
our
(3a)
target
2-methyl-1-
ketotetrathydrocarbazole
and
6-chloro-2-methyl-1-
ketotetrathydrocarbazole (3b) were synthesized from aniline and
p-chloroaniline respectively through diazotization followed by
Japp-Klingeman coupling with 2-formyl-6-methylcyclohexanone
(7) followed by Fischer indole cyclization[20] on the corresponding
2-methyl-(6-phenylhydrazono)cyclohexanaones (8a and 8b)
respectively.
Now
these
substituted
2-methyl-1-
ketotetrahydrocarbazoles (3a and 3b) on treatment with phenyl
magnesium bromide yielded directly 2-methyl-1-phenyl-
carbazoles (10a and 10b) wherein it may be speculated that
during work up with aqueous ammonium chloride the possible
intermediates 4a and 4b, the benzyl alcohols experience
dehydration to 9a and 9b respectively which undergoes aerial
oxidation directly to furnish 10a and 10b (Scheme 2)
respectively.
.
Scheme 4. Attempted selenium dioxide oxidation of 6-chloro-2-methyl-1-
phenyl-4,9-dihydro-3H-carbazole (9b)
The plausible steps for the selenium (IV) oxide mediated
reaction might be taken place through an ene reaction followed
by sigatropic [2,3]-rearrangement of intermediate selenium (IV)
acid to yield selenium (II) acid.[22] This selenium (II) acid then
undergoes electrophilic addition at the carbon-carbon double
bond to yield an intramolecular ester from which benzene is
eliminated to restore the double bond at its initial location. The
intermediate then hydrolyzed and a reverse of sigatropic [2,3]-
rearrangement proceeds to furnish 3b (Scheme 5).
Scheme 2. Grignard Reaction on 2-methyl-1-ketotetrahydrocarbazole
derivatives (3a) and (3b)
However, yet cautious handling of phenyl magnesium bromide
reaction on 3a under inert atmosphere, it was unsuccessful to
isolate highly unstable dehydrated product 9a which is extremely
susceptible to aerial oxidation. On the contrary, Grignard
reaction in inert atmosphere on 3b it was possible to isolate
stable dehydrated product 9b whose structure was confirmed
Scheme 5. Plausible mechanism of the selenium dioxide oxidation to furnish
3b
1
through H and 13C-NMR spectra. In addition, 9b on treatment
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800187
European Journal of Organic Chemistry
FULL PAPER
Modified Retrosynthetic Analysis
This disappointment motivated us to synthesize Hyellazole
through a different route where it is thought that suitably
substituted aromatic amine may be employed to acquire the
precise substitution pattern of Hyellazole and the necessitated
phenyl group at 1-postion will be incorporated through Suzuki
cross-coupling on the corresponding 1-boromocarbazole (11).
Required 1-bromocarbazole (11) may be synthesized through
the Japp-Klingeman reaction directly from the corresponding
amine (14) and 2-formylcyclohexanone (24) followed by Fischer
indole cyclization and aromatization (Scheme 6).
Scheme 7. Synthesis of 2-bromo-4-methoxy-3-methylaniline hydrochloride
(23)
Afterwards the convergent synthesis of 12 was initiated by
means of Claisen condensation[26] of cyclohexanone with ethyl
formate utilizing metallic sodium in dry ether in presence of one
drop of ethanol to afford 2-formylcyclohexanone (24) which was
then undergo Japp-Klingemann coupling with 2-bromo-4-
methoxy-3-methylbenzene diazonium chloride (25) to furnish
substituted phenylhydrazonocyclohexanone (26). Fischer indole
cyclization[26] of 26 in glacial acetic acid and conc. hydrochloric
acid mixture yielded 1-ketotetrahydrocarbazole (12). Then the
Wolff-Kishner reduction of this 1-ketotetrahydrocarbazole
derivative (12) followed by aromatization[27] without isolating the
intermediate tetrahydrocarbazole derivative using 10%
palladized charcoal afforded the mixture of 3-methoxy-2-methyl-
9H-carbazole (27) with 11% yield and 1-bromo-3-methoxy-2-
methyl-9H-carbazole (11) as 65% yield. At the final stage 1-
bromo-3-methoxy-2-methyl-9H-carbazole (11) was subjected to
Suzuki cross-coupling[28] with phenylboronic acid and
methylboronic acid respectively in presence of palladium
catalyst to afford hyellazole (1, 71% yield) and 4-
deoxycarbazomycin B (1A, 56% yield) (Scheme 8).
Scheme 6. Retrosynthetic analysis for the synthesis of Hyellazole
Total Synthesis of Hyellazole
On the basis of the above retrosynthetic analysis a
convergent synthesis of the target molecule (1) was initiated
from the commercially accessible 2-methyl-3-nitroaniline (15),
which on Sandmeyer reaction[23] led to the formation of 2-methyl-
3-nitrobromobenzene (16). This bromo compound (16) was on
simple reduction with iron powder in aqueous methanolic
ammonium chloride provided 3-bromo-2-methylaniline (17). The
amino group of 17 was then altered[24] to phenolic hydroxyl
group through diazotization to incur 3-bromo-2-methylphenol
(18). The essential amino group at the para-position with respect
to phenolic hydroxyl group of 18 was incorporated through[25] the
classical diazo-coupling with diazotized 4-aminobenzenesulfonic
acid and then subsequent reduction of 19 by means of
commercially cheap sodium dithionate to furnish 4-amino-3-
bromo-2-methylphenol (20). Required amine hydrochloride (23)
was then synthesized from 20 on protecting the amino group via
acetylation, O-methylation followed by hydrolysis of acetamide
derivative (22) with aqueous ethanolic hydrochloric acid
(Scheme 7).
Scheme 8. Synthesis of Hyellazole and 4-deoxycarbazomycin B
Conclusions
We have achieved the total synthesis of hyellazole as well
as 4-deoxycarbazomycin B from an easily available starting
material, 2-methyl-3-nitroaniline. Required amine hydrochloride
was synthesized from 2-methyl-3-nitroaniline utilizing common
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800187
European Journal of Organic Chemistry
FULL PAPER
This on crystallization from aqueous methanol 8a (18.5 g, yield 86%) was
obtained as yellow crystals; m.p. 98 °C (ref.26 97 °C); Rf = 0.8
(benzene/chloroform/diethylamine, 14:5:1); 1H NMR (500 MHz, CDCl3): δ
= 1.21 (d, J = 7.0 Hz, 3H, CH3), 1.51–2.78 (m, 7H, 2 × 3-H, 2 × 4-H, 2 ×
5-H, 2-H), 6.98 (d, J =7.5 Hz, 2H, Ar-H), 7.21–7.30 (m, 3H, Ar-H), 13.71
(s, 1H, NH; exch.) ppm. 13C NMR and DEPT (125 MHz, CDCl3): δ = 14.8
(CH3), 16.3 (CH2), 22.0 (CH2), 31.6 (CH2), 43.7 (CH), 114.3 (CH), 122.8
(CH), 125.9 (CH), 128.9 (CH), 129.4 (CH), 132.2 (C), 143.3 (C), 200.1
(C=O) ppm. IR spectrum (KBr): ν = 3495 (br), 3292, 2965, 1678, 1620,
1536, 1498, 1442 cm−1. UV/Vis (MeOH): λmax = 236, 300, 358 nm. HRMS
(Q-TOF): calcd. for C13H16N2ONa [M + Na]+ 239.1154; found 239.1156.
classical reactions through eight possible steps. Subsequent
Japp-Klingemann coupling of 2-formylcyclohexanone with 2-
bromo-4-methoxy-3-methylbenzene diazonium chloride followed
by Fischer indole cyclization and aromatization afforded 1-
bromo-3-methoxy-2-methyl-9H-carbazole.
Finally
Suzuki-
Miyaura cross-coupling of 1-bromo-3-methoxy-2-methyl-9H-
carbazole with phenylboronic acid and methylboronic acid
respectively in presence of palladium catalyst afforded
hyellazole and 4-deoxycarbazomycin B.
Similarly 8b was prepared in analogous way utilizing 4-chlorophenyl
diazonium chloride (prepared from 0.1 mol, 12.75 g p-chloroaniline) in
place of phenyldiazonium chloride. The crude product on crystallization
from aqueous methanol afforded 8b (22.5 g, yield 90%) as yellow solid;
m.p. 91 °C Rf = 0.8 (benzene/chloroform/diethylamine,14:5:1); 1H NMR
(500 MHz, CDCl3): δ = 1.23 (d, J = 3.0 Hz, 3H, CH3), 1.52–2.76 (m, 7H, 2
× 3-H, 2 × 4-H, 2 × 5-H, 2-H), 6.97 (d, J =8.0 Hz, 2H, Ar-H), 7.22 (d, J
=8.0 Hz, 2H, Ar-H), 13.70 (s, 1H, NH; exch.) ppm. 13C NMR and DEPT
(125 MHz, CDCl3): δ = 14.6 (CH3), 16.3 (CH2), 22.0 (CH2), 30.5 (CH2),
43.4 (CH), 114.2 (CH), 122.6 (CH), 125.8 (CH), 128.8 (CH), 129.4 (C),
132.2 (C), 142.3 (C), 198.1 (C=O) ppm. IR spectrum (KBr): ν = 3493 (br),
3295, 2897, 1682, 1618, 1545, 1445 cm−1. UV/Vis (MeOH): λmax = 242,
310, 362 nm. HRMS (Q-TOF): calcd. for C13H15N2OClNa [M + Na]+
273.0764; found 273.0768.
Experimental Section
General Methods: All reactions were carried out using anhydrous
solvents. Melting points were determined in open capillaries in melting
point instrument and are uncorrected. Reagent grade chemicals were
purchased from commercial sources and used without further purification.
Column chromatography was performed to obtain pure compounds using
silica gel (60 - 120 mesh). All reaction mixtures and column eluents were
monitored by TLC using commercial aluminium TLC plates (Merck
Kieselgel 60 F254). The plates were observed under UV light at 254 and
365 nm. The structure of known compounds was further corroborated by
comparing their 1H NMR, 13C NMR data and MS data with those in
literature. IR spectra were recorded in KBr discs with a Shimadzu FTIR-
8300 spectrophotometer, and 1H and 13C NMR spectra were recorded
with a Bruker AV 300 MHz and 400 MHz instrument. High-resolution
mass spectra (HRMS) were performed with a QTOF Micro YA263
instrument.
2-Methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one (3a)[26] and 6-Chloro-
2-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one (3b): A solution of 8a
(10.8 g, 0.05 mol) in glacial acetic acid (80 mL) containing conc.
hydrochloric acid (20 mL) was heated to reflux for 4 min. The reaction
mixture was poured into ice-water (300 mL) and the solid thus obtained
was collected by filtration, washed with water, and dried. The residue
was subjected to flash chromatography (hexane/CH2Cl2, 7:3) on silica gel
3-Methyl-2-oxocyclohexanecarbaldehyde (7)[26]
: A solution of 2-
methylcyclohexanone (11.2 g, 0.1 mol) and ethyl formate (18.0 mL, 0.15
mol) in sodium dried diethyl ether (200 mL) was taken in a conical flask
(500 mL) with a magnetic stirrer and CaCl2 guard tube and placed it in a
cold water bath. To start Claisen condensation, metallic sodium (2.3 g,
0.1 mol) and five drops of ethanol were added to the stirred mixture and
stirring was continued for 4 hr, whereupon the sodium salt of 3-methyl-2-
oxocyclohexanecarbaldehyde was separated as a cake-like mass. To
remove some unused metallic sodium ethanol (5 mL) was added, and
the mixture was stirred for an additional 30 min. Sodium salt of 3-methyl-
2-oxocyclohexanecarbaldehyde was then dissolved in water (150 mL)
and the aqueous layer was collected. The organic layer was further
extracted with water (50 mL) and the combined aqueous extract was
washed with diethyl ether (50 mL). The aqueous layer was then acidified
with 6(N) hydrochloric acid (8.0 mL) and oily organic part was extracted
with diethyl ether (2×80 mL). The organic layer was then washed with
brine and dried over anhydrous sodium sulfate. The organic layer, on
evaporation followed by vacuum distillation (70 °C, 0.5 Torr), gave
product 7 (10 g, 70% yield) as a colorless oil. 1H NMR (500 MHz, CDCl3):
δ = 1.21 (d, J = 7.0 Hz, 3H, CH3), 1.37–1.42 (m, 1H), 1.57–1.60 (m, 1H),
1.76–1.80 (m, 1H), 1.85–1.89 (m, 1H), 2.32–2.35 (m, 2H), 2.45–2.49 (m,
1H), 8.60 (s, 1H, CHO), 14.55 (br. s, 1H, enol-OH) ppm. 13C NMR and
DEPT (125 MHz, CDCl3): δ = 17.4 (CH3), 20.9 (CH2), 23.7 (CH2), 30.0
(CH2), 35.8 (CH), 108.3 (CH), 187.0 (C), 188.6 (C) ppm. HRMS (QTOF):
calcd. for C8H13O2 [M + H]+ 141.0912; found 141.0917.
to give
dichloromethane/hexane provided 3a (8.4 g, yield 84%) as white crystals;
m.p. 172–173 °C 173 °C); Rf 0.7
(ref.26
a
white solid. Recrystallization of the solid from
=
(benzene/chloroform/diethylamine, 14:5:1); 1H NMR (500 MHz, CDCl3): δ
= 1.38 (d, J = 8.0 Hz, 3H, CH3), 2.02 (m, 1H, C3-H), 2.32 (m, 1H, C3-H),
2.72 (m, 1H, C2-H), 2.97 (m, 1H, C4-H), 3.09 (m, 1H, C4-H), 7.13 (t, 1H,
Ar-H), 7.35 (t, 1H, Ar-H), 7.46 (d, J = 8.5 Hz, 1H, Ar-H), 7.64 (d, J = 8.5
Hz, 1H, Ar-H), 9.68 (s, 1H, NH; exch) ppm. 13C NMR (125 MHz, CDCl3):
δ = 15.2 (CH3), 20.6 (CH2), 33.2 (CH2), 41.9 (CH), 112.7 (CH), 120.2
(CH), 121.2 (CH), 125.8 (CH), 126.8 (C), 129.0 (C), 130.9 (C), 138.3 (C),
194.5 (C=O) ppm. IR spectrum (KBr): ν = 3284, 2932, 1688, 1516, 1492
cm−1. UV/Vis (MeOH): λmax = 238, 312 nm. HRMS (Q-TOF): calcd. for
C13H13NONa [M + Na]+ 222.0890; found 222.0892.
Similar Fischer Indole Cyclization of 8b (12.5 g, 0.05 mol) in glacial
acetic acid (100 mL) containing conc. hydrochloric acid (25 mL) led to the
formation of 6-chloro-2-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one (3b)
which on flash chromatography (hexane/CH2Cl2, 7:3) on silica gel
provided 3b (10.1 g, yield 87%) as white crystals; m.p. 198 °C. Rf = 0.6
(benzene/chloroform/diethylamine, 14:5:1); 1H NMR (300 MHz, CDCl3): δ
= 1.34 (d, J = 6.9 Hz, 3H, CH3), 1.98-2.08 (m, 1H, C3-H), 2.30-2.36 (m,
1H, C3-H), 2.70-2.75 (m, 1H, C2-H), 2.93-3.06 (m, 2H, C4-H), 7.30 (d, J
= 8.5 Hz, 1H, Ar-H), 7.41 (d, J = 8.7 Hz, 1H, Ar-H), 7.6 (s, 1H, Ar-H),
10.06 (s, 1H, NH; exch) ppm. 13C NMR (75 MHz, CDCl3): δ = 15.3 (CH3),
20.6 (CH2), 33.2 (CH2), 42.1 (CH), 114.0 (CH), 120.5 (CH), 126.0 (CH),
126.7 (C), 127.3 (C), 128.4 (C), 132.0 (C), 136.7 (C), 194.9 (C=O) ppm.
IR spectrum (KBr): ν = 3286, 2930, 1685, 1518, 1490 cm−1. UV/Vis
(MeOH): λmax = 236, 315 nm. HRMS (Q-TOF): calcd. for C13H12NOClNa
[M + Na]+ 256.0500; found 256.0503.
2-Methyl-6-(2-phenylhydrazono)cyclohexanone (8a)[26] and 2-Methyl-
6-[2-(4-chlorophenyl)hydrazono]cyclohexanone (8b): To a solution of
7 (14 g, 0.1 mol) in methanol (160 mL), aqueous solution (80 mL) of
sodium acetate trihydrate (20 g) was added and it was cooled to 0 °C.
Then a solution of phenyldiazonium chloride (prepared from 0.1 mol
aniline) was allowed to add in drop-wise manner with stirring. The yellow
solid 8a, thus formed, was collected by filtration and washed with water.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800187
European Journal of Organic Chemistry
FULL PAPER
2-Methyl-1-phenyl-9H-carbazole (10a) and 6-Chloro-2-methyl-1-
phenyl-9H-carbazole (10b): Magnesium turnings (270.0 mg, 10.0 mmol)
and a few crystals (2-3) of iodine were taken in a round bottom flask and
warmed to activate the Mg. To it 5.0 mL. dry tetrahydrofuran (THF), 1,2-
dibromoethane (5 drops) were placed and stirred at room temperature.
Bromobenzene (1.05 mL., 10 mmol) was taken in 10.0 mL dry THF.
Initially 3.0 mL solution of boromobenzene was added to the reaction
mixture and warmed at 60-70 °C. When the reaction mixture started to
boil remaining solution of bromobenzene was added to it and the reaction
mixture was allowed to boil for about 30 min. Afterwards the solution of 2-
methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one (3a, 995.0 mg, 5.0 mmol) in
dry THF (15 mL) was added in drop-wise manner to the hot solution of
Grignard reagent with stirring only and then allowed to come at room
temperature within 1 hr. Saturated aqueous solution of NH4Cl (45 mL)
was added to the reaction mixture with stirring for about 1 hr. The
reaction mixture was then extracted with ether (5 × 40 mL) and then the
ether layer was washed with brine solution (2 × 20 mL) followed by water
(1 × 30mL). Ether solution was then dried over anhydrous Na2SO4. After
evaporation of ether, the product was flash chromatographed over silica
gel and eluted with hexane:dicholromethane (50:1) to obtain 2-methyl-1-
phenyl-9H-carbazole (10a, 976.6 mg, yield 76%) as white crystals.
(20.0 mL) was added in drop-wise manner to the hot solution of Grignard
reagent with stirring only and then allowed to come at room temperature
within 1 hr. maintaining the inert atmosphere throughout. Then with the
cautious handling saturated aqueous solution of NH4Cl (45 mL) was
added to the reaction mixture and stirred for about 1 hr under N2-
atmosphere. The reaction mixture was then extracted with ether (5 × 40
mL) and then the ether layer was washed with brine solution (2 × 20 mL)
followed by water (1 × 30mL). Ether solution was then dried over
anhydrous Na2SO4. After evaporation of ether, the product, 6-chloro-2-
methyl-1-phenyl-4,9-dihydro-3H-carbazole (9b, 2.4 g, yield 83%) was
obtained. It was recrystallized from hexane-dichloromethane mixture to
furnish white crystals; m.p. 98 °C; 1H NMR (300 MHz, CDCl3): δ = 1.85 (s,
3H, CH3), 2.63 (t, 2H, C3-CH2), 2.94 (t, 2H, C4-CH2), 6.99 (dd, J = 1.8 Hz,
J = 2.1 Hz, 2H, Ar-H), 7.26 – 7.31 (m, 3H, Ar-H), 7.39 – 7.49 (m, 3H, Ar-
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 19.2 (CH3), 20.6 (CH2), 31.7
(CH2), 111.8 (CH), 117.5 (CH), 119.3 (CH), 121.0 (C), 122.4 (CH), 125.4
(C), 125.5 (CH), 126.3 (C), 127.3 (C), 127.7 (CH), 128.8 (CH), 129.7
(CH), 134.1 (C), 134.2 (C), 136.9 (C), 136.7 (C) ppm. IR spectrum (KBr):
ν = 3404, 3030, 2896, 2848, 1608 cm−1. HRMS (Q-TOF): calcd. for
C19H14NClNa [M + Na]+ 314.0707; found 314.0706.
1-Bromo-2-methyl-3-nitrobenzene (16)[23]: Copper (II) sulfate (17.5 g,
70.0 mmol) and sodium bromide (8.0 g) was dissolved in water (60 mL)
on warming in hot water bath. To this warm solution sodium dithionate
(4.6 g) solution in water (40 mL) was added portion-wise with occasional
shaking and warming in hot water bath. Afterwards solid sodium
dithionate (1 g) was added in portion-wise to the reaction mixture and
thereby the color of the solution was changed from greenish blue to
yellowish grey. The supernatant aqueous part was decanted off to obtain
solid mass of cuprous bromide to which conc. HBr (20.5 mL) and water
(50 mL) were added and the resulting solution was allowed to cool in ice-
water bath for 1 hr. In the mean time 2-methyl-3-nitroaniline (15, 7.7 g,
50.0 mmol) was suspended in water (65 mL) and then heated to reflux.
To this boiling solution conc. HBr (26.0 mL) was added in drop-wise
manner and refluxing was continued for further 20 min. This hot acid
solution of 2-methyl-3-nitroaniline (15) was then allowed to cool to 0 °C in
ice-water bath. To this solution cooled aq. solution of sodium nitrite (3.6 g
in 18 mL water) was added in drop-wise manner maintaining reaction
temperature below 0 °C using ice-acetone bath. This diazotization was
completed in 20 min. Cooled diazotized solution was added in drop-wise
manner to the cooled solution of CuBr-HBr under cold condition during 1
hr. with good stirring and stirring was continued for further 30 min. During
this period the color of the solution was changed from reddish violet to
yellowish green with the evolution of nitrogen gas which resulted in
frothing. The reaction mixture was then heated on water bath for about
20 min. with occasional shaking. This was kept overnight at room
temperature. The solid thus separated out was steam distilled and
extracted with ether (500 mL). The ether layer was washed with brine
and dried over anhydrous Na2SO4. After evaporation of ether under
vacuum, white solid compound 16 (9.0 g, yield 84%) was obtained, m.p.
37 °C (ref.23 36-39 °C); 1H NMR (300 MHz, CDCl3): δ = 2.55(s, 3H, Ar-
CH3), 7.19 (q, 1H, Ar-H), 7.71 (dd, J = 0.9, 0.9 Hz, 1H, Ar-H), 7.78 (dd, J
= 1.2, 1.2 Hz, 1H, Ar-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 19.4 (CH3),
123.2 (CH), 127.3 (CH), 127.5 (C), 132.4 (CH), 136.6 (C ×2) ppm. IR
spectrum (KBr): ν = 3452, 3434, 3082, 3004, 1595, 1529 cm−1. HRMS
(Q-TOF): calcd. for C7H6BrNO2H [M + H]+ 215.9657; found 215.9660.
2-Methyl-1-phenyl-9H-carbazole (10a): m.p. 102 °C; Rf
= 0.9
(benzene/chloroform/diethylamine, 14:5:1); 1H NMR (500 MHz, CDCl3): δ
= 2.37 (s, 3H, CH3), 7.19 – 7.26 (m, 2H, Ar-H), 7.31 (d, J = 7.5 Hz, 1H,
Ar-H), 7.36 (t, 1H, Ar-H), 7.47 (t, 3H, Ar-H), 7.56 (t, 2H, Ar-H), 7.97 (d, J =
8.0 Hz, 1H, Ar-H), 8.07 (d, J = 7.5 Hz, 1H, Ar-H) ppm. 13C NMR (125
MHz, CDCl3): δ = 20.2 (CH3), 110.6 (CH), 118.8 (C), 119.2 (CH), 119.4
(CH), 120.2 (CH), 121.2 (C), 122.1 (CH), 123.8 (C), 125.4 (CH), 127.7
(CH), 129.2 (2×CH), 129.9 (2×CH), 133.2 (C), 137.7 (C), 138.9 (C),
139.5 (C) ppm. IR spectrum (KBr): ν = 3396, 3055, 3026, 2918, 1604
cm−1. HRMS (Q-TOF): calcd. for C19H15NNa [M + Na]+ 280.1097; found
280.1099.
Similar Grignard reaction on 6-chloro-2-methyl-2,3,4,9-tetrahydro-1H-
carbazol-1-one (3b, 1.16 g, 5 mmol) with phenylmagnesium bromide
afforded 6-Chloro-2-methyl-1-phenyl-9H-carbazole (10b, 1.04 g, yield
72%) as white crystals.
6-Chloro-2-methyl-1-phenyl-9H-carbazole (10b): m.p. 99 °C; Rf = 0.8
1
(benzene/chloroform/diethylamine, 14:5:1; H NMR (500 MHz, CDCl3): δ
= 2.33 (s, 3H, CH3), 7.15 – 7.21 (m, 2H, Ar-H), 7.26 (d, J = 8.5 Hz, 1H,
Ar-H), 7.32 (t, 1H, Ar-H), 7.40 – 7.45 (m, 2H, Ar-H), 7.53 (t, 2H, Ar-H),
7.92 (d, J = 8.0 Hz, 1H, Ar-H), 8.02 (d, J = 7.5 Hz, 1H, Ar-H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 19.2 (CH3), 111.6 (CH), 117.5 (CH), 119.3
(CH), 120.4 (CH), 121.0 (C), 122.5 (CH), 124.9 (C), 125.5 (CH), 127.3
(C), 127.7 (CH), 128.8 (CH), 129.6 (CH), 129.7 (CH), 129.9 (C), 134.0
(C), 134.2 (C), 136.9 (C), 137.4 (C) ppm. IR spectrum (KBr): ν = 3400,
3026, 2916, 2858, 1604 cm−1. HRMS (Q-TOF): calcd. for C19H14NClNa
[M + Na]+ 314.0707; found 314.0706.
6-chloro-2-methyl-1-phenyl-4,9-dihydro-3H-carbazole
(9b):
Magnesium turnings (540.0 mg, 20.0 mmol) and a few crystals (2-3) of
iodine were taken in a two necked round bottom flask and warmed to
activate the Mg. To it 6.0 mL. dry THF, 1,2-dibromoethane (6-8 drops)
were placed and the flask was flashed with nitrogen gas followed by
stirred at room temperature in N2-atmosphere. Then in an another flask
bromobenzene (2.1 mL., 20 mmol) was taken in 15.0 mL dry THF.
Initially 5.0 mL solution of boromobenzene was injected to the reaction
mixture through stoppered inlet of the flask and warmed at 70-80 °C
under inert condition. When the reaction mixture started to boil remaining
solution of bromobenzene was injected to it and the reaction mixture was
allowed to boil for about 30 min. Afterwards the solution of 2-methyl-
2,3,4,9-tetrahydro-1H-carbazol-1-one (3a, 2.3 g, 10.0 mmol) in dry THF
3-Bromo-2-methylaniline (17): To the methanol (50 mL) solution of 1-
bromo-2-methyl-3-nitrobenzene (16, 5.4 g, 25.0 mmol), NH4Cl solution
(2.5 g in 100 mL water), iron powder (12.5 g) and charcoal (1.0 g) were
added and the reaction mixture was heated under reflux for 4 hr. After
cooling to room temperature the reaction mixture was filtered and the
residue was washed with ether. Then the filtrate portion was extracted
with ether (4 × 25 mL). Ether layer was washed with brine solution and
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800187
European Journal of Organic Chemistry
FULL PAPER
then dried over anhydrous Na2SO4. Evaporation of ether afforded 3-
bromo-2-methylaniline (17, 4.3 g, yield 92%) as pale yellow oil,30 b.p.
245 °C; 1H NMR (300 MHz, CDCl3): δ = 2.28 (s, 3H, Ar-CH3), 3.65 (s, 2H,
NH2), 6.60 (d, J = 7.2, 1H, Ar-H), 6.88 (t, 1H, Ar-H), 7.03 (d, J = 7.2 Hz,
1H, Ar-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 16.8 (CH3), 114.0 (CH),
121.8 (CH), 122.6 (CH), 125.8 (C), 127.5 (C), 145.8 (C) ppm. IR
spectrum (KBr): ν = 3352, 3323, 2982, 2947, 1573 cm−1. HRMS (Q-TOF):
calcd. for C7H8BrNNa [M + Na]+ 207.9734; found 207.9736.
4-Acetamido-3-bromo-2-methylphenol (21): To the warm (~60°C)
aqueous suspension of 4-amino-3-bromo-2-methylphenol (20, 2.0 g, 10.0
mmol in 25.0 mL water), acetic anhydride (1.0 mL, 10.0 mmol) was
added in all at once with stirring. The whole reaction mixture was kept on
hot water bath for 1 hr. with occasional shaking. This was cooled to room
temperature and then cooled in freeze overnight. The brownish solid thus
formed was collected through filtration and then crystallized from water
along with the charcoal treatment for purification to afford N-(2-bromo-4-
hydroxy-3-methylphenyl)acetamide
or
4-acetamido-3-bromo-2-
methylphenol (21, 2.1 g, yield 89%) as white crystals, m.p. 159 °C; 1H
NMR (300 MHz, DMSO-d6): δ = 1.97 (s, 3H, CH3), 2.20 (s, 3H, Ar-CH3),
6.76 (d, J = 5.1, 1H, Ar-H), 7.04 (d, J = 5.1 Hz, 1H, Ar-H), 9.25, (s, 1H,
OH), 9.77 (s, 2H, NH2) ppm. 13C NMR (75 MHz, DMSO-d6): δ = 16.3
(CH3), 23.0 (CH3), 113.5 (CH), 123.6 (CH), 124.3 (C), 126.0 (C), 128.0
(C), 153.8 (C), 168.5 (C) ppm. IR spectrum (KBr): ν = 3531, 3220, 3053,
2925, 1625 cm−1. HRMS (Q-TOF): calcd. for C9H10BrNO2H [M + H]+
243.9969; found 243.9971.
3-Bromo-2-methylphenol (18): 3-Bromo-2-methylaniline (17, 6.3 g, 34.0
mmol) was taken in dilute H2SO4 solution (6.2 mL conc. H2SO4 in 30 mL
water) and cooled to 0 °C in ice-salt bath. This was diazotized with aq.
NaNO2 solution (2.76 g, 40 mmol in 10 mL water) under cold condition
maintaining reaction temperature around 0-5 °C during 45 min. After
diazotization the reaction mixture was diluted with ice-water (60 mL) and
treated with pinch of urea to remove excess nitrous acid. In the mean
time mixture of anhydrous Na2SO4 (12.75 g), conc. H2SO4 (15.3 mL) and
water (10 mL) was heated in oil bath at about 150 °C. To this hot solution
cooled diazotized solution was added in portion-wise during half an hour
and when the evolution of nitrogen was ceased the reaction mixture was
heated under reflux for 1 hr. The reaction mixture was then allowed to
cool at room temperature and extracted with ether (5×50mL). Ether
extract was washed with brine solution (1×40mL) followed by water
(1×40mL) and then dried over anhydrous Na2SO4. Evaporation of ether
yielded low melting 3-bromo-2-methylphenol (18, 4.6 g, yield 73%) as
needle like crystals of m.p. 97 °C (ref.31 95 °C); 1H NMR (300 MHz,
CDCl3): δ = 2.32 (s, 3H, Ar-CH3), 4.41 (s, br, 1H, OH), 6.70 (d, J = 4.8,
1H, Ar-H), 6.90 (t, 1H, Ar-H), 7.13 (d, J = 4.8 Hz, 1H, Ar-H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 15.15 (CH3), 113.66 (CH), 124.14 (CH),
124.58 (C), 125.68 (CH), 127.04 (C), 153.93 (C) ppm. IR spectrum (KBr):
ν = 3288, 2923, 2854, 1579 cm−1. HRMS (Q-TOF): calcd. for C7H7BrOH
[M + H]+ 186.9756; found 186.9759.
N-(2-bromo-4-methoxy-3-methylphenyl)acetamide (22): To the
solution of N-(2-bromo-4-hydroxy-3-methylphenyl)acetamide (21, 2.4 g,
10.0 mmol) in acetone (25 mL) anhydrous potassium carbonate (1.38 g,
10.0 mmol) and iodomethane (0.6 mL, 10.0 mmol) were added. The
reaction mixture was heated under reflux on hot water bath with
circulation of ice cold water through condenser for 2 hr. Afterwards the
reaction mixture was poured in ice-water (100 mL) whereby the required
methoxy derivative 22 was separated out. This crude product was
collected by filtration and leached with cold solution 1% NaOH (15 mL)
followed by cold water. It was then crystallized from aqueous methanol to
afford N-(2-bromo-4-methoxy-3-methylphenyl)acetamide (22, 2.4 g, yield
94%) as bright white crystals, m.p. 137 °C; 1H NMR (300 MHz, CDCl3): δ
= 2.21 (s, 3H, CH3), 2.33 (s, 3H, Ar-CH3), 3.81(s, 3H, -OCH3), 6.80 (d, J
= 5.4, 1H, Ar-H), 7.51 (s, 2H, NH2), 7.98 (d, J = 5.1, 1H, Ar-H) ppm. 13C
NMR 75 MHz, CDCl3): δ = 16.0 (CH3), 24.2 (CH3), 55.6 (CH3), 109.0
(CH), 118.1 (CH), 120.1 (C), 126.7 (C), 128.4 (C), 154.3 (C), 167.8 (C)
4-Amino-3-bromo-2-methylphenol (20): In 250 mL conical flask 5.25 g
(30.0 mmol) of sulfanilic acid was suspended in 50 mL of water. It was
then neutralized by using 1.6 g (15.0 mmol) of sodium carbonate in 50
mL of water. Resulted clear solution was cooled to 0 °C in ice-water bath.
To this cold solution sodium nitrite solution (2.0 g, 30.0 mmol in 10 mL
water) was added and this reaction mixture was then poured into ice-
hydrochloric acid mixture (5.5 mL of conc. HCl and 30 g of ice) to obtain
ppm. IR spectrum (KBr): ν = 3267, 2925, 2844, 1652 cm−1
. HRMS (Q-
TOF): calcd. for C10H12BrNO2Na [M + Na]+ 279.9944; found 279.9946.
2-Bromo-4-methoxy-3-methylbenzenaminium chloride (23): N-(2-
bromo-4-methoxy-3-methylphenyl)acetamide (22, 2.5 g, 10.0 mmol) was
dissolved in ethanol (15.0 mL) by boiling and concentrated HCl (15.0 mL)
was added drop-wise under reflux during 1 hr. After 3 hr, the solution was
cooled when the crystals of amine hydrochloride (23) separated out,
which was collected by filtration to furnish colourless crystals (2.2 g, yield
86%), m.p. 218 °C (dec.). 1H NMR (400 MHz, DMSO-d6): δ = 2.24 (s, 3H,
Ar-CH3), 3.79 (s, 3H, -OCH3), 7.05 (d, J = 8.8 Hz, 1H, Ar-H), 7.07 (d, J =
8.8 Hz, 1H, Ar-H), 7.50 (s, 2H, NH2) ppm. 13C NMR (100 MHz, DMSO-d6)
δ = 16.00 (CH3), 56.29 (-OCH3), 110.34 (CH), 119.58 (CH), 121.93 (C),
124.87 (C), 127.38 (C), 156.44 (C) ppm..
finely divided crystals of diazobenzene sulfonate.
The aqueous
suspension was then kept in freeze. In the mean time 3-bromo-
2methylphenol (18, 5.6 g, 30.0 mmol in 20 mL 10% NaOH) was
dissolved in aq, alkali and solution was cooled to 0-5 °C in ice-water bath.
To this cold solution the aqueous suspension of diazobenzene sulfonate
was added all at once with stirring. Colored dye with pasty mass
appeared instantly. The whole reaction mixture was then kept in freeze
for 30 min. The reaction mixture was then warmed on water bath to
dissolve the pasty mass and then 25 g of sodium chloride was dissolved
in the warm solution. To this warm alkaline solution solid sodium
dithionate (25.0 g) was added in portions with stirring until the dark red
color of the solution was discharged. The reaction mixture was then
cooled in freeze. A solid mass was separated out which was collected
through filtration and washed with very little amount of cold water to
obtain 4-amino-3-bromo-2-methylphenol (20, 3.9 g, yield 66%) as light
brown solid, m.p. 161 °C; 1H NMR (400 MHz, DMSO-d6): δ = 2.15 (s, 3H,
Ar-CH3), 4.79 (s, br, 1H, OH), 6.54 (d, J = 5.1, 1H, Ar-H), 6.60 (d, J = 5.1,
1H, Ar-H), 8.76 (s, 2H, NH2) ppm. 13C NMR (100 MHz, DMSO-d6): δ =
16.1 (CH3), 112.3 (CH), 113.2 (CH), 114.8 (C), 123.6 (C), 137.9 (C),
146.7 (C) ppm. IR spectrum (KBr): ν = 3350, 3261, 2923, 2804, 1604
cm−1. HRMS (Q-TOF): calcd. for C7H8BrNOH [M + H]+ 201.9864; found
201.9866.
2-(2-Bromo-4-methoxy-3-methylphenyl)hydrazono)cyclohexanone
(26): 2-Hydroxymethylene-cyclohexanone[20] (24, 1.26 g,10.0 mmol) in
methanol (10 mL) was added to an aqueous solution of sodium acetate
(2.2 g, 15 mL of water). To this a solution of 2-bromo-4-methoxy-3-
methylphenyldiazonium chloride (25, prepared from 2.52 g, 10.0 mmol of
2-bromo-4-methoxy-3-methylbenzenaminium chloride, 23) was added
under mechanical agitation and the stirring was continued for 4 hr. when
red solid of 26 was obtained. Filtration and crystallization from methanol
yielded red crystals of 26 (2.6 g, yield 82%), m.p. 127 °C. Rf = 0.7
(benzene/chloroform/diethylamine, 14:5:1); 1H NMR (500 MHz, DMSO-
d6): δ = 1.76 (q, 4H, CH2), 2.22 (s, 3H, Ar-CH3), 2.48 (t, 2H, CH2), 2.61 (t,
2H, CH2), 3.84 (s, 3H, -OCH3), 7.02 (d, J = 11.0, 1H, Ar-H), 7.43 (d, J =
11.5, 1H, Ar-H), 13.85 (s, 1H, NH) ppm. 13C NMR (125 MHz, DMSO-d6):
δ = 16.0 (CH3), 21.7 (CH2), 22.8 × 2 (CH2), 31.8 (CH2), 56.3 (CH3), 111.5
× 2 (CH), 112.5 (C), 126.3 (C), 134.0 (C), 134.6 (C), 153.3 (C), 197.5
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800187
European Journal of Organic Chemistry
FULL PAPER
(C=O) ppm. IR spectrum (KBr): ν = 3467, 3006, 2939, 1660, 1625 cm−1
HRMS (Q-TOF): calcd. for C14H17BrN2O2Na [M + Na]+ 347.0346; found
347.0349.
;
(CH), 119.6 (CH), 120.4 (C), 121.3 (CH), 124.1 (C), 125.5 (C), 125.8 (C),
133.6 (C), 139.4 (C), 152.7 (C) ppm. IR spectrum (KBr): ν = 3410, 2932,
1632 cm−1. HRMS (Q-TOF): calcd. for C20H17NONa [M + Na]+ 310.1202;
found 310.1204.
8-Bromo-6-methoxy-7-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one
(12): 2-(2-Bromo-4-methoxy-3-methylphenyl)hydrazono)cyclohexanone
(26, 1.6 g, 5.0 mmol) was heated under reflux with glacial acetic acid
(12.8 mL) containing concentrated HCl (3.2 mL) for 3 min. and the hot
reaction mixture was poured in ice water (50.0 mL). The semi-solid mass
thus obtained was collected by filtration, washed with water, dried, and
then chromatographed over silica gel (10 g) and the column was eluted
with hexane–dichloromethane (3:2). The eluent gave colourless crystals
Deoxycarbazomycin B (1A): Similar Suzuki cross-coupling reaction
over 1-Bromo-3-methoxy-2-methyl-9H-carbazole (11, 290.0 mg, 1.0
mmol) with methylboronic acid (70.0 mg, 1.2 mmol) and
tetrakis(triphenylphosphine)-palladium (0) (25.0 mg, 0.022 mmol) for 60
hr. yielded 3-methoxy-1,2-dimethyl-9H-carbazole, 4-deoxycarbazomycin
B (1A) as a white solid (126.0 mg, 56% yield), m.p. 131 °C (ref.[20a] 129 -
130 °C). Rf = 0.7 (benzene/chloroform/diethylamine, 14:5:1); 1H NMR
(500 MHz, CDCl3): δ = 2.45 (s, 3H, Ar-CH3), 2.52 (s, 3H, Ar-CH3), 3.94
(s, 3H, -OCH3), 7.18 (d, J = 7.5 Hz, 1H, Ar-H), 7.25-7.32 (m, 2H, Ar-H),
7.36 (s, 1H, Ar-H), 7.66 (s, 1H, NH), 7.80 (d, J = 8.5 Hz, 1H, Ar-H) ppm.
13C NMR (125 MHz, CDCl3): δ = 12.3 (CH3), 13.8 (CH3), 56.3 (OCH3),
99.0 (CH), 110.4 (CH), 119.0 (C), 119.8 (CH), 120.1 (C), 124.0 (CH),
124.3 (C), 126.3 (CH), 128.2 (C), 134.5 (C), 137.9 (C), 152.5 (C) ppm. IR
spectrum (KBr): ν = 3428, 2944, 1640 cm−1. HRMS (Q-TOF): calcd. for
C15H15NONa [M + Na]+ 248.1051; found 248.1054.
of 12 (1.2 g, yield 78%), m.p. 212 °C (dec.). Rf
=
0.5
(benzene/chloroform/diethylamine, 14:5:1); 1H NMR (400 MHz, DMSO-
d6): δ = 2.26 (q, 2H, CH2), 2.47 (s, 3H, Ar-CH3), 2.63-2.69 (m, 2H, CH2),
3.04 (t, 2H, CH2), 3.97 (s, 3H, -OCH3), 7.26 (s, 1H, Ar-H), 11.38 (s, 1H,
NH) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 16.1 (CH3), 21.0 (CH2),
24.5 (CH2), 38.3 (CH2), 56.0 (CH3), 99.7 (CH), 108.0 (C), 123.9 (C),
126.3 (C), 128.8 (C), 131.6 (C), 132.4 (C), 152.4 (C), 189.8 (C) ppm. IR
spectrum (KBr): ν = 3288, 3261, 2945, 2914, 1666, 1642 cm−1. HRMS
(Q-TOF): calcd. for C14H14BrNO2Na [M + Na]+ 330.0100; found 330.0102.
Supporting Information (see footnote on the first page of this article):
1-Bromo-3-methoxy-2-methyl-9H-carbazole (11): Compound 12 (1.5 g,
5.0 mmol) in ethylene glycol (10 mL) was heated with hydrazine hydrate
(80%, 4.5mL ) and KOH (1.7g) at 190 °C for 1 hr. and then up to 210 °C
under reflux for 3 hr. The reaction mixture was poured into ice-water and
then extracted with diethyl ether (3 × 75 mL). The combined ether layers
were dried (Na2SO4) and the solvent was distilled off, when a residue
(1.4 g) of the corresponding tetrahydrocarbazole derivative was obtained.
The residue was used for the next step without further purification. Crude
tetrahydrocarbazole derivative (1.4 g) was taken in decalin (10 mL) and
then Pd-C (l0%, 500 mg) added. The mixture was then refluxed for 5 hr.
After reaction, decalin was removed by distillation under vacuum. The
residue was subjected to flash chromatography on silica gel G and eluted
with hexane to afford 3-methoxy-2-methyl-9H-carbazole (27) (120.0 mg,
yield 11%) and with hexane-dichloromethane (9:1) to furnish 1-bromo-3-
methoxy-2-methyl-9H-carbazole32 (11, 950 mg, yield 65%), m.p. 168 °C.
Rf = 0.8 (benzene/chloroform/diethylamine, 14:5:1); 1H NMR (300 MHz,
CDCl3): δ = 2.50 (s, 3H, CH3) 3.95 (s, 3H, -OCH3), 7.21 - 7.26 (m, 1H, Ar-
H), 7.39 - 7.46 (m, 3H, Ar-H), 7.99 (d, J = 6.0 Hz, 1H, Ar-H) 8.07 (s, 1H,
NH) ppm. 13C NMR (75 MHz, CDCl3): δ = 16.0 (CH3), 56.7 (CH3), 100.8
(CH), 107.4 (C), 111.1 (CH), 119.6 (C), 120.4 (CH), 121.3 (CH), 124.1
(C), 125.5 (C), 125.8 (CH), 133.6 (C), 139.4 (C), 152.7 (C) ppm. IR
spectrum (KBr): ν = 3384, 2952, 2924, 1608, 1588 cm−1. HRMS (Q-TOF):
calcd. for C14H12BrNOH [M + H]+ 290.0176; found 290.0174.
1H and 13C NMR spectra for all key intermediates.
Acknowledgements
The author (S.C.) is grateful to Dr. Samir kanti Dutta (Vice
Principle, Science) of The Bhawanipur Education Society
College, Kolkata for his interest and support in this work and the
laboratory provided by the college. The authors are also thankful
to the Department of Clinical & Experimental Pharmacology of
the School of Tropical Medicine, Kolkata.
Keywords: marine alkaloid• natural product • Suzuki-Miyaura
cross-coupling • hyellazole • 4-deoxycarbazomycin B • total
synthesis
[1]
[2]
W. Fröhner, M. P. Krahl, K. R. Reddy, H.-J. Knölker, Heterocycles 2004,
63, 2393-2407.
D. P. Chakraborty, S. Roy in Progress in the Chemistry of Organic
Natural Products, Vol. 57 (Eds.: W. Herz, H. Grisebach, G. W. Kirby, W.
Steglich, C. Tamm), Springer- Wien, 1991, pp. 71-77.
D. P. Chakraborty in The Alkaloids, Vol. 44 (Eds.: G. A. Cordell),
Academic Press: New York, 1993, pp. 257-268.
[3]
Hyellazole (1): 1-Bromo-3-methoxy-2-methyl-9H-carbazole (11, 725.0
mg, 2.5 mmol) and tetrakis(triphenylphosphine)-palladium (0) (50.0 mg,
0.044 mmol) were stirred in 1,2-dimethoxyethane (25 mL) for 30 min. A
solution of phenylboronic acid (312.0 mg,, 2.55 mmol) and potassium
carbonate (345.0 mg, 2.5 mmol) in water (10 mL) was added to it and the
mixture was refluxed for 72 hr. The solvent was then removed by
evaporation and the residue was extracted with dichloromethane. The
organic layer was washed with brine solution and the dried over
anhydrous sodium sulfate. After evaporation of dichloromethane the
residue was subjected to flash chromatography on silica gel G with
hexane-dichloromethane (9:1) to afford 3-methoxy-2-methyl-1-phenyl-
9H-carbazole, Hyellazole (1) as a white solid (510.0 mg, 71% yield), m.p.
134 °C (ref.[14] 132-134 °C). Rf = 0.8 (benzene/chloroform/diethylamine,
[4]
[5]
H.-J. Knölker , K. R. Reddy, Chem. Rev. 2002, 102, 4303-4428.
D. P. Chakraborty, S. Roy in Progress in the Chemistry of Organic
Natural Products, Vol. 85 (Eds.: W. Herz, H. Grisebach, G. W. Kirby, W.
Steglich, C. Tamm), Springer- Wien, 2003, pp.125-134.
H.-J. Knölker, Curr. Org. Synth. 2004, 1, 309-331.
[6]
[7]
J. H. Cardellina II, M. P. Kirkup, R. E. Moore, , J. S. Mynderse, K. Seff,
C. J. Simmons, Tetrahedron Lett. 1979, 4915-4916.
[8]
[9]
a) S. Kano, E. Sugino, S. Hibino, J. Chem. Soc., Chem. Commun. 1980,
1241-1242; b) S. Kano, E. Sugino, S. Shibuya, S. Hibino, J. Org. Chem.
1981, 46, 3856-3859.
S. Takano, Y. Suzuki, K. Ogasawara, Heterocycles 1981, 16, 1479-
1480.
1
14:5:1); H NMR (300 MHz, CDCl3): δ = 2.50 (s, 3H, CH3) 3.95 (s, 3H, -
[10] a) T. Kawasaki, Y. Nonaka, M. Sakamoto, J. Chem. Soc., Chem.
Commun. 1989, 43-44; b) T. Kawasaki, Y. Nonaka, M. Akahane, N.
Maeda, M. Sakamoto, J. Chem. Soc., Perkin Trans. 1. 1993, 1777-
1781.
OCH3), 6.59 (d, J = 8.4 Hz, 1H, Ar-H), 6.90 – 7.14 (m, 2H, Ar-H), 7.21-
7.30 (m, 2H, Ar-H), 7.36 (d, J = 9.0 Hz, 1H, Ar-H), 7.47-7.63 (m, 3H, Ar-
H), 7.69-7.72 (m, 1H, Ar-H), 7.98 (s, br, 1H, NH) ppm. 13C NMR (125
MHz, CDCl3): δ = 14.6 (CH3), 56.3 (CH3), 110.6 (CH), 107.4 (CH), 111.1
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800187
European Journal of Organic Chemistry
FULL PAPER
[11] a) C. J. Moody, P. Shah, J. Chem. Soc., Perkin Trans. 1. 1989, 376-
377; b) C. J. Moody, P. Shah, J. Chem. Soc., Perkin Trans. 1. 1989,
2463-2471.
[12] R. L. Danheiser, R. G. Brisbois, J. J. Kowalczyk, R. F. Miller, J. Am.
Chem. Soc. 1990, 112, 3093-3100.
[13] E. M. Beccalli, A. Marchesini, T. Pilati, J. Chem. Soc., Perkin Trans. 1.
1994, 579-587.
[14] a) H.-J. Knölker, E. Baum, T. Hoffmann, Tetrahedron Lett. 1995, 36,
5339-5342; b) H.-J. Knölker, E. Baum, T. Hoffmann, Tetrahedron 1999,
55, 10391-10412.
[15] a) T. Choshi, T. Sada, H. Fujimoto, C. Nagayama, E. Sugino, S. Hibino,
Tetrahedron Lett. 1996, 37, 2953-2956; b) T. Choshi, T. Sada, H.
Fujimoto, C. Nagayama, E. Sugino, S. Hibino. J. Org. Chem. 1997, 62,
2535-2543.
[16] a) B. Witulski, C. Alayrac, Angew. Chem. Int. Ed. 2002, 41, 3281-3284;
b) B. Witulski, C. Alayrac, Angew. Chem. 2002, 114, 3415-3418.
[17] E. Duval, G. D. Cuny, Tetrahedron Lett. 2004, 45, 5411-5413.
[18] a) H.-J. Knölker, W. Fröhner, R. Heinrich, Synlett. 2004, 15, 2705–
2708; b) A. Banerjee, S. Sahu, M. S. Maji, Adv. Synth. Catal. 2017, 359,
1860-1866.
[19] a) N. Miyaura, K. Yamada, A. Suzuki, Tetrahedron Lett. 1979, 36,
3437-3440; b) T. Oh-e, N. Miyaura, A. Suzuki, J. Org. Chem. 1993, 58,
2201-2208; c) N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457-2483;
d) A. Suzuki in Metal-Catalyzed Cross-Coupling Reactions, (Eds.: F.
Diederich, P. J. Stang), Wiley-VCH: Weinheim, Germany, 1998, pp.
Chapter 2; e) A. Suzuki, J. Organomet. Chem. 1999, 576, 147-168; f) N.
Miyaura, Top. Curr. Chem. 2002, 219, 11-59.
[20] a) C. Saha, A. Chakraborty, B. K. Chowdhury, Indian J. Chem. 1996,
35B, 677–680; b) C. Saha, B. K. Chowdhury, Phytochemistry 1998, 48,
363–366; c) W. He, B. Zhang, Synth. Comm. 2005, 35, 1359-1368; d)
S. Chakraborty, G. Chattopadhyay, C. Saha, Indian J. Chem. 2011,
50B, 201-206.
[21] K. R. Dahnke, L. A. Paquette, Org. Synth. 1993, 71, 181-184.
[22] J. Młochowski, H. Wójtowicz-Młochowska, Molecules 2015, 20, 10205-
10243.
[23] P. J. Harrington, L. S. Hegedus, J. Org. Chem. 1984, 49(15), 2657-
2662.
[24] H. E. Ungnade, E. F. Orwoll, Org. Synth. 1943, 23, 11-12.
[25] B. S. Furniss, A. J. Hannaford, P. W. G. Smith, A. R. Tatchell in Vogel’s
Textbook of Practical Organic Chemistry, (Eds.: 4th, ELBS), Longan,
London, 1986, pp. 718-780.
[26] S. Chakraborty, C. Saha, Eur. J. Org. Chem. 2013, 25, 5731-5736.
[27] D. P. Chakraborty, P. Bhattacharyya, S. Roy, S. P. Bhattacharyya, A. K.
Biswas, Phytochemistry 1978, 17, 834-855.
[28] a) T. Ishiyama, H. Kizaki, N. Miyaura, A. Suzuki, Tetrahedron Lett. 1993,
34, 7595-7596; b) T. Oh-e, N. Miyaura, A. Suzuki, J. Org. Chem. 1993,
58, 2201-2208.
[29] H. K. Sen, S. K. Ghosh, J. Indian Chem. Soc. 1927, 4, 477-480.
[30] S. B. Larsen, B. A. Benny, T. N. Johansen, M. Jorgensen, Tetrahedron
2008, 64(13), 2938-2950.
[31] B. E. Cross, J. Chem. Soc. 1960, 3038-3040.
[32] A. Hänchen, R. D. Süssmuth, Synlett 2009, 15, 2483-2486.
This article is protected by copyright. All rights reserved.