Short synthesis of carbazole alkaloids: Ekeberginine, murrayaquinone A, and glycozoline

Article abstract of DOI:10.1080/00397911.2016.1192652

Three differently substituted, naturally occurring, biologically active carbazole derivatives (viz. ekeberginine, murrayaquinone A, and glycozoline) were synthesized in good yield using short and simple routes. The prenyl group was selectively introduced at the C4 position using a Stille coupling reaction in the synthesis of ekeberginine. Murrayaquinone A was synthesized using Raney nickel–mediated desulfurization of dithiane as a key step. Synthesis of glycozoline was achieved in two steps from 3-methyl carbazole via an intermediate 3-bromo-6-methyl carbazole.

Full text of DOI:10.1080/00397911.2016.1192652

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
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A Short Synthesis of Carbazole Alkaloids -
Ekeberginine, Murrayaquinone a and Glycozoline
Aadil A. Momin, Tukaram D. Urmode, Shrikar M. Bhosale & Radhika S.
Kusurkar
To cite this article: Aadil A. Momin, Tukaram D. Urmode, Shrikar M. Bhosale & Radhika S.
Kusurkar (2016): A Short Synthesis of Carbazole Alkaloids - Ekeberginine, Murrayaquinone a
and Glycozoline, Synthetic Communications, DOI: 10.1080/00397911.2016.1192652
To link to this article: http://dx.doi.org/10.1080/00397911.2016.1192652
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Date: 22 June 2016, At: 04:19

A SHORT SYNTHESIS OF CARBAZOLE ALKALOIDS - EKEBERGININE,
MURRAYAQUINONE A AND GLYCOZOLINE
1
1
1
1
Aadil A. Momin , Tukaram D. Urmode , Shrikar M. Bhosale , Radhika S. Kusurkar
1
Department of Chemistry, Savitribai Phule Pune University, Pune, India-411 007.
Address correspondence to Radhika. S. Kusurkar, Department of Chemistry, Savitribai
Phule Pune University, Pune-411007, Maharashtra, India.
E-mail: rsk@chem.unipune.ac.in
Abstract
Three differently substituted naturally occurring, biologically active carbazole derivatives
viz. ekeberginine, murrayaquinone A and glycozoline were synthesized in good yield
using short and simple routes. Prenyl group was selectively introduced at C4 position
using Stille coupling reaction in the synthesis of ekeberginine. Murrayaquinone A was
synthesized using Raney nickel mediated desulfurization of dithiane as a key step.
Synthesis of glycozoline was achieved in two steps from 3-methyl carbazole via an
intermediate 3-bromo-6-methyl carbazole.
KEYWORDS: ekeberginine, murrayaquinone A, glycozoline, Stille coupling
1

INTRODUCTION
Several carbazole derivatives have been isolated from different natural sources especially
from angiosperms of the family Rutaceae. The C-prenyl carbazole alkaloid, ekeberginine
[
1]
(
1, Figure 1), was first isolated from the stem bark of the plant Ekebergia senegalensis
[
2]
of Meliaceae family and later from Clausena anisata of Rutaceae family. Ekeberginine
showed antitumor activity and was shown to be more effective against TPA-induced
[
3]
EBV-EA activation in Raji cells.
[
4]
Murrayaquinone A (2, Figure 1) was the first carbazole-1,4-quinone alkaloid, isolated
from root bark of the plant Murraya euchrestifolia HAYATA and was found to show
[
5]
cardiotonic activity on guinea pig papillary muscle.
[
6]
Glycozoline (3, Figure 1) was initially isolated from stem bark of the Indian medicinal
plant Glycosmis pentaphylla and subsequently from roots of the plant Clausena
[
7]
[8]
lansium from Rutaceae family. Recently, it was isolated from the roots and twigs of
Glycosmis macrophylla. Glycozoline was proved to have antibacterial, antifungal,
[
9a-b]
antifeedant and antiinflammatory activities.
[
10]
There are two methods reported so far for the synthesis of ekeberginine and several
[
11]
routes are known for the synthesis of murrayaquinone A and glycozoline. Earlier we
[
12]
have reported three different routes for the synthesis of murrayaquinone A. In
continuation with this, we are here in describing a new simple and short synthetic method
for each of these alkaloids.
2

RESULTS AND DISCUSSION
Synthesis of Ekeberginine (1)
Synthesis of ekeberginine was started with carbazole 4 (Scheme 1) which was in turn
[
12]
synthesized in two steps using our reported procedure. Compound 4 was selectively
protected using triflic anhydride and triethylamine to get triflate ester 5 in 90% yield.
Subsequently ester 5 was subjected to Stille coupling by treatment with tributyl (3-
methylbut-2-en-1-yl) stannane and tetrakistriphenylphosphine palladium, to get prenyl
substituted carbazole 6 (85% yield) in which the coupling has taken place selectively at
C4, replacing –OTf in presence of C-Br bond. This result was in accordance with our
[
13]
earlier observation. Finally, the synthesis of the target compound ekeberginine (1) was
achieved (80% yield) by methoxylation of compound 6 using excess of sodium
methoxide and stoichiometric amount of copper (I) iodide.
Synthesis of Murrayaquinone A (2)
As shown in Scheme 2, synthesis of murrayaquinone A was achieved in three steps from
[
12]
3
-formyl-4-hydroxy carbazole 7. Aldehyde group of compound 7 was protected using
propane-1,3-dithiol to furnish compound 8 in 90% yield. Further, treatment of dithiane 8
with PCC in DCM gave a brown solid product which was shown to be quinone 9 using
spectral and analytical data. Having compound 9 in hand, the desulfurization was
successfully achieved using Raney nickel in a Parr reactor under hydrogen gas pressure at
o
1
00 C to get the target compound 2.
Synthesis of Glycozoline (3)
3

Synthesis of glycozoline (3) was an accidental outcome of a planned synthesis of a
carbazole alkaloid murrayanine (11) from 3-methyl carbazole (10) as shown in
retrosynthetic analysis in Scheme 3. Carbazole 10 was synthesized from 4-methyl
[
14]
cyclohexanone and phenyl hydrazine using reported procedure.
Bromination of compound 10 using N-bromosuccinimide in DMF, gave a white solid
product. Considering the reactivity of carbazole towards electrophilic substitution
reaction, the two expected products were 12 and 13 (Scheme 4). The spectral data
indicated a disubstituted carbazole structure for the product having methyl and bromine
[
15]
as the substituents and it was not matching with the reported data of compound 12.
Thus, the product could be having structure 13. As the expected intermediate 12 was not
obtained, the plan was diverted towards the synthesis of glycozoline (3). Thus,
methoxylation of the above product on treatment with sodium methoxide and CuI
resulted into a white solid as shown in Scheme 4. The structure of final product was
[
9a]
confirmed as glycozoline (3) by comparing the NMR data with the reported data. The
formation of glycozoline (3) confirmed the structure of the bromination product in the
previous reaction as 13.
Thus, the synthesis of glycozoline was achieved coincidentally instead of the synthesis of
targeted carbazole. Subsequently, the importance of compound 13 was revealed from its
[
16]
use as an intermediate for the synthesis of a significantly active anticancerous
compound.
4

EXPERIMENTAL
Preparation of 1-Bromo-4-(3-Methylbut-2-Enyl)-9H-Carbazole-3-Carbaldehyde (6)
To a solution of compound 5 (0.2 g, 0.47 mmol) in dry DMF (10 ml) kept under nitrogen
atmosphere, were added tetrakistriphenylphosphine palladium (0.054 g, 0.047 mmol) and
tributyl (3-methylbut-2-en-1-yl) stannane (0.169 g, 0.47 mmol).Reaction mixture was
o
then heated at 90 C for 2 hours. Then water was added to the reaction mixture and
extracted with ethyl acetate (3 X 15 ml). Combined organic layer was washed with brine
and dried on anhydrous sodium sulphate. The residue obtained after evaporation of
organic layer was chromatographed using 2% ethyl acetate/hexane as an eluent system
o
1
which gave white colored product 6 in 85% yield (0.139 g). M. p. 210 C; H NMR (300
MHz, CDCl ) δ: 1.72 (s, 3H), 1.92 (s, 3H), 4.35 (d, J = 6.2 Hz, 2H), 5.29 (t, J = 6.2 Hz,
H), 7.33-7.65 (m, 3H), 8.16 (s overlapped on d, J = 7.7 Hz, 2H), 8.60 (br. s, 1H), 10.37
3
1
1
3
(
s, 1H); C NMR (75 MHz, CDCl
3
) δ: 18.2, 25.9, 27.8, 102.7, 111.5, 121.1, 121.3,
1
1
3
23.5, 123.9, 126.7, 127.6, 129.6, 133.8, 139.4, 141.4, 189.9; FT-IR (KBr): 3174, 2920,
-1
+
723, 1654, 729 cm ; HRMS (ESI): (M+Na) calculated for C18
H16BrNO is m/z
64.0313; found at m/z 364.0304.
Preparation of 1-Methoxy-4-(3-Methylbut-2-En-1-Yl)-9H-Carbazole-3-
Carbaldehyde (1)
To a solution of compound 6 (0.1 g, 0.292 mmol) in dry DMF (10 ml) were added, CuI
(0.061 g, 0.322 mmol) and sodium methoxide (0.158 g, 2.92 mmol) in methanol (3 ml).
o
Reaction was degassed by nitrogen and kept at 120 C for 4 hours. Then reaction was
quenched by addition of water (30 ml). Reaction mixture was extracted with ethyl acetate
5

2 4
(3 X 10 ml) and combined organic layers were dried on Na SO , filtered, filtrate was
concentrated under reduced pressure using rota vapor and the residue was purified by
column chromatography (using 7% ethyl acetate/hexane as an eluent), which gave white
o
[10a]
colored solid compound 1 in 80% yield (0.069 g). M. p. 228-230 C (lit.
M. p. 227.5-
) δ: 1.64 (s, 3H), 1.87 (s, 3H), 4.01 (s, 3H), 4.29 (d, J
6.2 Hz, 2H), 5.31 (t, J = 5.9 Hz, 1H), 7.28 (t, J = 7.8 Hz, 1H), 7.41-7.53 (m, 3H), 8.12
o
1
2
29 C); H NMR (300 MHz, CDCl
3
=
1
3
(
d, J = 7.2 Hz, 1H), 8.62 (br. s, 1H), 10.41 (s, 1H); C NMR (75 MHz, CDCl
3
) δ: 18.7,
5.9, 27.2, 56.1, 105.0, 111.8, 121.0, 122.6, 122.9, 123.4, 124.0, 126.3, 126.8, 133.2,
34.6, 137.0, 139.8, 144.4, 190.9.
2
1
Preparation of 3-(1,3-Dithian-2-Yl)-9H-Carbazol-4-Ol (8)
Thionyl chloride (2.0 g, 1.23 ml) was added drop wise to the stirred mixture of silica (2.0
o
g) in DCM (5 ml) at 0 C. After addition, the DCM was evaporated at room temperature
to get thionyl chloride loaded dry silica powder. Transfer the above silica into 100 ml
round bottom flask containing magnetic needle and dry toluene (25 ml). Then compound
7
(0.5 g, 2.37 mmol) and propane-1,3-dithiol (0.256 g, 2.37 mmol) were added. The
mixture was stirred at room temperature for 5 hours and then filtered, filtrate was
concentrated under vacuum. The crude product obtained was further purified by column
chromatography (using 3% ethyl acetate/hexane as an eluent) to get pale yellow colored
o
1
3
solid product 8 in 90% yield (0.643 g). M. p. 180-183 C; H NMR (300 MHz, CDCl ) δ:
1
7
.93 (m, 1H), 2.14 (m, 1H), 2.88-3.09 (m, 4H), 5.44 (s, 1H), 6.83 (d, J = 8.3 Hz, 2H),
13
2
.15-7.38 (m, 4H), 7.95 (br. s, 1H exchangeable with D O), 8.37 (d, J = 7.7 Hz, 1H); C
NMR (75 MHz, CDCl
3
) δ: 24.8, 31.8, 48.6, 102.8, 109.9, 112.6, 112.9, 119.8, 122.4,
6

-1
1
23.1, 125.1, 126.8, 138.9, 141.2, 151.9; FT-IR (KBr): 3433, 2920, 1610, 1454 cm ;
+
GCMS (ESI): m/z 301; HRMS (ESI): [M+H] calculated for C16
H
15NOS
2
m/z 302.07;
found at 302.07.
Preparation of 3-(1,3-Dithian-2-Yl)-9H-Carbazole-1,4-Dione (9)
The compound 8 (0.5 g, 1.66 mmol) was dissolved in DCM (15 ml) and the solution was
o
cooled to 0 C. Then three equivalent of PCC (1.073 g, 4.98 mmol) was added portion
o
wise to the solution and the mixture was strirred at 0 C for 2 hours. The mixture was
then passed through column loaded with silica (60-120 mesh size) using DCM:Hexane
o
mixture (1:1) to get brown solid product 9 in 70% yield (0.366 g). M. p.210 C
1
(
Decomposed); H NMR (500 MHz, DMSO-d
6
) δ: 1.80 (m, 1H), 2.12 (m, 1H), 2.95 (m,
2
1
1
2
H), 3.15 (m, 2H), 5.49 (s, 1H), 6.69 (s, 1H), 7.55, & 7.33 (2xm, 3H), 8.06 (d, J = 7.9 Hz,
1
3
H), 12.51 (br. s, 1H); C NMR (125 MHz, DMSO-d
6
) δ: 25.2, 30.8, 40.7, 114.5, 115.4,
22.1, 124.1, 124.7, 127.1, 133.3, 136.1, 138.2, 148.0, 179.7, 179.8; FT-IR (KBr): 3232,
-1
+
2 2
916, 1739, 1641 cm ; HRMS (ESI): [M+H] calculated for C16H13NO S m/z 316.0466;
found at m/z 316.0458.
Preparation of 3-Methyl-9H-Carbazole-1,4-Dione (2)
To a solution of compound 9 (0.1 g, 0.32 mmol) in methanol (10 ml), was added catalytic
o
amount of Raney nickel and the mixture was heated at 100 C overnight under hydrogen
gas pressure (100 atmosphere) using Parr reactor. The completion of reaction was
confirmed by TLC. Then the reaction mass was filtered through celite bed and washed
with methanol. Collected filtrate was concentrated on rota vapor to obtain crude mass
7

which was column chromatographed using 5% ethyl acetate/hexane as an eluent. A pure
o
.[13]
yellow solid compound 2 was furnished in 77% yield (0.051 g). M. p. 195 C (lit
M. p.
o
1
1
7
95 C); H NMR (300 MHz, DMSO-d
.41 (m, 2H), 7.54 (d, J = 8.6 Hz, 1H), 8.04 (d, J = 8.1 Hz, 1H), 12.82 (br. s, 1H); C
) δ: 15.5, 113.7, 115.3, 121.5, 123.5, 123.7, 126.1, 131.5,
6
) δ: 2.05 (s, 3H), 6.58 (d, J = 1.4 Hz, 1H), 7.28-
13
NMR (75 MHz, DMSO-d
6
-
1
1
2
7
35.8, 137.3, 147.8, 179.9, 182.9; FT-IR (KBr): 3398, 1680 cm ; Ms (EI, 70 ev): m/z
11; CHN %: Anal. Calcd for C13
9 2
H NO , C 73.92, H 4.29, N 6.63, O 15.15%; Found C
3.75, H 4.60, N 4.30%.
Preparation of 3-Bromo-6-Methyl-9H-Carbazole (13)
To a stirred solution of compound 10 (0.5 g, 2.76 mmol) in dry DMF (15 ml) at room
temperature, was added drop wise, a solution of freshly recrystallized NBS (0.492 g, 2.76
mmol) in dry DMF (8 ml). The reaction mixture was stirred at room temperature for 2
hours and then poured into ice cold water (30ml). The crude solid obtained, was filtered
and then recrystallized in ethanol to get white and shiny crystals of product 13 in 90%
o
1
yield (0.646 g). M. p. 178 C (decomposed); H NMR (300 MHz, CDCl
3 6
+DMSO-d ) δ:
2
.50 (s, 3H), 7.26 (d, J = 8.2 Hz, 1H), 7.45 (m, 3H), 7.92 (s, 1H), 8.25 (s, 1H), 11.25 (br.
1
3
2 3 6
s, 1H exchangeable with D O); C NMR (75 MHz, CDCl +DMSO-d ) δ: 21.1, 110.1,
1
1
10.6, 112.5, 119.9, 121.4, 122.2, 124.0, 127.3, 127.4, 138.2, 138.4; FT-IR (KBr): 3390,
-
1
+
442, 810, 567 cm ; HRMS (ESI): [M+H] calculated for C13H10BrN m/z 260.0075;
found m/z 260.0073.
Preparation of 3-Methoxy-6-Methyl-9H-Carbazole (Glycozoline, 3)
8

A mixture of compound 13 (0.2 g, 0.769 mmol), cuprous iodide (0.161 g, 0.846 mmol),
sodium methoxide (0.415 g, 7.69 mmol) in methanol (4 ml) and dry DMF (15 ml) as a
o
solvent, was refluxed at 120 C for 4 hours under nitrogen atmosphere. Then water (30
ml) was added to the reaction mixture and was extracted with ethyl acetate (3 X 10 ml).
Combined organic layers were dried over anhydrous Na
concentrated using rota vapor. The residue was purified by column chromatography
using 6% ethyl acetate/hexane as an eluent), which gave pure white crystalline
2 4
SO , filtered, filtrate was
(
o
.[17]
o
1
compound 3 in 85 % yield (0.138 g). M. p. 179 C (lit
300 MHz, CDCl ) δ: 2.52 (s, 3H), 3.92 (s, 3H), 7.04 (dd, J = 1.7 & 8.8 Hz, 1H), 7.26 (m,
J = 8.8 Hz, 3H), 7.52 (s, 1H), 7.83 (s, 2H); C NMR (75 MHz, CDCl
03.1, 110.4, 111.2, 114.8, 120.1, 123.5, 123.6, 127.1, 128.3, 134.7, 138.5, 153.7; FT-IR
M. p. 181-182 C) H NMR
(
3
13
3
) δ: 21.3, 56.0,
1
-1
+
(
KBr): 3398, 2999, 1492, 810 cm ; GCMS (EI, 70 eV): [M] found m/z 211.
CONCLUSION
We have successfully developed a short and easy route for ekeberginine, which can be
visualized as an intermediate for the synthesis of other natural products having prenyl
group. A new route for the synthesis of murrayaquinone A was presented using
desulfurization strategy. An unplanned synthesis of glycozoline was demonstrated in two
simple steps.
FUNDING
A.A.M. is thankful to CSIR, New Delhi, for financial support.
9

SUPPLEMENTARY MATERIAL
1
13
Full experimental details, H and C NMR spectra can be found via the
“
Supplementary Content” section of this article’s webpage.
ACKNOWLEDGEMENTS
We are thankful to Mrs. J. P. Chaudhary and Mr. Datta Ukale for NMR spectra.
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[17] Peng, H.; Chen, X.; Chen,Y.; He, Q.; Xie, Y.; Yang, C. Article Title. Tetrahedron
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1
2

2 3
Scheme 1. Synthesis of ekeberginine; a) 1.2 eq. Tf O, 1.0 eq. NEt , cat. DMAP, DCM, 0
o
C rt, 30 min, 90%; b) 1.1 eq. tributyl(3-methylbut-2-en-1-yl)stannane, 10 mol%
o
o
Pd(PPh
3 4
) , DMF, 90 C, 2 h, 85%; c) 10 eq. NaOMe, 1.1 eq. CuI, DMF, 120 C, 4 h,
8
0%.
1
3

Scheme 2. Synthesis of murrayaquinone; a) 1.0 eq. propane-1,3-dithiol, SOCl
2
on silica,
o
toluene, 0 C- rt, 5 h, 90%; b) 3.0 eq. PCC, DCM, 2 h, 70%; c) Raney Ni, H
2
gas, MeOH,
o
1
00 C, 12 h, 77%.
1
4

Scheme 3. Retrosynthetic analysis for murrayanine (11)
1
5

o
Scheme 4. a) 1.0 eq. NBS, DMF, 0 C- rt, 2 h, 90%; b) 10 eq. NaOMe, 1.1 eq. CuI,
DMF, 4 h, 83%.
1
6

Figure 1.
1
7