Synthesis of some analogues of (±)gelliusine F, (±)gelliusine E, and total synthesis of 2,2-di(6′-bromo-3′-indolyl)ethylamine

Article abstract of DOI:10.1016/j.tetlet.2011.11.063

Synthesis of some analogues of indole based marine alkaloid (±)gelliusine F, (±)gelliusine E, and total synthesis of 2,2-di(6′-bromo-3′-indolyl)ethylamine are reported.

Full text of DOI:10.1016/j.tetlet.2011.11.063

Tetrahedron Letters 53 (2012) 426–428
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Tetrahedron Letters
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Synthesis of some analogues of ( )gelliusine F, ( )gelliusine E, and total
synthesis of 2,2-di(60-bromo-30-indolyl)ethylamine
⇑
P. Seetham Naidu, Pulak J. Bhuyan
Medicinal Chemistry Division, North East Institute of Science & Technology, Jorhat 785006, Assam, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis of some analogues of indole based marine alkaloid ( )gelliusine F, ( )gelliusine E, and total syn-
thesis of 2,2-di(60-bromo-30-indolyl)ethylamine are reported.
Received 11 October 2011
Revised 11 November 2011
Accepted 13 November 2011
Available online 19 November 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
3,30-Diindolylmethane
( )Gelliusine F
( )Gelliusine E
2,2-Di(60-bromo-30-indolyl)ethylamine
Amino acetaldehyde dimethyl acetal
Phthalic anhydride
3,30-Diindolylmethane (DIM) is a major digestive product of in-
dole-3-methanol, a potential anti-cancer component of cruciferous
vegetables.1 It is a potent activator of the immune response system
in vivo.2 It activates and potentiates interferon-gamma signalling
in human cells3 and its use as supplement in human increases
the 2-hydroxylation of oestrogen metabolites.4 3,30-Diindolylme-
thane reduces the growth of breast cancer cells by 95%5 and exhib-
its potent antiproliferative and antiandrogenic properties in
androgen-dependant human prostate cancer cells.6 DIM is cur-
rently used to treat Recurring Respiratory Papillomatosis, a rare
respiratory disease with tumours in the upper respiratory tracts.
It is additionally in Phase III clinical trials for Cervical Dysplasia,7
a pre-cancerous condition. Another significant discovery that has
recently been made about DIM that has fuelled international inter-
est in this unique phytochemical is its synergy with the number
one cancer drug worldwide (Taxol) in the promotion of apoptosis.8
Because of its various potent anticancer properties, the National
Cancer Institute of the United States has begun clinical trials of
DIM as a therapeutic for numerous forms of cancer.
( )Gelliusine F, ( )gelliusine E and 2,2-Di(60-bromo-30-indo-
lyl)ethylamine (Fig. 1) are a few important alkaloids having DIM
molecular unit which were isolated from the marine sources that
possess significant biological activity. 2,2-Bis(60-bromo-30-indo-
lyl)ethylamine was first isolated from the gulf of California
Tunicate didemnum candidum in 1991.10 The ( )gelliusine E and
( )gelliusine F as enantiomeric pair were isolated from the less
polar extract of marine source Caledonian sponge Gellius or orina
sp. and was reported in 1995.11 ( )Gelliusine E and ( )gelliusine
F exhibit the inhibition of specific ligand binding at neuropeptide
Y receptor and somatostatin receptor sites.11 They are also potent
inhibitor of specific ligand binding in the human B2 bradykinin
NH2
Br
Br
HN
2,2-Di(6 -bromo-3 -indolyl)ethylamine
NH
Considering the importance of diindolmethanes lots of efforts
have been made towards the synthesis of these compounds. Re-
cently, an excellent review was published on the synthesis of
DIM’s.9 However, due to versatile application, possibility of these
compounds, there is a continuous quest for more efficient methods
for the synthesis of diindolylmethanes.
NH2
NH2
Br
HO
NH
NH
HN
H2N
HN
H2N
( )gelliusine F
Br
Br
( )gelliusine E
⇑
Corresponding author. Tel.: +91 376 2370121; fax: +91 376 2370011.
E-mail address: pulak_jyoti@yahoo.com (P.J. Bhuyan).
Figure 1. Some marine alkaloids having DIM molecular unit.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.063

P. Seetham Naidu, P. J. Bhuyan / Tetrahedron Letters 53 (2012) 426–428
427
receptor-binding assay. These activities are interesting for
developing immuno-chemical studies on these neuropeptides.12
( )Gelliusine E, and F inhibit the release of enteramine. However,
so far only one group has reported the total synthesis of 2,2-
di(60-bromo-30-indolyl)ethylamine13 and no reports for the synthe-
sis of ( )gelliusine F and ( )gelliusine E have been reported
although attempts were made.14
for the synthesis of some very close analogues of ( )gelliusine F,
( )gelliusine E, and total synthesis of 2,2-di(60-bromo-30-indolyl)-
ethylamine (Scheme 1).
First we attempted the synthesis of some analogues of ( )gelliu-
sine F and ( )gelliusine E. In our reaction strategy, phthalimidoacet-
aldehyde dimethylacetal 318 was first prepared from amino
acetaldehyde dimethyl acetal 1 by protection of the amino group
withpthalicanhydride2.19 Then, deprotectionofthealdehydegroup
from its acetal 3 was done with 10% HCl acid in acetonitrile20 at room
temperature to afford the aldehyde 4 in a 95% yield.21 In a simple
three-components reaction procedure compound 4, 6-bromoindole
5a and N,N-dimethyl barbituric acid 6 were treated at room temper-
ature using D–L proline as catalyst and acetonitrile as solvent to af-
ford the compound 7a as solid compound in high yield which needs
no further purification.22 In the key reaction step compound 7a was
reacted with 2(3-indolyl)ethylphthalimide 923 in the presence of io-
dine as catalyst in refluxing acetonitrile to afford the compound
10a.24 The eliminated barbituric acid 6 was isolated and character-
ized. The deprotection of the amine groups25 with hydrazine hy-
drate20 gave the compound 11a, a close analogue of ( )gelliusine F
in a 60% yield. The structures of all the compounds were ascertained
from the spectroscopic data and elemental analysis.
As a part of the work on diindolylmethanes15 recently we re-
ported the synthesis of some novel 3-alkylated indoles utilizing in-
dole, aldehydes and N,N-dimethylbarbituric acid.16 The 3-alkylated
indoles so obtained were then utilized for the synthesis of unsym-
metrical diindolylmethanes.17 The reaction also demonstrated the
good leaving nature of N,N-dimethylbarbituric acid. On the basis of
these reaction strategies, we have developed an efficient method
O
O
OMe
OMe
i
OMe
OMe
ii
O
H2N
+
N
1
O
O
3
2
O
O
H
N
Initially, we performed the three-component reaction of 4, 5a &
6 under MW irradiation in solvent-free conditions following our
reported procedure.16 However, we could not get the desired com-
pound 7a. Then we performed the reaction under various base cat-
alysed conditions and D–L proline was found to be the best catalyst
which afforded the compound 7a in high yield even at room tem-
perature. Again, no reaction occurred when compound 7a was
treated with compound 9 in protic solvent following our reported
procedure17 to obtain compound 10a. But, when the reaction was
performed in refluxing acetonitrile using iodine as catalyst, the
compound 10 was obtained in an excellent yield. In the deprotec-
tion step we could isolate only a 60% yield although the reaction
shows full conversion.
After establishing suitable conditions for the reaction we have
synthesized a close analogue of ( )gelliusine E 11b by using 6-hy-
droxy indole instead of 6-bromoindole in the three-component
reaction step. Other reaction steps are similar to the synthesis of
11a. Similarly, compound 11c was synthesised and characterized
(Scheme 1).
Then we have applied the reaction strategy in the total synthe-
sis of 2,2-di(60-bromo-30-indolyl)-ethylamine 11d (Scheme 2). For
this purpose, compound 7a was treated with 6-bromoindole 5a
in refluxing acetonitrile in the presence of iodine as catalyst and
deprotection of amine was done using hydrazine hydrate as in
the earlier cases. The structures of the compounds were ascer-
tained from their physical and spectroscopic data and by compar-
ing with the authentic data. In comparison to the authentic spectra
the shift of chemical shift value of NH proton to upfield at d 8.28
O
4
O
N
O
O
iii
H
H3CN
O
+
N
+
N
H
R
O
CH3
O
5a: R = Br,
4
5b: R = OH,
5c: R = H
6
O
N
O
R
O
H3CN
O
7a: R = Br,
7b: R = OH,
7c: R = H
NH
O
N
CH3
O
NH2
N
O
O
iv
O
+
N
N
H
O
9
2
H
8
O
O
N
N
O
R
v
O
O
H3CN
O
+
NH
7a-c
O
N
N
H
9
CH3
O
N
O
O
H3CN
O
HN
O
+
NH
O
N
O
N
CH3
N
10a: R=Br,
6
O
i, ii
10b: R=OH,
10c: R=H
R
O
O
+
R
H3CN
O
N
H
R
i: Toluene, reflux, 3 h;
NH
O
N
NH2
5a: R = Br
CH3
ii: 10% HCl, CH3CN, 10-15 h;
iii: D,L-proline, CH3CN, r.t.
iv: Toluene, Et3N, 8 h, reflux
v: I2, CH3CN, reflux;
7a: R=Br
5c: R = H
NH
NH2
vi
Br
R
HN
10
i: I2, CH3CN, reflux;
vi: N2H4:H2O, 3 h, EtOH, r.t.
R
ii: N2H4:H2O, 3 h, EtOH, r.t.
H2N
11a: R=Br, 11b: R=OH, 11c: R=H
Scheme 1. Synthesis of analogues of ( )gelliusine F and ( )gelliusine E.
HN
NH
11d: R = Br, 11e. R = H
Scheme 2. Total synthesis of 2,2-di(60-bromo-30-indolyl)ethylamine.

428
P. Seetham Naidu, P. J. Bhuyan / Tetrahedron Letters 53 (2012) 426–428
mixture was refluxed for 3 h. The solvent was evaporated under reduced
pressure and the compound obtained was purified by column chromatography
(s, 2H) is due to the use of TFA as solvent (with CDCl3). When
DMSO was used as solvent the NH protons appear at d 10.95 but
good resolution of the protons at d 2.19 (here d 3.89) is not ob-
tained due to the DMSO peak and thus (CDCl3 + TFA) is found to
be suitable solvent for 1H NMR study. When first isolated the com-
pound 11d was reported as a yellow oil,10 and later on it was found
as amorphphous solid.13a We observed that the compound is a so-
lid with sharp melting point at 156–157 °C. The overall yield of the
compound is also found to be very high (65%) in comparison to the
earlier reported method (24%).13a Following a similar reaction
pathway, we have synthesized an analogue of diindolylethylamine
11e by utilizing simple indole 5c with compound 7a followed by
deprotection of the amino group. The structures of the compounds
were ascertained from the spectroscopic data and elemental anal-
ysis. Due to the absence of electron withdrawing bromide group,
chemical shift values of one NH proton in compound 11e was in
the up field in comparison to the compound 11d even though
DMSO was used as solvent.
In conclusion, we have reported a highly efficient method for
the synthesis of 2,2-di(60-bromo-30-indolyl)ethylamine, its ana-
logues and close analogues of ( )gelliusine F and ( )gelliusine E.
The reaction strategy which can be further explored towards the
synthesis of many other indole alkaloids of marine origin of biolog-
ical importance is a valuable addition to the chemistry of dii-
ndolylmethanes in particular and indoles in general. Further
study of the reaction is in progress.
using petroleum ether:ethyl acetate (8:2) as eluent. The product
3 was
obtained in a 60% yield (0.282 g) as white crystalline solid. m.p. 97–98 °C. 1H
NMR (300 MHz, CDCl3): d 3.38 (s, 6H), 3.83 (d, 2H), 4.77 (t, 1H), 7.70–7.75 (m,
2H), 7.83–7.88(m, 2H).
19. Borgström, M.; Ott, S.; Lomoth, R.; Bergquist, J.; Hammarström, L.; Johansson,
O. Inorg. Chem. 2006, 45, 4820.
20. Boisbrun, M.; Vassileva, E.; Raoul, M.; Laronze, J.-Y.; Sapi, J. Monatsh. Chem.
2003, 134, 1641.
21. Synthesis of (1,3-dioxo-1,3-dihydro-isoindole-2-yl)-acetaldehyde 4: To a stirred
solution of compound 3 (0.470 g, 2 mmol) in a round bottom flask containing
10 mL of CH3CN was added 10 mL of 10% HCl solution. The reaction mixture
was stirred at room temperature for 24 h. The organic solvent was evaporated
under reduced pressure, and the aqueous residue was extracted with ethyl
acetate, dried in anhydrous Na2SO4, and concentrated to give a white solid. The
product 4 was obtained in a 95% yield (0.359 g), m.p 87–88 °C. 1H NMR
(300 MHz, CDCl3): d 4.58 (s, 2H), 7.72–7.80 (m, 2H), 7.84–7.91 (m, 2H), 9.66 (s,
1H).
22. General method for the synthesis of compound 7: Phthalimidoacetaldehyde 4
(0.378 g, 2 mmol) was dissolved in 6 mL of acetonitrile. To this solution added
6-bromoindole 5a (0.780 g, 2 mmol), barbituric acid 6 (0.312 g, 2 mmol), and
catalytic amount of D–L–Proline under nitrogen atmosphere. The reaction
mixture was stirred at room temperature for 24 h. The resulting suspension
was filtered and the precipitate was washed with acetonitrile (2 ꢀ 50 mL) to
obtain a white compound 7a. The product 7a was obtained in a 95% yield
(1.00 g), m.p 107–108 °C. 1H NMR (300 MHz, CDCl3): d 2.84 (s, 3H), 3.05 (s, 3H),
3.86 (d, 1H), 4.33 (m,1H), 4.70 (d, 2H), 7.05–8.01 (m, 8H), 8.23 (br s, 1H).
Similarly compound 7b–c were synthesised and characterised.
23. Adla, S. K.; Gotz, G.; Jones, P. G.; Lindel, T. Synthesis 2010, 2161.
24. General experimental procedure for the synthesis of compound 10: Equimolar
amounts of compound 7a (0.523 g, 1 mmol), and 9 (0.117 g) were taken in a
round bottom flask and dissolved in 6 mL of acetonitrile. To this solution added
10 mol % of iodine. The reaction mixture was stirred at 80 °C for 6–8 h. After
completion of the reaction as monitored by TLC, the reaction mixture was
treated with Na2S2O3. The compound obtained was purified by column
chromatography (ethyl acetate:petrolium ether = 3: 7) to afford pure product
10a. m.p 225–226 °C. Yield 70% (0.459 g). 1H NMR (300 MHz, CDCl3): d 3.25 (m,
2H), 3.87 (m, 2H), 4.33 (dd, 1H), 4.5 (dd, 1H), 5.41 (t, 1H), 6.99–7.78 (m, 16H),
8.06 (br s, 1H), 8.31 (br s, 1H). The eliminated barbituric acid 6 was also
isolated, characterized and found to be comparable with authentic sample.
Similarly compound 10b–c were synthesised and characterised.
Acknowledgments
The authors thank CII and GITA, New Delhi for financial support.
Mr. P.S.N. thanks UGC for a research fellowship.
25. General experimental procedure for the synthesis of compound 11: Compound 10a
(0.657 g, 1 mmol) was taken in a round bottom flask and dissolved in 15 mL of
dry ethanol. To this added 0.33 mL of hydrazine hydrate. The reaction mixture
was stirred for 3 h at room temperature. The solvent was evaporated and the
residue was dissolved in a mixture of 5 mL of aqueous K2CO3 solution and 8 ml
of ethyl acetate. The two layers were separated and the aqueous phase was
extracted with ethyl acetate, dried with anhydrous Na2SO4 and concentrated
under vacuum. The compound 11a obtained was purified by column
chromatography using ethyl acetate:methanol (9:1) as eluent. 11a: Yield 60%
(0.238 g). m.p 209–210 °C. 1H NMR (300 MHz, CDCl3): d 1.45 (s, 2H), 1.56 (s,
2H), 2.90 (dd, 2H), 3.15 (d, 1H), 3.81 (dd, 2H), 5.25 (t,1H), 6.95-7.62 (m, 8H),
References and notes
1. (a) Bradfield, C. A.; Bjeldanes, L. F. J. Agric. Food Chem. 1987, 35, 46; (b)
Broadbent, T. A.; Broadbent, H. S. Curr. Med. Chem. 1998, 5, 337; (c) Broadbent,
T. A.; Broadbent, H. S. Curr. Med. Chem. 1998, 5, 469.
2. Xue, L.; Pestka, J. J.; Maoxiang, L.; Firestone, G. L.; Bjeldanes, L. F. J. Nutr.
Biochem. 2008, 19, 336.
3. Riby, J. E.; Xue, L.; Chatterji, U.; Bjeldanes, E. L.; Firestone, G. L.; Bjeldanes, L. F.
Mol. Pharmacol. 2006, 69, 430.
4. Dalessandri, K. M.; Firestone, G. L.; Fitch, M. D.; Bradlow, H. L.; Bjeldanes, L. F. J.
Nutr. Cancer—Int. J. 2004, 50, 161.
5. Hong, C.; Firestone, G. L.; Bjeldanes, L. F. Biochem. Pharmacol. 2002, 63, 1085.
6. Le, H. T.; Schaldach, C. M.; Firestone, G. L.; Bjeldanes, L. F. J. Biol. Chem. 2003,
278, 21136.
7. Bell, M. C.; Crowley-Nowick, P.; Bradlow, H. L.; Sepkovic, D. W.; Schmidt-
Grimminger, D.; Howell, P.; Mayeaux, E. J.; Tucker, A.; Turbat-Herrera, E. A.;
Mathis, J. M. Gynecol. Oncol. 2000, 78, 123–129.
8. McGuire, K.; Ngoubilly, N.; Neavyn, M.; Lanza-Jacoby, S. J. Surg. Res. 2006, 132,
208.
9. Shiri, M.; Ali-Zolfigol, M.; Kruger, H. G.; Tanbakouchain, Z. Chem. Rev. 2010, 110,
2250.
8.25 (br s, 1H), 8.41 (br s, 1H). IR (KBr): mmax 3410, 3344, 2926. MS: m/z = 398.4
[M+H]+. CHN analyses (calcd): C, 60.45; H, 5.29;
(found): C, 60.95; H, 4.97; N, 14.27%.
N 14.10% (C20H21N4Br)
Similarly compound 11b–e were prepared and characterized.
11b: Yield 59% (0.197 g). m.p. 216–217 °C. 1H NMR (300 MHz, CDCl3): d 1.53 (s,
2H), 1.61 (s, 2H), 2.86 (dd, 2H), 3.25 (d, 1H), 3.89 (dd, 2H), 4.81 (t, 1H), 7.05–
7.76 (m, 8H), 8.18 (br s, 1H), 8.54 (br s, 1H). IR (KBr): mmax 3423, 3391, 2926.
MS: m/z = 335.6 [M+H]+. CHN analyses (calcd): C, 71.85; H, 6.58; N, 16.76%
(C20H22N4O) (found): C, 71.96; H, 6.48; N, 16.83%.
11c: Yield 65% (0.206 g). m.p. 205–206 °C. 1H NMR (300 MHz, CDCl3): d 1.58 (s,
2H), 1.61 (s, 2H), 3.00 (dd, 2H), 3.20 (d, 1H), 3.89 (dd, 2H), 5.37 (t, 1H), 6.91–
10. Fahy, E.; Potts, B. C. M.; Faulkner, D. J.; Smith, K. J. Nat. Prod. 1991, 54, 564.
11. Bifulco, G.; Bruno, I.; Riccio, R.; Lavayre, J.; Bourdy, G. J. Nat. Prod. 1995, 58,
1254.
7.42 (m, 9H), 8.29 (br s, 1H), 8.38 (br s, 1H). IR (KBr): mmax 3423, 3394. MS: m/
z = 319.2 [M+H]+. CHN analyses (calcd): C, 75.47; H, 6.91;
N 17.61%
(C20H22N4O) (found): C, 75.40; H, 6.97; N, 17.75%.
12. Gul, W.; Hamann, T. Life Sci. 2005, 78, 442.
2,2-Di(60-bromo-30-indolyl)ethylamine 11d: Brown solid. Yield = 65% (0.26 g). 1H
NMR (300 MHz, CDCl3 + TFA): d 1.67 (s, 2H), 3.89 (d, 2H), 4.86 (t, 1H), 7.17 (s,
2H), 7.20 (d, 2H), 7.26 (d, 2H), 7.34 (s, 2H), 8.28 (s, 2H). IR (KBr): mmax 3409,
2920. MS: m/z = 434.4 [M+H]+. CHN analyses (calcd): C, 49.88; H, 3.46; N 9.69%
(C18H15N3Br2) (found): C, 49.65; H, 3.78; N, 9.95%.
13. (a) Mauger, H. C.; Denis, J.-N.; Pouchot, M.-T.; Vallee, Y. Tetrahedron 2000, 56,
791; (b) Denis, j.-N.; Mauger, H.; Valle, Y. Tetrahedron Lett. 1997, 38, 8515.
14. Chakrabarty, M.; Basak, R.; Ghosh, N.; Harigaya, Y. Tetrahedron 2004, 60, 1941.
15. (a) Deb, M. L.; Bhuyan, P. J. Tetrahedron Lett. 2006, 47, 1441; (b) Deb, M. L.;
Bhuyan, P. J. Synlett 2008, 325; (c) Deb, M. L.; Bhuyan, P. J. Synthesis 2008, 286.
16. Deb, M. L.; Bhuyan, P. J. Tetrahedron Lett. 2007, 48, 2159.
17. Deb, M. L.; Bhuyan, P. J. Synthesis 2008, 2891.
18. Synthesis of 2-(2,2-dimethyl-ethyl)-isoindole-1,3-dione 3: Amino acetaldehyde
dimethylacetal 1 (0.210 g, 2 mmol) and phthalic anhydride 2 (0.296 g, 2 mmol)
were taken in a round bottom flask containing toluene (7 mL), and the reaction
2,2-Di(1H-indol-3-yl)ethanamine 11e: Brown solid. Yield = 67% (0.184 g) 1H
NMR (300 MHz, DMSO-d6): d 1.65 (s, 2H), 3.15 (d, 2H), 4.51 (t, 1H), 6.89–7.53
(m, 10H), 8.32 (br s, 1H), 9.23 (br s, 1H). IR (KBr): mmax 3418, 2925. MS: m/
z = 276.5, [M+H]+. CHN analyses (calcd): C, 78.54; H, 6.18; N 15.27% (C18H17N3)
(found): C, 78.32; H, 6.32; N, 15.46%.