Three-Component Coupling-Oxidative Amidation-Heterocycloannulation: Synthesis of the Indole Alkaloids Hamacanthin A and trans -2,5-Bis(3′-Indolyl)piperazine

Article abstract of DOI:10.1055/s-0036-1588961

Concise and highly convergent syntheses of antifungal marine bis(indole) alkaloids, hamacanthin A and trans-2,5-bis(3′-indolyl)piperazine is described. The total synthesis of hamacanthin A is accomplished via the oxidative amidation-chemoselective heterocycloannulation of 2,2-dibromo-1-(1H-indol-3-yl)ethanone with 1-(1H-indol-3-yl)ethane-1,2-diamine. The reduction of desbromo hamacanthin with aluminum borohydride afforded the alkaloid trans-2,5-bis(3′-indolyl)piperazine. Two novel and convenient protocols for the synthesis of indolyl-1,2-diaminoethane are also developed in moderate to good yields.

Full text of DOI:10.1055/s-0036-1588961

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–H
letter
A
A. K. Srinivasan et al.
Letter
Synlett
Three-Component Coupling–Oxidative Amidation–Heterocy-
cloannulation: Synthesis of the Indole Alkaloids Hamacanthin A
and trans-2,5-Bis(3′-Indolyl)piperazine
A. Kaliyaperumal Srinivasana
H
N
NH
R1
Shyamapada Banerjeea
Sharad S. Pachoreb
U. K. Syam Kumar*b
H
N
NH2
N
R2
N
R1
R2
NH2
H
1. TMG, H2O
O
N
H
N
H
+
O
2. HCl or Pd/C
N
H
HN
BocHN
R1
N
H
a Technology Development Center, Custom Pharmaceutical
Services, Dr. Reddy’s Laboratories Ltd, Miyapur, Telangana
500049, India
b Integrated Product Development Organization, Dr. Reddy’s
Laboratories, Innovation Plaza, Bachupally, Telangana 500072,
India
R1 = H, R2 = H
H
trans-
+
R1 = R2 = Br, hamacanthin A
2,5-bis(3'-Indolyl)piperazine
⋅2 HCl
RNH2
syam_kmr@yahoo.com
Received: 15.11.2016
Accepted after revision: 07.02.2017
Published online: 08.03.2017
H
N
DOI: 10.1055/s-0036-1588961; Art ID: st-2016-b0765-l
R2
N
Abstract Concise and highly convergent syntheses of antifungal ma-
rine bis(indole) alkaloids, hamacanthin A and trans-2,5-bis(3′-indo-
lyl)piperazine is described. The total synthesis of hamacanthin A is
accomplished via the oxidative amidation–chemoselective heterocy-
cloannulation of 2,2-dibromo-1-(1H-indol-3-yl)ethanone with 1-(1H-in-
dol-3-yl)ethane-1,2-diamine. The reduction of desbromo hamacanthin
with aluminum borohydride afforded the alkaloid trans-2,5-bis(3′-indo-
lyl)piperazine. Two novel and convenient protocols for the synthesis of
indolyl-1,2-diaminoethane are also developed in moderate to good
yields.
R3
O
R1
N
H
N
H
1a: R1 = R2 = Br, R3 = H; hamacanthin A
1b: R1 = H, R2 = Br, R3 = H; 6'-desbromohamacanthin A
1c: R1 = R2 = H, R3 = H; 6',6''-didesbromohamacanthin A
1d: R1 = H, R2 = H, R3 = Br; 5'-desbromohamacanthin A
Br
Key words bis(indole) alkaloids, hamacanthin A, trans-2,5-bis(3′-in-
dolyl)piperazine, oxidative amidation, regioselective heterocycloannu-
lation
NH
HN
N
Br
H
N
O
N
H
R1
N
Hamacanthin A (1) and hamacanthin B (2) are two bio-
logically active bisindole alkaloids isolated from deep water
marine sponges Hamacantha Raphisia and Spongosorites by
Gunasekera et al. in 1994.1 Other members of this bisindole
alkaloid family are topsentines, nortopsentines, dragmacid-
ines and spongotine A (Figure 1). These bisindole alkaloids
exhibit a myriad of biological responses.2 The hamacan-
thins 1a–d specifically demonstrated significant antimicro-
bial properties against Candida albicans and Cryptococcus
neoformans.3 The broad spectrum of potent biological prop-
erties associated with these bisindole alkaloids coupled
with their limited availability for biomedical studies gar-
nered interest to develop efficient and economic synthetic
protocols for their syntheses.
2: hamacanthin B
X
X
N
R2
N
H
3a: X = R1 = R2 = H; trans-2,5-bis(3'-indolyl)piperazine
3b: X = Br, R1 = Me, R2 = H; dragmacidin A
3c: X = Br, R1 = R2 = Me; dragmacidin B
3d: X = Br, R1 = R2 = H; dragmacidin C
Figure 1 Bisindole alkaloids
condensation between two appropriately substituted in-
dole precursors. Jiang et al.,4 reported the enantioselective
synthesis of (–)-hamacanthin A (1a) via the intramolecular
transamidation of 3-indolyl-α-oxoacetyl chloride with 3-
indolyl azidoethyl amine followed by cyclocondensation
under aza-Wittig reaction conditions. Denis and co-work-
The total synthesis of hamacanthins in racemic, as well
as in enantiomerically pure forms are well reported in liter-
ature.3–5 These synthetic strategies predominantly focus on
the construction of spacer 3,5- or 3,6-pyrazin-2(1H)-one
framework in the final stage of the synthesis via the cyclo-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–H

B
A. K. Srinivasan et al.
Letter
Synlett
ers5 adapted intermolecular amidation–heterocyclization
strategy for the synthesis of racemic hamacanthin A (1a). In
a series of reports, Horne et al.6 demonstrated the synthesis
of dihydrohamacanthins via self-dimerization of appropri-
ately substituted α-amino ketone in moderate yields.
zine (3a) could be obtained by the global reduction of 6′,6′′-
didesbromohamacanthin A (1c) with suitable reducing
agent. The oxidative amidation–cyclocondensation reaction
between appropriately substituted indolediamine 4 and
2,2′-dibromoindole-3-ethanone (5) in one-pot reaction
would provide hamacanthin A (1a), 6-desbromohamacan-
thin A (1b), 6′,6′′-didesbromohamacanthin A (1c) and 5′-
desbromohamacanthin A (1d). The diamines 4a and 4b re-
quired for the synthesis could be obtained by an early stage
synthesis of ketoamide 8 followed by the reduction of indo-
lyl-2-(hydroxyimino)acetamide 6 under suitable reaction
conditions.
Our novel strategy for the synthesis of (1H-indol-3-
yl)ethane-1,2-diamine 4 is described in Scheme 2. Indole 7a
was converted into the corresponding keto amide 8a as per
the known literature procedure.9 The keto amide 8a was
then treated with hydroxyl amine in ethanol at room tem-
perature and afforded 2-(hydroxyimino)-2-(1H-indol-3-
yl)acetamide 6a in good yields. In a similar way 6b was also
synthesized starting from bromoindole 8b. The hydrogena-
tion of 6a with H2/Pd/C conditions resulted in the amino ac-
etamide derivative 9a in moderate yield. Irrespective of the
nature of Pd catalyst and its loading, the reduction of oxime
6a to the amino acetamide derivative 9a requires hydrogen
pressure above 20 Psi under these conditions. However,
during the transformation of bromo-oxime 6b to the corre-
sponding bromo amino acetamide derivative 9b, extensive
dehalogenation was observed and the required product 9b
was formed in disappointing yield (6%) and deshalo deriva-
tive 9a was isolated as the major product.
As a part of our endeavors to develop new methodolo-
gies for the synthesis of biologically active natural and un-
natural products,7 herein we disclose a concise and highly
convergent approach for the total syntheses of bisindole al-
kaloids hamacanthin A (1a) and trans-2,5-bis(3′-indo-
lyl)piperazine (3a) via oxidative amidation–heterocycliza-
tion sequence in good yields. Commercially non-available
1-(indol-3′-yl)-1,2-diaminoethane (4a), as well as 1-(6-bro-
mo-1H-indol-3-yl)ethane-1,2-diamine (4b) are the key
starting materials required for the synthesis of hamacan-
thin A (1a) and trans-2,5-bis(3′-indolyl)piperazine (3a), re-
spectively. Except the syntheses reported by Denis et al.5
and Kawasaki et al.8 to the best of our knowledge, no other
precedence is reported in literature for their synthesis. Con-
sidering the constraints associated with availability of 4a
and 4b as well as the limited practical procedure available
for their synthesis, development of new synthetic routes to
these diamines in minimum number of steps are always in
demand. Thus as a part of total syntheses of hamacanthin A
(1a), and trans-2,5-bis(3′-indolyl)piperazine (3a) alkaloids,
two novel synthetic protocols have been developed for the
synthesis of 1-(indol-3′-yl)-1,2-diaminoethane (4a) and 1-
(6-bromo-1H-indol-3-yl)ethane-1,2-diamine (4b) in good
yields which also provide strategic advantages to the syn-
thesis of these natural products.
The retrosynthetic design for the synthesis of hamacan-
thin A (1a) and trans-2,5-bis(3′-indolyl)piperazine (3a) are
outlined in Scheme 1. The trans-2,5-bis(3′-indolyl)pipera-
Reduction of 9a to the diamine 4a was attempted with
several conventional reducing agents such as NaBH4/TFA,
NaBH4/CaCl2, LiAlH4, NaBH4/AcOH, vitride, etc. under differ-
NH
NH
H
N
N
R1
R2
R1
R2
N
O
N
H
H
HN
HN
3a
1a: R1 = Br, R2 = Br: hamacanthin A
1c: R1 = H, R2 = H: 6',6''-didesbromohamacanthin A
R1 = H, R2 = H
trans-2,5-bis(3'-indolyl)piperazine
Br
OH
NH2
O
O
N
Br
NH2
⋅2 HCl
NH2
indole
+
R1
R2
N
H
R1
N
H
N
H
5a: R2 = H
5b: R2 = Br
6a: R1 = H
6b: R1 = Br
4a: R1 = H
4b: R1 = Br
Scheme 1 Retrosynthetic approaches towards hamacanthin and trans-2,5-bis(3′-indolylpiperazine) alkaloids
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–H

C
A. K. Srinivasan et al.
Letter
Synlett
OH
N
O
NH2
O
O
NH2
1) oxalyl chloride
Et2O, 0 °C
NH2OH⋅HCl
R1
N
H
R1
N
H
2) NH3, CH2Cl2
0 °C
N
H
NaOAc, EtOH
70 °C
R1
7a: R1 = H
7b: R1 = Br
8a: R1 = H (85%)
8b: R1 = Br (80%)
6a: R1 = H (81%)
6b: R1 = Br (79%)
O
NH2
H2N
NH2
NH2
LAH, TMSCl
THF, 0 °C
H2, Pd (10 mol%)
MeOH, 130 °C
⋅2 HCl
R1
N
H
R1
N
H
9a: R1 = H (70%)
9b: R1 = Br (<6%)
4a: R1 = H (68%)
Scheme 2 Synthesis of 1-(indol-3′-yl)-1,2-diaminoethane
ent reaction conditions and molar ratios; however complex
mixture of products or unreacted starting material was left
out in these reactions. On the other hand, when the reduc-
tion of 9a was carried out under LiAlH4/TMSCl conditions,10
excellent reaction conversion into the expected product 1-
(indol-3′-yl)-1,2-diaminoethane (4a) was observed. The
work up of the reaction mixture after reduction with
LiAlH4/TMSCl condition was found to be little tedious. Also
the free base 4a underwent quick degradation during the
storage; hence 4a was isolated as its dihydrochloride salt.
The highly competitive dehalogenation reaction during the
hydrogenation of 6b, coupled with decomposition of di-
amine 4a during the work up of LiAlH4/TMSCl-assisted re-
duction of 9a as well as its storage prompted us to develop
alternate concise, operation friendly and environmentally
benign protocol for the synthesis of indolyl diamines 4a and
4b.
In our alternate three-component Mannich coupling ap-
proach11 developed for the synthesis of 4a, and 4b (Scheme
3), a mixture of N-Boc-glycinal (11),12 benzylamine (10)
R3
O
NH2
H
BocHN
R1
R2
H
N
11
+
NHBoc
R1
R2
TMG (10 mol%)
H2O, 45 °C
N
H
R3
N
H
12a: R1 = R2 = R3 = H (74%)
7a: R1 = R2 = H
10a: R3 = H
10b: R3 = OMe
12b: R1 = H, R2 = Br, R3 = H (70%)
12c: R1 = Br, R2 = R3 = H (78%)
12d: R1 = CN, R2 = R3 = H (68%)
12e: R1 = Br, R2 = H, R3 = OMe (79%)
12f: R1 = H, R2 = Br, R3 = OMe (71%)
7b: R1 = H, R2 = Br
7c: R1 = Br, R2 = H
7d: R1 = CN, R2 = H
NH2⋅HCl
NH2⋅HCl
R1 = H: H2, Pd(OH)2
MeOH, HCl–MeOH, r.t.
R1 = Br: TFA, HCl–MeOH
R1
N
H
4a: R1 = H (90%)
4b: R1 = Br (crude compound used as such for the next reaction)
Scheme 3 TMG-catalyzed three-component synthesis of indole diamine
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–H

D
A. K. Srinivasan et al.
Letter
Synlett
Br
Br
Br
Br
O
O
O
O
Ac2O
Br2
MeOH
KOH
1,4-dioxane
Et3N, THF
N
N
N
N
H
5a (60%)
Br
H
O
O
7a
13a (60%)
O
O
R1
R1
R2
Br
R1
R2
Br2
1,4-dioxane
Ac2O
SnCl4, CH2Cl2
R2
N
H
N
N
H
H
5b: R1 = H, R2 = Br (80%)
5c: R1 = Br, R2 = H (81%)
7b: R1 = H, R2 = Br
7c: R1 = Br, R2 = H
13b: R1 = H, R2 = Br (90%)
13c: R1 = Br, R2 = H (92%)
Scheme 4 Preparation of 2,2-dibromo-1-(1H-indol-3-yl)ethanones
and indole (7) was stirred together in the presence of cata-
lytic quantity of tetramethylguanidine (TMG) at 45 °C in
water and the product N,N′-protected indolyl-1,2-diami-
noethane 12a was isolated in good yield. In a similar way,
the other N,N′-protected aryl-substituted indolyl-1,2-diam-
inoethane 12b–12f were also synthesized in high yields.
The global deprotection of indole diamine derivative 12a
was then performed under hydrogenation conditions using
palladium hydroxide. Faster global deprotection was ob-
served, when the reaction was carried out using
Pd(OH)2/MeOH/MeOH–HCl combination. The deprotection
of bromo indolyl-1,2-diaminoethane 12b was done under
non hydrogenation conditions. Thus 12b was subjected to
deprotection reaction with a 1:1 mixture of trifluoroacetic
acid (TFA) as well as methanolic HCl solution at 0–10 °C,
and 1-(6-bromo-1H-indol-3-yl)ethane-1,2-diamine 4b was
isolated as the diacid salt. The attempted purifications of
crude diamine hydrochloride 4b was unsuccessful; and the
crude diamine dihydrochloride 4b was used for further
transformation without any purification.13
After the successful development of novel process for
the synthesis of indolyl-1,2-diaminoethane, we focused our
attention towards the synthesis of other coupling partner,
2,2-dibromo-1-(1H-indol-3-yl)ethanones (5a–c) required
for the natural products 1a and 3a (Scheme 4). Thus 3-acyl
indoles 13a–c14 were subjected to bromination with bro-
mine in dioxane as per our earlier reported procedure.15
During the bromination of 3-acyl indole 13a, ring bromina-
NH2•HCl
NH2•HCl
Br
Br
O
NH
N
R1
R2
R1
DMSO
R2
+
N
O
Et3N, r.t.
N
R3
H
R3
N
H
H
HN
5a: R1 = H, R2 = Br
5b: R1 = R2 = H
5c: R1 = Br, R2 = H
4a: R3 = Br
4b: R3 = H
1a: R1 = R3 = Br, R2 = H; hamacanthin A (60%)
1b: R1 = H, R2 = Br, R3 = H; 6'-desbromohamacanthin A (66%)
1c: R1 = R2 = R3 = H; 6',6''-didesbromohamacanthin A (68%)
1d: R1 = R2 = H, R3 = Br; 5'-desbromohamacanthin A (64%)
Br
Br
O
S
O
2
NH
1
HN
O
N
N
Br
Br
N
H
O
H
14
2: hamacanthin B
Scheme 5 Synthesis of hamacanthin derivatives by oxidative amidation–heterocycloannulation approaches
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–H

E
A. K. Srinivasan et al.
Letter
Synlett
tion at C-5 position also occurred. Hence orthogonal pro-
tection–deprotection strategy was adopted for the synthe-
sis of 2,2-dibromo-1-(1H-indol-3-yl)ethanone (5a).
canthin 1a took almost 24 hours for the completion. After
completion of the reaction (by TLC) and usual workup pro-
cedure, hamacanthin A (1a) was isolated by column chro-
matography in 60% yield. This sequential intermolecular
amidation followed by heterocyclization was found to be
highly chemoselective towards the formation of hamacan-
thin 1a and no traces of hamacanthin B (2) was observed
under these reaction conditions. This approach subse-
quently was then extended to produce a number of hama-
canthin derivatives (1b–1d). The products were then well
characterized by 1H NMR, mass spectra, and by other spec-
tral and analytical methods.17 The 1H NMR and 13C NMR
chemical shift values and coupling constant values of syn-
thetic hamacanthin A (1a) are in agreement with those re-
ported for hamacanthin A isolated from natural sources.
The mechanism for the formation of hamacanthin A
(1a) from the corresponding 2,2-dibromo-1-(6-bromo-1H-
indol-3-yl)ethanone (6) is depicted in Scheme 6. The reac-
tion of dimethyl sulfoxide with 2,2-dibromo-1-(6-bromo-
1H-indol-3-yl)ethanone (6) would in situ generate sulfoxo-
nium bromide (14). The 1-(indol-3′-yl)-1,2-diaminoethane
(4b) could then react with sulfoxonium bromide 14 via ei-
Recently we have disclosed a straightforward one-pot
synthesis of aryl and heteroaryl ketoesters and ketoamides
via oxidative amidation and esterification of aryl and het-
eroaryl dibromoethanones,16 which are otherwise accessi-
ble by multistage process. We envisioned that oxidative
amidation methodology can be elaborated for the synthesis
of hamacanthin A (1a) and other hamacanthin family mem-
bers (1b–1d).
The protocol adapted for the synthesis of hamacanthins
(1a–1d) is described in Scheme 5. The synthetic sequence
commenced with the in situ generation of oxosulfonium in-
termediate 14 from 2,2-dibromo-1-(6-bromo-1H-indol-3-
yl)ethanone (5a) by reacting it with dimethyl sulfoxide at
75–80 °C. A solution of 1-(6-bromoindol-3′-yl)-1,2-diami-
noethane (4a) in DMSO was added to the in situ generated
oxosulfonium intermediate 14. The reaction mixture was
then maintained at room temperature for the completion of
sequential intermolecular amidation and heterocyclization.
The reaction sequences leading to the formation of hama-
Br
O
Br
O
NH2⋅HCl
S
2
O
2
NH2⋅HCl
Br
1
1
O
DMSO
+
N
Br
H
N
H
Br
N
Br
H
6
4
14
path b
path a
path c
NH2
N
Br
O
S
HN
Br
Br
H2N
2
O
Br
H
NH2
1
Br
N
O
O
O
N
H
N
H
HN
NH
N
H
Br
NH
O
16
15
H
N
O
NH
Br
Br
N
Br
N
N
NH
Br
O
H
HN
HN
hamacanthin B (2)
hamacanthin A (1a)
Scheme 6 Plausible mechanism for the formation of hamacanthin
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–H

F
A. K. Srinivasan et al.
Letter
Synlett
H
N
NH
H
N
N
NaBH4, AlCl3
N
O
N
AcOH, THF
r.t.
H2
OAc
H
HN
HN
H
H
H
1c
3a (72%)
B
H
H
H
H
H
H
B
H
B
Al
H
H
Scheme 7 Preparation of trans-2,5-bis(3′-indolyl)piperazine
ther path a, path b or path c. In path a, the terminal amino
group in 1-(indol-3′-yl)-1,2-diaminoethane 4b could react
at the keto carbonyl carbon in 14 to form the intermediate
15. The subsequent heteroanulation of 15 would result in
hamacanthin (1a). Alternatively, the amino group on C2
carbon of 4b (path c) could also react at the oxosulfonium
carbonyl carbon C2 in 14, leading to the formation of pri-
mary amide 16 which upon subsequent cyclization could
result in hamacanthin B (2).
tal synthesis of natural product (±)-hamacanthin A (1a) and
other hamacanthin family members by reacting indole di-
amines with in situ generated [2-(1H-indol-3-yl)-2-oxoace-
toxy]dimethylsulfonium bromide in sequential oxidative
amidation–heteroannulation protocols. The global reduc-
tion of didebromo hamacanthin A (1c) with aluminium bo-
rohydride provided the trans-2,5-bis(3′-indolyl)piperazine.
The applications of this methodology for the synthesis of
other natural products are under progress.
However, the reaction was found to be highly site selec-
tive, and to our delight only hamacanthin A (1a) was the
only product formed in the reaction. The reactivity differ-
ence between the carbonyl carbons attached at C1 carbon
of 14 against the C2 carbon of 14, and the nucleophilicity
difference between the C1 amine against C2 amine in 4 are
assumed to be the responsible factors for the near exclusive
formation of hamacanthin A (1a). Thus it can be concluded
that the reaction followed path a or path b rather than path
c in this oxidative amidation–heteroanulation process.
After successful synthesis of several hamacanthin deriv-
atives (1a–d) under oxidative amidation–dehydrative het-
erocyclization conditions, we focused our attention to-
wards the synthesis of trans-2,5-bis(3′-indolyl)piperazine
(3a; Scheme 7). Thus the desbromo hamacanthin (1c) was
subjected to global reduction of imine, and amide in a sin-
gle-pot process. The global reduction of 1c was convenient-
ly carried out with in situ generated aluminium borohy-
dride18 in THF/acetic acid mixture at room temperature
over a period of 10–12 hours. The trans-2,5-bis(3′-indo-
lyl)piperazine (3a) was isolated in 72% yield as acetate
salt.19 The synthetic trans-2,5-bis(3′-indolyl)piperazine ac-
etate salt (3a) has the comparative spectroscopic data to the
naturally derived material.20
Acknowledgment
The authors would like to thank Dr. Vilas Dahanukar, Chief Scientific
Officer, Dr. Reddy’s Laboratories for useful discussions. We also thank
the analytical department, Dr. Reddy’s Laboratories Ltd, for providing
the support.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588961.
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Wright, A. E. U.S. Patent 6087363, Chem. Abstr. 2000, 133, 99589.
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(b) Jiang, B.; Yang, C. D.; Wang, J. J. Org. Chem. 2002, 67, 1396.
(c) Jiang, B.; Wang, J.; Yang, C. D. Tetrahedron Asymmetry 2002,
13, 383.
In summary, a novel practical and operation friendly
two-step three-component coupling process has been de-
veloped for the synthesis of functionalized (1H-indol-3-
yl)ethane-1,2-diamines in excellent yields with minimal
side products. The synthetic potential of these indole di-
amine building blocks was further demonstrated in the to-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–H

G
A. K. Srinivasan et al.
Letter
Synlett
(5) (a) Guinchard, X.; Vallee, Y.; Denis, J. N. J. Org. Chem. 2007, 72,
3972. (b) Guinchard, X.; Vallee, Y.; Denis, J. N. Org. Lett. 2007, 9,
3761.
(6) (a) Miyake, F. Y.; Yakushijin, K.; Horne, D. A. Org. Lett. 2000, 2,
2121. (b) Miyake, F. Y.; Yakushijin, K.; Horne, D. A. Org. Lett.
2000, 2, 3185. (c) Miyake, F. Y.; Yakushijin, K.; Horne, D. A. Org.
Lett. 2002, 4, 941.
pressure. To the crude product, methanolic HCl solution (15 mL)
was added and stirred for 20–30 min at r.t. The solvent in the
reaction mixture was then evaporated under reduced pressure
and triturated with Et2O. The diamine dihydrochloride salt 4a
was then filtered under nitrogen as a brown solid (0.51 g, 74%
yield); mp 168–170 °C (dec.). IR (KBr): 3863, 3404, 3019, 2905,
2834, 2400, 1602, 1426, 1215 cm–1. 1H NMR (400 MHz, MeOD):
δ = 3.68–3.76 (m, 2 H), 5.02 (dd, J = 5.4, 10.3 Hz, 1 H), 7.15–7.26
(m, 2 H), 7.47 (d, J = 7.8 Hz, 1 H), 7.65 (s, 1 H), 7.77 (d, J = 7.8
Hz, 1 H). 13C NMR (MeOD, 100 MHz): δ = 43.1, 47.6, 107.6,
113.6, 119.6, 121.7, 124.1, 127.3, 138.6, 138.8. LRMS (ESI):
m/z = 176 (for C10H14N3) [M + H – 2HCl]+, 159 (for C10H11N2) [M –
2HCl – NH2]+. HRMS (ESI): m/z [M – NH2]+ calcd for C10H11N2:
159.0922; found: 159.0924.
(7) (a) Gajare, V. S.; Khobare, S. R.; Datrika, R.; Reddy, K. S.; Rajana,
N.; Babu, K. B.; Rao, B. V.; Syam Kumar, U. K. Tetrahedron Lett.
2016, 57, 1486. (b) Madhubabu, M. V.; Shankar, R.; More, S. S.;
Rao, M. V. B.; Syam Kumar, U. K.; Raghunadh, A. RSC Adv. 2016,
6, 36599. (c) Khobare, S. R.; Gajare, V. S.; Rajana, N.; Datrika, R.;
Reddy, K. S.; Syam Kumar, U. K.; Siddaiah, V. Tetrahedron Lett.
2015, 56, 2207. (d) Vikas, S.; Gajare, V. S.; Sandip, R.; Khobare,
M. B.; Rajana, N.; Rao, B. V.; Syam Kumar, U. K. Tetrahedron Lett.
2015, 56, 3743. (e) Suresh Babu, M.; Ramamohan, M.;
Raghunadh, A.; Raghavendra Rao, K.; Dahanukar, V. H.; Pratap,
T. V.; Syam Kumar, U. K.; Dubey, P. K. Tetrahedron Lett. 2014, 54,
4739. (f) Srinivasan, A. K.; Shyamapada, B.; Syam Kumar, U. K.
Org. Biomol. Chem. 2014, 12, 61. (g) Manoj, B. W.; Shankar, R.;
Syam Kumar, U. K. Synlett 2011, 84. (h) Shankar, R.; Manoj, B.
W.; Syam Kumar, U. K. Synlett 2011, 844. (i) Khobare, S. R.;
Gajare, V.; Vishnuvardhan Reddy, E.; Datrika, R.; Banda, M.;
Siddaiah, V.; Pachore, S. S.; Upadhya, T.; Dahanukar, V. H.; Syam
Kumar, U. K. Carbohydrate Res. 2016, 435, 1.
(8) Kawasaki, T.; Kuoko, T.; Totsuka, H.; Hiramatsu, K. Tetrahedron
Lett. 2003, 44, 8849.
(9) Garg, N. K.; Sarpong, R.; Stoltz, B. M. J. Am. Chem. Soc. 2002, 124,
13179.
(10) Ravinder, B.; Rajeswar, S. R.; Panasa, A.; Rakeshwar, R. Tetrahe-
dron Lett. 2013, 54, 4908.
(11) (a) Cordova, A. Acc. Chem. Res. 2004, 37, 102. (b) Kobayashi, S.;
Ishitani, S. Chem. Rev. 1999, 99, 1069. (c) Arend, M.;
Westermann, B.; Risch, N. Angew. Chem. Int. Ed. 1998, 37, 1044.
(12) Myers, M. C.; Pokorski, J. K.; Appella, D. H. Org. Lett. 2004, 6,
4699.
(14) Ottoni, O.; Neder, A. V. F.; Dias, A. K. B.; Cruz, R. P. A.; Aquino, L.
B. Org. Lett. 2001, 3, 1005.
(15) Shanmugapriya, D.; Shankar, R.; Satyanarayana, G.; Dahanukar,
V. H.; Vembu, N.; Syam Kumar, U. K. Synlett 2008, 2945.
(16) (a) Shankar, R.; More, S. S.; Madhubabu, M. V.; Vembu, N.; Syam
Kumar, U. K. Synlett 2012, 7, 1013. (b) Raghunadh, A.; Suresh
Babu, M.; Anil Kumar, N.; Santosh Kumar, G.; Vaikunta Rao, L.;
Syam Kumar, U. K. Synthesis 2012, 44, 283.
(17) General Procedure for the Oxidative Amidation–Heterocy-
cloannulation; Synthesis of Hamacanthin A Derivatives: A
solution of 2,2-dibromo-1-(6-bromo-1H-indol-3-yl)ethanone
(5b; 0.2 g. 0.506 mmol) was prepared in anhyd dimethyl sulfox-
ide (6 mL; moisture content should be less than 0.5%, otherwise
some keto acid will form in the reaction) under an argon atmo-
sphere and the reaction mixture was slowly heated to 70–75 °C
over a period of 1–2 h. The reaction mixture was then main-
tained at that temperature further for about 14–16 h. The reac-
tion mixture was cooled to 50–55 °C. In another round bottom
flask charged with diamine 4b (0.192 g, 0.757 mmol), Et3N
(0.255 g, 2.53 mmol) and anhyd dimethyl sulfoxide (4 mL) and
stirred for 10–15 min the above prepared sulfonium bromide
was added into the reaction mass, slowly heated to 80–85 °C
and stirred for 24 h. The progress of the reaction was monitored
by TLC. After completion of reaction, the reaction mass was
cooled to 30–35 °C, then diluted with H2O, (100 mL) and
extracted with EtOAc (4 × 30 mL). The combined organic layer
was then washed with H2O (3 × 30 mL) and brine solution and
dried over sodium sulfate. The EtOAc layer was then concen-
trated under reduced pressure. Pure sample was obtained by
column chromatography (0.145 g, 60% yield) as a brown-
colored solid. Hamacanthin A (1a): yield: 60%; brown-colored
solid. IR (KBr): 3418, 3372, 2839, 2940, 2843, 1665, 1578, 1431,
1130, 1113, 799 cm–1. 1H NMR (400 MHz, DMSO-d6): δ = 4.05–
4.17 (m, 2 H, H for CH2N), 5.02 (ddd, J = 1.6, 4.3, 11.3 Hz, 1 H,
CHN), 7.14 (dd, J = 1.8, 8.6 Hz, 1 H, H indole), 7.20 (dd, J = 1.8, 8.6
Hz, 1 H, H indole), 7.30 (d, J = 2.2 Hz, 1 H, H indole), 7.62 (d, J =
1.8 Hz, 1 H, H indole), 7.69 (d, J = 8.2 Hz, 1 H), 8.30 (d, J = 8.6 Hz,
1 H, H indole), 8.45 (d, J = 2.8 Hz, 1 H, H indole), 8.79 (d, J = 2.8
Hz, 1 H, H indole), 11.16 (s, 1 H, NH indole), 11.60 (s, 1 H, NH
indole). 13C NMR (100 MHz, DMSO-d6): δ = 46.4 (CHN), 53.6
(CH2N), 110.6 (C indole), 111.7 (C indole), 112.7 (C indole),
113.2 (CH indole), 113.7 (CH indole), 118.7 (CH indole), 118.9 (C
indole), 121.3 (CH indole), 123.4 (CH indole), 124.5 (CH indole),
124.6 (CH indole), 125.6 (CH indole), 127.7 (CH indole), 133.1
(CH indole), 134.9 (C indole), 136.4 (C indole), 157.4, 157.7 (Cq,
C=O). LRMS (ESI): m/z = 485, 487, 489 [M + H]+. HRMS (ESI): m/z
[M + H]+ calcd for C20H15N4OBr2: 484.9613; found: 484.9622.
(18) Brown, H. C.; Rao, S. J. Am. Chem. Soc. 1956, 78, 2582.
(13) Preparation of 1-(1H-Indol-3-yl)ethane-1,2-diamine Dihy-
drochloride (4a)
Procedure 1: 2-Amino-2-(1H-indol-3-yl)acetamide (9a; 0.2 g,
1.1 mmol) was added to an oven-dried 50-mL round bottom
flask containing anhyd THF (10 mL). The solution was cooled to
0 °C. TMS chloride (0.120 g, 1.1 mmol) was added into it drop-
wise. LiAlH4 (0.050 g, 1.3 mmol) was then added into the reac-
tion mixture carefully in three equal portions over 5 min. The
solution was stirred for 40 min at 0 °C, and then the reaction
mixture was quenched with sat. NaHSO4 solution (4 mL) at 0 °C.
The reaction mixture was then transferred into a 50-mL sepa-
rating funnel, washed with H2O (5 mL), and layers were sepa-
rated. The aqueous layer was then extracted with EtOAc (2 × 10
mL) and concentrated on a rotary evaporator at ambient tem-
perature, a solution of methanolic HCl (3 N, 4 mL) was added at
r.t. under argon atmosphere into it and stirred for 30 min. The
solvent was then evaporated and the crude product was then
triturated with Et2O and the indolic-1,2-diamine hydrochloride
salt 4a was obtained as a brown colored solid (0.19 g, 68% yield).
Procedure 2: In a Parr shaker, diprotected indole diamine 12a
(1.0 g, 1.20 mmol), MeOH (20 mL) and AcOH (5 mL) were added
and maintained under nitrogen atmosphere. Palladium hydrox-
ide (0.1 g) was added into it at under a nitrogen atmosphere.
The nitrogen atmosphere was then replaced by hydrogen gas.
The resulting mixture was then stirred at r.t. for 24 h. It was
then filtered through a celite bed under nitrogen atmosphere.
The resulting filtrate was then concentrated under reduced
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–H

H
A. K. Srinivasan et al.
Letter
Synlett
(19) trans-2,5-Bis(3′-indolyl)piperazine (3a): Into an oven-dried
round-bottom flask a mixture of 6′,6′′didebromohamacanthin
(1c; 0.2 g, 0.609 mmol), NaBH4 (0.035 g, 0.914 mmol) and
anhyd AlCl3 (0.182 g, 1.371 mmol) in THF (4 mL) and AcOH (2
mL) was stirred for 6 h at r.t. and a solid was slowly precipitated
out. It was filtered and washed with Et2O which afforded the
title compound (3a; 0.168 g, 72% yield) as its acetate salt.
6.9 Hz, 2 H), 3.18 (dd, J = 11.3, 2.3 Hz, 2 H), 4.44 (dd, J = 10.7, 2.3
Hz, 2 H), 7.03 (t, J = 7.8 Hz, 2 H), 7.11 (t, J = 7.3 Hz, 2 H), 7.39 (d, J
= 8.3 Hz, 2 H), 7.44 (s, 2 H), 7.75 (d, J = 7.9 Hz, 2 H), 11.13 (br s, 2
H). 13C NMR (100 MHz, DMSO-d6): δ = 22.9, 45.4, 49.8, 111.8,
121.5, 123.5, 125.7, 136.0, 170.5. LRMS (ESI): m/z = 317 [M +
H]+. HRMS (ESI): m/z [M + H]+ calcd for C20H21N4: 317.1776;
found: 317.1766.
Light yellow solid; yield: 72%. IR (KBr): 3146, 1629, 1501, 1456,
(20) Tonsiengsom, F.; Miyake, F. Y.; Yakushijin, K.; Horne, D. A. Syn-
thesis 2006, 49.
1386 cm–1. 1H NMR (400 MHz, DMSO-d6): δ = 2.67 (dd, J = 13.7,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–H