Palladium-catalyzed heteroannulation approach to 1,2-bis(3-indolyl)ethanes

Article abstract of DOI:10.1055/s-0033-1338969

Palladium-catalyzed heteroannulation between indole-3-butanal and various o-iodoanilines provides a straightforward synthesis of 1,2-bis(3-indolyl) ethanes, which are useful precursors to valued indolo[2,3a]carbazoles. 1,2-Bis(3-indolyl)ethanes bearing a

Full text of DOI:10.1055/s-0033-1338969

LETTER
▌1931
letter
Palladium-Catalyzed Heteroannulation Approach to 1,2-Bis(3-indolyl)ethanes
Synthesis of 1,2-Bis(3-indolyl)ethanes
Lachlan M. Blair, Jonathan Sperry*
School of Chemical Sciences, University of Auckland, 23 Symonds Street, Auckland, New Zealand
Fax +64(9)3737422; E-mail: j.sperry@auckland.ac.nz
Received: 30.05.2013; Accepted after revision: 23.06.2013
The limited applications of the chemistry outlined in
Abstract: Palladium-catalyzed heteroannulation between indole-3-
Scheme 1 is presumably due to the lack of synthetic
butanal and various o-iodoanilines provides a straightforward syn-
methods6 available to access 1,2-bis(3-indolyl)ethanes of
type 1, making it particularly unappealing when a struc-
thesis of 1,2-bis(3-indolyl)ethanes, which are useful precursors to
valued indolo[2,3a]carbazoles. 1,2-Bis(3-indolyl)ethanes bearing a
variety of substituents are available by using this methodology, with turally diverse series of indolocarbazoles are desired. To
one transformed into the natural product 1,2-bis(3-indolyl)ethane-
1,2-dione through a novel double Yonemitsu oxidation.
make this methodology more attractive for indolocarba-
zole synthesis programmes, including our own, a facile
Key words: indole, heteroannulation, indole derivatives, palladi-
um, natural products
synthesis of 1,2-bis(3-indolyl)ethanes 1 was sought.
The palladium-catalyzed heteroannulation of o-iodoani-
lines with carbonyl compounds is a mild and straightfor-
ward method for the synthesis of indoles.7 This reaction
was envisaged as the defining step in the synthesis of 1,2-
bis(3-indolyl)ethanes 1 from indole-3-butanal (5) and
o-iodoanilines 6 (Scheme 2).
The Mannich cyclization of 1,2-bis(3-indolyl)ethane (1)
provides tetrahydroindolocarbazole (2), a key intermedi-
ate in the total synthesis of (+)-tjipanazole F2 (3; Scheme
1).1,2 Although the chemistry outlined in Scheme 1 facili-
tates easy access to indolo[2,3a]carbazoles3 4, unsubsti-
tuted at C5 and C6, most synthetic routes to these
compounds ignore this methodology and rely on Fischer
indolizations4 or the cyclization of an appropriately sub-
stituted 2,2-bisindole.5
H
heteroannulation
O
R
I
N
N
N
H
Pd
H
H
R
1
5
H2N
TFA
6
N
N+
H
N
N
H
H
Scheme 2 Proposed synthesis of 1,2-bis(3-indolyl)ethanes 1
H
1
Mannich
H
97%
Although it has been reported that aldehyde 5 is available
by reducing the ethyl ester of butyric acid 7,8 this was not
selective in our hands and a two-step reduction–oxidation
sequence was employed (Scheme 3). Carboxylic acid 7
was reduced to the alcohol 8,9,10 which, upon oxidation
with 2-iodoxybenzoic acid (IBX), delivered aldehyde
5,8,11 which could not be purified due to its instability and
had to be used immediately in the subsequent heteroannu-
lation.
6
5
7
N
H
H
N
H
8
4
3
2
9
11
4 steps
N
H
2
N 12
10
1
H
indolo[2,3a]carbazole
Cl
4
Upon subjecting freshly prepared aldehyde 5 and o-iodo-
aniline 6a to the heteroannulation conditions reported by
Chen,7b 1,2-bis(3-indolyl)ethane (1a) was isolated in de-
cent overall yield (Table 1, entry 1). With this pleasing re-
sult in hand, the scope of the reaction was investigated
with a range of o-iodoanilines12 (Table 1). The methodol-
ogy can be used to access unsymmetrical 1,2-bis(3-in-
dolyl)ethanes13 bearing electron-donating alkyl (entry 2)
and alkoxy substituents (entry 3). Chlorinated (entry 4)
and fluorinated (entry 5) products are also available, as are
those possessing trifluoromethyl (entry 6), nitrile (entry 7)
and nitro (entry 8) substituents. 1,2-Bis(3-indolyl)ethanes
possessing more than one substituent are also readily
available (entry 9).
N
H
N
O
OH
OH
HO
3
Scheme 1 Van Vranken’s total synthesis of (+)-tjipanazole F2 (3)
SYNLETT 21709013, 2415, 1931–1936
Advanced online publication: 12.08.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1338969; Art ID: ST-2013-D0496-L
© Georg Thieme Verlag Stuttgart · New York

1932
L. M. Blair, J. Sperry
LETTER
A minor drawback of this methodology is the extended
times required for the heteroannulation to reach comple-
tion (Table 1). Attempts to address this issue by increasing
the reaction temperature resulted in significantly reduced
yields due to degradation of indole-3-butanal (5) at tem-
peratures above 85 °C. We felt that faster reactions may
be possible by using the more reactive o-bromoaniline (9)
in the reaction, however, because the mild, ligandless con-
ditions used in Table 1 fail to effect heteroannulation of
aldehydes with o-bromoanilines, the modified conditions
reported by Zhu7d were employed (Scheme 4). Unfortu-
nately, no reaction occurred between 5 and 9 at 85 °C and
attempts to heat the reaction further caused degradation of
5. Thus, it appears that o-iodoanilines cannot be replaced
by other haloanilines in this process.
OH
OH
O
LiAlH4, THF
0 °C to r.t.
18 h
96%
N
N
H
H
8
7
H
IBX
EtOAc
75 °C
5 h
O
N
H
5 (unstable)
Scheme 3 Synthesis of indole-3-butanal (5)
Table 1 Synthesis of 1,2-Bis(3-indolyl)ethanes 1a–i
H
Pd(OAc)2
O
(5 mol%)
DABCO
(3 equiv)
DMF, 85 °C
I
+
R
R
N
N
N
H
5
H2N
H
H
6a–i
1a–i
Entry
1
6 (1.1 equiv)
Time (h)
60
Product
Yield (%)a
I
19
N
H
H2N
N
H
6a
1a
1b
1c
1d
1e
1f
I
Me
Me
2
3
4
5
6
42
17
18
60
21
26
22
17
21
33
N
H
H2N
N
H
6b
I
OMe
OMe
N
H
H2N
N
H
6c
I
Cl
Cl
N
H
N
H
H2N
6d
I
F
F
N
H
H2N
N
H
6e
I
CF3
CF3
N
H
H2N
N
H
6f
Synlett 2013, 24, 1931–1936
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 1,2-Bis(3-indolyl)ethanes
1933
Table 1 Synthesis of 1,2-Bis(3-indolyl)ethanes 1a–i (continued)
H
Pd(OAc)2
O
(5 mol%)
DABCO
(3 equiv)
DMF, 85 °C
I
+
R
R
N
N
H
5
N
H2N
H
H
6a–i
1a–i
Entry
7
6 (1.1 equiv)
Time (h)
90
Product
Yield (%)a
I
CN
CN
32
50
N
H
N
H
H2N
6g
1g
1h
I
8
9
20
19
N
H
H2N
NO2
Cl
N
H
NO2
Cl
6h
I
N
H
H2N
N
H
51
F
F
6i
1i
a Yield over two steps from alcohol 8.
O
Pd(dba)2
(5 mol%)
X-Phos
O
DDQ
(10 mol%)
THF–H2O
KOAc, DMF
Br
27%
N
H
N
N
H
N
H
H
5
+
10
1a
85 °C; no reaction
120 °C; degradation
H2N
N
N
H
9
H
1a
O
O
HO
Scheme 4 Failed heteroannulation with o-bromoaniline (9)
OH
N
N
H
In a related project, we wished to investigate whether the
double Yonemitsu oxidation14 of 1a would furnish 1,2-
bis(3-indolyl)ethane-1,2-dione (10), an alkaloid from the
marine sponge Smenospongia sp.15 and the core structure
of the natural product hyrtiosin B16 (11), itself a potent in-
hibitor of isocitrate lyase from Candida albicans.17 Upon
treating 1a with an excess of 2,3-dichloro-5,6-dicyano-
1,4-benzoquinone (DDQ) in aqueous tetrahydrofuran
(THF), double Yonemitsu oxidation successfully oc-
curred to afford the natural product 10 (Scheme 5).18
H
11
Scheme 5 A double Yonemitsu oxidation
Because this reaction relies on readily available sub-
strates,12,19 it is anticipated that this methodology can be
extended to examples well beyond those reported herein.
It has also been demonstrated that 1a can be transformed
into the natural product 10 by a novel double Yonemitsu
oxidation.
In conclusion, the palladium-catalyzed heteroannulation
between 5 and various o-iodoanilines 6a–i provides a gen-
eral synthetic route to 1,2-bis(3-indolyl)ethanes. The 1,2-
bis(3-indolyl)ethanes reported herein possess a range of
substituents, many of which constitute useful handles
upon which to conduct further synthetic manipulations.
Acknowledgment
The University of Auckland is thanked for support.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1931–1936

1934
L. M. Blair, J. Sperry
LETTER
1047, 1033, 1007, 984, 932, 911, 749, 739, 687, 667, 615
cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.93 (br s, 1 H, NH),
7.61 (d, J = 7.9 Hz, 1 H, ArH), 7.35 (d, J = 8.0 Hz, 1 H,
ArH), 7.19 (td, J = 7.6, 1.1 Hz, 1 H, ArH), 7.12 (td, J = 7.6,
1.1 Hz, 1 H, ArH), 6.98 (s, 1 H, ArH), 3.69 (t, J = 6.5 Hz,
2 H, CH2OH), 2.81 (t, J = 7.3 Hz, 2 H, CH2), 1.74 (m, 4 H,
2 × CH2); OH not observed. 13C NMR (100 MHz, CDCl3):
δ = 136.5 (C), 127.7 (C), 122.0 (CH), 121.3 (CH), 119.3
(CH), 119.1 (CH), 116.8 (C), 111.2 (CH), 63.1 (CH2), 32.8
(CH2), 26.4 (CH2), 25.0 (CH2). ESI-MS: m/z (%) = 212 (100)
[M + Na]+, 196 (8), 190 (5). ESI-HRMS: m/z [M + Na]+
calcd for [C12H15NO + Na]+: 212.1046; found: 212.1047.
(11) Indole-3-butanal (5): A solution of indole-3-butanol (8;
0.10 g, 0.53 mmol) and IBX (0.59 g, 2.11 mmol) in EtOAc
(15 mL) was heated to 75 °C for 5 h. The reaction mixture
was cooled, filtered through a short plug of Celite, and the
cake was washed with EtOAc (10 mL). The filtrate was then
concentrated in vacuo to afford aldehyde 5 (ca. 100 mg) as
an unstable yellow oil which was used immediately in the
subsequent heteroannulation. Note: Using aldehyde 5 that
has been stored in a freezer under argon leads to significantly
reduced yields in the heteroannulation reaction.
References and Notes
(1) (a) Gilbert, E. J.; Van Vranken, D. L. J. Am. Chem. Soc.
1996, 118, 5500. (b) Gilbert, E. J.; Ziller, J. W.; Van
Vranken, D. L. Tetrahedron 1997, 53, 16553. For further
applications of this Mannich dimerization, see: (c) Gilbert,
E. J.; Chisholm, J. D.; Van Vranken, D. L. J. Org. Chem.
1999, 64, 5670. (d) Voldoire, A.; Moreau, P.; Sancelme, M.;
Matulova, M.; Léonce, S.; Pierré, A.; Hickman, J.; Pfeiffer,
B.; Renard, P.; Dias, N.; Bailly, C.; Prudhomme, M. Bioorg.
Med. Chem. 2004, 12, 1955.
(2) For an early example of an intramolecular acid-promoted
indole dimerization, see: Gribble, G. W.; Pelcman, B. J. Org.
Chem. 1992, 57, 3636.
(3) For reviews on the isolation and synthesis of
indolocarbazoles, see: (a) Janosik, T.; Wahlström, N.;
Bergman, J. Tetrahedron 2008, 64, 9159. (b) Sánchez, C.;
Mendéz, C.; Salas, J. A. Nat. Prod. Rep. 2006, 23, 1007.
(4) (a) Strappaghetti, A.; Rabere, G.; Fravolini, A.; Jacquignon,
P. Heterocycles 1980, 14, 935. (b) Royer, H.; Joseph, D.;
Prim, D.; Kirsch, G. Synth. Commun. 1998, 28, 1239.
(c) Balamurali, R.; Prasad, K. J. R. Farmaco 2001, 56, 229.
(d) Hu, Y.-Z.; Chen, Y.-Q. Synlett 2005, 42. (e) Curiel, D.;
Cowley, A.; Beer, P. D. Chem. Commun. 2005, 236.
(5) Using (dimethylamino)acetaldehyde dialkyl acetals, see:
(a) Chang, K.-J.; Chae, M. K.; Lee, C.; Lee, J.-Y.; Jeong,
K.-S. Tetrahedron Lett. 2006, 47, 6385. (b) Kuethe, J. T.;
Wong, A.; Davies, I. W. Org. Lett. 2003, 5, 3721. (c) For
reductive cyclization of 2,2-bisindole-3,3-dicarbaldehydes
with SmI2, see: Banerji, A.; Bandyopadhyay, D.; Basak, B.;
Biswas, P. K.; Banerji, J.; Chatterjee, A. Bull. Chem. Soc.
Jpn. 2007, 80, 1199. (d) For ring-closing metathesis, see:
Pelly, S. C.; Parkinson, C. J.; van Otterlo, W. A. L.; de
Koning, C. B. J. Org. Chem. 2005, 70, 10474.
(12) o-Iodoanilines 6a–i were purchased from commercial
sources.
(13) Synthesis of 1,2-bis(3-indolyl)ethanes 1a–i;
Heteroannulation General Procedure: A quantitative
yield for the oxidation step (8→5)16 is presumed and hence
the molar amounts of each reagent are based on alcohol 8. A
sealed tube charged with DMF (1–2 mL) was degassed with
nitrogen for 30 min. Freshly prepared aldehyde 5 (0.15–0.26
mmol) was added, followed by the appropriate o-iodoaniline
6a–i (0.17–0.29 mmol), DABCO (0.45–0.79 mmol) and
Pd(OAc)2 (5 mol%). The tube was then sealed under a
blanket of nitrogen and stirred at 85 °C for 18–90 h. The
cooled solution was poured onto H2O (10 mL) and extracted
with Et2O (3 × 10 mL). The combined organic extracts were
dried (MgSO4), filtered, and concentrated in vacuo.
Purification by flash chromatography on silica gel (hexanes–
EtOAc) gave the desired products 1a–i, the yields of which
were calculated over two steps from alcohol 8.
(6) Existing methods only allow access to symmetrical
products, see: (a) Bergman, J.; Venemalm, L. Tetrahedron
1990, 46, 6061. (b) Aoki, K.; Peat, A. J.; Buchwald, S. L.
J. Am. Chem. Soc. 1998, 120, 3068. (c) Mohanakrishnan, A.
K.; Ramesh, N.; Prakash, C. Tetrahedron Lett. 2005, 46,
6983. (d) Banerjee, S.; Barnea, E.; Odom, A. L.
Organometallics 2008, 27, 1005. (e) Koshima, H.; Ding, K.;
Matsuura, T. J. Chem. Soc., Chem. Commun. 1994, 2053.
(f) Bergman, J.; Carlsson, R. J. Heterocycl. Chem. 1972, 9,
833. For the only example of an unsymmetrical 1,2-bis(3-
indolyl)ethane, see ref. 1b.
Compound 1a: According to the general procedure, a
mixture of aldehyde 5, 2-iodoaniline (6a; 60 mg, 0.27
mmol), DABCO (83 mg, 0.74 mmol) and Pd(OAc)2 (3 mg,
0.012 mmol, 5 mol%) in DMF (2.0 mL) was heated at 85 °C
for 60 h. The title compound (12 mg, 0.046 mmol, 19% over
two steps) was obtained after flash chromatography (4:1) as
a yellow solid; mp 210 –220 °C (dec.) [Lit.6e 263–265 °C
(MeCN)], (Lit.6f 161–162 °C). IR: 3390, 3049, 2900, 2847,
1618, 1456, 1423, 1355, 1337, 1301, 1267, 1248, 1220,
1090, 1051, 1007, 930, 808, 766, 738 cm–1. 1H NMR
[400 MHz, (CD3)2CO]: δ = 10.74 (br s, 2 H, 2 × NH), 7.56
(d, J = 7.8 Hz, 2 H, 2 × ArH), 7.33 (d, J = 8.1 Hz, 2 H,
2 × ArH), 7.15 (d, J = 2.0 Hz, 2 H, 2 × ArH), 7.06 (td, J =
7.4, 1.0 Hz, 2 H, 2 × ArH), 6.98 (td, J = 7.4, 1.0 Hz, 2 H,
2 × ArH), 3.06 (s, 4 H, 2 × CH2). 13C NMR [100 MHz,
(CD3)2CO]: δ = 136.3 (2 × C), 127.2 (2 × C), 122.2
(2 × CH), 120.8 (2 × CH), 118.3 (2 × CH), 118.1 (2 × CH),
114.8 (2 × C), 111.3 (2 × CH), 25.9 (2 × CH2). ESI-MS:
m/z (%) = 283 (100) [M + Na]+, 156 (80), 144 (13), 130 (80).
ESI-HRMS: m/z [M + Na]+ calcd for [C18H16N2 + Na]+:
283.1206; found: 283.1197.
(7) (a) Iida, H.; Yuasa, Y.; Kibayashi, C. J. Org. Chem. 1980,
45, 2938. (b) Chen, C.-Y.; Lieberman, D. R.; Larsen, R. D.;
Verhoeven, T. R.; Reider, P. J. J. Org. Chem. 1997, 62,
2676. (c) Cho, C. S.; Shim, H. S.; Choi, H.-J.; Kim, T.-J.;
Shim, S. C. Bull. Kor. Chem. Soc. 2004, 25, 441. (d) Jia, Y.;
Zhu, J. J. Org. Chem. 2006, 71, 7826.
(8) Pedras, M. S. C.; Minic, Z.; Thongbam, P. D.; Bhaskar, V.;
Montaut, S. Phytochemistry 2010, 71, 1952.
(9) Perregaard, J.; Moltzen, E. K.; Meier, E.; Sánchez, C.
J. Med. Chem. 1995, 38, 1998.
(10) Indole-3-butanol (8): To a solution of indole-3-butyric acid
(7; 0.50 g, 2.46 mmol) in THF (30 mL) at 0 °C was slowly
added LiAlH4 (0.47 g, 12.31 mmol) and the reaction mixture
was allowed to warm to r.t. over 18 h. EtOAc (10 mL) was
added slowly followed by H2O (10 mL) and the mixture was
poured onto a solution of Rochelle’s salt (40 mL). The
resulting suspension was extracted with EtOAc (3 × 40 mL)
and the combined organic extracts were dried (MgSO4),
filtered and concentrated in vacuo. Purification by filtration
through a short plug of silica gel (hexanes–EtOAc, 1:3) gave
the title compound as a yellow oil (0.45 g, 2.36 mmol, 96%).
Spectroscopic data were consistent with literature data.9 IR:
3385, 3288, 2927, 1455, 1423, 1340, 1225, 1091, 1062,
Compound 1b: According to the general procedure, a
mixture of aldehyde 5, 2-iodo-4-methylaniline (6b; 68 mg,
0.29 mmol), DABCO (89 mg, 0.79 mmol) and Pd(OAc)2 (3
mg, 0.013 mmol, 5 mol%) in DMF (2.0 mL) was heated at
85 °C for 42 h. The title compound (19 mg, 0.069 mmol,
26% over two steps) was obtained after flash
Synlett 2013, 24, 1931–1936
© Georg Thieme Verlag Stuttgart · New York

LETTER
chromatography (7:3) as a brown solid; mp 193–196 °C. IR:
Synthesis of 1,2-Bis(3-indolyl)ethanes
1935
(dec.). IR: 3401, 1579, 1483, 1453, 1423, 1358, 1332, 1260,
1215, 1167, 1092, 1041, 1008, 938, 866, 797, 769, 739, 695,
610 cm–1. 1H NMR [400 MHz, (CD3)2CO]: δ = 10.02 (br s,
1 H, NH), 9.92 (br s, 1 H, NH), 7.63 (d, J = 8.0 Hz, 1 H,
ArH), 7.37 (m, 2 H, 2 × ArH), 7.29 (dd, J = 10.0, 2.5 Hz,
1 H, ArH), 7.23 (d, J = 2.3 Hz, 1 H, ArH), 7.15 (d, J =
2.3 Hz, 1 H, ArH), 7.09 (td, J = 7.5, 1.2 Hz, 1 H, ArH), 7.02
(td, J = 7.5, 1.0 Hz, 1 H, ArH), 6.88 (td, J = 9.1, 2.5 Hz, 1 H,
ArH), 3.13 (m, 4 H, 2 × CH2). 13C NMR [100 MHz,
(CD3)2CO]: δ = 158.3 (d, JC–F = 231.4 Hz, C), 137.8 (C),
134.3 (C), 129.0 (d, JC–F = 9.4 Hz, C), 128.7 (C), 125.0 (CH),
122.8 (CH), 122.0 (CH), 119.4 (CH), 119.3 (CH), 116.9 (d,
JC–F = 4.9 Hz, C), 116.5 (C), 112.9 (d, JC–F = 9.7 Hz, CH),
3393, 2918, 2848, 1483, 1456, 1423, 1330, 1230, 1250,
1223, 1182, 1090, 1047, 1005, 927, 874, 794, 771, 742, 694
cm–1. 1H NMR (400 MHz, DMSO-d6): δ = 9.91 (br s, 1 H,
NH), 9.77 (br s, 1 H, NH), 7.64 (d, J = 7.8 Hz, 1 H, ArH),
7.39 (m, 2 H, 2 × ArH), 7.26 (d, J = 8.2 Hz, 1 H, ArH), 7.15
(d, J = 2.2 Hz, 1 H, ArH), 7.10 (m, 2 H, 2 × ArH), 7.02 (td,
J = 7.4, 1.0 Hz, 1 H, ArH), 6.93 (dd, J = 8.3, 1.0 Hz, 1 H,
ArH), 3.14 (m, 4 H, 2 × CH2), 2.41 (s, 3 H, Me). 13C NMR
(100 MHz, DMSO-d6): δ = 137.8 (C), 136.2 (C), 128.9 (C),
128.7 (C), 128.0 (C), 123.6 (CH), 122.8 (CH), 122.7 (CH),
122.0 (CH), 119.4 (CH), 119.3 (CH), 119.1 (CH), 116.7 (C),
116.2 (C), 112.1 (CH), 111.8 (CH), 27.11 (CH2), 27.07
(CH2), 21.7 (Me). ESI-MS: m/z (%) = 297 (100) [M + Na]+,
170 (9). ESI-HRMS: m/z [M + Na]+ calcd for [C19H18N2 +
Na]+: 297.1362; found: 297.1366.
112.1 (CH), 109.9 (d, JC–F = 26.4 Hz, CH), 104.0 (d, JC–F
=
23.2 Hz, CH), 26.9 (2 × CH2). ESI-MS: m/z (%) = 301 (100)
[M + Na]+, 242 (4), 210 (3). ESI-HRMS: m/z [M + Na]+
calcd for [C18H15FN2 + Na]+: 301.1111; found: 301.1124.
Compound 1f: According to the general procedure, a
mixture of aldehyde 5, 2-iodo-4-(trifluoromethyl)aniline (6f;
47 mg, 0.165 mmol), DABCO (51 mg, 0.450 mmol) and
Pd(OAc)2 (2 mg, 0.008 mmol, 5 mol%) in DMF (1.1 mL)
was heated at 85 °C for 21 h. The title compound (16 mg,
0.049 mmol, 33% over two steps) was obtained after flash
chromatography (7:3) as a brown solid; mp 142–145 °C. IR:
3388, 1458, 1328, 1282, 1261, 1215, 1153, 1130, 1096,
1080, 1044, 1026, 1006, 904, 891, 802, 771, 751, 714, 661
cm–1. 1H NMR [400 MHz, (CD3)2CO]: δ = 10.38 (br s, 1 H,
NH), 9.92 (br s, 1 H, NH), 7.93 (s, 1 H, ArH), 7.61 (d, J =
7.9 Hz, 1 H, ArH), 7.56 (d, J = 8.7 Hz, 1 H, ArH), 7.37 (d,
J = 8.2 Hz, 2 H, 2 × ArH), 7.33 (s, 1 H, ArH), 7.14 (d, J = 2.1
Hz, 1 H, ArH), 7.08 (td, J = 7.4, 0.8 Hz, 1 H, ArH), 7.00 (t,
J = 7.4 Hz, 1 H, ArH), 3.19 (m, 4 H, 2 × CH2); 13C NMR
[100 MHz, (CD3)2CO]: δ = 139.1 (C), 137.8 (C), 128.6 (C),
128.0 (CF3), 125.1 (CH), 125.0 (C), 122.9 (CH), 122.0 (CH),
121.3 (C), 119.3 (2 × CH), 118.5 (d, JC–F = 3.5 Hz, CH),
117.9 (C), 117.1 (q, JC–F = 4.2 Hz, CH), 116.3 (C), 112.7
(CH), 112.1 (CH), 27.0 (CH2), 26.6 (CH2). ESI-MS:
m/z (%) = 351 (100) [M + Na]+, 250 (7). ESI-HRMS: m/z
[M + Na]+ calcd for [C19H15F3N2 + Na]+: 351.1080; found:
351.1076.
Compound 1c: According to the general procedure, a
mixture of aldehyde 5, 2-iodo-4-methoxylaniline (6c; 72
mg, 0.29 mmol), DABCO (89 mg, 0.79 mmol) and
Pd(OAc)2 (3 mg, 0.013 mmol, 5 mol%) in DMF (2.0 mL)
was heated at 85 °C for 17 h. The title compound (17 mg,
0.059 mmol, 22% over two steps) was obtained after flash
chromatography (4:1) as a brown solid; mp 136 –140 °C. IR:
3400, 1484, 1454, 1435, 1335, 1294, 1266, 1207, 1168,
1093, 1052, 1030, 1008, 967, 923, 829, 811, 795, 770, 747
cm–1. 1H NMR (400 MHz, DMSO-d6): δ = 10.73 (s, 1 H,
NH), 10.57 (s, 1 H, NH), 7.57 (d, J = 7.8 Hz, 1 H, ArH), 7.34
(d, J = 8.0 Hz, 1 H, ArH), 7.22 (d, J = 8.7 Hz, 1 H, ArH),
7.13 (m, 2 H, 2 × ArH), 7.07 (td, J = 7.5, 0.9 Hz, 1 H, ArH),
6.97 (m, 2 H, 2 × ArH), 6.70 (dd, J = 8.7, 2.4 Hz, 1 H, ArH),
3.72 (s, 3 H, OMe), 3.05 (m, 4 H, 2 × CH2). 13C NMR
(100 MHz, DMSO-d6): δ = 152.9 (C), 136.3 (C), 131.4 (C),
127.6 (C), 127.3 (C), 122.9 (CH), 122.3 (CH), 120.8 (CH),
118.3 (CH), 118.1 (CH), 114.8 (C), 114.6 (C), 111.9 (CH),
111.3 (CH), 110.9 (CH), 100.2 (CH), 55.3 (OMe), 25.8
(2 × CH2). ESI-MS: m/z (%) = 313 (100) [M + Na]+, 143 (9).
ESI-HRMS: m/z [M + Na]+ calcd for [C19H18N2O + Na]+:
313.1311; found: 313.1315.
Compound 1d: According to the general procedure, a
mixture of aldehyde 5, 4-chloro-2-iodoaniline (6d; 49 mg,
0.193 mmol), DABCO (60 mg, 0.535 mmol) and Pd(OAc)2
(2 mg, 0.009 mmol, 5 mol%) in DMF (1.3 mL) was heated
at 85 °C for 18 h. The title compound (9 mg, 0.031 mmol,
17% over two steps) was obtained after flash
Compound 1g: According to the general procedure, a
mixture of aldehyde 5, 4-amino-3-iodobenzonitrile (6g; 71
mg, 0.29 mmol), DABCO (89 mg, 0.79 mmol) and
Pd(OAc)2 (3 mg, 0.013 mmol, 5 mol%) in DMF (2.0 mL)
was heated at 85 °C for 90 h. The title compound (24 mg,
0.085 mmol, 32% over two steps) was obtained after flash
chromatography (3:2) as a brown solid; mp 162–165 °C. IR:
3406, 2223, 1614, 1469, 1456, 1422, 1361, 1322, 1221,
1098, 1082, 1066, 1008, 883, 827, 813, 801, 787, 764, 737
cm–1. 1H NMR (400 MHz, DMSO-d6): δ = 11.36 (s, 1 H,
NH), 10.74 (s, 1 H, NH), 8.05 (s, 1 H, ArH), 7.53 (m, 2 H,
2 × ArH), 7.37 (m, 3 H, 3 × ArH), 7.15 (s, 1 H, ArH), 7.06
(t, J = 7.5 Hz, 1 H, ArH), 6.97 (t, J = 7.5 Hz, 1 H, ArH), 3.08
(m, 4 H, 2 × CH2). 13C NMR (100 MHz, DMSO-d6): δ =
137.9 (C), 136.2 (C), 127.2 (C), 127.1 (C), 125.0 (CH),
124.3 (CH), 123.5 (CH), 122.4 (CH), 121.0 (C), 120.8 (CH),
118.4 (CH), 118.1 (CH), 116.2 (C), 114.4 (C), 112.5 (CH),
111.3 (CH), 100.2 (C), 25.8 (CH2), 25.4 (CH2). ESI-MS:
m/z (%) = 308 (100) [M + Na]+. ESI-HRMS: m/z [M + Na]+
calcd for [C19H15N3 + Na]+: 308.1158; found: 308.1153.
Compound 1h: According to the general procedure, a
mixture of aldehyde 5, 2-iodo-5-nitroaniline (6h; 77 mg,
0.29 mmol), DABCO (89 mg, 0.79 mmol) and Pd(OAc)2 (3
mg, 0.013 mmol, 5 mol%) in DMF (2.0 mL) was heated at
85 °C for 20 h. The title compound (40 mg, 0.131 mmol,
50% over two steps) was obtained after flash
chromatography (7:3) as a brown solid; mp 175 –178 °C
(Lit.1b 178–180 °C). IR: 3397, 2907, 1454, 1421, 1394,
1328, 1299, 1283, 1251, 1214, 1091, 1043, 1007, 927, 895,
871, 797, 777, 768, 738 cm–1. 1H NMR (400 MHz, DMSO-
d6): δ = 10.96 (s, 1 H, NH), 10.74 (s, 1 H, NH), 7.55 (m, 2 H,
2 × ArH), 7.34 (m, 2 H, 2 × ArH), 7.24 (d, J = 2.2 Hz, 1 H,
ArH), 7.15 (d, J = 2.0 Hz, 1 H, ArH), 7.06 (m, 2 H,
2 × ArH), 6.97 (td, J = 7.3, 0.7 Hz, 1 H, ArH), 3.04 (s, 4 H,
2 × CH2). 13C NMR (100 MHz, DMSO-d6): δ = 136.2 (C),
134.6 (C), 128.4 (C), 127.2 (C), 124.2 (CH), 122.8 (C),
122.3 (CH), 120.8 (CH), 120.7 (CH), 118.3 (CH), 118.1
(CH), 117.6 (CH), 114.8 (C), 114.5 (C), 112.8 (CH), 111.3
(CH), 25.8 (CH2), 25.5 (CH2). ESI-MS: m/z (%) = 317 (100)
[M + Na]+, 143 (18). ESI-HRMS: m/z [M + Na]+ calcd for
[C18H1535ClN2 + Na]+: 317.0816; found: 317.0807.
Spectroscopic data is consistent with the literature.1b
Compound 1e: According to the general procedure, a
mixture of aldehyde 5, 4-fluoro-2-iodoaniline (6e; 46 mg,
0.194 mmol), DABCO (60 mg, 0.535 mmol) and Pd(OAc)2
(2 mg, 0.009 mmol, 5 mol%) in DMF (1.3 mL) was heated
at 85 °C for 60 h. The title compound (10 mg, 0.037 mmol,
21% over two steps) was obtained after flash
chromatography (7:3) as a brown solid; mp 200 – 220 °C
chromatography (7:3) as an orange solid; mp 170–173 °C.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1931–1936

1936
L. M. Blair, J. Sperry
LETTER
IR: 3416, 3218, 1494, 1458, 1420, 1345, 1310, 1291, 1241,
1216, 1124, 1105, 1095, 1076, 1053, 1010, 865, 815, 782,
738, 724, 665 cm–1. 1H NMR (400 MHz, DMSO-d6): δ =
11.58 (s, 1 H, NH), 10.75 (s, 1 H, NH), 8.31 (d, J = 1.9 Hz,
1 H, ArH), 7.86 (dd, J = 8.9, 1.9 Hz, 1 H, ArH), 7.70 (d, J =
8.9 Hz, 1 H, ArH), 7.62 (s, 1 H, ArH), 7.56 (d, J = 8.0 Hz,
1 H, ArH), 7.34 (d, J = 8.0 Hz, 1 H, ArH), 7.14 (s, 1 H,
ArH), 7.07 (t, J = 7.5 Hz, 1 H, ArH), 6.97 (t, J = 7.5 Hz, 1 H,
ArH), 3.10 (m, 4 H, 2 × CH2). 13C NMR (100 MHz, DMSO-
d6): δ = 141.7 (C), 136.3 (C), 134.5 (C), 131.9 (C), 129.8
(CH), 127.2 (C), 122.3 (CH), 120.8 (CH), 118.6 (CH), 118.3
(CH), 118.1 (CH), 116.3 (C), 114.3 (C), 113.4 (CH), 111.3
(CH), 108.2 (CH), 25.8 (CH2), 25.4 (CH2). ESI-MS:
m/z (%) = 328 (100) [M + Na]+. ESI-HRMS: m/z [M + Na]+
calcd for [C18H15N3O2 + Na]+: 328.1056; found: 328.1063.
Compound 1i: According to the general procedure, a
mixture of aldehyde 5, 4-chloro-2-fluoro-6-iodoaniline (6i;
79 mg, 0.29 mmol), DABCO (89 mg, 0.79 mmol) and
Pd(OAc)2 (3 mg, 0.013 mmol, 5 mol%) in DMF (2.0 mL)
was heated at 85 °C for 19 h. The title compound (42 mg,
0.134 mmol, 51% over two steps) was obtained after flash
chromatography (3:1) as a yellow solid; mp 132–135 °C. IR:
3386, 1474, 1457, 1435, 1363, 1297, 1221, 1085, 1071,
1061, 1008, 968, 890, 862, 855, 821, 812, 772, 746, 705 cm–1.
1H NMR [400 MHz, (CD3)2CO]: δ =10.56 (br s, 1 H, NH),
9.93 (br s, 1 H, NH), 7.61 (d, J = 7.6 Hz, 1 H, ArH), 7.43 (d,
J = 2.0 Hz, 1 H, ArH), 7.38 (d, J = 8.3 Hz, 1 H, ArH), 7.30
(d, J = 1.9 Hz, 1 H, ArH), 7.14 (d, J = 2.2 Hz, 1 H, ArH),
7.09 (td, J = 7.6, 1.2, 1 H, ArH), 7.01 (td, J = 7.6, 1.0 Hz,
1 H), 6.93 (dd, J = 10.8, 1.7 Hz, 1 H, ArH), 3.15 (s, 4 H,
2 × CH2). 13C NMR [100 MHz, (CD3)2CO]: δ =150.0 (d,
JC–F = 246.3 Hz, C), 137.8 (C), 132.9 (d, JC–F = 6.5 Hz, C),
128.6 (C), 125.7 (CH), 124.1 (C), 123.9 (d, JC–F = 8.6 Hz, C),
129.9 (CH), 122.0 (CH), 119.33 (CH), 119.31 (CH), 117.8
(d, JC–F = 5.9 Hz, C), 116.2 (C), 115.3 (d, JC–F = 3.2 Hz, CH),
112.2 (CH), 107.7 (d, JC–F = 20.4 Hz, CH), 26.9 (CH2), 26.6
(CH2). ESI-MS: m/z (%) = 335 (100) [M + Na]+, 278 (23).
ESI-HRMS: m/z [M + Na]+ calcd for [C18H1435ClFN2 + Na]+:
335.0722; found: 335.0734.
(d) Sessler, J. L.; Cho, D.-G.; Lynch, V. J. Am. Chem. Soc.
2006, 128, 16518. (e) Krayushkin, M. M.; Yarovenko, V.
N.; Sedishev, I. P.; Zavarzin, I. V.; Vorontsova, L. G.;
Starikova, Z. A. Russ. J. Org. Chem. 2005, 41, 875; See also
ref. 6a.
(16) Isolation: (a) Kobayashi, J.; Murayama, T.; Ishibashi, M.;
Kosuge, S.; Takamatsu, M.; Ohizumi, Y.; Kobayashi, H.;
Ohta, T.; Nozoe, S.; Sasaki, T. Tetrahedron 1990, 46, 7699.
(b) For a previous synthesis, see: Bergman, J.; Janosik, T.;
Johnsson, A.-L. Synthesis 1999, 4, 580.
(17) Lee, H.-S.; Moon, K.-M.; Han, Y.-R.; Lee, K. J.; Chung,
S.-C.; Kim, T.-I.; Lee, S.-H.; Shin, J.; Oh, K.-B. Bioorg.
Med. Chem. Lett. 2009, 19, 1051.
(18) 1,2-Bis(3-indol-3-yl)ethane-1,2-dione (10): To a mixture
of 1a (30 mg, 0.12 mmol) in THF–H2O (3 mL, 9:1) at 0 °C
was added DDQ (58 mg, 0.25 mmol) and the reaction
mixture was stirred at r.t. for 2.5 h. A second portion of DDQ
(58 mg, 0.25 mmol) was added and the reaction mixture
stirred for a further 2.5 h. The mixture was poured onto a
saturated solution of NaHCO3 (20 mL) and extracted with
EtOAc (20 mL). The organic extract was further washed
with a saturated solution of NaHCO3 (5 × 20 mL), dried
(MgSO4), filtered, and concentrated in vacuo. Purification
by flash chromatography on silica gel (hexanes–EtOAc, 1:1)
gave the title compound (9 mg, 0.031 mmol, 27%) as an
orange solid; mp 278–280 °C [Lit.6a 278–280 °C].
Spectroscopic data is consistent with the literature.6a IR:
3297, 1595, 1505, 1454, 1430, 1410, 1357, 1336, 1308,
1237, 1115, 1098, 1084, 1009, 874, 775, 757, 745, 732
cm–1. 1H NMR (400 MHz, DMSO-d6): δ = 12.22 (s, 2 H,
2 × NH), 8.27 (m, 2 H, 2 × ArH), 8.22 (d, J = 2.8 Hz, 2 H,
2 × ArH), 7.54 (m, 2 H, 2 × ArH), 7.29 (m, 4 H, 4 × ArH).
13C NMR (100 MHz, DMSO-d6): δ = 188.8 (2 × C), 137.3
(2 × CH), 136.7 (2 × C), 125.6 (2 × C), 123.4 (2 × CH),
122.4 (2 × CH), 121.3 (2 × CH), 112.54 (2 × CH), 112.47
(2 × C). ESI-MS: m/z (%) = 311 (100) [M + Na]+, 178 (36),
109 (9). ESI-HRMS: m/z [M + Na]+ calcd for [C18H12N2O2 +
Na]+: 311.0791; found: 311.0787.
(19) Indole-3-butanals are readily available from the
corresponding butanols or butanoic acids, which are
themselves easily assembled, see: (a) Soubhye, J.; Prévost,
M.; Van Antwerpen, P.; Boudjeltia, K. Z.; Rousseau, A.;
Furtmüller, P. G.; Obinger, C.; Vanhaeverbeek, M.; Ducobu,
J.; Néve, J.; Gelbcke, M.; Dufrasne, F. J. Med. Chem. 2010,
53, 8747. (b) Csende, F. Arch. Pharm. Pharm. Med. Chem.
2001, 334, 253.
(14) Oikawa, Y.; Yoshioka, T.; Mohri, K.; Yonemitsu, O.
Heterocycles 1979, 12, 1457.
(15) Isolation: (a) McKay, M. J.; Carroll, A. R.; Quinn, R. J.;
Hooper, J. N. A. J. Nat. Prod. 2002, 65, 595. For previous
syntheses, see: (b) Bergman, J.; Carlsson, R.; Sjöberg, B.
J. Heterocycl. Chem. 1977, 14, 1123. (c) Wang, T.; Bai, Y.;
Ma, L.; Yan, X.-P. Org. Biomol. Chem. 2008, 6, 1751.
Synlett 2013, 24, 1931–1936
© Georg Thieme Verlag Stuttgart · New York

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