Palladium-catalyzed cyanoalkenylation of indoles

Article abstract of DOI:10.1016/j.tet.2013.04.066

A palladium-catalyzed one-pot, three component method for the synthesis of indolyl diphenyl(-or dialkyl)acrylonitriles using 3-iodoindoles, alkynes and safe and nontoxic K₄[Fe(CN)₆]·3H₂O as the cyanating agent has been developed.

Full text of DOI:10.1016/j.tet.2013.04.066

Tetrahedron 69 (2013) 5193e5196
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Palladium-catalyzed cyanoalkenylation of indoles
*
Ebrahim Kianmehr , Hamed Hashemi, Ali Darvish
School of Chemistry, College of Science, University of Tehran, Tehran 1417614411, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A palladium-catalyzed one-pot, three component method for the synthesis of indolyl diphenyl(-or dia-
lkyl)acrylonitriles using 3-iodoindoles, alkynes and safe and nontoxic K4[Fe(CN)6]∙3H2O as the cyanating
agent has been developed.
Received 25 November 2012
Received in revised form 22 March 2013
Accepted 15 April 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Available online 25 April 2013
Keywords:
Heterocycles
Palladium
Nitriles
Homogeneous catalysis
Indoles
1. Introduction
H
N
N
O
O
Indole and its derivatives have captured the imagination of or-
ganic chemists for more than a century. The name indole was given
by Baeyer and Knop to a structural skeleton of products obtained by
reduction of isatin in 1866 and the structural formula of indole was
proposed by the same group in 1869.1 Since the isolation of indole
alkaloids from medicinal plants it has been shown that this class of
compounds exhibits a broad range of useful pharmacological ef-
fects, including antibiotic, anti-inflammatory, antihypertensive,
and antitumor activities, and the indole nucleus has taken on
considerable pharmacological importance2 (e.g., 1 and 2, Fig. 1).
Inhibition of the human serotonin reuptake transporter (hSERT)
has proven utility for the treatment of depression and other related
affective disorders and homotryptamine derivatives, which are
indole-based structures (e.g., 5e7, Fig. 1), have been known to show
hSERT potency.3
N
H
2
N
N
N
CN
N
N
H
R2
R2
1
3
CN
4
N
R1
N
NC
NC
N
N
H
N
H
7
N
NC
5
N
H
6
Due to the need for efficient ways to synthesize more elaborate
structures possessing biological activity, the development of novel
and convenient methods for the preparation of indole derivatives is
of considerable importance in organic chemistry.4
Fig. 1. Some bioactive compounds with an indole core structure.
Triarylethylene-derived compounds including triphenylacrylo-
nitrile derivatives are known for their antiestrogenic properties and
are used clinically for ovulation induction, treatment of hormone
dependent cancers and diagnostic purposes5 (3, Fig. 1).
Nitriles have broad synthetic applications in organic and ma-
terial chemistry and they are valuable motifs for the installation of
other functional groups such as aldehydes, amines, amidines, tet-
razoles, acids, and acid derivatives.6 So far, several transition metal-
catalyzed or -mediated synthetic methods have been reported for
the preparation of alkenyl nitriles, such as additions of cyanides to
alkynes7 and cyanation of alkenyl halides.8
* Corresponding author. Tel.: þ98 21 61113301; fax: þ98 21 66495291; e-mail
address: kianmehr@khayam.ut.ac.ir (E. Kianmehr).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.04.066

5194
E. Kianmehr et al. / Tetrahedron 69 (2013) 5193e5196
Table 2
2. Results and discussion
Scope of cyanoalkenylation of 3-iodoindoles
R2
CN
As part of our ongoing research program on the development of
efficient methods for indole functionalization we turned our at-
tention to the synthesis of indolyl diphenyl(-or dialkyl)acryloni-
triles (4) via a palladium catalyzed three component reaction using
N-substituted indoles, alkynes and K4[Fe(CN)6] as the cyanating
agent.9
R2
PdCl2 (2 mol %)
I
K4Fe(CN)6 (0.3 equiv)
NaHCO3 (1 equiv)
R2
R2
+
DMF:H2O (80:20)
N
N
R1
R1
8
9
4
At the outset of our study, we investigated the reaction of 1-
methylindole 8a and diphenylacetylene 9a, as model substrates,
in the presence of sodium hydrogen carbonate, with 2 mol % of
palladium acetate, in acetonitrile at 120 ꢀC for 24 h, which led to
the formation of 3-(1-methyl-3-indolyl)-2,3-diphenyl-2-propeneni
trile 4a in less than 5% yield (Table 1, entry 1).
Ph
CN
Ph
CN
Ph
Ph
CN
N
N
Me
4b (72%)
N
Me
Et
4a (75%)
4c (77%)
Table 1
Ph
CN
Ph
CN
Selected results of screening the optimal conditionsa
Ph
Ph
CN
Ph
Ph
I
CN
N
Propyl
N
Et
N
Bu
120°C
Cat., K4Fe(CN)6
+
Ph
Ph
N
CH3
N
CH3
4d (79%)
4e(81%)
4f (80%)
8a
9a
4a
Ph
CN
Ph
Entry
Pd catalyst
Solventb
Base
Yield (%)
CN
CN
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
Pd(PPh3)2Cl2
PdCl2/PPh3
PdCl2
PdCl2
PdCl2
CH3CN
DMF
DMFeH2O
DMAC
DME
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
KHCO3
<5
29
63
8
5
19
0
75
16
0
N
N
N
Bu
Pentyl
Pentyl
4g (84%)
4h (79%)
4i (82%)
DMSO
DMSOeH2O
DMFeH2O
DMFeH2O
DMFeH2O
DMFeH2O
DMFeH2O
DMFeH2O
DMFeH2O
DMFeH2O
DMFeH2O
DMFeH2O
DMFeH2O
Et
CN
Ph
CN
Et
CN
Et
Ph
Et
9
10
11
12
13
14
15
16
17
18
4
NaOAc
Trace
<5
10
17
15
36
0
N
N
Bn
N
Pyridine
Ag2CO3
Cs2CO3
Na2CO3
KHCO3
Pentyl
Bu
PdCl2
PdCl2
PdCl2
PdCl2
4j (73%)
4k (84%)
4l (82%)
PdCl2
K2CO3
a
confirmed by previous report by Hiyama7a on physical properties
and spectroscopic data of 4b and also the NOESY spectrum of
4g (see the Supplementary data for details). The NOESY spectrum of
4g shows through-space spin-spin coupling between the indole
nucleus and the A chain of the structure (Scheme 1, cis) and no
spinespin coupling interaction is observed between the B chain
and H-2 or H-4 of the indole moiety (Scheme 1, trans), which is in
accordance with the cis stereochemistry of the product.
Reaction conditions: 8a (1.5 mmol), 9a (1.0 equiv), catalyst (2 mol %), base
(1.0 mmol), K4[Fe(CN)6] (0.3 equiv), solvent (4 ml), 120 ꢀC, 24 h.
b
DMFeH2O (80:20 v/v).
To optimize the reaction conditions, catalysts, bases, solvents,
and temperatures of the reaction were investigated. As for the sol-
vents, the best results were obtained in DMFeH2O (80:20) at 120 ꢀC,
under otherwise identical reaction conditions (Table 1, entries 1e7).
Different Pd based catalysts were tested and under the optimized
reaction conditions, 2 mol % PdCl2 was sufficient to achieve 75%
yield of 4a (Table 1, entries 8e10). The base played an important role
in this reaction. Less than 5% of the desired product 4a was obtained
when pyridine was used as the base (Table 1, entry 13) and poor
yields were obtained using K2CO3, CsCO3, Ag2CO3, KHCO3, or
NaOAc (Table 1, entries 14e18). The best result was observed with
NaHCO3, which furnished the highest yield (Table 1, entry 8).
The reaction provided a lower conversion at lower temperature.
No reaction occurred in the absence of Pd catalyst. Once the opti-
mized conditions for the desired reaction had been established, we
investigated the scope and limitations. A variety of combinations of
substrates including N-alkyl or N-benzyl indoles and diphenyl or
dialkylacetylenes were examined and the results are summarized
in Table 2.
3. Conclusion
In summary, we have developed an efficient method for cya-
noalkenylation of N-substituted 3-iodoindoles via a domino cou-
pling of 3-iodoindoles, alkynes, and a cyanide anion. The reaction
uses safe and nontoxic K4[Fe(CN)6]∙3H2O as the cyanating agent.
This protocol provides a facile route to synthesis of the title prod-
ucts by a one-pot three-component sequence.
4. Experimental section
4.1. General
All reactions were performed under anhydrous conditions.
Glassware was flame-dried and reactions were performed under an
argon atmosphere. Catalytic reactions were performed employing
The reaction proceeded with high stereoselectivity and gave the
cis-addition product. The cis stereochemistry of the products was

E. Kianmehr et al. / Tetrahedron 69 (2013) 5193e5196
5195
d
0.90 (t, J¼7.9 Hz, 3H), 1.08 (t, J¼7.4 Hz, 3H), 1.39 (sextet, J¼7.5 Hz,
B chain
B chain
CN
A chain
2H), 1.74 (sextet, J¼7.3 Hz, 2H), 2.43 (t, J¼7.8 Hz, 2H), 2.69 (t, J¼7.8 Hz,
2H), 3.84 (s, 3H), 7.2 (t, J¼8.0 Hz, 1H), 7.29e7.31 (m, 2H), 7.37 (d,
J¼8.1 Hz, 1H), 7.61 (d, J¼8.0 Hz, 1H). 13C NMR (125.7 MHz, CDCl3)
NC
d
13.6, 13.9, 21.8, 22, 32.4, 35.24, 41.1, 109.4, 109.7, 114.3, 119.9, 120.2,
A chain
120.8, 122, 126.4, 128.7, 136, 152.6. IR(KBr) 3113, 2958, 2869, 2197,
1602, 1524, 1456, 1402, 1377, 1316, 1268, 1208, 1110, 1079, 1014, 980,
848, 802, 751, 668. Mass (%). 266 (3), 259 (10), 245 (50), 231 (35), 221
(30), 215 (28), 207 (30), 167 (42), 149 (59), 91 (30), 71 (91), 57 (46), 43
(100). Anal. Calcd for C18H22N2: C, 81.16; H, 8.32; N, 10.52; found: C,
81.09; H, 8.36; N, 10.55.
cis
N
N
A chain
4.2.3. (z)-3-(1-Ethyl-3-indolyl)-2,3-diphenyl-2-propenenitrile
B chain
(4c). Yellow oil, 1H NMR (500.1 MHz, CDCl3)
d
1.6 (t, J¼7.3 Hz, 3H), 4.3
CN
N
CN
(q, J¼7.3 Hz, 2H), 6.59 (d, J¼8.1 Hz, 1H), 6.94 (t, J¼8.0 Hz, 1H), 7.22 (m,
8H), 7.3 (m, 3H), 7.41 (d, J¼8.3 Hz, 1H), 7.94 (s, 1H). 13C NMR
A chain
B chain
(125.7 MHz, CDCl3)
d 15.8, 42, 106.3, 110.2, 115.1, 120.8, 121.8, 122.4,
trans
N
122.6, 127.7, 127.9, 128.6, 128.7, 129.3, 130.4, 131.4, 131.5, 135.9, 136.9,
139.4, 152. IR(KBr) 2952, 2204, 1522, 1463, 1377, 1273, 1216, 1159, 1131,
1074, 1021, 742, 696, 640 Mass (%). 348 (100), 333 (8), 318 (6), 279 (10),
271 (2), 242 (11), 205 (14), 167 (19), 149 (52), 91 (33), 71 (32), 57 (38),
43 (32), 41 (30). Anal. Calcd for C25H20N2: C, 86.17; H, 5.79; N, 8.04;
found: C, 86.14; H, 5.78; N, 8.08.
Scheme 1.
microwave vials. Solvents were distilled before use. Chemicals were
purchased from commercial sources and were used as received.
Substituted indoles were prepared according to the literature.10
Thin layer chromatography (TLC) analysis was performed using
Silicycle precoated TLC plates (silica gel 60 F254). The products were
purified by preparative column chromatography on silica gel
(0.063e0.200 mm; Merck). IR Spectra: Bruker Equino 55 spec-
4.2.4. (z)-3-(1-Ethyl-3-indolyl)-2-propyl-2-hexenenitrile (4d). Yellow
oil, 1H NMR (500.1 MHz, CDCl3)
d
0.91 (t, J¼7.4 Hz, 3H), 10.8 (t,
J¼7.4 Hz, 3H), 1.4 (sextet, J¼7.4 Hz, 2H), 1.53 (t, J¼7.2 Hz, 3H), 1.74
(sextet, J¼7.3 Hz, 2H), 2.4 (t, J¼7.7 Hz, 2H), 2.7 (t, J¼6.3 Hz, 2H), 4.22
(q, J¼7.3 Hz, 2H), 7.1 (t, J¼7.1 Hz, 1H), 7.27 (t, J¼7.3 Hz,1H), 7.28 (S,1H),
7.39 (d, J¼9.4 Hz, 1H), 7.62 (d, J¼8.0 Hz, 1H). 13C NMR (125.7 MHz,
CDCl3)
d 13.3, 13.6, 21.8, 22, 32.4, 33.5, 35.2, 41.1, 109.6, 109.7, 114.3,
trometer; in cmꢁ1
Bruker DRX -500-Advance instrument; in CDCl3 at 500.1 and
125.7 MHz, resp.; in parts per million, J in Hertz. EI-MS (70 eV): HP
.
1H and 13C NMR Spectra: were recorded on
119.8, 120.3, 120.8, 121.8, 126.4, 127.4, 136, 152.6. IR(KBr) 3113, 2958,
2869, 2197, 1602, 1524, 1456, 1402, 1377, 1316, 1268, 1208, 1110, 1079,
1014, 980, 848, 802, 751, 668. Mass (%) 280 (100), 265 (6), 251 (91),
237 (10), 221 (5), 209 (9), 130 (5), 55 (7), 41 (2). Anal. Calcd for
C19H24N2: C, 81.38; H, 8.63; N, 9.99; found: C, 81.47; H, 8.57; N, 9.96.
d
5973 GCeMS instrument; in m/z. Melting points: Electrothermal
9200 apparatus.
4.2. General procedure for cyanoalkenylation of indoles
4.2.5. (z)-3-(1-Propyl-3-indolyl)-2,3-diphenyl-2-propenenitrile
(4e). Pale yellow solid, mp¼85e87 ꢀC, 1H NMR (500.1 MHz, CDCl3)
A 10 ml microwave vial equipped with a magnetic stirring bar
was charged with 1.0 mmol internal alkynes, 2 mol % of PdCl2,
1.0 mmol NaHCO3, 0.3 mmol [K4Fe(CN)6]∙3H2O, 1.5 mmol 3-
iodoindole and 4 ml of DMFeH2O (80:20). The vial was sealed
and immersed in an oil bath, which was preheated at 120 ꢀC, for
24 h. After this time the reaction mixture was cooled to room
temperature and diluted with ethyl acetate (5 ml) and H2O (5 ml).
The aqueous layer was extracted twice with ethyl acetate (5 ml) and
combined organic layers were dried over Na2SO4. The solvent was
removed under vacuum and the product was purified by column
chromatography (silica gel, Merck 230e400 mesh) using hex-
aneeethyl acetate (95:5) as the eluent.
d
1.29 (t, J¼7.1 Hz, 3H), 1.94 (sextet, J¼7.2 Hz, 2H), 4.24 (t, J¼7.1 Hz,
2H), 6.57 (d, J¼8.1 Hz, 1H), 6.93 (t, J¼7.9 Hz, 1H), 7.21 (m, 8H), 7.29 (m,
3H), 7.4 (d, J¼8.3 Hz, 1H), 7.91 (s, 1H). 13C NMR (125.7 MHz, CDCl3)
d
14.1, 32.5, 47.1, 109.4, 109.6, 115.1, 120.7, 121.8, 122.1, 122.6, 127.7,
127.8, 128.6, 128.7, 129.3, 130.4, 131.4, 132.3, 135.9, 137.1, 139.3, 152. IR
(KBr) 3053, 2927, 2866, 2200,1522,1464,1395,1334,1200, 1133, 1073,
1020, 917, 839, 741, 697. Mass (%) 362 (100), 333 (31), 319 (23), 304
(10), 291 (10), 256 (7). Anal. Calcd for C26H22N2: C, 86.15; H, 6.12; N,
7.73; found: C, 86.10; H, 6.14; N, 7.76.
4.2.6. (z)-3-(1-Butyl-3-indolyl)-2,3-diphenyl-2-propenenitrile
(4f). Pale yellow solid, mp¼51e53 ꢀC, 1H NMR (500.1 MHz, CDCl3)
d
1.29 (t, J¼7.1 Hz, 3H), 1.46 (sextet, J¼7.6 Hz, 2H), 1.94 (quintet,
4.2.1. (z)-3-(1-Methyl-3-indolyl)-2,3-diphenyl-2-propenenitrile
J¼7.4 Hz, 2H), 4.24 (t, J¼7.1 Hz, 2H), 6.56 (d, J¼8.1 Hz, 1H), 6.93 (t,
J¼7.9 Hz, 1H), 7.21 (m, 8H), 7.29 (m, 3H), 7.4 (d, J¼8.3 Hz, 1H), 7.91 (s,
(4a). Pale yellow solid, mp¼141e142 ꢀC, 1H NMR (500.1 MHz,
CDCl3)
d
3.93 (s, 3H), 6.59 (d, J¼8.1 Hz, 1H), 6.95 (t, J¼8.0 Hz, 1H),
1H). 13C NMR (125.7 MHz, CDCl3)
d 14.1, 20.5, 32.5, 47.1, 106, 110.4,
7.21 (m, 9H), 7.28 (m, 2H), 7.38 (d, J¼8.3 Hz, 1H), 7.86 (s, 1H). 13C
115.1, 120.7, 121.8, 122.2, 122.6, 127.8, 127.9, 128.6, 128.7, 129.3, 130.4,
131.4, 132.3, 135.9, 137.1, 139.3, 152. IR(KBr) 3053, 2927, 2866, 2200,
1522, 1464, 1395, 1334, 1200, 1133, 1073, 1020, 917, 839, 741, 697.
Mass (%) 376 (100), 347 (2), 333 (23), 319 (7), 149 (16), 97 (6), 71 (7),
57 (20), 41 (18). Anal. Calcd for C27H24N2: C, 86.13; H, 6.43; N, 7.44;
found: C, 86.11; H, 6.42; N, 7.47.
NMR (125.7 MHz, CDCl3)
d 39.1, 106.3, 110.2, 115.1, 120.9, 121.7,
122.4, 122.8, 127.5, 127.9, 128.6, 129.3, 130.4, 131.3, 133, 135.8, 137.8,
139.3, 151.9. IR(KBr): 3055, 2924, 2200, 1524, 1458, 1367, 1228, 1127,
1075, 1018, 913, 841, 739, 694, 645. Mass (%): 344 (3), 279 (10), 246
(10), 167 (40), 149 (100), 113 (8), 105 (70), 83 (6), 71 (15), 57 (30), 43
(15), 41 (15). Anal. Calcd for C24H18N2: C, 86.20; H, 5.43; N, 8.38;
found: C, 86.25; H, 5.45; N, 8.31.
4.2.7. (z)-3-(1-Butyl-3-indolyl)-2-propyl-2-hexenenitrile (4g). Yellow
oil, 1H NMR (500.1 MHz, CDCl3)
J¼7.4 Hz, 3H), 1.09 (t, J¼7.4 Hz, 3H), 1.4 (m, 4H), 1.75 (sextet, J¼7.5 Hz,
2H), 1.88 (sextet, J¼7.4 Hz, 2H), 2.44 (t, J¼7.7 Hz, 2H), 2.7 (t, J¼7.8 Hz,
d
0.91 (t, J¼7.4 Hz, 3H), 0.99 (t,
4.2.2. (z)-3-(1-Methyl-3-indolyl)-2-propyl-2-hexenenitrile
(4b).7a Pale yellow solid, mp¼74e76 ꢀC, 1H NMR (500.1 MHz, CDCl3)

5196
E. Kianmehr et al. / Tetrahedron 69 (2013) 5193e5196
2H), 4.17 (t, J¼7.1 Hz, 2H), 7.19 (t, J¼7.0 Hz, 1H), 7.27 (t, J¼8.1 Hz, 1H),
7.37 (s, 1H), 7.4 (d, J¼8.2 Hz, 1H), 7.62 (d, J¼8.0 Hz, 1H). 13C NMR
J¼7.4 Hz, 3H), 1.28 (t, J¼7.4 Hz, 4H), 1.35 (m, 3H), 1.87 (quintet,
J¼6.7 Hz, 2H), 2.45 (q, J¼7.4 Hz, 2H), 2.72 (q, J¼7.3 Hz, 2H), 4.14 (t,
J¼7.0 Hz, 2H), 7.16 (t, J¼7.2 Hz,1H), 7.25 (t, J¼7.7 Hz,1H), 7.37 (m, 2H),
(125.7 MHz, CDCl3)
d 14, 14.1, 14.3, 20.5, 22.3, 22.4, 32.5, 32.9, 35.6,
46.7, 109.7, 110.3, 114.6, 120.2, 120.7, 121.3, 122.3, 126.8, 128.7, 136.8,
153. IR(KBr) 2959, 2930, 2869, 2203, 1607, 1530, 1462, 1374, 1200,
1139, 1110, 1017, 738, 671. Mass (%) 308 (100), 279 (85), 265 (37), 237
(9), 223 (5), 207 (7),130 (5), 57 (5), 41 (8). Anal. Calcd for C21H28N2: C,
81.77; H, 9.15; N, 9.08; found: C, 81.81; H, 9.17; N, 9.02.
7.6 (d, J¼7.85 Hz, 1H). 13C NMR (125.7 MHz, CDCl3)
d 13.2, 13.5, 13.9,
22.3, 23.8, 26.4, 29.0, 29.7, 46.5, 109.7, 109.9, 113.9, 119.8, 120.3, 120.7,
121.8, 126.4, 128.5, 136.4, 153.4. IR (KBr) 2961, 2931, 2872, 2204, 1612,
1532, 1464, 1374, 1226, 1185, 1110, 890, 812, 741, 667, 631. Mass (%):
294 (100), 279 (52), 265 (45), 237 (89), 223 (10), 209 (16), 193 (12),
180 (9), 167 (9), 154 (8), 130 (10), 117 (7), 43 (22). Anal. Calcd for
C20H26N2: C, 81.59; H, 8.90; N, 9.51; found: C, 81.67; H, 8.88; N, 9.45.
4.2.8. (z)-3-(1-Pentyl-3-indolyl)-2,3-diphenyl-2-propenenitrile
(4h). Pale yellow solid, mp¼91e92 ꢀC, 1H NMR (500.1 MHz, CDCl3)
d
1.29 (t, J¼7.1 Hz, 3H), 1.45 (sextet, J¼7.5 Hz, 2H), 1.74 (quintet,
Acknowledgements
J¼7.4 Hz, 2H), 1.90 (quintet, J¼7.2 Hz, 2H), 4.24 (t, J¼7.1 Hz, 2H), 6.57
(d, J¼8.1 Hz,1H), 6.93 (t, J¼7.9 Hz,1H), 7.21 (m, 8H), 7.29 (m, 3H), 7.4
We gratefully acknowledge the financial support from the Re-
search Council of the University of Tehran. We thank Dr. Karol
Gajewski, Canadian Intellectual Property Office, for helpful com-
ments on this work.
(d, J¼8.3 Hz, 1H), 7.91 (s, 1H). 13C NMR (125.7 MHz, CDCl3)
d 14.1,
20.5, 22.3, 32.5, 47.1, 106.3, 110.2, 115.1, 120.7, 121.8, 122.1, 122.6,
127.7, 127.8, 128.6, 128.7, 129.3, 130.4, 131.4, 132.3, 135.9, 137.1, 139.3,
152. IR (KBr) 3055, 2927, 2864, 2201, 1524, 1490, 1466, 1447, 1396,
1374, 1224, 1181, 1158, 1135, 1074, 1019, 918, 843, 739, 697, 643.
Mass (%) 390 (100), 361 (7), 333 (18), 319 (14), 304 (6), 291 (5), 255
(2), 43 (8). Anal. Calcd for C28H26N2: C, 86.12; H, 6.71; N, 7.17; found:
C, 86.09; H, 6.70; N, 7.21.
Supplementary data
Supplementary data related to this article can be found at
http://dx.doi:10.1016/j.tet.2013.04.066.
4.2.9. (z)-3-(1-Pentyl-3-indolyl)-2-propyl-2-hexenenitrile (4i). Yellow
oil, 1H NMR (500.1 MHz, CDCl3)
d
0.91 (m, 6H), 10.9 (t, J¼7.4 Hz, 3H),
References and notes
1.38 (m, 6H), 1.75 (sextet, J¼7.4 Hz, 2H), 1.90 (quintet, J¼7.2 Hz, 2H),
2.44 (t, J¼7.8 Hz, 2H), 2.7 (t, J¼7.8 Hz, 2H), 4.16 (t, J¼7.2 Hz, 2H), 7.19 (t,
J¼7.3 Hz, 1H), 7.27 (t, J¼7.5 Hz, 1H), 7.36 (s,1H), 7.39 (d, J¼8.2 Hz,1H),
1. (a) Baeyer, A.; Emmerling, A. Chem. Ber. 1869, 2, 679; (b) Baeyer, A.; Knop, C. A.
Ann. Chem. 1866, 140, 1.
7.62 (d, J¼8.0 Hz, 1H). 13C NMR (125.7 MHz, CDCl3)
d 13.3, 13.6, 13.9,
2. (a) Gribble, G. W.; Berthel, S. J. In Studies in Natural Products Chemistry; Attaur-
Rahman, Ed.; Elsevier: New York, NY, 1993; Vol. 12, pp 365e409; (b) Omura, S.;
Sasaki, Y.; Iwai, Y.; Takeshita, H. J. Antibiot. 1995, 48, 535; (c) Pindur, U.; Kim, Y. S.;
Mehrabani, F. Curr. Med. Chem. 1999, 6, 29; (d) Bergman, J.; Janosik, T.;
Wahlstrom, N. Adv. Heterocycl. Chem. 2001, 80, 1; (e) Ballini, R.; Palmieri, A.;
Petrini, M.; Shaikh, R. R. Adv. Synth. Catal. 2008, 350, 129; (f) Dischia, M.;
Napolitano, A.; Pezzella, A.; Meredith, P.; Sarna, T. Angew. Chem., Int. Ed. 2009,
48, 2; (g) Ito, S. Pigment Cell Res. 2003, 16, 230; (h) Crich, D.; Banerjee, A. Acc.
Chem. Res. 2007, 40, 151; (i) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873; (j)
Kruger, K.; Tillack, A.; Bellera, M. Adv. Synth. Catal. 2008, 350, 2153.
3. (a) Spinks, D.; Spinks, G. Curr. Med. Chem. 2002, 9, 799; (b) Marcin, L. R.;
Mattson, R. J.; Gao, Q.; Wu, D.; Molski, T. F.; Mattson, G. K.; Lodge, N. J. Bioorg.
Med. Chem. Lett. 2010, 20, 1027.
21.8, 21.9, 22.2, 29, 29.6, 32.4, 35.1, 46.5, 109.2, 109.8, 114.1, 119.7,
120.2, 120.8, 121.8, 126.3, 128.2, 136.3, 152.4. IR(KBr) 2958, 2928,
2886, 2201, 1608, 1530, 1462, 1375, 1183, 1107, 1020, 802, 738, 669.
Mass (%) 322 (100), 293 (65), 279 (13), 265 (21), 251 (3), 237 (5), 223
(6), 207 (5), 130 (4), 43 (11). Anal. Calcd for C22H30N2: C, 81.94; H,
9.38; N, 8.69; found: C, 82.02; H, 9.35; N, 8.64.
4.2.10. (z)-3-(1-Benzyl-3-indolyl)-2,3-diphenyl-2-propenenitrile
(4j). Yellow solid, mp¼68e70 ꢀC, 1H NMR (500.1 MHz, CDCl3)
4. (a) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045; (b) Hegedus, L. S.
Angew. Chem. 1988, 100, 1147; (c) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105,
2873; (d) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875.
d
5.42 (s, 2H), 6.58 (d, J¼8.0 Hz, 1H), 6.91 (t, J¼7.5 Hz, 1H), 7.18 (m,
8H), 7.35 (m, 9H), 7.95 (s, 1H). 13C NMR (125.7 MHz, CDCl3)
d 50.9,
ꢀ
5. (a) Gilbert, J.; Miquel, J. F.; Precigoux, G.; Hospital, M.; Raynaud, J. P.; Michel, F.;
106.4, 110.3, 113.9, 120.5, 120.6, 121, 121.1, 121.9, 126.4, 127.5, 127.9,
128.2, 128.3, 128.6, 128.8, 129.8, 130, 130.9, 132.1, 135.3, 136.4, 138.7,
151.3. IR(KBr) 3031, 2200, 1522, 1492, 1445, 1388, 1239, 1173, 1077,
1025, 908, 842, 741, 695, 623. Mass (%) 419 (64), 316 (19), 290 (17),
275 (3), 263 (13), 250 (3), 241 (22), 214 (14), 201 (5), 105 (10), 91
(100), 77 (26), 65 (88), 55 (31), 43 (68). Anal. Calcd for C30H22N2: C,
87.77; H, 5.40; N, 6.82; found: C, 87.69; H, 5.44; N, 6.86.
Paulet, A. C. J. Med. Chem. 1983, 26, 693; (b) Bignon, E.; Pons, M.; Paulet, A. C.;
Dore, J. C.; Gilbert, J.; Abecassis, J.; Miquel, J. F.; Ojasoo, T.; Raynaud, J. P. J. Med.
Chem. 1989, 32, 2092.
6. (a) Rappoport, Z. The Chemistry of the Cyano Group; Interscience: London,
United Kingdom, 1970; (b) Larock, R. C. Comprehensive Organic Transformations:
a Guide to Functional Group Preparations; VCH: New York, NY, 1989; (c) Yang, C.;
Williams, J. M. Org. Lett. 2004, 6, 2837e2840.
7. (a) Nakao, Y.; Yada, A.; Ebata, S.; Hiyama, T. J. Am. Chem. Soc. 2007, 129, 2428; (b)
Nakao, Y.; Kanyiva, K. S.; Oda, S.; Hiyama, T. J. Am. Chem. Soc. 2006, 128, 8146; (c)
Kobayashi, Y.; Kamisaki, H.; Yanada, R.; Takemoto, Y. Org. Lett. 2006, 8, 2711; (d)
Cheng, Y.; Duan, Z.; Yu, L.; Li, Z.; Zhu, Y.; Wu, Y. Org. Lett. 2008, 10, 901; (e)
Nakao, Y.; Hirata, Y.; Hiyama, T. J. Am. Chem. Soc. 2006, 128, 7420; (f) Suginome, M.;
Yamamoto, A.; Murakami, M. Angew. Chem., Int. Ed. 2005, 44, 2380; (g)
Nishihara, Y.; Inoue, Y.; Itazaki, M.; Takagi, K. Org. Lett. 2005, 7, 2639; (h) Nakao, Y.;
Oda, S.; Hiyama, T. J. Am. Chem. Soc. 2004, 126, 13904; (i) Taw, F. L.; White, P. S.;
Bergman, R. G.; Brookhart, M. J. Am. Chem. Soc. 2002, 124, 4192; (j) Nakao, Y.;
Yukawa, T.; Hirata, Y.; Oda, S.; Satoh, J.; Hiyama, T. J. Am. Chem. Soc. 2006, 128,
7116; (k) Garcia, J. J.; Brunkan, N. M.; Jones, W. D. J. Am. Chem. Soc. 2002, 124,
9547; (l) Chatani, N.; Takeyasu, T.; Horiuchi, N.; Hanafusa, T. J. Org. Chem. 1988,
53, 3539.
4.2.11. (z)-3-(1-Butyl-3-indolyl)-2-ethyl-2-propenenitrile (4k). Yellow
oil, 1H NMR (500.1 MHz, CDCl3)
d
0.99 (m, 6H), 1.28 (t, J¼7.5 Hz, 3H),
1.38 (sextet, J¼7.5 Hz, 2H), 1.86 (quintet, J¼7.5 Hz, 2H), 2.46 (q,
J¼7.5 Hz, 2H), 2.71 (q, J¼7.5 Hz, 2H), 4.15 (t, J¼7.0 Hz, 2H), 7.16 (t,
J¼7.5 Hz, 1H), 7.25 (m, 1H), 7.37 (m, 2H), 7.59 (d, J¼7.5 Hz, 1H). 13C
NMR (125.7 MHz, CDCl3)
d 13.2, 13.5, 13.6, 20.1, 23.8, 26.4, 32.1, 46.3,
109.7, 109.9, 113.9, 119.8, 120.3, 120.7, 121.9, 126.4, 128.6, 136.4, 153.4.
IR (KBr) 2958, 2932, 2873, 2199, 1607, 1535, 1464, 1390, 1236, 1184,
1157, 1136, 1107, 1056, 1015, 964, 928, 822, 740, 631. Mass (%): 280
(100), 265 (42), 251 (39), 237 (61), 223 (9), 209 (16),193 (18),130 (11),
117 (6), 57 (4), 41 (12). Anal. Calcd for C19H24N2: C, 81.38; H, 8.63; N,
9.99; found: C, 81.30; H, 8.66; N, 10.04.
8. (a) Wang, C. Y.; Wang, C.; Wang, Q. F.; Wang, Z. H.; Sun, H.; Guo, X. Y.; Xi, Z. F.
Chem.dEur. J. 2007, 13, 6484; (b) Li, G.; Watson, K.; Buckheit, R. W.; Zhang, Y.
Org. Lett. 2007, 9, 2043; (c) Boyd, D. R.; Sharma, N. D.; Coen, G. P.; Gray, P. J.;
Malone, J. F.; Gawronski, J. Chem.dEur. J. 2007, 13, 5804.
9. Schareina, T.; Zapf, A.; Beller, M. Chem. Commun. 2004, 1388.
10. (a) Aidi, K.; Xiuling, H.; Xiyan, L. Org. Lett. 2006, 1339; (b) Roy, S.; Eastman, A.;
Gribble, G. W. Tetrahedron 2006, 62, 7838; (c) Guida, W. C.; Mathre, D. J. J. Org.
Chem. 1980, 45, 3172; (d) Huang, Y. Z.; Miao, H.; Zhang, Q. H.; Chen, C.; Xu, J.
Catal. Lett. 2008, 122, 344.
4.2.12. (z)-3-(1-Pentyl-3-indolyl)-2-ethyl-2-propenenitrile(4l). Yellow
oil, 1H NMR (500.1 MHz, CDCl3)
d
0.9 (t, J¼6.8 Hz, 3H), 1.00 (t,