A short, novel, and practical synthesis of 3-alkenylated indoles

Article abstract of DOI:10.1080/00397911.2012.666817

Direct metal-free alkenylation of 2-methylindole via acid-mediated Michael addition-elimination reaction with ethoxymethylenemalononitrile or ethyl ethoxymethylenecyanoacetate affords 3-indolyl-2-cyanoacrylonitrile and ethyl 3-indolyl-2-cyanoacrylate. Behavior of 1H-indole is predictably different. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2012.666817

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A Short, Novel, and Practical Synthesis of
3-Alkenylated Indoles
Mojgan Kargar a , Rahim Hekmatshoar a & Abdol Jalil Mostashari b
a School of Chemistry, College of Science, University of Alzahra,
Vanak, Tehran, Iran
b Industrial Chemical Research and Development Organization,
Tehran, Iran
Accepted author version posted online: 08 Aug 2012.Version of
record first published: 06 Mar 2013.
To cite this article: Mojgan Kargar , Rahim Hekmatshoar & Abdol Jalil Mostashari (2013): A Short,
Novel, and Practical Synthesis of 3-Alkenylated Indoles, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 43:12, 1743-1749
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Synthetic Communications1, 43: 1743–1749, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2012.666817
A SHORT, NOVEL, AND PRACTICAL SYNTHESIS OF
3-ALKENYLATED INDOLES
Mojgan Kargar,1 Rahim Hekmatshoar,1 and
Abdol Jalil Mostashari2
1School of Chemistry, College of Science, University of Alzahra,
Vanak, Tehran, Iran
2Industrial Chemical Research and Development Organization, Tehran, Iran
GRAPHICAL ABSTRACT
Abstract Direct metal-free alkenylation of 2-methylindole via acid-mediated Michael
addition–elimination reaction with ethoxymethylenemalononitrile or ethyl ethoxymethyle-
necyanoacetate affords 3-indolyl-2-cyanoacrylonitrile and ethyl 3-indolyl-2-cyanoacrylate.
Behavior of 1H-indole is predictably different.
Keywords Ethoxymethylenemalononitrile; ethyl ethoxymethylenecyanoacetate; indole
alkenylation; Michael addition–elimination
INTRODUCTION
Ethoxymethylenemalononitrile and ethoxymethylenecyanoacetate belong to a
special Michael acceptor group that is utilized extensively in organic synthesis, parti-
cularly in preparation of pharmacologically active substances.[1] They react with a
variety of nucleophiles, and a broad range of their applications in the synthesis of
chain, cyclic, heterocyclic, and fused heterocyclic structures has been reported and
reviewed.[2]
Substituted indoles form the core skeletons of a wide range of pharmaceuticals
and naturally occurring alkaloids.[3] [(2-Arylindol-3-yl)methylene]propanedinitriles
inhibit the growth of breast cancer cells by cell cycle arrest in G2=M phase and apop-
tosis.[4] The 3-position of indoles is the preferred site for an electrophilic substitution
reaction.[5]
Received November 5, 2011.
Address correspondence to Rahim Hekmatshoar, School of Chemistry, College of Science,
University of Alzahra, Vanak, Tehran, Iran. E-mail: rhekmatus@yahoo.com
1743

1744
M. KARGAR, R. HEKMATSHOAR, AND A. MOSTASHARI
Although alkylation and arylation of indoles have been well documented,[6,7]
there are only a few reports of their alkenylation.[8] These alkenylation reactions include
palladium-catalyzed vinylation using alkenes,[8a] platinum- and nickel-catalyzed
addition of indole to electron-poor alkynes,[8b,c] acid-promoted reaction,[8d] modified
Heck reaction,[8e] reaction of indoles with electron-deficient ethoxyethylenes,[8f]
and Knoevenagel condensation of indole-3-carbaldehyde with active methylene
compounds.[4]
RESULTS AND DISCUSSION
Diethyl ethoxymethylenemalonate (DEEM), ethoxymethylenemalononitrile
(EMMN), ethoxymethylenecyanoacetate (EMCA), and molecules with similar
structures are ‘‘push–pull olefins,’’ variously referred to as b-alkoxyacrylate or
b-akoxyolefins, none of which can truly and exclusively represent the structure.
They can be considered functionalized C4 synthons, capable of adding a
methylenemalonate-type moiety to the nucleophile attacking them. In contrast to
most ordinary Michael acceptors, they usually form Michael monoadducts with
retention of the double bond. The reactions of nucleophilic nitrogen atoms with
the so-called alkoxyacrylate compounds prevail in literature, but there are also a
few reports about reactions of nucleophilic carbons.[2]
To find new routes in application of these C4 synthons with carbon nucleo-
philes and a simple method for alkenylation of indole, we examined a novel and
simple process of p-TsOH-catalyzed addition of 2-methylindole to EMMN or
EMCA (Scheme 1). Needless to say, both the reagent and catalyst are easily avail-
able and low cost.
In our model experiment, p-TsOH-catalyzed reactions of EMCA and EMMN
with 2-methylindole in refluxing ethanol afforded the 1:1 adducts 1 and 2. In the case
of EMMN, the main product is 3 (Scheme 1). Using a polar aprotic solvent such as
CH3CN increased the yield of compound 2 from 12% to 35%. Results of the solvent
effect on the reaction are presented in Table1, and CH3CN was found to be most
suitable solvent. EMCA monoadduct 1 has previously been reported in the
literature[9] to have been produced by the reaction of 3-formyl-2-methylindole with
ethyl cyanoacetate.
A plausible mechanism for the formation of 3 is proposed in Scheme 2. In the
first step, double Michael addition of 2-methylindole to EMMN leads to unisolated
bis(30-indolyl)methanes 5, which undergoes a facile elimination reaction and loses a
malononitrile group to produce the unisolated intermediate (A). Michael addition of
Scheme 1. Double Michael addition of 2-methyl indole to EMCA and EMMN.

NOVEL SYNTHESIS 3-ALKENYLATED INDOLES
1745
Table 1. Study on the effect of the solvent on the preparation of 2
Entry
Reaction conditions
Time
Product (Yield) %
1
2
3
4
CH2Cl2, reflux
C2H5OH, reflux
Toluene. reflux
CH3CN, reflux
2 d
2a (22), 3(55)
2a (12), 3 (75), 4 (4)
2a (28), 3(60)
15 h
22 h
15 h
2a (35), 3 (50), 4 (5)
the third 2-methylindole to this intermediate affords tris(2-methylindolyl)methane 3
(Scheme 2).[10]
Curiously enough, 1H-indole itself did not lead to the corresponding 3-alkeny-
latedindole but furnished novel ethyl-3-(f2-[2,2-bis(1H-indol-3-yl)ethyl]phenylg
amino)-2-cyanoprop-2-enoate 6 instead, in moderate yield (55%). In the case of
EMMN, a similarly expected product 7 is not produced in tangible amounts
(Scheme 3). A plausible explanation is that EMCA is a better Michael acceptor than
EMMN under reaction conditions.
Under acidic conditions, 1H-indole is in equilibrium with 3-(indolin-2-yl)
indole (indole dimer) (Scheme 4).[10c,11] Reaction of indoline NH group of indole
dimer with an electrophile such as EMCA causes a drain of reaction equilibrium
toward production of intermediate B. Addition of a third molecule of indole to B
leads to the formation of novel substituted trimer 6 (Scheme 5).
In the mass spectrum, compound 6 shows a base peak at m=z 245, assignable to
the bis-(indolyl)methyl moiety. The infrared (IR) spectrum shows two NH bands at
3416, 3354; two carbonyl bands at 1673, 1634, and CN at 2207 cmꢀ1. The 1H NMR
spectrum (500 MHz, DMSO-d6) shows a singlet ascribable to two indolic NH group
at dH 10.71, a doublet at 10.86 (J ¼ 13.4, NH-CH), 14 aromatic protons [set a (d 6.79,
6.96 and 7.03), set b (7.15, 7.21, 7.26, 7.33 and 7.38)], together with a triplet at 4.76
(J ¼ 7.7, CH2-CH), and a doublet at 3.54 (J ¼ 7.7, CH2-CH).1H NMR signals of NH
(dH 10.83) and CH (dH 8.04) for product 6 are coupled with J ¼ 13.4 Hz. This was
confirmed by spin-spin decoupling of NH signal at dH 10.84, which resulted in the
appearance of the CH signal as a singlet.
Compound 6 is a potential precursor of novel 4-[1,1-bis(30)indolyl]quinoline-
4-ole-3-cyanide, through a Gould–Jacobs reaction, and compounds 1 and 2 are
potential precursors for bioactive fused pyran derivatives.[12]
Scheme 2. A plausible mechanism for the formation of 3.

1746
M. KARGAR, R. HEKMATSHOAR, AND A. MOSTASHARI
Scheme 3. Reaction of 1H-indole with EMMN and EMCA.
Scheme 4. 1H-indole=indole dimer equilibrium.
Scheme 5. A plausible mechanism for the formation of 2.
CONCLUSION
In conclusion, we have found a simple process for the synthesis of 3-alkenylin-
doles, using p-TsOH-catalyzed addition of 2-methylindole to EMMN or EMCA and
also new application of a group of push–pull olefins (C4 synthons) with indole as
carbon nucleophiles.
EXPERIMENTAL
Procedure for the Synthesis of 1, 2, 3, and 4
A 50-mL round-bottom flask was charged with a solution of 2-methylindole
(30 mmol, 4 g) in 10 mL 96% ethanol, and a solution of EMCA (purity 98%)

NOVEL SYNTHESIS 3-ALKENYLATED INDOLES
1747
(30 mmol, 5.1 g) in 10 mL 96% ethanol and p-TsOH (1 mmol, 0.2 g) was added. The
reaction mixture was stirred at reflux for 15 h, until complete consumption of
2-methylindole was confirmed by thin-layer chromatography (TLC; petroleum ether:
EtOAc; 3:1). TLC chromatogram showed two spots corresponding to compounds 1
and 3 with a trace of 4. When the reaction mixture was cooled to room temperature,
it deposited copiously, a solid which was separated by filtration. The filtrate showed
traces of all three products, worthless for workup. The precipitate was dispersed in
hot methanol to dissolve 3, filtered hot, and cooled to obtain 1 as a yellow powder.
Evaporation of the filtrate furnished compound 3 as a pinkish solid.
Exact replication of this reaction with EMMN in refluxing ethanol produced 2
in only poor yield, the major product being 3 in 38% yield. Performing the reaction
in acetonitrile increased the yield of 2 to 35%.
Ethyl 2-cyano-3(2-methyl-1H indol-3-yl)prop-2-enoate (C15H14N2O2, 1)[9]
Yellow powder; yield 6 g (80%); mp: 245–246 ꢁC.
.
[(2-Methylindol-3-yl)methylene]propanedinitriles (C13H9N3, 2). Yellow
powder; yield 2.1 g (35%); mp: 233.7–235 ꢁC; IR (nmax=cmꢀ1): 3446, 3328, 2214,
1569, 1514, 1458, 1388, 1350, 1253, 1166, 1098, 746; MS (70 eV): m=z ¼ 207 (Mþ,
1
18), 160 (11), 154 (65), 142 (15), 84 (25), 74 (39), 44 (100%); H NMR (500 MHz,
DMSO-d6): d ¼ 2.50 (3H, s, CH3), 7.21 (2H, m, ArH), 7.43 (1H, d, J ¼ 6.9, ArH),
8.08 (1H, d, J ¼ 7.1, ArH), 8.25 (1H, s, -CH ¼), 12.72 (1H, s, NH); 13C NMR
(125.7 MHz, DMSO-d6): d ¼ 13.5, 110.2, 112.1, 114.9, 117.2, 121.9, 123.2, 126.0,
131.8, 135.4, 150.2. Anal. calc. for C13H9N3: C, 75.35; H, 4.38; N, 20.28. Found:
C, 75.29; H, 4.31; N, 20.35.
3-[Bis(2-methyl-1H indol-3-yl)methyl]-2-methyl-1H-indole (C28H25N3, 3)[13]
.
Pink powder; yield 6 g (50%); mp: 333–335 ꢁC.
3-[3H-Indol-3-ylidenemethyl]-1H-indole (C19H18N2, 4)[10c]. Orange pow-
der; mp: 272 ꢁC (decomp.).
Ethyl-3-(f2-[2,2-bis(1H-indol-3-yl)ethyl]phenylgamino)-2-cyanoprop-
2-enoate (C30H26N4O2, 6). White powder; mp: 190 ꢁC; yield: 5.2 g (55%); IR
(KBr) (nmax=cmꢀ1): 3354, 3324, 2207, 1673, 1634, 1599, 1456, 1416, 1379, 1250,
1
1172, 743; H NMR (500 MHz, DMSO-d6): d ¼ 1.22 (3H, t, J ¼ 7.0 Hz, OCH2CH3),
3.54 (2H, d, J ¼ 7.7, CH-CH2), 4.15 (2H, q, J ¼ 7.1, OCH2CH3), 4.76 (1H, t,
J ¼ 7.7 Hz, CH-CH2), 6.79 (2H, t, J ¼ 7.6 Hz), 6.96 (2H, t, J ¼ 7.5 Hz), 7.03 (1H, t,
J ¼ 7.4 Hz), 7.15 (1H, t, J ¼ 8.3 Hz), 7.21 (2H, d, J ¼ 2 Hz, CH), 7.26 (3H, t,
J ¼ 8.02 Hz), 7.33 (1H, d, J ¼ 8.0 Hz), 7.37 (2H, d, J ¼ 7.9 Hz), 8.04 (1H, d,
J ¼ 13.4 Hz, CH-NH), 10.71 (2H, s, 2NHindolic), 10.86 (1H, d, J ¼ 13.4 Hz, CH-N-
H);13C NMR (125.7 MHz, DMSO-d6): d ¼ 15.0, 15.2, 35.5, 37.3, 37.5, 60.9, 61.3,
74.1, 112.1, 112.2, 118.2, 118.5, 118.6, 118.7, 118.8, 118.9, 119.7, 121.4, 123.1,
123.2, 126.1, 127.3, 128.1, 131.8, 132.1, 137.1, 138.1, 155.2, 157.1, 167.8 ppm; MS
(70 eV): m=z ¼ 474 (Mþ, 22), 358 (16), 311 (12), 282 (9), 245 (100), 218 (83), 189
(10), 155 (15), 117 (22), 90 (8%), Anal. calc. for C30H26N4O2: C, 75.93; H, 5.52;
N, 11.81. Found: C, 75.89; H, 5.51; N, 11.83.

1748
M. KARGAR, R. HEKMATSHOAR, AND A. MOSTASHARI
ACKNOWLEDGMENT
We gratefully acknowledge partial financial support from Alzahra University
Research Council.
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