β,β-Disubstituted C- and N-vinylindoles from one-step condensations of aldehydes and indole derivatives

Article abstract of DOI:10.1021/jo900526p

(Chemical Equation Presented) Direct preparation of β,β- disubstituted C- and N-vinyl-indoles from condensation of aldehydes on indole derivatives is presented. Heating 1-methyl- and 1-benzylindole 3a,b with alkyl and aryl α-branched aldehydes and TFAin a

Full text of DOI:10.1021/jo900526p

pubs.acs.org/joc
the Wittig reaction employing 3-formylindoles and various
β,β-Disubstituted C- and N-Vinylindoles from
One-Step Condensations of Aldehydes and Indole
Derivatives
ylides.8 Preparation of C-vinylindoles via direct condensa-
tion of indole derivatives and carbonyl compounds such as
ketones9 and aldehydes10 was also reported; however, this
route is less common. In principle, almost all of the reports in
which the above-mentioned methods were used describe the
preparation of C-vinylindoles with only one substituent on
the olefin at the β position; only a few describe entry to β,β-
disubstituted C-vinylindoles (Scheme 1).
Gil Fridkin, Nicolas Boutard, and William D. Lubell*
Deꢀpartement de chimie, Universiteꢀ de Montreꢀal, C.P. 6128,
ꢀ ꢀ
Succursale Centre Ville, Montreal, Quebec, Canada H3C 3J7
N-Vinylindoles serve as monomers in radical and cationic
polymerizations to produce poly(N-vinylindoles),11 materi-
als that possess semiconducting and photosensitive capabil-
ities.11c,11d In spite of their utility, N-vinylindoles have been
made by few methods, which have been typically limited in
scope. For example, they are commonly prepared by the
condensation of indole and 2- and 3-methylindole with
acetylene11a,11c and acetylene derivatives,12 albeit using
harsh conditions. Reports on the preparation of N-vinylin-
doles from condensation of 3-substituted indoles and alde-
hydes are rare and refer only to dicarbonyl compounds such
as malondialdehyde.13 N-Vinylindoles have also been pre-
pared by palladium-catalyzed cross-couplings of lithiated
indoles and vinyl bromides14 and indole derivatives with
vinyl triflates.15 Gold(III)-catalyzed double hydroamination
of O-alkynylaniline with terminal alkynes,16 and treatment
of magnesium alkylidene carbenoids with N-lithiated in-
dole,17 were also reported to provide N-vinylindoles. Current
methods, which typically utilize alkynes or alkenes as re-
agents and involve multiple steps, offer, however, only
limited substitution around the double bond and indole ring.
To the best of our knowledge, only two preparations of β,β-
disubstituted N-vinylindoles have been reported requiring
two and five synthetic steps with yields in the last step
ranging from 18 to 65% (Scheme 1).15,17
william.lubell@umontreal.ca
Received March 13, 2009
Direct preparation of β,β-disubstituted C- and N-vinyl-
indoles from condensation of aldehydes on indole deriva-
tives is presented. Heating 1-methyl- and 1-benzylindole
3a,b with alkyl and aryl R-branched aldehydes and TFA in
acetonitrile using microwave irradiation furnished 3-vinyl-
indoles 1a-e in 18-76% yields. Under similar conditions,
3-substituted indoles 4a-c provided N-vinylindoles 2a-h
in 16-98% yields.
The effective synthesis of 2-vinylpyrroles was recently
achieved by reacting 4-aminopyrrole-2-carboxylates in
condensations with aldehydes catalyzed by TFA.18 Consi-
dering their applications in medicinal chemistry and materi-
als science, and limitations for their procurement, C- and
N-vinylindoles were targeted using condensations of
C-Vinylindoles are building blocks for the preparation of
biologically active compounds and natural products, such as
indole alkaloids,1 carbazoles,2 and carbolines.3 In particular,
3-vinylindoles have served as dienes in regio- and stereocon-
troled [4 + 2] cycloaddition reactions as entry to polycyclic
heterocycles.4 3-Vinylindoles are typically prepared by pal-
ladium-catalyzed cross-coupling reactions of suitably func-
tionalized indole and alkene precursors, including Heck,5
oxidative Heck,6 and Suzuki cross-couplings,7 as well as by
(9) (a) Noland, W. E.; Robinson, D. N. J. Org. Chem. 1957, 22, 1134.
(b) Jaisankar, P.; Srinivasan, P. C. Synth. Commun. 2005, 35, 923. (c) Freter,
K. J. Org. Chem. 1975, 17, 2525.
(10) Guazzeli, G.; Settambolo, R. Tetrahedron Lett. 2007, 48, 6034.
(11) (a) Gipstein, E.; Hewett, W. A. Macromolecules 1969, 2, 82.
(b) Priola, A.; Gatti, G.; Cesca, S. Makromol. Chem. 1979, 180, 1.
(c) Brustolin, F.; Castelvetro, V.; Ciardelli, F.; Ruggeri.; Colligiani, A. J.
Polym. Sci., A: Polym. Chem. 2001, 39, 253. (d) Maki, Y.; Mori, H.; Endo, T.
Macromolecules 2007, 40, 6119.
(12) (a) Tzalis, D.; Koradin, C.; Knochel, P. Tetrahedron Lett. 1999, 40,
6193. (b) Trofimov, B. A.; Tarasova, O. A.; Shemetova, M. A.; Afonin, A. V.;
Klyba, L. V.; Baikalova, L. V.; Mikhaleva, A. I. Russ. J. Org. Chem. 2003, 39,
408.
(13) (a) Foettinger, A.; Melmer, M.; Leitner, A.; Lindner, W. Biconjugate
Chem. 2007, 18, 1678. (b) Teuber, H. J.; Cornelius, D.; Pfaff, H. Chem. Ber.
1963, 96, 2617. (c) Teuber, H. J.; Glosauer, O.; Hochmuth, U. Chem. Ber.
1964, 97, 557.
(14) Lebedev, A. Y.; Izmer, V. V.; Kazyul’kin, D. N.; Beletskaya, I. P.;
Voskoboynikov, A. Z. Org. Lett. 2002, 4, 623.
(1) (a) Yokoyama, Y.; Matsumoto, T.; Murakami, Y. J. Org. Chem.
1995, 60, 1486. (b) Grieco, P. A.; Kaufman, M. D. J. Org. Chem. 1999, 64,
7586.
(2) (a) Noland, W. E.; Xia, G. -M.; Gee, K. R.; Konkel, M. J.;
Wahlstrom, M. J.; Condoluci, J. J.; Rieger, D. L. Tetrahedron 1996, 52,
4555. (b) Hagiwara, H.; Choshi, T.; Fujimoto, H.; Sugino, E.; Hibino, S.
Tetrahedron 2000, 56, 5807. (c) Fayol, A.; Fang, Y. -Q.; Lautens, M. Org.
Lett. 2006, 8, 4203.
(3) Love, B. E.; Raje, P. S. Synlett 1995, 1061.
(4) Pindur, U. Heterocycles 1988, 27, 1253.
(5) (a) Frank, W. C.; Kim, Y. C.; Heck, R. F. J. Org. Chem. 1978, 43,
2947. (b) Harrington, P. J.; Hegedus, L. S. J. Org. Chem. 1984, 49, 2657.
(6) Grimster, N. P.; Gauntlett, C.; Godfrey, C. R. A.; Gaunt, M. J.
Angew. Chem., Int. Ed. 2005, 44, 3125.
(7) Zheng, Q.; Yang, Y.; Martin, A. R. Tetrahedron Lett. 1993, 34, 2235.
(8) (a) Ley, S. V.; Smith, S. C.; Woodward, P. R. Tetrahedron 1992, 48,
1145. (b) Kawasaki, I.; Terano, M.; Kurume, A.; Hara, S.; Yamashita, M.;
Ohta, S. Tetrahedron Lett. 2005, 46, 6549. (c) Kusurkar, R. S.; Goswami, S.
K. Tetrahedron 2004, 60, 5315.
(15) Movassaghi, M.; Ondrus, A. E. J. Org. Chem. 2005, 70, 8638.
(16) Zhang, Y.; Donahue, J. P.; Li, C.-J. Org. Lett. 2007, 9, 627.
(17) Sakurada, J.; Satoh, T. Tetrahedron 2007, 63, 3806.
(18) Fridkin, G.; Lubell, W. D. Org. Lett. 2008, 10, 849.
DOI: 10.1021/jo900526p
r
Published on Web 06/04/2009
J. Org. Chem. 2009, 74, 5603–5606 5603
2009 American Chemical Society

JOCNote
SCHEME 1. Representative Examples of β,β-Disubstituted C-
and N-Vinylindoles and Yields for Their Synthesis by Past Methods
diminished by replacing toluene with acetonitrile. Heat-
ing 1-methyl- and 1-benzylindoles with isobutyraldehyde
(300 mol %) and TFA (300 mol %) in CH3CN for 3 h at
140 °C, followed by chromatography on silica gel, furnished,
respectively, 3-vinylindoles 1a and 1b in 76% and 65% yields
(Scheme 2). Vinylindole 1a was previously obtained in a
comparable yield of 80% by employing a Wittig reaction8b
(Scheme 1). 1-Phenylsulfonylindole did not react with iso-
butyraldehyde under our optimized conditions and was
recovered, demonstrating the necessity for a nucleophilic
pyrrole ring. Vinylindole products were detected by LC/MS
1
and H NMR analyses of the condensation products from
1-methylindole with propanal, isovaleryl aldehyde, and
phenylacetaldehyde under the same conditions; however,
the olefins could not be purified effectively from their com-
plex reaction mixtures. Vinylindoles 1c and 1d were also
made from condensations of 1-methyl- and 1-benzylindoles
with diphenylacetaldehyde, albeit in 25% and 18% yields,
due to purification issues with removal of excess aldehyde
and an aldehyde derived trimer which coeluted with the
products. Attempts to facilitate purification by reducing
excess aldehyde to its corresponding alcohol were unsuccess-
ful. 1-Methyl-3-(2-phenylprop-1-enyl)indole 1e was, how-
ever, isolated in a combined yield of 62% by condensation of
1-methylindole with 2-phenylpropionaldehyde. In this case,
reduction of excess aldehyde to its corresponding alcohol
using LiBH4 proved useful, the E (53%) and Z (9%) isomers
of 1e were effectively separated by silica gel chromatography.
Their structure was determined by NOESY experiments,
which showed transfer of magnetization between the protons
of the vinylic CH3 and the indolic proton at position 2 for the
E isomer, as well as between these protons and the vinylic
proton in the case of the Z isomer. 1-Methylindole reacted
with cyclohexane- and cyclopentanecarboxaldehydes to pro-
vide mixtures of the desired 3-vinyl derivative contaminated
with a product arising from olefin reduction as ascertained
by 1H NMR spectroscopy and LC/MS. The similar retention
times of the unsaturated and reduced products hampered
isolation of 3-vinyl derivatives by chromatography; how-
ever, 3-cylohexyl-1-methylindole 6 was isolated in 21% yield.
The vinyl and reduced products ratios were 1:1 and 1:2 for
cyclohexane- and cyclopentanecarboxaldehyde, respec-
tively, suggesting ring strain relief may drive reduction. To
avoid reduction, variations of the amounts of TFA and
aldehyde, the solvent (THF, DMSO), and the acid (TCA)
all proved unsuccessful.
SCHEME 2. Isolated Yields of C-Vinylindoles from Microwave
Heating of Indole Derivatives and Aldehydesa,b
a Isolated yields: E isomer 53% and Z isomer 9%. b Performed in
neat isobutyraldehyde for 2.5 h.
commercially available indoles and aldehydes in this one-step
approach.
Indole was first heated in neat isobutyraldehyde (0.02 M)
with TFA (300 mol %) in a sealed tube at 140 °C for 2.5 h
using microwave irradiation. 1,3-Divinylindole 5 was iso-
lated as the major product in 53% yield (Scheme 2). Alkeny-
lation on both the N1 and C3 positions was evident from the
disappearance of the corresponding protons in the 1H NMR
spectrum. 1,3-Divinylindole 5 was similarly the major pro-
duct in experiments using a decreased amount of TFA (down
to 10%), shorter reaction times (down to 1 h), and less
aldehyde (110 mol %). 3-C- and 1-N-vinylindoles were next
respectively pursued employing 1- and 3-substituted indoles.
1-Methylindole, isobutyraldehyde, and TFA were heated
at 140 °C for 2.5 h using microwave irradiation. Analysis of
the crude reaction mixture by LC/MS indicated the forma-
tion of both mono- and bis-vinylated derivatives. When the
amount of aldehyde was reduced to 300 mol % and toluene
was used as the solvent, bisvinylation was avoided and
1-methyl-3-vinylindole 1a was produced according to the
1H NMR spectrum of the crude reaction mixture; however,
1a could not be purified from side products that were
N-Vinylation of 3-methylindole was first tried using the
optimized conditions for C-vinylation, with heating for 1 h;
however, incomplete conversion and side products were
detected by analysis of the crude product by 1H NMR
spectroscopy and LC/MS. Under optimized conditions
using 1000 mol % of aldehyde, 3-methylindole was respec-
tively condensed with isobutyraldehyde, diphenylacetal-
dehyde, and 2-phenylpropionaldehyde to furnish N-vinylin-
doles 2a-c in 40, 64, and 65% yield, respectively (Scheme 3).
Purification of the latter two products from excess alde-
hyde was easier than that of their C-vinyl isomers because of
their increased hydrophobicity. In the case of 2c, reduction
of aldehyde to alcohol, as described for 1e, also facilitated
purification, which provided 2c as a 6:1 mixture of E/Z
1
isomers as determined by H NMR. NOESY experiments
showed transfer of magnetization between the protons of the
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JOCNote
SCHEME 4. Possible Mechanism for 3-Vinylindole Formation
SCHEME 3. Isolated yields of N-Vinylindoles from Microwave
Heating of Indole Derivatives and Aldehydesa
Insight into the mechanism of C-vinylation was obtained
during optimization studies. Bisindolylalkane 9 formed dur-
ing production of 3-vinylindole (Scheme 4). On heating 1-
methylindole with isobutyraldehyde (300 mol %) and TFA
(300 mol %) in toluene at 140 °C for 5, 10, 20, 60, and
120 min, the 1H NMR-determined ratio of 3-vinylindole 1a
and bisindolylalkane 9 changed from 7:3, 8:2, 9:1, 96:4 to
100:0, respectively. Bisindolylalkanes have been reported as
typical products of condensations of indoles with aldehydes
under various catalytic conditions.21 This kinetically formed
product may arrive from nucleophilic attack of a second
indole onto the unsaturated iminium intermediate 7 to
provide intermediate 8, which transforms to 9 by pyrrole
proton abstraction and rearomatization (Scheme 4). Inter-
mediate 8 may alternatively eliminate indole to give 3-
vinylindole 1a, which could also be generated directly from
intermediate 7. The amount of TFA was crucial for control-
ling this equilibrium. Bisindolylalkane 9 was obtained in
72% yield with only a trace amount of 1a by using 10 mol %
of TFA in neat isobutyraldehyde for 10 min. Furthermore,
isolation of bisindolylalkane 9 and its retreatment with TFA
and heating in toluene for 1 h provided C-vinylindole 1a,
bisindolylalkane 9, and 1-methylindole in a 32:56:12 ratio as
determined by 1H NMR analysis. Similarly, temperature
played a factor in vinylindole formation. Heating of 1-
methylindole, isobutyraldehyde (300 mol %), and TFA
(300 mol %) in acetonitrile at reflux for 3 h provided a
43:39:18 mixture of C-vinylindole 1a, bisindolylalkane 9, and
1-methylindole as ascertained by 1H NMR analysis; similar
conditions with microwave heating at 140 °C yielded vinyl-
indole 1a in 76% yield. Heating the same reagents at lower
temperatures of 60 and 110 °C for 3 h under microwave
irradiation conditions provided, respectively, bisindolylalk-
ane 9 quantatively and a 1:2.5 mixture of C-vinylindole 1a
and bisindolylalkane 9, as ascertained by 1H NMR analysis,
suggesting again the important effect that temperature has
on the reaction outcome. Although, in principle, bisindolyl-
type products may also be generated in the N-vinylation
a Isolated as a 6:1 mixture of E/Z isomers.
vinylic CH3 and the indolic proton at position 2 for the
E isomer, as well as between these protons and the vinylic
proton in the case of the Z isomer. 3-Methylindole was
similarly treated with cyclohexanecarboxaldehyde to pro-
vide the desired N-vinyl derivative 2d, albeit in 16% yield.
3-Methylindole reacted with phenylacetaldehyde and pro-
panal according to 1H NMR and LC/MS analyses; however,
vinyl products could not be purified from the reaction
mixtures.
The scope of N-vinylation was studied on other 3-
substituted indole derivatives. Indole-3-acetic acid and
5-methoxyindole-3-acetic acid were respectively treated
with isobutyraldehyde and diphenylacetaldehyde to pro-
vide N-vinylindoles 2e-j in 31-98% yields, demonstrat-
ing tolerance of carboxylic acid functionality. Purification
of the diphenylacetaldehyde derivatives 2f and 2h from
excess aldehyde and trimer was facile due to their relative
high polarity. Indole-3-carboxaldehyde and isobutyralde-
hyde failed to react under the condensation conditions,
again indicating the importance of pyrrole electron density
for reactivity. Crystals of N-vinylindole 2b were grown
from EtOAc and examined by X-ray diffraction. To the
best of our knowledge, the crystal structure of 2b repre-
sents the first example of a β,β-branched N-vinylindole.19
˚
The olefin bond length (1.34 A) was in agreement with the
typical ethylene bond length (1.32 A)20 and in conjugation
˚
with the phenyl rings as ascertained from their connec-
˚
ting bond length (1.49 A) which corresponded with bond
˚
lengths in butadiene and biphenyl (1.48 A).
20
(19) The crystal structure has been deposited at the Cambridge Crystal-
lographic Data Centre and allocated deposition no. CCDC 717034.
(20) Smith, M. B.; March, J. Advanced Organic Chemistry, 5th ed.;
Wiley-Interscience: New York, 2001; Chapter 1, p 20.
(21) (a) Gibbs, T. J. K.; Tomkinson, N. C. O. Org. Biomol. Chem. 2005, 3,
4043. (b) Bandgar, B. P.; Shaikh, K. A. Tetrahedron Lett. 2003, 44, 1959.
J. Org. Chem. Vol. 74, No. 15, 2009 5605

JOCNote
reactions, in practice they were not observed. Presumably,
the large excess of aldehyde and steric hindrance present
prevented this route from occurring. Nor were byproducts
arising from other possible mechanisms identified in the
N-vinylation reactions.
One-step approaches to C- and N-vinylindoles were respec-
tively developed by acid-catalyzed condensations of alkyl and
aryl R-branched aldehydes and indole derivatives. Comple-
menting existing methods, which typically rely on multiple
steps, these approaches delivered effectively β,β-disubstituted
vinylindole products in one step from commercially available
starting materials, expanding the diversity of vinylindole pro-
ducts. Considering the utility of C- and N-vinylindoles, these
reactions offer novel means for furthering their investigations
in medicinal chemistry and materials science, respectively.
Representative Procedure for N-Vinylindole Formation: Pre-
paration of 2-(1-(2,2-Diphenylvinyl)-1H-indol-3-yl)acetic Acid
(2f). A solution of indole 4b (0.364 mmol) in acetonitrile
(17.84 mL) was placed in a 10-20 mL microwave (MW) flask,
treated with diphenylacetaldehyde (3.64 mmol, 1000 mol %)
and TFA (0.273 mmol, 84 μL, 300 mol %), and flushed with
argon. The flask was immediately capped and heated to 140 °C
using microwave irradiation for 1 h. The crude reaction mixture
was evaporated to dryness and purified by silica chromatogra-
phy using a gradient of 10-50% EtOAc in hexanes to provide 3-
vinylindole 2f as a beige solid (125.7 mg, 98%): mp 174-175 °C;
Rf 0.36 (30% EtOAc in hexanes); IR (KBr) 3052, 2518, 2255,
1948, 1715, 1632, 1494, 1460, 1365, 1231 cm-1; 1H NMR (400
MHz, DMSO-d6) δ 12.30 (br s, 1H), 7.63 (d, J = 8.2 Hz, 1H),
7.59 (s, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.38-7.32 (m, 8H), 7.20-
7.12 (m, 4H), 6.59 (s, 1H), 3.46 (s, 2H); 13C NMR (100 MHz,
DMSO-d6) δ 172.3, 140.7, 138.3, 136.4, 129.8, 129.7, 129.0,
128.6, 128.4, 127.9, 127.6, 127.4, 125.3, 122.5, 121.5, 120.5,
119.0, 110.7, 110.6, 30.6; HRMS (m/z) calcd for C24H20NO2
(M + H)+ 354.1489, found 354.1486.
Experimental Section
Representative Procedure for C-Vinylindole Formation: Prepara-
tion of 1-Benzyl-3-(2-methylprop-1-enyl)-1H-indole (1b). A solution
of 1-benzylindole 3b (0.364 mmol) in acetonitrile (17.84 mL) was
placed in a 10-20 mL microwave (MW) flask and was treated with
isobutyraldehyde (1.092 mmol, 300 mol %) and 300 mol % of TFA
(0.273 mmol, 84 μL). The mixture (0.02 M) was flushed with argon,
and the flask was immediately capped and heated to 140 °C using
microwave irradiation for 3 h. The crude reaction mixture was
diluted with EtOAc and was washed with a saturated solution of
NaHCO3. The aqueous phase was extracted with EtOAc. The
combined organic layers were washed with brine, dried over
MgSO4, and evaporated to dryness to provide a residue that was
purified by triethylamine-pretreated silica chromatography using
1% Et2O in hexanes to furnish 3-vinylindole 1b as a yellow oil
(61.0 mg, 65%): Rf 0.33 (1% EtOAc in hexanes); IR (CHCl3) 3019,
Acknowledgment. This research was supported by the
Natural Sciences and Engineering Research Council of
ꢀ
Canada (NSERC), the Fonds Quebecois de la Recherche
surlaNatureet les Technologies (FQRNT), andtheCanadian
Institutes of Health Research (CIP-79848). G.F. thanks the
MCETC/FRSQ/CIHR Strategic training program in Cancer
Experimental Therapeutics for a postdoctoral fellowship.
ꢀ
We thank Mrs. Francine Belanger-Gariepy (U. Montreal)
for X-ray crystal structure determination and Mrs. Sylvie
ꢀ
ꢀ
ꢀ
Bilodeau (U. Montreal) for performing part of the NOESY
experiments.
1
2977, 2931, 1702, 1604, 1523, 1468, 1424, 1335, 1216 cm-1; H
NMR (400 MHz, CDCl3) δ 7.72 (qd, J = 7.7 Hz, J = 0.8 Hz, 1H),
7.38-7.10 (m, 9H), 6.48 (qd, J = 1.2 Hz, J = 1.4 Hz, 1H), 5.36
Supporting Information Available: General experimental
1
(s, 2H), 2.03 (d, J = 1.2 Hz, 3H), 1.97 (d, J = 0.6 Hz, 3H); 13
C
methods, copies of H NMR and 13C NMR spectra of com-
NMR (100 MHz, CDCl3) δ 138.4, 136.8, 133.5, 129.6, 129.2, 129.1,
128.4, 127.5, 126.9, 122.9, 120.2, 116.5, 114.7, 110.4, 50.9, 27.7,
21.3; HRMS (m/z) calcd for C19H20N (M+H)+ 262.1590, found
262.1586.
pounds 1, 2, 5, 6, and 9, selected NOESY correlations expan-
sions for 1e (E), 1e (Z), 2c (E), and 2c (Z), and X-ray structure
data of compound 2b. This material is available free of charge
via the Internet at http://pubs.acs.org.
5606 J. Org. Chem. Vol. 74, No. 15, 2009