Synthesis of N-vinyl substituted indoles and their acid-catalyzed behavior

Article abstract of DOI:10.1016/j.tetlet.2010.10.072

A mild cross-coupling reaction has been used to access several N-vinyl substituted indoles. When treated with acid, these unique enamines produce novel dimeric and trimeric products derived from a preferred protonation reaction at the enamine π-bond.

Full text of DOI:10.1016/j.tetlet.2010.10.072

Tetrahedron Letters 52 (2011) 2062–2064
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of N-vinyl substituted indoles and their acid-catalyzed behavior
⇑
Hao Li, Nawong Boonnak, Albert Padwa
Department of Chemistry, Emory University, Atlanta, GA 30322, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 26 October 2010
A mild cross-coupling reaction has been used to access several N-vinyl substituted indoles. When treated
with acid, these unique enamines produce novel dimeric and trimeric products derived from a preferred
protonation reaction at the enamine p-bond.
Dedicated with admiration and fondness to
Harry Wassexman on the occasion of his
90th anniversary
Ó 2010 Elsevier Ltd. All rights reserved.
Substituted indoles form the core of numerous natural products
and have considerable pharmacological potential.1,2 Over many
years, countless efforts have been devoted to the development of
methods that enable the synthesis of functionalized indoles.3 How-
ever, the exploration of new methodologies that allow for rapid
introduction of functionality onto the indole skeleton in a single
operation still remains an important challenge facing organic
chemistry. In this context, transition metal-catalyzed transforma-
tions for the synthesis of 2,3-disubstituted indoles, starting from
o-alkynylanilines or derivatives thereof4 as well as o-haloanilines5,
have been intensively studied. Another effective strategy for the
introduction of an alkenyl side chain into the indole skeleton is
the palladium-catalyzed oxidative reaction of alkenes via C–H
bond cleavage.6 The vinylation generally occurs at the electron-
rich C3 position of the indole ring due to the electrophilic nature
of the reaction.7 In an effort to further expand the diversity of sub-
stituents that can be positioned on the indole scaffold, we became
interested in accessing indole derivatives substituted at the N-po-
sition with various alkenyl groups. Such derivatives, in addition to
incorporating structural elements that expand the potential for
natural product synthesis, also provide an opportunity for manip-
ulating the electronic characteristics of the indole ring itself.
Surprisingly, N-vinylindoles are not generally represented in the
chemical literature8 and their application as an enamine equiva-
lent in electrophile reactions has not been investigated. In this
communication, we report a synthetically useful procedure that al-
lows generation of a variety of N-vinylindoles and a study of their
acid-promoted electrophilic addition reactions.
amine derivatives to alkynes and styrenes.9f The drawbacks of
these methods are elevated temperatures and a lack of generality
and/or substrate scope. We found that by using a N-vinylation pro-
tocol originally developed by Lam and co-workers8a and more re-
cently employed by Xi,10 we were able to prepare a series of N-
vinylindoles in good yield. The coupling procedure involved treat-
ing a NH-indole with various vinyl bromides using a combination
of 10 mol % copper(I) iodide and 20 mol % of ethylenediamine as
the catalyst in dioxane at 110 °C in the presence of K3PO4 as the
base (Scheme 1).
Enamines are among the most widely used building blocks in
organic synthesis.11 A conventional enamine acts as a nucleophile
in a chemical transformation by enlisting its nitrogen lone pair to-
ward nucleophilic attack. We became interested in examining the
extent of interaction between the indole nitrogen lone pair of elec-
trons and the enamine double bond present in systems such as 1.
In particular, we recognized that N-vinylindoles represent a unique
class of enamines that bear a multitude of nucleophilic sites, which
could lead to various products (i.e., 2–4) when allowed to react
with an electrophile (Scheme 2).
The electrophilic substitution reaction of 1-(prop-1-en-2-yl)-
1H-indole (1a) with Eschenmoser’s salt was initially explored.
N-Vinylindole 1a was treated with 1.1 equiv of Eschenmoser’s salt
in CH2Cl2 at 40 °C for 1 h and provided a mixture of N-substituted
indoles 5–7 in a 1:1:2 ratio (Scheme 3, Eq. 1). When the related
R1
R1
Cu(I)
R2
N-Vinylation has previously been carried out employing a vari-
ety of methods including mercuric acetate/sulfuric acid-catalyzed
vinylation of NH-heteroaromatics with vinyl acetate,9a alkylation
with dibromoethane followed by elimination,9b palladium(II)-
catalyzed vinylation of amides with electron-deficient acrylates,9c
palladium(0)-catalyzed vinylation with vinyl bromides9d, and tri-
flates,9e and cesium hydroxide-catalyzed addition of alcohols and
+
K3PO4
heat
N
Br
N
H
R2
1a; R1 = H, R2 = Me, 79%
1b; R1 = COOMe, R2 = Me, 85%
1c; R1 = Me, R2 = Me, 42%
1d; R1 = CN, R2 = Me, 98%
1e; R1 = COOMe, R2 = Et, 90%
⇑
Corresponding author. Tel.: +1 404 27 283; fax: +1 404 27 629.
E-mail address: chemap@emory.edu (A. Padwa).
Scheme 1. Copper catalyzed cross-coupling of NH-indoles with vinyl bromides.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.072

H. Li et al. / Tetrahedron Letters 52 (2011) 2062–2064
2063
R1
for 1 min, afforded a 1:1-mixture of the novel indole trimers 14
and 15 which were isolated in 50% overall yield (Scheme 4). We as-
sume that the formation of indole trimer 14 proceeds via a
Brønsted acid-promoted electrophilic addition/Friedel–Crafts reac-
E
and/or
E
N
N
R1
tion cascade. In the first step, protonation of the enamine
p-bond
R2
R2
of 1a by p-TsOHÁH2O occurs to give iminium ion 12. Further reac-
tion of 12 with another equivalent of N-vinylindole 1a leads to a
second dimeric iminium ion 13. Rather than undergoing deproto-
nation, this iminium ion reacts with 1H-indole by either a Fri-
edel–Crafts reaction at the 3-position of the indole ring to give
trimer 14 or else reacts with an additional molecule of 1a at the
nitrogen position of the indole to provide aminal 15. Products 14
and 15 are most likely formed from the free indole, that is, liber-
ated in the reaction by the hydrolysis of intermediate 12 by the
water present in p-TsOHÁH2O. Interestingly, only methyl 1H-in-
dole-3-carboxylate (10) was isolated in 99% yield when N-vinylin-
dole 1b was submitted to the action of p-TsOHÁH2O. However,
when the N-vinylindole 1b was allowed to react with a milder Le-
wis acid such as MgI2, the dimeric indole 16 was formed in 63%
yield (Scheme 5)13 and this reaction presumably proceeds via a
mechanism related to that outlined in Scheme 4. The exclusive for-
mation of 16 is likely due to the lack of water present in the reac-
tion mixture.
2
3
+
E
R1
R1 = H, alkyl
N
and/or
R2
N
E
H
1
R2
4
Scheme 2. Reaction of N-vinyl indoles with a global electrophile E+.
N-vinylindole 1b was exposed to the same reaction conditions, the
N-substituted indoles 8 and 9 were obtained as a 1:1-mixture in
86% yield (Scheme 3, Eq. 2), thereby indicating that the enamine
portion of 1b was the more nucleophilic site toward electrophilic
addition when a methyl carboxylate substituent was incorporated
into the 3-position of the indole ring. The electrophilic reaction of
N-vinylindole 1b with the more reactive Vilsmeier reagent only
afforded the corresponding unmasked indole 10, formed by C–N
bond cleavage upon aqueous workup (Scheme 3, Eq. 3). Of notable
interest was the finding that when 3-methyl-1-(prop-1-en-2-yl)-
1H-indole (1c) was allowed to react with Eschenmoser’s salt, the
N-substituted indole 11 was the only product isolated in 77% yield
(Scheme 3, Eq. 4).12
When N-vinylindole 1b was treated with trifluoroacetic acid in
the presence of methanol, a near quantitative yield of hemiaminal
17 was obtained. None of the dimeric product 16 could be detected
under these experimental conditions. It would appear as though
the initially formed iminium ion derived by protonation of the en-
amine p-bond is trapped by the nucleophilic solvent before it has a
In a subsequent study, the behavior of N-vinylindoles 1a and 1b
toward Brønsted or Lewis acid-promoted electrophilic additions
was examined. Exposure of N-vinylindole 1a to 1.0 equiv of p-tol-
uenesulfonic acid monohydrate (p-TsOHÁH2O) in CH2Cl2 at 25 °C
chance to react with the starting indole 1b. Next, the electrophilic
addition of N-vinylindole 1b with isobutyraldehyde was studied
using BF3ÁOEt2 as the Lewis acid (Scheme 6). Unexpectedly, the
NMe2
NMe2
eq (1)
N
I-
+
N
+
N
NMe2
NMe2
N
H
H
Me
CH2Cl2, 40 oC, 1 h
Me
1a
Me
7; 24%
5; 12%
6; 12%
COOMe
COOMe
COOMe
NMe2
H
I-
+
eq (2)
H
N
N
CH2Cl2, 40 oC, 1 h
N
NMe2
NMe2
Me
Me
8; 43%
9; 43%
1b
COOMe
N
COOMe
NMe2
Cl-
H
Cl
eq (3)
N
CH2Cl2, 23 oC, 1 h
H
H2O workup
Me
1b
10; 70%
Me
N
NMe2
I-
Me
N
eq (4)
H
H
CH2Cl2, 40 oC, 2 h
NMe2
Me
1c
11; 77%
Scheme 3. Electrophilic reaction of N-vinylindole 1b with the Vilsmeier reagent.

2064
H. Li et al. / Tetrahedron Letters 52 (2011) 2062–2064
In conclusion, we have developed a mild cross-coupling reac-
p-TsOH
H2O
tion of NH-indoles with vinyl bromides using Cu(I) catalysis to give
a variety of N-vinyl substituted indoles in good yield. When treated
with acid, these unique enamines produce novel dimeric and tri-
meric products derived from a preferred protonation reaction at
+
Me
+
Me
N
N
1a
N
N
Me
Me
Me
Me
13
1a
12
the enamine p-bond.
1a
Acknowledgment
Me
Me
N
Me
Me
N
N
We appreciate the financial support provided by the National
Science Foundation (CHE-0742663).
N
+
Me
Me
N
References and notes
N
H
1. (a) Lounasmaa; Tolvanen, A. Nat. Prod. Rep. 2000, 17, 175; (b) Faulkner, D. J. Nat.
Prod. Rep. 1999, 16, 155; (c) Michael, J. P. Nat. Prod. Rep. 1998, 15, 571.
2. (a) Sundberg, R. J. The Chemistry of Indoles; Academic Press: New York, 1970; (b)
Joule, J. A. Indole and its Derivatives. In Science of Synthesis: Houben-Weyl
Methods of Molecular Transformations; Thomas, E. J., Ed.; George Thieme:
Stuttgart, Germany, 2000; Vol. 10, Chapter 10.13, Category 2.; (c) Gribble, G. W.
In Comprehensive Heterocyclic Chemistry II; Katritzky, A. F., Rees, C. W., Scriven,
E. F., Bird, C. W., Eds.; Pergamon: Oxford, 1996; Vol. 2, p 207.
3. (a) Gilchrist, T. L. Heterocyclic Chemistry; Addison-Wesley Longman Limited:
Singapore, 1997; (b) Joule, J. A.; Mills, K.; Smith, G. F. Heterocyclic Chemistry;
Stanley Thornes Ltd: Cheltenham, 1995.
4. (a) Tsuji, J. Palladium Reagents and Catalysts, 2nd ed.; Wiley: Chichester, 2004.
pp 211–216; (b) Leni, G.; Larock, R. C. Chem. Rev. 2004, 104, 2285.
5. Larock, R. C. J. Organomet. Chem. 1999, 576, 111.
15; 25%
14; 25%
Scheme 4. Lewis acid-promoted electrophilic addition of N-vinylindole 1a with
acid.
COOMe
COOMe
MgI2 (1 equiv)
Me
Me
N
N
COOMe
N
toluene, 100 oC
Me
6. (a) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873; (b) Gribble, G. W. J. Chem.
Soc., Perkin Trans. 1 2000, 1045; (c) Hegedus, L. S. Angew Chem., Int. Edit. Engl.
1988, 27, 1113.
1b
16; 63%
7. (a) Jia, C.; Kitamura, T.; Fujiwara, Y. Acc. Chem. Res. 2001, 34, 633; (b) Beccalli, E.
M.; Broggini, G.; Martinelli, M.; Sottocornola, S. Chem. Rev. 2007, 107, 5318; (c)
Grimster, N. P.; Gauntlett, C.; Godfrey, C. R. A.; Gaunt, M. J. Angew Chem., Int. Ed.
2005, 44, 3125.
Scheme 5. Lewis acid-promoted electrophilic addition of N-vinylindole 1b with
MgI2.
8. (a) Lam, P. Y. S.; Vincent, G.; Bonne, D.; Clark, C. G. Tetrahedron Lett. 2003, 44,
4927; (b) Dehli, J. R.; Legros, J.; Bolm, C. Chem. Commun. 2005, 973.
9. (a) Xiang, Y.; Chen, J.; Schinazi, R. F.; Zhao, K. Bioorg. Med. Chem. Lett. 1996, 6,
1051; (b) Iddon, B.; Hartley, D. J. Tetrahedron Lett. 1997, 38, 4647; (c) Hosokawa,
T.; Takano, M.; Kuroki, Y.; Murahashi, S.-I. Tetrahedron Lett. 1992, 33, 6643; (d)
Lebedev, A. Y.; Izmer, V. V.; Kazyulkin, D. N.; Beletskaya, I. P.; Voskoboynikov, A.
Z. Org. Lett. 2002, 4, 623; (e) Willis, M. C.; Brace, G. N. Tetrahedron Lett. 2002, 43,
9085; (f) Tzalis, D.; Koradin, C.; Knochel, P. Tetrahedron Lett. 1999, 40, 6193.
10. Liao, Q.; Wang, Y.; Zhang, L.; Xi, C. J. Org. Chem. 2009, 74, 6371.
11. Rappaport, Z. The Chemistry of Enamines; John Wiley & Sons: New York, 1994.
12. Typical procedure for electrophilic substitution of N-vinylindoles: To a round-
bottomed flask charged with N-vinylindole 1c (35 mg, 0.2 mmol) in CH2Cl2
(2 mL) was added Eschenmoser’s salt (1.1 equiv, 41 mg, 0.22 mmol) at room
temperature. The reaction mixture was heated to 40 °C for 2 h and the reaction
progress was monitored by TLC. At the end of the reaction, a saturated aqueous
NaHCO3 solution (2 mL) was added. The reaction mixture was extracted with
CH2Cl2 and the combined organic layer was washed with water, brine, and
dried over anhydrous MgSO4. The organic phase was concentrated under
reduced pressure and the residue was purified by silica gel column
COOMe
COOMe
10 mol% TFA
N
N
Me
OMe
17; 99%
MeOH
Me
Me
1b
COOMe
(Me)2CHCHO
BF3 OEt2
N
N
Me
chromatography (10% MeOH in CH2Cl2) to give 35 mg (77%) of 11 as
a
Me
18; 17%
COOMe
colorless oil; 1H NMR (400 MHz, CDCl3) d 2.21 (s, 6H), 2.32 (s, 3H), 2.34 (t,
J = 7.6 Hz, 2H), 2.74 (t, J = 7.6 Hz, 2H), 5.11 (s, 1H), 5.16 (s, 1H), 6.99 (s, 1H), 7.13
(t, J = 8.0 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), and 7.55 (br t, J = 8.8 Hz, 2H).
13. Synthesis of indole dimer 16: To a flame dried glass microwave tube charged
with N-vinylindole 1b (43 mg, 0.2 mmol) in toluene (2 mL) was added MgI2
(1.0 equiv, 56 mg, 0.2 mmol) at room temperature under an argon atmosphere.
The microwave reaction vial was sealed with a septum cap and was heated to
100 °C for 19 h under microwave irradiation. The reaction mixture was cooled
to room temperature and filtered through a short plug of Celite. The filtrate
was concentrated under reduced pressure and was purified by silica gel
column chromatography (33% ethyl acetate in hexanes) to give 27 mg (63%) of
16 as a colorless oil; 1H NMR (400 MHz, CDCl3) d 1.66 (s, 6H), 3.41 (s, 2H), 3.87
(s, 6H), 4.86 (s, 1H), 5.16 (s, 1H), 7.15 (t, J = 7.2 Hz, 1H), 7.19 (d, J = 7.2 Hz, 1H),
7.21–7.24 (m, 2H), 7.26–7.29 (m, 1H), 7.48 (s, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.65
(s, 1H), 8.03–8.05 (m, 1H), 8.10 (d, J = 7.6 Hz, 1H.
Scheme 6. Electrophilic addition of N-vinylindole 1b with isobutyraldehyde.
only product that could be isolated from this reaction in 17% yield
corresponded to aminal 18. In this case, the decomposition of 1b
to NH-indole 10 takes place at a faster rate than addition of the
enamine onto the carbonyl group of the aldehyde. Once formed,
NH-indole 10 then reacts with isobutyraldehyde on the nitrogen
atom of the indole to give the observed product.14
14. Dittmann, K.; Pindur, U. Heterocycles 1986, 24, 1079.