Single-flask synthesis of N-acylated indoles by catalytic dehydrogenative coupling with primary alcohols

Article abstract of DOI:10.1021/ol900306v

Indoles and alcohols can be coupled in a dehydrogenative process catalyzed by tetrapropylammonium perruthenate. This efficient approach to indolylamides proceeds in a single flask under mild conditions. By employing substituted indoles and alkyl, branched

Full text of DOI:10.1021/ol900306v

ORGANIC
LETTERS
2009
Vol. 11, No. 7
1651-1654
Single-Flask Synthesis of N-Acylated
Indoles by Catalytic Dehydrogenative
Coupling with Primary Alcohols
Brooks E. Maki and Karl A. Scheidt*
Department of Chemistry, Northwestern UniVersity, EVanston, Illinois 60208
scheidt@northwestern.edu
Received February 12, 2009
ABSTRACT
Indoles and alcohols can be coupled in a dehydrogenative process catalyzed by tetrapropylammonium perruthenate. This efficient approach
to indolylamides proceeds in a single flask under mild conditions. By employing substituted indoles and alkyl, branched, or benzylic alcohols,
a variety of indolylamides can be formed. Aryl indolylamides can be functionalized through an additional dehydrogenative coupling to furnish
elaborated polycyclic heterocycles similar to biologically active structures previously reported.
Amides are important, abundant, compounds that are utilized
in a broad range of chemical disciplines.1 Given the ubiquity
of this stable functional group and its central place in proteins
and polymers, amide formation remains a fundamental
transformation in organic synthesis.2 The formation of amides
by the oxidation of the acyl C-H of aldehydes is an
attractive, direct method3 that circumvents the need for
coupling agents and prerequisite oxidation. Of particular
interest is the potential application of this method toward
the synthesis of indolylamides. In addition to their function
as protected carboxylate derivatives,4 indolylamides are
desirable synthetic targets. N-Acyl indoles are present in
numerous biologically active molecules (Figure 1) such as
the nonsteroid anti-inflammatory agent indomethacin (1),5
(1) Humphrey, J. M.; Chamberlin, A. R. Chem. ReV. 1997, 97, 2243–
2266.
Figure 1. Bioactive indolylamides.
(2) Larock, R. C. ComprehensiVe Organic Transformations, 2nd ed.;
Wiley-VCH: New York, 1999.
(3) (a) Yoo, W. J.; Li, C. J. J. Am. Chem. Soc. 2006, 128, 13064–13065.
(b) Suto, Y.; Yamagiwa, N.; Torisawa, Y. Tetrahedron Lett. 2008, 49, 5732–
5735. (c) Fang, C.; Qian, W. X.; Bao, W. L. Synlett 2008, 2529–2531. (d)
Colombeau, L.; Traore, T.; Compain, P.; Martin, O. R. J. Org. Chem. 2008,
73, 8647–8650. (e) Chan, J.; Baucorn, K. D.; Murry, J. A. J. Am. Chem.
Soc. 2007, 129, 14106–14107. (f) The oxidative amidation of aldehydes
has been recently reviewed: Ekoue-Kovi, K.; Wolf, C. Chem.-Eur. J. 2008,
14, 6302–6315.
members of the pyrrolophenanthridone class of natural
products6 isolated from the Amaryllidaceae family (2-7),7
and 6H-isoindolo[2,1-a]indol-6-ones (vide infra).
The dehydrogenative coupling of indoles and alcohols8
(Figure 2) is an efficient approach to these synthetically
10.1021/ol900306v CCC: $40.75
Published on Web 03/11/2009
2009 American Chemical Society

starting materials in the readily available alcohol oxidation
state. To the best of our knowledge this transformation
represents the first intermolecular dehydrogenative coupling
of aromatic amines and alcohols.
Our previous work, utilizing nucleophilic N-heterocyclic
carbene (NHC) catalysts in tandem oxidation reactions,12 led
us to investigate the acylation potential of that process with
respect to amines.13 With indole as the nucleophile, we were
pleased to observe the formation of the N-acylated product
10a under reaction conditions employing various azolium
salts and oxidants (results not shown). The reaction was
found to also proceed in the absence of the nucleophilic
catalyst (Table 1, entry 1), presumably due to the formation
Table 1. N-Acylation of Indole with Hydrocinnamaldehyde
Figure 2. Dehydrogenative coupling of indoles and alcohols.
useful N-acylated indole structures. Furthermore, a strategy
that accesses higher oxidation states in a single operation
(i.e., alcohol to amide) simultaneously exploits the advan-
tages of tandem processes and facilitates the functionalization
of challenging substrates. Indoles and pyrroles were attractive
targets for this process due to the stability of the aminal
intermediate (A).9,10 Herein we report the dehydrogenative
coupling of indoles and alcohols, which does not require the
use of strong hydride or alkyllithium bases and also obviates
the need for sensitive or less accessible acid chloride or
anhydride acylating agents.11 In addition, this process utilizes
entry
oxidant
MnO2
additive
none
9a:8 solventa yield (%)b
1
2
3
4
5
6
7
10:1 toluenec
10:1 toluenec
12
16
PCC
none
TPAP/NMO 4 Å mol sieves 10:1 CH2Cl2
TPAP/NMO 4 Å mol sieves 10:1 CH3CN
TPAP/NMO 4 Å mol sieves
TPAP/NMO 4 Å mol sieves
TPAP/NMO 4 Å mol sieves
4
15
5:1 CH3CN
1:1 CH3CN
1:1 CH3CNd
36
18
81 (74)
a At 25 °C with 8 at 0.33 M. b Yields calculated by GC (isolated yield
(4) For examples of carboxylic acids protected as indolylamides, see:
(a) Reference 9a. (b) De Oliveira Baptista, M. J. V.; Barrett, A. G. M.;
Barton, D. H. R.; Girijavallabhan, M.; Jennings, R. C.; Kelly, J.; Papadimi-
triou, V. J.; Turner, J. V.; Usher, N. A. J. Chem. Soc., Perkin Trans. 1
1977, 1477–1500. (c) Barrett, A. G. M.; Dhanak, D. Tetrahedron Lett. 1987,
28, 3327–3330. (d) Barrett, A. G. M.; Bezuidenhoudt, B. C. B.; Dhanak,
D.; Gasiecki, A. F.; Howell, A. R.; Lee, A. C.; Russell, M. A. J. Org.
Chem. 1989, 54, 3321–3324. (e) Buller, M. J.; Gilley, C. B.; Nguyen, B.;
Olshansky, L.; Fraga, B.; Kobayashi, Y. Synlett 2008, 2244–2248. (f)
Isaacson, J.; Loo, M.; Kobayashi, Y. Org. Lett. 2008, 10, 1461–1463. (g)
Linda, P.; Stener, A.; Cipiciani, A.; Savelli, G. J. Heterocycl. Chem. 1983,
in parentheses). c At 100 °C. d 8 at 0.6 M.
and oxidation of an aminal intermediate, similar to A, which
results from indole acting as a nucleophile and attacking the
aldehyde in place of the heterocyclic catalyst.14 This reaction
occurs specifically at the nitrogen atom of indole. Previous
reports indicating nucleophilicity at the C3 position of the
heterocycle generally require activation through Lewis acid15
or other catalyst.16 The divergence of the reactivity in this
system is a particularly interesting observation and further
mechanistic investigations are being carried out to elucidate
the causes for this reactivity. A screen of oxidants and
20, 247–248
.
(5) Shen, T. Y.; Lucas, S.; Sarett, L. H.; Rosegray, A.; Nuss, G. W.;
Willett, J. D.; Ellis, R. L.; Holly, F. W.; Matzuk, A. R.; Wilson, A. N.;
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Witzel, B. E. J. Am. Chem. Soc. 1963, 85, 488–489
.
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.
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4301–4302. (d) Min, B. S.; Gao, J. J.; Nakamura, N.; Kim, Y. H.; Hattori,
(11) Acylation of indoles with carboxylic acids has been reported with
heat and extended reaction times: Terashima, M.; Fujioka, M. Heterocycles
1982, 19, 91–92. Additionally, acylation has been reported utilizing DCC
as a coupling agent: Bremner, J. B.; Samosorn, S.; Ambrus, J. I. Synthesis
2004, 2653–2658.
M. Chem. Pharm. Bull. 2001, 49, 1217–1219
.
(12) (a) Maki, B. E.; Chan, A.; Phillips, E. M.; Scheidt, K. A. Org.
Lett. 2007, 9, 371–374. (b) Maki, B. E.; Scheidt, K. A. Org. Lett. 2008, 10,
4331–4334. (c) Maki, B. E.; Chan, A.; Phillips, E. M.; Scheidt, K. A.
Tetrahedron 2009,In press, DOI: 10.1016/j.tet.2008.10.033.
(8) For synthesis of amides via coupling of amines and alcohols, see:
(a) Gunanathan, C.; Ben-David, Y.; Milstein, D. Science 2007, 317, 790–
792. (b) Nordstrøm, L. U.; Vogt, H.; Madsen, R. J. Am. Chem. Soc. 2008,
130, 17672–17673. (c) Zweifel, T.; Naubron, J.-V.; Gru¨tzmacher, H. Angew.
Chem., Int. Ed. 2009, 48, 559–563. (d) Reddy, K. R.; Maheswari, C. U.;
(13) For examples of amidation of aldehydes using NHCs, see: (a) Chan,
A.; Scheidt, K. A. Org. Lett. 2005, 7, 905–908. (b) Vora, H. U.; Rovis, T.
J. Am. Chem. Soc. 2007, 129, 13796–13797. (c) Bode, J. W.; Sohn, S. S.
J. Am. Chem. Soc. 2007, 129, 13798–13799. (d) Wong, F. T.; Patra, P. K.;
Seayad, J.; Zhang, Y.; Ying, J. Y. Org. Lett. 2008, 10, 2333–2336.
(14) Although the possibility exists for coupling of the indole with a
substrate in the carboxylic acid oxidation state,11 significant amounts of
the carboxylic acid were not observed with prolonged exposure of 3-phenyl-
1-propanol or hydrocinnamaldehyde to oxidation conditions in the absence
of indole.
Venkateshwar, M.; Kantam, M. L. Eur. J. Org. Chem. 2008, 361, 9–3622
.
(9) (a) Arai, E.; Tokuyama, H.; Linsell, M. S.; Fukuyama, T. Tetrahedron
Lett. 1998, 39, 71–74. (b) Evans, D. A.; Borg, G.; Scheidt, K. A. Angew.
Chem., Int. Ed. 2002, 41, 3188–3191. (c) Dixon, D. J.; Scott, M. S.;
Luckhurst, C. A. Synlett 2003, 2317–2320
.
(10) For oxidation of aminals derived from intramolecular scaffolds with
chromium-based oxidants, see: Node, M.; Nagasawa, H.; Fuji, K. J. Org.
Chem. 1990, 55, 517–521
.
1652
Org. Lett., Vol. 11, No. 7, 2009

solvents (entries 1-4) revealed that the catalytic (5 mol %)
oxidant tetrapropylammonium perruthenate (TPAP) in com-
bination with 4-methylmorpholine-N-oxide (NMO)17 allowed
this oxidation to take place at ambient temperature,18 albeit
in similarly poor yields. Acetonitrile was found to be a more
optimal solvent for this transformation than dichlorome-
thane.
from the combination of 2-substituted or 7-substituted indoles
and the alcohol were not capable of undergoing this oxidation
(entries 8 and 9), most likely due to the bulky nature of the
oxidizing agent. Indoles were found to be superior to pyrrole,
indazole, and 7-aza-indole, all of which resulted in no
acylation. Carbazole was also investigated and gave poor
results (<40% yield of acylated product).
The concentration of the nucleophilic indole 9a had a
significant effect on the results of this oxidation (entries
4-7). When the concentration was greater than 1.5 M
(entries 4 and 5), lower yields were observed, while
concentrations in the range of 0.5-1.5 M provided the
highest yields (entry 7). Further dilution (entry 6) had a
negative effect on the yield of the N-acylated heterocycle.
Because TPAP is known to oxidize alcohols to aldehydes,
we explored the use of 3-phenyl-1-propanol (11) as a
coupling partner. After initial oxidation to an aldehyde,
formation of the aminal via nucleophilic addition of the
indole derivative allowed further oxidation to the N-acyl
heterocycle (Table 2, entry 1). This oxidative process is
Variation of the acylating alcohol shows steric interactions
influencing the oxidation of the aminal intermediate. Un-
branched alkyl alcohols (Table 3, entries 1-4) gave the best
Table 3. Dehydrogenative Coupling with Alcoholsa
Table 2. Dehydrogenative Coupling of Indolesa
entry
indole
R1
R2
R3
yield (%)b
1
2
3
4
5
6
7
8
9
9a
9b
9c
9d
9e
9f
9g
9h
9i
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
CO2Me
Me
H
81
86
76
73
74
70
63
0
5-OMe
5-Br
5-CO2Me
4-Br
H
H
7-Me
H
H
0
a See Supporting Information for full experimental details. b Isolated
yield.
viable using a variety of indole derivatives. 5-Substituted
indoles (Table 2, entries 2-4) were suitable substrates. The
more nucleophilic 9b gave the highest yield, while an
electron-withdrawing group at this position decreased the
yield (entry 4). 3-Substituted indoles (entries 6 and 7) yielded
acylated product, but the more encumbered aminal resulting
a See Supporting Information for full experimental details. b Isolated
yield.
results, while increased substitution at the R-position de-
creased the yield (entries 6 and 7). This process tolerates
the presence of silyl ethers (entry 4) and olefins (entries 3
and 5). The sterically demanding substrate derived from 2,2-
dimethyl-1-propanol was afforded in low yield (entry 8). The
use of a benzylic alcohol provided the N-acyl product as
well (entry 9).
A modification of the procedure using TPAP and mole-
cular oxygen as the oxidative system19 gave the product in
comparable yields (Scheme 1). This green oxidative cou-
pling20 of alcohols and indole derivatives allows for the
(15) (a) Soueldan, M.; Collin, J.; Gil, R. Tetrahedron Lett. 2006, 47,
5467–5470. (b) Dong, H. M.; Lu, H. H.; Lu, L. Q.; Chen, C. B.; Xiao,
W. J. AdV. Synth. Catal. 2007, 349, 1597–1603.
(16) (a) To¨ro¨k, B.; Abid, M.; London, G.; Esquibel, J.; To¨ro¨k, M.;
Mhadgut, S. C.; Yan, P.; Prakash, G. K. S. Angew. Chem., Int. Ed. 2005,
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4063–4065.
(17) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 63, 9–666.
(18) Optimal results were observed with utilization of TPAP freshly
prepared via the method of Bailey, A. J.; Griffith, W. P.; Mostafa, S. I.;
Sherwood, P. A. Inorg. Chem. 1993, 32, 268–271.
Org. Lett., Vol. 11, No. 7, 2009
1653

N-Acylated heterocycles can be synthesized from aromatic
amines and alcohols or aldehydes. A variety of indole
derivatives and acylating agents, restricted by steric interac-
tions about the resultant aminal, can be used in this process.
The oxidation is carried out with a catalytic oxidant (TPAP),
which can be used in low catalyst loadings (<5 mol %) to
efficiently provide these useful substrates from readily
available starting materials in an environmentally friendly
manner. This method has been applied to the preparation of
potentially bioactive 6H-isoindolo[2,1-a]indol-6-one frame-
works. Further investigations of the mechanism and new
applications of this dehydrogenative coupling process are
underway and will be reported in due course.
Scheme 1. Synthesis of Bioactive Tetracycles
further elaboration of substrates such as 10q. This process
was also effective for other alcohols, as 10a and 10m were
successfully obtained in 72% and 66% yields, respectively,
using molecular oxygen as the oxidant.21
Acknowledgment. Research support was generously
provided by NIH/NIGMS (GM73072), Abbott Laboratories,
Amgen, AstraZeneca, GlaxoSmithKline, the Sloan Founda-
tion, and Boehringer-Ingelheim. B.E.M. was supported by a
GAANN Fellowship.
The direct acylation of indole using a benzaldehyde
derivative yields acylated indole 10q, which when treated
with palladium(II) acetate (employing the conditions of
DeBoef22), cyclizes to form tetracyclic compound 12 from
the sequential dehydrogenation of indole and a simple benzyl
alcohol (Scheme 1). 6H-Isoindolo[2,1-a]indol-6-ones of this
type have been shown to mimic melatonin23 and batracy-
clin.24 These compounds possess several modes of biological
activity,25 including binding to MT3 melatonin receptors,
topisomerase inhibition, cytotoxicity, and antiproliferative
activity against L1210 leukemia cells.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL900306V
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(21) See Supporting Information for full procedural and experimental
details.
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