Indoles synthesized from amines via copper catalysis

Article abstract of DOI:10.1021/ol400444g

N-Substituted indoles are synthesized from primary amines through a tandem reaction sequence. Initial condensation of the amine with an α-(o-haloaryl)ketone or aldehyde is followed by intramolecular aryl amination catalyzed by CuI. A variety of anilines and alkyl amines, including those with significant steric demands, are converted to indoles in high yields and with varying indole substitution.

Full text of DOI:10.1021/ol400444g

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Indoles Synthesized from Amines via
Copper Catalysis
Ronald Besandre, Miguel Jaimes, and Jeremy A. May*
Department of Chemistry, University of Houston, 136 Fleming Building, Houston,
Texas 77204-5003, United States
jmay@uh.edu
Received February 16, 2013
ABSTRACT
N-Substituted indoles are synthesized from primary amines through a tandem reaction sequence. Initial condensation of the amine with an
R-(o-haloaryl)ketone or aldehyde is followed by intramolecular aryl amination catalyzed by CuI. A variety of anilines and alkyl amines, including
those with significant steric demands, are converted to indoles in high yields and with varying indole substitution.
Methods for indole synthesis are important in natural
product synthesis1 and medicinal chemistry.2 Consequently,
a myriad of methods for their synthesis have been reported.3
A noticeably underexploited synthetic strategy is to build
indoles from amines.3b Such an approach would allow for
indoles with large and/or complex N-substituents, which
are difficult to introduce to existing indoles, to be built
from the appropriate amines.4 An implementation of this
approachcouldusereadily availableR-aryl ketones25 viaa
tandem6 imine formation/N-arylation sequence (Scheme 1).7
While a few examples of palladium-catalyzed indole for-
mation similar to this approach have been disclosed,8,9 few
reports use copper-catalyzed arylation of imines to form
indoles,10,11 even though copper catalysis offers advan-
tages over palladium.12 The few examples of copper cata-
lysis do not use the facile formation of imines from R-aryl
ketones and aldehydes to set up CÀN bond formation, but
require more roundabout syntheses of enamines via con-
densations or conjugate additions that limit substrate
scope.13 Attempts at initial copper-catalyzed amino-arylation
to form aniline 3, which would be followed by dehydrative
cyclization to indole 6, produced only benzofurans 4.14
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r
10.1021/ol400444g
XXXX American Chemical Society

reaction was implemented by the addition of the reagents
to this same flask under an inert atmosphere.
Scheme 1. Indoles from Amines and R-Aryl Ketones
Table 1. Imine Formation
entry
additive
MgSO4
solvent
PhMe
SM/iminea
1b
2
3:97
MgSO4
PhMe
70:30
20:80
4:96
˚
3
3 A mol sieves
PhMe
4
p-TsOH (0.1 equiv)
p-TsOH (0.1 equiv)
PhMe (-H2O)c
PhH (-H2O)c
5
1:99
We envisioned that a reversal of these steps, namely
dehydrative formation of imine 5, followed by arylation
of the intermediate imine or enamine, would be more suc-
cessful. We report herein facile, scalable conditions for
dehydrative imine formation and copper-catalyzed indole
formation from a variety of amines and R-aryl carbonyl
compounds.
a Measured by GC. Each entry is a single experiment. b 2-(2-
Bromophenyl)acetaldehyde used. c DeanÀStark apparatus used to re-
move water.
Initial attempts at intramolecular imino-arylation of the
ketimine followed protocols using CuI and K3PO4 in
DMF.13,15 However, hydrolysis proved to be competing
with indole formation (Table 2, entry 1). Finely ground
and anhydrous base proved to be essential for an excellent
yield of the indole (entry 2). Other bases were less effective
(entries 3 and 4). Unfortunately, many attempts to effect
As the formation of imines from ketones is not a trivial
process, we first examined several approaches for the
condensation reaction. While magnesium sulfate is suffi-
cient to form an imine from an aldehyde (Table 1, entry 1),
it was ineffective for the complete condensation to the
imine from the corresponding ketone (entry 2). Stronger in
situ dehydrating agents also proved unsatisfactory (entry 3).
Fortunately, a catalytic amount of acid and azeotropic
removal of water turned out to be simple and effective
(entries 4 and 5). Care had to be taken not to expose the
ketimines to the atmosphere, as hydrolysis back to the
ketone is quite rapid. Concentration of the reaction by
distillative removal of the solvent without opening the
reaction vesselassured thatthe imine was obtainedwithout
hydrolysis. While toluene was effective for imine forma-
tion, the distillation of benzene was more facile and its
lower boiling point allows amines with lower molecular
weights to be used without loss. Toluene could still be used
for more difficult imine formations. The next stage of the
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Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Intramolecular Imino-Arylation
Table 4. Diverse Indole Products
indole/benzofuran/
ketonea
entry base
ligand
solvent
DMF
1
K3PO4
À
À
À
62:37:0
23%:0%:10%b
99:1:0
c
2
K3PO4
DMF
80%:0%:0%b
68:32:0
d
3
4
5
6
7
Cs2CO3
DMF
DMF
PhMe
PhMe
NaOtBudÀ
81:9:0e
c
K3PO4
À
0:0:100
c
K3PO4 H2N(CH2)2NH2
0:0:100
c
K3PO4 Me2N(CH2)2NMe2 PhMe
10:0:90
a Measured by GC. Each entry is a single experiment. b Isolated
yields. c Base flame-dried under vacuum. d Anhydrous from a glovebox.
e Formation of side products observed.
Table 3. Amine-Based Indole Synthesis
a Isolated yield averaged from multiple runs. b 4 A molecular sieves
at rt. c Toluene at reflux used as solvent.
This experimentalprotocol proved tobeamenabletothe
formation of a wide variety of N-functionalized indoles
(Table 3). Anilines, benzylamines, and aliphatic amines
were all incorporated into the product indole with good
yields. Substituents on the aniline aryl ring showed little
effect on the reaction (entries 1À4). The N-benzyl indoles
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Org. Lett., Vol. XX, No. XX, XXXX
C

are important motifs in their own right18 but also allow
for access to indoles without substitution on N1 through
hydrogenolysis.19 Despite the potential for copper species20
and/or base21 to isomerize N-alkyl imines, products derived
from such an isomerization were not observed and N-alkyl
indoles were generated in uniformly good yields.
A benefit of R-arylketones as indole precursors is that
the simplicity of their synthesis allows for a variety of
functional groups to be present to either side of the ketone
and/or around the aryl ring.22 Thus, further diversifica-
tion of the indole products is possible from this one-pot,
two-stage sequence. Notably, aldehydes work very well
(entries 1À4, Table 4). Substituents are easily incorporated
at the benzylic carbon to give 3-substituted indoles (entries 3
and 4). Importantly, even highly hindered amines may be
used to build indoles. Ketones allow for controlled instal-
lation of C2 substituents in the products (entries 5À6).
Cyclic ketones afford ring-fused indoles, which is a motif
common in pharmaceuticals23 and natural products (entry 7).24
In conclusion, a strategy to build indoles around a variety
of primary amines has been designed and reduced to
practice. Both simple and sterically hindered amines read-
ily produce indoles. The conditions employed are inexpen-
sive and amenable to large-scale implementation.
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Acknowledgment. The Welch Foundation (Grant E-1744),
the ACS Organic Division (SURF fellowship to R.B.), and
the University of Houston financially supported this work.
Supporting Information Available. Additional optimi-
zation data, experimental procedures, and characterization
data for all compounds are included. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
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The authors declare no competing financial interest.
D
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