New organolithium addition methodology to diversely functionalized indoles

Article abstract of DOI:10.1021/ja034283h

A novel synthetic approach to diversely functionalized indoles is described. Boc-protected ortho-aminostyrenes undergo an alkyllithium addition reaction, thereby generating a lithiated intermediate, which upon reaction with specific electrophiles sets up

Full text of DOI:10.1021/ja034283h

Published on Web 03/15/2003
New Organolithium Addition Methodology to Diversely Functionalized Indoles
Claire M. Coleman and Donal F. O’Shea*
Centre for Synthesis and Chemical Biology, Conway Institute, Department of Chemistry, UniVersity College Dublin,
Belfield, Dublin 4, Ireland
Received January 22, 2003; E-mail: donal.f.oshea@ucd.ie
4
The key biochemical roles played by the indole ring in nature
ensure that this modest heterocyclic system continues to attract
intense scrutiny from medicinal and synthetic chemists. It is a
common motif for drug targets, and as such the development of
new diversity-tolerant routes to this privileged biological scaffold
chose Boc-protected ortho-amino substituted styrenes (X-R )
NHBoc) with dimethylformamide (DMF) or a substituted nitrile
as the electrophile in an effort to make diversely functionalized
indoles.
Generation of the required starting materials was achieved by
employing a recently developed protocol for the synthesis of
functionalized styrenes from aryl bromides 1 by Suzuki-Miyaura
cross coupling with 2,4,6-trivinylcyclotriboroxane 2 (Scheme 1).
This method routinely provided the Boc-protected ortho-vinyl
aniline derivatives 3 in high yields.
1
continues to be of significant benefit. New multicomponent routes,
which would facilitate the introduction of molecular diversity at
all positions of the indole ring, would have applications for
combinatorial library formation and natural product synthesis. Many
recent advances in indole synthesis have focused on metal mediated
procedures with copper, palladium, tin, titanium, and zirconium
being the most prevalent.2 Our novel approach is to exploit
organolithium addition to functionalized styrenes with the C-C
bond formation reaction as the key synthetic step. A significant
benefit of this strategy is that it can provide a direct route for the
introduction of further molecular diversity into the ring system.
Other methods for indole synthesis utilizing organolithium reagents
have been previously reported.3
5
Scheme 1. Vinylation of Substituted ortho-(Bromo-aryl)-carbamic
Acid tert-Butyl Esters 1
The anionic polymerization of styrenes using organolithiums is
a well-established process, but recently it has been reported that
polymerization can be avoided, thereby facilitating the development
of its synthetic use. It was shown that addition of the organo group
to the terminal carbon of styrene generated a new organolithium
The viability of the reaction sequence was tested using three
ortho N-Boc vinyl anilines 3, substituted with electron-donating
or -withdrawing groups, and three alkyllithiums, tert-butyl, sec-
butyl, and n-butyl, as a representative sample. The first electrophile
investigated was DMF, which in the reaction sequence provides
the C-2 carbon of the indole ring. The reaction of each combination
of alkyllithium and 3 gave the desired N-Boc substituted indoles
3
species which when trapped with electrophiles (E-R ) provided a
4
viable route to substituted aryl rings (eq 1). This methodology
exploits the window of opportunity for synthetic utility due to the
difference in reactivity of the organolithium used for the addition
and the resulting organolithium generated.
4, with isolated purified yields up to 84% (Table 1). We found
that the addition reaction was most effective for tert-butyllithium
at -78 °C, whereas for n-butyllithium it was advantageous to
include TMEDA as an additive and raise the reaction temperature
to -25 °C, as this achieved a more effective addition to the vinyl
double bond.6
A proposed reaction sequence would be as follows: initial
deprotonation of the carbamic ester NH of 3, followed by addition
of alkyllithium to the vinyl double bond providing the lithiated
intermediate; subsequent addition of the electrophile DMF, which
reacts with the anion generating an aldehyde precursor; and addition
of aqueous acid facilitates ring closure by intramolecular attack of
the carbamic ester nitrogen at the aldehyde to form a 2-hydroxy-
indole 6, which subsequently in situ dehydrates to the indole. If
the acidification conditions are sufficiently mild, it is possible to
isolate the substituted 2-hydroxy-2,3-dihydro-indole 6 as a mixture
of isomers (Figure 1). Subsequent treatment with aqueous hydro-
chloric acid efficiently converts 6 into the corresponding indole 4.
The deprotection of indoles 4 was readily accomplished by
stirring at room temperature with 12 M HCl in ethyl acetate,
generating 5 in excellent yields (Table 1). This deprotection method
complements our indole synthesis as it allows either the protected
Our aim is to greatly expand the synthetic utility of this chemistry
for the specific case of ortho-substituted styrenes. For these
derivatives, it should be possible that upon generation of the lithiated
intermediate via organolithium addition, and subsequent reaction
with specific electrophiles, a cascade reaction process could be set
3
up between the reacted electrophile (E-R ) and ortho-substituent
4
(
X-R ) components, facilitating an in situ ring-closing reaction to
generate benzo-fused ring systems (eq 2). For this approach to be
successful, it would require the correct combination of a reacting
pair of ortho-substituent and electrophile. To test this concept, we
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J. AM. CHEM. SOC. 2003, 125, 4054-4055
10.1021/ja034283h CCC: $25.00 © 2003 American Chemical Society

C O MMU N I C A T I O N S
Table 2. Synthesis of 2,3,5-Substituted Indoles 8
Table 1. Synthesis of 1,3,5- and 3,5-Substituted Indoles 4 and 5
entry
8
R1
R2
R3
8 yielda
1
2
3
4
a
b
c
H
H
H
H
t-Bu
Ph
t-Bu
COCH3
65%
67%
44%
60%
t-Bu
n-Bub
n-Bub
d
entry
4/5
R1
R2
4 yielda
5 yieldb
5
6
7
8
e
f
g
h
F
F
t-Bu
Ph
t-Bu
Ph
40%
54%
57%
68%
n-Bub
t-Bu
1
2
3
4
5
6
7
8
a
b
c
d
e
f
H
H
H
F
F
F
t-Bu
n-Bu
s-Bu
t-Bu
n-Bu
s-Bu
t-Bu
n-Bu
75%
84%
62%
70%
71%
43%
77%
80%
88%
97%
83%
87%
90%
70%
85%
65%
c
c
c
OCH3
OCH3
n-Bub
Ph
a
Isolated purified yield. b Reference 6.
observed, implying a reaction pathway similar to the DMF
electrophile examples.
g
h
OCH3
OCH3
The combination of a vinylation procedure using boronic acid
coupling chemistry with an organolithium addition-cyclization
methodology gives a new entry into functionalized indole ring
systems. The methodology is diversity tolerant, facilitating the
introduction of aryl, hetero-aryl, alkyl, keto, halo, and ether
substituents in varying positions around the indole scaffold.
Utilization of this synthetic methodology for the generation of other
heterocycles by modification of the reacting pair of the ortho-
substituent and electrophile is currently underway.
a
Isolated purified yield. b Conversion of isolated 4 into 5. c Reference
6
.
Acknowledgment. We gratefully acknowledge the Centre for
Synthesis and Chemical Biology, UCD and Enterprise Ireland for
financial support.
Figure 1. Proposed reaction intermediates.
or the deprotected indole to be isolated depending on the acidifica-
tion conditions chosen.
The use of DMF as an electrophile precludes the direct
introduction of a substituent at C-2 of the indole ring. The inclusion
of functionality at this position can be achieved by a change in
electrophile to a substituted nitrile. The addition of organolithium
Supporting Information Available: Experimental procedures and
compound characterization data for all indoles (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
References
7
species to nitriles for heterocyclic synthesis is known. Conse-
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reaction of nitriles is slower than that with DMF, and an efficient
reaction was achieved by stirring at -25 °C for 3 h. Subsequent
treatment of the reaction mixture with 12 M HCl in ethyl acetate
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substituted indoles 8 in acceptable yields (Table 2). This reaction
sequence was tolerant to the introduction of a range of C-2
substituents, including aryl (entries 1, 5, 7, 8), heteroaryl (entry 4),
and sterically bulky alkyl groups (entries 2, 6) (Table 2). It was
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(
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(
(
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(
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°
C, the temperature was raised to -25 °C for 2 h.
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3
mild, reaction intermediates of type 7 (R ) nitrile substituent) are
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