A new route to α-carbolines based on 6π-electrocyclization of indole-3-alkenyl oximes

Article abstract of DOI:10.1021/ol403191k

Indoles are converted into α-carbolines in four steps by acylation at C-3, Boc-protection, olefination of the resulting 3-indolyl aldehydes or ketones to give N-Boc-3-indolyl alkenyl oxime O-methyl ethers, which upon heating to 240 C under microwave irradiation undergo loss of the Boc-group, and 6π-electrocyclization to α-carbolines, following aromatization by loss of methanol (11 examples, 30-90% yield).

Full text of DOI:10.1021/ol403191k

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
A New Route to r‑Carbolines Based on
6π-Electrocyclization of Indole-3-alkenyl
Oximes
Sophie J. Markey, William Lewis, and Christopher J. Moody*
School of Chemistry, University of Nottingham, Nottingham NG7 2RD, U.K.
c.j.moody@nottingham.ac.uk
Received November 5, 2013
ABSTRACT
Indoles are converted into R-carbolines in four steps by acylation at C-3, Boc-protection, olefination of the resulting 3-indolyl aldehydes or ketones to
give N-Boc-3-indolyl alkenyl oxime O-methyl ethers, which upon heating to 240 °C under microwave irradiation undergo loss of the Boc-group, and
6π-electrocyclization to R-carbolines, following aromatization by loss of methanol (11 examples, 30À90% yield).
In contrast to β-carbolines that are widely represented
among natural products and synthetic bioactive com-
pounds,1À3 R-carbolines (pyrido[2,3-b]indoles) are consid-
erably less well investigated.4,5 Nevertheless there are some
important examples such as the naturally occurring antic-
ancer compounds grossularine-1 and -26À9 and the neuronal
cell protective agent mescengricin (Figure 1).10 In the medi-
cinal chemistry arena, R-carbolines such as the GABA
modulator,11 and the inhibitor of microsomal triglyceride
transport protein implitapide,12,13 have also been widely
studied.
As a consequence, routes for the construction of the
R-carboline nucleus are of interest, but unlike their
β-carboline counterparts that are almost invariably pre-
pared from tryptophan or tryptamine derivatives, there is
no main synthetic access to the isomeric R-carbolines. Thus,
R-carbolines have been obtained from 2-aminoindoles,14À16
by a variation of the GraebeÀUllmann synthesis of
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r
10.1021/ol403191k
XXXX American Chemical Society

carbazoles,17 by intramolecular DielsÀAlder reaction
of pyrazinones,18 from palladium-catalyzed reactions
of anilines with 2,3-dihalopyridines,19,20 by cyclization
of 2-isocyanato-indoles,6À8 and of iminyl radicals.21À24
However, we were attracted by the possibility of developing
a more general route based on a 6π-electrocyclic process,
and we now report our initial results.
Scheme 1. Projected Route to R-Carbolines by 6π-Electro-
cyclization of 3-Indolyl Alkenyl Oxime Ethers
Figure 2. X-ray crystal structure of (E)-3-(1-methyl-1H-indol-3-yl)-
propenal (Z)-methyl oxime.
acylation at the 3-position. The participation of oxime
ethersin6π-electrocyclicprocessesisknownfrom thework
of Hibino,25 and the possible intermediacy of imines rela-
ted to 1 has been implicated in other work23 and in a bio-
mimetic synthesis of grossularine-1.9
Figure 1. Structures of naturally occurring and bioactive
R-carbolines.
The precursors to the desired oxime ethers were 3-acyl-
indoles 2 and phosphonates 3. The phosphonates were
prepared by reaction of the corresponding carbonyl
compound with O-methyl hydroxylamine, with the aldoxime
precursor being prepared by acid hydrolysis of the commer-
cially available diethyl (2,2-diethoxy)ethylphosphonate.
The subsequent HornerÀWadsworthÀEmmons reaction
with N-Boc-protected 3-indolyl aldehydes or ketones gave
the required alkenyl oxime ethers 4 generally as mixtures
of E/Z-alkene isomers that could be readily separated and
characterized, apart from alkene 4g which was formed as the
E-alkene.
The projected precursors to R-carbolines were the 3-in-
dolyl alkenyl oxime ethers 1, accessible from 3-acylindoles
2 (Scheme 1). 3-Acylindoles are readily available by ex-
ploiting the natural reactivity of indoles to undergo facile
´
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2005, 78, 1659–1664.
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In general only one oxime isomer was observed which,
on the basis of the chemical shift of the oxime RCHd
1
NOMe proton in the H NMR spectrum, suggested that
2007, 4041–4043.
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J. C. J. Org. Chem. 2008, 73, 8124–8127.
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Org. Lett., Vol. XX, No. XX, XXXX
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Table 1. Preparation of Indolyl Alkenyl Oxime Ethers 4 [Indoles, Phosphonates, 3a, R2 = H; 3b, R2 = Me] and Their Conversion into
R-Carbolines 5 by 6π-Electrocyclization
entry
2
Xa
R4
3
R2
4
E yield/%
Z yield/%
Xb
5
yield/%
1
a
b
c
d
a
c
b
e
f
H
H
H
H
H
H
H
H
a
a
a
a
b
b
b
a
a
b
b
H
a
b
c
d
e
f
46
37
38
49
11
38
25
60
42
22
62
À
H
a
b
c
d
e
f
73
36
30
55
90
77
41
52
62
65
51
2
5-OMe
6-OMe
5-Cl
H
H
6-OMe
7-OMe
6-Cl
H
3
H
4
H
5
Me
Me
Me
H
6
6-OMe
5-OMe
H
28
34c
38c
49
45
52
7-OMe
6-OMe
H
7
g
h
i
g
h
i
8
CO2Me
Me
49
16c
23
29
9
H
H
H
10
11
f
H
Me
Me
Me
j
H
j
e
H
CO2Me
k
H
k
a Indole numbering. b R-Carboline numbering. c Mixture of oxime geometric isomers.
the oximes have the (Z)-geometry. In the case of oxime 4a,
removal of the Boc-protecting group gave the crystalline
E-alkene-Z-oxime (Figure 2), confirming the Z-stereo-
chemistry of the oxime double bond. The olefination reac-
tion was then extended to indole-3-carbaldehydes bearing
chloro- and alkoxy-groups, and indolyl ketones with methyl
or ester groups (Table 1).
assumed that it would be cleaved under the high tempera-
ture conditions. In the event, heating 4a, as a mixture
of geometric isomers, to 180 °C in 1,2-dichlorobenzene
gave a mixture of the desired R-carboline 5a (12%) plus the
Boc-deprotected starting material. Increasing the tempera-
ture to 240 °C under microwave irradiation delivered the
R-carboline 5a in 73% yield. We assume that the reaction
involves initial thermal removal of the Boc-group to give
the NH indole in which isomerization of the alkene into the
cis-isomer required for electrocyclization is facilitated. In
support of this, prior removal of the Boc-group in 4a under
hydrolytic conditions (82%) gave the corresponding NH
indole that cyclized to R-carboline 5a (54%) upon heating
to 240 °C. It would appear that the NH is essential for
cyclization since the corresponding N-methyl compound
does not give 9-methyl-R-carboline under the same condi-
tions. Electrocyclization of the indolyl alkenyl oxime ethers
4bÀ4k, starting with either (Z)- or (E)-alkene isomers,
proceeded similarly to give a range of R-carbolines 5 in
30À90% yield (Table 1). The structures of the carbolines 5f
and 5h were confirmed by X-ray crystallography (Figure 3).
In conclusion, we have developed a new general route to
R-carbolines that proceeds in just four steps from indoles.
Acknowledgment. We thank the EPSRC for DTA
studentship support to S.J.M.
Supporting Information Available. All experimental
1
Figure 3. X-ray crystal structures of R-carbolines 5f and 5h.
procedures, copies of H and 13C NMR spectra, and
cif files for X-ray structures. This material is available
free of charge via the Internet at http://pubs.acs.org.
With a range of oxime ethers 4 in hand, their thermal
cyclization reactions were studied. Initially, these were
investigated leaving the Boc-group in place since it was
The authors declare no competing financial interest.
Org. Lett., Vol. XX, No. XX, XXXX
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