Novel α-carboline synthesis using tandem aza-Wittig- electrocyclization reaction of indol-2-yl phosphorane with enone

Article abstract of DOI:10.1055/s-2006-944182

Mild thermal reaction of indol-2-yl triphenyl- and methyldiphenyl- phosphorane derived from 2-azido-1-methylindole with enones provides a novel entry to 9-methyl-9H-pyrido[2,3-b]indoles through a tandem aza-Wittig- electrocyclization process. Georg Thieme

Full text of DOI:10.1055/s-2006-944182

1574
LETTER
Novel a-Carboline Synthesis Using Tandem aza-Wittig–Electrocyclization
Reaction of Indol-2-yl Phosphorane with Enone
N
a
ovel
a
-Carbolin
a
e
Synthesisrlo Bonini,a Maria Funicello,*a Piero Spagnolob
Dipartimento di Chimica, Università della Basilicata, Via N. Sauro 85, 85100 Potenza, Italy
Fax +39(0971)202223; E-mail: funicello@unibas.it
b
Dipartimento di Chimica Organica ‘A. Mangini’, Viale Risorgimento 4, 40136 Bologna, Italy
E-mail: spagnolo@ms.fci.unibo.it
Received 2 March 2006
class of compounds involve construction of either pyri-
dine ring from 2-amino-3-substituted indole derivatives5,8
or synthesis of pyrrole (B ring) ring via cross-coupling
between an appropriately substituted pyridine and aniline
derivative.9 Other approaches involve intramolecular
Diels–Alder reaction of 2(1H)-pyrazinones10 and con-
jugated carbodiimides,11 reaction of 1-methyl-2-oxyin-
dole enolate with a-oxoketene dithioacetals,7a
condensation of 2-amidinylindole-3-carbaldehydes with
arylmethylketones12 as well as reaction of indol-2(3H)-
one derivatives with enamines.13 Very recently, a-carbol-
ines have also been prepared by copper-catalyzed radical
cyclization of b-(3-indolyl)ketone O-pentafluorobenzo-
yloximes.14 However, the existing methods often suffer
from limitations such as not easily accessible starting
materials, overall poor yields or inflexibility for substitu-
ent introduction.
Abstract: Mild thermal reaction of indol-2-yl triphenyl- and
methyldiphenyl-phosphorane derived from 2-azido-1-methylindole
with enones provides a novel entry to 9-methyl-9H-pyrido[2,3-b]in-
doles through a tandem aza-Wittig–electrocyclization process.
Key words: indolyl phosphoranes, enones, aza-Wittig, electro-
cyclization, a-carbolines
In the past thirty years iminophosphoranes, first prepared
at the beginning of the last century by Staudinger in the
reaction of organic azides with triphenylphosphine, have
become a powerful tool in synthetic methods for the con-
struction of nitrogen-containing heterocycles.1 In particu-
lar, the aza-Wittig reaction of suitable iminophosphoranes
with (unsaturated) carbonyl compounds followed by 6p-
electrocyclization of resultant azahexatrienes has found
important applications in the synthesis of simple as well
as c-fused pyridines.2
2-Azido-1-methylindole (1) was prepared by azidation of
commercial 1-methylindole by ‘azido group transfer’
from tosyl azide, following the previously reported proce-
dure.4 The crude azido compound was directly treated
with triphenylphosphine and methyldiphenylphosphine in
diethyl ether at 0 °C furnishing N-(1-methylindol-2-
yl)iminotriphenylphosphorane (2a) and N-(1-methylin-
dol-2-yl)iminomethyldiphenylphosphorane (2b) in 70%
and 55% yield, respectively, based on the starting indole
(Scheme 1).15 The triphenylphosphorane (2a) was isolat-
ed as a fairly stable solid compound, whereas the methyl-
diphenyl analogue 2b was obtained as a crude viscous oil
which showed a tendency to decompose and thence was
directly used without purification.
Our recent studies have discovered that iminophos-
phoranes derived from 2-azido- and 3-azido-benzothio-
phene can be efficiently employed in the tandem aza-
Wittig–electrocyclization strategy for the synthesis of b-
fused pyridines such as benzothieno[2,3-b]pyridines and
benzothieno[3,2-b]pyridines.3
In this communication we report that such strategy can
successfully be extended to iminophosphoranes derived
from 2-azido-1-methylindole (1) for the construction of
pyrido[2,3-b]indoles (a-carbolines). The use of N-(indol-
2-yl)iminophosphoranes in a-carboline synthesis is un-
precedented; indeed, these heteroaryl phosphoranes are to
date unknown compounds, despite the fact that a synthetic
route to a potential precursor such as azide 1 has been
available since 1989.4 Iminophosphoranes derived from
b-(indol-3-yl)vinyl azides have found previous use in the
production of b-carbolines via analogous aza-Wittig–
electrocyclization process.1c
1) BuLi
2) TsN3
PPh2R
N3
N=PPh2R
N
N
N
Me
Me
Me
1
2a: R = Ph (70%)
2b: R = Me (55%)
The biological importance of a-carboline ring system is
well known. This ring is found in several alkaloids5 and in
carcinogenic metabolites.6 Moreover, some synthetic a-
carboline derivatives are anxiolytic or neuroprotectant
agents.7 The best known synthetic approaches for this
Scheme 1 Synthesis of indolylphosphoranes
The triphenylphosphorane (2a) underwent smooth reac-
tion with equimolar amounts of acrylaldehyde, trans-cro-
tonaldehyde, trans-cinnamaldehyde, and methyl trans-4-
oxo-2-pentenoate in toluene solution at 70 °C over 18–24 h
to give directly the corresponding a-carbolines 3a–d
SYNLETT 2006, No. 10, pp 1574–1576
2
1
.0
6
.2
0
0
6
Advanced online publication: 12.06.2006
DOI: 10.1055/s-2006-944182; Art ID: G08406ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Novel a-Carboline Synthesis
1575
which were isolated by column chromatography in satis- Under analogous conditions the methyldiphenylphospho-
factory to excellent yields (Scheme 2 and Table 1, entries rane (2b) with the above unsaturated aldehydes and oxo-
1–4).16 Our additional reaction of 2a with but-3-en-2-one pentenoate similarly furnished the carbolines 3a–d, but in
also furnished a useful yield of the respective carboline 3e these cases the resultant yields always were markedly
(Scheme 2 and Table 1, entry 5); this finding was espe- lower (Scheme 2 and Table 1, entries 6–9).16 Thus, our
cially rewarding in light of the relative inertness previous- original expectation that replacement of phenyl with
ly displayed by this ketone with benzothiophenyl electron-donating methyl P-substituent might improve re-
phosphoranes.3a–c
action of indolyl phosphorane with enone19 was unfortu-
nately frustrated as a probable consequence of significant
decomposition of the hardly stable phosphorane 2b under
the reaction conditions.
R2
toluene,
70 °C
+
2a,b
R2CH=CHCOR1
+ O=PPh2R
Evidently, the phosphoranes 2b and, especially, 2a with
our enones could initially form formal aza-Wittig aza-
hexa-1,3,5-triene intermediates. These intermediates then
underwent thermal electrocyclization eventually leading
to the isolated pyridines 3a–e after further dehydrogena-
tion of the cyclized dihydropyridines (Scheme 2). With
both phosphoranes 2a,b the exclusive occurrence of the
tandem aza-Wittig–electrocyclization process was dictat-
ed by the fact that with crotonaldehyde, cinnamaldehyde,
methyl 4-oxo-2-pentenoate as well as butenone the
outcoming substituted carbolines 3b–e were always
produced as single compounds in the expected regio-
chemistry.3 Under these circumstances replacement of
phenyl with methyl substituent did not affect the reaction
mode of indol-2-yl phosphorane with the enone reagent.
In this respect, the phosphoranes 2a,b were consistent
with their benzothiophen-2-yl counterparts which,
irrespective of phenyl or methyl P-substituent, similarly
furnished only aza-Wittig–electrocyclization benzo-
thienopyridines in their reactions with enones.3a,3c,19 The
benzothiophen-3-yl phosphoranes, instead, were found to
exhibit a different trend since progressive replacement of
phenyl with methyl group(s) on phosphorus caused an in-
creasing propensity of the phosphorane itself for addition
to the enone carbonyl moiety by adopting the b-(a-thie-
nyl)carbon instead of the imino nitrogen; this fact then
caused progressive suppression of the b-fused pyridines
due to aza-Wittig–electrocyclization in favor of those due
to opposite regiochemistry.3a,b,19
R1
N
N
Me
R2
– 2 H
R1
N
N
Me
3a: R1 = R2 = H
3b: R1 = H, R2 = Me
3c: R1 = H, R2 = Ph
3d: R1 = Me, R2 = COOMe
3e: R1 = Me, R2 = H
Scheme 2 Synthesis of a-carbolines
Table 1 a-Carbolines 3a–e Prepared from Iminophosphoranes 2a,b
and Enones
Entry
Iminophos- Enone
phorane
Carboline
(yield, %)a
1
2
3
4
5
6
7
8
9
2a
2a
2a
2a
2a
2b
2b
2b
2b
R1 = R2 = H
3a (70)
3b (80)
3c (45)
3d (90)
3e (38)
3a (50)
3b (43)
3c (35)
3d (48)
R1 = H, R2 = Me
R1 = H, R2 = Ph
R1 = Me, R2 = COOMe
R1 = Me, R2 = H
R1 = R2 = H
R1 = H, R2 = Me
R1 = H, R2 = Ph
However, the present indolyl triphenylphosphorane 2a,
unlike the rather disappointing methyldiphenyl analogue
2b, proved to be superior to both previous phenyl/methyl-
substituted benzothiophen-2-yl and benzothiophen-3-yl
congeners as it was usually able to provide enhanced
amounts of (single) b-fused pyridines with the same un-
saturated aldehydes and ketones.
R1 = Me, R2 = COOMe
a Yields isolated by column chromatography.
The carboline 3a was a well-known compound which had
been prepared in several instances, but in modest to poor
yields, through multistep processes;17 the 4-methyl deriv-
ative 3b had been produced in poor yield by reaction of 2-
amino-1-methylindole with 3-buten-2-one;18 the 2-methyl
derivative 3e was very recently prepared in fairly good
yield by radical cyclization of the O-pentafluorobenzoyl
derivative of 4-(1-methyl-3-indolyl)butan-2-one oxime;14
the remaining two carbolines 3c,d were previously un-
known.
In conclusion, we have shown that the mild thermal reac-
tion of enones with the readily accessible 1-methylindol-
2-yl phosphoranes 2a,b can offer a novel synthesis of 9-
methyl-9H-pyrido[2,3-b]indoles 3, which is especially
appealing when using triphenylphosphorane 2a instead of
hardly stable methyldiphenylphosphorane 2b. The practi-
cal procedure is very simple since, at the end of the reac-
tion, the crude reaction mixture just requires evaporation
of the toluene solvent under reduced pressure and even-
tual chromatographic purification. It is presumable that
the present protocol might be of wide utility for the
Synlett 2006, No. 10, 1574–1576 © Thieme Stuttgart · New York

1576
C. Bonini et al.
LETTER
(15) Preparation of the 1-Methylindol-2-yl Phosphoranes
preparation of other variously substituted 9H-pyrido[2,3-
b]indole compounds from appropriate enones and simple
indole precursors. Studies are in progress to explore the
actual scope of our protocol.
2a,b.
2-Azido-1-methylindole (1), freshly obtained after filtration
through a Florisil® pad of the crude product from azido
transfer reaction of 1-methylindole (1 mmol) with tosyl
azide,4 was dissolved in dry Et2O (2 mL) and then slowly
added to an anhyd Et2O solution (2 mL) of PPh3 (1 mmol) at
0 °C under nitrogen. The reaction mixture was stirred at 0 °C
for ca. 1 h after which the separated solid material was
filtered off to give the triphenylphosphorane (2a, 0.7 mmol,
70%) as a dark-yellow powder, mp 90–92 °C. 1H NMR (300
MHz, CDCl3): d = 7.90–7.33 (m, 15 H), 7.20–7.15 (m, 1 H),
7.10–6.95 (m, 1 H), 6.90–6.80 (m, 2 H), 5.15 (s, 1 H), 3.87
(s, 3 H). 13C NMR (50 MHz, CDCl3): d = 149.5, 144.4,
137.0, 134.5, 132.4, 132.0, 131.1, 130.0, 129.3, 127.8,
127.0, 125.5, 125.0, 124.3, 121.5, 118.7, 117.5, 117.0,
114.0, 113.7, 111.0, 109.3, 39.0.
The methyldiphenylphosphorane (2b) was similarly pre-
pared in 55% yield by azidation of 1-methylindole (1 mmol)
followed by direct treatment with methyldiphenylphosphine
(1 mmol). The compound 2b was obtained as a viscous oil
which showed a tendency to decompose under work-up
conditions and was thus employed without purification.
1H NMR (300 MHz, CDCl3): d = 7.95–7.65 (m, 5 H), 7.58–
7.40 (m, 5 H), 7.21–7.18 (m, 1 H), 7.15–7.10 (m, 1 H), 6.90–
6.80 (m, 2 H), 5.20 (s, 1 H), 3.87 (s, 3 H), 2.23 (d, 3 H,
2JPH = 12.8 Hz). 13C NMR (50 MHz, CDCl3): d = 143.6,
141.0, 134.6, 133.0, 132.3, 131.6, 131.5, 130.7, 129.5,
129.2, 129.2, 128.2, 126.1, 125.9, 118.8, 117.0, 116.5,
107.5, 37.0, 14.88.
Acknowledgment
The authors gratefully acknowledge MIUR (Ministry of Instruction,
University and Research-Rome) for financial support (PRIN 2005),
the University of Bologna and the University of Basilicata.
References and Notes
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Synlett 2006, No. 10, 1574–1576 © Thieme Stuttgart · New York