A new protecting-group strategy for indoles

Article abstract of DOI:10.1016/S0040-4039(01)02047-0

The 2-phenylsulfonylethyl group is a useful alkyl protecting group for nitrogen during indole synthesis; it is readily removed from the indole nitrogen under basic conditions.

Full text of DOI:10.1016/S0040-4039(01)02047-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 135–137
A new protecting-group strategy for indoles
Katherine E. Bashford,a Anthony L. Cooper,b Peter D. Kaneb and Christopher J. Moodya,*
aSchool of Chemistry, University of Exeter, Stocker Road, Exeter EX4 4QD, UK
bTripos Receptor Research Ltd., Bude-Stratton Business Park, Bude, Cornwall EX23 8LY, UK
Received 20 September 2001; accepted 26 October 2001
Abstract—The 2-phenylsulfonylethyl group is a useful alkyl protecting group for nitrogen during indole synthesis; it is readily
removed from the indole nitrogen under basic conditions. © 2001 Elsevier Science Ltd. All rights reserved.
The wide-ranging biological activity associated with
many indole derivatives, both naturally occurring and
synthetic, ensures that the synthesis of this important
ring system remains a topic of current interest.1,2
Although many synthetic routes to indoles lead directly
to N-unsubstituted derivatives, many also lead to N-
substituted or -protected indoles, and whereas protect-
ing group strategies for basic nitrogen atoms are well
worked out,3,4 the choice of suitable protecting groups
for non-basic heterocyclic NH groups is more problem-
atic. Electron-withdrawing carbonyl or sulfonyl based
protecting groups, although easy to remove, often
markedly affect the reactions leading to, and the reac-
tivity of, the heterocyclic ring, and therefore one usu-
ally has to resort to alkyl-based groups, which are often
less easy to remove.5
methodology, we required an alkyl protecting group
that functioned as a simple N-alkylaniline but was
readily removable following the conversion of the ani-
line into the corresponding indole. Since indole is a
much better leaving group than aniline in a 1,2-elimina-
tion reaction, as reflected in the difference of ca. 15 in
their pKa values, it seemed that a protecting group that
could be removed in a base-mediated elimination reac-
tion would be suitable. Therefore, a retro-Michael strat-
egy involving a CH2CH2Z group (Z=SO2R, CO2R)
was considered (Scheme 1). Although there are reports
of the 2-arenesulfonylethyl group being used as a pro-
tecting group for the NH group of other heterocyclic
rings,7–9 and also for amides, carbamates and b-lac-
tams,10 it has apparently not been used for indoles. We
now report the use of this alkyl protecting group for
nitrogen during indole synthesis, its facile introduction
into preformed indoles, and its base-mediated removal.
We recently encountered this exact problem in our
modified version of the Bischler indole synthesis.6
Whereas N-methylanilines were readily converted into
N-methylindoles by dirhodium(II) acetate catalysed
reaction with diazoketones to give a-(N-aryl-
amino)ketones followed by cyclisation, the correspond-
ing sequence with N-acetyl- or -tosyl anilines was
unsatisfactory, and hence N-unsubstituted indoles
could not be obtained. Therefore, in order to extend the
The starting N-alkylanilines 1 were readily prepared by
reaction of the corresponding anilines with commer-
cially available phenyl vinyl sulfone and treated with
methyl 2-diazo-3-oxo-butanoate or -pentanoate in boil-
ing chloroform in the presence of dirhodium(II) acetate.
This resulted in NꢀH insertion reaction of the interme-
Scheme 1. –CH2CH2Z group stable to base when attached to aniline (pKaꢀ31) but labile to base when attached to indole
(pKaꢀ16).
* Corresponding author.
0040-4039/02/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02047-0

136
K. E. Bashford et al. / Tetrahedron Letters 43 (2002) 135–137
Scheme 2.
Table 1. Synthesis of N-(2-phenylsulfonylethyl)indoles
Entry
X
1 Yield (%)
R3
2 Yield (%)a
3
X
3 Yield (%)
1
2
3
4
5
6
7
4-Me
–
4-MeO
2-Me
2-MeO
4-Br
99
–
Me
Et
62
63
78
73
90
36
63
a
b
c
d
e
f
5-Me
5-Me
5-MeO
7-Me
7-MeO
5-Br
71
66
49
51
48
79
30
68
68
74
17
75
Me
Me
Me
Me
Me
3-MeO
g
h
4-MeO (6%)
6-MeO (24%)
a Compounds not characterised; yields refer to partially purified material.
diate rhodium carbene, and gave the N-arylamino
ketones 2 in reasonable yield. The intermediate N-aryl-
amino ketones 2 were not completely purified, but were
cyclised by treatment with acidic ion-exchange resin
Amberlyst 15® in toluene to give the required indoles 3
(Scheme 2, Table 1).11
The base mediated deprotection of the 1-alkylindoles 3
was first investigated with the 1-(2-phenylsulfonylethyl)
derivative 3a, the most suitable conditions being potas-
sium tert-butoxide in DMF (Table 2). These conditions
were applied to a range of indoles 3, and resulted in
deprotection to give the N-unsubstituted compounds 4
in variable yield (Table 2).
Scheme 3.
Acknowledgements
We thank the EPSRC and Tripos Receptor Research
Ltd. for a CASE award (to K.E.B.), Dr. Elizabeth
Swann for helpful discussions, and the EPSRC Mass
Spectrometry Service at Swansea for mass spectra.
Finally, the use of the 2-phenylsulfonylethyl protecting
group on preformed indoles was briefly investigated.
The group was readily introduced by reaction of the
indole with 2-chloroethyl phenyl sulfone in DMF using
sodium hydride as base, and removed using potassium
tert-butoxide in DMF (Scheme 3).
Table 2. Deprotection of N-(2-phenylsulfonylethyl)indoles
References
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3
a
X
R3
Conditions
Yield (%)
5-Me
Me
t-BuOK, DMF/DBN
Et3N, DMF/DBU
Et3N, DMF
DBN, toluene
t-BuOK, DMF
t-BuOK, DMF
87
59
42
27
55
34
b
e
h
5-Me
7-MeO
6-MeO
Et
Me
Me

K. E. Bashford et al. / Tetrahedron Letters 43 (2002) 135–137
137
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11. Typical experimental procedure: A solution of 1 (1.25
mmol), diazo compound (2.50 mmol, 2 equiv.) and
dirhodium(II) acetate (10 mg) in distilled chloroform (10
ml) was heated at reflux for 1.5 h. The reaction mixture
was concentrated in vacuo and passed through a silica gel
column eluting with ethyl acetate–light petroleum (1:9) to
give the intermediate 2, which was dissolved in toluene (3
ml) and heated under reflux overnight in the presence of
Amberlyst 15® (110 mg). The reaction mixture was
filtered, concentrated in vacuo and purified on silica gel
eluting with ethyl acetate–light petroleum (1:9) to give the
indole 3.
.