Radical dearomatising spirocyclisations onto the C-2 position of benzofuran and indole

Article abstract of DOI:10.1016/j.tetlet.2004.09.148

New spirolactams were obtained in radical dearomatising spirocyclisations of alkyl, vinyl and aryl radicals tethered at the C-2 positions of benzofuran and indole. Spirolactams were obtained via an intramolecular radical ipso-type spirocyclisation in benzofuran and indole systems. Alkyl, vinyl and aryl radicals, tethered at the C-2 position of the heterocycle underwent radical cyclisation to produce novel tricyclic partially dearomatised heterocycles in moderate yields. Fragmentation of the furan ring was observed subsequent to spirocyclisation of a vinyl radical onto a benzofuran.

Full text of DOI:10.1016/j.tetlet.2004.09.148

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8931–8934
Radical dearomatising spirocyclisations onto the
C-2 position of benzofuran and indole
Afua S. Kyei, Kirill Tchabanenko, Jack E. Baldwin* and Robert M. Adlington
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK
Received 19 August 2004; revised 13 September 2004; accepted 21 September 2004
Abstract—Spirolactams were obtained via an intramolecular radical ipso-type spirocyclisation in benzofuran and indole systems.
Alkyl, vinyl and aryl radicals, tethered at the C-2 position of the heterocycle underwent radical cyclisation to produce novel tricyclic
partially dearomatised heterocycles in moderate yields. Fragmentation of the furan ring was observed subsequent to spirocyclisation
of a vinyl radical onto a benzofuran.
Ó 2004 Elsevier Ltd. All rights reserved.
A spirocyclic fragment consisting of two fused five-
membered saturated heterocycles appears in many natu-
rally occurring compounds. Marine amathaspiramides1
1 and pseudoindoxyl alkaloids2 2 of plant origin are
potent antiviral agents that display promising anticancer
properties. Due to their biological activity and complex
structure, spirocycles represent challenging synthetic
targets thus prompting development of better ways for
such quaternary centre generation. In this context we
decided to explore radical dearomatising spirocyclisa-
tions onto benzofuran and indole nuclei as outlined in
Scheme 1.
Radical ipso-type substitution onto aryl rings is well
precedented and usually proceeds with rearomatisa-
tion.3 One of the first examples of a radical spirocyclisa-
tion, which resulted in a dearomatised spirocycle was
reported by Zard and co-workers.4 Parsons et al.5 have
Br
OMe
O
MeO
H
N
N
Br
H
OH
N
N
MeO
OMe
Mytraginine pseudoindoxyl 2
O
O
Amathaspiramide A 1
H
source
5 - exo
N
X
N
N
X
X
R
O
R
R
O
O
3
X = O, NMe
R = Alkyl
Scheme 1.
Keywords: Alkyl radical; Vinyl radical; Aryl radical; Spirocyclisation; Benzofuran; Indole; Spirocycle.
*
Corresponding author. Tel.: +44 (0) 1865 275 671; fax: +44 (0) 1865 275 670; e-mail: jack.baldwin@chem.ox.ac.uk
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.148

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A. S. Kyei et al. / Tetrahedron Letters 45 (2004) 8931–8934
demonstrated vinyl radical ipso-type substitutions on
furan, which proceeded with subsequent fragmentation
of the dearomatised heterocycle, and this strategy was
applied in synthesis by Pattenden.6 Jones et al. have
studied aryl radical spirocyclisations onto pyrroles7
and the C-3 position of indoles,8 which produced spiro-
cycles in moderate to good yields. However no system-
atic study of the radical ipso-type spirocyclisation on
heterocycles generating novel partially or fully dearoma-
tised spirocycles has been presented to date. It is our aim
to establish the scope and limitation of such a process
and the initial findings on additions of aryl, vinyl and
alkyl radicals onto the C-2 position of benzofuran and
indole are presented in this letter.
Our choice of the models for the initial investigation
was based on the prediction that the intermediate
radical 3 (Scheme 1) will receive extra stabilisation via
O
O
i, ii
O
N
iii
R
X
X
X
OH
NH
Br
Br
X = O, NMe
4a : X = O, R = Me 98%
4b : X = O, R = Bn quant.
iv
5
: X = NMe, R = Me 95%
N
R
X
O
6a : X = O, R = Me 80%
6b : X = O, R = Bn 88%
7
: X = NMe, R = Me 89%
Scheme 2. Reagents: (i) (COCl)2, DCM; (ii) 2-bromoaniline, Et3N, DCM 92–98% for two steps; (iii) NaH, DMF, then MeI or BnBr; (iv) Bu3SnH,
AIBN, benzene, reflux, then PhSH.
O
N
i, ii
O
iii
O
X
X
X
Bn
Br
NH
OH
Bn
X = O, NMe
8 : X = O 50%
9 : X = NMe 32%
iv
9
N
N
Bn
N
O
10 : 41%
iv
8
N
Bn
Bn
Bn
O
O
O
O
Bn
O
12
11
HSnBu3
HSnBu3
N
N
O
Bn
O
O
13
SnBu3
OH
OSnBu3
PhSH
N
N
Bn
O
O
14
15 : 46%
Scheme 3. Reagents: (i) (COCl)2, DCM; (ii) benzylamine, Et3N, DCM, quant. for two steps; (iii) NaH, DMF, then 2,3-dibromo-1-propene; (iv)
Bu3SnH, AIBN, benzene, reflux, then PhSH.

A. S. Kyei et al. / Tetrahedron Letters 45 (2004) 8931–8934
8933
O
N
O
N
O
i, ii
iv
X
R
X
X
OH
X = O, NMe
PhSe
15 : X = O 80%
16 : X = NMe 83%
R = OH
R = Cl
iii
v
O
N
+
N
X
X
O
X = O
X = NMe
17 : 48%
18 : 49%
19 : 37%
20 : 33%
Scheme 4. Reagents: (i) (COCl)2, DCM; (ii) 2-(methylamino)ethanol, Et3N, DCM, quant. for two steps; (iii) MsCl, Et3N, DCM, 80–85%; (iv)
(PhSe)2, NaBH4, EtOH, reflux (see Ref. 11); (v) Bu3SnH, AIBN, benzene, reflux.
conjugation with the adjacent aryl ring and will not
undergo unwanted fragmentation prior to the hydrogen
transfer step.
17 and 18, respectively. The yields of isolated spirocy-
cles10 were similar to the vinyl radical addition cases
but significant amounts of reduced starting materials
19 and 20 were isolated in this case.
At first we investigated the cyclisations of the higher
energy aryl radicals. Radical cyclisation precursors
4a,b and 5 were prepared as shown in Scheme 2. To
our delight, when these were subjected to standard radi-
cal cyclisation conditions,9 the spirocycles 6a,b and 7
were formed in excellent yields with only traces of
reduced materials detectable by the 1H NMR of the
crude reaction mixture (Scheme 2).
In summary, we have investigated alkyl, vinyl and aryl
radical dearomatising spirocyclisations onto the C-2
position of benzofuran and indole. Additions of tethered
aryl radicals proceeded in near quantitative yields while
vinyl and alkyl radical cyclisations provided novel spiro-
cycles in moderate yields. Addition of a vinyl radical to
benzofuran proceeded with fragmentation due to instabi-
lity of the intermediate radical.
Next, we set out to investigate vinyl radical additions
and the cyclisation precursors 8 and 9 were prepared
via alkylation of secondary benzyl amides with 2,3-di-
bromo-1-propene as indicated in Scheme 3.
Acknowledgements
We would like to acknowledge the NMR staff of the
Chemistry Research Laboratory, especially Dr. Barbara
OÕDell for her help with establishing product structures.
Also, we are grateful to Dr. Jeremy Robertson for dis-
cussions and suggestions.
Under the radical cyclisation conditions, the indole
derivative 9 was converted into the spirocycle 10 while
the benzofuran derivative 8 underwent spirocyclisation
followed by a reductive fragmentation to 15. Our mech-
anistic proposal for the rearrangement is outlined in
Scheme 3. The spirocyclic radical 11 undergoes fragment-
ation with formation of a more stable phenoxy radical
12. Reduction of the quinone resonance form 13 by tribut-
yltin hydride results in the oxystannane 14, which is
hydrolysed to the phenol 15 on work up. The different
outcome of the two reactions is mostly attributed to
the greater stabilisation of the intermediate spirocyclic
radical by the lone pair of nitrogen in the indole case.
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lower in this case compared to the aryl radical additions,
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selenides underwent spirocyclisation forming spirocycles

8934
A. S. Kyei et al. / Tetrahedron Letters 45 (2004) 8931–8934
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9. The typical radical cyclisation conditions as in the
experimental procedure for spirocycle (6a). To a stirred
solution of aryl bromide (4a) (200mg, 0.6mmol) and
AIBN (12mg, 0.07mmol) in degassed benzene (25mL) at
reflux was added a solution of tributyltin hydride (178lL,
0.66mmol) and AIBN (6mg, 0.04mmol) in degassed
benzene (10mL) over a period of 4h via a syringe pump.
After 9h of further reflux the solvent was removed in
vacuo, thiophenol (62lL, 0.66mmol) was added and the
resulting mixture was purified by column chromatography
(P.E.30-40:EtOAc;2:1) to give the product (121mg, 80%)
as a pale yellow oil. kmax (film) cmÀ1 1653; dH (500MHz,
CDCl3) 7.42 (1H, t, J 7.5), 7.34 (1H, d, J 7.0), 7.31(1H, d,
J 7.5), 7.24 (1H, d, J 7.0), 7.11 (1H, t, J 7.0), 7.01(1H, dd,
J 7.5, 7.0), 6.92 (2H, m), 3.78 (1H, d, J 15.5), 3.50 (1H, d, J
15.5), 3.30 (3H, s); dC (100MHz, CDCl3) 174.9, 158.9,
143.5, 133.9, 130.6, 129.9, 129.6, 128.9, 126.6, 124.9, 123.7,
122.3, 109.9, 85.1, 39.1, 26.4; m/z (CI+) 252 (MH+, 59%),
234 (12), 224 (8); HRMS found 252.1031 (MH+);
C16H14NO2 requires 252.1025.
10. The use of alkyl selenides for the radical cyclisations had
an extra advantage. Thiophenol was not required in the
workup as the byproduct tributyltin phenylselenide was
easily separable by column chromatography.
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