First radical addition onto ketenimines: A novel synthesis of indoles

Article abstract of DOI:10.1016/S0040-4039(03)00562-8

A novel radical-mediated synthesis of 2-alkyl indoles is described. The method is a nonchain process based on the intramolecular addition of benzylic radicals onto the central carbon atom of a ketenimine function, resulting in a 5-exo-dig cyclization.

Full text of DOI:10.1016/S0040-4039(03)00562-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3027–3030
First radical addition onto ketenimines: a novel synthesis of
indoles
Mateo Alajarin, Angel Vidal* and Maria-Mar Ortin
Departamento de Quimica Organica, Facultad de Quimica, Universidad de Murcia, Campus de Espinardo, Espinardo 30071,
Murcia, Spain
Received 18 February 2003; accepted 27 February 2003
Abstract—A novel radical-mediated synthesis of 2-alkyl indoles is described. The method is a nonchain process based on the
intramolecular addition of benzylic radicals onto the central carbon atom of a ketenimine function, resulting in a 5-exo-dig
cyclization. © 2003 Elsevier Science Ltd. All rights reserved.
The intramolecular cyclization by addition of carbon
centered free-radicals to carbonꢀcarbon or car-
bonꢀheteroatom multiple bonds has become a very
useful and standard strategy for the construction of
complex carbocyclic and heterocyclic compounds, in
the growing field of the modern synthetic radical
chemistry.1
Amongst all the common functionalities for producing
carbon-centered radicals we selected the xanthate
group. In the last few years Zard has nicely shown that
xanthates behave as clean and efficient sources of car-
bon radicals.9 Furthermore, the xanthate group is com-
patible with our methodology for the preparation of
ketenimines, via aza-Wittig reaction of phosphazenes
and ketenes,2–5 and ketenimines should not be altered
under the reaction conditions generally applied to con-
vert xanthates into radicals.
Over the past several years, we have been involved in
the study of the reactivity of ketenimines. In our hands,
these heterocumulenes were particularly useful in the
synthesis of nitrogen-containing heterocycles through
their participation in electrocyclic ring closures,2
intramolecular [2+2]3 and [4+2]4 cycloadditions, and
imino-ene type reactions.5 We have now focused our
attention on the development of radical processes
involving ketenimines as substrates. To the best of our
knowledge, no inter- or intramolecular free radical
addition to ketenimines has been reported. Moreover,
the free radical chemistry of heterocumulenes is practi-
cally unknown,6 with the exception of that of ketenes
which is being currently investigated by Tidwell.7
Ketenimines 4 were specifically designed for generating
benzylic radicals which could undergo intramolecular
5-exo-dig cyclization onto the central carbon atom of
the ketenimine function. The presence of phenyl groups
at the terminal carbon atom of the ketenimine is aimed
to favor the cyclization by conferring stability to the
resulting radicals. Compounds 4 were readily obtained
in high overall yields from 2-azidobenzylbromides or
chlorides 110 in three steps, namely by (i) substitution of
the bromine or chlorine atom by the xanthate group
using the commercially available xanthate salt
KSC(S)OEt, (ii) reaction of the azide function in xan-
thates 2 with triphenylphosphane and (iii) treatment of
the resulting triphenylphosphazenes 3 with methyl
phenyl ketene or diphenyl ketene (Scheme 1).
We present here the intramolecular addition of benzylic
radicals, generated from xanthates, onto a ketenimine
function with its N atom linked to the ortho position of
the aromatic ring. These radical cyclizations represent a
new protocol for the synthesis of indoles.8
Radical cyclization of ketenimines 4 was explored
under different conditions. The addition, in small por-
tions, of a stoichiometric amount of benzoyl peroxide
as radical initiator to a solution of ketenimine 4c (0.01
M) in boiling benzene did not proceed at all leaving 4c
unaltered. However, the reaction initiated by lauroyl
peroxide and conducted in refluxing cyclohexane pro-
Keywords: cyclization; indoles; ketenimines; radical reactions.
* Corresponding author. Tel.: +34 968 367418; fax: +34 968 364149;
e-mail: vidal@um.es
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00562-8

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M. Alajarin et al. / Tetrahedron Letters 44 (2003) 3027–3030
duced the indole 6a, which incorporated the lauroyloxy
fragment, in 38% yield, along with a small amount (4%)
of the reduced indole 5c. The 2-(methoxy-
diphenyl)methylindole 6b (R5=CH3) was obtained in
43% yield when lauroyl peroxide was used as initiator
and a mixture of methanol/1,2-dichloroethane (1:3; v/v)
as solvent.11 When a stoichiometric amount of t-butyl
peroxide was portionwise added to a solution of com-
pound 4c (0.01 M) in boiling chlorobenzene 5-chloro-2-
diphenylmethylindole 5c was obtained in 60% yield, as
the only product which could be isolated. Cyclization
of ketenimines 4a,b,d–h under the same reaction condi-
tions furnished further examples of 2-substituted
indoles 5 in moderate yields (Table 1).12
A reasonable mechanism for explaining the conversions
4“5/6 is shown in Scheme 2. The thermal decomposi-
Scheme 1. Reagents and conditions: (i) KSC(S)OEt, acetone,
rt, 1 h; (ii) PPh3, diethyl ether, rt, 6 h; (iii) PhR4CꢁCꢁO,
dichloromethane, rt, 30 min; (iv) lauroyl peroxide (1.5 equiv.),
cyclohexane, reflux, 30 h, to give 6a; (v) lauroyl peroxide (1.2
equiv.), methanol/1,2-dichloroethane, reflux, 24 h, to give 6b;
(vi) t-butyl peroxide (1.2 equiv.), chlorobenzene, reflux, 24 h.
Scheme 2. Proposed mechanism for the conversions 4“5/6.
Table 1. 2-Substituted indoles 5 from ketenimines 4
’
tion of the peroxide initiator produces radical (R0) ,
which exchanges the xanthate group with ketenimines 4
giving rise to the expected benzylic radicals 12. The
intermediate species 12 undergo a 5-exo addition of the
radical moiety onto the central carbon of the keten-
imine function, followed by a prototropic imine–enam-
ine equilibrium favoring the indole form 14. The
stabilized tertiary radicals 14 did not react with a new
molecule of 4 to sustain the radical chain sequence.13
Instead they underwent reduction to give indoles 5, or
electron transfer to the lauroyl peroxide to furnish
Compd
R1
R2
R3
R4
Yield (%)
5a
5b
5c
5d
5e
5f
H
H
H
H
H
NO2
H
H
H
H
H
H
CH3
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
CH3
50
24
60
47
64
60
52
44
Br
Cl
CH3
H
H
5g
5h
C6H4
H
H
H

M. Alajarin et al. / Tetrahedron Letters 44 (2003) 3027–3030
3029
carbocations 15, which finally were quenched by the
carboxylate anion generated in the redox process (to
furnish 6a)14 or the methanol used as solvent (to furnish
6b).14b
1996, 37, 8945–8948; (b) Alajarin, M.; Molina, P.; Vidal,
A.; Tovar, F. Tetrahedron 1997, 53, 13449–13472; (c)
Alajarin, M.; Vidal, A.; Tovar, F.; Arrieta, A.; Lecea, B.;
Cossio, F. P. Chem. Eur. J. 1999, 5, 1106–1117; (d)
Cossio, F. P.; Arrieta, A.; Lecea, B.; Alajarin, M.; Vidal,
A.; Tovar, F. J. Org. Chem. 2000, 65, 3633–3643; (e)
Alajarin, M.; Vidal, A.; Tovar, F.; Ramirez de Arellano,
M. C.; Cossio, F. P.; Arrieta, A.; Lecea, B. J. Org. Chem.
2000, 65, 7512–7515.
The conversion 4“5 is a reductive process and the
source of the hydrogen atom that quenched the radical
14 is not obvious.15 We reasoned that the yield of the
reaction might be improved by addition to the reaction
mixture of hydrogen donors, but many of them are
incompatible with the ketenimine function. Addition of
1,4-cyclohexadiene to one of the initial reaction mix-
tures led to a cleaner reaction, but the yield of the
corresponding indole 5 did not improve.
4. (a) Alajarin, M.; Vidal, A.; Tovar, F.; Conesa, C. Tetra-
hedron Lett. 1999, 40, 6127–6130; (b) Alajarin, M.; Vidal,
A.; Tovar, F. Tetrahedron Lett. 2000, 41, 7029–7032; (c)
Alajarin, M.; Vidal, A.; Ortin, M.-M. Synthesis 2002,
2393–2398.
5. Alajarin, M.; Vidal, A.; Tovar, F.; Sanchez-Andrada, P.
Tetrahedron Lett. 2002, 43, 6259–6261.
Attempts of trapping intermolecularly the benzylic rad-
ical 12 by carrying out the radical cyclization of keten-
imines 4 in the presence of an excess of allyl acetate or
benzyl acrylate failed, proving that the intramolecular
cyclization is a more favorable path due to the great
stability of the triarylmethyl-type radicals 13 and 14.
6. To our knowledge no examples of radical reactions
involving carbodiimides or isocyanates have been
reported. For examples of radical addition to isothio-
cyanates, see: (a) Barton, D. H. R.; Jaszberenyi, J. Cs.;
Theodorakis, E. A. Tetrahedron 1992, 48, 2613–2626; (b)
Bachi, M. D.; Denenmark, D. J. Org. Chem. 1990, 55,
3442–3444; (c) Bachi, M. D.; Bar-Ner, N.; Melman, A. J.
Org. Chem. 1996, 61, 7116–7124; (d) Benati, L.; Leardini,
R.; Minozzi, M.; Nanni, D.; Spagnolo, P.; Zanardi, G. J.
Org. Chem. 2000, 65, 8669–8674.
7. (a) Sung, K.; Tidwell, T. T. J. Org. Chem. 1998, 63,
9690–9697; (b) Allen, A. D.; Cheng, B.; Fenwick, M. H.;
Huang, W.; Missiha, S.; Tahmassebi, D.; Tidwell, T. T.
Org. Lett. 1999, 1, 693–696; (c) Huang, W.; Henry-Riyad,
H.; Tidwell, T. T. J. Am. Chem. Soc. 1999, 121, 3939–
3943; (d) Allen, A. D.; Cheng, B.; Fenwick, M. H.;
Givehchi, B.; Henry-Riyad, H.; Nikolaev, V. A.;
Shikhova, E. A.; Tahmassebi, D.; Tidwell, T. T.; Wang,
S. J. Org. Chem. 2001, 66, 2611–2617; (e) Allen, A. D.;
Fenwick, M. H.; Henry-Riyad, H.; Tidwell, T. T. J. Org.
Chem. 2001, 66, 5759–5765; (f) Allen, A. D.; Porter, J.;
Tahmassebi, D.; Tidwell, T. T. J. Org. Chem. 2001, 66,
7420–7426; (g) Tidwell, T. T.; Fenwick, M. H. Eur. J.
Org. Chem. 2001, 3415–3419.
In conclusion, we have shown how ketenimines react
with free carbon-centered radicals in an intramolecular
process providing a new radical tin-free route to
indoles. Extension of this radical cyclization onto
ketenimines to a variety of carbon- and nitrogen-cen-
tered radicals is currently under investigation.
Acknowledgements
This work was supported by the MCYT and FEDER
(Project BQU2001-0010), and Fundacion Seneca-
CARM (Project PI-1/00749/FS/01). One of us (M.-M.
O.) thanks the Fundacion Seneca-CARM for
fellowship.
a
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M. Alajarin et al. / Tetrahedron Letters 44 (2003) 3027–3030
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5-Chloro-2-diphenylmethylindole (5c): yield 60%; IR
(Nujol) 3417, 1600, 1575, 1309, 1218, 1137, 1061, 919,