Vinyl isonitriles in radical cascade reactions: Formation of cyclopenta-fused pyridines and pyrazines

Article abstract of DOI:10.1039/a908630g

The formation of cyclopenta-fused pyridines and pyrazines were studied by using radical cascade reactions. The intramolecular addition to an aryl or vinyl isonitrile combined with intramolecular trapping of the intermediate imidoyl radical was also investigated for the synthesis of biologically active natural products. It was shown that the vinyl isonitriles were required substrates in 4 + 1 radical annulations with iodoalkynes and iodonitriles for the formation of cyclopenta-fused pyridines and pyrazines respectively.

Full text of DOI:10.1039/a908630g

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Vinyl isonitriles in radical cascade reactions:
formation of cyclopenta-fused pyridines and pyrazines
Isabelle Lenoir and Marie L. Smith*
1
The Centre for Chemical Synthesis, Department of Chemistry, Imperial College of Science,
Technology and Medicine, London, UK SW7 2AY
Received (in Cambridge, UK) 29th October 1999, Accepted 18th January 2000
The 4 ؉ 1 radical annulation reaction of vinyl isonitriles
with iodoalkynes or iodonitriles affording cyclopenta-fused
pyridines and pyrazines respectively and the first example
of an intramolecular radical addition to an aryl isonitrile
are described.
The application of tandem radical processes has proved to be
both an effective and efficient approach for the preparation of a
wide range of polycyclic molecules.1 Recently, isonitriles have
been utilized in tandem radical processes for the formation of a
number of heterocyclic moieties.2,3 Precursors to the antitumor
agent campthothecin and related natural products have been
prepared by such an approach.4 The 4 ϩ 1 radical annulation
strategy adopted, involving intermolecular addition to the iso-
nitrile and subsequent cyclisation, has, however, only been
described with aromatic isonitriles. Herein we describe our
efforts to further extend the scope of this methodology by util-
izing vinylic isonitriles in place of aryl isonitriles as well as
our initial investigations into the feasibility of tandem radical
reactions in which addition to an isonitrile occurs in the intra-
molecular sense.
Four vinyl isonitriles 1a–d were chosen for our study and
prepared via trifluoromethanesulfonic anhydride mediated
dehydration of the corresponding vinyl formamides in reason-
able yield (66, 87, 93, and 46% respectively).5 The vinyl form-
amides may themselves be readily prepared according to the
methods of Baldwin or Barton from the corresponding thio-
oxime or oxime.6,7 Vinyl isonitriles 1a–d were treated with
5-iodopentyne 2a at 150 ЊC and hexabutylditin (1.5 mmol) in
tert-butylbenzene under sunlamp irradiation for 48 hours.2,4 In
each case a tetrasubstituted pyridine was obtained via the
desired 4 ϩ 1 annulation (Scheme 1 and Table 1) in 46–72%
yield. Unfortunately, despite extensive studies we were unable
to significantly increase the yield of pyridine formation by vary-
ing solvent (benzene, toluene), radical source (hexamethylditin)
variation of reactant ratios, time and temperature. The form-
ation of intractable material suggests isonitrile polymerisation
is a competing pathway.
The likely mechanism for pyridine formation involves initial
addition of the alkyl radical 3 to the isonitrile carbon followed
by 5-exo ring closure of the imidoyl radical 4 onto the alkyne to
afford vinyl radical 5, Scheme 1. In theory radical 5 may cyclize
to either of two positions on the alkene, Scheme 1, via either a
6-endo or 5-exo ring closure and thence to products 6 or 7. With
each of the examples investigated only one pyridine product
was obtained. For isonitrile 1a (where R ≠ R1) with alkyne 2a
the product was identified by X-ray analysis as 6a† rather than
the alternative 7a thereby suggesting 6-endo closure as the
preferred route.
The scope of the methodology was expanded by the use of a
substituted iodoalkynes (namely 5-iodo-1-naphthylpent-1-yne
(Scheme 1, Table 1)) with vinyl isonitriles 1a and 1b which
afforded the desired products albeit in moderate yield. In
addition we have examined the use of iodonitrile 2c for the
formation of a cyclopenta-fused pyrazine in an analogous
manner.3 Pyrazine 6g was obtained in 66% yield with isonitrile
1a.
Scheme 1
In an attempt to further the utility of isonitriles in radical
cascade processes we are currently investigating intramolecular
radical addition to both vinyl and aryl isonitriles. Herein we
report the first example of intramolecular radical addition to an
aryl isonitrile and the subsequent intermolecular trapping
of the so formed imidoyl radical. Thus iodoisonitrile 8 was
prepared from 2,2Ј-dinitrobiphenyl. Treatment of 8 with tri-n-
butyltin hydride–AIBN resulted in the formation of phen-
anthridine 11 presumably via aryl and imidoyl radicals 9 and
10. Treatment of 8 with electron rich alkenes such as tert-
butyl vinyl ether with the slow addition of nBu3SnH–AIBN
resulted in the formation of 15 although phenanthridine 11
remained the major product. Not suprisingly this electron rich
alkene reacts more readily with the electron deficient imidoyl
radical than do more electron deficient alkenes and alkynes. No
trapping was observed with methyl propiolate and hex-1-ene
under identical conditions. Interestingly the use of a weaker
hydrogen atom donor tris(trimethylsilyl)silane with tert-butyl
vinyl ether resulted in increased addition of the imidoyl radical
to the enol ether although we now obtained a new product 16
which we believe to have resulted from rearrangement via 13
and 14. The driving force for the rearrangement is, however, not
DOI: 10.1039/a908630g
J. Chem. Soc., Perkin Trans. 1, 2000, 641–643
This journal is © The Royal Society of Chemistry 2000
641

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Table 1
Isonitrile
Alkyne or nitrile
Pyridine
Yield (%)
Scheme 2
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immediately obvious (Scheme 2). The intramolecular addition
to an aryl or vinyl isonitrile combined with intramolecular
trapping of the intermediate imidoyl radical is currently under
investigation for the synthesis of biologically active natural
products.
Vinyl isonitriles have rarely been utilised in synthetic applica-
tions.8,9 Herein we have demonstrated that vinyl isonitriles are
reasonable substrates in 4 ϩ 1 radical annulations with iodo-
alkynes and iodonitriles for the formation of cyclopenta-fused
pyridines and pyrazines respectively. Both of these moieties
constitute interesting pharmacophores for pharmaceuticals and
agrochemicals. Finally we have shown that the intramolecular
radical addition to isonitriles for the formation of 6-membered
rings is synthetically viable and our efforts to utilize this
methodology for the preparation of biologically active natural
products will be reported in due course.
likely by-product with vinyl isonitriles would be the corresponding
ketone.§ However, we were unable to detect any ketone from reactions
of 1a–d. Other possibilities include radical disproportionation.2 Dis-
proportionation of two molecules of 18 would give 6 plus a dihydro-
pyridine moiety 23 which may be air-oxidised to 6 on work-up. On one
occasion each with 6c and 6d we detected small amounts of a com-
1
pound whose H NMR and mass spectra were consistent with a dihy-
dropyridine moiety. Each compound was subsequently oxidised to the
corresponding pyridine on standing in air. It seems likely then that
radical disproportionation of 18 plays at least some part in the form-
ation of 6 from 18.
§ By analogy with the aryl isonitriles described in ref. 3(a) should vinyl
isonitrile act as oxidising agent it may be expected to lead to formation
of a ketone as indicated in eqn. (1).
Acknowledgements
We thank Professor A. G. M. Barrett for helpful discussions and
support, the Royal Society for a Dorothy Hodgkin fellowship
(to M. L. S.), Zeneca Agrochemicals for research funds and the
Wolfson Foundation for establishing the Wolfson Centre for
Organic Chemistry in Medical Science at Imperial College.
Notes and references
† For 1c and 1d H and 13C NMR spectra suggested the product was
(1)
1
most likely 6c and 6d respectively. For 1b it is not possible to distinguish
between the pathways since R = R1. 6-endo Ring closure (or alter-
natively a radical accelerated electrocyclisation reaction) forms six-
membered ring product 18 which is then ultimately converted to prod-
uct 6, path 2.‡ Pyridine 6 may also arise from 5-exo cyclisation of 5 to
1 See for example: C. K. Sha, F. K. Lee and C. J. Chang, J. Am. Chem.
Soc., 1999, 121, 9875; M. Kizil, B. Patro, O. Callaghan, J. A.
Murphy, H. B. Hursthouse and D. Hibbs, J. Org. Chem., 1999, 64,
7856; F. Belval, A. Fruchier, C. Chavis, J. L. Montero and M. Lucas,
J. Chem. Soc., Perkin Trans. 1, 1999, 697; S. R. Baker, K. I. Burton,
A. F. Parsons, J. F. Pons and M. Wilson, J. Chem. Soc., Perkin Trans.
1, 1999, 427, S. A. Hitchcock, S. J. Houldsworth, G. Pattenden, D. C.
Pryde and N. M. Thomson, J. Chem. Soc., Perkin Trans. 1., 1998,
3181.
2 D. P. Curran and H. Liu, J. Am. Chem. Soc., 1991, 113, 2127; I. Ryu,
N. Sonoda and D. P. Curran, Chem. Rev., 1996, 96, 177.
3 (a) C. M. Camaggi, R. Leardini, D. Nanni and G. Zanardi,
Tetrahedron, 1998, 54, 5587; (b) D. Nanni, P. Pareschi, C. Rizzoli,
P. Sgarabotto and A. Tundo, Tetrahedron, 1995, 51, 9045.
4 D. P. Curran, H. Liu, H. Josien and S.-B. Ko, Tetrahedron, 1996, 52,
11385; H. Josien, D. Bom and D. P. Curran, Bioorg. Med. Chem.
Lett., 1997, 24, 3189; H. Josien and D. P. Curran, Tetrahedron,
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5 J. E. Baldwin and I. A. O’Neil, Synlett, 1990, 603.
6 J. E. Baldwin, D. J. Aldous, C. Chan, L. M. Harwood, I. A. O’Neil
and J. M. Peach, Synlett, 1989, 9.
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A. E. A. Porter and S. Z. Zard, Tetrahedron Lett., 1988, 29, 3343.
8 For the application of vinyl isonitriles in Ugi 4-component
condensations see: T. A. Keating and R. W. Armstrong, J. Am.
Chem. Soc., 1996, 118, 2574.
9 For the use of alkyl isonitriles in synthesis see: G. Stork and P. M.
Sher, J. Am. Chem. Soc., 1983, 105, 6765.
10 P. Dowd and S.-C. Choi, Tetrahedron, 1989, 45, 77; A. L. J.
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11 M. Barbier, D. H. R. Barton, M. Devys and R. S. Topgi, J. Chem.
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form 17 followed by rearrangement, path 1c. Alternative product 7 may
arise from rearrangement of 17 to 22 via either 19, path 1a or 20, path
1b. With each of the isonitriles 1a–d investigated only one pyridine
product was obtained. The type of ring expansion depicted in paths 1b
and 1c is well precedented for simple β-multiply bonded alkyl rad-
icals2,10 but has rarely been observed for allyl or dienyl radicals.11 For
aryl isonitriles, at least, some experimental evidence exists to suggest
that path 1c is not operable12 and semiempiral calculations3a suggest it
is likely to be less favourable than a path 2 type process. We therefore
believe that path 2 is likely to be the dominant pathway for the conver-
sion of 1 to 6.
‡ It is necessary to invoke an oxidation step to form 6 from 18. The
formation of aromatised products from dihydroaryl radicals under
reductive conditions is not uncommon13 but as with the aryl isonitriles
the oxidant is not immediately obvious. Some evidence exists for the
isonitrile itself acting as an oxidising agent.3a Should this be the case a
12 R. Leardini, D. Nanni, G. F. Pedulli, A. Tundo and G. Zanardi,
J. Chem. Soc., Perkin Trans. 1, 1986, 1591.
13 W. R. Bowman, H. Heaney and B. M. Jordan, Tetrahedron, 1991, 47,
10119; D. Crich and J.-H. Hwang, J. Org. Chem., 1998, 63, 2765.
Communication a908630g
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