Synthesis of heterocyclic compounds using radical reactions

Article abstract of DOI:10.1016/S0040-4039(02)01537-X

A generalised radical reaction has been used to synthesise heterocyclic compounds which could serve as ligands for drug discovery. Attempt also have been made to rationalise the formation of oxidation products formed during TBTH reaction.

Full text of DOI:10.1016/S0040-4039(02)01537-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6865–6868
Synthesis of heterocyclic compounds using radical reactions
A. K. Ganguly,a,* C. H. Wang,a M. David,a P. Bartnerb and T. M. Chanb
aStevens Institute of Technology, Hoboken, NJ 07030, USA
bSchering-Plough Research Institute, Kenilworth, NJ 07033-1300, USA
Received 4 June 2002; accepted 3 July 2002
Abstract—A generalised radical reaction has been used to synthesise heterocyclic compounds which could serve as ligands for drug
discovery. Attempt also have been made to rationalise the formation of oxidation products formed during TBTH reaction.
© 2002 Elsevier Science Ltd. All rights reserved.
We have investigated the following general reaction
(Scheme 1) and in this communication we wish to
disclose our preliminary results. Compound 1 on treat-
ment with tributyltin hydride (TBTH) generates radical
2, which then undergoes further reactions and depend-
ing upon the substituents R and R1 gives a number of
structurally different ligands which could possibly be
used in drug discovery.
Scheme 1.
Keywords: radical reactions; heterocyclic chemistry.
* Corresponding author. E-mail: akganguly1@aol.com
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01537-X

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A. K. Ganguly et al. / Tetrahedron Letters 43 (2002) 6865–6868
Several reactions of this kind are known in the litera-
ture.1–5 However in the present work we were interested
to synthesise compounds 3–8.
TBTH reaction. It has been speculated2 that this type
of conversion involves pseudo SRN1 mechanism. Thus,
the radical 16 undergoes rearrangement to 18 either by
direct endo cyclisation or through the intermediacy of
the exo cyclisation product, which rearranges rapidly to
the more stable radical 18. In the presence of TBTH
which acts both as a radical generator and a base, the
radical 18 is converted to the radical anion 19. Single
electron transfer of 19 yields 17 and 16 and the chain
reaction continues (Scheme 4).
Although the above structures are varied in nature but
they could all be derived from 2. Thus, bromoaniline 9
was converted to 11 and 12, as shown in Scheme 2.
Reaction of 11 in toluene solution with TBTH in the
presence of AIBN at 100°C for 2 h yielded compound
36 (25%).7
Similarly following the above condition compound 12
gave 4 as the major product (75%) and 5 as the minor
component (8%).
This mechanism intrigued us and we argued that if
compound 20 is treated with TBTH it should initially
yield the radical 21 which could then rearrange in two
different pathways to yield the radicals 21a and 21b. In
the presence of TBTH as a base, these radicals are
converted to the radical anions 23 and 22 which then
yield 25 and 24, respectively, following the steps out-
lined above. The radical 21b could be obtained as in the
case of 16 to 18, whereas 21a could arise from the
initial radical 26. It should be mentioned that we have
no evidence for the formation of 26 (Scheme 5).
Reaction of compound 12 to give 4 and 5 could be
rationalised, as shown in Scheme 3. Thus, the initial
radical 13 undergoes exo cyclisation followed by the
capture of the newly formed radical by hydride gives 5.
Compound 4 on the other hand is formed by the
rearrangement of 13 to the more stable radical 14
followed by exo cyclisation.
The reaction of 11 to yield 3 is more difficult to
rationalise, however, it should be noted that there are
several reports in the literature2 describing the forma-
tion of oxidation products during TBTH reactions. One
such reaction involves the conversion of 15 to 17 using
Thus, when 20 was treated with TBTH it indeed yielded
25 (50%) and 24 (23%). We explored further the above
radical reactions with compound 27 and obtained 25
(5%), 24 (27%) and 28 (54%). We did not detect the
Scheme 2.
Scheme 3.

A. K. Ganguly et al. / Tetrahedron Letters 43 (2002) 6865–6868
6867
Scheme 4.
Scheme 5.
formation of 29 in the above reaction. The origin of
these products is explained in Scheme 6. Once again the
formation of 25 and 28 could be explained as for the
conversion of 16 and 17 and the formation of 24 could
proceed via the formation of the initial radical 30.
the rearranged product. Presumably in this case the
intermediate spiro radical 33 is more stable and cap-
tures hydride radical before undergoing rearrangement
(Scheme 7).
Compound 32 shows the presence of two mutually
coupled vinyl hydrogens at l 5.3 and l 6.5 and a CH2
group at l 3.9 and l 3.4. In the CNMR spectrum the
quarternary spiro carbon appears at 62 ppm and CH2
appears at 41 ppm.
NMR spectra of 25, 24 and 28 indicate that Ha in these
compounds appear at l 9.7, l 8.3 and l 8.8, respec-
tively. Hd in 25 appears at l 8.1 and l 9.7 in 24,
whereas Hb appears at l 8.8 and l 7.5 in 24 and 28,
respectively. Hc in 25 appears at l 8.8 and at l 9.0 for
28. It should be noted that Ha and Hd are shifted
downfield in these compounds from their predicted
chemical shift positions in pyridine.
Acknowledgements
With the hope of quenching the intermediate spiro
radical before it underwent further rearrangement, we
investigated the radical reaction of 31 and obtained 32
(76%) and there was no evidence for the formation of
We would like to sincerely thank Schering-Plough
Research Institute, Kenilworth, NJ, for financial
support.

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Scheme 6.
4. Estevez, J. C.; Villaverde, M. C.; Estevez, R.; Castedo, L.
Tetrahedron Lett. 1991, 32, 529.
5. Sainsbury, M. Tetrahedron 1980, 36, 3327.
6. NMR and high-resolution mass spectra of all the com-
pounds described in this communication were consistent
with the assigned structures. Assignments of structures
were further confirmed using HMBC and NOE experi-
ments.
Scheme 7.
7. The percentages in parenthesis indicate yields. All the
compounds described in this paper were crystalline except-
ing compound 4 which was an oil. The melting points of
compounds 3, 5, 14, 25, 24, 28 and 32 were 133–135,
124–125, 96–98, 194–196, 197–199, 173–175 and 114–
115°C, respectively. Crystals were obtained from
dichloromethane and hexane.
References
1. Storey, J. M. D. Tetrahedron Lett. 2000, 41, 8173.
2. Bowman, W. R.; Heaney, H.; Jordan, B. Tetrahedron
1991, 47, 10119 and references cited therein.
3. Togo, H.; Kikuchi, O. Tetrahedron Lett. 1988, 29, 4133.