Synthesis of highly condensed heterocycles using radical reactions

Article abstract of DOI:10.1016/j.tetlet.2004.09.181

Using radical chemistry novel highly condensed heterocycles have been synthesized. The mechanism for their formation is discussed.

Full text of DOI:10.1016/j.tetlet.2004.09.181

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8909–8912
Synthesis of highly condensed heterocycles using radical reactions
A. K. Ganguly,a,* C. H. Wang,a J. Misiaszek,a T. M. Chan,b
B. N. Pramanikb and A. T. McPhailc
aStevens Institute of Technology, Hoboken, NJ 07030, USA
bSchering-Plough Research Institute, Kenilworth, NJ 07033-1300, USA
cP.M. Gross Chemical Laboratory, Duke University, Box 90346, Durham, NC 27708-0346, USA
Received 14 September 2004; accepted 27 September 2004
Available online 14 October 2004
Abstract—Using radical chemistry novel highly condensed heterocycles have been synthesized. The mechanism for their formation is
discussed.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
structure 7 wherein X is a heteroatom that is oxygen or
substituted nitrogen atoms. As will be evident these
reactions have provided us with a novel route for the
synthesis of highly condensed heterocycles such as 25
and 38.
In our search for novel heterocycles, which could serve
as pharmacophores in drug discovery, we have been
exploring radical chemistry1 to assemble these mole-
cules. Recently we have demonstrated2 that when com-
pounds such as 1 and 2 are treated with tributyl tin
hydride (TBTH) they yield 3 and 4, respectively. In a
separate paper3 we have discussed the details of the
assignments of stereochemistries of the syn and anti iso-
mers of compound 4. It should be noted that both 3 and
4 arise through the spiro radicals 5 and 6, respectively.
Thus reaction of 8 with TBTH gave mainly the dehalo-
genated product5 9 and a small amount of 10, which pre-
sumably is formed via 11 with the loss of carbon dioxide
(Scheme 1). A similar reaction was observed6 in the case
of phenyl sulfonamides wherein the biphenyls were
formed with the loss of sulfur dioxide.
Me
N
Me
Me
N
O
N
O
O
R
Br
N
O
S
S
S
1
5
3
X
Br
Me
N
Br Me
N
O
7
O
CH3
CH3
dimer
4
X= O or N R
H3C
H3C
2
6
2. Present work
We then investigated the radical reaction of compound
12 and obtained 13 (11.0%) and 14 (16.9%) along with
the starting material (45%).
In this communication we would like to report the
results of the radical reactions of compounds4 of general
The formation of 13 and 14 can be rationalized, as shown
in Scheme 2. Thus, the initial radical 15 undergoes spiro
cyclization to give the intermediate 16, which undergoes
further rearrangement, bond cleavage and subsequent
Keywords: Radical reactions; Heterocyclic chemistry.
*
Corresponding author. Tel.: +1 201 216 5540; fax: +1 201 216
8240; e-mail: akganguly1@aol.com
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.181

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A. K. Ganguly et al. / Tetrahedron Letters 45 (2004) 8909–8912
Me
N
O
O
Me
N
Me
N
9
O
O
Me
O
O
Me
NH
Br
N
O
8
O
11
10
Scheme 1.
Me
N
O
N
Me
O
N
Me
N
Me
N
Me
Me
N
Me
O
O
N
O
Path A
Path B
N
Me
N
Me
16a
N
Br
14
Me
Me
Me
16
O
12
15
O
N
N
N
Me
N
Me
H
13
Scheme 2.
oxidative cyclization (path A) to yield benzimidazole 14
via 16a, alternatively (path B) the intermediate 16 under-
goes bond migration followed by the loss of hydrogen
radical to yield 13. To study the effect in the above
radical reaction of an ortho substituent to the bromoan-
iline nitrogen we treated 17 in the usual way with
TBTH and obtained 18 (21.6%) and 19 (10.8%) along
with the dehalogenated compound 20 (32.4%). The for-
mation of 18 and 19 proceed through the spiro radical
21 as shown in Scheme 3. As suspected in this case we
did not detect the formation of the corresponding
benzimidazole.
lar sense. Thus when the diallyl derivative 22 was treated
with TBTH we obtained 23 (34%) by the cyclization of
radical 27 to the allyl group, along with 24 (7%), 25
(13%) and 26 (4.0%). Compounds 24, 25 and 26 are
formed through the intermediacy of the spiro radical
27a. The structure of 25 was confirmed using X-ray crys-
7
tallographicstudies (see Scheme 5).
We then studied the substitution effects in the above
reaction by changing R00 to Cl 28, OCH3 29 and
OCH2CH3 30. Interestingly radical reaction with 28
gave 31 (18.4%), 32 (39.8%), 33 (7.2%) and 34 (3.4%)
whereas 29 gave 35 (6.7%), 36 (36%), 37 (5.6%) and 38
(7.2%). Similarly 30 gave 39 (24.8%), 40 (39.6%), 41
(14.2%) and 42 (5.8%). The formation of 38 and 42 fol-
lows a cascade reaction as shown in Scheme 4.
As we intended in the present study to prepare highly
condensed heterocycles we explored the possibility of
capturing the radical intermediate 16 in an intramolecu-
F
Me
N
F
Me
N
F
Me
N
H
N
O
O
O
O
Me
F
N
N
Me
N Me
Me
N
F
Br
F
F
Me
F
17
21
18
F
Me
N
Me
F
O
O
Me
N
N
Me
N
F
F
20
19
Scheme 3.

A. K. Ganguly et al. / Tetrahedron Letters 45 (2004) 8909–8912
8911
R''
N
O
N
O
O
N
N
N
R'
Br
N
R'
N
O
R''
R'
R'
HN
R''
25: R'=R''=H
R''
24: R'=R''=H
23: R'= R''=H
32: R'=F, R''=Cl
22: R'= R''=H
33: R'=F, R''=Cl
37: R'=H, R''=OMe
41: R'=H, R''=OEt
28: R'=F, R''=Cl
29: R'=H, R''=OMe
30: R'=H, R''=OEt
31: R'=F, R''=Cl
36: R'=H, R''=OMe
40: R'=H, R''=OEt
35: R'=H, R''=OMe
39: R'=H, R''=OEt
O
N
N
O
N
N
R'
R'
R''
26: R'=R''=H
34: R'=F, R''=Cl
38: R'=H, R''=OMe
42: R'=H, R''=OEt
R''
N
O
N
O
N
O
N
N
N
R'
38
R'
R'
R''
R''
27
27a
R''
Scheme 4.
and 128.85, respectively, which shift in 38 to d 35.7
and 40.36, respectively. In compounds 25 and 38 C-11
appear at d 63.46 and d 63.86, respectively.
3. Conclusion
Using radical reaction we have synthesized several
highly condensed heterocycles. Although the yields
reported in this communication are not optimized,
sufficient amounts of the products described have
been made and these will be undergoing biological
testing.
Acknowledgements
We wish to sincerely thank Schering-Plough Research
Institute, Kenilworth, NJ for generous financial
assistance.
Scheme 5.
The numbering system used in this communication is
shown in Scheme 5. In the H NMR spectrum of 25
References and notes
1
the methyl group appears at d 1.23 (d), which is absent
in 38. Compound 38 shows H-19 at d 1.75 (m) and C-19
at d 34.66. H-9 and H-10 in structure 25 appear at d 5.9
and 5.7, respectively, which are absent in 38. In the 13C
NMR spectrum of 25 C-9 and C-10 appear at d 113.75
1. Ganguly, A. K.; Wang, C. H.; David, M.; Bartner, P.;
Chan, T. M. Tetrahedron Lett. 2002, 43, 6865, and
references cited therein.
2. Ganguly, A. K.; Wang, C. H.; Chan, T. M.; Ing, Y. H.;
Buevich, A. V. Tetrahedron Lett. 2004, 45, 883.

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A. K. Ganguly et al. / Tetrahedron Letters 45 (2004) 8909–8912
3. Ganguly, A. K.; Buevich, A. V.; Chan, T. M.; Wang, C. H.;
McPhail, A. T. J. Magn. Reson. Chem., submitted for
publication.
were 132–134, 104–106, 120–122, 160–162, 109–111, 80–82,
121–123, 105–107, 60–61 and 72–74°C, respectively. Yields
are indicated in parentheses.
4. NMR and high-resolution mass spectra of all the com-
pounds described in this paper were consistent with the
assigned structures. Assignments were further confirmed
using HMBC, HSQC and COSY experiments.
5. Excepting compounds 23, 24, 26, 28, 29, 30, 32, 33, 34, 35,
36, 37, 41 and 42, which were oil, all the other compounds
described in this paper were crystalline. Crystals were
obtained from dichloromethane and hexane. The melting
points of compounds 13, 14, 18, 19, 20, 25, 31, 38, 39 and 40
6. da Mata, M. L. E. N.; Motherwell, W. B.; Ujjainwalla, F.
Tetrahedron Lett. 1997, 38, 137.
7. Crystallographic data (excluding structure factors) for
compound 25 have been deposited with the Cambridge
CrystallographicData Centre as supplementary publication
number CCDC 250067. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road,
Cambridge, CB2 1EX, UK [e-mail: deposit@ccdc.cam.
ac.uk].