Synthesis of heterocyclic compounds using radical reactions and evidence for the formation of spiro radical intermediates

Article abstract of DOI:10.1016/j.tetlet.2003.10.204

Synthesis of novel heterocycles using radical reactions have been described. Reaction mechanism of their formation is also presented.

Full text of DOI:10.1016/j.tetlet.2003.10.204

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 883–886
Synthesis of heterocyclic compounds using radical reactions and
evidence for the formation of spiro radical intermediates
A. K. Ganguly,a,* C. H. Wang,a T. M. Chan,b Y. H. Ingb and A. V. Buevichb
aStevens Institute of Technology, Hoboken, NJ 07030, USA
bSchering-Plough Research Institute, Kenilworth, NJ 07033-1300, USA
Received 29 September 2003; accepted 15 October 2003
Abstract—Synthesis of novel heterocycles using radical reactions have been described. Reaction mechanism of their formation is
also presented.
Ó 2003 Elsevier Ltd. All rights reserved.
In a recent publication1 we have shown, for example,
that compound 1 when treated with tributyl tin hydride
(TBTH) yields 2, 3, and 4. Presumably they are for-
med1–3 through the intermediacy of radicals 5 and 6.
However in our earlier studies we were unable to capture
the spiro radical derived products. We then investigated1
the radical reaction with the thiophene carboxyamide 7
and obtained exclusively compound 8 suggesting that
the intermediate spiro radical 9 was more stable than 6.
Intrigued by this observation we decided to extend our
studies with the following general structures 10 wherein
x ¼ –CH@CH–, –S–, –O–, or –N–R and in this com-
munication we wish to report our results. It should be
Me
N
O
A
Me
N
Br
B
N
O
O
N
1
Me
N
Me
2
Me
N
O
N
O
Me
N
O
N
4
6
5
N
N
3
N
Me
Me
Me
O
N
N
N
O
O
Br
S
S
9
S
7
8
Keywords: Radical reactions; Heterocyclic chemistry.
* Corresponding author. Tel.: +1-201-216-5528; fax: +1-201-216-8240; e-mail: akganguly1@aol.com
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.204

884
A. K. Ganguly et al. / Tetrahedron Letters 45 (2004) 883–886
noted that although the yields have not been optimized
the reactions described in this communication yield a
variety of heterocycles some of which could serve as
pharmacophores for making libraries of compounds for
biological testing.
We investigated the substitution effect on the phenyl
ring that is the ring B of the benzamide residue to detect
the formation of spiro radical derived products. Spe-
cifically we were interested in the results with benz-
amides such as 2:6-dimethyl and 2:4:6-trimethyl
substituted benzamides 24 and 25, respectively. When
24 was treated with TBTH it yielded 26 (62.5%) and a
pair of anti dimers 27 (6.2%) and 28 (10.8%) and a syn
dimer 29 (7.5%). The reaction of 25 with TBTH yielded
30 (52.3%), 31 (17.6%), and again a pair of anti dimers
32 (3.9%) and 33 (4.5%) and a syn dimer 34 (4.5%) were
obtained. These dimers were presumably formed via
spiro radical such as 35 (differently substituted by
methyl groups) and 31 was formed by rearrangement of
35 to 35a followed by the loss of a methyl radical. It
should be noted that we did not observe this rear-
rangement in every case studied.
R'
O
N
Br
X
10
Reaction of the thiophene carboxyamide 114 with
TBTH yielded the spiro indole 12 (62%) and compound
13 (20%) indicating that given a chance the radical such
as 11a will add to the thiophene double bond or the allyl
substituent without undergoing rearrangement to the
fused aromatic compound 14.
S
O
O
O
N
O
S
N
N
N
N
O
Br
S
S
S
12
11
11a
1
3
14
In the case of furan-3-carboxyamide 15 the reaction with
TBTH yielded the spiro compound 16 (59%) and no
rearrangement product 17 was detected. These results
are in contrast with the one seen with compound 10 in
which x is –CH@CH– wherein no spiro oxindole was
formed.1
15
8
N
1
3
O
5
16
14
10
12
18
17
Me
N
Me
Me
N
The structures of the above dimers were assigned based
on extensive NMR studies,5 details of which will be
published elsewhere. A brief summary is presented here.
O
N
O
O
O
Br
O
O
Energy minimization calculations of 32, 33, and 34 were
performed using software PCModel (Serena Software,
version 7) and MMX force field. In the minimum energy
conformations the two methyl groups (3H-17) are in anti
positions. These dimers give rise to four possible struc-
tures as shown in Figure 1. In structures 32 and 33 the
oxindole ring carbonyl groups are anti to each other and
they are syn to each other in 34 and 34a. The structures
34 and 34a are, however, identical and therefore there
are three distinct dimeric structures possible. Similarly
29 and 29a are identical.
15
16
17
We then investigated the TBTH reaction with com-
pound 18 and obtained 19 (20%), 20 (16%), 21 (47.2%),
and 22 (8%). As is evident in this case the spiro radical
intermediate derived compound 22 was obtained as a
minor component and the main products were derived
by rearrangement of the spiro radical to the radical 23,
which either accepts hydrogen radical to give cis 20 and
trans 19 and in addition the radical 23 also undergoes
oxidation to yield compound 21.
Me
N
Me
N
Me
N
Me
O
N
O
O
H
O
Br
Me
H
N
N
N
18
N
23
19
Me
Me
Me
Me
Me
N
Me
N
N
O
O
H
O
H
N
N
N
22
21
20
Me
Me
Me

A. K. Ganguly et al. / Tetrahedron Letters 45 (2004) 883–886
885
Figure 1.
All three structures 32, 33, and 34 have a plane of
symmetry containing the C-methyl and N-methyl
groups. For each anti isomers there is also a center of
symmetry therefore the NMR (proton and carbon)
spectra of 32 and 33 are very simple. Besides the aro-
matic hydrogens the NMR spectra of 32 and 33 show
(the figures in parentheses represent 33) singlets at 1.30
(1.27) ppm (3H-17), 1.35 (1.33) ppm (3H-16 and 3H-18),
3.27 (3.26) ppm (3H-15) and 5.81 (5.77) ppm (H-11 and
H-13). The two anti isomers can be distinguished from
each other by the size of the NOE observed between H-5
and 3H-17. The distance between these hydrogens is
parentheses refers to 28) at 1.34 (1.38) ppm (3H-16 and
3H-18), 3.11 (3.33) ppm (H-17), 3.24 (3.28) ppm (3H-15),
and 5.84 (5.80) ppm (H-11and H-13). NOE experiments
confirmed the assignment of the structures of 27 and 28.
syn Dimer 29 again showed double the number of peaks
compared to the anti dimers.
Acknowledgements
ꢀ
ꢀ
2.5 A in 32 compared to 3.5 A in 33 and hence larger
NOE was observed with 32.
We would like to sincerely thank Schering-Plough
Research Institute, Kenilworth, NJ for generous finan-
cial support.
In the case of syn isomer 34 there is a plane of symmetry
but the two halves of the molecule are not equivalent
and therefore the NMR spectra are more complicated
that is there are twice the number of signals in 34
compared to 32 and 33.
References and notes
1. Ganguly, A. K.; Wang, C. H.; David, M.; Bartner, P.;
Chan, T. M. Tetrahedron Lett. 2002, 43, 6865.
2. Storey, J. M. D. Tetrahedron Lett. 2000, 41, 8173;
Beckwith, A. L. J.; Storey, J. M. D. J. Chem. Soc., Chem.
Commun. 1995, 977.
The above arguments for assigning the structures of the
dimers are also valid for the dimers 27, 28, and 29. For
example in the anti dimers 27 and 28 besides the aro-
matic protons there are four singlets (the figures in

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A. K. Ganguly et al. / Tetrahedron Letters 45 (2004) 883–886
3. Bowman, W. R.; Heanney, H.; Jordan, B. Tetrahedron
1991, 47, 10119, and references cited therein.
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 and NOESY experiments.
solids, all the other compounds described in this paper were
crystalline. Crystals were obtained from dichlorome-
thane and hexane. The melting points of compounds
11, 12, 13, 15, 16, 18, 19, 20, 21, 24, 25, 26, and 31 were
89–91, 65–67, 75–77, 67–69, 79–80, 142–143, 127–128,
148–149, 177–178, 105–107, 64–66, 51–52, and 138–
140 °C, respectively. Yields are indicated in paren-
theses.
5. Excepting compound 30, which was oil, and com-
pounds 22, 27, 28, 29, 32, 33, and 34, which were white