Free radical reactions for heterocycle synthesis. Part 4: A double ipso substitution reaction for azacoumarins

Article abstract of DOI:10.1016/S0040-4039(01)01089-9

A highly efficient route to azacoumarins with an unusual mechanism of double ipso substitutions is described.

Full text of DOI:10.1016/S0040-4039(01)01089-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5613–5615
Free radical reactions for heterocycle synthesis. Part 4: A double
ipso substitution reaction for azacoumarins
Wei Zhang* and Georgia Pugh
Lead Discovery, DuPont Crop Protection, Stine-Haskell Research Center, Newark, DE 19714, USA
Received 6 April 2001; accepted 11 June 2001
Abstract—A highly efficient route to azacoumarins with an unusual mechanism of double ipso substitutions is described. © 2001
Elsevier Science Ltd. All rights reserved.
Intramolecular nucleophilic and electrophilic ipso sub-
stitution reactions are typical aromatic substitution
processes. The radical versions of these reactions, how-
ever, have not received much attention until very recent
studies on homolytic substitutions of aromatic com-
pounds. Extensive effort in this area has been focused
on the development of new synthetic methods and
investigation of reaction mechanisms.1 We recently
reported the synthetic utilities of enol benzonate radi-
cals in the construction of isoindolinones, isoquinoli-
nones, and various spiro ring systems.2 Herein, we
describe our new findings on the radical reaction of aryl
benzonates in the synthesis of coumarin-based ring
systems. Coumarins and their aza-analogs are naturally
occurring lactones which possess valuable pharmaceuti-
cal properties along with crop protection and analytical
utilities.3
A radical precursor aryl benzoate 1 is prepared by O-
acylation of 3-methoxy-2(1H)-pyridone with 2-bromo-
benzoyl chloride in the presence of K2CO3 and
tetrabutylammonium bromide (TBAB). This intermedi-
ate is then treated with 1.5 equiv. of tris(trimethylsi-
lyl)silane under a standard radical reaction condition
(cat. AIBN, benzene, 80°C) to afford azacoumarin 2 in
75% yield (Scheme 1). We were surprised to find that
the structure of the product was 10-oxa-4-azaphenan-
thren-9-one (2) instead of the anticipated direct 1,6-ipso
substitution product 10-oxa-1-azaphenanthren-9-one
(3).4
Based on the structure of 2, we proposed a mechanism
as shown in Scheme 2 to illustrate this transformation.
It is believed that the rearrangement is initiated with a
1,5-ipso substitution of radical 4 via intramolecular
Scheme 1.
* Corresponding author. Current address: Fluorous Technologies, Inc., 970 William Pitt Way, Pittsburgh, PA 15238, USA. Fax: 1-412-826-3053;
e-mail: w.zhang@fluorous.com
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01089-9

5614
W. Zhang, G. Pugh / Tetrahedron Letters 42 (2001) 5613–5615
Scheme 2. A double ipso substitution mechanism.
Scheme 3.
attack at the 2-position of the pyridine ring to gener-
ate a carbonyloxy radical 6. Since the decarboxylation
rate of aromatic carbonyloxy radicals (k=104–105
s−1)5 is significantly slower than alkyl carbonyloxy
radicals (k=108–1010 s−1), it gives radical 6 a chance
to undergo a second 1,6-ipso substitution to displace
the methoxy group. Further support for ipso substitu-
tion of aromatic carbonyloxy radicals comes from a
study by Togo and Yokoyama in oxidative cycliza-
tion of o-arylaromatic acids.6 The first ipso displace-
completion. The methoxy group seems to be critical
to promote the whole rearrangement process. To test
this hypothesis, we carried out a control reaction
using a radical precursor similar to aryl benzoate 1
with the exception that it has no methoxy group at
the 3-position of the pyridine. In this case, cyclized
product 2 is obtained in less than 10% yield, while
the major component (85%) is the direct reduction
product.
ment process described in Scheme
reversible. However, extrusion of the methoxy radical
is essentially irreversible, which drives the reaction to
2
may be
Two other methoxy-substituted azacoumarins are pre-
pared (Scheme 3). The structure of 9b7 is confirmed
by an X-ray diffraction study (Fig. 1). This reaction
has been applied to the synthesis of coumarins, but
yields are relatively low compared to the azacou-
marins. Since benzene is a less activated ring system
than pyridine, the competition between the cyclization
and the direct reduction of the initial radicals yields a
mixture of the cyclized product 11 and the direct
reduction product 12 (Scheme 4).
In brief, we have discovered a mechanistically inter-
esting reaction that is synthetically useful for the syn-
thesis of azacoumarins.
Acknowledgements
The authors thank William Marshall for the X-ray
structural analysis of 9b.
Figure 1. X-Ray structure of 9b.

W. Zhang, G. Pugh / Tetrahedron Letters 42 (2001) 5613–5615
5615
Scheme 4.
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