Competitive 3+2 and 2+2 cycloadditions of ester stabilized azaallyl anions to benzynes. Ring expansion of initial 3+2 products to isoquinolin-3-ones

Article abstract of DOI:10.1016/S0040-4039(01)00130-7

Reaction of the azaallyllithiums derived from imines of α-amino esters with benzynes results in the formation of 1,3-dihydroisoindoles and 4-hydroxyisoquinolines via 3+2 and 2+2 cycloadditions, respectively. The initially formed 1-carboethoxy-1,3-dihydroisoindoles rearrange under basic reaction conditions to form 3-(2H)-isoquinolinones.

Full text of DOI:10.1016/S0040-4039(01)00130-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2245–2248
Competitive 3+2 and 2+2 cycloadditions of ester stabilized
azaallyl anions to benzynes. Ring expansion of initial 3+2
products to isoquinolin-3-ones
Helmi Hussain, Ebrahim Kianmehr and Tony Durst*
Department of Chemistry, University of Ottawa, Ottawa, Canada K1N 6N5
Received 11 December 2000; revised 19 January 2001; accepted 22 January 2001
Abstract—Reaction of the azaallyllithiums derived from imines of a-amino esters with benzynes results in the formation of
1,3-dihydroisoindoles and 4-hydroxyisoquinolines via 3+2 and 2+2 cycloadditions, respectively. The initially formed 1-carbo-
ethoxy-1,3-dihydroisoindoles rearrange under basic reaction conditions to form 3-(2H)-isoquinolinones. © 2001 Published by
Elsevier Science Ltd.
Cycloaddition of the 1,3-diphenyl-2-azaallyl anion 1
with reactive double and triple bonds was studied
carefully in the 1970s as an example of an anionic
3+2 Woodward–Hoffmann symmetry controlled reac-
tion.1
As part of our interest in the addition of nucleophiles
to benzynes generated from bromo- or iodobenzenes
with LTMP,3a,b we have examined the reaction of a
number of azaallyllithium species 3 with several benzy-
nes. These reactions led to the formation of a fascinat-
ing series of products that we interpreted as emanating
from competitive 3+2 and 2+2 cycloaddition reactions
followed by rearrangements. The precursors of 3 are
readily derived from the reaction of a-amino esters with
a variety of aldehydes.
In a review of this topic, Kauffmann2 cited an unpub-
lished observation that reaction of 1 with benzyne
resulted in the formation of 1,3-diphenylisoindole, 2,
presumably via initial formation of the corresponding
1,3-dihydroindole (Scheme 1). To the best of our
knowledge, no subsequent reports of this reaction have
appeared.
Typically, addition of imines 4 to slightly more than 2
equiv. of LTMP in THF at −78°C followed by addition
Scheme 1.
(1)
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(01)00130-7

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H. Hussain et al. / Tetrahedron Letters 42 (2001) 2245–2248
Table 1. Reaction of azaallyllithium 3 with benzynes
of bromobenzenes and subsequent warming to room
temperature, led to formation of two or three isolable
products. In the specific example shown in Eq. (1),
single-crystal X-ray structure determination of 6b, 1-
phenyl-4-methyl-3(2H)-isoquinolone,8 (Fig. 2),6 and a
comparison of the spectroscopic properties of 6b with
those of the other compounds in this series. All showed
the unusually low 13C NMR amide carbonyl resonance
in the 192–207 ppm range. The CꢀC bond lengths in
imine 4a, derived from (L)-valine methyl ester and
benzaldehyde, was converted into the 1,3-dihydroisoin-
dole, 5a, 1-phenyl-4-isopropyl-3(2H)-isoquinolinone, 6a,
and 1-isopropyl-3-phenyl-4-hydroxyisoquinoline, 7a, in
38, 17 and 14% isolated yields, respectively.4 Similar
,
the carbocyclic ring of 6b vary from 1.35 to 1.43 A as
required by the o-quinonoid structure. The preferred
existence of these compounds as 3(2H)-isoquinolinones
6 rather than the tautomeric 3-hydroxyisoquinolines 8
has been noted previously.9
results were obtained with the benzalimine of (L)-
ethyl alanine. These results, and those of the reaction
with related lithiated imines with benzyne and 3-
methoxybenzyne (1–2 mmol scale), are summarized in
Table 1.4
The 1,3-dihydroisoindoles 5 were always obtained as
single stereoisomers as shown by NMR. The relative
stereochemistry, a cis relationship between the 1-carbo-
ethoxy group and the 3-aryl or alkyl substituent, is
consistent with a concerted cycloaddition between the
benzynes and the azaallyllithium species, 3, which
allows lithium complexation to both oxygen and nitro-
gen.5 This stereochemistry was verified in the case of 5e
by a single-crystal X-ray structure determination6 (Fig.
1). The isoindole 2-carboxylates, available in a stereo-
chemically defined form, represent new novel proline
analogs.
The relative stability of structures of type 6 versus 8 is
reported to be highly dependent on the solvent and the
nature of the substituents at C(1) and C(4).9 Derivatives
of 3(2H)-isoquinolinone have been reported to show
diverse biological effects including antidepressant, car-
diotonic and analgesic activity.10,11
The assignment of structure 6b, the most polar of the
three products, was problematic due to seemingly con-
tradictory spectroscopic evidence. The 13C NMR spec-
trum of 6b showed a low field peak at l=207 ppm,
consistent with a ketone carbonyl carbon.7 However,
the only IR absorption assignable to a carbonyl group
stretching frequency occurred at 1594 cm−1, signifi-
cantly lower than expected for an unsaturated ketone.
The observed IR frequency is plausible for a highly
conjugated amide, but the 13C peak is far downfield
from the typical amide carbon.7 In the end, the struc-
tures of series of this compounds was secured by a
Figure 1. X-Ray structure of 5e.

H. Hussain et al. / Tetrahedron Letters 42 (2001) 2245–2248
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Figure 3. X-Ray structure of 7b.
Figure 2. X-Ray structure of 6b.
(2)
Scheme 2.
The 3(2H)-isoquinolinones are rearrangement products
derived by prolonged exposure of the corresponding
1,3-dihydroindoles with base at temperatures above
0°C. A plausible mechanism for the conversion of 5a12
to 6a is shown in Eq. (2). This observation allows one
to design reaction conditions which favor the formation
of either 5 or 6. For example, when the reaction of 4h
with benzyne was quenched after 3 h of reaction time at
−78°C, the dihydroisoindole 5h was obtained in 66%
yield; no 6h was observed. This compares with the
results shown in Table 1 where the reaction mixtures
were quenched after warming to 25°C; 3(2H)-isoquino-
linones were generally the major product under these
conditions.
observed in 7c is consistent with, but does not demand,
a stepwise process for the formation of 9 from 3c and
3-methoxybenzyne.
Acknowledgements
Financial support of the NSERC (Canada) is greatly
appreciated. The authors also thank Dr. Sasmita
Triphathy for valuable discussions.
References
We propose that the 4-hydroxyisoquinolines 7, includ-
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involving the ketene acetal-like double bond (Scheme
2). The formation of a benzocyclobutene intermediate,
such as 9, could occur via a concerted or a stepwise
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absorption for this peak was a sharp singlet near l=9.5
ppm due to intramolecular hydrogen bonding with the
peri-methoxy group at C(5). The regiochemistry
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H. Hussain et al. / Tetrahedron Letters 42 (2001) 2245–2248
1
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129.0, 129.3, 142.4, 145.0, 145.7, 175.5.
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1
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3H), 1.01 (d, J=6.6 Hz, 3H), 1.34 (t, J=7.17 Hz, 3H),
.