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Table 3 Aza-Wittig reactions using polymer-bound triphenylphosphinea
be via intermediate ‘E’. However, it can be argued that it could be
formed via aromatic amines generated from the corresponding
azides at higher temperatures in protic solvents such as MeOH.23
To probe this issue, reaction of 5 with 2f was conducted in the
aprotic solvent, THF, which resulted in isolation of the corre-
sponding 3-arylaminophthalide 6f. This suggests the reaction
proceeded via aza-Wittig adduct (Scheme 2).
Product ratio
Entry Substrate Azides Timeb (h) 3 (%)
4 (%)
Yielde (%)
76
In summary, a new entry into the synthesis of N-substituted
isoindolinones and 3-arylaminophthalides was developed through
aza-Wittig/cyclisation reaction. The reaction of o-phthalaldehydic
acid methyl ester with azides gave novel N-isoindolinones and the
electronic and steric effects were investigated. Reaction of o-phthal-
aldehydic acid with aromatic azides gave novel 3-arylaminophtha-
lides, whereas reaction with benzylic and aliphatic azides failed.
We are grateful to National Health & Medical Research
Council (NHMRC Australia Fellowship AF511105) for financial
support.
18c
3
3
3a (00)
3a (00)
3a (00)
4a (100)
4a (100)
4a (00)
1
1
2a
80
d
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1a
1b
1c
2b
2e
2g
2h
2j
2k
2b
2b
2b
3
3
3b (00) 4b (100) 72
3e (00)
3g (00)
3h (100) 4h (00)
3j (100) 4j (00)
3k (100) 4k (00)
3ab (00) 4ab (100) 56
3bb (00) 4bb (100) 60
3cb (00) 4cb (100) 68
4e (100)
4g (100)
59
79
47
72
64
24
24
24
24
12
12
12
10
a
Notes and references
Conditions: 1 (0.1 mmol), azide 2a (0.2 mmol) and polymer-bound
PPh3 (0.2 mmol) in THF (2.5 mL), RT, 3 h, then filter the resin, added
NaBH3CN (0.2 mmol). Reaction time for cyclisation at reflux tempera-
ture. Reaction time for cyclisation at RT. Reaction performed in
MeOH at reflux temperature. Isolated yields.
b
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c
d
e
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Table 4 Aza-Wittig/cyclisation reaction using o-phthalaldehydic acida
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Entry
Azides
Product
Solvent
Yieldc (%)
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1
2
2a
2e
6a
6e
MeOH
MeOH
MeOHb
MeOH
THF
MeOH
MeOH
MeOH
00
00
50
78
54
66
48
36
3
2f
6f
4
5
6
2g
2j
2m
6g
6j
6m
a
Conditions: 5 (0.15 mmol), azide 2a (0.3 mmol) and polymer-bound
b
PPh3 (0.3 mmol), MeOH (5.0 mL), reflux, 5 h. Reaction using PPh3.
c
Isolated yields.
¨
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´
´
´
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Scheme 2 Proposed mechanism for aza-Wittig/cyclisation reaction of o-phthal-
aldehydic acid/methyl ester derivatives.
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 8407--8409 8409