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O
H
O
1/2H2O
O2
(5)
Pd+2
HX
Pd0
π−complex
formation
O
eliminative
reduction
H
O
HPdX
(24)
Pd+2
-elimination
β
AcONa
O
O
O
O
O
O
δ+
H
δ−
Pd
AcOH
Oxopalladation
Pd+2
(23)
(26)
(25)
Figure 3. Rationale for the synthesis of isocoumarin 23.
reaction of methyl vinyl ketone with arenediazonium 4. Gratify-
ingly, the reaction went smoothly providing the anticipated phthal-
ide 11 in 65% yield. Since two important frameworks can now be
obtained from this type of Heck reaction, a more extensive investiga-
tion on the electronic nature of the starting olefin was carried out
(Table 2).
In agreement with the mechanistic proposal (Fig. 2), we found
that olefins bearing electron-withdrawing groups provide the
phthalide core (Table 2, entries 6–8), whereas those bearing elec-
tron-donating groups generate the dihydroisocoumarin core
(Table 2, entries 1–5).
The one-pot cyclization took place only in the synthesis of com-
pounds 9, 11, and 14. In the case of dihydroisocoumarins 12, 16,
and 18, the desired product was obtained after reaction with the
acid. On the other hand, phthalides 20 and 22 were formed after
reaction with the base. It is worth mentioning that yields can be
improved if the cyclization step is preceded by chromatographic
purification of the Heck product. For example, the overall yield
for dihydroisocoumarins 12 goes up to 94% if the Heck product is
isolated and then submitted to cyclization under acidic conditions.
Nevertheless, we found the one-pot sequence advantageous on
practical and economic grounds.
3. Conclusion
Expeditious and concise syntheses of 3,4-dihydroisocoumarins
and phthalides can be accomplished from the Heck–Matsuda reac-
tion of styrenes, methylvinyl ketones, and acrylates. 6-Membered
dihydroisocoumarins or the 5-membered phthalide can be assem-
bled quickly using a one-pot procedure from some substrates.
These preliminary results indicate that the type of skeleton
generated depends upon the electronic nature of the group
attached to the olefin. Electron rich styrenes provided the dihydro-
isocoumarin skeleton, whereas electron deficient olefins provided
the phthalide skeleton. The protocol can also be used for the direct
synthesis of isocoumarins by converting the Pd(0) generated
during the Heck arylation into the mild Lewis acid Pd(II) in a
sequential manner.
Acknowledgments
The authors thank the Brazilian National Research Council
(CNPq) and the Research Supporting Foundation of the State of
São Paulo (FAPESP) for fellowships and financial support of this
work.
Another interesting feature of this protocol is the fact that the
Pd catalyst used in the Heck reaction can be converted into a mild
Lewis acid thus promoting the acid catalyzed cyclization of the
Heck adduct into the isocoumarin system in a sequential manner.
To achieve that, ethanol was simply evaporated, replaced by
DMSO,17 and the reaction placed under O2. This procedure pro-
vided the unsaturated isocoumarin 23 in 63% yield from styrene
3 in a one-pot procedure (Scheme 2). Attempts to oxidize dihydro-
isocoumarin 12 into 23 using the same reaction conditions
(Pd(OAc)2, O2, DMSO) failed, which indicates that compound 12
is not an intermediate in this process.
References and notes
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Formation of the isocoumarin 23 can be explained by the oxida-
tion of the Pd(0), generated in the Heck step, to Pd(II) by oxygen,
followed by the formation of the
p–olefin palladium(II) complex
2418 (Fig. 3). Next, the added base (sodium acetate) forms a carbox-
ylate anion 25, which attacks the double bond regioselectivity.
Subsequent b-hydride elimination affords the isocoumarin 23
and Pd(0), which undergoes re-oxidation by O2, closing the cata-
lytic cycle. Further applications of this protocol and the reuse of
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