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Organic Letters
pubs.acs.org/OrgLett
Letter
the amount of MgCl2 up to 100 mol %. However, it only led to
a slightly lower yield (entry 4). This might be due to the poor
solubility of too much magnesium salt. MgCl2 could be
displaced by a variety of magnesium salts with different anions,
such as MgBr2·Et2O, affording the lactone product in a 73%
yield (entry 5). Alkaline and alkali metal salts, such as CaCl2
and LiCl, could also render the transformation successfully,
although NaCl and KCl failed (entries 6−9). It is worth
mentioning that a positive effect was observed when the
amount of LiCl was doubled (entry 8). Moreover, the first-row
transition metal salts, including but not limited to MnCl2,
FeCl3·6H2O, Fe(NO3)3·9H2O, CoCl2·6H2O, NiCl2·6H2O, and
CuCl2, showed good capability to catalyze the lactonization
reaction (entries 10−15). These control experiments suggested
that the metal salt might play a role as a Lewis acid. It is
notable that the reaction furnished a 67% yield of the phthalide
when only 0.3 equiv of the oxidant NaBrO3 was used (entry
16). Finally, NaClO3 and KIO3 proved to be ineffective for this
oxidative reaction (entries 17 and 18).
With the optimal reaction conditions in hand, we sought to
evaluate the generality of this C(sp3)−H lactonization
Figure 2. Gram-scale synthesis of the medicine NBP.
protocol. As illustrated in Scheme 1, MgCl2 was applicable
to a variety of 2-alkylbenzoic acid substrates with different
functionalities and substitution patterns, while NiCl2·6H2O
and Fe(NO3)3·9H2O could afford higher yields for some
substrates. First, 2-methylbenzoic acids with versatile sub-
stituents at the phenyl ring were examined, such as methyl,
methoxy, acetoxy, fluoro, chloro, bromo, nitro, cyano, and
trifluoromethyl groups, to provide the phthalides in 38−76%
yields (1−20). Typically, NiCl2·6H2O was superior to MgCl2
for the substrates with electron-donating groups (2−5). In
addition, 2-methyl-1-naphthoic acid was converted into the
lactonization product in 70% yield (20). However, it was
found that 2-methylnicotinic acid did not work for the
reaction. We then turned our attention to the benzoic acids
with an extra alkyl or aryl group at the ortho benzylic position.
3-Substituted phthalides were formed smoothly by this
protocol (21−36, 36−81% yields). Remarkably, the ester
(30), ether (31 and 32), amide (33), and imide (34 and 35)
functionalities attached to the side chain were tolerated well in
the reaction. Furthermore, 2-benzylbenzoic acid performed
quite well to give a 81% yield of 36 with the Fe(III) catalyst.
Lastly, this lactonization protocol was applied to the benzoic
acids with two alkyl or aryl groups at the ortho benzylic
positions using Fe(NO3)3·9H2O as the optimal catalyst to
furnish the products 37−43 in 36−98% yields. Gratifyingly,
spiro phthalides could be forged rapidly via this operationally
simple cyclization method (39−41), while 3,3-bis(aryl)-
phthalides were obtained in excellent yields (42 and 43, 95
and 98% yields).
Figure 1. Synthetic approaches to phthalides.
a
Table 1. Optimization for the Lactonization Reaction
entry
variation from standard conditions
no light
yield (%)
1
0
0
0
2
no NaBrO3
3
4
5
6
no MgCl2 (427 or 370 nm LED)
increase the amount of MgCl2 to 100 mol %
MgBr2·Et2O instead of MgCl2
CaCl2 instead of MgCl2
61
73
56
45
64
0
31
50
41
16
69
34
67
0
7
LiCl instead of MgCl2
8
9
20 mol % LiCl instead of MgCl2
NaCl or KCl instead of MgCl2
MnCl2 instead of MgCl2
FeCl3·6H2O instead of MgCl2
Fe(NO3)3·9H2O instead of MgCl2
CoCl2·.6H2O instead of MgCl2
NiCl2·6H2O instead of MgCl2
CuCl2 instead of MgCl2
10
11
12
13
14
15
16
17
18
reduce the amount of NaBrO3 to 0.3 equiv
NaClO3 instead of NaBrO3
KIO3 instead of NaBrO3
0
a
Yield determined by 1H NMR using 1,3-benzodioxole as the internal
standard in CDCl3. LED = light-emitting diode.
The practical application of our C(sp3)−H lactonization
protocol was demonstrated by the gram-scale synthesis of 3-n-
butylphthalide (NBP), a medicine for the treatment of cerebral
ischemia (Figure 2).1d The lactonization of 2-pentylbenzoic
5843
Org. Lett. 2021, 23, 5842−5847