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Table 1. Preparation of optically active a-chloro-b-keto esters.[a]
Table 3. SN2 reaction of a-chloro-b-keto esters with phenol.[a]
[a] See the Supporting Information for details. Tf=trifluoromethanesul-
fonyl.
Table 2. Optimization of reaction conditions.[a]
[a] Reactions were carried out with 1.5 equiv of PhOH and 2.0 equiv of
Cs2CO3 in toluene under reflux conditions, unless otherwise noted. [b] In
1,4-dioxane at room temperature. [c] At 508C; [d] 10 equiv of PhOH and
12 equiv of K2CO3 were employed. [e] In N-methylpyrrolidone (NMP) at
room temperature. [f] In the presence of 3 molecular sieves (MS). [g] In
1,4-dioxane at 808C for 24 h.
Entry
Base
Solvent
Time [h]
Yield[b] [%]
ee/es[c] [%]
1[d]
2[e]
3
NaH
Et3N
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
THF
DMF
MeCN
toluene
toluene
toluene
15
18
18
2
24
24
24
2
0
n.r.[f]
0
19
0
0
0
77
70
96
–
–
–
Next, we attempted to expand the range of possible sub-
strates under the optimized reaction conditions. However, nu-
cleophilic substitution was quite sensitive to the reaction con-
ditions and the best reaction conditions for each substrate
were dependent on the structure of the substrate. For exam-
ple, Cs2CO3 in 1,4-dioxane provided the best results for the re-
action of indanone-derived substrates 3a, 3d, and 3e. Howev-
er, compounds 4g and 4h were obtained in acceptable yields
only when the reactions were carried out in amide solvents.
After examining a variety of reaction conditions, various cyclic
and acyclic a-phenoxy-b-keto esters were successfully obtained
(Table 3). a-Chloromalonate 3k was also substituted in a similar
manner. To our delight, the enantiopurity of the resulting com-
pound 4 was exactly the same as that of the starting com-
pound 3 in almost all cases, which suggested that substitution
proceeded by the SN2 mechanism. In addition, the results from
single-crystal X-ray crystallographic analyses showed that this
substitution involved Walden inversion (see the Supporting In-
formation for details). It is interesting that cyclic a-chloro-b-
keto ester 3l underwent Favorskii rearrangement[12] to yield
the corresponding 1,2-diesters 5 with slightly decreased enan-
tiopurity under similar reaction conditions (Scheme 2).
DBU[g]
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
4[e]
5
40/46
–
–
6
7
–
8[e]
9[e,h]
10[e,h]
49/56
66/76
87/100
0.5
4
[a] Reactions were quenched after the complete consumption of 3c,
except for entries 2 and 3. [b] Isolated yield; [c] es=enantiospecificity.
[d] Reaction was carried out with PhONa prepared with 3.0 equiv of NaH
and phenol at room temperature. [e] Under reflux conditions; [f] n.r.=no
reaction. [g] DBU=1,5-diazabicyclo[5.4.0]undec-5-ene; [h] 10 equiv of
PhOH and 12 equiv of base were employed.
(Table 2, entry 1). The use of organic bases such as Et3N and
DBU was also ineffective (Table 2, entries 2 and 3, respectively).
On the other hand, when the substitution reaction was con-
ducted with Cs2CO3 in 1,4-dioxane, desired product 4c was ob-
tained in a yield of 19% with decreased enantiopurity (Table 2,
entry 4). Most of reactant 3c decomposed in this case. It is evi-
dent from entries 4–8 in Table 2 that this reaction was highly
influenced by the nature of the reaction solvent. Whereas the
use of Cs2CO3 in toluene resulted in high yields of 4c, the
enantiopurity of 4c was diminished significantly (Table 2,
entry 8). Finally, we succeeded in suppressing the loss of enan-
tiopurity by employing an excess of K2CO3 in toluene. Product
4c was obtained in a high yield with a high enantiopurity
(Table 2, entry 10).
Various substituted phenols were then allowed to react with
3 to yield the corresponding a-aryloxy-b-keto esters 4 with
high enantiopurity (Table 4). Notably, even reactions that in-
volved low-nucleophilic phenols, such as pentafluorophenol,
afforded the desired products with good yields and high enan-
tiopurity. The use of 5-hydroxy-1-methylindole also yielded the
corresponding product 4 fg, although the enantiopurity was
slightly diminished in this case. Next, we demonstrated the
Chem. Eur. J. 2015, 21, 14095 – 14098
14096
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