Organic Letters
Letter
Scheme 1. (a) Representative Examples of
Spirotetrahydrofuran Oxindoles with Various Biological
Activities; (b) Previous Reactions of 2-
Methylidenetrimethylene Carbonate and Its Derivatives; (c)
Our Design for the Synthesis of Spirotetrahydrofuran
Oxindoles
Table 1. Optimization of the Conditions for Catalytic [4 +
1] Cycloaddition of Diphenyl 1-Methyl-2-oxoindolin-3-yl
Phosphate (1a) and 2-Methylidenetrimethylene Carbonate
a
(2)
b
entry
cat.
base
solvent
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Pd(PPh3)4
Pd2(dba)3
Pd(OAc)2
−
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
Cs2CO3
K3PO4
Et3N
toluene
toluene
toluene
toluene
xylene
MeCN
CH2Cl2
DCE
12
12
12
12
12
12
12
12
12
12
12
12
12
6
88
NR
NR
NR
79
73
74
86
65
48
96
30
76
96
DMF
toluene
toluene
toluene
toluene
toluene
Cs2CO3
a
Reaction conditions: 1a (0.15 mmol, 1.0 equiv), 2 (0.225 mmol, 1.5
equiv), catalyst (3.75 μmol, 2.5 mol %), base (0.3 mmol, 2.0 equiv) in
the indicated solvent (1.5 mL) at the indicated temperature (rt, ∼25
°C) for the indicated time (6−12 h) in a sealed Schlenk tube under
an argon atmosphere. DCE = 1,2-dichloroethane. DMF = N,N-
b
dimethylformamide. Isolated yields. NR = no reaction.
(3j and 3m, 91% and 92% yield, respectively), and 5-MeO (3s,
85% yield), weak electron-withdrawing groups, including 5-F
(3n, 56% yield), 5- or 6-Cl (3k and 3o, 94% and 80% yield,
respectively), and 5-Br (3p and 3r, 89% and 64% yield,
respectively), and strong electron-withdrawing groups, includ-
ing 5-NO2 (3q, 77% yield), provided satisfactory results.
Therefore, the present method shows a wide substrate scope
and tolerance of functional groups, and it will find extensive
application in the synthesis of spirooxindole derivatives. In
order to ascertain the structures of the newly synthesized
products 3, a single crystal of 3j was prepared in a mixed
solvent of n-hexane and ethyl acetate (4:1 v/v), and its
structure was unambiguously confirmed by X-ray diffraction
We attempted a one-pot two-step synthesis of 3a using 1-
methylindoline-2,3-dione (4), diphenyl phosphonate (5), and
2 as the starting materials: addition of the P−H bond in 5 (1.0
equiv) to the carbonyl at the 3-position of 4 and subsequent
phospha-aldol-Brook rearrangement in the presence of 4-
dimethylaminopyridine (DMAP) at room temperature for 10
min provided 1a, and then 2.0 equiv of 2 was added to the
resulting solution. The reaction of 1a with 2 in the system was
carried out under the standard conditions in Scheme 2, and the
target product 3a was obtained in 80% yield (Scheme 3a). A
scaled-up synthesis of 3a was also surveyed. As shown in
Scheme 3b, the palladium-catalyzed reaction of 1a (1 mmol,
395 mg) and 2 (2 mmol, 228 mg) under the standard
conditions afforded 3a in 95% yield, representing almost no
loss of yield relative to the reaction of smaller amounts of the
substrates. The results above show that our method is very
efficient and practical.
in 88% yield using Pd(PPh3)4 as the catalyst, K2CO3 as the
base, and toluene as the solvent for 12 h (entry 1). We tested
Pd2(dba)3 and Pd(OAc)2 as the catalysts (entries 2 and 3,
respectively), and they were inferior to Pd(PPh3)4 (compare
entries 1−3). No reaction occurred in the absence of catalyst
(entry 4). Five other solvents were tested (entries 5−9), and
we found that toluene was suitable (compare entries 1 and 5−
9). When Na2CO3, Cs2CO3, K3PO4, or Et3N was used in place
of K2CO3 as the base (entries 10−13), Cs2CO3 afforded the
highest yield (96%) (entry 11). We investigated the reaction
time and found that 6 h was satisfactory (compare entries 11
and 14).
With the optimized conditions in hand, the substrate scope
for the [4 + 1] cycloaddition of 1 and 2 was surveyed (Scheme
2). First, we investigated variation of the R2 substituent in 1
and found that methyl (3a, 96% yield), n-butyl (3b, 90%
yield), allyl (3c, 94% yield), benzyl (3d, 97% yield), o-
methylbenzyl (3e, 99% yield), p-methoxybenzyl (3f, 97%
yield), methoxymethyl (3g, 92% yield), and phenyl (3h, 87%
yield) were feasible. Subsequently, the effect of the R1
substituent on the phenyl ring of 1 was surveyed, and
substrates 1 containing electron-donating groups, including 5-
Me (3i and 3l, 99% and 90% yield, respectively), 7- or 6-Me
B
Org. Lett. XXXX, XXX, XXX−XXX