BF3·Et2O catalyzed allylation of oxindoles with allyl trichloroacetimidate

Article abstract of DOI:10.1016/j.tetlet.2015.01.155

An efficient Lewis acid catalyzed allylation of 3-substituted oxindoles has been developed for the first time using allyl trichloroacetimidate as an electrophile under mild reaction conditions.

Full text of DOI:10.1016/j.tetlet.2015.01.155

Tetrahedron Letters 56 (2015) 1501–1504
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BF3ꢀEt2O catalyzed allylation of oxindoles with allyl
trichloroacetimidate
⇑
Jiao Ma, Ling Zhou, Jie Chen
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, Department of Chemistry & Materials Science, Northwest University, Xi’an
710069, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient Lewis acid catalyzed allylation of 3-substituted oxindoles has been developed for the first
time using allyl trichloroacetimidate as an electrophile under mild reaction conditions.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 24 November 2014
Revised 15 January 2015
Accepted 23 January 2015
Available online 30 January 2015
Keywords:
Allylation
Lewis acid
Catalysis
Allyl trichloroacetimidate
Oxindole
The 3,30-disubstituted oxindole derivatives are structural motifs
often found in a number of alkaloid natural products and pharma-
ceutically active compounds.1,2 Therefore, many remarkable ende-
vours have been made to develop general and efficient methods for
the preparation of this structural motif.3–9 Typically, synthesis of
an all-carbon quaternary center at the C-3 of oxindole is attractive
owing to its manifold bioactive properties and as the intermediate
for the synthesis of other indole ring systems. To date, transition-
metal-catalyzed allylic alkylation of 3-substituted oxindole has
been shown to be the most efficient and synthetic useful method
for the construction of quaternary carbon centers (Scheme 1, Eq.
1).3,5 For example, Trost and co-workers developed Pd, Mo-cata-
lyzed allylic alkylation of 3-substituted oxindoles.6 On the other
hand, organocatalytic allylic alkylation of 3-substituted oxindole
has also been reported.8,10 For example, Ooi and co-workers devel-
oped 1,2,3-triazoliums as cationic organic catalysts to realize
asymmetric alkylation of 3-substituted oxindoles.10 However,
most of these reactions are performed under basic conditions.3–11
Here we report the first Lewis acid catalyzed allylic alkylation of
3-substituted oxindoles by using allyl trichloroacetimidate as the
electrophile (Scheme 1, Eq. 3).
Previous work:
R1
R1
N
Metal/base;or
+
O
(1)
(2)
X
O
none metal, base
N
R2
R2
NH
Acid
ROH
+
RO
Cl3C
O
This work:
R1
R1
N
NH
Lewis acid
Cl3C
O
(3)
O
O
N
R2
R2
Scheme 1. Allylation of oxindoles and alcohols.
protecting groups. However, studies on the construction of C-ally-
lation using this reagent are rare.13 Inspired by the O-allylation
reactions,12 we envisage that a relative stable allylic carbocation
ion intermediate may be generated from allyl trichloroacetimidate
under acidic conditions, which may be captured by 3-substituted
oxindoles to form a new carbon–carbon bond, leading to 3,30-
disubstituted oxindole derivatives bearing an allyl group.
Allyl trichloroacetimidate has been widely used as a convenient
reagent for the O-allylation of hydroxyl groups under acidic condi-
tions in oligosaccharide and natural products synthesis (Scheme 1,
Eq. 2),12 which is compatible with ester, imide, and acetal
To test this hypothesis, an acid catalyzed reaction of 1-methyl-
3-benzylindolin-one (1a) with allyl trichloroacetimidate (2) was
⇑
Corresponding author.
http://dx.doi.org/10.1016/j.tetlet.2015.01.155
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

1502
J. Ma et al. / Tetrahedron Letters 56 (2015) 1501–1504
Table 1
Table 2
Optimization of the reaction conditionsa
Substrate scope of allylation of 3-substituted oxindolesa
R1
R1
N
Bn
Bn
NH
conditions
BF3 Et2O (0.4 equiv)
O
+
O
+
2
O
O
R
R
Cl3C
O
N
N
N
R2
R2
1a-l
3a-l
1a
2
3a
Entry Substrate
Bn
1
Product
Bn
3
Yieldb (%)
Entry
2 (equiv)
Acid (equiv)
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
2.0
3.0
2.0
CF3CO2H (0.4)
CF3SO3H (0.4)
BF3ꢀEt2O (0.4)
AlCl3(0.4)
DCM
DCM
DCM
DCM
DCM
THF
3
7
1
2
3
4
5
6
1a
3a 81c
3b 78
3c 75
3d 74
3e 76
3f 93
O
O
30
—
Trace
—
N
N
Bn
Bn
Cu(CF3SO2)2 (0.4)
BF3ꢀEt2O (0.4)
BF3ꢀEt2O (0.4)
BF3ꢀEt2O (0.4)
BF3ꢀEt2O (0.4)
BF3ꢀEt2O (0.4)
BF3ꢀEt2O (0.4)
BF3ꢀEt2O (0.8)
BF3ꢀEt2O (0.2)
BF3ꢀEt2O (0.4)
BF3ꢀEt2O (0.4)
BF3ꢀEt2O (0.4)
F
F
1b
1c
1d
1e
1f
O
O
Toluene
ACN
4
N
N
Trace
31
58
61
57
44
63
75
80
9c
10
11
12
13
14d
15d
16d
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
Bn
Bn
Br
Br
O
O
N
N
2.0
Bn
Bn
1.0 * 2
1.0 * 3
0.5 * 6
O
O
N
N
a
Reactions were carried out with 1a (0.20 mmol), catalyst and 2 in solvent
(1.0 mL) at room temperature for 36 h.
Bn
Bn
O
O
b
Isolated yield.
Reaction time is 115 h.
Compound 2 was added portionwise over a 5 h interval.
c
O
O
N
N
d
Ph
Ph
O
O
examined (Table 1). As expected, the desired 3-allyl-3-benzyl-1-
methylindolin-2-one (3a) was obtained. Treatment of 1a with 2
in the presence of 0.4 equiv of trifluoromethanesulfonic acid in
CH2Cl2 at room temperature gave 3a in 7% yield (Table 1, entry
2). A variety of Lewis acids were evaluated in the model reaction
(Table 1, entries 1–5), and BF3ꢀOEt2 was found to give the desired
3a in 30% yield (Table 1, entry 3). Other Brønsted acids (H3PO4,
H2SO4) and Lewis acids (SnCl4, FeCl3, ZnCl2) all resulted in only a
trace amount of product. Other solvents such as toluene, THF,
and acetonitrile diminished the reaction clearly (Table 1, entries
6–8). Notably, the starting material 1a was always recovered dur-
ing the process. So the reaction time was prolonged, however, sim-
ilar results were obtained (Table 1, entry 9). To our delight, the
yields were clearly increased when 2.0 equiv of 2 was employed
(Table 1, entry 10). The reason may be ascribed to the correspond-
ing allylic carbocation intermediate being unstable. Indeed, using a
large excess of 2 resulted in a higher yield (Table 1, entries 10, 11
vs entry 3). In contrast, no improvement was achieved by changing
the catalyst amount (Table 1, entry 12 vs entry 10). Further optimi-
zation of the reaction conditions revealed that addition of 3.0 equiv
of 2 by 6 times dramatically enhanced the yield to 80% (Table 1,
entry 16).
N
N
Ph
Ph
O
O
7
1g
3g 89
N
N
Bn
Bn
Ph
Ph
F
F
8
1h
1i
3h 90
3i 87
3j 85
3k 86
O
O
N
N
Ph
Ph
Br
Br
9
O
O
N
N
Ph
Ph
10
11
1j
O
O
N
N
Ph
Ph
O
O
1k
O
O
N
N
Bn
Bn
Having identified the optimized conditions, we next examined
this new method in a range of substrates with different substitu-
tion patterns. The results are summarized in Table 2. Overall, a
variety of 3-allyl-30-substituted oxindole derivatives were success-
fully prepared, and various substituents on the aromatic ring were
found to be tolerable in this process. Substrates with electron-defi-
cient or electron-rich substitutions at the aromatic ring offered
good yields (Table 2, entries 2–5), indicating that the electron
effect plays little role in this reaction. Reaction of 1,3-dimethylin-
dolin-2-one with 2 under the optimal conditions gave the desired
product in only 24% yield. It seemed that the reaction started from
an acid catalyzed enolization of oxindole at 3-position, thus a 3-
aryl substituted group will be beneficial to such a ketone-enol
O
O
12
1l
3l 73
N
Bn
N
Bn
a
Reactions were carried out with 1a–l (0.20 mmol), BF3ꢀEt2O (0.08 mmol,
0.4 equiv) and 2 (0.60 mmol, 3.0 equiv) in DCM (1.0 mL) at room temperature for
36 h.
b
Isolated yield.
2.0 mmol scale.
c
Generally, the desired 3-allylation oxindole products were
obtained with higher yields than those of 3-benzyl substituted
oxindole substrates (Table 2, entries 6–11 vs entries 1–5). Similar
a previous observation, electron-deficient or electron-rich
substituted 3-phenyl oxindole substrates all gave the desired ally-
to
equilibrium through
p–p conjugation. Then 3-phenyl substituted
oxindole substrates were prepared and subjected to this reaction.

J. Ma et al. / Tetrahedron Letters 56 (2015) 1501–1504
1503
R1
R1
N
Research Foundation for the Returned Overseas Chinese Scholars,
Ministry of Education, and the Northwest University for financial
support.
O
O
b
[3,3]
N
R2
R2
R1
1a
BF3 Et2O
R1
3a
Supplementary data
a
O
Supplementary data (experiment details, copies of 1H and 13C
NMR spectra for products. This material is available free of charge
via the Internet at doi.) associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.01.
155. These data include MOL files and InChiKeys of the most
important compounds described in this article.
N
R2
a
III
b
NH
I
NH
O
BF3 Et2O
N
Cl3C
O
H
O
CCl3
R2
2
II
Scheme 2. Proposed mechanism.
References and notes
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Ph
Ph
Bn
NH
BF3 Et2O (0.4 equiv)
+
O
O
53%
Cl3C
OBn
N
CH3
1f
N
CH3
4
5
Scheme 3. Benzylation of 1f.
lation products with excellent yields. Notably, the steric size of the
N-protecting group does not seem to be important as benzyl (1g)
and gave essentially identical results as methyl (1f). Other N-pro-
tecting groups such as Ts and Boc gave no positive results, only
complex mixtures were observed. Substrates with the free NH
group resulted in the desired product in low yield (30% for 3-
phenylindolin-2-one). Additionally, crotylation of 1a by using (E)-
2-butenyl trichloroacetimidate has also been attempted, 1H NMR
revealed the presence of a mixture of products maybe including
regio- and diastereoisomers,14 while cinnamylation of 1a by using
cinnamyl trichloroacetimidate resulted in no desired product.
Finally, the reaction was readily scalable without losing any effi-
ciency (Table 2, entry 1).
The proposed mechanism is shown in Scheme 2. Imidate 2 was
transformed to the allylic carbocation intermediate I with the
assistance of BF3ꢀEt2O; at the same time, BF3ꢀEt2O catalyzed enoli-
zation of 1a to give enol II. Next nucleophilic attack of I by enol II
through a pathway followed by deprotonation with trichloroace-
timidate ion to generate C-allylation product 3a. On the other
hand, this reaction may follow the other possible pathway
(Scheme 2, pathway b): O-allylation of II to give III, followed by
[3,3]-Claisen rearrangement promoted by BF3ꢀEt2O to give the
desired product 3a. To further probe the mechanism, benzylation
of 1f with benzyl trichloroacetimidate (4) under the optimal condi-
tions was attempted. Interestingly, the desired product 5 was
obtained in 53% yield (Scheme 3), suggesting the reaction mecha-
nism may follow our proposal that involves a direct C-allylation.
In summary, we have developed an efficient allylation of 3-
substituted oxindoles with allyl trichloroacetimidate catalyzed by
BF3ꢀEt2O for the first time. This method allows for the facile synthe-
sis of 3-allyl-30-substituted oxindoles which are fundamental units
of many pharmaceutically important molecules. Further investiga-
tion to extend the scope of this acid catalyzed allylation reaction,
and to develop new applications is underway.
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We thank the National Natural Science Foundation of China
(NSFC-21203148, 21302151), Science and Technology Department
of Shaanxi Province (2013JQ2012), Education Department of Sha-
anxi Province Government (2013JK0644, 13JS115), the Scientific

1504
J. Ma et al. / Tetrahedron Letters 56 (2015) 1501–1504
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¯
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