Zinc-Mediated C-3 α-Prenylation of Isatins with Prenyl Bromide: Access to 3-Prenyl-3-hydroxy-2-oxindoles and Its Application

Article abstract of DOI:10.1021/acs.joc.6b00836

A convenient and highly α-regioselective strategy for the synthesis of 3-prenyl-3-hydroxy-2-oxindoles has been developed starting from isatins and prenylzinc with good to excellent yields. This protocol provides a straightforward and practical way to introduce an α-prenyl moiety into the C-3 position of isatins. The advantages of this reaction are use of the cheap and readily available reagents, operational simplicity, and wide substrate scope. Furthermore, this transformation was applied to the synthesis of several oxindole-containing natural products, which further demonstrated the synthetic utility of this methodology.

Full text of DOI:10.1021/acs.joc.6b00836

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Article
Zinc-Mediated C-3 alpha-Prenylation of Isatins with Prenyl Bromide:
Access to 3-Prenyl-3-hydroxy-2-oxindoles and Its Application
Li-Ming Zhao, Ai-Li Zhang, Jie-Huan Zhang, Hua-Shuai Gao, and Wei Zhou
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00836 • Publication Date (Web): 06 Jun 2016
Downloaded from http://pubs.acs.org on June 6, 2016
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Zinc-Mediated C-3 α-Prenylation of Isatins with Prenyl Bromide:
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Access to 3-Prenyl-3-hydroxy-2-oxindoles and Its Application
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Li-Ming Zhao,* Ai-Li Zhang, Jie-Huan Zhang, Hua-Shuai Gao, and Wei Zhou
School of Chemistry and Chemical Engineering, and Jiangsu Key Laboratory of Green
Synthetic Chemistry for Functional Materials, Jiangsu Normal University, Xuzhou 221116,
Jiangsu, China
lmzhao@jsnu.edu.cn
R3
R3
O
R4
HO
BrZn
R4
R1
O
R1
O
DMF
120 °C, 8 h
N
R2
N
R2
R1 = H, CH3, CH3O, F, Cl, Br, NO2
R2 = H, CH3, C2H5, allyl, substituted benzyl
R3 = R4 = CH3 or R3 = H, R4 = phenyl
28 examples
up to 98% yield
Abstract A convenient and highly α-regioselective strategy for the synthesis of
3-prenyl-3-hydroxy-2-oxindoles has been developed starting from isatins and prenylzinc with
good to excellent yield. This protocol provides a straightforward and practical way to
introduce an α-prenyl moiety to the C-3 position of isatins. The advantages of this reaction are
use of the cheap and readily available reagents, operational simplicity, and wide substrate
scope. Furthermore, this transformation was applied to the synthesis of several
oxindole-containing natural products, which further demonstrated the synthetic utility of this
methodology.
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INTRODUCTION
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3-Substituted-3-hydroxy-2-oxindoles have attracted increasing interest because of their
potential biological activities and their role as key precursors in the synthesis of bioactive
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molecules
and
natural
products.1
Among
those
oxindole
derivatives,
3-allyl-3-hydroxy-2-oxindoles are one of the most versatile building blocks to access various
alkaloids and molecules with biological importance.2 Accordingly, over the decades, many
methods have been reported for the synthesis of this class of compounds via the reactions of
isatins with allyl metal reagents such as indiums3a, 3b, stannanes3c, 3g, and silanes3d, 3e, 3f as
nucleophilic allyl sources. However, in contrast to the well-established allylation of isatins,
the analogous prenylation of isatins for the generation of 3-prenyl-3-hydroxy-2-oxindoles has
rarely been explored due to the challenging issue of regioselectivity. Generally,
α-regioselective prenylation of isatins is difficult to achieve when using α-substituted
allylmetal reagents such as prenylmetal.3a, 3b, 3d Consequently, these oxindole derivatives are
often assembled in a stepwise fashion by the initial preparation of a 3-substituted-2-oxindole
intermediate, which is then further elaborated to the target (Scheme 1a).4a In 2014,
Viswanathan and coworkers reported a potentially rate-accelerated “anionic-oxy-Cope”
rearrangement for prenylating the C4-position of oxindoles. Coincidentally they observed an
internal prenyl migratory event leading to C3-normal prenylated derivatives (Scheme 1b).4b
Considering the importance of the prenyl moiety, which represents an important natural
product substructure5 and plays a significant role in metabolism of living organisms,6 it is
conceivable that the development of a simple and general method for the synthesis of
3-prenyl-3-hydroxy-2-oxindoles via a one-step procedure featuring facile operation and
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readily available starting materials will be highly desirable.
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Scheme 1. Methods for the Preparation of 3-Prenyl-3-hydroxy-2-oxindoles
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9
Previous works:4a-b
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2013, by Krische group
OH
O
HO
Ru3(CO)12
PCy3
NaBH4
(a)
R
R
O
O
R
O
CH2Cl2/EtOH
-30 °C
PhMe
110 °C, 24 h
N
N
N
Bn
Bn
Bn
2014, by Viswanathan group
O
HO
HO
0.1 M phosphate buffer
pH = 8.8
R
R
R
(b)
O
O
O
W
N
N
H
N
H
H
150 W, 150 °C
Present work:
O
HO
BrZn
R1
O
R1
O
(c)
DMF
120 °C, 8 h
N
R2
N
R2
one-step preparation of 3-prenyl-3-hydroxy-2-oxindoles using cheap
and readily available reagents with a broader substrate scope
In the recent past, our research group was interested in the development of
methodologies towards simple and efficient regioselective prenylation using prenylzinc as the
allyl metal reagent for the synthesis of various α-prenylated compounds7 and their
applications.8 As a logical extension of our previous work and to explore the use of prenylzinc
in the preparation of structurally interesting compounds that may otherwise be inaccessible,
we report herein a powerful zinc-mediated prenylation reaction that allows direct access to
3-prenyl-3-hydroxy-2-oxindoles from simple and commercially available stating materials
(Scheme 1c). This method has several significant advantages. First, it provides a
straightforward route to these structurally interesting molecules in a single step, which
represents high synthetic efficiency. Second, the reaction shows a broader substrate scope,
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tolerating different types of substituted isatins. Third, isatins, prenyl bromide, and zinc as well
as N,N-dimethylformamide (DMF) are all cheap and readily available chemicals, which
brings great efficiency and convenience for the construction of the corresponding compound
library. Fourth, a Bn-protecting group at the N1 position is necessary for oxindoles in Scheme
1a. For the synthetic method reported in this paper, a Bn-protecting group (or any group) is
unnecessary. This is a practical advantage as it is well known that removal of such a
protecting group (especially late in a multi-step synthetic effort) may prove to be a challenge
in reality and that many oxindole-containing natural products do not carry a protecting group
at N1.9
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RESULTS AND DISCUSSION
Exposure of 1-methyl isatin 1a as a model substrate to the previously reported reaction
conditions7a that involve heating the reaction mixture to 120 °C in hexamethylphosphoramide
(HMPA) resulted in the formation of the desired product 2a in excellent yield (Table 1, entry
1). Under the previous conditions, a high yield of 2a was attained, but the carcinogenic
solvent HMPA was employed. The use of hazardous and toxic solvents in chemical
laboratories is considered a very important problem for the health and safety of chemists.
Furthermore, the solvent is the major source of waste in a chemical reaction, therefore, the
replacement of toxic solvents with greener alternatives is a crucial point in designing
environmentally improved methods toward functionalized molecules. Thus, other polar
aprotic solvents including 1,3-dimethyl-2-imidazolidinone (DMI) (entry 2), tetramethylurea
(TMU) (entry 3), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidinone (DMPU) (entry 4), and
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DMF (entry 5) were evaluated, and DMI and DMF were proven to be optimal, affording 2a in
93% and 92% yields, respectively. Compared with DMI, which is relatively expensive and
can be difficult to process due to its high boiling point (222 °C), DMF has obvious economic
and operational attractiveness. Consequently, DMF was chosen as the optimal solvent for the
reaction. We also noticed that a temperature of 120 °C was necessary to achieve the highly
α-regioselective result. When the reaction temperature was decreased from 120 °C to 110 °C,
the yield of the desired product 2a was reduced to 69% and was accompanied by 15% of
γ-adduct 3a (entry 6). When the temperature was decreased to 80 °C, the γ-isomer was almost
exclusively formed (entry 7). An attempt to conduct the reaction for a shorter reaction time
gave a decreased yield of 2a as well as a trace amount of 3a (entry 8). Therefore, we decided
to perform the subsequent reactions of isatins and prenylzinc at 120 °C in DMF for 8 h.
Table 1. Optimization of the Reaction Conditionsa
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O
HO
HO
BrZn
conditions
+
O
O
O
N
N
N
1a
entry
2a
3a
solvent
HMPA
DMI
T (°C)
120
120
120
120
120
110
t (h)
2a (%)b
95
3a (%)b
1
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8
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0
93
0
TMU
DMPU
DMF
52
0
67
0
92
0
DMF
69
15
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THF/DMF
DMF
80
8
6
trace
84
80
120
trace
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a Reactions were performed with 1a (0.5 mmol), prenyl bromide (1.0 mmol), and zinc (1.5
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mmol). b Isolated yield.
With the optimal conditions in hand, the reaction scope was examined by using various
isatins (Table 2). Initial investigation of the scope of the reaction was focused on varying the
substituents on the phenyl ring of isatins. Pleasingly, the reaction tolerated well all the
N-methylisatin derivatives with either an electron-donating or an electron-withdrawing group,
giving the corresponding α-prenylated products in good to excellent yields (entries 1-5). For
instance, N-methylisatin substrates with a methyl (1b) or a methoxy group (1c) at C-5
position led to the corresponding products 2b and 2c in 85% and 90% yields, respectively
(entries 1 and 2). Similarly, 5-bromo-N-methylisatin worked equally well (entry 3). More
importantly, the conditions showed noteworthy tolerance to the nitro group, albeit with a
decreased yield (entry 4). In addition, we assessed the influence of a bromo group at the C-4
position of N-methylisatin. Despite the possible steric interaction, the reaction of 1f proceeded
smoothly to afford 2f in 75% yield (entry 5). Further exploration into different N-protective
groups reveals that various groups such as ethyl, allyl, and benzyl were appropriate for the
reaction. For example, when the N-methyl protective group at the isatin framework (1a) was
changed into an N-ethyl (1g), N-allyl (1i), or N-benzyl groups (1m), the corresponding isatins
were smoothly converted into the 3-prenyl-3-hydroxy-2-oxindoles 2g, 2i, and 2m in 81%,
90%, and 85% yields, respectively (entries 6, 8, and 12). Moreover, almost all isatins with
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N-ethyl groups (1g-h), N-allyl groups (1i-l) and N-benzyl groups (1m-o) gave the desired
products in excellent yields (entries 6-14) with the exception of adducts 2o containing a nitro
group (entry 14) for which the isolated yields were somewhat lower but still acceptable. It is
noteworthy that the N-unprotected isatins 1p-w were also suitable reaction partners for this
regioselective prenylation and afforded the corresponding α-products 2p-w with good yields
(entries 15-22). This is particularly advantageous because the introduction and removal of
protective groups imposes extra labor on the synthesis of target compounds. These results
show that the reaction is quite general and the variation of the protective group on the N atom
or substituents on the phenyl ring of isatins have no significant influence on the reaction
efficiency. This methodology thus provides a practical and efficient means of realizing the
rapid introduction of an α-prenyl moiety to the C-3 position of isatins. All the products were
identified through NMR and HRMS. The structure of 2p was further confirmed by X-ray
crystallography (see the Supporting Information).
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Table 2. Formation of 3-Prenyl-3-hydroxy-2-oxindoles from Various Isatins 1 under the
Zinc-Mediated Prenylation Conditions
O
HO
BrZn
R1
O
R1
O
DMF
N
R2
N
120 °C, 8 h
R2
1
2
entry
1
R1, R2
2
yield (%)a α/γb
1
2
3
1b
1c
1d
5-CH3, CH3
5-OCH3, CH3
5-Br, CH3
2b
2c
2d
85
90
84
> 95:5
> 95:5
> 95:5
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4
1e
1f
5-NO2, CH3
4-Br, CH3
H, C2H5
2e
2f
60
75
81
92
90
91
85
98
85
89
53
83
80
71
62
73
55
72
82
> 95:5
> 95:5
> 95:5
> 95:5
> 95:5
> 95:5
> 95:5
> 95:5
> 95:5
> 95:5
> 95:5
> 95:5
> 95:5
> 95:5
> 95:5
> 95:5
> 95:5
> 95:5
> 95:5
5
6
1g
1h
1i
2g
2h
2i
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7
5-CH3, C2H5
H, allyl
8
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1j
5-CH3, allyl
5-OCH3, allyl
5-Br, allyl
H, 4-FC6H4CH2
H, 4-BrC6H4CH2
H, 4-NO2C6H4CH2
H, H
2j
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1k
1l
2k
2l
1m
1n
1o
1p
1q
1r
1s
2m
2n
2o
2p
2q
2r
2s
5-CH3, H
5-OCH3, H
5-F, H
1t
5-Br, H
2t
1u
1v
1w
5-NO2, H
2u
2v
2w
4-Cl, H
4-Br, H
a Isolated yield. b Determined by NMR.
To demonstrate the practicality of this protocol, a gram-scale synthesis of 2a was carried
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out under the standard conditions. As shown in Scheme 2, when 1.61 g of 1a was utilized,
1.86 g of product 2a was obtained in 81% yield without significant loss of efficiency (small
scale 92%, entry 5 in Table 1). Thus, this simple, one-step protocol could be extended as a
practical and efficient method to prepare various potentially bioactive
3-prenyl-3-hydroxy-2-oxindoles. The straightforward one-step process constitutes an
important practical feature of this method.
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Scheme 2. Gram-Scale α-Prenylation of Isatin 1a
O
HO
DMF
+
O
BrZn
O
120 °C
N
N
1.86 g, 81%
2a
1a
1.61 g
The synthesis of natural products constitutes one of the most demanding tests of the
viability of a new synthetic methodology. Therefore, a synthesis of soulieotine 4 was
undertaken in order to further test the viability of our zinc-mediated prenylation procedure as
an entry into some natural products.
Soulieotine 4 is an alkaloid isolated from the rhizomes of Souliea vaginata, a widely
distributed plant in China used as an anti-inflammatory analgesic.9d Taylor and coworkers
described the first synthesis of 4 by starting from 2-bromo-5-methoxybenzenamine via a
four-step procedure in an overall yield of 22%.10 More recently, Curti and coworkers have
synthesized soulieotine through
a
condensation of 6-methoxyoxindole with
3-methyl-2-butenal in 50% yield.11 In contrast, using our novel method, soulieotine 4 can be
obtained via 2x, prepared from commercially available 6-methoxyisatin 1x, in two steps with
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an overall yield of 66% (Scheme 3). More importantly, our procedure is highly stereoselective
to produce almost exclusively E geometry (soulieotine). This is particularly advantageous
because it is not always an easy task to prepare certain natural products with specific
geometry. For example, Taylor's procedure resulted in the formation of a mixture of
soulieotine (E geometry) and its Z isomer in a 2:1 ratio, although they could be separated by
chromatography.10 Curti's procedure yielded a 3:1 (E/Z) mixture of soulienotine.11 This result
thus highlights the usefulness of our procedure for synthesis of oxindole-containing natural
products.
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Scheme 3. Synthesis of Soulieotine via the Zinc-mediated Prenylation of 6-Methoxyisatin
O
HO
BrZn
O
O
DMF
120 °C, 8 h
N
N
O
O
H
H
1x
2x
(93%)
p-TsOH
O
toluene
reflux, 0.5 h
N
O
H
4
(71%)
E/Z > 95:5
Encouraged by the efficiency and high stereoselectivity observed in the synthesis of
soulieotine, we sought to examine the effects of this chemistry with respect to other
oxindole-containing natural products. (E)-3-(3-Methyl-2-butenylidene)-2-indolinone 5 was
isolated from the rhizomes of Cimicifuga foetida, a traditional Chinese medicine
"Shengma".12 It has in the past been synthesized through Wittig reaction of isatin with
γ,γ-dimethylallylphosphonium bromide via a short route.13 Unfortunately, the practical use of
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this route is limited by low yield (12%) and low stereoselectivity (E/Z = 2:1) in the Wittig
reaction. In our laboratory, zinc-mediated prenylation of isatin 1p followed by dehydration of
2p provided a 54% overall yield of (E)-3-(3-methyl-2-butenylidene)-2-indolinone 5 (Scheme
4). No stereoisomer was found in the reaction product, thus demonstrating the stereospecific
character of the process.
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Scheme 4. Synthesis of (E)-3-(3-Methyl-2-butenylidene)-2-indolinone
O
Table 2
entry 15
HO
O
O
N
N
H
H
1p
2p
p-TsOH
O
toluene
reflux, 0.5 h
N
H
5
(65%)
E/Z > 95:5
On the basis of the experimental results and previous reports,4b,7a two plausible pathways
for this one-step method to generate 3-prenyl-3-hydroxy-2-oxindoles were proposed as shown
in Scheme 5. Both pathway I and patheway II are initiated by the nucleophilic attack of the
γ-carbon of prenylzinc at 3-carbonyl of isatin to yield the zinc alcoholate A via a
six-membered cyclic transition state (TS) analogous to that reported previously.14 Then, in
path I, DMF acts as a Lewis base interacting with the zinc atom of initially formed zinc
alcoholate A15 and the resulting intermediate further coordinates the isatin, which results in
the formation of B. Subsequently, a metallo[3,5]-sigmatropic shift at an elevated temperature
via a eight-membered TS occurs to generate C. Finally, elimination of parent isatin from C
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could produce intermediate D, which could convert to the target product 2 after work-up.
Alternatively, at high temperature, the thermolysis of zinc alcoholate A could also occur
leading to the homolytic cleavage of C3-reverse prenyl σ bond to afford the prenyl radical
intermediate and a carbon radical as shown in intermediate E. Subsequent recombination of
these two radicals and final work-up would furnish the α-adduct 2 (path II).
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Scheme 5. Two Potential Mechanistic Pathways
Br DMF
Br DMF
path I
DMF
O
BrZnO
Zn O
Zn O
R
R
R'
O
O
prenylzinc
[3,5]
R'
R1
O
R1
O
R
R
N
R2
N
R2

R'
R'
1
B
A
C
I
I
s
i
h
s
t
R, R' = oxindole
y
l
a
p
o
m

o
h
1
DMF
Br
Zn
HO
O
OZnBr
O
H3O+
work-up
recombination
work-up
R1
R1
O
R1
O
N
R2
N
R2
N
R2
D
E
2
To obtain mechanistic insight, 1p was treated with hydroquinone or
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) under the standard conditions. It was
observed that the addition of the radical-trapping reagents did not inhibit the reaction and 2p
was obtained in 85% and 81% yields, respectively. These results indicate that the radical
process might not be involved in the regioselective prenylation (path II) (See the Supporting
Information).
For verification of the path I, an experiment involving the reaction of zinc alcoholate A
with N-methylisatin 1a was carried out. 3-γ-Prenyl-3-hydroxy-2-oxindoles 3a was first
transformed to its zinc alkoxide in the presence of BuLi and zinc bromide. Then, the zinc
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alkoxide was treated with N-methylisatin 1a in DMF in 120 °C, and after 7 h, the -product
2a was obtained in 85% yield (Scheme 6). Based on the above observations, we consider that
it is possible that the reaction proceeded via the former mechanism.
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Scheme 6. Reaction of Zinc Alcoholate and N-Methylisatin
HO
BrZnO
BuLi
ZnBr2
O
O
O
N
N
N
3a
O
O
HO
N
1a
DMF
2a
Due to the above success, other 3-substituted allylmetal reagents, such as cinnamylzinc
bromide, were also investigated in the reaction with isatins. As clearly shown in Table 3, it
was also found that cinnamyl bromide worked well for various isatins bearing different
substituents on the phenyl ring of isatins including electron-donating (methyl, entries 1 and 3)
and electron-withdrawing (bromo, entries 2 and 4) groups as well as different N-protective
groups such as methyl (entries 1 and 2), ethyl (entry 3), allyl (entry 4), and benzyl groups
(entry 5) under the standard reaction conditions to afford the corresponding α-products in
good yields.
Table 3. α-Selective Allylation of Isatins 1 Using Cinnamyl Bromide as the Allylation
Reagent
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BrZn
O
HO
6
7
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R1
O
R1
O
DMF
120 °C, 8 h
N
R2
N
R2
1
6
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entry
1
R1, R2
6
yield (%)a α/γb
1
2
3
4
5
1b
1d
1h
1l
5-CH3, CH3
5-Br, CH3
6b
6d
6h
6l
80
72
77
75
84
> 95:5
> 95:5
> 95:5
> 95:5
> 95:5
5-CH3, C2H5
5-Br, allyl
1n
H, 4-BrC6H4CH2
6n
a Isolated yield. b Determined by NMR.
CONCLUSIONS
In conclusion, we show that 3-prenyl-3-hydroxy-2-oxindoles can be directly prepared from
isatins and prenyl bromide by means of a convenient and efficient procedure based on a
zinc-mediated highly α-regioselective prenylation. A wide range of isatins were tolerated in
this method, and all the α-prenylated products could be obtained in good to excellent yields.
Due to the easy accessibility and low cost of the reactants and reagents and the simple
manipulations of the reaction, this method is very practical and has good economical and
environmental advantages. Furthermore, the utility of this reaction has been demonstrated via
the syntheses of some natural products and this procedure provides an efficient and
stereoselective route to those natural products. Thus, the reaction, obviously, offers significant
advantages over the previous protocols for the synthesis of 3-prenyl-3-hydroxy-2-oxindoles
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and some related natural products. Moreover, the importance of these compounds would
render this protocol attractive for both synthetic and medicinal chemistry.
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EXPERIMENTAL SECTION
General Methods Melting points are uncorrected. H NMR and 13C NMR spectra were
1
recorded at 400 MHz and 100 MHz in CDCl3 or DMSO-d6 with chemical shift (δ) given in
ppm relative to TMS as internal standard. Multiplicities were indicated, s (singlet), d (doublet),
t (triplet), m (multiplet), dd (doublet of doublets), etc; coupling constant (J) were given in
Hertz (Hz). High resolution mass spectra (HRMS) were recorded using atmospheric pressure
chemical ionization (APCI) or electrospray ionization (ESI) and time-of-flight (TOF) mass
analysis.
General Procedure for the Synthesis of 2 and 6. Allyl bromide (1.0 mmol) was added
into a suspension of activated zinc powder (1.5 mmol) in dry THF (10 ml); the reaction
mixture was stirred for 1 h at room temperature (reflux 1 h for cinnamyl bromide). Filtered
the solution through a Schlenk filter and kept under N2 for the following reaction. A solution
of isatins 1 (0.5 mmol) in dry THF (3 ml) was added to the solution of allylzinc bromide
prepared above. Then DMF (1.5 ml) was added to the reaction mixture, followed by removal
of initial reaction solvent (THF). The mixture was heated to 120 °C under N2 for 8 h.
Analysis of the final reaction mixtures by 1H NMR showed that no γ-products were observed.
After cooling to room temperature, the residue was purified by flash column chromatography
(petroleum ether/ethyl acetate, 3/1) to afford the α-product 2 and 6.
3-Hydroxy-1-methyl-3-(3-methylbut-2-enyl)indolin-2-one (2a). White solid (106 mg,
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92% yield); mp 101-103 ºC. 1H NMR (400 MHz, CDCl3) δ: 7.42-7.28 (m, 2H), 7.13-7.04 (m,
1H), 6.82 (d, J = 7.8 Hz, 1H), 5.03 (t, J = 7.6 Hz, 1H), 3.18 (s, 3H), 3.00 (s, 1H), 2.63 (d, J =
7.7 Hz, 2H), 1.65 (s, 3H), 1.54 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 178.2, 143.4, 137.4,
130.2, 129.6, 124.1, 123.1, 115.9, 108.4, 76.3, 37.5, 26.3, 26.1, 18.1. HRMS (APCI): m/z
calcd for C14H18NO2 [M + H]+: 232.1338; found: 232.1341.
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3-Hydroxy-1,5-dimethyl-3-(3-methylbut-2-enyl)indolin-2-one (2b). White solid (105 mg,
85% yield); mp 142-144 ºC. 1H NMR (400 MHz, CDCl3) δ: 7.20 (s, 1H), 7.11-7.09 (m, 1H),
6.70 (d, J = 7.9 Hz, 1H), 5.08-4.93 (m, 1H), 3.17 (s, 1H), 3.15(s, 3H), 2.68-2.55 (m, 2H), 2.34
(s, 3H), 1.65 (s, 3H), 1.55 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 178.2, 141.0, 137.2, 132.6,
130.3, 129.7, 124.9, 116.0, 108.1, 76.4, 37.5, 26.3, 26.1, 21.2, 18.1. HRMS (APCI): m/z calcd
for C15H20NO2 [M + H]+: 246.1494; found: 246.1524.
3-Hydroxy-5-methoxy-1-methyl-3-(3-methylbut-2-enyl)indolin-2-one (2c). Pale yellow
1
solid (117 mg, 90% yield); mp 148-150 ºC. H NMR (400 MHz, CDCl3) δ: 7.01 (d, J = 2.6
Hz, 1H), 6.84 (dd, J = 8.5, 2.6 Hz, 1H), 6.72 (d, J = 8.5 Hz, 1H), 5.04-5.01 (m, 1H), 3.80 (s,
3H), 3.15-3.13 (m, 4H), 2.62 (d, J = 7.6 Hz, 2H), 1.66 (s, 3H), 1.54 (s, 3H). 13C NMR (100
MHz, CDCl3) δ: 178.0, 156.4, 137.3, 136.8, 131.5, 116.0, 114.2, 111.3, 108.8, 76.7, 56.0, 37.5,
26.4, 26.1, 18.2. HRMS (APCI): m/z calcd for C15H20NO3 [M + H]+: 262.1443; found:
262.1441.
5-Bromo-3-hydroxy-1-methyl-3-(3-methylbut-2-enyl)indolin-2-one (2d). White solid
(130 mg, 84% yield); mp 155-157 ºC. 1H NMR (400 MHz, CDCl3) δ: 7.54-7.39 (m, 2H), 6.70
(d, J = 8.2 Hz, 1H), 5.05-5.00 (m, 1H), 3.16 (s, 3H), 2.82 (s, 1H), 2.60 (d, J = 7.7 Hz, 2H),
1.68 (s, 3H), 1.56 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 177.6, 142.5, 138.2, 132.5, 132.2,
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127.5, 115.8, 115.3, 109.9, 76.2, 37.5, 26.4, 26.1, 18.2. HRMS (APCI): m/z calcd for
C14H17BrNO2 [M + H]+: 310.0443; found: 310.0460.
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3-Hydroxy-1-methyl-3-(3-methylbut-2-enyl)-5-nitroindolin-2-one (2e). Yellow solid (83
mg, 60% yield); mp 154-156 ºC. 1H NMR (400 MHz, DMSO-d6) δ: 8.25 (dd, J = 8.7, 2.4 Hz,
1H), 8.09 (d, J = 2.4 Hz, 1H), 7.18 (d, J = 8.7 Hz, 1H), 4.77-4.76 (m, 1H), 3.13 (s, 3H),
2.69-2.47 (m, 2H), 1.49 (s, 3H), 1.34 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ: 178.2, 149.7,
143.0, 136.0, 132.7, 126.7, 119.5, 116.6, 109.1, 75.4, 36.6, 26.7, 26.0, 18.2. Negative ion
HRMS (ESI): m/z calcd for C14H15N2O4 [M - H]-: 275.1032; found: 275.1018.
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4-Bromo-3-hydroxy-1-methyl-3-(3-methylbut-2-enyl)indolin-2-one (2f). Pale yellow
solid (116 mg, 75% yield); mp 136-138 ºC. 1H NMR (400 MHz, DMSO-d6) δ: 7.22-7.07 (m,
2H), 6.91 (dd, J = 7.6, 0.9 Hz, 1H), 4.40-4.36 (m, 1H), 3.00 (s, 3H), 2.95 (dd, J = 13.6, 7.5 Hz,
1H), 2.52 (dd, J = 13.6, 7.5 Hz, 1H), 1.40 (s, 3H), 1.36 (s, 3H). 13C NMR (100 MHz, DMSO)
δ: 177.1, 146.0, 135.6, 131.3, 128.9, 126.6, 118.9, 116.5, 108.1, 77.6, 34.2, 26.3, 26.0, 18.3.
Negative ion HRMS (ESI): m/z calcd for C14H15BrNO2 [M - H]-: 308.0286; found: 308.0309.
1-Ethyl-3-hydroxy-3-(3-methylbut-2-enyl)indolin-2-one (2g). White solid (99 mg, 81%
1
yield); mp 110-113 ºC. H NMR (400 MHz, CDCl3) δ: 7.39 (dd, J = 7.3, 0.8 Hz, 1H),
7.36-7.23 (m, 1H), 7.09-7.05 (m, 1H), 6.82 (d, J = 7.8 Hz, 1H), 4.93-4.89 (m, 1H), 3.87-3.78
(m, 1H), 3.65-3.56 (m, 1H), 3.19 (s, 1H), 2.79-2.53 (m, 2H), 1.60 (s, 3H), 1.52 (s, 3H), 1.22 (t,
J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ: 177.9, 142.5, 137.0, 130.5, 129.5, 124.2,
122.86, 116.0, 108.4, 76.4, 37.7, 34.7, 26.0, 18.1, 12.7. HRMS (APCI): m/z calcd for
C15H20NO2 [M + H]+: 246.1494; found: 246.1505.
1-Ethyl-3-hydroxy-5-methyl-3-(3-methylbut-2-enyl)indolin-2-one (2h). Pale yellow
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solid (119 mg, 92% yield); mp 150-153 ºC. H NMR (400 MHz, CDCl3) δ: 7.21 (d, J = 1.1
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8
9
Hz, 1H), 7.10-7.08 (m, 1H), 6.71 (d, J = 7.9 Hz, 1H), 4.91-4.89 (m, 1H), 3.84-3.75 (m, 1H),
3.62-3.53 (m, 1H), 3.29-3.26 (m, 1H), 2.72-2.58 (m, 2H), 2.34 (s, 3H), 1.60 (s, 3H), 1.53 (s,
3H), 1.20 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ: 177.8, 140.1, 136.9, 132.4,
130.5, 129.7, 125.0, 116.1, 108.2, 76.5, 37.7, 34.7, 26.0, 21.2, 18.1, 12.70. HRMS (APCI):
m/z calcd for C16H22NO2 [M + H]+: 260.1651; found: 260.1658.
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1-Allyl-3-hydroxy-3-(3-methylbut-2-enyl)indolin-2-one (2i). White solid (116 mg, 90%
yield); mp 117-118 ºC. 1H NMR (400 MHz, CDCl3) δ: 7.40 (d, J = 8.1 Hz, 1H), 7.30-7.26 (m,
1H), 7.10-7.06 (m, 1H), 6.79 (d, J = 7.8 Hz, 1H), 5.89-5.67 (m, 1H), 5.24-5.12 (m, 2H),
4.94-4.90 (m, 1H), 4.50-4.45 (m, 1H), 4.14-4.08 (m, 1H), 3.20 (s, 1H), 2.75-2.64 (m, 2H),
1.60 (s, 3H), 1.52 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 178.0, 142.7, 137.3, 131.2, 130.2,
129.5, 124.1, 123.0, 117.3, 116.0, 109.3, 76.5, 42.3, 37.7, 26.0, 18.1. HRMS (APCI): m/z
calcd for C16H20NO2 [M + H]+: 258.1494; found: 258.1513.
1-Allyl-3-hydroxy-5-methyl-3-(3-methylbut-2-enyl)indolin-2-one (2j). Pale yellow solid
(123 mg, 91% yield); mp 112-114 ºC. 1H NMR (400 MHz, CDCl3) δ: 7.22 (d, J = 1.1 Hz, 1H),
7.08-7.05 (m, 1H), 6.67 (d, J = 7.9 Hz, 1H), 5.83-5.73 (m, 1H), 5.23-5.11 (m, 2H), 4.91-4.87
(m, 1H), 4.52-4.36 (m, 1H), 4.13-4.02 (m, 1H), 3.38 (s, 1H), 2.76-2.61 (m, 2H), 2.33 (s, 3H),
1.60 (s, 3H), 1.53 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 178.0, 140.3, 137.1, 132.6, 131.3,
130.18, 129.7, 124.9, 117.2, 116.1, 109.0, 76.6, 42.3, 37.7, 26.0, 21.2, 18.1. HRMS (APCI):
m/z calcd for C17H22NO2 [M + H]+: 272.1651; found: 272.1677.
1-Allyl-3-hydroxy-5-methoxy-3-(3-methylbut-2-enyl)indolin-2-one (2k). Pale yellow
1
solid (122 mg, 85% yield); mp 109-111 ºC. H NMR (400 MHz, CDCl3) δ: 7.02 (d, J = 2.6
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Hz, 1H), 6.80 (dd, J = 8.5, 2.6 Hz, 1H), 6.70 (d, J = 8.5 Hz, 1H), 5.83-5.74 (m, 1H), 5.26-5.10
(m, 2H), 4.94-4.90 (m, 1H), 4.48-4.42 (m, 1H), 4.15-4.01 (m, 1H), 3.80 (s, 3H), 3.15 (s, 1H),
2.79-2.57 (m, 2H), 1.62 (s, 3H), 1.54 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 177.7, 156.3,
137.3, 136.0, 131.4, 131.4, 117.3, 116.0, 114.3, 111.1, 109.8, 76.8, 56.0, 42.4, 37.8, 26.1,
18.14. HRMS (APCI): m/z calcd for C17H22NO3 [M + H]+: 288.1600; found: 288.1619.
1-Allyl-5-bromo-3-hydroxy-3-(3-methylbut-2-enyl)indolin-2-one (2l). Pale yellow solid
(164 mg, 98% yield); mp 93-94 ºC. 1H NMR (400 MHz, CDCl3) δ: 7.51 (d, J = 2.0 Hz, 1H),
7.40 (dd, J = 8.3, 2.0 Hz, 1H), 6.67 (d, J = 8.3 Hz, 1H), 5.82-5.72 (m, 1H), 5.22-5.14 (m, 2H),
4.92-4.89 (m, 1H), 4.49-4.43 (m, 1H), 4.12-4.06 (m, 1H), 3.19 (s, 1H), 2.74-2.61 (m, 2H),
1.62 (s, 3H), 1.54 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 177.5, 141.7, 138.0, 132.4, 132.2,
130.8, 127.5, 117.6, 115.8, 115.4, 110.8, 76.4, 42.4, 37.7, 26.1, 18.1. HRMS (APCI): m/z
calcd for C16H19BrNO2 [M + H]+: 336.0599; found: 336.0583.
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1-(4-Fluorobenzyl)-3-hydroxy-3-(3-methylbut-2-enyl)indolin-2-one (2m). Pale yellow
solid (138 mg, 85% yield); mp 146-148 ºC. 1H NMR (400 MHz, CDCl3) δ: 7.42-7.39 (m, 1H),
7.26-7.17 (m, 3H), 7.09-7.05 (m, 1H), 7.0-6.96 (m, 2H), 6.65 (d, J = 7.8 Hz, 1H), 5.07 (d, J =
15.7 Hz, 1H), 4.89-4.85 (m, 1H), 4.59 (d, J = 15.7 Hz, 1H), 3.31 (s, 1H), 2.83-2.68 (m, 2H),
1.60 (s, 3H), 1.54 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 178.4, 162.3 (J = 244.6 Hz), 142.5,
137.4, 131.5, 131.4, 130.1, 129.6, 129.0, 128.9, 124.2, 123.3, 116.0 (J = 3.0 Hz), 115.7, 109.3,
76.5, 43.2, 37.7, 26.1, 18.2. HRMS (APCI): m/z calcd for C20H21FNO2 [M + H]+: 326.1556;
found: 326.1562.
1-(4-Bromobenzyl)-3-hydroxy-3-(3-methylbut-2-enyl)indolin-2-one (2n). Pale yellow
solid (171 mg, 89% yield); mp 186-188 ºC. 1H NMR (400 MHz, CDCl3) δ: 7.44-7.40 (m, 3H),
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7.22-7.18 (m, 1H), 7.13 (d, J = 8.4 Hz, 2H), 7.09-7.06 (m, 1H), 6.62 (d, J = 7.8 Hz, 1H), 5.06
(d, J = 15.9 Hz, 1H), 4.90-4.86 (m, 1H), 4.57 (d, J = 15.9 Hz, 1H), 2.99 (s, 1H), 2.82-2.68 (m,
2H), 1.62 (s, 3H), 1.56 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 178.2, 142.4, 137.6, 134.8,
132.1, 132.1, 130.0, 129.7, 129.0, 129.0, 124.2, 123.3, 121.7, 115.9, 109.3, 76.5, 43.3, 37.7,
26.1, 18.2. HRMS (APCI): m/z calcd for C20H21BrNO2 [M + H]+: 386.0756; found:
386.0742.
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3-Hydroxy-3-(3-methylbut-2-enyl)-1-(4-nitrobenzyl)indolin-2-one (2o). Pale yellow
solid (93 mg, 53% yield); mp 136-137 ºC. 1H NMR (400 MHz, CDCl3) δ: 8.19-8.15 (m, 2H),
7.62-7.34 (m, 3H), 7.26-7.20 (m, 1H), 7.13-7.08 (m, 1H), 6.58 (d, J = 7.8 Hz, 1H), 5.20 (d, J
= 16.5 Hz, 1H), 4.91-4.87 (m, 1H), 4.73 (d, J = 16.5 Hz, 1H), 3.17 (s, 1H), 2.87-2.69 (m, 2H),
1.64 (s, 3H), 1.56 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 178.4, 147.6, 143.2, 142.1, 137.8,
130.0, 129.8, 127.9, 127.9, 124.5, 124.2, 124.2, 123.7, 115.8, 109.0, 76.5, 43.3, 37.7, 26.2,
18.2. HRMS (APCI): m/z calcd for C20H21N2O4 [M + H]+: 353.1501; found: 353.1477.
3-Hydroxy-3-(3-methylbut-2-enyl)indolin-2-one (2p). Pale yellow solid (90 mg, 83%
1
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yield); mp 144-146 ºC. This compound has been previously reported and H and C NMR
spectral data match described.4b 1H NMR (400 MHz, CDCl3) δ: 8.08 (s, 1H), 7.37 (d, J = 7.4
Hz, 1H), 7.28-7.23 (m, 1H), 7.06 (td, J = 7.6, 0.9 Hz, 1H), 6.86 (d, J = 7.7 Hz, 1H), 5.06-5.02
(m, 1H), 3.13 (s, 1H), 2.65 (d, J = 7.6 Hz, 2H), 1.65 (s, 3H), 1.55 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ: 180.4, 140.4, 137.6, 130.7, 129.7, 124.5, 123.1, 115.7, 110.3, 76.7, 37.4, 26.1, 18.1.
HRMS (APCI): m/z calcd for C13H16NO2 [M + H]+: 218.1181; found: 218.1178.
3-Hydroxy-5-methyl-3-(3-methylbut-2-enyl)indolin-2-one (2q). Pale yellow solid (92
1
mg, 80% yield); mp 194-196 ºC. H NMR (400 MHz, CDCl3) δ: 7.70 (s, 1H), 7.18 (s, 1H),
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7.05 (d, J = 7.8 Hz, 1H), 6.74 (d, J = 7.9 Hz, 1H), 5.03 (t, J = 7.2 Hz, 1H), 2.93 (s, 1H),
2.76-2.50 (m, 2H), 2.33 (s, 3H), 1.66 (s, 3H), 1.62 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ:
179.5, 139.7, 134.5, 132.4, 130.6, 129.4, 125.1, 117.8, 109.5, 76.1, 37.0, 26.1, 21.2, 18.3.
HRMS (APCI): m/z calcd for C14H18NO2 [M + H]+: 232.1338; found: 232.1333.
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3-Hydroxy-5-methoxy-3-(3-methylbut-2-enyl)indolin-2-one (2r). Pale yellow solid (87
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mg, 71% yield); mp 142-144 ºC. H NMR (400 MHz, CDCl3) δ: 8.51 (s, 1H), 6.97 (s, 1H),
6.77 (d, J = 1.9 Hz, 2H), 5.03-5.0 (m, 1H), 3.78 (s, 3H), 3.66 (s, 1H), 2.64 (d, J = 8.6 Hz, 2H),
1.64 (s, 3H), 1.53 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 180.8, 156.2, 137.3, 133.7, 132.0,
115.8, 114.6, 111.1, 110.9, 77.5, 55.9, 37.4, 26.1, 18.1. HRMS (APCI): m/z calcd for
C14H18NO3 [M + H]+: 248.1287; found: 248.1291.
5-Fluoro-3-hydroxy-3-(3-methylbut-2-enyl)indolin-2-one (2s). Pale yellow solid (72 mg,
1
62% yield); mp 188-190 ºC. H NMR (400 MHz, DMSO-d6) δ: 10.12 (s, 1H), 7.02 (dd, J =
8.2, 2.7 Hz, 1H), 6.95-6.90 (m, 1H), 6.67 (dd, J = 8.4, 4.3 Hz, 1H), 4.70-4.64 (m, 1H),
2.42-2.34 (m, 2H), 1.44 (s, 3H), 1.34 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ: 179.47,
158.4 (J = 235.4 Hz), 138.3, 135.0, 134.2 (J = 7.4 Hz), 117.3, 115.4 (J = 23.1 Hz), 112.2 (J =
24.1 Hz), 110.5 (J = 7.8 Hz), 76.3, 36.8, 26.1, 18.2. Negative ion HRMS (ESI): m/z calcd for
C13H13FNO2 [M - H]-: 234.0930; found: 234.0936.
5-Bromo-3-hydroxy-3-(3-methylbut-2-enyl)indolin-2-one (2t). Pale yellow solid (107
mg, 73% yield); mp 214-216 ºC. This compound has been previously reported and 13C NMR
spectral data match described.4b The proton signals were not quite superimposed with those of
previously reported compound since a different solvent was used in the NMR measurement.
1H NMR (400 MHz, DMSO-d6) δ: 10.25 (s, 1H), 7.41-7.21 (m, 2H), 6.67 (d, J = 8.1 Hz, 1H),
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4.71-4.67 (m, 1H), 2.43-2.36 (m, 2H),1.54 (s, 3H), 1.43 (s, 3H). C NMR (100 MHz,
DMSO-d6) δ: 179.0, 141.4, 135.2, 134.8, 131.9, 127.4, 117.2, 113.6, 111.8, 76.2, 36.8, 26.1,
18.3. HRMS (APCI): m/z calcd for C13H15BrNO2 [M + H]+: 296.0286; found: 296.0316.
3-Hydroxy-3-(3-methylbut-2-enyl)-5-nitroindolin-2-one (2u). Pale yellow solid (72 mg,
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55% yield); mp 231-233 ºC. H NMR (400 MHz, DMSO-d6) δ: 10.87 (s, 1H), 8.11 (dd, J =
8.6, 2.4 Hz, 1H), 8.03 (d, J = 2.4 Hz, 1H), 6.92 (d, J = 8.6 Hz, 1H), 4.75-4.72 (m, 1H),
2.57-2.44 (m, 2H), 1.47 (s, 3H), 1.33 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ: 179.8, 148.7,
142.5, 135.9, 133.3, 126.7, 120.0, 116.8, 110.1, 75.8, 36.6, 26.1, 18.2. HRMS (APCI): m/z
calcd for C13H15N2O4 [M + H]+: 263.1032; found: 263.1058.
4-Chloro-3-hydroxy-3-(3-methylbut-2-enyl)indolin-2-one (2v). Pale yellow solid (90 mg,
72% yield); mp 211-213 ºC. 1H NMR (400 MHz, DMSO-d6) δ: 10.33 (s, 1H), 7.12 (t, J = 8.0
Hz, 1H), 6.85 (dd, J = 8.2, 0.8 Hz, 1H), 6.66 (dd, J = 7.7, 0.8 Hz, 1H), 4.45 (s, 1H), 2.85 (dd,
J = 13.5, 7.4 Hz, 1H), 2.51 (dd, J = 13.5, 7.7 Hz, 1H), 1.40 (s, 3H), 1.38 (s, 3H). 13C NMR
(100 MHz, DMSO-d6) δ: 178.6, 144.4, 135.4, 131.1, 130.8, 127.9, 122.8, 116.9, 108.8, 77.2,
34.4, 26.1, 18.2. Negative ion HRMS (ESI): m/z calcd for C13H13ClNO2 [M - H]-: 250.0635;
found: 250.0650.
4-Bromo-3-hydroxy-3-(3-methylbut-2-enyl)indolin-2-one (2w). White solid (121 mg,
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82% yield); mp 208-210 ºC. H NMR (400 MHz, CDCl3) δ: 8.03 (s, 1H), 7.18 (dd, J = 8.2,
0.9 Hz, 1H), 7.11 (t, J = 7.9 Hz, 1H), 6.80 (dd, J = 7.6, 0.9 Hz, 1H), 4.84-4.80 (m, 1H),
3.10-2.97 (m, 2H), 2.91 (dd, J = 13.6, 8.5 Hz, 1H), 1.60 (s, 3H), 1.59 (s, 3H). 13C NMR (100
MHz, DMSO-d6) δ: 178.7, 144.6, 135.3, 131.3, 129.5, 125.9, 119.2, 116.9, 109.3, 77.8, 34.2,
26.1, 18.3. HRMS (APCI): m/z calcd for C13H15BrNO2 [M + H]+: 296.0286; found:
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3-Cinnamyl-3-hydroxy-1,5-dimethylindolin-2-one (6b). Yellow oil (117 mg, 80% yield);
1H NMR (400 MHz, CDCl3) δ: 7.32-7.18 (m, 6H), 7.13 (d, J = 7.9 Hz, 1H), 6.71 (d, J = 7.9
Hz, 1H), 6.46 (d, J = 15.9 Hz, 1H), 6.20-5.93 (m, 1H), 3.15 (s, 3H), 3.03-2.76 (m, 2H),
2.77-2.68 (m, 1H), 2.35 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 177.7, 141.0, 137.2, 135.3,
132.9, 130.1, 129.8, 128.6, 128.6, 127.6, 126.4, 126.4, 125.0, 122.1, 108.4, 76.3, 42.4, 26.4,
21.3. HRMS (APCI): m/z calcd for C19H20NO2 [M + H]+: 294.1494; found: 294.1480.
5-Bromo-3-cinnamyl-3-hydroxy-1-methylindolin-2-one (6d). Yellow oil (129 mg, 72%
yield); 1H NMR (400 MHz, CDCl3) δ: 7.53 (d, J = 1.9 Hz, 1H), 7.43 (dd, J = 8.3, 2.0 Hz, 1H),
7.27-7.12 (m, 5H), 6.66 (d, J = 8.3 Hz, 1H), 6.41 (d, J = 15.8 Hz, 1H), 6.12-5.78 (m, 1H),
4.12 (s, 1H), 3.09 (s, 3H), 2.89-2.84 (m, 1H), 2.80-2.66 (m, 1H). 13C NMR (100 MHz, CDCl3)
δ: 177.8, 177.7, 142.2, 136.9, 135.6, 132.5, 132.1, 132.0, 128.6, 127.6, 127.5, 126.4, 121.3,
116.0, 110.1, 76.5, 42.1, 26.4. HRMS (APCI): m/z calcd for C18H17BrNO2 [M + H]+:
358.0443; found: 358.0458.
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3-Cinnamyl-1-ethyl-3-hydroxy-5-methylindolin-2-one (6h). White solid (119 mg, 77%
yield); mp 137-139 ºC. 1H NMR (400 MHz, CDCl3) δ: 7.29-7.22 (m, 5H), 7.19 (d, J = 8.6 Hz,
1H), 7.11 (d, J = 8.8 Hz, 1H), 6.72 (d, J = 7.9 Hz, 1H), 6.43 (d, J = 15.8 Hz, 1H), 6.04-5.82
(m, 1H), 3.81-3.72 (m, 1H), 3.64-3.55 (m, 1H), 3.04 (dd, J = 15.3, 6.0 Hz, 1H), 2.94-2.69 (m,
2H), 2.35 (s, 3H), 1.15 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ: 177.4, 140.0,
137.2, 135.2, 132.7, 130.0, 130.0, 128.6, 128.6, 127.5, 126.4, 126.4, 125.2, 122.1, 108.5, 76.5,
42.5, 34.8, 21.2, 12.8. HRMS (APCI): m/z calcd for C20H22NO2 [M + H]+: 308.1651; found:
308.1671.
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1-Allyl-5-bromo-3-cinnamyl-3-hydroxyindolin-2-one (6l). White solid (143 mg, 75%
yield); 1H NMR (400 MHz, CDCl3) δ: 7.56 (d, J = 1.8 Hz, 1H), 7.41 (dd, J = 8.3, 2.0 Hz, 1H),
7.28-7.17 (m, 5H), 6.67 (d, J = 8.3 Hz, 1H), 6.44 (d, J = 15.8 Hz, 1H), 6.04-5.81 (m, 1H),
5.72-5.62 (m, 1H), 5.08 (dd, J = 18.8, 13.9 Hz, 2H), 4.42-4.36 (m, 1H), 4.10 (dd, J = 16.9, 4.8
Hz, 1H), 3.40 (s, 1H), 2.92-2.78 (m, 2H). 13C NMR (100 MHz, CDCl3) δ: 177.2, 141.6, 136.8,
135.9, 132.6, 131.8, 130.7 128.6, 128.6, 127.8, 127.6, 126.4, 126.4, 121.1, 118.1, 116.0, 111.1,
76.5, 42.5, 42.5.HRMS (APCI): m/z calcd for C20H19BrNO2 [M + H]+: 384.0599; found:
384.0569.
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1-(4-Bromobenzyl)-3-cinnamyl-3-hydroxyindolin-2-one (6n). White solid (182 mg, 84%
yield); mp 179-181 ºC. 1H NMR (400 MHz, CDCl3) δ: 7.46 (d, J = 7.2 Hz, 1H), 7.27-7.22 (m,
4H), 7.24-7.13 (m, 3H), 7.11 (t, J = 7.5 Hz, 1H), 7.05-6.99 (m, 3H), 6.61 (d, J = 7.8 Hz, 1H),
6.45 (d, J = 15.8 Hz, 1H), 5.94-5.71 (m, 1H), 5.09 (d, J = 15.9 Hz, 1H), 4.47 (d, J = 15.9 Hz,
1H), 3.36 (s, 1H), 3.07-2.84 (m, 2H). 13C NMR (100 MHz, CDCl3) δ: 177.9, 142.4, 136.8,
135.6, 134.3, 132.0, 132.0, 130.0, 129.6, 128.9, 128.9, 128.7, 128.7, 127.9, 126.5, 126.5,
124.3, 123.6, 121.6, 121.6, 109.5, 76.6, 43.5, 42.5. HRMS (APCI): m/z calcd for
C24H21BrNO2 [M + H]+: 434.0756; found: 434.0733.
Synthesis of soulieotine 4. Compound 2x (100 mg, 0.4 mmol) was dissolved in toluene
(5.0 mL). Then p-toluenesulfonic acid (0.2 equiv) was added. The mixture was heated to
reflux for 0.5 h. After being cooled to room temperature, the solvent was evaporated in
vacuum. The residue was purified by flash column chromatography (petroleum ether/ethyl
acetate, 3/1) to afford 4 (66 mg, 71% yield) as a yellow solid. The product was identified as a
E geometry by a typical trans coupling constant of 12.6 Hz for the double bond. Mp 201-203
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ºC. 1H NMR (400 MHz, CDCl3) δ: 7.72 (br s, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.45 (d, J = 12.6
Hz, 1H), 6.73 (ddd, J = 12.6, 2.4, 1.2 Hz, 1H), 6.55 (dd, J = 8.5, 2.4 Hz, 1H), 6.45 (d, J = 2.3
Hz, 1H), 3.83 (s, 3H), 2.04 (s, 3H), 2.03 (s, 3H). 13C NMR (100 MHz, CDCl3) δ: 171.2, 160.4,
150.7, 142.0, 130.2, 124.8, 122.9, 121.5, 116.5, 107.2, 96.8, 55.7, 27.6, 19.1. HRMS (ESI):
m/z calcd for C14H16NO2 [M + H]+: 230.1175; found: 230.1134. All spectral data is consistent
with that previously reported. 9d, 10
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Synthesis
of
(E)-3-(3-methyl-2-butenylidene)-2-indolinone
5.
(E)-3-(3-methyl-2-butenylidene)-2-indolinone 5 was prepared according to the procedure for
the synthesis soulieotine 4 from commercially available isatin 1p as the starting material to
afford 5 as a yellow solid. The product was identified as a E geometry by a typical trans
1
coupling constant of 12.8 Hz for the double bond. Mp 196-198 ºC. (lit.13 mp 200-203 ºC) H
NMR (400 MHz, CDCl3) δ: 7.88 (brs, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 12.8 Hz, 1H),
7.19 (dt, J = 7.7, 1.0 Hz, 1H), 7.03 (dt, J = 7.6, 1.0 Hz, 1H), 6.87 (d, J = 7.6 Hz, 1H), 6.78
(ddd, J = 12.8, 2.4, 1.2 Hz, 1H), 2.07 (s, 3H), 2.06 (s, 3H). 13C NMR (100 MHz, CDCl3) δ:
170.6, 152.4, 140.5, 132.9, 128.4, 123.8, 123.4, 123.1, 122.1, 121.6, 109.9, 27.7, 19.2. HRMS
(ESI): m/z calcd for C13H14NO [M + H]+: 200.1070; found: 200.1036.
Acknowledgments We are thankful for financial support from Major Program of Natural
Science Foundation (12KJA150005) and PAPD of Jiangsu Higher Education Institutions,
Natural Science Foundation of Jiangsu Province (BK2012576), and Innovation Training
Program for the Jiangsu College Students (201513988003Y).
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Supporting Information Available Copies of H and 13C NMR spectra for all prepared
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products and X-ray crystal structure of 2p and crystal data of 2p in CIF format. This material
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is available free of charge via the Internet at http://pubs.acs.org.
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References
(1) For reviews about 3-substituted-3-hydroxy-2-oxindoles, see: (a) Peddibhotla, S. Curr.
Bioact. Compd. 2009, 5, 20. (b) Zhou, F.; Liu, Y.-L.; Zhou, J. Adv. Synth. Catal. 2010, 352,
1381.
(2) (a) Kawasaki, T.; Nagaoka, M.; Satoh, T.; Okamoto, A.; Ukon, R.; Ogawa, A. Tetrahedron
2004, 60, 3493. (b) Kitajima, M.; Mori, I.; Arai, K.; Kogure, N.; Takayama, H. Tetrahedron
Lett. 2006, 47, 3199. (c) Kawasaki, T.; Takamiya, W.; Okamoto, N.; Nagaoka, M.; Hirayama,
T. Tetrahedron Lett. 2006, 47, 5379. (d) Ghosh, A. K.; Schiltz, G.; Perali, R. S.; Leshchenko,
S.; Kay, S.; Walters, D. E.; Koh, Y.; Maeda, K.; Mitsuya, H. Bioorg. Med. Chem. Lett. 2006,
16, 1869. (e) Wu, H.; Xue, F.; Xiao, X.; Qin, Y. J. Am. Chem. Soc. 2010, 132, 14052.
(3) For syntheses of 3-allyl-3-hydroxy-2-oxindoles from isatin, see: (a) Nair, V.; Ros, S.;
Jayan, C. N.; Viji, S. Synthesis 2003, 2542. (b) Alcaide, B.; Almendros, P.; Rodriguez-Acebes,
R. J. Org. Chem. 2005, 70, 3198. (c) Vyas, D. J.; Froehlich, R.; Oestreich, M. J. Org. Chem.
2010, 75, 6720. (d) Meshram, H. M.; Ramesh, P.; Reddy, B. C.; Kumar, G. S. Chem. Lett.
2011, 40, 357. (e) Cao, Z.-Y.; Zhang, Y.; Ji, C.-B.; Zhou, J. Org. Lett. 2011, 13, 6398. (f)
Hanhan, N. V.; Tang, Y. C.; Tran, N. T.; Franz, A. K. Org. Lett. 2012, 14, 2218. (g) Ghosh, D.;
Gupta, N.; Abdi, S. H. R.; Nandi, S.; Khan, N. H.; Kureshy, R. I.; Bajaj, H. C. Eur. J. Org.
Chem. 2015, 2801.
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(4) For other methods to access 3-prenyl-3-hydroxy-2-oxindoles, see: (a) Chen, T.-Y.; Krische,
M. J. Org. Lett. 2013, 15, 2994. (b) Thandavamurthy, K.; Sharma, D.; Porwal, S. K.; Ray, D.;
Viswanathan, R. J. Org. Chem. 2014, 79, 10049.
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(5) For selected examples of natural products containing oxo-α-prenylated alcohols motifs,
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