1,5,7-Triazabicylodec-5-ene-promoted direct vinylogous aldol reaction for the synthesis of 3-hydroxy-2-oxoindole derivatives

Article abstract of DOI:10.1055/s-0037-1612107

A simple and efficient method has been developed for the synthesis of 3-hydroxy-2-oxoindole derivatives through a direct vinylogous aldol reaction of allylic esters with isatins, catalyzed by 1,5,7-triazabicyclodec-5-ene. This method affords a variety of 3-hydroxy-2-oxoindole derivatives in moderate to excellent yields with high regioselectivities. An asymmetric version of this reaction catalyzed by Corey's chiral guanidine proceeded with moderate enantioselectivity. The protocol can also be used to synthesize isatin spiro ethers.

Full text of DOI:10.1055/s-0037-1612107

SYNLETT
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© Georg
Thieme Ver-
lag Stuttgart
· New York
2019, 30,
A
A
–
D
X. Zhang et al.
Letter
Synlett
1,5,7-Triazabicylodec-5-ene-Promoted Direct Vinylogous Aldol
Reaction for the Synthesis of 3-Hydroxy-2-oxoindole Derivatives
Xianhui Zhanga,b
Li Zhoua,b
Qaiser Mahmooda
Mengmeng Zhaoa
Xiaowu Wanga
O
HO
OR3
O
R1
R1
Cat.
O
OR3
O
+
O
N
R2
N
R2
Cat. 1
Cat. 2
0
0
0
0-0
0
0
1-
7
9
1
6-0
1
0
0
Qinggang Wang*a
0
0
0
0-0
0
0
3-
1
8
5
1-7
0
7
8
N
N
tBu
tBu
N
N
N
N
H
a Key Laboratory of Biobased Materials, Qingdao Institute of
Bioenergy and Bioprocess Technology, Chinese Academy of
Sciences, 189 Songling Road, Qingdao 266101, P. R. of China
wangqg@qibebt.ac.cn
b Center of Materials Science and Optoelectronics Engineering,
University of Chinese Academy of Sciences, Beijing 10049,
P. R. of China
H
R1 = H; R2 = Me; R3 = Bn
60% yield, 65% ee
γ/α > 99:1
11 examples
up to 95% yield
γ/α up to > 99:1
Received: 16.12.2018
Accepted after revision: 14.01.2019
Published online: 11.02.2019
HO
HO
SMe
N
H
O
O
S
DOI: 10.1055/s-0037-1612107; Art ID: st-2018-r0810-l
N
N
H
H
Dioxibrassinin
Donaxaridine
Abstract A simple and efficient method has been developed for the
synthesis of 3-hydroxy-2-oxoindole derivatives through a direct vinylo-
gous aldol reaction of allylic esters with isatins, catalyzed by 1,5,7-triaz-
abicyclodec-5-ene. This method affords a variety of 3-hydroxy-2-oxoin-
dole derivatives in moderate to excellent yields with high
regioselectivities. An asymmetric version of this reaction catalyzed by
Corey’s chiral guanidine proceeded with moderate enantioselectivity.
The protocol can also be used to synthesize isatin spiro ethers.
O
O
N
O
O
O
O
N
N
H
Spiro ether I
Spiro lactone II
Figure 1 Representative examples of biologically active 3-substituted
Key words hydroxyoxoindoles, vinylogous aldol reaction, triazabi-
3-hydroxy-2-oxoindoles
cyclododecene, isatins, isatin spiro ethers, asymmetric catalysis
3-Substituted 3-hydroxy-2-oxoindoles and their deriva-
tives collectively belong to a class of structurally diverse
natural or bioactive products.1 Because of their widespread
applications in biology and medicine, 3,3-disubstituted oxo-
indoles have attracted considerable attention from organic
and pharmaceutical chemists.2 For example, donaxaridine,3
spiro lactones,4 and the spiro ethers5 are prominent prod-
ucts that exhibit a wide range of biological activities (Figure
1). Spiro lactone II is a well-known cytotoxic compound.
Spiro ether I has been reported to be CB2 agonist that might
be useful for reducing neuropathic or bone pain, or as a lead
structure for the treatments of diseases such as osteoarthri-
tis, atherosclerosis, osteoporosis, or cancers. Thus, the syn-
thesis of these drugs has been intensely pursued by syn-
thetic chemists.
During the last two decades, significant efforts have
been made to develop new methods for the synthesis of 3-
substituted 3-hydroxy-2-oxoindoles.4b,6 Among these
methods, the synthesis of the compounds by means of the
vinylogous aldol reaction is a sophisticated and effective
protocol that can be used to generate multifunctional chiral
alcohols bearing unsaturated long-chain carbon skeletons.7
In 2009, Shibasaki and co-workers demonstrated, for
the first time, a direct enantioselective vinylogous aldol re-
action with an acyclic allyl cyanide as the nucleophile.8
Jiang and co-workers developed a highly enantioselective
direct vinylogous aldol reaction of allyl ketones with isatins
catalyzed by an L-valine-derived tertiary amine/thiourea bi-
functional catalyst.6k,7a Wu’s group have demonstrated that
activated β,γ-unsaturated amides are suitable as γ-nucleo-
philes for asymmetric tandem reactions involving direct
vinylogous aldol processes, producing spirooxoindoles
when treated with isatin derivatives.9 However, these
methods focused mainly on the use of unsaturated ketones
or aldehydes as substrates. Although some of them em-
ployed unsaturated esters, these were limited to the use of
α-isocyanoacetate,10 α-cyanoacetate,11 α-diazoacetate,12 or
glycinate Schiff bases as donors.13
In general, unsaturated esters16 are less active compared
with the structurally similar aldehydes or ketones for the
vinylogous aldol reaction.14,15 In 2009, Shibasaki and co-
workers reported the use of ester donors in a dynamic
kinetic asymmetric transformation for catalytic asymmet-
ric synthesis of β-hydroxy esters.16c In their study, the
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

B
X. Zhang et al.
Letter
Synlett
authors pointed out that esters without α-heteroatoms
and/or electron-withdrawing substituents are less widely
used as substrates, compared with ketones or aldehydes, for
two major reasons. First, the much lower activity due to the
low acidity of the α-proton in the ester leads to undesirable
retro-aldol reactions under basic conditions. Secondly, the
regioselectivity at the α- and γ-positions is poor. Mean-
while, Maruoka and co-workers 13a introduced an electron-
withdrawing group onto the ester and obtained satisfactory
results.
Inspired by Shibasaki’s work, we were interested in de-
veloping a new protocol for controlling the addition prod-
ucts of β,γ-unsaturated esters with isatin to expand the
scope of the vinylogous aldol reaction. Here, we report a
new, simple, and efficient protocol for synthesizing benzyl
4-(3-hydroxy-1-methyl-2-oxoindolin-3-yl)but-2-enoate
and its derivatives by using 1,5,7-triazabicyclo[4.4.0]dec-5-
ene (TBD; 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]py-
rimidine) as a catalyst and tetrahydrofuran (THF) as a sol-
vent (Scheme 1). The reaction proceeded under mild condi-
tions and preferentially gave the γ-adduct with up to 99%
regioselectivity.
and acetonitrile) with TBD as catalyst (entries 6–11), and
THF was found to be the best solvent, giving the target
product in the highest yield of 28% (entry 6). Subsequently,
the effects of the amount of catalyst and the reaction tem-
perature were studied. When the amount of catalyst was
increased from 5 mol% to 10 mol%, the yield of the product
dramatically improved to 52% (entry 12). Meanwhile,
changes in the reaction temperature showed a pronounced
effect on the catalytic activity. When the reaction was per-
formed at 40 °C, the yield of the isolated product dramati-
cally improved to 87% (entry 13), but on raising the tem-
perature to 60 °C, the yield decreased slightly to 83% (entry 14).
Table 1 Optimization of the Reaction Conditionsa
O
HO
O
OBn
O
O
+
OBn
O
N
N
Me
Me
3a
2a
1a
Entry
Catalyst
Solvent
Temp (°C)
Yieldb (%)
1
2
DABCO
TEA
THF
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
40
trace
trace
trace
trace
20
OH
O
THF
Masakatsu
Shibasaki's work
O
R
OBn
3
TMP
DMAP
DBU
TBD
THF
OBn
(S)-BINOL
Ba(O-iPr)2
4
THF
α-adduct
5
THF
HO
OBn
This work
N
6
THF
28
O
O
N
O
7
TBD
Et2O
27
tBu
tBu
OBn
8
TBD
toluene
1,4-dioxane
CH2Cl2
MeCN
THF
21
N
N
Me
H
γ-adduct
9
TBD
20
Scheme 1 Organocatalytic aldol reaction of benzyl but-3-enoate for
the synthesis of chiral α/γ-adduct products
10
11
12
13
14
TBD
27
TBD
25
TBDc
TBDc
TBDc
52
With a view to exploring the feasibility of the proposed
strategy, we performed an initial test reaction between N-
methylisatin (1a) and benzyl but-3-enoate (2a) in THF at
room temperature (25 °C). Initially, we tested 1,4-diazabi-
cyclooctane (DABCO) as a catalyst for this reaction, but un-
fortunately the product was obtained in trace even after
prolonging the reaction time to 48 hours (Table 1, entry 1).
It is possible that DABCO is too weak a base for this reaction.
To identify more-suitable catalysts, then turned our atten-
tion to the use of other bases [triethylamine (TEA), 2,2,6,6-
tetramethylpiperidine (TMP), and 4-(dimethylamino)pyri-
dine (DMAP)] as potential catalysts (entries 2–4). However,
all of these bases were essentially inactive and they gave
only trace amounts of the product. Next we tried a stronger
base, 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU), but in this
case only a 20% yield of the target product was obtained
(entry 5). However, when TBD was used to catalyze the re-
action, the yield of the product increased slightly to 28%
(entry 6). Next, the reaction was performed in various sol-
vents (diethyl ether, toluene, 1,4-dioxane, dichloromethane,
THF
87
THF
60
83
a Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), catalyst (5 mol%),
solvent (1 mL), 12 h.
b Yield of the isolated product, based on the isatin 1a.
c 10 mol% of the catalyst was used.
The substrate scope of this protocol under the opti-
mized reaction conditions was investigated for a variety of
allylic esters and isatins (Table 2). When R1 = H, both N-pro-
tected isatins (R2 = Me) and N-unprotected isatins (R2 = H)
reacted with benzyl but-3-enoate (2a) to give the corre-
sponding 3-substituted 3-hydroxyoxoindoles in excellent
yields with a γ/α ratio of more than 99:1 (Table 2, entries 1
and 2). When the protecting group (R2) was changed from
methyl to ethyl, the yield of desired product improved to
91%, and γ/α ratio remained above 99:1 (entry 3). However,
when R2 = benzyl, the yield of final product decreased to
65% with a γ/α ratio of more than 99:1 (entry 4). Next, we
examined the reactions of N-methylisatins bearing various
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

C
X. Zhang et al.
Letter
Synlett
substituents with benzyl but-3-enoate (2a). N-methylisat-
ins bearing electron-withdrawing groups, 1 (R1 = 5-F, 5-Cl,
5-Br), gave slightly lower yields of the desired products (en-
tries 5–7). In contrast, N-methylisatins bearing electron-
donating substituents gave much higher yields (entries 8
and 9). These findings might be attributed to the positive
electronic effect of the R1substituent of the isatin.
ever, the yield improved to 60% with 63% ee on performing
the reaction at 40 °C for three days in the presence of 30
mol% the catalyst.17
O
O
tBu
N
N
tBu
HO
OBn
Me
1a
N
N
H
Table 2 Substrate Scopea
O
+
O
THF, 40 °C
60% yield and 63% ee
O
N
Me
3a
HO
OR3
OBn
R1
2a
O
R1
O
O
Scheme 2 Reagents and conditions: 1a (32.2 mg, 0.2 mmol, 1 equiv),
2a (70.4 mg, 0.4 mmol, 2 equiv), chiral catalyst (13.3 mg, 0.06 mmol,
0.3 equiv), 40 °C, 3 d.
N
O
R2
N
R2
γ-adduct
3
1
TBD
+
+
OR3
O
THF, 40 °C
O
The spiro lactone 4a is in high demand for use as a cyto-
toxic drug and it can be readily prepared by using a report-
ed protocol.6k Selective reduction of the aldol adduct 3a
prepared by our protocol and subsequent cyclization in the
presence of N,N′-dicyclohexylcarbodiimide (DCC) and
DMAP in CH2Cl2 afforded the spiro lactone 4a in 92% yield
(Scheme 3).
HO
R1
OR3
O
N
2
R2
α-adduct
Entry
R1
R2
R3
γ/αb
>99:1
Yieldc (%)
1
2
H
H
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
95
87
91
65
62
77
59
76
83
80
69
H
Me
Et
>99:1
>99:1
>99:1
8:1
O
3
H
HO
O
OBn
4
H
Bn
1) hydrogenation
2) esterification
O
O
O
5
5-F
Me
Me
Me
Me
Me
Me
Me
N
N
Me
Me
6
5-Cl
5-Br
5-Me
5-OMe
H
>99:1
20:1
4a (92%)
3a
7
Scheme 3 Reagents and conditions: (1) Pd/C (2 equiv), H2, MeOH
(6 mL), r.t., overnight, 95% yield; (2) DCC (0.2 equiv), DMAP (2 equiv),
CH2Cl2 (5 mL), 0° to r.t., overnight, 92% yield.
8
>99:1
>99:1
> 99:1
> 99:1
9
10
11
CH2-4-ClC6H4
iPr
H
In summary, we have developed an efficient synthesis of
3-substituted 3-hydroxy-2-oxoindoles catalyzed by TBD as
an organocatalyst through a direct vinylogous aldol reac-
tion under mild conditions.18 By controlling the tempera-
ture and the amount of catalyst, good to excellent yields of
3-substituted 3-hydroxy-2-oxoindoles were obtained. This
protocol shows good functional-group tolerance and is gen-
erally applicable to a variety of allyl esters and isatin sub-
strates. In addition, an asymmetric version of this reaction
catalyzed by Corey’s chiral guanidine gave moderate enan-
tioselectivities. The protocol provided an alternative meth-
od for synthesizing isatin spiro ether derivatives. Further
exploration of the chiral TBD-catalyzed asymmetric reac-
tion is currently in progress in our laboratory.
a Reactions conditions: 1 (0.1 mmol), 2 (0.2 mmol), TBD (0.01 mmol,) THF
(1 mL), 40 ℃, 12 h.
b Determined by 1H NMR spectroscopy of the crude product.
c Yield of the isolated product, based on isatin 1
Under identical reaction conditions with 4-chloro-
benzyl but-3-enoate (2, R3 = CH2-4-ClC6H4) as a reactant, a
high yield of the γ-adduct was again obtained with a γ/α
ratio exceeding 99:1 (Table 2, entry 10). However, in the
i
case of isopropyl but-3-enoate (2, R3 = Pr) as reactant, the
yield of the γ-adduct fell to 69%, although the γ/α ratio re-
mained more than 99:1 (entry 11).
With a view to examining the applicability of this pro-
tocol for an asymmetric vinylogous aldol reaction, chiral
(2R,6R)-2,6-di-tert-butyl-2,3,5,6-tetrahydro-1H-imidazo[1,2-
a]imidazole base (Corey’s chiral guanidine) was used as or-
ganocatalyst for the reaction of N-methylisatin (1a) with
benzyl but-3-enoate (2a). At room temperature, a low yield
was obtained after a run time of two days (Scheme 2). How-
Funding Information
Generous support by the National Key R&D Plan (2017YFC1104800),
the CAS Hundred Talents Program (Y5100719AL), the Young Taishan
Scholars’ Program of Shandong Province, the ‘135’ Projects Fund of
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

D
X. Zhang et al.
Letter
Synlett
CAS-QIBEBT Director Innovation Foundation, the DICP& QIBEBT Unit-
ed Foundation (UN201701), and the National Natural Science Founda-
tion of China (21702215) is gratefully acknowledged.()
G.; Zanardi, F. Chem. Rev. 2000, 100, 1929. (d) Denmark, S. E.;
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yl)but-2-enoates 3; General Procedure
A clean septum-capped vial equipped with a stirring bar was
charged with the appropriate isatin 1 (0.1 mmol), ester 2 (0.2
mmol), TBD (0.02 mmol), and anhyd THF (1 mL), and the
mixture was heated to 40 °C until the starting material was fully
consumed (TLC). The solvent was removed under reduced pres-
sure, and the residue was purified by column chromatography
[silica gel, EtOAc–hexane (6:1)].
Benzyl (2E)-4-(3-Hydroxy-1-methyl-2-oxo-2,3-dihydro-1H-
indol-3-yl)but-2-enoate (3a)
White solid; yield: 29.3 mg (87%). 1H NMR (600 MHz,
CDCl3): δ = 7.36–7.26 (m, 7 H), 7.11–7.09 (t, J = 7.6 Hz, 1 H),
6.89–6.83 (m, 2 H), 5.91–5.88 (d, J = 15.6 Hz, 1 H), 5.13 (s, 2 H),
3.47 (s, 1 H), 3.16 (s, 3 H), 2.91–2.88 (m, 1 H), 2.70–2.67 (m, 1
H). 13C NMR (150 MHz, CDCl3): δ = 177.6, 165.7, 143.1, 141.6,
136.0, 130.1, 129.2, 128.6, 128.3, 128.2, 125.6, 124.4, 123.5,
108.8, 75.8, 66.2, 41.1, 26.4. HRMS (ESI): m/z [M + H]+ calcd for
(7) (a) Jing, Z.; Bai, X.; Chen, W.; Zhang, G.; Zhu, B.; Jiang, Z. Org.
Lett. 2016, 18, 260. (b) Casiraghi, G.; Battistini, L.; Curti, C.;
Rassu, G.; Zanardi, F. Chem. Rev. 2011, 111, 3076. (c) Casiraghi,
C
20H20NO4: 338.1387; found: 338.1385.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D