Amino acid-derived phosphonium salts-catalyzed michael addition of 3-substituted oxindoles

Article abstract of DOI:10.1002/adsc.201300383

A new type of phosphonium phase-transfer catalyst prepared from easily available chiral amino acids was evaluated in a model reaction between oxindole and methyl vinyl ketone, and the catalyst derived from isoleucine was found to be the best. Michael additions of 3-monosubstituted oxindoles to methyl vinyl ketone, acrolein or propargyl aldehyde proceeded smoothly to afford 3,3-disubstituted oxindoles in good to excellent yields with moderate to excellent ees. Copyright

Full text of DOI:10.1002/adsc.201300383

UPDATES
DOI: 10.1002/adsc.201300383
Amino Acid-Derived Phosphonium Salts-Catalyzed Michael
Addition of 3-Substituted Oxindoles
Xiaoyu Wu,a,* Qin Liu,a Yong Liu,a Qun Wang,a Ying Zhang,a Jie Chen,a
Weiguo Cao,a,* and Gang Zhaob,*
a
Department of Chemistry, Shanghai University, 99 Shangda Rd, Shanghai 200444, Peopleꢀs Republic of China
Fax : (+86)-21-6613-4594; e-mail: wuxy@shu.edu.cn or wgcao@shu.edu.cn
China and Key Laboratory of Synthetic Organic Chemistry of Natural Substances, Shanghai Institute of Organic
b
Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, Peopleꢀs Republic of China
Fax : (+86)-21-6416-6128; e-mail: zhaog@mail.sioc.ac.cn
Received: May 4, 2013; Revised: July 8, 2013; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300383.
Abstract: A new type of phosphonium phase-trans-
fer catalyst prepared from easily available chiral
amino acids was evaluated in a model reaction be-
tween oxindole and methyl vinyl ketone, and the
catalyst derived from isoleucine was found to be
the best. Michael additions of 3-monosubstituted
oxindoles to methyl vinyl ketone, acrolein or prop-
argyl aldehyde proceeded smoothly to afford 3,3-
disubstituted oxindoles in good to excellent yields
with moderate to excellent ees.
ferent side chains, would serve as a rich source for
catalyst design to accommodate a broad range of sub-
strates.
In contrast to chiral ammonium salts, as most of the
successful PTCs are, application of chiral phosphoni-
um salts to phase-transfer catalysis has been rarely
studied.[4–6] In 2008, Maruoka and co-workers de-
signed a phosphonium salt based on an axially chiral
dibromide that showed excellent catalytic activity
toward the amination of b-keto esters.[4a] In 2009, Ooi
and co-workers prepared a D2-symmetric tetraamino-
phosphonium salt and applied it to the enantioselec-
tive alkylation of azlactones.[5a] In our search for
a new type of efficient PTCs, we envisioned that
phosphonium salts 1 derived from chiral amino acids
would be suitable catalysts for certain asymmetric re-
actions by formation of ion pairs between the phos-
phonium ions and the deprotonated substrates, and
Keywords: asymmetric catalysis; Michael addition;
oxindoles; phase-transfer catalysts; phosphonium
salts
Through 30 years of development, asymmetric phase- interactions between amide functionality in 1 and hy-
transfer catalysis has become a very important and drogen-bonding sites in the substrates. Adopting
practical tool in synthetic organic chemistry.[1] Among a similar strategy, recently a new type of thiourea-
the chiral phase-transfer catalysts (PTCs) developed phosphonium PTCs was developed in our group and
in the past few decades, ammonium salts derived successfully applied to the aza-Henry reaction
from Cinchona alkaloids and chiral 1,1’-binaphthol (Figure 1).[7]
(or similar biphenols) showed excellent catalytic ac-
tivity in various type of reactions, especially in asym- doles, which are common moieties found in biologi-
metric alkylation.[1]
cally active natural products and pharmaceutical com-
Asymmetric construction of 3,3’-disubstituted oxin-
Besides, tartaric acid has also been developed into pounds, is a significant challenge for contemporary or-
PTCs.[1] Although chiral amino acids and their deriva-
tives are widely employed in organocatalysis,[2] cata-
lytic processes promoted by PTCs derived from this
easily available chiral pool have rarely been investi-
gated.[3] It is well understood that structural diversity
plays a key role in catalyst design since subtle struc-
tural alterations in a catalyst might cause drastic
changes in the outcome of a catalytic process. Chiral
amino acids, either natural or unnatural, bearing dif- acids.
Figure 1. Design of phosphonium PTCs from chiral amino
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Xiaoyu Wu et al.
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ward method involved the conjugate addition of pro-
chiral oxindoles to Michael acceptors promoted by
chiral PTCs as reported by a number of groups recen-
tly.[4b,9] However, the substituents on the C-3 position
of oxindoles in these reports are limited to aryl, aryl-
methyl and simple alkyl groups, while there are rare
examples utilizing oxindoles bearing functionalized
alkyl groups as nucleophiles.[9k] Furthermore, acrolein
was scarcely employed as a reaction partner for this
reaction,[10] although the Michael adducts thus ob-
tained would be of high synthetic value.[4b,10] In our
endeavor to overcome these limitations, we prepared
a library of phosphonium salts 1 (see Figure 2) in
three steps from the corresponding chiral amino alco-
hols in moderate overall yields by following literature
procedures with slight modifications.[11] Herein we
wish to report the application of phosphonium salts
1 in asymmetric phase-transfer catalysis of the Mi-
chael addition of oxindoles to MVK, acrolein and
propargyl aldehyde.
With 3-phenyloxindole 2a and MVK 3a as model
substrates, phosphonium salts 1a–j were screened in
the conjugate addition and the results are listed in
Table 1. Since a strong background reaction between
2a and 3a under basic conditions in the absence of
a PTC was observed at relatively higher temperatures
Figure 2. Catalysts 1a–j with different substitution patterns.
ganic synthesis.[8] In the past few years, a number of (08C or above), screening was performed either at
successful methods have been developed to address À458C with KOAc as the base or at À708C with
this challenge.[8] Among them, the most straightfor- K2CO3 as the base. With the background reaction
Table 1. Screening studies on the reaction conditions.[a]
Entry
Catalyst
Solvent
Base
Temperature [oC]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1a
1g
1h
1i
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CHCl3
KOAc
KOAc
K2CO3
K2CO3
KOAc
KOAc
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
À45
À45
À70
À70
À45
À45
À70
À70
À70
À70
À70
À70
À70
À70
99
99
99
99
85
99
99
89
99
99
99
99
99
99
79
52
21
24
39
70
89
66
83
81
88
0
9
10
11
12
13
14
1j
1a
1a
1a
Et2O
36
15
MTBE[d]
[a]
General conditions: 1 (0.01 mmol), 2a (0.1 mmol), 3a (0.12 mmol) and base (5 equiv.) in solvent (0.2 mL).
Yield referred to isolated pure product.
Enantiomeric excess of 4a was determined by chiral HPLC analysis.
MTBE: methyl tert-butyl ether.
[b]
[c]
[d]
2
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Amino Acid-Derived Phosphonium Salts-Catalyzed Michael Addition of 3-Substituted Oxindoles
fully inhibited under cryogenic conditions, the reac- as the solvent (entries 7–11). Substrate 1a with an iso-
tion proceeded smoothly to afford the adduct in butyl group derived from isoleucine and 1j with a tert-
quantitative yield for almost all the catalysts except butyl group derived from tert-butyleucine provided
for 1e (entry 5) and 1g (entry 8). A survey of the the product quantitatively in almost the same high ee
effect of the substituents on the phosphonium center (entry 7 vs. entry 11); catalyst 1h with an isopropyl
on the enantioselectivity revealed that catalyst 1a group and 1i with a phenyl group worked almost
bearing three phenyl groups excelled over the other equally well to give the product albeit in slightly
catalysts 1b–d with different substitution patterns lower ee than that for 1a (entries 9 and 10); while cat-
(entry 1 vs. entries 2-4). It is notable that catalyst 1c, alyst 1g with a benzyl group delivered the product in
which is quite similar to the in situ generated phos- lowest yield and lowest ee value (entry 8). Thus, cata-
phonium from the corresponding diphenylphosphine lyst 1a proved to be the best in all aspects (entry 7).
catalyst and MVK reported by Lu and co-workers,[10a] Attempts to further improve the enantioselectivity by
resulted in poor selectivity in our test, although an ex- changing the solvents were unsuccessful (entries 12–
cellent ee was achieved for the same substrates in 14). Note that the test reaction in CHCl3 resulted in
Luꢀs catalytic system. Replacing the counterion BrÀ in racemization of the product in our study, while in
1a with IÀ resulted in a slight drop in yield and sharp contrast this solvent was the optimal reaction
a severe decline in ee (entry 5). Catalyst 1f with a tri- medium in Luꢀs work.[10a] Different bases, such as
fluoroacetyl amide on the chiral center afforded the NaHCO3, KF, and NaOH, were also evaluated for
product with slightly lower ee as compared with 1a this reaction and found to be inferior to KOAc and
with a 3,3-bis(trifluoromethyl)benzoyl amide (entry 1 K2CO3.[11]
vs. entry 6).
As the optimal reaction conditions had been estab-
To probe the influence of the side chains on the lished, expanding the scope of oxindoles became our
performance of the catalysts, phosphonium salts 1g–j next focus. The exploration was conducted using 3-
and 1a were examined under the same reaction condi- monosubstituted oxindoles as the Michael donor and
tion: at À708C, with K2CO3 as the base and toluene with MVK 3a or acrolein 3b as the Michael acceptor
Table 2. Michael reaction between 3-aryloxindoles 2a–f and activated alkenes 3a and 3b.[a]
Entry
R; Ar (2)
3
Time
Product 4 or 5
Yield [%][b]
ee [%][c]
1
2
H; Ph (2a)
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
3b
3b
10 h
16 h
20 h
72 h
10 h
10 h
6 h
8 h
8 h
24 h
6 h
6 h
4a
4b
4c
4d
4e
4f
5a
5b
5c
5d
5e
5f
99
99
99
74 (98)
99
99
91
86
80
89
88
80
80 (15)
58
77
81
75
94
CH3; Ph (2b)
MeO; Ph (2c)
F; Ph (2d)
Br; Ph (2e)
H; CH3C6H4 (2f)
H; Ph (2a)
CH3; Ph (2b)
MeO; Ph (2c)
F; Ph (2d)
Br; Ph (2e)
H; CH3C6H4 (2f)
3
4[d]
5
6
7
8
9
10[d]
11
12
87 (89)
83
90
87 (21)
85
86
[a]
General condtions: 1a (0.01 mmol), 2 (0.1 mmol), 3 (0.12 mmol) and K2CO3 (5 equiv.), at À708C in toluene (0.2 mL); see
the Supporting Information for details of the Wittig reaction.
Yield referred to isolated pure product; in the cases of using 3b as electrophile yield was calculated over 2 steps.
Enantiomeric excess of the products was determined by chiral HPLC analysis.
[b]
[c]
[d]
PhCO2K (5 equiv.) as the base; yields and ees in parentheses obtained under general conditions.
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under the optimal conditions. Notably, in order to iso-
late and characterize the products, Michael adducts
obtained from 3b were subjected to a Wittig reaction.
At first we investigated the effect of the substituents
at C-5 of the oxindoles on the yield and enantioselec-
tivity (Table 2, entries 1–5, 7–11). All the reactions
proceeded well to afford the conjugate adducts in
high yields. Typically, a longer reaction time was re-
quired for reactions employing the less reactive MVK
3a in order to secure high yields (entries 1–5 vs. en-
tries 7–11).
It is noteworthy that oxindole 2d with a strong elec-
tron-withdrawing fluoro group led to poor ee values
(entries 4 and 10). Fortunately the awkward situation
was reversed and high ee values were attained (80%
ee, entry 4; 87% ee, entry 10) when PhCO2K was used
instead as the base. This could be accounted for by
the fact that 2d is more acidic than the other oxin-
doles evaluated in this study and liable to suffer
a severe background reaction with K2CO3 instead of
PhCO2K as the base. Oxindole 2f with a para-methyl-
phenyl group at C-3 was also employed as nucleophile
(entries 6 and 12). Generally, good to excellent enan-
tioselectivities were achieved for the substrates
screened except for the combination of 2e and 3a
(58% ee, entry 5).
As already mentioned, oxindoles with functional-
ized alkyl groups at C-3 are of special interest and
have not been tackled yet. An array of such oxindoles
was prepared and explored in our current catalytic
system and the results are listed in Figure 3. Oxin-
doles with a cyanomethyl group or a benzyl group de-
livered the desired adducts in high ee values, while ad-
ducts obtained from oxindoles with a 2-ethoxy-2-oxo-
Figure 3. Further expanded substrate scope.
ACHTUNGTRENNUNGethyl group, a 2-tert-butoxy-2-oxoethyl group or a 2-
[(ethoxycarbonyl)amino]ethyl group had only moder-
ate ee values. Propiolaldehyde 3c fitted well in our
current system to afford adduct 5l in high ee value
albeit in low Z/E selectivity. To the best of our knowl-
edge, this is the first case using propiolaldehyde as
the electrophile for this type of reaction.[13]
The absolute configuration of 4a was determined
by comparison of its optical rotation with the known
value reported by Maruoka and co-workers.[4b] The
absolute stereochemistry of other products was as-
signed by analogy. Based on a mechanism proposed
previously by Lu,[10a] the stereoselectivity in the for-
mation of chiral all-carbon quaternary stereogenic
centers could be rationalized by the transition states
depicted in Figure 4.
Figure 4. Proposed transition state.
By comparison with Luꢀs method using an amino
acid-derived phosphine catalyst,[10a] we performed par-
allel experiments employing phosphonium 1j and
phosphine 6 as catalysts,[14] and they worked equally
well to give almost the same results (Scheme 1), while
a longer reaction time was needed for phosphine 6.
Scheme 1. Comparison of 1j with 6.
4
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Amino Acid-Derived Phosphonium Salts-Catalyzed Michael Addition of 3-Substituted Oxindoles
References
The advantage of our system is obvious, since phos-
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In conclusion, we have developed a new type of
phosphonium PTCs from readily available chiral
amino acids. These catalysts were successfully applied
in the conjugate addition of 3-monosubstituted oxin-
doles to MVK, acrolein and propiolaldehyde to
afford 3,3-disubstituted oxindoles in high yields with
moderate to excellent ees. The synthetic usefulness of
the current method was initially exemplified by the
transformation of 5a into indolenine 7.
Experimental Section
Typical Procedure
A mixture of catalyst 1a (0.01 mmol, 0.1 equiv.), oxindole 2a
(0.1 mmol) and K2CO3 (0.5 mmol, 5 equiv.) in toluene
(1 mL) was stirred under an N2 atmosphere at À708C for
15 min, followed by addition of 3a (0.12 mmol, 1.2 equiv.).
The resulting mixture was stirred at the same temperature
and followed by TLC. After full consumption of 2a, the re-
action mixture was loaded on a silica-gel column directly,
and purified by eluting with a petroleum ether and ethyl
acetate mixture to afford pure product 4a; yield: 99%.
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Acknowledgements
The generous financial support from the National Natural
Science Foundation of China (No. 21072125 and No.
21272150) is acknowledged. Dr. Hanwei Hu at Shanghai
Medicilon is also gratefully acknowledged for helpful discus-
sions.
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UPDATES
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[10] During the progress of this work, two reports about
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UPDATES
Amino Acid-Derived Phosphonium Salts-Catalyzed Michael
Addition of 3-Substituted Oxindoles
7
Adv. Synth. Catal. 2013, 355, 1 – 7
Xiaoyu Wu,* Qin Liu, Yong Liu, Qun Wang, Ying Zhang,
Jie Chen, Weiguo Cao,* Gang Zhao*
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