Synthesis of Chiral 3-Substituted 3-Amino-2-oxindoles through Enantioselective Catalytic Domino and Tandem Reactions

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Synthesis of Chiral 3-Substituted 3-Amino-2-oxindoles through Enantioselective Catalytic Domino and Tandem

Reactions

Hélène Pellissier

To cite this version:

Hélène Pellissier. Synthesis of Chiral 3-Substituted 3-Amino-2-oxindoles through Enantioselective

Catalytic Domino and Tandem Reactions. SYNTHESIS, Georg Thieme Verlag, 2019, 51 (06), pp.1311-

1318. �10.1055/s-0037-1610350�. �hal-02106143�

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Synthesis of Chiral 3-Substituted 3-Amino-2-oxindoles through Enantioselective Catalytic Domino and Tandem Reactions

Hélène Pellissier*

0000-0003-0773-5117

Aix Marseille Univ, CNRS, Centrale Marseille, iSm2, Marseille, France

h.pellissier@univ-amu.fr N

R² N

O R¹

R³ R⁴ R⁵

A + B + (C)

*

catalyst*

[D]

one-pot

Received: 01.10.2018

Accepted after revision: 07.11.2018 Published online: 19.12.2018

DOI: 10.1055/s-0037-1610350; Art ID: ss-2018-m0666-sr

Abstract The goal of this review is to collect the major developments in the catalytic asymmetric synthesis of 3-substituted 3-amino-2-oxin- doles through enantioselective catalytic domino and tandem reactions reported since 2011.

1 Introduction

2 Organocatalyzed Reactions 3 Metal-Catalyzed Reactions 4 Conclusion

Key words asymmetric catalysis, chirality, oxindoles, domino reac- tions, enantioselectivity, tandem reactions

1 Introduction

Chiral oxindoles are widely present in nature and exhib- it many biological activities.

¹

Among them, chiral 3-substi- tuted 3-amino-2-oxindoles exhibiting a quaternary stereo- genic center at the 3-position have been recognized as priv- ileged substructures in new drug discovery. For example, their skeleton is present in many bioactive molecules and drug candidates for the treatment of malaria and stress re- lated disorders as well as in marine alkaloids, such as the chartellines or in terrestrial alkaloids isolated from the leaves of the Malaysian plant Psychotria rostrate. The bio- logical activity of these compounds is greatly affected by the nature of the substituent at the C3 position as well as the absolute configuration of the stereogenic center. Conse- quently, the development of efficient methods to synthe- size such products is of great importance and constitutes a current open area of research in asymmetric catalysis,

²

with a special mention for organocatalysis. The principal methodology to prepare chiral quaternary 3-amino-2-oxin- doles is based on enantioselective catalytic nucleophilic ad- ditions to isatin imines, such as Mannich reactions, aza- Morita–Baylis–Hillman reactions, aza-Henry reactions, ad- ditions of heteronucleophiles, Strecker reactions, or hydro- phosphonylations. In addition to these classical methodolo- gies, a range of more modern asymmetric catalytic domino

and tandem reactions have been recently developed, allow- ing many 3-substituted 3-amino-2-oxindoles to be achieved in high enantioselectivities. These one-pot trans- formations have been promoted with various chiral or- ganocatalysts, but also chiral metal catalysts. The goal of this review is to collect the major developments in the cata- lytic asymmetric synthesis of 3-substituted 3-amino-2-ox- indoles through enantioselective catalytic domino and tan- dem reactions reported since 2011. It is divided into two parts, dealing successively with enantioselective organocat- alyzed reactions, and enantioselective metal-catalyzed transformations. The economic interest in combining asymmetric catalysis with the concept of domino

³

and tan- dem reactions is obvious, and has allowed high molecular complexity to be easily reached with remarkable levels of stereocontrol on the basis of simple operational one-pot procedures, and advantages of savings in solvent, time, en- ergy, and costs. In the last decade, an increasing number of these fascinating one-pot processes catalyzed by various types of chiral organocatalysts as well as chiral metals have been developed.

⁴

Hélène Pellissier carried out her PhD under the supervision of Dr G. Gil

in Marseille (France) in 1987. The work was focused on the reactivity of

isocyanides. In 1988, she entered The National Center for Scientific Re-

search (CNRS) as a researcher. After a postdoctoral period in Professor

K. P. C. Vollhardt's group at the University of California, Berkeley, she

joined the group of Professor M. Santelli in Marseille in 1992, where she

focused on the chemistry of allylsilanes and their applications to the de-

velopment of novel very short total syntheses of unnatural steroids

starting from 1,3-butadiene and benzocyclobutenes. She is currently

researcher (CNRS) at Aix-Marseille Université.

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2 Organocatalyzed Reactions

Among chiral 3-substituted 3-amino-2-oxindoles, many alkaloids exhibit a spirocyclic structure.

⁵

In 2011, Yuan and co-workers described the synthesis of chiral spirooxindoles 1 based on an enantioselective organocatalytic domino al- dol/cyclization reaction of 2 with 3 (Scheme 1).

⁶

The reac- tion was catalyzed at –40 °C by organocatalyst 4 in mesity- lene as solvent, leading to the corresponding highly func- tionalized chiral domino products 1 in good to high yields (75–95%) combined with moderate to high diastereoselec- tivities (40–90% de) and enantioselectivities (64–98% ee).

The optimal substrates were found to be acetophenones.

In 2014, Wu and co-workers reported the enantioselec- tive domino Mannich/cyclization reaction of isatin imines 5 with 4-bromo-3-oxobutanoates 6 catalyzed by catalyst 7

(Scheme 2).

⁷

The corresponding highly functionalized chiral domino products 8 were obtained in both excellent yields (90–97%) and enantioselectivities (94–98% ee).

Enantioselective organocatalytic domino Michael/cy- clization reactions have been recently developed. For exam- ple, in 2013 Wang and co-workers reported a highly diaste- reo- and enantioselective domino Michael/cyclization reac- tion of 3-isothiocyanato-2-oxindoles 9 with electron- deficient alkenes 10 catalyzed by 11 (Scheme 3).

⁸

The reac- tion was performed in dichloromethane at room tempera- ture and led to the corresponding chiral products 12 as al- most single diastereomers (>90% de) in high to quantitative yields (86–99%) and good to excellent enantioselectivities (78–96% ee). By employing another chiral cinchona alka- loid-derived thiourea catalyst such as 13a , the authors de- veloped the domino reaction of 9 with 3-methylene-2-ox- indoles 14 (Scheme 3), which provided the corresponding

Scheme 1 Domino aldol/cyclization reaction of 3-isothiocyanato-2-ox- indoles with ketones catalyzed by a thiourea

+ N H

NCS O

N H 75–95% yield

40–90% de 64–98% ee (20 mol%)

mesitylene, –40 °C

R

¹

= Ph, p-Tol, m-MeOC

6

H

4

, p-BrC

6

H

4

, p-FC

6

H

4

, m-F

3

CC

6

H

4

, 2-Naph R

²

= Me

R

¹

, R

²

= (CH

2

)

5

R

³

= H, F, Me

O

R

¹

R

²

O

HN R

³

O S

R

³

R

²

R

¹

S

N H NHAr Ph

NMe

2

Ph

Ar = 3,5-(CF

3

)

2

C

6

H

3

1 2

3

4

Scheme 2 Domino Mannich/cyclization reaction of isatin imines with 4-bromo-3-oxobutanoates catalyzed by a cinchona alkaloid-derived squaramide

+ N

NBoc O

90–97% yield N 94–98% ee

7 (1 mol%)

CH

2

Cl

2

, 25 °C R

¹

R

¹

= Me, Ph

R

²

= H, 5-Me, 5-OMe, 5-Cl, 5-Br, 6-Cl, 6-Br, 7-Me, 7-F, 7-Cl, 7-Br R

³

= Et, Me, Bn

R

¹

NHBoc

O R

²

Br

O O

OR

³

Na

2

CO

3

R

²

O R

³

O

O N

NH

O O

NHAr

N

Ar = 3,5-(CF

₃

)

₂

C

₆

H

₃ 5

6

8

Scheme 3 Domino Michael/cyclization reactions of 3-isothiocyanato- 2-oxindoles with electron-deficient alkenes and 3-methylene-2-oxin- doles catalyzed by cinchona alkaloid derived thioureas

+ N

NCS O

N O

86–99% yield >90% de 78–96% ee

11 (15 mol%)

CH

2

Cl

2

, r.t.

R

¹

R

¹

R

¹

= Me, Bn R

²

= H, Me, F

R

³

= Ph, p-FC

6

H

4

, p-ClC

6

H

4

, p-BrC

6

H

4

, m-BrC

6

H

4

, o-BrC

6

H

4

, o-O

2

NC

6

H

4

, p-MeOC

6

H

4

,

m-MeOC6

H

4

, o-Tol, 2,4-Cl

2

C

6

H

3

, 1-Naph, 2-thienyl, 2-furyl, 3-indolyl, i-Bu

R

³

Bz

HN

S Bz

Bz R

³

N

H N H N

N

MeO S

i-Pr

+ N

NCS O

N O

92–99% yield 86–>90% de 86–98% ee

13a (15 mol%)

CH

2

Cl

2

, r.t.

R

¹

R

¹

R

¹

= Me, Bn R

²

= H, Me, F X = N-Me, Bn, N(allyl), S

R

³

= 5-F, 7-F, 5-Cl, 6-Cl, 7-Cl, 5-Br, 5-OCF

₃

, 5-Me, 5-MeO, 5-Cl-7-Me R

⁴

= Et, t-Bu, Bn

HN S

CO

₂

R

⁴

N

H N NHAr

N

MeO S

X O O R

⁴

O

X R

²

R

²

R

²

R

²

O

R

³

R

³

Ar = 3,5-(F

₃

C)

₂

C

₆

H

₃ 9

10

12

15 9

14

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chiral spirocyclic oxindoles 15 with uniformly excellent yields (92–99%), good to excellent diastereoselectivities (86–>90% de), and high enantioselectivities (86–98% ee).

Concurrently with this, Huang, Wang, and co-workers also developed the reactions between 3-isothiocyanato-2- oxindoles 9 with 3-methylene-2-oxindoles 16 performed in the presence of a trifunctional catalyst 17 (Scheme 4) to provide the corresponding chiral spirocyclic oxindoles 18 in uniformly excellent yields (96–99%), diastereoselectivity (>90% de), and enantioselectivities (90–99% ee).

⁹

On the other hand, catalyst 13b (Scheme 4) emerged as the opti- mal catalyst to promote the reaction between 3-methy- lene-2-oxindoles 19 bearing an ester moiety with 9 to give the corresponding domino products 20 in low to quantita-

tive yields (29–99%), excellent diastereoselectivity, (>90%

de), and high enantioselectivities (85–99% ee).

In 2013, an asymmetric domino Michael/cyclization re- action between 3-isothiocyanato-2-oxindoles 9 and various aryl-substituted 4-methylene-3H-pyrazol-3-ones 21 was reported by Wang and co-workers, providing the corre- sponding chiral products 22 exhibiting three contiguous stereogenic centers (Scheme 5).

¹⁰

The process was cata- lyzed by 23 , and afforded these complex highly functional- ized polycyclic products in good to quantitative yields (72–

96%), moderate to excellent diastereoselectivities (66–>90%

de), and high enantioselectivities (80–99% ee). In the case of alkyl-substituted 4-methylene-3H-pyrazol-3-ones, only low enantioselectivities were observed (11% ee) along with high yield (82%) and excellent diastereoselectivity (90% de).

Scheme 5 Domino Michael/cyclization reaction of 3-isothiocyanato-2- oxindoles with 4-(arylmethylene)-3 H -pyrazol-3-ones catalyzed by a ter- tiary amine-thiourea

The utility of N-heterocyclic carbenes (NHCs) as or- ganocatalysts in domino/tandem reactions has received growing attention in the past few years.

¹¹

In 2012, Jiao, Ye, and co-workers demonstrated the application of this type of organocatalysts for the addition of ,-unsaturated alde- hydes to N-arylisatin imines to develop a one-pot proce- dure for the synthesis of chiral spirocyclic -lactam oxin- doles.

¹²

Therefore, by using 10 mol% of a NHC catalyst such as 24 , the homoenolate equivalent of 25 was added to an isatin imine 26 to give, after subsequent acid hydrolysis, the corresponding spirocyclic -lactam oxindole 27 in 80%

yield, 72% de, and 74% ee (Scheme 6). The mechanism of this domino reaction involves the addition of the NHC cata- lyst to the ,-unsaturated aldehyde to give a Breslow inter- mediate serving as homoenolate equivalent. Then, the latter adds to the isatin imine to give an intermediate, which then cyclizes to afford the final product.

Scheme 4 Domino Michael/cyclization reactions of 3-isothiocyanato- 2-oxindoles with 3-methylene-2-oxindoles catalyzed by cinchona alka- loid derived thioureas

+ N

NCS O

N O

96–99% yield >90% de 90–99% ee

17 (15 mol%)

CH

₂

Cl

₂

, r.t.

R

¹

R

¹

R

¹

= Me, Bn

R

²

= H, Cl, Me R

³

= Me, Ac

R

⁴

= 5-F, 5-Cl, 5-NO

2

, 5-CF

3

O, 5-Me, 5-OMe, 6-Br, 7-F R

⁵

= Ph, p-MeOC

6

H

4

, p-FC

6

H

4

, furyl, thienyl

HN S

COR

⁵

N

H N NH

N

MeO S

N O O R

⁵

N R

²

R

²

O

R

⁴

R

⁴

+ N

NCS O

N O

29–99% yield >90% de 85–99% ee

13b (15 mol%)

CH

₂

Cl

₂

, r.t.

R

¹

R

¹

R

¹

= Me, Bn R

²

= H, Cl, MeO R

³

= Me, Ac, Bn

R

⁴

= 5-F, 5-Cl, 5-NO

2

, 5-Me, 5-OMe R

⁵

= Et, t-Bu

HN S

CO

2

R

⁵

N H

N NHAr

N

MeO S

N O O R

⁵

O

N R

²

R

²

O

R

³

Ar = 3,5-(F

3

C)

2

C

6

H

3

R

³

R

³

H

2

N

R

³

R

⁴

R

³ 9

16

18

20 9

19

+ N

NCS O

N O

72–96% yield 66–>90% de 80–99% ee

23 (10 mol%)

MTBE, 0 °C R

¹

R

¹

R

¹

= Me, Bn, n-Pr R

²

= H, Me

R

³

= Ph, o-MeOC

6

H

4

, m-MeOC

6

H

4

, p-MeOC

6

H

4

, o-ClC

6

H

4

, p-ClC

6

H

4

,

p-Tol, p-BrC6

H

4

, 3,4-Me

2

C

6

H

3

, 2-furyl, 2-Naph

HN S

R

³

H

N NH

S

N N

N N R

²

Ph

R

²

Ph N

i-Pr

R

³

O

21 9

22

(5)

Scheme 6 NHC-catalyzed domino addition/cyclization reaction of an N -phenylisatin imine with cinnamaldehyde

This type of reactions was also investigated by Chi and co-workers by using another NHC catalyst such as 28 (Scheme 7).

¹³

Thus, the reaction of various ,-unsaturated aldehydes 29 with a series of N-arylisatin imines 5 led to the corresponding chiral spirocyclic--lactams 30 in mod- erate to good yields (51–84%), moderate to high diastereo- selectivities (60–>90% de), and uniformly excellent enanti- oselectivities (94–>99% ee).

Scheme 7 NHC-catalyzed domino addition/cyclization reaction of isat- in imines with ,-unsaturated aldehydes

In 2016, Ye, Sun, and co-workers reported enantioselec- tive NHC-catalyzed formal [3+2] annulations occurring be- tween -bromoenals 31 and 3-amino-2-oxindoles 32 (Scheme 8).

¹⁴

The domino process was catalyzed at room temperature by 15 mol% of the same NHC catalyst 28 in the presence of two bases, such as Cs

₂

CO

₃

and DABCO. The reac- tion occurs through the Michael addition of the 3-amino-2- oxindole via its enolate to an ,-unsaturated acyl azolium, generated from the -bromoenal and the catalyst, to give an intermediate which subsequently cyclizes through lact- amization to give the final chiral product 33 . A series of these cycloadducts 33 were synthesized in moderate to quantitative yields (58–99%), high to complete diastereose- lectivities (84–>90% de), and uniformly excellent enantiose- lectivities (91–99% ee).

Scheme 8 NHC-catalyzed domino Michael/lactamization reaction of 3-amino-2-oxindoles with -bromoenals

The same year, Li, Li, and co-workers described an effi- cient asymmetric [3+2] annulation reaction between isatin imines 5 and 1,4-dithiane-2,5-diol ( 34 ) as equal equivalent of 2-mercaptoacetaldehyde (Scheme 9).

¹⁵

The domino reac- tion catalyzed by 35 begins with the addition of 34 to 5 , leading to an aldehyde intermediate that subsequently cy- clizes into the corresponding chiral product 36 . A range of these products were achieved in high yields (75–95%), low to good diastereoselectivities (34–80% de), and good to high enantioselectivities (78–97% ee).

Scheme 9 Domino addition/cyclization reaction of isatin imines with 1,4-dithiane-2,5-diol catalyzed by a squaramide

Earlier in 2013, an asymmetric tandem Mannich/hy- droamination reaction was developed by Jiang, Liu, and co- workers.

¹⁶

It occurred between isatin imines 37 and prop- argylated malononitrile 38 (Scheme 10), affording the cor- responding densely functionalized chiral tricyclic products 39 in moderate to high yields (56–91%) and enantioselectiv-

+ N

NPh O

N O 80% yield

72% de 74% ee

24 (10 mol%)

dioxane/toluene (1:1) MeOH, r.t.

Bn

Bn N

O

Ph Ph

CHO Ph

BF

4–

N N

N Bn Ar

Ar OH +

Ar = 3,5-(CF

3

)

2

C

6

H

3

1)

K

2

CO

3

(40 mol%)

2) 1M HCl/MeOH, 65 °C

26

25 27

+ N

NBoc O

N O 51–84% yield

60–>90% de 94–>99% ee

28 (10 mol%)

THF, 40 °C R

¹

R

¹

R

¹

= Me, Bn, Ac, H

R

²

= H, Me, MeO, Cl

R

³

= Ph, p-Tol, m-FC

6

H

4

, p-ClC

6

H

4

, p-BrC

6

H

4

N O

R

³

Boc

CHO R

³

O

N N

N Mes + BF

4–

Cs

2

CO

3

R

²

R

² 5

29

30

+ N

NHBoc O

N O 58–99% yield

84–>90% de 91–99% ee 28 (15 mol%)

Et

2

O, r.t.

R

X = H, F, Cl, Me, OMe R = H, Me, n-Pr, Bn

Ar = Ph, p-FC

₆

H

₄

, p-ClC

₆

H

₄

, p-NCC

₆

H

₄

, p-Tol, p-MeOC

₆

H

₄

,

m-ClC6

H

4

, m-MeOC

6

H

4

, o-ClC

6

H

4

, o-Tol, o-MeOC

6

H

4

N O

Ar X

X Boc

CHO Br Ar

O

N N

N Mes + BF

4–

Cs

2

CO

3

(1 equiv) DABCO (1.2 equiv)

32

31

33

+ N

NBoc O

N O 75–95% yield

34–80% de 78–97% ee

35 (1 mol%)

CH

2

Cl

2

, 0 °C R

²

R

²

R

¹

= H, 5-Me, 5-OMe, 5-F, 5-Cl, 6-Cl, 7-Cl, 4,7-Cl

2

, 5-Br

R

²

= Bn, p-Tol, p-(t-Bu)C

₆

H

₄

CH

₂

, p-F

₃

CC

₆

H

₄

CH

₂

CH

₂

, p-FC

₆

H

₄

CH

₂

CH

₂

,

p-ClC6

H

4

CH

2

CH

2

, p-BrC

6

H

4

CH

2

CH

2

, m-FC

6

H

4

CH

2

CH

2

, 3,4-F

2

C

6

H

3

CH

2

, Ph

S N R

¹

HO

R

¹

Boc 3Å MS

O O

ArHN N

H Ph

NMe

₂

Ph

Ar = 3,5-(CF

₃

)

₂

C

₆

H

₃

S S OH

OH

5

34

36

(6)

ities (64–96% ee). This multicatalyzed process involved the sequential treatment of the substrates with chiral cinchona alkaloid catalyst 40 , BF

₃

·Et

₂

O, and XPhosAuNTf

₂

.

Scheme 10 Tandem multicatalyzed Mannich/hydroamination reaction of isatin imines with a propargylated malononitrile

3 Metal-Catalyzed Reactions

In 2013, Matsunaga, Kanai, and Kato reported the first catalytic asymmetric addition of 3-isothiocyanato-2-oxin- doles to aldehydes by using a chiral dinuclear nickel Schiff base catalyst (Scheme 11).

¹⁷

The reaction of a range of ali- phatic aldehydes 41 with 3-isothiocyanato-2-oxindoles 42 afforded the corresponding spirooxindoles 43 in high yields and diastereo- and enantioselectivities of up to 99%, 82% de, and 99% ee, respectively. The process, evolving through a domino aldol-type/cyclization reaction, was generally pro- moted at room temperature by 10 mol% of 44 in 1,4-diox- ane as solvent. It was demonstrated that the catalyst load- ing could be reduced to 0.1 mol% still providing a remark- able enantioselectivity of up to 98% ee (PG = Me, X = Y = H, R

= n-Pent). It was found that the dinuclear nickel catalyst was much more efficient than the corresponding dinuclear copper and cobalt complexes, which provided lower enanti- oselectivities (2–21% ee). The scope of the domino aldol- type/cyclization reaction showed that -branched aliphatic aldehydes led to the corresponding chiral tricyclic products in 66–78% de and 80–92% ee, while linear aliphatic alde- hydes exhibited slightly higher diastereo- and enantioselec- tivities than the -branched ones, providing the corre- sponding products in 88–99% ee and up to 82% de. In con-

trast to aliphatic aldehydes, poor results were obtained with aromatic aldehydes. For example, a low enantioselec- tivity of 33% ee was observed in the reaction of benzalde- hyde with unsubstituted N-methyl-2-oxindole 42 (X = Y = H, PG = Me) in combination with a low diastereoselectivity of 10% de.

Scheme 11 Nickel-catalyzed domino aldol-type/cyclization reaction of 3-isothiocyanato-2-oxindoles with aldehydes

In 2014, Xiao and co-workers developed an unprece- dented zinc-catalyzed asymmetric domino Michael/cycliza- tion reaction of 3-nitro-2H-chromenes 45 with 3-isothio- cyanato-2-oxindoles 46 .

¹⁸

This reaction constituted an effi- cient access to various synthetically important polycyclic spirooxindoles 47 in a highly stereoselective manner under mild conditions. Remarkably, these complex and densely functionalized chiral products 47 , which exhibited three consecutive stereogenic centers including 1,3-nonadjacent tetrasubstituted carbon stereocenters, were achieved as al- most single diastereomers (>90% de in all cases) in good to quantitative yields (72–99%) and with general excellent en- antioselectivities of 91–>99% ee (Scheme 12). These results were obtained by using a combination of Zn(OTf)

₂

with li- gand 48 bearing a free NH group, which could act as a Lewis base through hydrogen-bonding interaction.

In 2015, Xu and Yuan reported related asymmetric dom- ino Michael/cyclization reactions by using the (R,R)-enan- tiomer of the same ligand ent- 48 .

¹⁹

The reaction occurred between 3-isothiocyanato-2-oxindoles 9 and 3-nitroin- doles 49 to afford the corresponding chiral polycyclic deriv- atives 50 exhibiting three contiguous stereocenters. For ex- ample, the reaction of N-methyl protected 3-isothiocyana- to-2-oxindoles performed in the presence of the (R,R)- bisoxazoline ligand combined with Zn(OTf)

₂

as precatalyst in toluene at 50 °C led to 50 in quantitative yields as single stereomers (>98% de and >99% ee) in almost all cases of substrates examined (Scheme 13).

toluene, –70 °C N

NR

³

O

N O 56–91% yield

64–96% ee

R

¹

= H, 5-Me, 5-OMe, 5-OCF

₃

, 5-F, 5-Cl, 5-Br, 5-I, 6-Br, 6-Cl, 7-Cl, 7-CF

₃

R

²

= Me, Et, Bn

R

³

= Boc, Cbz

40 (5 mol%)

+

N

R

²

R

²

O

N OH 1)

2) BF

3

·Et

2

O (20 mol%)/r.t.

3) XPhosAuNTf

₂

(10 mol%)/r.t.

R

¹

R

¹

N R

³

CN CN

CN NC

37

38

39

XPhos PCy

₂

i-Pr i-Pr

i-Pr

1,4-dioxane, r.t.

+

44 (10, 1 or 0.1 mol%)

N

N O

O O

Ni Ni

O

3Å MS N

PG O NCS X

Y

O

R H

O O HN

N

Y X R S

PG 82-99% yield 42-82% de 80-99% ee PG = Me, allyl

X = H, Me Y = H, Cl

R = Cy, c-Pent, i-Pr, i-Pent, CH

2

Bn, (CH

2

)

2

CH=CH(CH

2

)

4

Me, (CH

2

)

3

OTBS, n-Pent

42 41

43

(7)

In 2013, a synthesis of chiral 3-amino-2-oxindoles was developed by Gong and co-workers on the basis of a multi- catalytic asymmetric three-component aldol-type reaction of 3-diazo-2-oxindoles 51 with anilines 52 and glyoxylate 53 (Scheme 14).

²⁰

This domino process was catalyzed by a rhodium complex, such as [Rh

₂

(OAc)

₄

], combined with chi- ral phosphoric acid 54 . The reaction proceeded via rhodi- um-catalyzed generation of ammonium ylides from 3-di- azo-2-oxindoles and anilines, followed by chiral Brønsted acid-catalyzed enantioselective aldol-type reaction with glyoxylates to give the corresponding chiral products 55 in

moderate to quantitative yields (63–99%), moderate to high diastereoselectivities (50–94% de), and low to excellent en- antioselectivities (13–99% ee).

In 2015, an enantioselective magnesium-catalyzed tan- dem reaction was reported by Wang and co-workers, in- volving 3-isothiocyanato-2-oxindoles 9 and aziridines 56 as substrates.

²¹

It constituted the first asymmetric formal [3+3] cycloaddition with aziridines. This tandem reaction was mediated by a magnesium catalyst in situ generated from MgBu

₂

and ligand 57 in toluene at 0 °C to room tem- perature. It begins with the ring-opening of aziridines with 3-isothiocyanato-2-oxindoles to give intermediates A which subsequently cyclize into the final products 58 by Scheme 12 Zinc-catalyzed domino Michael/cyclization reaction of 3-

nitro-2 H -chromenes with 3-isothiocyanato-2-oxindoles R

¹

= H, 6-F, 6-Cl, 6-Br, 6,8-Br

2

, 6-NO

2

, 6-Me, 6-OMe, 7-OMe, 8-OMe R

²

= H, 5-F, 5-Me, 5-OMe

R

³

= Me, Bn X = O, CH

₂

toluene, r.t.

+

48 (11 mol%)

Zn(OTf)

₂

(10 mol%)

N

R

²

O

R

³

R

²

NCS

X NO

₂

R

¹

N N

R

³

O S NO

2

X

R

¹

H N H

O N N O

Ph Ph Ph Ph

72–99% yield >90% de 91–>99% ee

45

46

47

Scheme 13 Zinc-catalyzed domino Michael/cyclization reaction of 3- nitroindoles with 3-isothiocyanato-2-oxindoles

toluene, 50 °C +

ent-48 (11 mol%)

R

¹

= H, F, Me R

²

= Me, Bn, Ph

R

³

= 5-Cl, 5-Br, 5-OMe, 5-OBn, 5-CN, 4-Cl, 4-Br, 6-Cl, 7-Me, H R

⁴

= Ts, Bs, Mes, Ns, Ac, Cbz, CO

2

Et, CO

2

Me, Boc

Zn(OTf)

2

(10 mol%)

N O R

²

NCS R

³

N HN

R

²

O S NO

₂

H N

H

O N N O

Ph Ph Ph Ph N

NO

2

R

⁴

R

¹

R

¹

N

R

⁴

R

³

4 Å MS 96–99% yield 70–>98% de 91–99% ee

49

9

50

Scheme 14 Three-component aldol-type reaction of 3-diazo-2-oxindoles, anilines, and glyoxylates catalyzed by a combination of [Rh

2

(OAc)

4

] and a chiral phosphoric acid

toluene, 25 °C

+

54 (10 mol%)

R

¹

= H, 4-Cl, 5-F, 5-Me, 5-OMe, 6-Br, 7-Br

R

²

= H, 2-Br, 2-Cl, 2-CN, 2-CO

2

Me, 2-Bz, 2-Ac, 2-CO2Me-4-Br, 2-CO

2

Me-4-Cl, 2,5-(CO

2

Me)

2

, 4-NO

2

, 2-CO

2

Me-4-Me, 2-CO

2

Me-4-Cl, 2-CO

2

Me-4-F, 2-CO

2

Me-3-F, 2-CO

2

Me-5-F, 2-CO

2

Me, 4,5-F

2

, 3-NO

2

[Rh

2

(OAc)

4

] (2 mol%) R

¹

N HN

i-Pr

O N

N

2

i-Pr

63–99% yield 50–94% de 13–99% ee Ar

Ar O O P

O OH

Ar = 2,4,6-(i-Pr)

₃

C

₆

H

₂

R

¹

O

NH

2

R

²

+

O H CO

₂

Et

R

²

OH CO

2

Et

51

53

52 55

(8)

treatment with t-BuOK/MeI (Scheme 15). This novel tan- dem ring-opening/ring-closing reaction allowed a range of densely functionalized chiral products 58 to be synthesized in moderate to high yields (37–92%) with uniformly high diastereo- and enantioselectivities (88–>90% de and 89–

>99% ee, respectively).

In 2014, a synthesis of chiral 3-amino-2-oxindoles was based by Zhou and co-workers on a rare example of one-pot process involving asymmetric triple relay catalysis (Scheme 16).

²²

The sequence began with the hydrogenation of 59 into the corresponding malonate-aniline derivative. Then, this compound reacted with an isatin derivative 60 in the presence of TsOH to give the corresponding ketimine. When the latter was submitted to catalyst 13a , it underwent a [1,5]-electrocyclic reaction to afford the corresponding chi- ral products 61 in moderate to good yields (45–85%) and high enantioselectivities (80–97% ee).

4 Conclusion

Chiral 3-amino-2-oxindoles are important and ubiqui- tous motifs in many natural products and biologically ac- tive compounds with a range of significant pharmaceutical properties. Along with more traditional methodologies to prepare these compounds, such as enantioselective nucleo- philic additions to isatin imines and direct aminations of 3- substituted 2-oxindoles, this review demonstrates that more recently developed enantioselective catalytic domino and tandem reactions of various types are also highly effi- cient to this aim. These one-pot processes have been achieved with often excellent enantioselectivities by using both chiral metal and organocatalysts of many types. In particular, the catalytic potential of chiral organocatalysts, including cinchona alkaloids, phosphoric acids, thioureas, squaramides, and N-heterocyclic carbenes among others, has been successfully exploited in the last few years. Re- markable enantioselectivities of up to 99% ee have also been described in reactions catalyzed by metal complexes derived from magnesium, zinc, rhodium, and nickel. Fur- thermore, excellent enantioselectivities of up to 97% ee were also described in several enantioselective multicata- lyzed tandem reactions. In the near future, the ever-grow- ing need for achieving these biologically important prod- ucts will prompt organic chemists to develop other enanti- oselective catalytic domino and tandem reactions. Indeed, designing novel catalytic asymmetric transformations by different combination of substrates and catalysts will in- crease the library of potentially bioactive 3-amino-2-oxin- doles. In this context, a great challenge will be to design and develop efficient (organo)catalysts providing high stereose- lectivity at low catalyst loading.

Scheme 15 Magnesium-catalyzed tandem ring-opening/ring-closing reaction of 3-isothiocyanato-2-oxindoles with N -(2-pyridylcarbon- yl)aziridines

57 (15 mol%)

37–92% yield 88–>90% de 89–>99% ee toluene, 0 °C to r.t.

MgBu

2

(15 mol%) OH OH F

F 1)

2) KOt-Bu, MeI THF, 0 °C O

N N

R

³

R

³

+

N C S N O

R

¹

R

²

N R

¹

R

²

O N N R

³

R

³

SMe O

N

R

¹

= Me, n-Pr, Bn R

²

= H, Me

R

³

, R

³

= (CH

2

)

4

, (CH

2

)

5

, (CH

2

)

3

, R

³

= Me, Et, Ph

N R

¹

R

²

O N

C N

^-

R

³

R

³

O N

S aziridine

ring-opening

ring-closing

Me

A

I

9

56

58

Scheme 16 Multicatalyzed tandem hydrogenation/imine forma- tion/[1,5]-electrocyclic reaction of malonate-nitroarenes with isatin de- rivatives

13a (10 mol%)

45–85% yield 80–97% ee +

X N

O O

X N

O NH EtO

₂

C EtO

2

C

X = CH, N R

¹

= H, F, Me R

²

= H, CO

2

Me, F, Me R

³

= H, F

R

¹

R

²

N

NH N

OMe

S NHAr

Ar = 3,5-(CF

₃

)

₂

C

₆

H

₃

CH(CO

2

Et)

2

NO

2

R

¹

R

²

R

³

R

³

1) H

2

(1 atm) Pd/C, Et

2

O, 25 °C 2) TsOH, Et

2

O, 60 °C

3)

Et

2

O, 40 °C

60

59

61

(9)

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