Diastereoselective Construction of 3-Aminooxindoles with Adjacent Stereocenters: Stereocontrolled Addition of γ-Substituted Allylindiums to Isatin Ketimines

FULL PAPER

DOI: 10.1002/ejoc.201500340

Diastereoselective Construction of 3-Aminooxindoles with Adjacent

Stereocenters: Stereocontrolled Addition of γ-Substituted Allylindiums to Isatin

Ketimines

Nayyar Ahmad Aslam,^[a]Srinivasarao Arulananda Babu,*^[a]Soniya Rani,^[a]

Shivam Mahajan,^[a]Jagmohan Solanki,^[a]Makoto Yasuda,^[b]and Akio Baba^[b]

Keywords: Synthetic methods / Allylation / Indium / Nitrogen heterocycles / Diastereoselectivity

The diastereoselective construction of 3-allyl-3-aminooxind-

oles that have two adjacent stereocenters has been achieved

by the In-promoted Barbier-type addition of γ-substituted all-

ylic halides to the C=N bond of isatin ketimines. The reac-

isatin ketimine in EtOH gave oxindole-based β-amino acid

scaffolds. In all of these processes, the reaction conditions

were screened to obtain the respective 3-allyl-3-aminooxind-

oles with very high stereoselectivity. In addition, plausible TS

tions of cinnamyl-, crotyl-, and geranylindium compounds models are proposed, and representative synthetic transfor-

with isatin ketimines proceeded in either aqueous or alcohol

solution. The addition of a cyclohexenylindium species to an

isatin ketimine was carried out in N,N-dimethylformamide

(DMF), and the addition of ethyl 4-bromocrotonate to an

mations were carried out by using the oxindole-based β-

amino acid scaffolds. Furthermore, the stereochemistry of

representative compounds were unequivocally established

by single-crystal X-ray structure analysis.

heteroatom-substituted oxindoles^[4–7]that have pharmaco-

logical activity, the 3-amino-2-oxindole compound AG-

041R (IIa)^[5a,7a]acts as a gastrin/CCK-B receptor antago-

nist, and 3-amino-2-oxindole IIb acts as an HIV protease

inhibitor.^[7b]Waldmann’s group also discovered spirooxind-

oles with a nitrogen atom at the C-3 position. Compound

IIc, a thiazolidinone spiro-fused to an indolin-2-one, is a

potent and selective inhibitor of the Mycobacterium tuber-

culosis protein tyrosine phosphatase B.^[7c]Rottmann and

co-workers discovered spirotetrahydro β-carboline IId, an-

other spirooxindole with a nitrogen atom at the C-3 posi-

tion, which is a potential antimalarial agent.^[5e]Crosignani

described^[7d]spiroindolinone IIe, which is a CRTH2 antago-

nist with a similar spirooxindole core structure (Figure 1).

AstraZeneca’s spirohydantoin^[7e,7f]acts as a TRPV1 antago-

nist for chronic pain control, and the 3-aminooxindole-

based drug molecule SSR-149415^[5b,5c,8]is under clinical

trials for the treatment of anxiety and depression.

The nucleophilic addition of allylic metals to imine

(C=N) systems is one of the standard C–C bond-forming

reactions to synthesize homoallylic amine building blocks

with one or more stereocenters.^[9]The allylation of imine

(C=N) systems can be performed by using Grignard rea-

gents, and in this case, prior preparation of the Grignard

reagent (e.g., allylmagnesium bromide or cinnamylmagnes-

ium bromide) is necessary. On the other hand, the allylation

of imine (C=N) systems can also be carried out under

Barbier-type reaction^[10–16]conditions by using metals, such

as In,^[11]Zn,^[12]Ga,^[13]Bi,^[14]Mg,^[15]and Sn.^[16]The

Barbier-type reaction has the following advantages:^[10–18]

Introduction

An oxindole framework that contains a tetrasubstituted

carbon is a promising bioactive heterocyclic motif as well

as the core unit of several pharmaceutical lead compounds

and synthetic and naturally occurring oxindoles.^[1–3]Repre-

sentative examples of bioactive spirooxindoles are shown in

Figure 1 (e.g., spirotryprostatins A and B, rhynchophylline,

and chartellines A–C). Oxindole molecules that have a het-

eroatom (N, O, or S) substituted at the C-3 position are

also found in nature and considered to be pharmaceutically

important heterocyclic building blocks^[1–7][e.g., convoluta-

mydine A^[6a](a 3-substituted 3-hydroxy-2-oxindole frame-

work), spirobrassinin^[6b](a spirooxindole with a sulfur atom

at the C-3 position), and chartellines A–C^[6c,6d](spirooxind-

ole derivatives with a nitrogen atom at the C-3 position).

Inspired by the promising biological activity of naturally

occurring heterocycles, chemists have synthesized numerous

oxindole and 3-heteroatom-substituted oxindole scaffolds,

which are known to exhibit a variety of biological activities

and promising drug-like behaviors.^[1–3]With regard to 3-

[a] Department Chemical Sciences, Indian Institute of Science

Education and Research (IISER) Mohali,

Knowledge City, Sector 81, SAS Nagar, Mohali, Manauli P.O.,

Punjab, 140306, India

E-mail: sababu@iisermohali.ac.in

http://ww w .iisermohali.ac.in/html/faculty/babu.html

[b] Department of Applied Chemistry, Graduate School of

Engineering, Osaka University,

2-1 Yamadaoka, Suita, Osaka 565-0871, Japan

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201500340.

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Addition of γ-Substituted Allylindiums to Isatin Ketimines

Figure 1. Representative examples of biologically active 3-heteroatom-substituted oxindole scaffolds (Tol = p-tolyl).

(a) the direct use of indium powder or another metal pow- tert-butanesulfinyl ketimines, which in this case afforded

der and an allylic halide is possible, (b) the prior prepara- various 3-allyl-3-aminooxindoles in yields of 25–46% with

tion of the allylic reagent is not necessary, (c) notably, the diastereomeric excess (de) values of up to 78%. Recently,

indium-based allylation reaction is performed in aqueous Xu and co-workers reported^[23d]the Zn-mediated addition

or alcohol solution, and many reactive functionalities, such of allyl bromide to isatin-derived chiral N-tert-butanesulf-

as a hydroxyl or an amino group, can be present without a inyl ketimines in

a

THF/hexamethylphosphoramide

protecting group in the starting material. Consequently, the (HMPA) medium and an example of a Zn-mediated crotyl-

Barbier-type nonstereoselective and stereoselective ad- ation of N-tert-butanesulfinyl isatin ketimine in THF/

ditions of simple and γ-substituted allylic halides to several HMPA (10:1), which gave the corresponding chiral 3-

C=N bond systems^[9–19](e.g., aldimines, ketimines, hydraz- aminooxindoles as diastereomers [diastereomeric ratio (dr)

ones, oximes, and sulfonimines) have been well-studied by 77:23]. Apart from these works, the direct and diastereo-

using metals such as In, Zn, Ga, and Bi.

selective Barbier-type indium-mediated addition of γ-sub-

Given the importance of the 3-heteroatom-substituted stituted allylic reagents to isatin ketimines (ketimines de-

oxindole motifs, various approaches have been developed rived from isatins), especially in aqueous or alcohol solu-

for their synthesis, especially in the case of 3-aminooxindole tion, has not yet been explored.

molecules. Methods for their preparation include the asym-

Recently, we reported^[19a,19b]the direct and diastereo-

metric amination of 3-substituted oxindoles,^[20]addition re- selective Barbier-type indium-mediated addition of various

actions to isatin ketimines,^[21]and various other ap- γ-substituted allylic halides to N-aryl-α-imino- and N-aryl-

proaches.^[22]In relation to this, the stereoselective addition α-hydrazono esters for the construction of γ,δ-unsaturated

of carbon nucleophiles to isatin-derived ketimines is a β,βЈ-disubstituted N-aryl-α-amino acid derivatives and N-

straightforward route to functionalized 3-aminooxindoles aryl and N-acyl/tosyl hydrazono β-vinyl aspartates that

that have one or more stereocenters. A survey of the litera- have two contiguous stereocenters (Scheme 1). In continua-

ture, however, indicates that only a few reports are available tion of our interest in the synthesis of biologically relevant

in this regard.^[23a–23e]Alcaide and Almendros^[23a]have re- molecules and homoallylic amine derivatives that have mul-

ported the In-mediated addition of simple allylic halides to tiple stereocenters, we herein report the direct diastereo-

isatin ketimines, and Zhou’s group^[23b]has reported the selective Barbier-type indium-mediated addition of cinna-

Hg(ClO₄)₂·3H₂O-catalyzed Sakurai–Hosomi allylation of myl bromide, crotyl bromide, cyclohexenyl bromide, geranyl

isatin ketimines by using allyltrimethylsilane. In these cases, bromide, neryl bromide, and ethyl 4-bromocrotonate, which

the construction of racemic 3-allyl-3-aminooxindoles with are γ-substituted allylic halides, to the C=N bond of isatin

one stereocenter was successfully demonstrated. Silvani et ketimines (ketimines derived from isatins) for the diastereo-

al. reported^[23c]the addition of a simple allylmetal reagent, selective construction of oxindole-based homoallylic amine

such as allylmagnesium bromide, to isatin-derived chiral systems that have two adjacent stereocenters. This method

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Scheme 1. Synthesis of 3-aminooxindole motifs (Fg = functional group, THF = tetrahydrofuran).

enables the synthesis of various 3-aminooxindole scaffolds

that contain two adjacent stereocenters.

Results and Discussion

To study the metal-mediated Barbier-type addition of γ-

substituted allyl halides to the C=N bond of isatin ket-

imines and assemble the 3-allyl-3-aminooxindoles, various

isatin ketimines and isatin hydrazones were prepared from

anilines that contained an electron-donating or electron-

withdrawing group, tosylhydrazide, or benzoylhydrazide

(Figure 2). Generally, the geometry of the C=N bond of

isatin ketimines (predominant isomers) is reported to have

the (E) configuration (see the Supporting Information for

the X-ray crystal structures of isatin ketimines 1i and

1k).^[23f]

To begin, we carried out the metal-mediated Barbier-type

addition of cinnamyl bromide [(E) isomer] to isatin ket-

imine 1a (Table 1). Several reactions were performed to de-

termine the best solvent and reaction conditions and give

3-aminooxindole 3a (γ-adduct) with two contiguous

stereogenic centers and high diastereoselectivity. Initially, a

mixture of isatin ketimine 1a, cinnamyl bromide (2a), and

indium metal powder in anhydrous THF was stirred at

30 °C for 24 h to furnish 3-aminooxindoles (γ-adducts) 3a

(major isomer) and 4a (minor isomer) with two adjacent

Figure 2. Isatin ketimines and γ-substituted allylic halides used in

this work.

stereocenters in 59% yield as a mixture of diastereomers (dr

86:14) along with α-adduct 5a in 20% yield (Table 1, En-

try 1). Repeating the same reaction in anhydrous N,N-di-

methylformamide (DMF) afforded 3-aminooxindole dia- Next, we carried out the reaction in 1,4-dioxane, which gave

stereomers 3a and 4a as a mixture (dr 50:50) in 30% yield 3-aminooxindole diastereomers 3a and 4a in 65% yield with

along with α-adduct 5a in 65% yield (Table 1, Entry 2). high diastereoselectivity (dr 90:10, Table 1, Entry 3). When

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Addition of γ-Substituted Allylindiums to Isatin Ketimines

the reaction of the isatin ketimine 1a, cinnamyl bromide ried out for the shorter period of time of 3 or 1.5 h (Table 1,

(2a), and indium metal powder was carried out in EtOH, Entries 11 and 12). In all of these cases, the formation of

3-aminooxindole diastereomers 3a and 4a were obtained in α-adduct 5a was not detected. Next, we carried out the cin-

a higher yield (78%) and with high diastereoselectivity (dr namylation of 1a in THF/water at 70 °C, which gave dia-

95:5, Table 1, Entry 4).

stereomers 3a and 4a in 13% yield (Table 1, Entry 13).

However, the reaction in THF/water at 5 °C afforded the

diastereomers 3a and 4a in 70% yield with very good dia-

stereoselectivity (dr 95:5, Table 1, Entry 14). We also carried

out the cinnamylation of 1a in a DMF/H₂O mixture, which

furnished diastereomers 3a and 4a in 13% yield (Table 1,

Entry 15). In addition, the employment of Zn dust and Sn

powder furnished diastereomers 3a and 4a in 23 and Ͻ5%

yields, respectively (Table 1, Entries 16 and 17). In consider-

ation of our results, the In metal powder and the THF/

water system were chosen for the cinnamylation of 1a,

which diastereoselectively afforded 3a and 4a with two con-

tiguous stereocenters. We also performed the Barbier-type

cinnamylation of isatin ketimine 1i with cinnamyl bromide

(2a) in the presence of Mg powder, instead of the In pow-

der. This reaction, however, did not afford the expected γ-

adducts but instead gave products 5b and 5c (Scheme 2).

The scope of the Barbier-type cinnamylation was then

examined by using various isatin ketimines to achieve the

diastereoselective synthesis of a number of cinnamylated 3-

aminooxindoles (Table 2). Under the optimized reaction

conditions, the In-mediated cinnamylation of various isatin

ketimines (derived from substituted anilines and isatin) in

THF/water gave the corresponding 3-aminooxindoles 3b–

3i, which contain two adjacent stereocenters, in yields of

50–95% with high diastereoselectivity (dr up to 95:5,

Table 2). It is notable that in THF/water the In-mediated

Barbier-type cinnamylation of isatin ketimine 1h, which has

a free hydroxyl group, successfully afforded cinnamylated

product 3i in 60% yield with high diastereoselectivity (dr

95:5, Table 2). Next, the reaction of tosylhydrazone 1l (de-

rived from N-methylisatin) afforded the corresponding 3-

aminooxindole 3j, which contains two adjacent stereocen-

ters, in 72% yield (dr 90:10, Table 2). Similarly, the cin-

namylation of benzoylhydrazone 1m (derived from N-meth-

ylisatin) furnished the corresponding 3-aminooxindole 4k

in 50% yield and with good diastereoselectivity (dr 95:5,

Table 2).

Table 1. Optimization of reaction conditions and diastereoselective

synthesis of 3-aminooxindole 3a.^[a]

Entry Metal Solvent (mL)

t [h] % Yield [dr 3a/4a]^[b]% Yield 5a

1

2

3

4

5

6

7

8

In

THF (2)

DMF (0.5)

1,4-dioxane (1)

EtOH (2)

24 59 (86:14)

24 30 (50:50)

24 65 (90:10)

20

65

n.d.^[c]

n.d.

6

78 (95:5)

THF (1)/H₂O (2)

THF (2)/H₂O (0.2)

THF (0.2)/H₂O (2)

DMF (0.2)/H₂O (2)

24 30 (95:5)

24 53 (95:5)

36 83 (95:5)

24 83 (95:5)

12 80 (95:5)

9

10

11

12

13

14

15

16

17

6

3

80 (95:5)

65 (95:5)

1.5 60 (95:5)

3

6

13 (–)^[d]

70 (95:5)^[e]

13 (–)

23 (95:5)

Ͻ5 (–)

Zn THF (0.2)/H₂O (2)

Sn THF (0.2)/H₂O (2)

[a] All of the reactions were performed with 1a (0.25 mmol), 2a

(0.75 mmol), and metal powder (0.5 mmol). [b] The total yield of

both diastereomers (3a and 4a) is reported. The ratio of the dia-

stereomers was determined by NMR analysis of the crude reaction

mixture and is provided in the parentheses. [c] n.d.: not detected.

[d] The reaction was carried out at 70 °C. [e] The reaction was car-

ried out at 5 °C.

Next, the reaction of isatin ketimine 1a, cinnamyl brom-

ide (2a), and indium metal powder was performed in vari-

ous THF/water combinations (Table 1, Entries 5–7). No-

tably, the THF/water mixture also promoted the stereose-

lective formation of 3-aminooxindole diastereomers 3a and

In many of the cinnamylation reactions, the correspond-

4a, which were obtained in yields of 80–83% with very high ing major isomers were isolated in pure form. The stereo-

diastereoselectivities (dr 95:5, the reaction period was 6– chemistry of products 3a–3j were assigned on the basis of

36 h, Table 1, Entries 5–10). Diastereomers 3a and 4a were single-crystal X-ray structure analyses of the representative

obtained in low yields (60–65%) when the reaction was car- major isomers 3b, 3i, and 3j (Figure 3). The exclusive for-

Scheme 2. Synthesis of 3-aminooxindoles 5b and 5c.

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Table 2. Diastereoselective synthesis of 3-aminooxindoles 3b–3j and

4k, which contain two adjacent stereocenters.^[a]

Figure 3. X-ray structures of the compounds 3b, 3i, 3j, 4k, 6d, and

6e.

Figure 4. Plausible TS models for the observed diastereoselectivity

(L = ligand).

[a] All of the reactions were performed with 1 (0.25 mmol), 2a

(0.75 mmol), and indium powder (0.5 mmol). The total yield of

both diastereomers is reported. The ratio of the diastereomers was

determined by NMR analysis of the crude reaction mixture and is

provided in the parentheses. [b] The reaction was carried out in

EtOH. [c] The reaction was performed with 1l or 1m (0.25 mmol),

2a (0.63 mmol), and indium powder (0.38 mmol) in a mixture of

THF (0.5 mL) and H₂O (1 mL) for 24 h (Ts = p-toluenesulfonyl).

to the isatin ketimine. Additionally, the high diastereoselec-

tivity observed in these reactions reveals that the addition

of allylindium compounds to the isatin ketimines is kinet-

ically controlled.^{[9,11,19a,19b]}Some recent papers by Ba-

ba,^{[11o,29a–29e]}Koszinowski,^[29f]and Singaram^[17o]convinc-

ingly suggest the involvement of an In^IIIspecies in the TS.

On the other hand, in agreement with the chelation-assisted

mation of 3-aminooxindoles 3a–3j as the major isomers in additions of allylindium compounds to C=O and C=N sys-

this Barbier-type cinnamylation reaction can be explained tems, which have been reported by various groups, it is also

by a chelation-assisted transition state (TS,^[9b,24–29]Fig- possible that the present reactions may involve an In^Ispe-

ure 4, model A for 3a–3j). Similarly, the formation of 3- cies as proposed by Chan^[29g]and Hilt.^[29h]As a chelation-

aminooxindole 4k (confirmed by the X-ray crystal structure assisted and rigid TS^[9b,24–29]is essential for the high dia-

analysis, Figure 3) as the major isomer in the cinnamylation stereoselectivity,^{[11p,9a,9b,29d,29e]}a low valent indium species

of benzoylhydrazone 1m can be explained by TS model B might be favored.

(Figure 4). This observation is in concurrence with a litera-

Next, we focused our attention on the optimization of

ture report on the addition of allylboronic acid to a hydraz- the Barbier-type In-mediated direct addition of crotyl

one system, in which the authors propose a TS that involves bromide [2b, (E) isomer] to the isatin ketimines (Table 3).

hydrogen bonding to support the observed diastereoselec- In this regard, isatin ketimine 1a was treated with crotyl

tivity.^[9y]

bromide (2b) in the presence of indium powder in DMF,

It is well-documented that allylindium compounds are THF, EtOH, or a THF/water mixture to afford crotylated

tolerant to water and protogenic solvents.^[9,11]In the Barb- diastereomers 6a and 7a in yields of 56–95% with moderate

ier-type reactions that involve the indium-mediated ad- diastereoselectivity (dr up to 70:30, Table 3, Entries 1–4).

dition of an allyl halide, that is, cinnamyl bromide to the

The best diastereoselectivity was achieved when the crot-

isatin ketimines as described herein, the aqueous solution ylation of isatin ketimine 1a was carried out in THF/water.

promotes rapid quenching of the transient indium amide, Consequently, we carried out the addition of crotyl bromide

which is formed after the addition of the allylindium species (2b) to the other isatin ketimines in this solvent mixture,

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Addition of γ-Substituted Allylindiums to Isatin Ketimines

Table 3. Diastereoselective synthesis of 3-amino-oxindoles 6a–6e, tion of 3-aminooxindoles 6a–6e as the major isomers can

which contain two adjacent stereocenters.^[a]

also be explained by a chelation-controlled TS^[9b,24–29](Fig-

ure 4, model A for 6a–6e).

We then focused on the preparation of 3-cyclohexenyl-3-

aminooxindole systems with two adjacent stereocenters by

using the metal-based direct addition of 3-bromocyclohex-

ene (2d, (Z) configuration) with isatin ketimine 1a. Several

reactions were performed to determine the best solvent and

reaction conditions and diastereoselectively afford 3-amino-

oxindole 10a with two contiguous stereogenic centers. Ac-

cordingly, the reaction of isatin ketimine 1a, 3-bromo-

cyclohexene (2d), and indium metal powder in THF and

1,4-dioxane gave the 3-cyclohexenyl-3-aminooxindole dia-

stereomers 10a and 11a in 34 and 36% yield, respectively,

with good diastereoselectivity (dr up to 80:20, Table 4, En-

tries 1 and 2). Similarly, the cyclohexenylation of 1a in di-

methyl sulfoxide (DMSO) afforded diastereomers 10a and

11a in moderate yield (57%) and low diastereoselectivity (dr

67:33, Table 4, Entry 3). The cyclohexenylation of 1a did

not occur when toluene was used as the solvent, and the

cyclohexenylated product was not detected (Table 4, En-

try 4). When the cyclohexenylation of 1a was performed in

EtOH, a protogenic solvent, diastereomers 10a and 11a

were obtained in moderate yield (65%, dr 77:23, Table 4,

Entry 5).

Table 4. Synthesis of 3-cyclohexenyl-3-aminooxindoles.^[a]

Entry Metal Solvent (mL)

t [h]

% Yield [dr 10a/11a]^[b]

[a] All reactions were performed with

1 (0.25 mmol), 2b

1

2

3

4

5

6

7

8

In

Bi

Sn

THF (2)

6

12

6

3

6

34 (60:40)

36 (80:20)

57 (67:33)

n.d.

65 (77:23)

n.d.

91 (80:20)

90 (80:20)

75 (79:21)

93 (79:21)^[c]

23 (67:33)^[d]

90 (80:20)^[e]

92 (80:20)^[f]

14 (–)

(0.75 mmol), and indium powder (0.5 mmol). The total yield of

both diastereomers is reported. The ratio of the diastereomers was

determined by NMR analysis of the crude reaction mixture and is

provided in the parentheses.

1,4-dioxane (1)

DMSO (0.5)

toluene (2)

EtOH (0.5)

THF (0.5)/H₂O (0.5)

DMF (0.5)

which successfully afforded the corresponding 3-aminoox-

indoles 6b–6e with moderate to good diastereoselectivity (dr

up to 70:30, Table 3, Entries 5–8). An explanation for the

relatively low diastereoselectivity observed in the cases of

the crotylation reactions of isatin ketimine may involve the

size of the methyl group (in the crotylindium species), which

is smaller than the phenyl group (in the cinnamylindium

species). As a result, the crotylation process may proceed

through a less rigid TS. We tried to separate the dia-

stereomers produced in the crotylation process by column

chromatography, and in a few cases, the major isomer was

isolated in pure form. The stereochemistry of products 6a–

6e were assigned on the basis of single-crystal X-ray struc-

ture analyses of the representative major isomers 6d and 6e

9

10

11

12

13

14

15

16

6

32 (58:42)

80 (82:18)

Zn DMF (0.5)

[a] All of the reactions were performed with 1a (0.25 mmol), 2d

(0.5 mmol), and metal powder (0.37 mmol). [b] The total yield of

both diastereomers (10a and 11a) is reported. The ratio of the dia-

stereomers was determined by NMR analysis of the crude reaction

mixture and is provided in the parentheses. [c] The reaction was

carried out at 5 °C. [d] The reaction was carried out at 80 °C.

[e] The reaction was performed with 1a (0.25 mmol), 2d (0.5 mmol),

and metal powder (0.5 mmol). [f] The reaction was performed with

(Figure 3). Similar to the cinnamylation process, the forma- 1a (0.25 mmol), 2d (0.75 mmol), and metal powder (0.5 mmol).

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The In-mediated addition of 3-bromocyclohexene (2d) Table 5. Diastereoselective synthesis of 3-cyclohexenyl-3-aminoox-

indole systems 10b–10g and 11h.^[a]

with isatin ketimine 1a in aqueous solution failed to give

diastereomers 10a and 11a (Table 4, Entry 6). Later, we

found that the addition of 3-bromocyclohexene (2d) and

isatin ketimine 1a in DMF smoothly underwent a reaction

and afforded diastereomers 10a and 11a in very high yield

(up to 91%) with good diastereoselectivity (dr up to 80:20,

Table 4, Entries 7–9). With the intension to obtain a very

good diastereoselectivity, we carried out the reaction in

DMF at 5 °C, which gave diastereomers 10a and 11a in

93% yield but with moderate diastereoselectivity (dr 79:21,

Table 4, Entry 10). In contrast, the cyclohexenylation of 1a

in DMF at 80 °C gave diastereomers 10a and 11a in 23%

yield and with low diastereoselectivity (dr 67:33, Table 4,

Entry 11). Increasing the equivalents of indium powder or

3-bromocyclohexene (2d) did not improve the diastereo-

selectivity (Table 4, Entries 12 and 13). In addition, em-

ploying Bi or Sn powder, instead of In powder, furnished

diastereomers 10a and 11a in low yields (Table 1, Entries 14

and 15). Finally, when we used Zn dust instead of the in-

dium powder for the addition of 3-bromocyclohexene (2d)

with isatin ketimine 1a in DMF, the reaction furnished 3-

cyclohexenyl 3-aminooxindoles 10a and 11a in 80% yield

with good diastereoselectivity (dr 82:18, Table 4, Entry 16).

The diastereoselectivity observed in this case was compar-

able to that of the reaction with the In powder (Table 4,

Entry 7).

Having established the optimized reaction conditions to

carry out the addition of 3-bromocyclohexene to isatin ket-

imines 1, we then investigated the generality of this reac-

tion. Under the optimized reaction conditions, the In-based

Barbier-type addition of 3-bromocyclohexene (2d) to vari-

ous ketimines was carried out and gave the corresponding

3-cyclohexenyl-3-aminooxindole scaffolds 10b–10g (major

isomer) and 11b–11g (minor isomer) with moderate to very

good diastereoselectivities (dr up to 90:10, Table 5). The

yield of the diastereomers 10b and 11b and the obtained

diastereoselectivity by using indium powder (93%, dr 70:30)

were comparable to that obtained by using Zn dust (92%,

dr 71:29). When the cyclohexenylation reaction was per-

formed in EtOH, instead of DMF, the diastereoselectivity

was altered, that is, the respective diastereomers 10e and

11e were obtained with moderate diastereoselectivity.

Furthermore, the cyclohexenylation of 1m (derived from N-

methyl isatin) afforded the corresponding 3-cyclohexenyl-3-

aminooxindole scaffolds 11h (major isomer) and 10h (minor

isomer) in 50% yield and with good diastereoselectivity (dr

90:10, Table 5).

[a] All of the reactions were performed with 1 (0.25 mmol), 2d

(0.5 mmol), and indium powder (0.37 mmol). The total yield of

both diastereomers is reported. The ratio of the diastereomers was

determined by NMR analysis of the crude reaction mixture and is

provided in the parentheses. [b] The reaction was carried out by

using zinc dust. [c] The reaction was carried out in EtOH.

the cinnamylation of benzoylhydrazone 1m, the stereo-

chemistry of 3-cyclohexenyl-3-aminooxindole 11h (major

isomer, confirmed by the X-ray crystal structure, Figure 5),

In many cases of the cyclohexenylation of isatin ket-

imines, the corresponding major isomer was isolated in pure

form, and the stereochemistry of the product (i.e., 10a–10g)

was assigned on the basis of single-crystal X-ray structure

analyses of the representative major isomers 10a, 10b, and

10c (Figure 5). The exclusive formation of the 3-cyclohex-

enyl-3-aminooxindoles 10a–10f as the major isomers can be

explained by chelation-assisted TS^[9b,24–29]model C (Fig-

ure 4). Similar to the discussion given with regard to the

stereochemistry of product 4k, which was obtained from Figure 5. X-ray structures of the 10a, 10b, 10c, and 11h.

4174 Eur. J. Org. Chem. 2015, 4168–4189

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Addition of γ-Substituted Allylindiums to Isatin Ketimines

which was obtained from the cyclohexenylation of 1m, can In-based Barbier-type addition of geranyl bromide [2e, (E)

be accounted for by TS model D (Figure 4), which presum- configuration] to various ketimines was further examined,

ably involves hydrogen bonding.^[9y]

and 3-aminooxindoles 13b–13f (major isomer) and 14b–14f

Next, we studied the reactivity pattern of geranyl brom- (minor isomer) scaffolds were obtained with good to very

ide [2e, (E) configuration] with isatin ketimines 1 to synthe- high diastereoselectivity (dr up to 87:13, Table 6).^[29j]Ad-

size 3-aminooxindole scaffolds that have a terpene unit and ditionally, we performed the reaction of neryl bromide [2f,

two contiguous stereocenters. Initially, we performed the re- (Z) configuration] with the corresponding isatin ketimines

action of geranyl bromide (2e), isatin ketimine 1a, and in- 1 in the presence of indium powder and sodium iodide as

dium powder in the presence of sodium iodide as an addi- an additive in EtOH at 30 °C. These reactions afforded dia-

tive in EtOH at 30 °C. This reaction furnished dia- stereomers 14a (major) and 13a (minor) in 58% yield as

stereomers 13a (major) and 14a (minor) with very good dia- well as 14f (major) and 13f (minor) in 42% yield, both of

stereoselectivity (dr 85:15) in 63% yield (Table 6). The ger- which occurred with very good diastereoselectivity

anylation of 1a in THF, instead of EtOH, gave dia- (Table 6).^[29j]

stereomers 13a (major) and 14a (minor) in 65% yield with

Subsequently, we extended the scope of this protocol to

good diastereoselectivity (dr 78:22). The generality of this synthesize oxindole-based unnatural β-amino acid deriva-

tives with multiple stereocenters by employing the addition

of ethyl 4-bromocrotonate with an isatin ketimine. In this

regard, several reactions were performed to determine the

best solvent and reaction conditions and provide the oxind-

ole-based unnatural β-amino acid scaffolds 16a (major iso-

mer) and 17a (minor isomer) with two contiguous stereo-

genic centers and very high diastereoselectivity. Initially, the

mixture of isatin ketimine 1a, ethyl 4-bromocrotonate (2c),

and indium metal powder in anhydrous THF was stirred at

30 °C for 24 h, which furnished the γ-adducts, dia-

stereomeric 3-aminooxindoles 16a (major isomer) and 17a

(minor isomer), in 30% yield with good diastereoselectivity

(dr 77:23). Notably, this reaction also afforded α-adduct 18a

Table 6. Stereoselective synthesis of 3-aminooxindole scaffolds 13a–

13f, 14a, and 14f, which contain a terpene unit.^[a]

Table 7. The addition of ethyl 4-bromocrotonate (2c) to 1a.^[a]

Entry Metal Solvent (mL)

t [h] % Yield [dr 16a/17a] % Yield 18a

1

2

3

4

5

6

7

8

9

10

In

THF (2)

24

12

6

30 (77:23)

53 (72:28)

75 (73:27)

93 (81:19)

93 (82:18)

92 (82:18)

5 (–)

40

42

20

–

DMF (0.5)

1,4-dioxane (1)

EtOH (1)

[a] Products 13a–13f were obtained from the reaction of

1

(0.25 mmol) with geranyl bromide (2e, 0.75 mmol) in the presence

of NaI (0.75 mmol) and indium powder (0.5 mmol). The total yield

of both diastereomers is reported. The ratio of the diastereomers

was determined by NMR analysis of the crude reaction mixture

and is provided in the parentheses. [b] The reaction of 1a with ger-

anyl bromide (2e) was carried out in THF, and the corresponding

α-adduct 15a was obtained in 10% yield in addition to dia-

stereomers 13a and 14a. [c] The reaction was carried in DMF. [d] In

3

2.5

12

Zn EtOH (1)

Bi EtOH (1)

Sn EtOH (1)

10 (–)

[a] All reactions were performed with 1a (0.25 mmol), 2c

this case, the major isomer is 14, and the minor isomer is 13. Prod- (0.75 mmol), and metal powder (0.5 mmol) The total yield of both

ucts 14a and 14f were obtained from the reaction of 1 (0.25 mmol) diastereomers is reported. The ratio of the diastereomers was deter-

with neryl bromide (2f, 0.75 mmol) in the presence of NaI

(0.75 mmol) and indium powder (0.5 mmol).

mined by NMR analysis of the crude reaction mixture and is pro-

vided in the parentheses.

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S. A. Babu et al.

FULL PAPER

in 40% yield (Table 7, Entry 1). Repeating the same reac- der in EtOH, which successfully gave the corresponding ox-

tion in DMF afforded diastereomeric 3-aminooxindoles 16a indole-based β-amino acid derivatives 16b–16h (major iso-

and 17a (γ-adducts) in 53% yield with moderate diastereo- mer) and 17b–17h (minor isomer, dr up to 92:8, Table 8).

selectivity (dr 72:28) along with α-adduct 18a in 42% yield Notably, the allylindium reagent generated from ethyl 4-

(Table 7, Entry 2). Next, the addition of 2c to 1a in 1,4- bromocrotonate (2c) is tolerant to a protogenic medium

dioxane also gave 3-aminooxindole diastereomers 16a and (e.g., EtOH), and isatin ketimine 1h, which has a free

17a in 75% yield with moderate diastereoselectivity (dr hydroxyl group, smoothly underwent the allylation reaction

73:27) along with α-adduct 18a in 20% yield (Table 7, En- in EtOH to afford product 16h. In many of the reactions

try 3). Encouragingly, the In-mediated addition of ethyl 4- for the addition of ethyl 4-bromocrotonate to the isatin ket-

bromocrotonate (2c) with isatin ketimine 1a in EtOH gave imines, the corresponding major isomers were isolated in

the 3-aminooxindoles 16a and 17a in very high yields (up to pure form. The stereochemistry of products 16a–16h was

93%) with high diastereoselectivity (dr up to 82:18, Table 7, assigned on the basis of single-crystal X-ray structure

Entries 4–7). The formation of the α-adduct 18a was not analyses of representative major isomers 16e and 16h (Fig-

observed when the reaction was performed in EtOH ure 6). The exclusive formation of oxindole-based β-amino

(Table 7, Entries 4–7). Employing other metal powders such acid derivative 16a–16h as the major isomers can be ex-

as Zn, Bi, and Sn in the reaction of ethyl 4-bromocrotonate plained by chelation-assisted TS^[9b,24–29]model A (Figure 4).

(2c) with isatin ketimine 1a provided very low yields of the

expected products 16a and 17a (Table 7, Entries 8–10).

Discussion

Under the optimized reaction conditions, we then carried

out the Barbier-type addition of 4-bromocrotonate (2c)

with several isatin ketimines in the presence of indium pow-

The very high diastereoselectivites observed in the ad-

dition of γ-substituted allylindium reagents to the C=N

bond of isatin ketimines may be the result of a chelation-

assisted TS under the experimental conditions. In concur-

rence with literature reports,^{[9,11,19a,19b,24–28]}the protogenic

media in the present investigation contributes to the rapid

quenching of the transient indium amide, which is formed

upon the addition of the allylindium compound to the

isatin ketamine. The high diastereoselectivites that are ob-

served indicate that the addition process is kinetically con-

trolled. Generally, the C=N bond of the isatin ketimines

(predominant isomers) is reported to have the (E) configu-

ration.^[31]This assumption is supported by reports describ-

ing the stereoselective addition of γ-substituted allylmetals

to the C=N bond of ketimine systems in which very high

diastereoselectivities are obtained.^[9b,18i,18s]Furthermore,

the proposed chelation-controlled TSs (Figure 4, models A–

D) in the current work are based on the observed high dia-

stereoselectivities (confirmed by the X-ray crystal structure

analysis of representative compounds as shown in Fig-

ures 3, 5, and 6). Various research groups have proposed a

chelation-assisted TS to explain the observed high dia-

stereoselectivities gained from the addition of allylindium

reagents to the C=O or C=N bond of compounds that have

heteroatom-based functional groups (e.g., OR, NR₂, or

carbonyl oxygen atom) at the α-carbon position. In many

cases, it is believed that the involvement of a chelation-

assisted and rigid TS is an essential factor to obtain high

diastereoselectivities irrespective of the solvent sys-

Table 8. Diastereoselective synthesis of oxindole-based β-amino

acid derivatives 16b–16h.^[a]

[a] All reactions were performed with

1 (0.25 mmol), 2c

(0.75 mmol), and indium powder (0.5 mmol) The total yield of

both diastereomers is reported. The ratio of the diastereomers was

determined by NMR analysis of the crude reaction mixture and is

provided in the parentheses.

Figure 6. X-ray structures of the 16e, 16h, and 19.

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Addition of γ-Substituted Allylindiums to Isatin Ketimines

tem.^{[9,11,19a,19b,24–28]}However, in general, very high dia- two adjacent stereocenters in each product. We also re-

stereoselectivities were obtained when the addition of an moved the p-methoxyphenyl (PMP) protecting group

allylindium reagent to the C=O or C=N bond of com- from (R*)-ethyl 2-{(R*)-3-[(4-methoxyphenyl)amino]-2-

pounds that have a heteroatom-based functional group oxoindolin-3-yl}butanoate (19) to give the 3-aminooxindole

(e.g., OR, NR₂, or carbonyl oxygen atom) at the α-carbon product, (R*)-ethyl 2-[(R*)-3-amino-2-oxoindolin-3-yl]-

were performed in protogenic solvents (e.g., aqueous or butanoate (22), which is equipped with two contiguous

alcohol solution).^{[9,11,19a,19b,24–28]}Along this line of stereocenters (Scheme 3).

reasoning and in concurrence with literature re-

ports,^{[9,11,19a,19b,24–28]}the chelation-controlled TSs (Fig-

Conclusions

ure 4, models A–D) that are proposed herein account for

the observed diastereoselectivity without considering the

solvation environment. Furthermore, in the present investi-

gation, on the basis of minor deviations in the diastereo-

selectivities for each solvent system, the involvement of

more than one possible TS under the experimental condi-

tions cannot be ignored, as deliberated in the litera-

ture.^[24–29]

Finally, we performed some representative synthetic

transformations to show the scope and utility of the prod-

ucts obtained in this work (Scheme 3). The catalytic

hydrogenation of the olefin moiety of oxindole-based β-

amino acid derivative 16b (major isomer) led to the synthe-

sis of (R*)-ethyl 2-{(R*)-3-[(4-methoxyphenyl)amino]-2-

oxoindolin-3-yl}butanoate (19), the stereochemistry of

which was confirmed by single-crystal X-ray structure

analysis (Figure 6). The reduction of the ester group present

in the oxindole-based β-amino acid derivatives 16b and 19

by treatment with LiAlH₄led to the corresponding oxind-

ole-based γ-amino alcohols 20 and 21, respectively, with

In summary, we have reported a synthetic protocol for

the diastereoselective indium-mediated Barbier-type C–C

bond formation. The addition of various γ-substituted all-

ylic reagents to the C=N bond of isatin ketimines afforded

several new 3-allyl-3-aminooxindole derivatives with two

contiguous stereocenters, which are valuable synthetic

building blocks. The addition of cinnamyl bromide, crotyl

bromide, and geranyl bromide to an isatin ketimine pro-

ceeded smoothly in aqueous or alcohol solution. The reac-

tion of cyclohexenyl bromide with an isatin ketimine in

DMF furnished the corresponding 3-cyclohexenyl-3-amino-

oxindole systems. The addition of ethyl 4-bromocrotonate

to an isatin ketimine in EtOH gave the corresponding ox-

indole-based β-amino acid scaffolds. Substantial efforts

towards screening the reaction conditions resulted in the

preparation of 3-allyl-3-aminooxindoles with a high degree

of stereocontrol and without the hydrolysis of the starting

isatin ketimines. We also presented representative synthetic

transformations that employ the oxindole-based β-amino

acid scaffolds obtained in this work. The observed high dia-

stereoselectivities were accounted for by a plausible chela-

tion-controlled TS, and the stereochemistry of the products

was unambiguously established by single-crystal X-ray

structure analysis of representative compounds.^[34,35]

Experimental Section

General Methods: FTIR spectra of the compounds were recorded

1

as neat samples or thin films. The H and ¹³C NMR spectroscopic

data were recorded with 400 and 100 MHz spectrometers, respec-

tively (using TMS as an internal standard). Column chromatog-

raphy was carried out on silica gel (100–200 mesh). Anhydrous sol-

vents were prepared by using standard drying procedures. Reac-

tions were performed in anhydrous solvent under nitrogen, when it

was required. Organic layers were dried with anhydrous sodium

sulfate. Reagents/solutions were added to the round-bottom (RB)

flask with the help of a syringe. TLC analysis was performed on

silica plates, and the components were visualized by using iodine.

Isolated yields of all products are reported (yields were not opti-

mized), and the total yield of both diastereomers is provided. The

ratios of the diastereomers were determined by NMR analysis of

the crude reaction mixtures, and in some cases, the ratios were de-

termined after isolation (see the Supporting Information). The dia-

stereoselectivity of dr 95:5 refers to the predominant presence of

the major diastereomer, and with the exception of a few cases, the

corresponding minor isomer is either undetected or not clearly vis-

ible in the ¹H NMR spectrum of the crude mixture. The dia-

stereomeric ratios in Tables 1, 2, 3, 4, 5, 6, 7, and 8 were obtained

from the integration of a ¹H NMR signal that corresponds to same

Scheme 3. Synthetic transformations of oxindole-based β-amino

acid scaffolds (CAN = ceric ammonium nitrate).

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4177

S. A. Babu et al.

FULL PAPER

proton in the major and minor isomers (see the Supporting Infor-

mation for the typical signals from which the diastereomeric ratios

were assigned). In some of the cases, purification of the crude reac-

tion mixture by column chromatography gave only the major dia-

stereomer in pure form, and in some cases, the product was isolated

as mixture of diastereomers. The stereochemistry of each major

isomer was assigned on the basis of the X-ray crystal structure

analysis of the representative compounds. During column

chromatography of all of the reactions, we focused on the isolation

of the oxindole derivatives in pure form. Other minor impurities/

byproducts were not isolated in pure form. Isatin ketimines 1a–1m

were prepared by using the standard literature procedures. In some

cases, the NMR spectroscopic data reveals that the samples of the

pure allylated oxindole compounds contain trace amounts ethyl

acetate. In such cases, the residual EtOAc could not be removed

after multiple column chromatographic purifications and drying

the sample under high vacuum. Furthermore, the allylated oxindole

compounds seem to have high affinity for moisture/grease, as can

be seen in a few of the NMR spectra.

(2 mL) was added indium powder (0.5 mmol, 2 equiv.), and the re-

sulting mixture was vigorously stirred at 30 °C for 6–12 h. The reac-

tion mixture was then transferred into a separatory funnel and ex-

tracted with EtOAc (3ϫ 15 mL). The combined organic layers were

dried with anhydrous Na₂SO₄, and the solvent was evaporated un-

der vacuum. Purification of the resulting crude mixture by column

chromatography on silica gel (EtOAc/hexanes) gave the corre-

sponding product 6 (Table 3).

General Procedure C: Indium-Mediated Addition of Cyclohexenyl

Bromide (2d) to Isatin Ketimines 1: To a vigorously stirred solution

of the corresponding isatin ketimine 1 (0.25 mmol, 1 equiv.) and

cyclohexenyl bromide (2d, 0.5 mmol, 2 equiv.) in DMF (1 mL) was

added indium powder (0.37 mmol, 1.5 equiv.), and the resulting

mixture was vigorously stirred at 30 °C for 6 h. The reaction mix-

ture was then transferred into a separatory funnel and extracted

with EtOAc (3ϫ 15 mL). The combined organic layers were dried

with anhydrous Na₂SO₄, and the solvent was evaporated under vac-

uum. Purification of the resulting crude mixture by column

chromatography on silica gel (EtOAc/hexanes) gave the corre-

General Procedure for the Synthesis of Isatin Ketimines 1a–1k:^[31,32]sponding products 10 and 11 (Tables 4 and 5).

Isatin ketimines 1a–1g,^[32a–32e]1h,^[32f,32g]1i,^[32a–32e]1j,^[32h]and 1k^[32i]

General Procedure D: Indium-Mediated Addition of (E)-Geranyl

are known in the literature and were synthesized by using the stan-

dard literature procedures. To the solution of the isatin (4 mmol)

in ethanol (6 mL) was added the corresponding aniline (4 mmol)

in one portion. Then, the reaction mixture was placed in a pre-

heated oil bath at 85 °C and stirred for 45 min. Once the solution

became clear, the RB flask was removed from the oil bath, and the

contents were cooled to room temp. The precipitated isatin ket-

imine was removed by filtration and then washed with a 10% eth-

anol/hexane mixture. The solid product was then air dried and used

without further purification. Generally, the C=N bond of isatin

ketimines (predominant isomers) is reported to have the (E) config-

uration. The isatin ketimines were obtained with an E/Z ratio up

to 99:1 (for the E/Z ratios of the synthesized isatin ketimines, see

the Supporting Information).

Bromide (2e) to Isatin Ketimines 1: To a vigorously stirred solution

of the corresponding isatin ketimine 1 (0.25 mmol, 1 equiv.) and

geranyl bromide (2e, 0.75 mmol, 3 equiv.) in EtOH (2 mL) were

added sodium iodide (0.75 mmol, 3 equiv.) and indium powder

(0.5 mmol, 3 equiv.), and the mixture was vigorously stirred at

30 °C for 24 h. The reaction mixture was then transferred into a

separatory funnel and extracted with EtOAc (3ϫ 15 mL). The

combined organic layers were dried with anhydrous Na₂SO₄, and

the solvent was evaporated under vacuum. Purification of the re-

sulting crude mixture by column chromatography on silica gel

(EtOAc/hexanes) gave the corresponding product 13 (Table 6).

General Procedure E: Indium-Mediated Addition of (E)-Ethyl 4-

Bromocrotonate (2c) to Isatin Ketimines 1: To a vigorously stirred

solution of the corresponding isatin ketimine 1 (0.25 mmol,

1 equiv.) and ethyl 4-bromocrotonate (2c, 0.75 mmol, 3 equiv.) in

EtOH (1 mL) was added indium powder (0.5 mmol, 2 equiv.), and

the resulting mixture was vigorously stirred at 30 °C for 3 h. Then,

the reaction mixture was transferred into a separatory funnel and

extracted with EtOAc (3ϫ 15 mL). The combined organic layers

were dried with anhydrous Na₂SO₄, and the solvent was evaporated

under vacuum. Purification of the resulting crude mixture by col-

umn chromatography on silica gel (EtOAc/hexanes) gave the corre-

sponding product 16 (Tables 7 and 8).

General Procedure for the Synthesis of Isatin Ketimines 1l and

1m:^[31,33]Isatin ketimines 1l and 1m^[33]are known in the literature

and were synthesized by using standard literature procedures. The

corresponding isatin (4 mmol) in methanol (20 mL) was dissolved

by warming the mixture to 70 °C. Then, tosylhydrazide or benzoyl-

hydrazide (4 mmol) was added in one portion to the hot methanolic

solution, and the reaction mixture was stirred at 70 °C for 35 min

to obtain a clear solution. The mixture was allowed to stay at room

temp. until the product crystallized. The crystalline product was

filtered and washed with methanol. The resulting solid was air

dried and used without further purification.

General Procedure F: Indium-Mediated Addition of (Z)-Neryl Brom-

ide (2f) to Isatin Ketimines 1: A THF (2 mL) solution of (Z)-3,7-

dimethylocta-2,6-dien-1-ol (nerol, 1 mmol, 1 equiv.) was cooled to

–10 °C. To this cooled solution was added phosphorus tribromide

(0.5 equiv.) dropwise, and the resulting mixture stirred at 0 °C for

3–5 h. After the starting material was consumed (as shown by

TLC), Et₂O (10 mL) was added. The mixture was successively

washed with 5% NaHCO₃solution (2 mL) and water (2 mL). The

organic layer was dried with anhydrous Na₂SO₄, and the evapora-

tion of solvent under vacuum gave the crude (Z)-1-bromo-3,7-di-

methylocta-2,6-diene [(Z)-neryl bromide, 2f], which was used as

such for further reactions with the isatin ketimines. To a stirred

solution of isatin ketimine 1 (0.25 mmol, 1 equiv.) in EtOH (2 mL)

were added neryl bromide (2f, 0.75 mmol, 3 equiv.), sodium iodide

General Procedure A: Indium-Mediated Addition of Cinnamyl Brom-

ide (2a) to Isatin Ketimines 1: To a vigorously stirred solution of

the corresponding isatin ketimine 1 (0.25 mmol, 1 equiv.) and (E)-

cinnamyl bromide (2a, 0.75 mmol, 3 equiv.) in THF (0.2 mL) and

H₂O (2 mL) was added indium powder (0.5 mmol, 2 equiv.), and

the resulting mixture was vigorously stirred at 30 °C for 6 h. The

reaction mixture was then transferred into a separatory funnel and

extracted with EtOAc (3ϫ 15 mL). The combined organic layers

were dried with anhydrous Na₂SO₄, and the solvent was evaporated

under vacuum. Purification of the resulting crude mixture by col-

umn chromatography on silica gel (EtOAc/hexanes) gave the corre-

sponding products 3 and 4 (Tables 1 and 2).

General Procedure B: Indium-Mediated Addition of Crotyl Bromide (0.75 mmol, 3 equiv.), and indium powder (0.5 mmol, 3 equiv.), and

(2b) to Isatin Ketimines 1: To a vigorously stirred solution of the

corresponding isatin ketimine 1 (0.25 mmol, 1 equiv.) and (E)-

crotyl bromide (2b, 0.75 mmol, 3 equiv.) in THF (0.2 mL) and H₂O

the resulting mixture was vigorously stirred at 30 °C for 24 h. The

mixture was transferred into a separatory funnel and extracted with

EtOAc (3ϫ 15 mL). The combined organic layers were dried with

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Addition of γ-Substituted Allylindiums to Isatin Ketimines

anhydrous Na₂SO₄, and the solvent was evaporated under vacuum.

Purification of the resulting crude residue by column chromatog-

raphy on silica gel (EtOAc/hexane) gave the corresponding product

14 (Table 6).

7.49 (d, J = 7.8 Hz, 2 H), 7.45 (d, J = 7.3 Hz, 1 H), 7.31–7.10 (m,

13 H), 7.08 (d, J = 7.3 Hz, 2 H), 6.73 (d, J = 7.8 Hz, 1 H), 6.19–

6.05 (m, 3 H), 5.64–5.57 (m, 1 H), 3.95 (dd, J = 14.7, 6.9 Hz, 1 H),

3.78 (dd, J = 14.7, 5.3 Hz, 1 H), 3.06 (s, 3 H), 2.84 (dd, J = 13.0,

6.4 Hz, 1 H), 2.69 (dd, J = 13.0, 8.6 Hz, 1 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 178.3, 147.2, 143.3, 137.3, 137.2, 134.2,

131.3, 130.4, 129.5, 128.8, 128.4, 128.3, 128.0, 127.2, 127.1, 126.3,

126.0, 125.3, 124.6, 123.0, 122.6, 107.9, 70.4, 54.2, 41.1, 25.9 ppm.

HRMS (ESI): calcd. for C₃₃H₃₁N₂O [M + H]⁺471.2436; found

471.2457.

(R*)-3-[(S*)-1-Phenylallyl]-3-(phenylamino)indolin-2-one (3a): Fol-

lowing general procedure A gave a crude mixture, which was puri-

fied by silica gel column chromatography (EtOAc/hexane, 30:70) to

afford 3a (68 mg, 80%) as a colorless solid; m.p. 160–162 °C. R_f=

0.60 (30% EtOAc/hexane). IR (thin film): ν = 3307, 3059, 1715,

˜

1

1602, 1504, 1200 cm^–1. H NMR (400 MHz, CDCl₃): δ = 8.12 (s,

1 H), 7.20 (d, J = 7.3 Hz, 1 H), 7.14–7.07 (m, 4 H), 7.01–6.98 (m,

3 H), 6.91 (dd, J = 8.2, 7.8 Hz, 2 H), 6.62–6.48 (m, 3 H), 6.24 (d,

J = 7.8 Hz, 2 H), 5.45–5.35 (m, 2 H), 4.70 (s, 1 H), 3.80 (d, J =

10.5 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 178.9, 145.0,

140.1, 136.6, 134.2, 129.1, 129.0, 129.0, 127.9, 127.4, 124.6, 122.7,

120.5, 119.0, 114.8, 110.1, 67.2, 59.6 ppm. HRMS (ESI): calcd. for

C₂₃H₂₁N₂O [M + H]⁺341.1654; found 341.1653.

(R*)-3-[(S*)-1-Phenylallyl]-3-(p-tolylamino)indolin-2-one (3b): Fol-

lowing general procedure A gave a crude mixture, which was puri-

fied by silica gel column chromatography (EtOAc/hexane, 30:70) to

afford 3b (78 mg, 88%) as a colorless solid; m.p. 152–154 °C. R_f=

0.66 (30% EtOAc/hexane). IR (thin film): ν = 3443, 3347, 1712,

˜

1

1623, 1468, 1155 cm^–1. H NMR (400 MHz, CDCl₃): δ = 7.75 (s,

1 H), 7.27 (d, J = 7.8 Hz, 1 H), 7.15–7.12 (m, 4 H), 7.06–7.01 (m,

3 H), 6.76 (d, J = 8.1 Hz, 2 H), 6.64–6.55 (m, 1 H), 6.56 (d, J =

7.9 Hz, 1 H), 6.22 (d, J = 8.1 Hz, 2 H), 5.49–5.39 (m, 2 H), 4.61

(br. s, 1 H), 3.83 (d, J = 10.5 Hz, 1 H), 2.12 (s, 3 H) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 178.7, 142.6, 140.0, 136.7, 134.3,

129.6, 129.5, 129.3, 129.0, 128.5, 127.9, 127.3, 124.6, 122.7, 120.5,

115.3, 109.9, 67.4, 59.6, 20.4 ppm. HRMS (ESI): calcd. for

C₂₄H₂₃N₂O [M + H]⁺355.1810; found 355.1804.

3-Cinnamyl-3-(phenylamino)indolin-2-one (5a): Further purification

by silica gel column chromatography (EtOAc/hexane, 30:70) of the

crude mixture, which gave 3a, also afforded 5a (55 mg, 65%) as a

colorless solid; m.p. 196–198 °C. R_f= 0.61 (30% EtOAc/hexane).

IR (thin film): ν = 3325, 2935, 1720, 1602, 1468, 1214 cm^–1. ¹H

˜

NMR (400 MHz, CDCl₃): δ = 8.61 (s, 1 H), 7.25–7.17 (m, 7 H),

7.00 (t, J = 7.5 Hz, 1 H), 6.90 (t, J = 8.0 Hz, 2 H), 6.85 (d, J =

7.5 Hz, 1 H), 6.58 (t, J = 7.5 Hz, 1 H), 6.48 (d, J = 15.7 Hz, 1 H),

6.21 (d, J = 8.0 Hz, 2 H), 6.13–6.05 (m, 1 H), 4.52 (br. s, 1 H),

2.84–2.79 (m, 1 H), 2.69–2.64 (m, 1 H) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 180.1, 145.1, 139.6, 136.7, 135.9, 130.3, 129.1, 128.6,

127.8, 126.4, 124.1, 123.1, 121.4, 119.0, 114.6, 110.7, 64.5,

43.9 ppm. HRMS (ESI): calcd. for C₂₃H₂₁N₂O [M + H]⁺341.1654;

found 341.1653.

(R*)-3-[(4-Methoxyphenyl)amino]-3-[(S*)-1-phenylallyl]indolin-2-

one (3c): Following general procedure A gave a crude mixture,

which was purified by silica gel column chromatography (EtOAc/

hexane, 30:70) to afford 3c (88 mg, 95%) as a semisolid; R_f= 0.62

(30% EtOAc/hexane). IR (thin film): ν = 3298, 2950, 1712, 1512,

˜

1

1240, 1031 cm^–1. H NMR (400 MHz, CDCl₃): δ = 8.26 (s, 1 H),

7.24 (d, J = 8.0 Hz, 2 H), 7.11–7.06 (m, 4 H), 7.01–6.98 (m, 2 H),

6.57–6.43 (m, 4 H), 6.27 (d, J = 8.0 Hz, 2 H), 5.43–5.33 (m, 2 H),

4.44 (s, 1 H), 3.81 (d, J = 10.5 Hz, 1 H), 3.53 (s, 3 H) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 179.4, 153.5, 140.3, 138.7, 136.9,

134.3, 129.3, 129.0, 127.9, 127.2, 124.8, 122.5, 120.4, 118.0, 114.3,

110.0, 68.4, 59.4, 55.4 ppm. HRMS (ESI): calcd. for C₂₄H₂₃N₂O₂

[M + H]⁺371.1760; found 371.1764.

Procedure for the Synthesis of the Compounds 5b and 5c: To a vigor-

ously stirred solution of the isatin ketimine 1i (0.25 mmol, 1 equiv.)

and (E)-cinnamyl bromide (2a, 0.5 mmol, 2 equiv.) in THF (2 mL)

was added magnesium powder (0.33 mmol, 1.3 equiv.), and the

mixture was stirred vigorously at 30 °C for 0.5 or 24 h. The reaction

mixture was transferred into a separatory funnel and extracted with

EtOAc (3ϫ 15 mL). The combined organic layers were dried with

anhydrous Na₂SO₄, and the solvent was evaporated under vacuum.

Purification of the resulting crude mixture by column chromatog-

raphy on silica gel (EtOAc/hexanes) gave products 5b (23 or 45%)

and 5c (13 or 23%, Scheme 2).

(R*)-3-[(4-Chlorophenyl)amino]-3-[(S*)-1-phenylallyl]indolin-2-one

(3d): Following general procedure A gave a crude mixture, which

was purified by silica gel column chromatography (EtOAc/hexane,

30:70) to afford 3d (67 mg, 71%) as a colorless solid; m.p. 134–

136 °C. R = 0.61 (30% EtOAc/hexane). IR (thin film): ν = 3363,

˜

f

2963, 1720, 1619, 1453, 1025 cm^–1. ¹H NMR (400 MHz, CDCl₃,

[D₆]DMSO): δ = 9.98 (s, 1 H), 7.06–7.02 (m, 5 H), 6.95–6.85 (m, 3

H), 6.81–6.76 (m, 2 H), 6.59–6.55 (m, 1 H), 6.45–6.37 (m, 1 H),

6.13–6.08 (m, 2 H), 5.36–5.25 (m, 2 H), 4.72 (br. s, 1 H), 3.74–3.69

(m, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃, [D₆]DMSO): δ =

177.6, 143.5, 141.0, 136.3, 134.0, 128.7, 128.6, 128.1, 127.8, 127.3,

126.8, 123.8, 122.4, 121.5, 119.6, 115.4, 109.8, 66.4, 58.6 ppm.

HRMS (ESI): calcd. for C₂₃H₁₉ClN₂NaO [M + Na]⁺397.1084;

found 397.1076.

3-Cinnamyl-1-methyl-3-(phenylamino)indolin-2-one (5b): Following

the procedure above gave a crude mixture, which was purified by

silica gel column chromatography (EtOAc/hexane, 20:80) to afford

compound 5b (40 mg, 45%) as a colorless, sticky liquid; R_f= 0.47

(20% EtOAc/hexane). IR (thin film): ν = 3356, 2926, 1714, 1602,

˜

1

1493, 1120, 747 cm^–1. H NMR (400 MHz, CDCl₃): δ = 7.40–7.25

(m, 7 H), 7.12 (t, J = 7.5 Hz, 1 H), 7.00–6.94 (m, 3 H), 6.66 (t, J

= 7.4 Hz, 1 H), 6.55 (d, J = 15.76 Hz, 1 H), 6.21 (d, J = 8.0 Hz, 2

H), 6.17–6.09 (m, 1 H), 4.48 (s, 1 H), 3.28 (s, 3 H), 2.88 (dd, J =

13.3, 7.0 Hz, 1 H), 2.74 (dd, J = 13.3, 8.2 Hz, 1 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 177.7, 145.1, 142.6, 136.7, 135.7, 129.9,

129.1, 129.1, 128.6, 127.7, 126.4, 123.8, 123.1, 121.6, 119.0, 114.6,

108.6, 64.2, 44.0, 26.5 ppm. HRMS (ESI): calcd. for C₂₄H₂₃N₂O

[M + H]⁺355.1810; found 355.1811.

(R*)-5-Chloro-3-[(4-chlorophenyl)amino]-3-[(S*)-1-phenylallyl]-

indolin-2-one (3e): Following general procedure A gave a crude mix-

ture, which was purified by silica gel column chromatography

(EtOAc/hexane, 30:70) to afford 3e (85 mg, 83%) as a colorless

solid; m.p. 150–152 °C. R_f= 0.63 (30% EtOAc/hexane). IR (thin

3-Cinnamyl-3-[cinnamyl(phenyl)amino]-1-methylindolin-2-one (5c):

Following the procedure above gave a crude mixture, which was

purified by silica gel column chromatography (EtOAc/hexane,

20:80) to afford compound 5c (27 mg, 23%) as a colorless, sticky

film): ν = 3192, 2846, 1721, 1600, 1495, 1182 cm^{–1 1}H NMR

.

˜

(400 MHz, CDCl₃): δ = 7.90 (s, 1 H), 7.33 (d, J = 4.3 Hz, 1 H),

7.25 (d, J = 1.6 Hz, 1 H), 7.18–7.14 (m, 3 H), 7.01 (d, J = 7.7 Hz,

1 H), 6.94 (d, J = 8.7 Hz, 2 H), 6.61–6.55 (m, 1 H), 6.51 (d, J =

7.7 Hz, 1 H), 6.20 (d, J = 8.7 Hz, 2 H), 5.50–5.43 (m, 2 H), 4.73

liquid; R = 0.57 (20% EtOAc/hexane). IR (thin film): ν = 3024,

˜

f

1711, 1611, 1429, 966, 749 cm^–1. H NMR (400 MHz, CDCl₃): δ = (s, 1 H), 3.78 (d, J = 10.5 Hz, 1 H) ppm. ¹³C NMR (100 MHz,

1

Eur. J. Org. Chem. 2015, 4168–4189

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4179

S. A. Babu et al.

FULL PAPER

CDCl₃): δ = 177.9, 143.3, 138.4, 135.8, 133.6, 130.7, 129.3, 129.1,

136.9, 134.3, 134.2, 129.0, 128.8, 128.7, 127.4, 127.0, 123.8, 122.5,

119.9, 119.8, 118.4, 114.3, 112.8, 107.8, 67.0, 59.8, 25.8 ppm.

128.9, 128.1, 127.7, 126.5, 124.8, 124.2, 121.1, 116.0, 111.1, 67.3,

59.7 ppm. HRMS (ESI): calcd. for C₂₃H₁₉Cl₂N₂O [M + H]⁺HRMS (ESI): calcd. for C₂₄H₂₂N₂NaO₂[M + Na]⁺393.1579;

409.0874; found 409.0868.

found 393.1593. The OH proton of the compound did not appear

clearly in the H NMR spectrum.

1

(R*)-5-Bromo-3-[(4-methoxyphenyl)amino]-3-[(S*)-1-phenylallyl]-

indolin-2-one (3f): Following general procedure A gave a crude mix-

ture, which was purified by silica gel column chromatography

(EtOAc/hexane, 30:70) to afford 3f (101 mg, 90%) as a colorless

solid; m.p. 127–129 °C. R_f= 0.63 (30% EtOAc/hexane). IR (thin

4-Methyl-NЈ-{(R*)-1-methyl-2-oxo-3-[(S*)-1-phenylallyl]indolin-3-

yl}benzenesulfonohydrazide (3j): Following general procedure A

gave a crude mixture, which was purified by silica gel column

chromatography (EtOAc/hexane, 40:60) to afford 3j (84 mg, 75%)

film): ν = 3405, 2831, 1706, 1617, 1510, 1241 cm^{–1 1}H NMR as a colorless solid; m.p. 168–170 °C. R_f= 0.48 (40% EtOAc/hex-

.

˜

(400 MHz, CDCl₃, [D₆]DMSO): δ = 9.96 (s, 1 H), 7.33 (d, J =

ane). IR (thin film): ν = 3420, 3229, 3059, 1697, 1616, 1471,

˜

1

1.6 Hz, 1 H), 7.23 (dd, J = 8.2, 1.9 Hz, 1 H), 7.16–7.14 (m, 3 H), 1167 cm^–1. H NMR (400 MHz, CDCl₃): δ = 7.61 (d, J = 8.3 Hz,

7.05–7.02 (m, 2 H), 6.55–6.48 (m, 4 H), 6.27 (dd, J = 8.9, 6.7 Hz,

2 H), 5.44–5.35 (m, 2 H), 4.44 (s, 1 H), 3.78 (d, J = 10.5 Hz, 1 H),

3.63 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃, [D₆]DMSO): δ =

178.1, 153.1, 140.5, 138.5, 136.6, 134.1, 131.6, 131.4, 128.8, 127.8,

127.3, 127.1, 120.2, 117.3, 114.3, 114.2, 111.5, 67.9, 59.0, 55.3 ppm.

2 H), 7.22 (d, J = 8.0 Hz, 2 H), 7.13–7.04 (m, 4 H), 6.88–6.79 (m,

4 H), 6.44 (d, J = 7.8 Hz, 1 H), 6.40–6.31 (m, 1 H), 5.84 (d, J =

3.9 Hz, 1 H), 5.32–5.21 (m, 2 H), 4.61 (d, J = 3.9 Hz, 1 H), 3.64

(d, J = 10.4 Hz, 1 H), 2.95 (s, 3 H), 2.46 (s, 3 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 176.2, 143.9, 143.5, 137.0, 134.3, 133.7,

HRMS (ESI): calcd. for C₂₄H₂₂BrN₂O₂[M + H]⁺449.0865; found 129.3, 128.8, 128.5, 127.6, 127.1, 126.6, 125.1, 122.5, 120.1, 107.5,

449.0855.

7 1 . 0 , 5 6 . 5 , 2 5 . 9 , 2 1 . 6 p p m . H R M S ( E S I ) : c a l c d . fo r

C₂₅H₂₅N₃NaO₃S [M + Na]⁺470.1514; found 470.1507.

(R*)-1-Benzyl-3-[(S*)-1-phenylallyl]-3-(phenylamino)indolin-2-one

(3g): Following general procedure A gave a crude mixture, which

was purified by silica gel column chromatography (EtOAc/hexane,

30:70) to afford 3g (54 mg, 50%) as a colorless solid; m.p. 158–

NЈ-{(S*)-1-Methyl-2-oxo-3-[(S*)-1-phenylallyl]indolin-3-

yl}benzoylhydrazide (4k): Following general procedure A gave a

crude mixture, which was purified by silica gel column chromatog-

160 °C. R = 0.67 (30% EtOAc/hexane). IR (thin film): ν = 3371, raphy (EtOAc/hexane, 40:60) to afford 4k (50 mg, 50%) as a color-

˜

f

2920, 1714, 1602, 1497, 1365, 1178 cm^–1

.

¹H NMR (400 MHz, less solid; m.p. 186–188 °C. R_f= 0.47 (40% EtOAc/hexane). IR

1

CDCl₃): δ = 7.36 (d, J = 7.2 Hz, 1 H), 7.25–7.24 (m, 3 H), 7.18–

(thin film): ν = 3384, 2925, 1725, 1614, 1378, 1180 cm^–1. H NMR

˜

7.02 (m, 7 H), 6.97–6.92 (m, 4 H), 6.77–6.67 (m, 2 H), 6.42 (d, J (400 MHz, CDCl₃): δ = 8.18 (d, J = 5.7 Hz, 1 H), 7.68 (d, J =

= 7.5 Hz, 1 H), 6.24 (d, J = 8.4 Hz, 2 H), 5.53–5.44 (m, 2 H), 5.02

(d, J = 15.5 Hz, 1 H), 4.77 (br. s, 1 H), 4.22 (d, J = 15.5 Hz, 1 H),

7.3 Hz, 1 H), 7.64 (d, J = 7.7 Hz, 2 H), 7.48–7.44 (m, 1 H), 7.38

(t, J = 7.7 Hz, 2 H), 7.29–7.25 (m, 1 H), 7.13–7.06 (m, 2 H), 7.02

3.88 (d, J = 10.6 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ (t, J = 7.7 Hz, 2 H), 6.69 (d, J = 7.7 Hz, 2 H), 6.54 (d, J = 7.3 Hz,

= 176.6, 145.1, 142.4, 136.7, 135.5, 134.5, 129.0, 129.0, 128.9, 128.6,

127.8, 127.7, 127.5, 127.2, 124.1, 122.7, 120.6, 119.3, 115.7, 109.2,

1 H), 6.52–6.42 (m, 1 H), 6.08 (d, J = 7.3 Hz, 1 H), 5.45 (d, J =

10.1 Hz, 1 H), 5.28 (d, J = 16.9 Hz, 1 H), 3.95 (d, J = 10.1 Hz, 1

67.0, 59.7, 43.9 ppm. HRMS (ESI): calcd. for C₃₀H₂₇N₂O [M + H]⁺H), 2.76 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 176.2,

431.2123; found 431.2126.

166.7, 144.2, 136.7, 133.9, 132.5, 131.8, 129.6, 128.5, 128.5, 127.6,

127.2, 127.0, 126.0, 125.6, 122.4, 120.8, 107.8, 72.4, 54.9, 25.8 ppm.

HRMS (ESI): calcd. for C₂₅H₂₃N₃NaO₂[M + Na]⁺420.1688;

found 420.1676.

(R*)-1-Methyl-3-[(S*)-1-phenylallyl]-3-(phenylamino)indolin-2-one

(3h): Following general procedure A gave a crude mixture, which

was purified by silica gel column chromatography (EtOAc/hexane,

30:70) to afford 3h (66 mg, 75%) as an orange oil; R_f= 0.65 (30% (R*)-3-[(R*)-But-3-en-2-yl]-3-(phenylamino)indolin-2-one (6a): Fol-

EtOAc/hexane). IR (thin film): ν = 3385, 2930, 1715, 1602, 1492, lowing general procedure B gave a crude mixture, which was puri-

˜

1

1119 cm^–1. H NMR (400 MHz, CDCl₃): δ = 7.31 (d, J = 7.3 Hz, fied by silica gel column chromatography (EtOAc/hexane, 30:70) to

1 H), 7.23 (t, J = 7.3 Hz, 1 H), 7.13–7.05 (m, 4 H), 6.97 (t, J = afford 6a (45 mg, 65%) as a colorless solid; m.p. 172–174 °C. R_f=

7.5 Hz, 2 H), 6.92 (d, J = 7.5 Hz, 2 H), 6.68–6.63 (m, 2 H), 6.54

(d, J = 7.8 Hz, 1 H), 6.21 (d, J = 7.8 Hz, 2 H), 5.51–5.43 (m, 2 H),

0.55 (30% EtOAc/hexane). IR (thin film): ν = 3302, 3081, 1706,

˜

1602, 1497, 1199, 914 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.82

4.75 (s, 1 H), 3.80 (d, J = 10.6 Hz, 1 H), 2.96 (s, 3 H) ppm. ¹³C (s, 1 H), 7.24 (td, J = 5.8, 1.4 Hz, 2 H), 7.03 (t, J = 7.4 Hz, 1 H),

NMR (100 MHz, CDCl₃): δ = 176.4, 145.1, 142.9, 136.6, 134.4,

129.1, 129.0, 128.8, 128.7, 127.6, 127.2, 123.8, 122.7, 120.5, 118.9,

114.7, 108.0, 66.9, 60.1, 25.9 ppm. HRMS (ESI): calcd. for

C₂₄H₂₃N₂O [M + H]⁺355.1810; found 355.1821.

6.93 (dd, J = 8.6, 7.4 Hz, 2 H), 6.82 (d, J = 7.4 Hz, 1 H), 6.61 (t,

J = 7.4 Hz, 1 H), 6.26 (dd, J = 8.6, 1.4 Hz, 2 H), 5.92–5.82 (m, 1

H), 5.31–5.19 (m, 2 H), 4.66 (s, 1 H), 2.74–2.67 (m, 1 H), 0.96 (d,

J = 6.9 Hz, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 179.8,

145.4, 140.6, 137.2, 129.7, 129.1, 124.0, 123.1, 119.0, 118.8, 114.7,

110.4, 67.0, 48.3, 14.3 ppm. HRMS (ESI): calcd. for C₁₈H₁₉N₂O

[M + H]⁺279.1497; found 279.1488.

(R*)-3-[(2-Hydroxyphenyl)amino]-1-methyl-3-[(S*)-1-phenylallyl]-

indolin-2-one (3i): Following general procedure A gave a crude mix-

ture, which was purified by silica gel column chromatography

(EtOAc/hexane, 30:70) to afford 3i (117 mg, 63%) as a colorless

solid; m.p. 175–177 °C. R_f= 0.45 (30% EtOAc/hexane). IR (thin

(R*)-3-[(R*)-But-3-en-2-yl]-3-[(4-chlorophenyl)amino]indolin-2-one

(6b): Following general procedure B gave a crude mixture, which

film): ν = 3381, 2930, 1702, 1611, 1521, 1372, 1120 cm^–1. ¹H NMR was purified by silica gel column chromatography (EtOAc/hexane,

˜

(400 MHz, CDCl₃, [D₆]DMSO): δ = 8.60 (s, 1 H), 7.27 (dd, J = 30:70) to afford 6b (63 mg, 80%) as a colorless solid; m.p. 208–

7.4, 2.8 Hz, 2 H), 7.18 (t, J = 7.4 Hz, 1 H), 7.08 (dd, J = 7.4, 210 °C. R = 0.57 (30% EtOAc/hexane). IR (thin film): ν = 3127,

˜

f

4.3 Hz, 2 H), 7.02 (t, J = 7.4 Hz, 1 H), 6.89 (d, J = 8.2 Hz, 2 H),

2985, 1717, 1600, 1505, 1317, 1196 cm^{–1 1}H NMR (400 MHz,

.

6.69 (d, J = 7.4 Hz, 1 H), 6.64–6.55 (m, 1 H), 6.51 (d, J = 8.2 Hz, CDCl₃): δ = 8.10 (s, 1 H), 7.33–7.27 (m, 2 H), 7.09 (t, J = 7.5 Hz,

1 H), 6.44 (t, J = 7.4 Hz, 1 H), 6.32 (t, J = 7.4 Hz, 1 H), 5.64 (d, 1 H), 6.94–6.89 (m, 1 H), 6.92 (d, J = 8.8 Hz, 2 H), 6.21 (d, J =

J = 7.4 Hz, 1 H), 5.46 (d, J = 16.3 Hz, 1 H), 5.36 (d, J = 10.3 Hz, 8.8 Hz, 2 H), 5.97–5.88 (m, 1 H), 5.35–5.25 (m, 2 H), 4.63 (br. s, 1

1 H), 5.32 (s, 1 H), 3.86 (d, J = 10.3 Hz, 1 H), 2.93 (s, 3 H) ppm. H), 2.73–2.69 (m, 1 H), 0.97 (d, J = 6.9 Hz, 3 H) ppm. ¹³C NMR

¹³C NMR (100 MHz, CDCl₃, [D₆]DMSO): δ = 176.8, 145.4, 142.8,

(100 MHz, CDCl₃): δ = 178.6, 144.0, 140.4, 137.0, 129.3, 129.3,

4180

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Eur. J. Org. Chem. 2015, 4168–4189

Addition of γ-Substituted Allylindiums to Isatin Ketimines

128.9, 124.0, 123.3, 119.1, 116.0, 110.2, 66.8, 48.4, 14.2 ppm. 110.3, 67.7, 44.7, 25.0, 23.4, 21.5 ppm. HRMS (ESI): calcd. for

HRMS (ESI): calcd. for C₁₈H₁₇ClN₂NaO [M + Na]⁺335.0927; C₂₀H₂₁N₂O [M + H]⁺305.1654; found 305.1659. This compound

found 335.0927.

contained trace amounts of the minor isomer.

(R*)-3-[(R*)-But-3-en-2-yl]-3-[(4-methoxyphenyl)amino]indolin-2-

one (6c): Following general procedure B gave a crude mixture,

which was purified by silica gel column chromatography (EtOAc/

(R*)-3-[(4-Chlorophenyl)amino]-3-[(S*)-cyclohex-2-en-1-yl]indolin-

2-one (10b): Following general procedure C gave a crude mixture,

which was purified by silica gel column chromatography (EtOAc/

hexane, 30:70) to afford 6c (38 mg, 50%) as a colorless solid; m.p. hexane, 30:70) to afford 10b (79 mg, 93%) as a colorless solid; m.p.

139–141 °C. R = 0.59 (30% EtOAc/hexane). IR (thin film): ν = 224–226 °C. R = 0.67 (30% EtOAc/hexane). IR (thin film): ν =

˜

f

3298, 3031, 1711, 1512, 1239 cm^–1. ¹H NMR (400 MHz, CDCl₃): 3333, 2995, 1710, 1601, 1492, 1310 cm^–1. ¹H NMR (400 MHz, [D₆]-

δ = 8.42 (s, 1 H), 7.36 (d, J = 7.4 Hz, 1 H), 7.29–7.25 (m, 1 H),

7.09 (t, J = 7.4 Hz, 1 H), 6.81 (d, J = 7.4 Hz, 1 H), 6.52 (d, J =

9.0 Hz, 2 H), 6.32 (d, J = 9.0 Hz, 2 H), 5.96–5.86 (m, 1 H), 5.33–

DMSO): δ = 10.71 (s, 1 H), 7.25 (t, J = 7.4 Hz, 1 H), 7.07 (d, J =

7.4 Hz, 1 H), 6.95–6.89 (m, 4 H), 6.50 (s, 1 H), 6.22 (d, J = 8.7 Hz,

2 H), 6.00 (d, J = 10.6 Hz, 1 H), 5.86–5.81 (m, 1 H), 2.76–2.72 (m,

5.21 (m, 2 H), 4.36 (br. s, 1 H), 3.60 (s, 3 H), 2.78–2.70 (m, 1 H), 1 H), 1.90–1.81 (m, 1 H), 1.70–1.29 (m, 4 H), 0.81–0.71 (m, 1

0.98 (d, J = 6.9 Hz, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 179.8, 179.7, 144.3,

179.7, 153.6, 140.8, 139.0, 137.3, 130.0, 129.0, 124.3, 123.0, 118.7,

118.1, 114.3, 110.1, 68.2, 55.4, 48.0, 14.4 ppm. HRMS (ESI): calcd.

for C₁₉H₂₁N₂O₂[M + H]⁺309.1603; found 309.1593.

144.0, 140.3, 140.0, 132.3, 131.7, 129.2, 129.1, 129.1, 128.9, 128.2,

125.6, 124.9, 124.0, 123.9, 123.8, 123.6, 122.8, 122.7, 116.4, 115.8,

110.6, 110.3, 67.7, 67.7, 44.9, 44.6, 25.0, 25.0, 23.4, 23.3, 21.9,

21.5 ppm. HRMS (ESI): calcd. for C₂₀H₂₀ClN₂O [M + H]⁺

339.1264; found 339.1276. This compound was isolated as a mix-

ture of diastereomers. The ¹H NMR spectroscopic data refers to

the major isomer, and the ¹³C NMR spectroscopic data corre-

sponds to both diastereomers.

(R*)-3-[(R*)-But-3-en-2-yl]-1-methyl-3-(phenylamino)indolin-2-one

(6d): Following general procedure B gave a crude mixture, which

was purified by silica gel column chromatography (EtOAc/hexane,

30:70) to afford 6d (51 mg, 70%) as a colorless solid; m.p. 153–

155 °C. R = 0.67 (30% EtOAc/hexane). IR (thin film): ν = 3365,

˜

f

2965, 1713, 1604, 1469, 1323 cm^–1. ¹H NMR (400 MHz, CDCl₃): (R*)-5-Chloro-3-[(4-chlorophenyl)amino]-3-[(S*)-cyclohex-2-en-1-yl-

δ = 7.38 (t, J = 7.7 Hz, 1 H), 7.31 (d, J = 7.3 Hz, 1 H), 7.11 (t, J ]indolin-2-one (10c): Following general procedure C gave a crude

= 7.7 Hz, 1 H), 6.98–6.91 (m, 3 H), 6.64 (t, J = 7.3 Hz, 1 H), 6.19 mixture, which was purified by silica gel column chromatography

(d, J = 7.6 Hz, 2 H), 5.93–5.84 (m, 1 H), 5.33–5.21 (m, 2 H), 4.56 (EtOAc/hexane, 30:70) to afford 10c (82 mg, 88%) as a colorless

(s, 1 H), 3.24 (s, 3 H), 2.77–2.69 (m, 1 H), 0.92 (d, J = 6.9 Hz, 3

H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 177.1, 145.4, 143.6,

137.3, 129.2, 129.1, 129.0, 123.7, 123.1, 118.9, 118.6, 114.7, 108.2,

solid; m.p. 253–255 °C. R_f= 0.68 (30% EtOAc/hexane). IR (thin

film): ν = 3388, 2931, 1727, 1498, 1312, 816 cm^{–1 1}H NMR

(400 MHz, CDCl₃, [D₆]DMSO): δ = 10.07 (s, 1 H), 7.10 (dd, J =

.

˜

66.5, 48.4, 26.1, 14.3 ppm. HRMS (ESI): calcd. for C₁₉H₂₁N₂O [M 8.3, 2.2 Hz, 1 H), 7.04 (t, J = 2.2 Hz, 1 H), 6.79 (d, J = 8.8 Hz, 2

+ H]⁺293.1654; found 293.1660.

H), 6.77–6.74 (m, 1 H), 6.10 (d, J = 8.8 Hz, 2 H), 5.98–5.93 (m, 1

H), 5.89–5.84 (m, 1 H), 4.61 (s, 1 H), 2.64–2.57 (m, 1 H), 1.88–1.71

(m, 2 H), 1.64–1.50 (m, 2 H), 1.42–1.31 (m, 1 H), 0.92–0.81 (m, 1

H) ppm. ¹³C NMR (100 MHz, CDCl₃, [D₆]DMSO): δ = 178.9,

144.4, 140.1, 132.2, 130.0, 128.9, 128.7, 127.2, 125.3, 123.9, 123.2,

116.0, 111.2, 67.5, 44.3, 24.8, 23.2, 21.4 ppm. HRMS (ESI): calcd.

for C₂₀H₁₉Cl₂N₂O [M + H]⁺373.0874; found 373.0877. This com-

pound was isolated with trace amounts of the minor isomer, and

the compound has poor solubility in most of the solvents.

(R*)-3-[(R*)-But-3-en-2-yl]-3-[(2-hydroxyphenyl)amino]-1-methyl-

indolin-2-one (6e): Following general procedure B gave a crude mix-

ture, which was purified by silica gel column chromatography

(EtOAc/hexane, 30:70) to afford 6e (58 mg, 75%) as a colorless

solid; m.p. 172–174 °C. R_f= 0.50 (30% EtOAc/hexane). IR (thin

film): ν = 3382, 2965, 1694, 1609, 1516, 1449, 1236 cm^–1. ¹H NMR

˜

(400 MHz, CDCl₃): δ = 7.42 (d, J = 7.4 Hz, 1 H), 7.35 (td, J = 7.4,

1.2 Hz, 1 H), 7.13 (t, J = 7.8 Hz, 1 H), 6.87 (d, J = 7.4 Hz, 1 H),

6.58–6.50 (m, 2 H), 6.38 (td, J = 7.8, 1.7 Hz, 1 H), 5.97 (dd, J = (R*)-3-[(S*)-Cyclohex-2-en-1-yl]-3-(p-tolylamino)indolin-2-one

7.8, 1.4 Hz, 1 H), 5.81–5.72 (m, 1 H), 5.32 (dd, J = 17.0, 1.4 Hz, 1

H), 5.20 (dd, J = 10.0, 1.8 Hz, 1 H), 4.73 (br. s, 1 H), 3.23 (s, 3

(10d): Following general procedure C gave a crude mixture, which

was purified by silica gel column chromatography (EtOAc/hexane,

H), 2.90–2.82 (m, 1 H), 1.02 (d, J = 6.9 Hz, 3 H) ppm. ¹³C NMR 30:70) to afford 10d (56 mg, 71%) as a colorless solid; m.p. 210–

(100 MHz, CDCl₃): δ = 179.5, 147.5, 143.3, 137.0, 133.2, 129.1, 212 °C. R = 0.67 (30% EtOAc/hexane). IR (thin film): ν = 3344,

˜

f

129.1, 124.2, 123.2, 121.3, 120.0, 118.6, 117.2, 115.0, 108.3, 68.4,

2934, 1707, 1618, 1521, 1318 cm^–1. ¹H NMR (400 MHz, CDCl₃):

47.9, 26.2, 14.5 ppm. HRMS (ESI): calcd. for C₁₉H₂₀N₂NaO₂[M δ = 8.58 (s, 1 H), 7.29 (d, J = 8.8 Hz, 1 H), 7.25 (d, J = 8.8 Hz, 1

+ Na]⁺331.1422; found 331.1405. This compound contained trace

amounts of the minor isomer, and the OH signal was not clearly

visible in the H NMR spectrum.

H), 7.02 (t, J = 7.5 Hz, 1 H), 6.84 (d, J = 7.5 Hz, 1 H), 6.77 (d, J

= 8.5 Hz, 2 H), 6.24 (d, J = 8.5 Hz, 2 H), 6.20–6.17 (m, 1 H), 6.00–

5.97 (m, 1 H), 4.31 (br. s, 1 H), 2.82–2.74 (m, 1 H), 2.12 (s, 3 H),

2.02–1.94 (m, 1 H), 1.90–1.82 (m, 1 H), 1.79–1.73 (m, 1 H), 1.70–

1.62 (m, 1 H), 1.53–1.42 (m, 1 H), 1.11–1.01 (m, 1 H) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 180.5, 180.4, 143.3, 143.0, 140.5,

140.2, 131.9, 131.3, 129.5, 128.9, 128.9, 128.8, 128.5, 128.2, 125.7,

124.9, 124.5, 124.2, 122.6, 122.5, 115.7, 115.1, 110.5, 110.2, 68.1,

68.0, 44.9, 44.6, 25.1, 25.0, 23.5, 23.3, 22.0, 21.6, 20.4, 20.4 ppm.

HRMS (ESI): calcd. for C₂₁H₂₃N₂O [M + H]⁺319.1810; found

319.1812. This compound was isolated as a mixture of dia-

stereomers, The ¹H NMR spectroscopic data refers to the major

isomer, and the ¹³C NMR spectroscopic data corresponds to both

diastereomers.

1

(R*)-3-[(S*)-Cyclohex-2-en-1-yl]-3-(phenylamino)indolin-2-one

(10a): Following general procedure C gave a crude mixture, which

was purified by silica gel column chromatography (EtOAc/hexane,

30:70) to afford 10a (68 mg, 90%) as a colorless solid; m.p. 199–

201 °C. R = 0.66 (30% EtOAc/hexane). IR (thin film): ν = 3316,

˜

f

2928, 1726, 1603, 1468, 1313 cm^–1. ¹H NMR (400 MHz, CDCl₃):

δ = 8.98 (br. s, 1 H), 7.27 (d, J = 7.0 Hz, 2 H), 7.03–6.95 (m, 3 H),

6.88 (d, J = 7.8 Hz, 1 H), 6.66 (t, J = 7.8 Hz, 1 H), 6.30 (d, J =

7.8 Hz, 2 H), 6.19 (d, J = 10.2 Hz, 1 H), 6.01–5.97 (m, 1 H), 4.51

(br. s, 1 H), 2.77–2.79 (m, 1 H), 1.98 (d, J = 17.5 Hz, 1 H), 1.89–

1.77 (m, 2 H), 1.69–1.64 (m, 1 H), 1.52–1.45 (m, 1 H), 1.11–1.02

(m, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 180.6, 145.7, (R*)-3-[(S*)-Cyclohex-2-en-1-yl]-1-methyl-3-(phenylamino)indolin-

140.4, 132.1, 129.1, 128.9, 128.7, 125.6, 124.4, 122.5, 119.0, 115.0, 2-one (10e): Following general procedure C gave a crude mixture,

Eur. J. Org. Chem. 2015, 4168–4189

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4181

S. A. Babu et al.

FULL PAPER

which was purified by silica gel column chromatography (EtOAc/

1 H), 1.60–1.42 (m, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

hexane, 30:70) to afford 10e (40 mg, 50%) as a colorless solid; m.p. 177.2, 166.5, 144.0, 132.7, 131.7, 130.2, 129.3, 128.5, 127.4, 127.0,

197–199 °C. R = 0.66 (30% EtOAc/hexane). IR (thin film): ν = 125.3, 124.6, 122.7, 108.0, 71.3, 41.2, 26.3, 25.0, 23.4, 21.9 ppm.

¹H NMR (400 MHz, HRMS (ESI): calcd. for C₂₂H₂₄N₃O₂[M + H]⁺362.1869; found

˜

f

3312, 2942, 1701, 1613, 1468, 1121 cm^–1

.

CDCl₃): δ = 7.37 (t, J = 7.4 Hz, 1 H), 7.31 (d, J = 7.4 Hz, 1 H), 362.1858.

7.06 (t, J = 7.4 Hz, 1 H), 6.98–6.91 (m, 3 H), 6.66 (t, J = 7.4 Hz,

(R*)-3-[(R*)-3,7-Dimethylocta-1,6-dien-3-yl]-3-(phenylamino)-

1 H), 6.21 (d, J = 7.7 Hz, 2 H), 6.20–6.16 (m, 1 H), 6.00–5.95 (m,

1 H), 4.33 (s, 1 H), 3.25 (s, 3 H), 2.79–2.73 (m, 1 H), 2.00–1.93 (m,

1 H), 1.89–1.80 (m, 1 H), 1.68–1.62 (m, 2 H), 1.51–1.41 (m, 1 H),

1.00–0.87 (m, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 177.9,

145.8, 143.4, 131.9, 129.0, 128.2, 125.3, 124.5, 122.6, 119.1, 115.1,

108.1, 67.2, 44.9, 26.2, 25.0, 23.4, 21.5 ppm. HRMS (ESI): calcd.

for C₂₁H₂₃N₂O [M + H]⁺319.1810; found 319.1812. The NH signal

indolin-2-one (13a): Following general procedure D gave a crude

mixture, which was purified by silica gel column chromatography

(EtOAc/hexane, 30:70) to afford 13a (57 mg, 63%) as a colorless

solid; m.p. 137–139 °C. R_f= 0.65 (30% EtOAc/hexane). IR (thin

film): ν = 3376, 2923, 1715, 1602, 1470, 1123 cm^{–1 1}H NMR

.

˜

(400 MHz, CDCl₃): δ = 8.53 (br. s, 1 H), 7.29–7.24 (m, 2 H), 7.01

(t, J = 7.4 Hz, 1 H), 6.92 (t, J = 8.0 Hz, 2 H), 6.77 (t, J = 7.4 Hz,

1 H), 6.61 (t, J = 7.4 Hz, 1 H), 6.43 (dd, J = 17.1, 10.9 Hz, 1 H),

6.19 (d, J = 8.0 Hz, 2 H), 5.56 (d, J = 10.9 Hz, 1 H), 5.39 (d, J =

17.1 Hz, 1 H), 4.92 (t, J = 6.6 Hz, 1 H), 4.61 (s, 1 H), 1.79–1.72

(m, 2 H), 1.68–1.60 (m, 1 H), 1.61 (s, 3 H), 1.56–1.52 (m, 1 H),

1.50 (s, 3 H), 1.33 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ

= 180.3, 145.8, 141.3, 140.4, 131.6, 129.1, 129.0, 128.7, 126.7, 124.1,

122.2, 118.8, 118.1, 114.6, 110.3, 69.8, 48.0, 33.8, 25.6, 22.7, 17.6,

16.2 ppm. HRMS (ESI): calcd. for C₂₄H₂₉N₂O [M + H]⁺361.2280;

found 361.2267.

1

was not clearly visible in the H NMR spectrum.

(R*)-1-Benzyl-3-[(S*)-cyclohex-2-en-1-yl]-3-(phenylamino)indolin-2-

one (10f): Following general procedure C gave a crude mixture,

which was purified by silica gel column chromatography (EtOAc/

hexane, 30:70) to afford 10f (89 mg, 90%) as a colorless solid; m.p.

157–159 °C. R = 0.68 (30% EtOAc/hexane). IR (thin film): ν =

˜

f

3331, 2930, 1702, 1602, 1498, 1343 cm^{–1 1}H NMR (400 MHz,

.

CDCl₃): δ = 7.37 (d, J = 7.4 Hz, 1 H), 7.28–7.26 (m, 4 H), 7.22–

7.19 (m, 2 H), 7.03 (t, J = 7.4 Hz, 1 H), 6.95 (t, J = 8.0 Hz, 2 H),

6.78–6.71 (m, 2 H), 6.28 (d, J = 8.0 Hz, 2 H), 6.24–6.21 (m, 1 H),

6.02–5.98 (m, 1 H), 5.10 (d, J = 15.5 Hz, 1 H), 4.75 (d, J = 15.5 Hz,

1 H), 2.85–2.81 (m, 1 H), 2.01–1.95 (m, 1 H), 1.91–1.83 (m, 1 H),

1.74–1.63 (m, 2 H), 1.54–1.44 (m, 1 H), 1.07–1.00 (m, 1 H) ppm.

¹³C NMR (100 MHz, CDCl₃): δ = 177.8, 145.7, 142.7, 135.6, 131.9,

129.0, 128.7, 128.3, 127.9, 127.7, 127.6, 125.4, 124.7, 122.5, 119.7,

116.5, 109.3, 67.6, 44.9, 44.0, 25.0, 23.5, 21.6 ppm. HRMS (ESI):

calcd. for C₂₇H₂₇N₂O [M + H]⁺395.2123; found 395.2124. This

compound was isolated with trace amounts of the minor isomer.

(R*)-3-[(S*)-3,7-Dimethylocta-1,6-dien-3-yl]-3-(phenylamino)-

indolin-2-one (14a): Following general procedure F gave a crude

mixture, which was purified by silica gel column chromatography

(EtOAc/hexane, 30:70) to afford 14a (52 mg, 58%) as a colorless

solid; m.p. 136–138 °C. R_f= 0.66 (30% EtOAc/hexane). IR (thin

film): ν = 3388, 2924, 1722, 1602, 1470, 1115 cm^{–1 1}H NMR

.

˜

(400 MHz, CDCl₃): δ = 8.40 (s, 1 H), 7.22 (t, J = 7.7 Hz, 1 H),

7.11 (d, J = 7.4 Hz, 1 H), 6.98–6.90 (m, 3 H), 6.84 (d, J = 7.7 Hz,

1 H), 6.59 (t, J = 7.4 Hz, 1 H), 6.23 (d, J = 8.6 Hz, 2 H), 6.04 (dd,

J = 17.7, 11.0 Hz, 1 H), 5.50 (d, J = 11.0 Hz, 1 H), 5.35 (d, J =

17.7 Hz, 1 H), 4.95 (t, J = 6.8 Hz, 1 H), 4.42 (s, 1 H), 1.90–1.82

(m, 1 H), 1.77–1.69 (m, 1 H), 1.64–1.54 (m, 2 H), 1.63 (s, 3 H),

1.52 (s, 3 H), 1.37 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ

= 179.4, 145.2, 141.2, 140.5, 131.6, 129.0, 128.9, 128.7, 126.0, 124.2,

122.2, 118.5, 117.7, 114.4, 110.0, 69.3, 47.5, 33.1, 25.7, 23.0, 17.7,

15.4 ppm. HRMS (ESI): calcd. for C₂₄H₂₉N₂O [M + H]⁺361.2280;

found 361.2283.

Ethyl 2-{(R*)-3-[(S*)-Cyclohex-2-en-1-yl]-2-oxo-3-(phenylamino)-

indolin-1-yl}acetate (10g): Following general procedure C gave a

crude mixture, which was purified by silica gel column chromatog-

raphy (EtOAc/hexane, 30:70) to afford 10g (87 mg, 89%) as a color-

less solid; m.p. 169–171 °C. R_f= 0.62 (30% EtOAc/hexane). IR

1

(thin film): ν = 3329, 2933, 1724, 1600, 1465, 1260, 1021 cm^–1. H

˜

NMR (400 MHz, CDCl₃): δ = 7.36–7.30 (m, 2 H), 7.07 (t, J =

7.5 Hz, 1 H), 6.98 (dd, J = 8.6, 7.5 Hz, 2 H), 6.80 (d, J = 7.5 Hz,

1 H), 6.67 (t, J = 7.5 Hz, 1 H), 6.31 (d, J = 8.6 Hz, 2 H), 6.22 (d,

J = 10.4 Hz, 1 H), 6.03–5.98 (m, 1 H), 4.60 (d, J = 17.5 Hz, 1 H),

4.44 (d, J = 17.5 Hz, 1 H), 4.38 (br. s, 1 H), 4.28–4.20 (m, 2 H),

2.82–2.77 (m, 1 H), 2.01–1.95 (m, 1 H), 1.92–1.83 (m, 1 H), 1.78–

1.73 (m, 1 H), 1.70–1.64 (m, 1 H), 1.52–1.42 (m, 1 H), 1.27 (t, J =

7.1 Hz, 3 H), 1.12–1.02 (m, 1 H) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 177.8, 167.6, 145.5, 142.0, 132.2, 129.0, 127.9, 125.5,

124.4, 122.8, 119.0, 115.2, 108.2, 67.0, 61.7, 45.0, 41.3, 25.0, 23.6,

21.6, 14.2 ppm. HRMS (ESI): calcd. for C₂₄H₂₇N₂O₃[M + H]⁺

391.2022; found 391.2018. This compound contains trace amounts

of the minor isomer, and the NMR spectroscopic data refers to the

major isomer.

(E)-3-(3,7-Dimethylocta-2,6-dien-1-yl)-3-(phenylamino)indolin-2-one

(15a): Purification by silica gel column chromatography (EtOAc/

hexane, 30:70) afforded compound 15a (9 mg, 10%) as a colorless

solid; m.p. 120–122 °C. R_f= 0.61 (30% EtOAc/hexane). IR (thin

1

film): ν = 3310, 2925, 1707, 1603, 1470 cm^–1. H NMR (400 MHz,

˜

CDCl₃): δ = 8.68 (s, 1 H), 7.22–7.18 (m, 2 H), 7.00–6.85 (m, 3 H),

6.86 (d, J = 7.4 Hz, 1 H), 6.60 (t, J = 7.4 Hz, 1 H), 6.23 (d, J =

7.7 Hz, 2 H), 5.13 (t, J = 8.4 Hz, 1 H), 5.03–5.01 (m, 1 H), 4.48

(br. s, 1 H), 2.71 (dd, J = 13.8, 8.4 Hz, 1 H), 2.57 (dd, J = 13.8,

7.7 Hz, 1 H), 2.01–1.94 (m, 1 H), 1.97 (s, 3 H), 1.67–1.63 (m, 1 H),

1.64 (s, 3 H), 1.57–1.53 (m, 2 H), 1.56 (s, 3 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 180.5, 145.2, 141.7, 139.7, 131.7, 130.5,

129.1, 128.8, 124.1, 123.9, 122.8, 118.7, 115.4, 114.4, 110.4, 64.7,

40.0, 38.9, 26.6, 25.7, 17.7, 16.4 ppm. HRMS (ESI): calcd. for

C₂₄H₂₉N₂O [M + H]⁺361.2280; found 361.2267. This compound

was isolated in only 9 mg, and the NMR spectrum shows the pres-

ence of trace amounts of some impurity.

NЈ-{(R*)-3-[(R*)-Cyclohex-2-en-1-yl]-1-methyl-2-oxoindolin-3-

yl}benzoylhydrazide (11h): Following general procedure C gave a

crude mixture, which was purified by silica gel column chromatog-

raphy (EtOAc/hexane, 40:60) to afford 11h (45 mg, 50%) as a color-

less solid; m.p. 148–150 °C. R_f= 0.40 (40% EtOAc/hexane). IR

1

(thin film): ν = 3440, 2926, 1706, 1612, 1469, 1120 cm^–1. H NMR

(R*)-3-[(R*)-3,7-Dimethylocta-1,6-dien-3-yl]-3-[(4-methoxyphenyl)-

amino]indolin-2-one (13b): Following general procedure D gave a

crude mixture, which was purified by silica gel column chromatog-

raphy (EtOAc/hexane, 30:70) to afford 13b (58 mg, 59%) as a color-

˜

(400 MHz, CDCl₃): δ = 8.09 (br. s, 1 H), 7.58 (d, J = 7.4 Hz, 2 H),

7.52 (d, J = 7.4 Hz, 1 H), 7.45 (t, J = 7.4 Hz, 1 H), 7.38–7.30 (m,

3 H), 7.07 (t, J = 8.0 Hz, 1 H), 6.84 (d, J = 8.0 Hz, 1 H), 5.74 (d,

J = 5.7 Hz, 1 H), 5.64–5.59 (m, 1 H), 5.34 (d, J = 10.4 Hz, 1 H), less solid; m.p. 152–154 °C. R_f= 0.64 (30% EtOAc/hexane). IR

1

3.26 (s, 3 H), 2.98–2.93 (m, 1 H), 1.97–1.87 (m, 3 H), 1.82–1.75 (m,

(thin film): ν = 3294, 2927, 1710, 1511, 1243, 1038 cm^–1. H NMR

˜

4182

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Eur. J. Org. Chem. 2015, 4168–4189

Addition of γ-Substituted Allylindiums to Isatin Ketimines

(400 MHz, CDCl₃): δ = 8.34 (s, 1 H), 7.35 (d, J = 7.6 Hz, 1 H), Ethyl 2-{(R*)-3-[(R*)-3,7-Dimethylocta-1,6-dien-3-yl]-2-oxo-3-

7.25 (t, J = 7.7 Hz, 1 H), 7.03 (t, J = 7.6 Hz, 1 H), 6.73 (d, J = (phenylamino)indolin-1-yl}acetate (13f): Following general pro-

7.7 Hz, 1 H), 6.46 (d, J = 9.0 Hz, 2 H), 6.44–6.36 (m, 1 H), 6.22

(d, J = 9.0 Hz, 2 H), 5.53 (d, J = 10.7 Hz, 1 H), 5.36 (d, J =

17.6 Hz, 1 H), 4.92 (t, J = 6.8 Hz, 1 H), 3.56 (s, 3 H), 1.79–1.71

(m, 3 H), 1.61 (s, 3 H), 1.53–1.46 (m, 1 H), 1.50 (s, 3 H), 1.34 (s, 3

H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 180.5, 153.3, 141.4,

140.6, 139.4, 131.6, 129.0, 129.0, 127.0, 124.2, 122.1, 118.0, 117.8,

114.3, 110.1, 71.1, 55.3, 47.8, 34.1, 25.6, 22.7, 17.6, 16.2 ppm.

cedure D gave a crude mixture, which was purified by silica gel

column chromatography (EtOAc/hexane, 30:70) to afford 13f

(67 mg, 60%) as a colorless solid; m.p. 100–102 °C. R_f= 0.65 (30%

EtOAc/hexane). IR (thin film): ν = 3353, 2984, 1732, 1601, 1502,

˜

1

1264, 1183 cm^–1. H NMR (400 MHz, CDCl₃): δ = 7.37–7.32 (m,

2 H), 7.07 (t, J = 7.6 Hz, 1 H), 6.95 (t, J = 7.4 Hz, 2 H), 6.79 (d,

J = 7.6 Hz, 1 H), 6.62 (t, J = 7.4 Hz, 1 H), 6.42 (dd, J = 17.5,

HRMS (ESI): calcd. for C₂₅H₃₁N₂O₂[M + H]⁺391.2386; found 11.0 Hz, 1 H), 6.19 (d, J = 7.4 Hz, 2 H), 5.54 (d, J = 10.9 Hz, 1

391.2377.

H), 5.37 (d, J = 17.6 Hz, 1 H), 4.95 (t, J = 6.7 Hz, 1 H), 4.60 (br.

s, 1 H), 4.61 (d, J = 17.4 Hz, 1 H), 4.41 (d, J = 17.4 Hz, 1 H), 4.28–

4.20 (m, 2 H), 1.79–1.72 (m, 2 H), 1.65–1.62 (m, 1 H), 1.62 (s, 3

H), 1.59 (s, 3 H), 1.59–1.44 (m, 1 H), 1.33 (s, 3 H), 1.26 (t, J =

7.1 Hz, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 177.6, 167.5,

145.4, 143.1, 140.5, 131.4, 129.1, 128.9, 127.7, 126.6, 124.3, 122.5,

118.7, 118.0, 114.8, 108.3, 69.2, 61.6, 48.4, 41.4, 33.7, 25.6, 22.8,

17.7, 16.3, 14.2 ppm. HRMS (ESI): calcd. for C₂₈H₃₅N₂O₃[M +

H]⁺447.2648; found 447.2638.

(R*)-5-Chloro-3-[(R*)-3,7-dimethylocta-1,6-dien-3-yl]-3-[(4-meth-

oxyphenyl)amino]indolin-2-one (13c): Following general procedure

D gave a crude mixture, which was purified by silica gel column

chromatography (EtOAc/hexane, 30:70) to afford 13c (66 mg, 62%)

as a colorless solid; m.p. 152–154 °C. R_f= 0.65 (30% EtOAc/hex-

ane). IR (thin film): ν = 3290, 2926, 1706, 1510, 1248, 1037 cm^–1.

˜

¹H NMR (400 MHz, CDCl₃): δ = 8.11 (s, 1 H), 7.34 (d, J = 2.2 Hz,

1 H), 7.25 (dd, J = 8.5, 2.2 Hz, 1 H), 6.67 (d, J = 8.5 Hz, 1 H),

6.50 (d, J = 9.0 Hz, 2 H), 6.38 (dd, J = 17.6, 10.7 Hz, 1 H), 6.22

(d, J = 9.0 Hz, 2 H), 5.55 (d, J = 10.7 Hz, 1 H), 5.37 (d, J =

Ethyl 2-{(R*)-3-[(S*)-3,7-Dimethylocta-1,6-dien-3-yl]-2-oxo-3-

(phenylamino)indolin-1-yl}acetate (14f): Following general pro-

17.6 Hz, 1 H), 4.92 (t, J = 6.9 Hz, 1 H), 4.32 (br. s, 1 H), 3.60 (s, cedure F gave a crude mixture, which was purified by silica gel

3 H), 1.79–1.72 (m, 2 H), 1.63–1.62 (m, 1 H), 1.62 (s, 3 H), 1.51 (s, column chromatography (EtOAc/hexane, 30:70) to afford 14f

3 H), 1.49–1.43 (m, 1 H), 1.33 (s, 3 H) ppm. ¹³C NMR (100 MHz, (46 mg, 42%) as a colorless solid; m.p. 104–106 °C. R_f= 0.65 (30%

CDCl₃): δ = 179.9, 153.6, 140.1, 139.9, 139.0, 131.7, 130.9, 129.1,

127.6, 127.2, 124.0, 118.3, 117.9, 114.4, 110.9, 71.3, 55.4, 47.9, 34.1,

EtOAc/hexane). IR (thin film): ν = 3411, 2922, 1726, 1602, 1466,

˜

1

1203 cm^–1. H NMR (400 MHz, CDCl₃): δ = 7.30 (t, J = 7.7 Hz,

25.6, 22.6, 17.6, 16.2 ppm. HRMS (ESI): calcd. for C₂₅H₃₀ClN₂O₂1 H), 7.16 (d, J = 7.4 Hz, 1 H), 7.01 (t, J = 7.7 Hz, 1 H), 6.95 (t,

[M + H]⁺425.1996; found 425.1981.

J = 8.6 Hz, 2 H), 6.77 (d, J = 7.7 Hz, 1 H), 6.60 (t, J = 7.4 Hz, 1

H), 6.23 (d, J = 8.6 Hz, 2 H), 6.04 (dd, J = 17.5, 10.7 Hz, 1 H),

5.49 (d, J = 10.7 Hz, 1 H), 5.34 (d, J = 17.5 Hz, 1 H), 4.95 (t, J =

6.8 Hz, 1 H), 4.64 (d, J = 17.4 Hz, 1 H), 4.47 (d, J = 17.4 Hz, 1

H), 4.44 (s, 1 H), 4.27 (q, J = 7.1 Hz, 2 H), 1.89–1.80 (m, 1 H),

1.76–1.67 (m, 1 H), 1.64–1.61 (m, 1 H), 1.63 (s, 3 H), 1.56–1.48 (m,

1 H), 1.52 (s, 3 H), 1.35 (s, 3 H), 1.29 (t, J = 7.1 Hz, 3 H) ppm.

¹³C NMR (100 MHz, CDCl₃): δ = 176.9, 167.6, 145.0, 143.0, 140.6,

131.5, 128.9, 128.9, 127.9, 125.8, 124.3, 122.5, 118.5, 117.7, 114.6,

108.0, 68.8, 61.7, 47.9, 41.5, 33.1, 25.7, 23.0, 17.7, 15.6, 14.2 ppm.

HRMS (ESI): calcd. for C₂₈H₃₄N₂NaO₃[M + Na]⁺469.2467;

found 469.2473.

(R*)-3-[(R*)-3,7-Dimethylocta-1,6-dien-3-yl]-1-methyl-3-(phenyl-

amino)indolin-2-one (13d): Following general procedure D gave a

crude mixture, which was purified by silica gel column chromatog-

raphy (EtOAc/hexane, 30:70) to afford 13d (37 mg, 40%) as a color-

less solid; m.p. 123–125 °C. R_f= 0.68 (30% EtOAc/hexane). IR

(thin film): ν = 3388, 2921, 1708, 1608, 1469, 1346, 1116 cm^–1. H

1

˜

NMR (400 MHz, CDCl₃): δ = 7.38 (t, J = 7.8 Hz, 1 H), 7.32 (d, J

= 7.3 Hz, 1 H), 7.06 (t, J = 7.8 Hz, 1 H), 6.94–6.90 (m, 3 H), 6.61

(t, J = 7.3 Hz, 1 H), 6.44–6.42 (m, 1 H), 6.09 (d, J = 7.8 Hz, 2 H),

5.53 (d, J = 11.0 Hz, 1 H), 5.36 (d, J = 17.6 Hz, 1 H), 4.91 (t, J =

6.8 Hz, 1 H), 4.61 (br. s, 1 H), 3.24 (s, 3 H), 1.78–1.72 (m, 2 H),

1.67–1.60 (m, 1 H), 1.63 (s, 3 H), 1.50 (s, 3 H), 1.39–1.30 (m, 1 H), (R*)-Ethyl 2-[(R*)-2-Oxo-3-(phenylamino)indolin-3-yl]but-3-enoate

1.33 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 177.8, 145.8, (16a): Following general procedure E gave a crude mixture, which

144.3, 140.6, 131.5, 129.2, 129.0, 128.2, 126.4, 124.2, 122.2, 118.7,

was purified by silica gel column chromatography (EtOAc/hexane,

117.9, 114.6, 108.1, 69.4, 48.1, 33.7, 26.1, 25.7, 22.7, 17.7, 30:70) to afford 16a (78 mg, 93%) as a colorless sticky solid; m.p.

16.4 ppm. HRMS (ESI): calcd. for C₂₅H₃₁N₂O [M + H]⁺375.2436;

found 375.2438.

142–144 °C. R = 0.58 (30% EtOAc/hexane). IR (thin film): ν =

˜

f

3288, 2975, 1715, 1605, 1470, 1242 cm^{–1 1}H NMR (400 MHz,

.

CDCl₃): δ = 8.99 (s, 1 H), 7.33–7.25 (m, 2 H), 7.04 (t, J = 7.6 Hz,

1 H), 6.98 (dd, J = 8.5, 7.6 Hz, 2 H), 6.85 (d, J = 7.6 Hz, 1 H),

6.69 (t, J = 7.6 Hz, 1 H), 6.33 (d, J = 8.5 Hz, 2 H), 5.95–5.86 (m,

1 H), 5.31–5.26 (m, 2 H), 4.23–4.13 (m, 2 H), 3.50 (d, J = 9.8 Hz,

1 H), 1.22 (t, J = 7.1 Hz, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃):

δ = 178.4, 170.3, 144.9, 140.3, 129.7, 129.7, 129.1, 127.4, 125.8,

122.7, 122.2, 119.6, 115.6, 110.6, 66.1, 61.5, 57.6, 14.0 ppm. HRMS

(ESI): calcd. for C₂₀H₂₀N₂NaO₃[M + Na]⁺359.1372; found

359.1369.

(R*)-1-Benzyl-3-[(R*)-3,7-dimethylocta-1,6-dien-3-yl]-3-(phenyl-

amino)indolin-2-one (13e): Following general procedure D gave a

crude mixture, which was purified by silica gel column chromatog-

raphy (EtOAc/hexane, 30:70) to afford 13e (85 mg, 70%) as a color-

less solid; m.p. 113–115 °C. R_f= 0.69 (30% EtOAc/hexane). IR

1

(thin film): ν = 3371, 2928, 1708, 1605, 1509, 1322, 1177 cm^–1. H

˜

NMR (400 MHz, CDCl₃): δ = 7.36–7.24 (m, 7 H), 7.02 (t, J =

7.4 Hz, 1 H), 6.90 (t, J = 7.8 Hz, 2 H), 6.81 (d, J = 7.8 Hz, 1 H),

6.65 (t, J = 7.4 Hz, 1 H), 6.53–6.47 (m, 1 H), 6.13 (d, J = 7.8 Hz,

2 H), 5.55 (d, J = 10.8 Hz, 1 H), 5.39 (d, J = 17.6 Hz, 1 H), 4.99–

(E)-Ethyl 4-[2-Oxo-3-(phenylamino)indolin-3-yl]but-2-enoate (18a):

4.86 (m, 3 H), 4.63 (br. s, 1 H), 1.77–1.69 (m, 2 H), 1.65 (s, 3 H), Purification by silica gel column chromatography (EtOAc/hexane,

1.50 (s, 3 H), 1.45–1.34 (m, 2 H), 1.35 (s, 3 H) ppm. ¹³C NMR

30:70) afforded compound 18a (33 mg, 40%) as a colorless solid;

(100 MHz, CDCl₃): δ = 177.8, 145.7, 143.7, 140.7, 135.8, 131.5, m.p. 182–184 °C. R = 0.55 (30% EtOAc/hexane). IR (thin film): ν

˜

f

129.1, 128.9, 128.6, 128.2, 127.9, 127.6, 126.6, 124.1, 122.1, 119.0,

= 3333, 2980, 1725, 1604, 1467, 1201 cm^–1. ¹H NMR (400 MHz,

118.0, 115.5, 109.2, 69.6, 48.3, 44.1, 34.3, 25.7, 22.6, 17.6, CDCl₃): δ = 8.91 (s, 1 H), 7.20 (t, J = 7.5 Hz, 2 H), 6.99 (t, J =

16.4 ppm. HRMS (ESI): calcd. for C₃₁H₃₅N₂O [M + H]⁺451.2749;

found 451.2738.

7.5 Hz, 1 H), 6.90 (t, J = 7.9 Hz, 2 H), 6.86–6.78 (m, 2 H), 6.60 (t,

J = 7.4 Hz, 1 H), 6.21 (d, J = 7.9 Hz, 2 H), 5.87 (d, J = 15.6 Hz,

Eur. J. Org. Chem. 2015, 4168–4189

www.eurjoc.org

4183

S. A. Babu et al.

FULL PAPER

1 H), 4.48 (s, 1 H), 4.11 (q, J = 7.1 Hz, 2 H), 2.83 (dd, J = 13.7, 7.1 Hz, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 178.0, 170.2,

7.4 Hz, 1 H), 2.64 (dd, J = 13.7, 8.0 Hz, 1 H), 1.21 (t, J = 7.1 Hz, 154.4, 139.7, 137.7, 132.5, 129.9, 129.4, 129.2, 122.5, 119.8, 115.4,

3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 179.8, 165.7, 144.9,

140.0, 139.6, 129.4, 129.4, 129.1, 126.6, 124.2, 123.3, 119.4, 114.8,

111.0, 64.3, 60.6, 42.6, 14.2 ppm. HRMS (ESI): calcd. for

C₂₀H₂₁N₂O₃[M + H]⁺337.1552; found 337.1550.

114.3, 111.8, 67.4, 61.5, 57.6, 55.3, 14.0 ppm. HRMS (ESI): calcd.

for C₂₁H₂₂BrN₂O₄[M + H]⁺445.0763; found 445.0760.

(R*)-Ethyl 2-[(R*)-1-Benzyl-2-oxo-3-(phenylamino)indolin-3-yl]but-

3-enoate (16f): Following general procedure E gave a crude mixture,

which was purified by silica gel column chromatography (EtOAc/

hexane, 30:70) to afford 16f (97 mg, 91%) as a colorless solid; m.p.

(R*)-Ethyl 2-{(R*)-3-[(4-Methoxyphenyl)amino]-2-oxoindolin-3-

yl}but-3-enoate (16b): Following general procedure E gave a crude

mixture, which was purified by silica gel column chromatography

(EtOAc/hexane, 30:70) to afford 16b (87 mg, 95%) as a colorless

solid; m.p. 106–108 °C. R_f= 0.59 (30% EtOAc/hexane). IR (thin

86–88 °C. R = 0.65 (30% EtOAc/hexane). IR (thin film): ν = 3351,

˜

f

2980, 1718, 1602, 1497, 1306, 1182 cm^–1

CDCl₃): δ = 7.43 (d, J = 7.5 Hz, 1 H), 7.28–7.23 (m, 4 H), 7.19–

¹H NMR 7.17 (m, 2 H), 7.06 (t, J = 7.5 Hz, 1 H), 6.96 (t, J = 8.2 Hz, 2 H),

(400 MHz, CDCl₃): δ = 8.42 (br. s, 1 H), 7.45 (d, J = 7.4 Hz, 1 H), 6.76 (t, J = 7.5 Hz, 2 H), 6.31 (d, J = 8.2 Hz, 2 H), 6.00–5.91 (m,

.

¹H NMR (400 MHz,

film): ν = 3265, 2980, 1720, 1511, 1242, 1034 cm^–1

.

˜

7.26 (t, J = 7.7 Hz, 1 H), 7.07 (t, J = 7.4 Hz, 1 H), 6.78 (d, J = 1 H), 5.33–5.29 (m, 2 H), 5.14 (s, 1 H), 5.09 (d, J = 15.5 Hz, 1 H),

7.7 Hz, 1 H), 6.52 (d, J = 8.9 Hz, 2 H), 6.39 (d, J = 8.9 Hz, 2 H), 4.69 (d, J = 15.5 Hz, 1 H), 4.24–4.13 (m, 2 H), 3.57 (d, J = 9.8 Hz,

6.01–5.92 (m, 1 H), 5.33–5.29 (m, 2 H), 4.18–4.09 (m, 2 H), 3.61

1 H), 1.23 (t, J = 7.2 Hz, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃):

δ = 175.8, 170.3, 144.8, 142.6, 135.5, 130.0, 129.6, 129.0, 128.6,

(s, 3 H), 3.56 (d, J = 9.9 Hz, 1 H), 1.18 (t, J = 7.1 Hz, 3 H) ppm.

¹³C NMR (100 MHz, CDCl₃): δ = 178.1, 170.4, 154.3, 140.7, 137.9, 127.7, 127.6, 127.0, 125.7, 122.7, 122.1, 120.3, 117.1, 109.5, 66.0,

129.9, 129.6, 127.6, 126.1, 122.6, 122.1, 120.0, 114.2, 110.2, 67.2,

61.3, 57.7, 55.3, 14.0 ppm. HRMS (ESI): calcd. for C₂₁H₂₂N₂NaO₄

[M + Na]⁺389.1477; found 389.1468. The NH signal was not

61.4, 57.8, 44.1, 14.1 ppm. HRMS (ESI): calcd. for C₂₇H₂₇N₂O₃

[M + H]⁺427.2022; found 427.2008.

(R*)-Ethyl 2-[(R*)-1-Methyl-2-oxo-3-(phenylamino)indolin-3-yl]but-

3-enoate (16g): Following general procedure E gave a crude mix-

1

clearly visible in the H NMR spectrum.

(R*)-Ethyl 2-{(R*)-3-[(4-Chlorophenyl)amino]-2-oxoindolin-3- ture, which was purified by silica gel column chromatography

yl}but-3-enoate (16c): Following general procedure E gave a crude

mixture, which was purified by silica gel column chromatography

(EtOAc/hexane, 30:70) to afford 16c (89 mg, 96%) as a colorless

solid; m.p. 122–124 °C. R_f= 0.59 (30% EtOAc/hexane). IR (thin

(EtOAc/hexane, 30:70) to afford 16g (70 mg, 80%) as a colorless

liquid; R = 0.61 (30% EtOAc/hexane). IR (thin film): ν = 3373,

˜

f

2930, 1725, 1603, 1470, 1031 cm^–1. ¹H NMR (400 MHz, CDCl₃):

δ = 7.40–7.35 (m, 2 H), 7.09 (t, J = 7.4 Hz, 1 H), 6.97 (dd, J = 8.6,

film): ν = 3275, 2985, 1731, 1492, 1325, 1178 cm^{–1 1}H NMR 7.4 Hz, 2 H), 6.89 (d, J = 7.4 Hz, 1 H), 6.68 (t, J = 7.4 Hz, 1 H),

.

˜

(400 MHz, CDCl₃): δ = 8.75 (s, 1 H), 7.32–7.27 (m, 2 H), 7.05 (t, 6.24 (d, J = 8.6 Hz, 2 H), 5.88–5.79 (m, 1 H), 5.31–5.26 (m, 2 H),

J = 7.6 Hz, 1 H), 6.92 (d, J = 8.9 Hz, 2 H), 6.86 (d, J = 8.3 Hz, 1 5.14 (br. s, 1 H), 4.21–4.11 (m, 2 H), 3.54 (d, J = 9.9 Hz, 1 H), 3.21

H), 6.25 (d, J = 8.9 Hz, 2 H), 5.96–5.86 (m, 1 H), 5.33–5.26 (m, 3 (s, 3 H), 1.22 (t, J = 7.2 Hz, 3 H) ppm. ¹³C NMR (100 MHz,

H), 4.22–4.12 (m, 2 H), 3.47 (d, J = 9.8 Hz, 1 H), 1.21 (t, J =

7.2 Hz, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 177.9, 170.3,

143.5, 140.2, 129.9, 129.5, 128.9, 127.0, 125.7, 124.5, 122.9, 122.4,

117.0, 110.6, 66.1, 61.6, 57.5, 14.0 ppm. HRMS (ESI): calcd. for

C₂₀H₁₉ClN₂NaO₃[M + Na]⁺393.0982; found 393.0975.

CDCl₃): δ = 175.7, 170.2, 144.9, 143.4, 129.9, 129.7, 129.0, 127.0,

125.4, 122.8, 121.9, 119.6, 115.8, 108.4, 65.6, 61.4, 57.8, 26.3,

14.1 ppm. HRMS (ESI): calcd. for C₂₁H₂₃N₂O₃[M + H]⁺

351.1709; found 351.1696.

(R*)-Ethyl 2-{(R*)-3-[(2-Hydroxyphenyl)amino]-1-methyl-2-oxo-

indolin-3-yl}but-3-enoate (16h): Following general procedure E gave

a crude mixture, which was purified by silica gel column

chromatography (EtOAc/hexane, 30:70) to afford 16h (70 mg, 76%)

as a colorless solid; m.p. 164–166 °C. R_f= 0.52 (30% EtOAc/hex-

(R*)-Ethyl 2-{(R*)-5-Chloro-3-[(4-methoxyphenyl)amino]-2-oxo-

indolin-3-yl}but-3-enoate (16d): Following general procedure E gave

a crude mixture, which was purified by silica gel column

chromatography (EtOAc/hexane, 30:70) to afford 16d (95 mg, 95%)

as a colorless solid; m.p. 140–142 °C. R_f= 0.60 (30% EtOAc/hex-

ane). IR (thin film): ν = 3316, 1733, 1696, 1610, 1469, 1317,

˜

ane). IR (thin film): ν = 3388, 2982, 1728, 1511, 1241, 1035 cm^–1.

1176 cm^–1. H NMR (400 MHz, CDCl₃): δ = 7.58 (d, J = 7.5 Hz,

1

˜

¹H NMR (400 MHz, CDCl₃): δ = 8.55 (br. s, 1 H), 7.45 (d, J = 1 H), 7.31 (t, J = 7.7 Hz, 1 H), 7.09 (t, J = 7.5 Hz, 1 H), 6.78 (d,

1.7 Hz, 1 H), 7.24 (dd, J = 8.3, 1.7 Hz, 1 H), 6.71 (d, J = 8.3 Hz,

1 H), 6.55 (d, J = 8.8 Hz, 2 H), 6.39 (d, J = 8.8 Hz, 2 H), 5.95–

5.86 (m, 1 H), 5.32–5.28 (m, 2 H), 4.75 (br. s, 1 H), 4.19–4.13 (m,

J = 7.7 Hz, 1 H), 6.70–6.64 (m, 2 H), 6.45–6.41 (m, 1 H), 6.24 (d,

J = 7.7 Hz, 1 H), 5.87–5.78 (m, 1 H), 5.36–5.26 (m, 2 H), 4.75 (br.

s, 1 H), 4.20–4.10 (m, 2 H), 3.70 (d, J = 9.7 Hz, 1 H), 3.18 (s, 3 H),

2 H), 3.63 (s, 3 H), 3.53 (d, J = 9.8 Hz, 1 H), 1.22 (t, J = 7.1 Hz, 1.21 (t, J = 7.1 Hz, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 178.0, 170.2, 154.4,

139.2, 137.7, 129.6, 129.5, 129.5, 128.1, 126.5, 122.5, 119.9, 114.3,

111.3, 67.4, 61.5, 57.6, 55.3, 14.0 ppm. HRMS (ESI): calcd. for

C₂₁H₂₁ClN₂NaO₄[M + Na]⁺423.1088; found 423.1069.

177.6, 170.6, 149.8, 143.5, 131.3, 129.9, 129.8, 126.4, 125.9, 124.0,

122.9, 122.0, 121.4, 120.0, 115.3, 108.3, 67.5, 61.4, 57.8, 26.3,

14.0 ppm. HRMS (ESI): calcd. for C₂₁H₂₃N₂O₄[M + H]⁺

367.1658; found 367.1649.

(R*)-Ethyl 2-{(R*)-5-Bromo-3-[(4-methoxyphenyl)amino]-2-oxo- (R*)-Ethyl 2-{(R*)-3-[(4-Methoxyphenyl)amino]-2-oxoindolin-3-

indolin-3-yl}but-3-enoate (16e): Following general procedure E gave

a crude mixture, which was purified by silica gel column

chromatography (EtOAc/hexane, 30:70) to afford 16e (109 mg,

98%) as a colorless solid; m.p. 116–118 °C. R_f= 0.62 (30% EtOAc/

yl}butanoate (19): A dry flask that contained 16b (0.5 mmol,

1 equiv.) in anhydrous THF (4 mL) was charged with Pd/C

(20 mol-%), and the reaction mixture was stirred under hydrogen

(1 atm) at room temp. After the starting material was consumed

hexane). IR (thin film): ν = 3193, 1734, 1510, 1244, 1179, (the reaction was monitored by TLC), the reaction mixture was

˜

1035 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.69 (s, 1 H), 7.57 (d,

J = 2.0 Hz, 1 H), 7.39 (dd, J = 8.2, 2.0 Hz, 1 H), 6.65 (d, J =

filtered through a Celite pad, and the filter cake was rinsed with

EtOAc (20 mL). The filtrate was evaporated, and the resulting resi-

8.2 Hz, 1 H), 6.54 (d, J = 9.0 Hz, 2 H), 6.38 (d, J = 9.0 Hz, 2 H), due was purified by column chromatography on silica gel (EtOAc/

5.95–5.85 (m, 1 H), 5.32–5.28 (m, 2 H), 4.76 (br. s, 1 H), 4.19–4.13 hexane, 30:70) to afford compound 19 (166 mg, 90%) as a colorless

(m, 2 H), 3.62 (s, 3 H), 3.52 (d, J = 9.8 Hz, 1 H), 1.21 (t, J = solid; m.p. 143–145 °C. R_f= 0.59 (30% EtOAc/hexane). IR (thin

4184

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Eur. J. Org. Chem. 2015, 4168–4189

Addition of γ-Substituted Allylindiums to Isatin Ketimines

film): ν = 3262, 2969, 1722, 1511, 1470, 1240 cm^{–1 1}H NMR treated with Na₂CO₃at 0 °C to attain pH = 8. The product was

.

˜

(400 MHz, CDCl₃): δ = 8.52 (s, 1 H), 7.51 (d, J = 7.4 Hz, 1 H), then extracted with DCM (5ϫ 1 mL). The combined organic layers

7.28 (t, J = 7.4 Hz, 1 H), 7.08 (t, J = 7.4 Hz, 1 H), 6.81 (d, J = were dried with anhydrous Na₂SO₄, and the solvent was evaporated

7.4 Hz, 1 H), 6.51 (d, J = 8.0 Hz, 2 H), 6.33 (d, J = 8.0 Hz, 2 H), under vacuum to obtain 3-aminooxindole 22 (32 mg, 60%) as a

4.78 (s, 1 H), 4.29 (q, J = 7.0 Hz, 2 H), 3.60 (s, 3 H), 2.83–2.79 (m, colorless solid; m.p. 134–136 °C. IR (thin film): ν = 3260, 2969,

˜

1 H), 1.67–1.59 (m, 1 H), 1.52–1.47 (m, 1 H), 1.33 (t, J = 7.0 Hz,

3 H), 0.85 (t, J = 7.1 Hz, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃):

δ = 179.5, 172.6, 154.0, 140.5, 138.4, 129.4, 128.0, 126.7, 122.7,

119.3, 114.2, 110.4, 67.7, 61.0, 55.3, 54.0, 20.0, 14.3, 11.9 ppm.

1722, 1471, 1188, 753 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 9.25

(s, 1 H), 7.57 (d, J = 7.4 Hz, 1 H), 7.24 (t, J = 7.4 Hz, 1 H), 7.05

(t, J = 7.4 Hz, 1 H), 6.91 (d, J = 7.4 Hz, 1 H), 4.19 (q, J = 7.1 Hz,

2 H), 2.85 (dd, J = 11.6, 3.5 Hz, 1 H), 1.91 (br. s, 2 H), 1.59–1.51

HRMS (ESI): calcd. for C₂₁H₂₅N₂O₄[M + H]⁺369.1814; found (m, 1 H), 1.38–1.32 (m, 1 H), 1.24 (t, J = 7.1 Hz, 3 H), 0.83 (t, J

369.1811.

= 7.4 Hz, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 181.9,

173.1, 140.8, 130.0, 129.3, 126.2, 122.7, 110.1, 62.6, 60.6, 54.4, 20.5,

14.2, 12.1 ppm. HRMS (ESI): calcd. for C₁₄H₁₈N₂NaO₃[M + Na]

General Procedure G: Reduction of 3-Aminooxindoles to N-Aryl-γ-

amino Alcohols: A dry flask was charged with anhydrous THF

(4 mL) and the corresponding oxindole derivative 16b or 19

(0.2 mmol) under nitrogen, and the reaction mixture was cooled to

0 °C. LiAlH₄(0.8 mmol) was then added in portions, and the mix-

ture was stirred at room temp. for 6–12 h. After the starting mate-

rial was consumed (as shown by TLC), EtOH (few drops) and

water (1–2 mL) were added sequentially. The resulting white sus-

pension was filtered through a Celite pad, and the filter cake was

rinsed with EtOAc (20 mL). The filtrate was dried with anhydrous

Na₂SO₄, and the solvent was removed by rotary evaporation. Puri-

fication of the crude reaction mixture by column chromatography

on silica gel (EtOAc/hexane) afforded the respective N-aryl-γ-

amino alcohol 20 or 21.

+

285.1215; found 285.1211.

Acknowledgments

This work was funded by the Department of Science and Technol-

ogy (DST), New Delhi (Fast Track Young Scientist Scheme) and

the Indian Institute of Science Education and Research (IISER),

Mohali. The authors thank IISER Mohali for the use of their

NMR, X-ray, and HRMS facilities. The authors also thank the

Department of Chemical Sciences, IISER Mohali for the use of

their single-crystal X-ray facility. N. A. A. thanks the University

Grants Commission (UGC), New Delhi for a SRF fellowship. S. R.

and J. S. thank the DST for the INSPIRE fellowship, and S. M.

thanks the IAS for the summer research fellowship.

(R*)-3-[(R*)-1-Hydroxybut-3-en-2-yl]-3-[(4-methoxyphenyl)amino]-

indolin-2-one (20): Following general procedure G gave a crude

mixture, which was purified by silica gel column chromatography

(EtOAc/hexane, 50:50) to afford 20 (44 mg, 68%) as a colorless

solid; m.p. 183–185 °C. R_f= 0.41 (50% EtOAc/hexane). IR (thin

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film): ν = 3458, 2916, 1716, 1511, 1392, 1239 cm^{–1 1}H NMR

.

˜

(400 MHz, [D₆]DMSO, CDCl₃): δ = 10.5 (s, 1 H), 7.24–7.19 (m, 2

H), 6.95 (t, J = 7.4 Hz, 1 H), 6.84 (d, J = 7.4 Hz, 1 H), 6.51 (d, J

= 8.9 Hz, 2 H), 6.15 (d, J = 8.9 Hz, 2 H), 5.84 (s, 1 H), 5.26–5.17

(m, 1 H), 5.09–5.04 (m, 2 H), 4.84 (t, J = 5.2 Hz, 1 H), 3.89–3.84

(m, 1 H), 3.54 (s, 3 H), 3.51–3.45 (m, 1 H), 2.71–2.65 (m, 1 H),

2.51–2.49 (m, 1 H) ppm. ¹³C NMR (100 MHz, [D₆]DMSO,

CDCl₃): δ = 183.4, 156.8, 147.1, 145.3, 139.4, 134.0, 133.9, 129.9,

126.7, 124.8, 120.7, 119.3, 114.9, 72.0, 65.4, 60.3, 58.4 ppm. HRMS

(ESI): calcd. for C₁₉H₂₁N₂NaO₃[M + Na]⁺347.1372; found

347.1364.

(R*)-3-[(R*)-1-Hydroxybutan-2-yl]-3-[(4-methoxyphenyl)amino]ind-

olin-2-one (21): Following general procedure G gave a crude mix-

ture, which was purified by silica gel column chromatography

(EtOAc/hexane, 50:50) to afford 21 (45 mg, 70%) as a sticky solid;

R = 0.42 (50% EtOAc/hexane). IR (thin film): ν = 3442, 2920,

˜

f

1714, 1511, 1238, 1037 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ =

8.38 (br. s, 1 H), 7.61 (d, J = 7.4 Hz, 1 H), 7.24 (t, J = 7.4 Hz, 1

H), 7.10 (t, J = 7.4 Hz, 1 H), 6.76 (d, J = 7.4 Hz, 1 H), 6.54 (d, J

= 8.5 Hz, 2 H), 6.49 (d, J = 8.5 Hz, 2 H), 4.03 (d, J = 6.9 Hz, 2

H), 3.60 (s, 3 H), 2.21–2.15 (m, 1 H), 1.34–1.26 (m, 2 H), 0.84 (t,

J = 7.4 Hz, 3 H), 0.83–0.73 (m, 1 H) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 179.6, 155.4, 141.0, 136.6, 129.4, 127.1, 126.6, 122.9,

122.7, 113.9, 110.4, 72.1, 62.7, 55.3, 47.7, 19.4, 12.1 ppm. HRMS

(ESI): calcd. for C₁₉H₂₃N₂O₃[M + H]⁺327.1709; found 327.1697.

(R*)-Ethyl 2-[(R*)-3-Amino-2-oxoindolin-3-yl]butanoate (22): To 3-

substituted N-aryl-3-aminooxindole 19 (0.2 mmol, 1 equiv.) in

MeCN (2 mL) were added an aqueous solution of (NH₄)₂S₂O₈

(2 equiv.) and ceric(III) ammonium nitrate (0.1 equiv.) at 0 °C. The

resulting mixture was stirred at 40 °C for 12 h. After the complete

consumption of the starting material (as shown by TLC), the reac-

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FULL PAPER

A. Chhatriwalla, J. Org. Chem. 1998, 63, 1836; h) L. A. Pa-

quette, T. M. Mitzel, M. B. Isaac, C. F. Crasto, W. W. Schomer,

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Org. Chem. 1999, 1551; j) see ref.^[9,11]

For selected papers on chelation-controlled stereoselective ad-

ditions of organoindium reagents to carbonyl compounds in a

nonprotogenic anhydrous solvent such as THF, see ref.^[25c,25f]

For selected papers on chelation-controlled stereoselective ad-

ditions of organoindium reagents to C=N bond systems in a

protogenic solvent such as alcohol, water, or THF/water, see:

a) ref.^{[9,11,18g,19a,19b]}; b) S.-S. Jin, M.-H. Xu, Adv. Synth. Catal.

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For selected papers on chelation-controlled stereoselective ad-

ditions of organoindium reagents to C=N bond systems in a

nonprotogenic anhydrous solvent such as THF, see

ref.^{[9,11,18i,18s]}

THF/water failed to afford the product, which may be a result

of the instability of the cyclohexenylindium species in THF/

water as noted in ref.^[11p]

[31]

a) All of the isatin ketimines were prepared by using standard

literature procedures with the corresponding isatins and anil-

ines. Generally, the C=N bond of isatin ketimines (predomi-

nant isomers) is reported to have the (E) configuration. For

details, see ref^[23f]; b) We have also characterized the stereo-

chemistry of representative isatin ketimines 1i and 1k. The X-

ray crystal structure analysis revealed that the C=N bond of 1i

and 1k (predominant isomers) has the (E) configuration (see

the Supporting Information for X-ray crystal structures of 1i

and 1k); c) The structures of the plausible TS models are pro-

posed (Figure 4) without considering the E/Z configuration of

the isatin ketimines. However, to understand whether the E/Z

configuration of the starting material (isatin ketimine) will af-

fect the diastereomeric ratio (diastereoselectivity) of the all-

ylated product, we performed the allylation of a typical sub-

strate 1f with E/Z ratios of 70:30 and 80:20. The cinnamylation

of substrate 1f with an E/Z ratio of 70:30 and 80:20 gave prod-

uct 3e with a dr of 95:5 and 90:10, respectively. Similarly, the

cyclohexenylation of the substrate 1f with an E/Z ratio of 70:30

and 80:20 gave product 10c with a dr of 80:20 and 80:20,

respectively. These experiments indicate that the outcome of

the diastereoselectivity may be independent of the E/Z ratio

(see ref.^[18i,18s]) of the isatin ketamine, as we cannot ignore the

possibility of E/Z isomerization occurring under the experi-

mental conditions to form one of the allylated compounds as

the major isomer. Our attempts to obtain the E/Z mixture with

the (Z) isomer as the predominant product were not fruitful.

The best case had an E/Z ratio of 70:30.

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ref.^[11a,11i]; j) noticeably, the reaction of isatin ketimines and

allyl halides that have the (E) configuration, such as cinnamyl

bromide (2a), crotyl bromide (2b), and ethyl 4-bromocrotonate

(2c), gave the corresponding γ-adducts 3, 6, and 16 in which

the N-aryl moiety and the respective groups (i.e., Ph, Me, and

COOEt) obtained from the corresponding allyl halides were

found to be anti to each other. Along this line of reasoning,

the stereochemistry of products 13a–13f, which were obtained

from geranyl bromide [(E) configuration], were proposed on

the basis of the stereochemistry of the products 3, 6, and 16

(major isomers). Accordingly, the stereochemistry of product

14 (major isomer), which was obtained from neryl bromide [(Z)

configuration], was proposed after assigning the stereochemis-

try of 13.

a) For reports on chelation-controlled stereoselective allyl-

ations of C=N systems in a nonprotogenic solvent such as

THF, see ref.^[28]; b) For an example of the effect of nonproto-

genic solvents on the reaction of cinnamyl bromide, crotyl

bromide, cyclohexenyl bromide, and ethyl 4-bromocrotonate

with isatin ketimines, there is the reaction of isatin ketimine

(1a) with cinnamyl bromide (2a) in THF, which gave α-adduct

5a and γ-adducts 3a and 4a (dr 86:14) with relatively low regio-

and diastereoselectivity. The reaction of 1a with 2a in 1,4-diox-

ane gave only γ-adducts 3a and 4a (dr 90:10) with high dia-

stereoselectivity (Table 1). However, in both of these cases,

longer times were required for the completion of the reaction,

and the γ-adducts were obtained in moderate yields (59 and

65%, respectively). On the other hand, the reaction of 1a and

2a in DMF gave γ-adduct 3a and 4a (dr 50:50) in an inferior

yield as well as with poor diastereoselectivity. Unlike the sol-

vents THF and 1,4-dioxane, which can provide the necessary

rigidity to the cyclic transition state because of their nature to

act as good ligands, the polar aprotic solvent DMF may not

be assisting the formation of the cyclic TS (Table 1). A similar

trend was observed in the reactions of crotyl bromide and ethyl

4-bromocrotonate with ketimine 1a (Tables 3 and 7, respec-

tively). The reaction of cyclohexenyl bromide and the isatin

ketimine behaved differently (Table 4), and DMF was deter-

mined as the best solvent to obtain appreciable diastereoselec-

tivity. Considering the reaction of cyclohexenyl bromide in

EtOH as an exceptional case, the cyclohexenylation of 1a in

[32]

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The stereochemistry of the products 3a–3i were assigned on the

basis of single-crystal X-ray structure analyses of the represen-

tative major isomers 3b and 3i (Figure 3) coupled with the simi-

larity of their NMR spectral patterns. The stereochemistry of

products 6a–6e were assigned on the basis of single-crystal X-

ray structure analyses of representative major isomers 6d and

6e (Figure 3) coupled with the similarity of their NMR spectral

patterns. The stereochemistry of the products 10a–10g were as-

signed on the basis of single-crystal X-ray structure analyses of

representative major isomers 10a, 10b, and 10c (Figure 5) cou-

pled with the similarity of their NMR spectral patterns. The

stereochemistry of products 16a–16h were assigned on the basis

of single-crystal X-ray structure analyses of representative

major isomers 16e and 16h (Figure 6) coupled with the similar-

ity of their NMR spectral patterns. See the Supporting Infor-

mation for a glance to compare the typical ¹³C NMR chemical

shift values for the stereocenters of the respective series of sim-

ilar compounds 3a–3i, 6a–6e, 10a–10g, 13a–13f, 14a, 14f, and

16a–16h.

4188

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Eur. J. Org. Chem. 2015, 4168–4189

Addition of γ-Substituted Allylindiums to Isatin Ketimines

[35] CCDC-1042716 (for 3b), -1042717 (for 3i), -1042718 (for 3j),

-1042726 (for 4k), -1042727 (for 6d), -1042728 (for 6e),

-1042729 (for 10a), -1042730 (for 10b), -1042731 (for 10c),

-1042732 (for 11h), -1042733 (for 16e), -1042734 (for 16h),

-1042735 (for 19), -1053607 (for 1i), and -1053608 (for 1k) con-

tain the supplementary crystallographic data for this paper.

These data can be obtained free of charge from The Cambridge

Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_

request/cif.

Received: March 13, 2015

Published Online: May 27, 2015

Eur. J. Org. Chem. 2015, 4168–4189

www.eurjoc.org

4189

Article Doi

Diastereoselective Construction of 3-Aminooxindoles with Adjacent Stereocenters: Stereocontrolled Addition of γ-Substituted Allylindiums to Isatin Ketimines

DOI: 10.1002/ejoc.201500340

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