Preparation of Alkyl Indium Reagents by Iodine-Catalyzed Direct

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Preparation of Alkyl Indium Reagents by Iodine-Catalyzed Direct Indium Insertion and Their Applications in Cross-Coupling Reactions Man-Ling Zhi, Bing-Zhi Chen, Wei Deng, Xue-Qiang Chu, Teck-Peng Loh, and Zhi-Liang Shen J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00204 • Publication Date (Web): 05 Feb 2019 Downloaded from http://pubs.acs.org on February 10, 2019

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The Journal of Organic Chemistry

Preparation of Alkyl Indium Reagents by Iodine-Catalyzed Direct Indium Insertion and Their Applications in Cross-Coupling Reactions

Man-Ling Zhi,†,# Bing-Zhi Chen,†,# Wei Deng,† Xue-Qiang Chu,† Teck-Peng Loh,*,†,‡ and ZhiLiang Shen*,† † Institute

of Advanced Synthesis, School of Chemistry and Molecular Engineering, Jiangsu National

Synergetic Innovation Center for Advanced Materials, Nanjing Tech University, Nanjing 211816, China E-mail: [email protected] ‡

Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore E-mail: [email protected]

Abstract: An efficient method for the synthesis of alkyl indium reagent by means of an iodine-catalyzed direct indium insertion into alkyl iodide in THF is reported. The thus-generated alkyl indium reagents effectively underwent Pd-catalyzed cross-coupling reactions with various aryl halides, exhibiting good compatibility to a variety of sensitive functional groups. By replacing THF with DMA and using 0.75 equiv. of iodine, less reactive alkyl bromide could be used as substrate for indium insertion with equal ease.

Alkyl

X

(X = I, Br)

In I2

Alkyl

InX2

Ar X Pd(PPh3)4 (5 mol%) LiCl, DMA

Alkyl Ar

Compatible with C=C, COR, CHO, CN, NO2, OTBS, OH

ACS Paragon Plus Environment

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Organometallic reagents have revolutionized modern organic synthesis.1 The past several decades have witnessed the fast development of organoindium reagents and their wide applications in organic synthesis and material science.2 The intrinsically mild reactivity of organoindium reagents enable them to undergo various organic transformations with good functional group tolerance and sometimes markedly enhanced chemo- and stereoselectivities, rendering them appealing alternatives to other more reactive but moisture-sensitive organometallics such as organolithium, organomagnesium, organoaluminium, and organozinc reagents. Till now, some representative organoindium reagents, such as allylindium,3 propargylindium,4 and indium enolate,5 which can be readily and in situ prepared by mixing indium with respective organic halides, have found extensive applications in various organic transformations, as demonstrated by Araki, Chan, Li, Paquette, Whitesides, Lee, Baba, our group, and others. Besides, triorganoindium reagents (R3In),6 which can be easily accessed by means of the transmetallation of indium(III) halides with either organolithium or organomagnesium reagents, has also found broad utilities in organic synthesis, especially in transition metal-catalyzed cross-coupling reactions. In contrast, the preparation of aryl,7 alkenyl,8 benzyl,9 and alkyl10 indium reagents as well as their applications in organic synthesis have not aroused too much attention from synthetic community until it was discovered that the use of stoichiometric amounts of lithium salt11 or copper salt10a-c could effectively facilitate the direct insertion of indium powder into the corresponding organic halides within recent ten years, as revealed by Knochel, Lee, Minehan, Yoshika, our group, and others.12 In our continued endeavor to seeking efficient method for the synthesis of organoindium reagent as well as their synthetic utilities, herein we report that a catalytic amount of iodide13 (20 mol%) was capable of efficiently catalyzing the direct insertion of indium into alkyl iodides, producing the desired alkyl indium reagent with high efficiency. The thus-generated alkyl indium reagents readily underwent palladium-catalyzed cross-


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coupling reactions with a wide variety of aryl halides to produce the cross-coupled products in moderate to good yields, exhibiting excellent functional group compatibility. Initially, we optimized the reaction conditions by using (2-iodoethyl)benzene (1a) as substrate in the presence of different equivalents of indium powder and iodine in THF at 60 oC for 24 h. As shown in Table 1, when 2 equiv. of indium and 1 equiv. of iodine were used, the formation of 90% NMR yield of alkyl indium reagent was detected (entry 1), as revealed by 1H NMR analysis of the crude reaction mixture against an internal standard of 1,4-dimethoxybenzene. Gratifyingly, when the amount of iodine decreased from 1 equiv. to 0.5 or 0.1 equiv., the insertion reaction proceeded with almost equal success to produce the corresponding alkyl indium compound in 84% and 82% NMR yields (entries 2-3), indicating that a catalytic amount of iodine was sufficient to catalyze the insertion reaction. In addition, when 0.1 equiv. of iodine was used and lowered the amount of indium powder from 2 equiv. to 1.5 equiv., the reaction worked equally well to give the desired product in 80% NMR yield (entry 4). However, when 1.0 equiv. of indium was employed under the same reaction conditions, the product yield decreased sharply (55%, entry 5).

Table 1. Optimization of Reaction Conditionsa I

Ph 1a

In (x equiv.) I2 (y equiv.)

Ph

THF, 60 oC, 24 h

)n InX(3-n)

y

yield (%)b

2

1

90

2

0.5

84

3

2

0.1

82

4

1.5

0.1

80

5

1

0.1

55

entry

x

1 2

a

The insertion was performed at 60 oC for 24 h by using (2-iodoethyl)benzene (1a, 1 mmol), indium powder (1-2 equiv.), and iodine (0.1-1 equiv.) in THF (2 mL). b The yield was determined by 1H NMR analysis of the crude reaction mixture by using 1,4-dimethoxybenzene as an internal standard.



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Subsequently, the substrate scope of the present reaction was examined by utilizing various aryl iodides as substrates. As listed in Table 2, both the indium insertion reaction and the ensuing crosscoupling reaction with a spectrum of aryl halides proceeded efficiently under optimized reaction conditions to afford the cross-coupling products 3a-n in moderate to good yields (entries 1-14). In addition to aryl halides, heteroaryl iodides 2k, 2m, and 2n containing oxygen or nitrogen atom worked equally well under the well-established conditions to furnish the target products in good yields (entries 11, 13, and 14). Besides aryl iodides, less reactive aryl bromides 2g/2i and chloride 2j were also proven to be effective coupling partners for the present reaction, generating the desired products 3g, 3i, and 3j in moderate yields (entries 7, 9, and 10). Especially noteworthy is that, the reaction exhibited remarkable tolerance to a range of sensitive functional groups, such as acetyl, nitrile, nitro, ester, and aldehyde (entries 1-11), allowing them amenable for downstream chemical modifications.

Table 2. Substrate Scope Study by Using Various Aryl Halidesa I

Ph 1a

entry

1. In, I2, THF, 60 oC, 24 h 2. ArX (2), Pd(PPh3)4, LiCl DMA, 100 oC, 12 h

substrate

Ar

Ph 3a-n

product

yield (%)b

I R

1

2a (R = Ac)

3a

96

2

2b (R = CN)

3b

96

3

2c (R = NO2)

3c

85

3d

95

3e

97

I

O 2N

4

2d I NO2

5

2e X EtO2C

6

2f (X = I)

3f

65

7

2g (X = Br)

3g

48


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X OHC

8

2h (X = I)

3h

97

9

2i (X = Br)

3i

67

10

2j (X = Cl)

3j

49

3k

78

3l

88

3m

82

3n

77

OHC

I

O

11

2k I

12

2l I N

13

2m N

I

N

14

2n

a

See the Supporting Information for detailed reaction conditions. b Yield of isolated product based on aryl halides 2a-n as limiting reagent.

To further demonstrate the generality of the method, a number of alkyl iodides were explored. As summarized in Table 3, an array of structurally varied alkyl iodides were effectively transformed into the anticipated alkyl indium reagents, which, upon undergoing palladium-catalyzed cross-coupling reactions with aryl iodide 2a, furnished the coupling products 4b-k in 46-97% yields (entries 1-10). Similarly, the mildness of the formed alkyl indium reagents entailed the presence of various functional groups in the substrates including C=C (1e), nitrile (1f), ester (1g), amide (1h), OTBS (1i), and even hydroxyl group (1j). Moreover, the approach could also be extended to the use of secondary iodide 1k as starting material, delivering the corresponding product 4k in an acceptable yield of 46% (entry 10).

Table 3. Substrate Scope Study by Using Various Alkyl Iodidesa R I 1b-k

entry

Ac

1. In, I2, THF, 60 oC, 24 h 2. 4-AcC6H4I (2a), Pd(PPh3)4 LiCl, DMA, 100 oC, 12 h

substrate Ph

R

product

4b-k

yield (%)b

I



1

1b ( )6

2

4b

79

4c

73

4d

67

4e

97

4f

79

4g

64

4h

75

4i

48

4j

49

4k

46

I

1c ( )3

3

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I

1d I

4

1e NC

I

5

1f EtO2C

6

I

1g O N

I

O

7

1h ( )4

TBSO

8

I

1i HO

9

I

1j I

10

1k

a

See the Supporting Information for detailed reaction conditions. b Yield of isolated product based on aryl iodide 2a as limiting reagent.

However, when the optimized reaction conditions were applied to the indium insertion into less reactive (2bromoethyl)benzene (5a) in the presence of 0.1 equiv. of iodine in THF, the reaction proceeded sluggishly to yield the alkyl indium reagent in

Preparation of Alkyl Indium Reagents by Iodine-Catalyzed Direct

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