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Synlett 2015; 26(05): 651-655
DOI: 10.1055/s-0034-1379885
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© Georg Thieme Verlag Stuttgart · New York

Metal-Free N-Arylation of Indolines with Diaryliodonium Salts

Stefan Riedmüller
a   Institut für Organische Chemie, Eberhard Karls Universität, Auf der Morgenstelle 18, 72076 Tübingen, Germany   Email: boris.nachtsheim@uni-tuebingen.de
b   Performance Materials Division, Merck KGaA, Frankfurter Straße 250, 64293 Darmstadt, Germany
,
Boris J. Nachtsheim*
a   Institut für Organische Chemie, Eberhard Karls Universität, Auf der Morgenstelle 18, 72076 Tübingen, Germany   Email: boris.nachtsheim@uni-tuebingen.de
› Author Affiliations
Further Information

Publication History

Received: 05 November 2014

Accepted after revision: 27 November 2014

Publication Date:
14 January 2015 (online)

 
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Abstract

The N-arylation of indolines using diaryliodonium salts as electrophilic arylating reagents is described. Without the use of any additional additives, the desired N-aryl indolines could be obtained in up to 85% yield.


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Key words

amination - hypervalent iodine - metal-free - arylation - indoline

Indoline (2,3-dihydroindole) and related congeners are widely found as a core structural element in alkaloid natural products[1] or other pharmaceutically interesting molecules.[2] In particular N-aryl indolines were found to be interesting structural elements due to their recently explored applications in different areas of organic electronics.[3]

In general, the N-aryl indoline framework is accessible via partial hydrogenation of the corresponding fully unsaturated N-aryl indole precursor.[4] Another recent methodology is utilizing styrenes as precursors for the introduction of the annelated nitrogen ring.[5] Completely different is the construction of the N-aryl indoline via arylation of amines with nonaromatic ketones through a palladium-catalyzed aerobic dehydrogenative aromatization.[6] For late-stage functionalization, the indoline-NH moiety is often used. Here, transition-metal-mediated N-arylation is a common procedure.[7] However, metal-free procedures involving arynes are also known.[8] In the last decade new chemical transformations based on hypervalent iodine reagents have become very popular in organic chemistry.[9] In particular, diaryliodonium salts[10] could demonstrate their great potential as efficient nontoxic, electrophilic arylating reagents which are particularly useful in metal-free arylations.[11] Examples from the literature describe arylation reactions of anilines,[12] oxygen nucleophiles,[13] [14] N-protected indoles,[15] pyrroles,[16] carbazoles,[17] benzoazoles,[18] or even ammonia to produce primary aromatic amines.[19]

The research interests of our group are focused on the development of new C–X coupling strategies involving hypervalent iodine reagents or (hypo)iodites.[20] Very recently, we could develop a novel palladium-catalyzed synthesis of N-aryl carbazoles using anilines and stable cyclic diaryliodonium salts.[21] As part of our ongoing research projects we were interested in direct metal-free arylation reactions of nitrogen heterocycles utilizing diaryliodonium salts. In this communication we want to present our initial results describing the first metal free N-arylation of indolines.

In an initial attempt, indoline 1a was treated with 1.1 equivalents of diphenyliodonium triflate in DMF at 130 °C (Table [1], entry 1). We were gratified to observe moderate conversion and isolated 25% of N-phenylindoline 3a. In the same experiment we also detected N-formylindoline as a side product in significant amounts which results from an undesired reaction of indoline with the solvent DMF.

Table 1 Optimization Studiesa

Entry

X–

Solvent

Additive (equiv)

Time (h)

Temp (°C)

Yield (%)b

 1

OTf

DMF

–

15

130

25

 2

OTf

DMF

–

14

 60

tracec

 3

OTf

DMAc

–

66

 60

tracec

 4

OTf

MeCN

–

14

 75

27

 5

OTf

EtCN

–

16

 90

76

 6

OTf

DMSO

–

18

110

tracec

 7

OTf

TFE

–

14

 70

83

 8

OTf

HFIP

–

23

 55

tracec

 9d

OTf

TFE

–

18

 70

85

10

OTf

TFE

NaOH (1.5)

15

 70

tracec

11

OTf

TFE

NaH (1.1)

96

 70

tracec

12

OTf

TFE

KOt-Bu (1.5)

13

 75

tracec

13

OTs

TFE

–

24

 70

44

14

CF3COO

TFE

–

30

 70

81

15

BF4

TFE

–

42

 70

73

a Typical reaction conditions: 1a (0.21 mmol), 2a (1.1 equiv), solvent (3–4 mL).

b Isolated yield after column chromatography.

c Product not isolated.

d 1a (0.21 mmol), 2a (1.3 equiv).

Running the reaction at lower temperatures (60 °C) to prevent side-product formation resulted only in trace amounts of 3a (Table [1], entry 2). Next, N,N-dimethylacetamide (DMAc) was tested as a solvent, but again, only trace amounts of 3a were observed (Table [1], entry 3). Acetonitrile showed comparable results to DMF (Table [1], entry 4). Interestingly, we observed a higher product formation with propionitrile giving 3a in 76% yield (Table [1], entry 5). Using DMSO as another polar aprotic solvent did not improve the outcome of the reaction (Table [1], entry 6). Finally, we investigated fluorinated solvents, in particular 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) and 2,2,2-trifluoroethanol (TFE). Here, we observed a further increase in product formation when we used TFE (Table [1], entry 7), while HFIP was completely inefficient in this transformation (Table [1], entry 8). Base additives, such as sodium hydroxide, sodium hydride, and potassium tert-butoxide did not improve the product yield (Table [1], entries 10–12). To complete the optimization, we investigated diphenyliodonium salts with other counterions (Table [1], entries 13–15).[22] The tosylate salt of 2a was not efficient at all (Table [1], entry 13), whereas 2a associated with trifluoroacetate or tetrafluoroborate performed similiarly to the triflate salt. Diphenyliodonium tetrafluoroborate showed a slightly reduced yield of 3a of 73%.

Next, we used a variety of iodonium salts with different substituents in 4-position of the arene moiety.[23] Diaryliodonium salts bearing electron-donating (4-Me or 4-MeO) and electron-withdrawing groups (4-Br or 4-F3C) were selected as arylating reagents. From the results summarized in Table [2, a] clear trend in aryl-group-transfer capability is visible. Compared to unsubstituted diphenyliodonium triflate, the more electron-rich 4-methyl-substituted congener reacted in lower yields giving 3b in 41% (Table [2], entry 1). By using the 4-methoxy-substituted iodonium salt (R1 = H, R2 = R3 = OMe), no N-aryl indoline 3c could be isolated at all. In contrast, electron-deficient di­aryliodonium salts bearing 4-bromo or 4-trifluoromethyl substituents furnished N-aryl indolines 3d and 3e in yields of 65 and 62%, respectively (Table [2], entries 3 and 4).

Table 2 Using Different Substituted Symmetrical and Unsymmetrical Iodonium Saltsa

Entry

R1

R2

R3

Time (h)

N-Aryl indoline 3

Yield (%)b

1

H

Me

Me

48

3b

41

2

H

OMe

OMe

88

3c

 0

3

H

Br

Br

22

3d

65c

4

H

CF3

CF3

 4

3e

62

5d

Me

Me

H

24

3a R1, R2 = H
3f R1, R2 = Me

16
 5e

a Typical reaction conditions: 1a (0.21 mmol), 2 (1.1 equiv), solvent (3–4 mL).

b Isolated yield after column chromatography.

c Average of two runs.

d Conditions: 1a (0.36 mmol), 2 (1.1 equiv).

e Isolated by column chromatography.

Unsymmetrically substituted diaryliodonium salts are known to react chemoselectively with different types of nucleophiles. However, the chemoselectivity strongly depends on the nature of the nucleophile[10a] [24] and the presence of a transition metal.[11f,12,14a,c,25]

To verify the chemoselectivity for the metal-free arylation of indolines, we reacted 1a under our standard protocol together with (2,4,6-trimethylphenyl)(phenyl)iodonium triflate.[23c] Here, we isolated a product mixture containing both possible N-arylated indolines, albeit in low yields. Compounds 3a and 3f were isolated in 16% and 5% yield. This result matches well with the general observed chemoselectivity trend in nonmetal-catalyzed reactions with hypervalent diaryliodonium salts. Furthermore, a recent report[25a] from Olofsson and coworkers stimulated us to investigate N-heteroaryl-containing diaryliodonium triflates. However, a variety of heteroaryl-containing iodonium triflates 4a–d did not react with indoline 1a under our optimized reaction conditions (Scheme [1]). We generally isolated significant amounts of the corresponding 4-substituted iodoarenes as the sole reaction products.

Zoom Image
Scheme 1 Attempts using N-heteroaryl diaryliodonium triflates as arylating reagents for indoline 1a

We next concentrated our work on the exploration of the substrate scope using other indolines and other nitrogen heterocycles (Figure [1]). Methyl-substituted indolines gave the corresponding products 6a and 6b in moderate yields (50% and 41%, respectively). When we used indolines with a hydroxy functionality, we were interested if we could observe a difference in chemoselectivity. However, from the reaction mixture we only isolated 6c and 6e as sole N-arylated products in low yields, which indicates that the free hydroxyl group remained untouched. 3-Nitrile-substituted indoline gave 6d in 18% yield, while the 2-methyl derivative yielded 6f in 29% yield.

Zoom Image
Figure 1 Scope of isolated N-arylated indolines and 2-arylated benzo­triazoles in our investigation

Nitrogen heterocycles, such as 1H-indole, 1H-benzo[d]imidazole gave trace amounts of product. 1,2,3,4-Tetrahydroquinoline did not react at all. With 1H-indazole at least 12% of the N-arylated product 7 was observed. Next, we submitted 1H-benzotriazole together with a variety of diaryliodonium salts. Under optimized reaction conditions (see Supporting Information) we observed a high N2-selectivity[26] and isolated the N2-arylated products 8a–d in moderate yields (25–46%).

Indolines with a phenyl or ester group in the 2-position of the indoline underwent reoxidation in the presence of the hypervalent iodine arylating reagent. In both cases the corresponding indoles 9a and 9b were isolated (Scheme [2]).

Zoom Image
Scheme 2 Arylation of 2-substituted indolines 1b and 1c yield the corresponding indoles

To conclude, we have demonstrated for the first time the transition-metal-free N-arylation of indolines by utilizing diaryliodonium salts as mild and nontoxic arylating reagents. Beside other indolines, 1H-benzotriazole could be used as well in our N-arylation procedure. The corresponding N-arylated products could be isolated in moderate to acceptable yields. In future research we want to look deeper into the side-product portfolio of this transformation to get a better idea about its mechanism and improve product yields, also for a more rational design of metal-free arylations of other N-heterocyclic nucleophiles.


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Acknowledgment

Financial support by the Deutsche Forschungsgemeinschaft (DFG) and the Fonds der Chemischen Industrie (Sachkostenzuschuss) is acknowledged. S.R. gratefully acknowledges Merck KGaA for financial support.

Supporting Information

    Supporting information for this article is available online at http://dx.doi.org.accesdistant.sorbonne-universite.fr/10.1055/s-0034-1379885.
  • Supporting Information


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Zoom Image
Scheme 1 Attempts using N-heteroaryl diaryliodonium triflates as arylating reagents for indoline 1a
Zoom Image
Figure 1 Scope of isolated N-arylated indolines and 2-arylated benzo­triazoles in our investigation
Zoom Image
Scheme 2 Arylation of 2-substituted indolines 1b and 1c yield the corresponding indoles