Diels–Alder cycloadditions of N-arylpyrroles via aryne intermediates using diaryliodonium salts

  1. Huangguan Chen1,
  2. Jianwei Han1,2ORCID Logo and
  3. Limin Wang1

1Key Laboratory for Advanced Materials, Institute of Fine Chemicals, School of Chemistry & Molecular Engineering, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, P. R. China
2Shanghai–Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, The Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China

  1. Corresponding author email

This article is part of the Thematic Series "Hypervalent iodine chemistry in organic synthesis".

Guest Editor: T. Wirth
Beilstein J. Org. Chem. 2018, 14, 354–363. doi:10.3762/bjoc.14.23
Received 08 Dec 2017, Accepted 26 Jan 2018, Published 06 Feb 2018

Abstract

With a strategy of the formation of benzynes by using diaryliodonium salts, a cycloaddition reaction of N-arylpyrroles with benzynes was reported. A wide range of bridge-ring amines with various substituents have been synthesized in moderate to excellent yields (35–96%). Furthermore, with a catalytic amount of TsOH·H2O, these amines can be converted into the corresponding N-phenylamine derivatives easily, which are potentially useful in photosensitive dyes.

Keywords: benzyne; cycloaddition; diaryliodonium salts; N-phenylamine; pyrrole

Introduction

Pyrrole is a very useful heterocyclic substrate to produce structural attributes of valuable chemicals, functional materials and pharmaceuticals [1-5]. Recently, arylation of pyrrole derivatives with diaryliodonium salts for pyrrole–aryl coupling products is generating tremendous academic interest in organic synthesis. In 2012, the Zhang and Yu group reported that sodium hydroxide promoted direct arylation of unprotected pyrroles with diaryliodonium salts at the temperature of 80 °C, the coupling products were obtained in moderate to good yields (Scheme 1a) [6]. Later in 2013, Xue and Xiao et al. developed a method of photoredox catalysis in the presence of [Ru(bpy)3]2+ with visible light for the coupling reaction of arenes with unprotected or N-substituted pyrroles, pyrrole substrates were well tolerated with N-methyl and N-phenyl groups (Scheme 1a) [7]. Ackermann et al. employed a 2,5-dimethylpyrrole derivative as substrate to deliver double arylated products at 3,4-positions of the pyrrole ring (Scheme 1b) [8]. Recently, the research group of Kita documented an oxidative biaryl coupling for pyrroles using a hypervalent iodine reagent and a stabilizer for pyrrolyliodonium intermediates (Scheme 1c) [9]. The reactions readily provided a variety of desired coupling products in good yields. In general, the mechanism of these arylations was postulated by generating aryl radicals with diaryiodonium salts in the literature.

[1860-5397-14-23-i1]

Scheme 1: Arylations of pyrrole derivatives with diaryliodonium salts.

In 1995, Kitamura prepared phenyl[o-(trimethylsilyl)phenyl]iodonium triflate which could be used as an efficient benzyne precursor in trapping furans [10]. Surprisingly, the research groups of Stuart [11,12] and Wang [13] independently discovered in 2016 that simple diaryliodonium salts can generate benzynes under severe basic conditions, the resulted benzynes were allowed to undergo cycloaddition reaction with furan or N-arylation of secondary amides and amines. Due to the easy accessibility of the diaryliodonium salts, this kind of benzyne precursor is attracting extensive attention [14-16]. Also as a five-membered heterocyclic ring, the cycloaddition reaction of N-substituted pyrroles is much less than that of furan [17-21]. As a matter of fact, the Diels–Alder adduct formation of pyrroles with benzyne has been postulated in 1965 as transient products under thermal conditions to afford arylamines [22]. Inspired by the pioneering work of Stuart and Wang [12,13], herein we reported the usage of diaryliodonium salts as aryne precursor for Diels–Alder cycloadditions of N-arylpyrroles (Scheme 1d).

Results and Discussion

We initially started the cycloaddition reaction of 1-phenylpyrrole (1a) using phenyl(mesityl)iodonium tosylate (2a) as benzyne precursor. To our delight, with LiHMDS as the base in toluene, the Diels–Alder adduct 3aa was obtained in 23% yield at room temperature (Table 1, entry 1). However, when the reaction temperature was increased to 100 oC or the solvent was changed to THF, we found a slight decrease in the yield of 3aa (Table 1, entries 2 and 3). Interestingly, the reaction stoichiometry of 1a and 2a had a significant influence on the yield of 3aa, which was similar to Stuart’s work [11,12] (Table 1, entry 4–8). Further examinations of bases did not lead to better results (Table 1, entries 9–14). We then chose LiHMDS as the optimal base for the reaction. The reaction yield could be improved to 85% when an excess amount of LiHMDS was used (Table 1, entries 15–17). However, a screening of reaction temperature, solvent, and reaction time did not improve the yield of 3aa (Table 1, entries 18–21).

Table 1: Optimization of reaction conditions.a

[Graphic 1]
entry 1a/2a (equiv) base (equiv) solvent 3aa (%)b
1 1:1.2 LiHMDS (1.2) toluene 23
2c 1:1.2 LiHMDS (1.2) toluene 22
3 1:1.2 LiHMDS (1.2) THF 20
4 1:3 LiHMDS (3) toluene 40
5 3:1 LiHMDS (1) toluene 59
6 4:1 LiHMDS (1) toluene 73
7 5:1 LiHMDS (1) toluene 80
8 6:1 LiHMDS (1) toluene 74
9 5:1 KHMDS (1.5) toluene 68
10 5:1 KOt-Bu (1) toluene 60
11 5:1 NaNH2 (1) toluene 39
12 5:1 KOt-Bu (2) toluene 65
13 5:1 NaOMe (2) toluene 40
14 5:1 NaH (2) toluene n. r.
15 5:1 LiHMDS (1.2) toluene 79
16 5:1 LiHMDS (1.5) toluene 85
17 5:1 LiHMDS (2) toluene 74
18d 5:1 LiHMDS (1.5) toluene 70
19 5:1 LiHMDS (1.5) THF 73
20 5:1 LiHMDS (1.5) MeCN n. r.
21e 5:1 LiHMDS (1.5) toluene 73

aReaction conditions: 1a or 2a (0.5 mmol, 1 equiv), base (0.5–0.75 mmol, 1–1.5 equiv), solvent (5 mL), 0 °C to rt, 9 h. bIsolated yield. cThe reaction temperature was 100 °C. dThe reaction temperature was 80 °C. eThe reaction was quenched after 13 hours. n. r. = no reaction.

With the optimal reaction conditions in hand, various aryl(mesityl)iodonium salts 2 were examined. As shown in Table 2, an extensive range of substituted aryl(mesityl)iodonium salts, bearing a wide variety of substituent groups, could react with 1a to afford the corresponding cycloaddition adducts 3. It was observed that the reaction gave the desired products 3ab and 3ac in moderate yields of 63% and 57% when iodonium salts 2 have electron-donating groups in the para-position of the aryl moiety, such as methyl groups and tert-butyl groups (Table 2, entries 2 and 3). For those bearing electron-withdrawing groups, such as halogens (F, Cl, Br), cyano, nitro, trifluoromethyl, and trifluoromethoxy groups, the corresponding products 3ad3aj were obtained in good to excellent yields of 67–96% (Table 2, entries 4–10). It was found that the reactions underwent smoothly to give the products 3ak, 3al in good yields of 89% and 82%, respectively, when there was a phenyl group on the para- or ortho-positions of the aryl moiety for diaryliodonium salts (Table 2, entries 11 and 12). Analogous to previous work [11,12], when 2m and 2n were employed, the cycloaddition regioselectively afforded 3am and 3an in good yields of 80% and 71%, respectively (Table 2, entries 13 and 14). Of note, substituents at the ortho-position on the aryl moiety with 2, regardless of their electronic properties, had a negative effect on the reactivity (Table 2, entries 15–19).

Table 2: Scope of diaryliodonium salts 2.a

[Graphic 2]
entry aryl(mesityl)iodonium salts product yield (%)b
1 [Graphic 3]
2a
[Graphic 4]
3aa
85
2 [Graphic 5]
2b
[Graphic 6]
3ab
63
3 [Graphic 7]
2c
[Graphic 8]
3ac
57
4 [Graphic 9]
2d
[Graphic 10]
3ad
77
5 [Graphic 11]
2e
[Graphic 12]
3ae
87
6 [Graphic 13]
2f
[Graphic 14]
3af
96
7 [Graphic 15]
2g
[Graphic 16]
3ag
71
8 [Graphic 17]
2h
[Graphic 18]
3ah
67
9 [Graphic 19]
2i
[Graphic 20]
3ai
77
10 [Graphic 21]
2j
[Graphic 22]
3aj
88
11 [Graphic 23]
2k
[Graphic 24]
3ak
89
12 [Graphic 25]
2l
[Graphic 26]
3al
82
13 [Graphic 27]
2m
[Graphic 28]
3am
80
14 [Graphic 29]
2n
[Graphic 30]
3an
71
15 [Graphic 31]
2o
[Graphic 32]
3ao
78
16 [Graphic 33]
2p
[Graphic 34]
3ap
60
17 [Graphic 35]
2q
[Graphic 36]
3aq
48
18 [Graphic 37]
2r
[Graphic 38]
3ar
62
19 [Graphic 39]
2s
[Graphic 40]
3as
58

aReaction conditions: 1a (2.5 mmol, 5 equiv), 2 (0.5 mmol), LiHMDS (1 M in toluene, 0.75 mL, 1.5 equiv), toluene (5 mL), 0 °C to rt, 9 h. bIsolated yield. Mes = 2,4,6-trimethylphenyl, OTs = 4-toluenesulfonate, OTf = trifluoromethansulfonate.

To further probe the scope of this reaction, a wide range of 1-arylpyrroles 1 was employed in the reaction under the standard conditions. Generally, the conditions proved to be efficient for this Diels–Alder cycloaddition. As shown in Table 3, the electronic properties of aryl substituents had a little influence on the reaction outcome. For example, 1-phenylpyrrole with electron-donating groups (Me, t-Bu, OMe) gave 3ba3da in good yields of 62–83% (Table 3, entries 1–3). Meanwhile, 1-phenylpyrrole with electron-withdrawing groups (F, Cl, Br, CF3, OCF3, CN) also gave the corresponding products 3ea3ja in good to excellent yields of 71–93% (Table 3, entry 4–9). However, when R was biphenyl, the desired product 3ka was only obtained in moderate yield of 35%, probably due to the poor solubility of the starting materials (Table 3, entry 10). In contrast, when N-substituents (R) were Ts, Boc, Bn or methyl, no desired product was detected by thin layer chromatography (TLC) experiments (Table 3, entries 11–13). Interestingly, the method of Lautens works with an N-Boc pyrrole [21].

Table 3: Scope of N-substituted pyrroles 1.a

[Graphic 41]
entry R product yield (%)b
1 [Graphic 42]
1b
[Graphic 43]
3ba
77
2 [Graphic 44]
1c
[Graphic 45]
3ca
83
3 [Graphic 46]
1d
[Graphic 47]
3da
62
4 [Graphic 48]
1e
[Graphic 49]
3ea
82
5 [Graphic 50]
1f
[Graphic 51]
3fa
81
6 [Graphic 52]
1g
[Graphic 53]
3ga
71
7 [Graphic 54]
1h
[Graphic 55]
3ha
90
8 [Graphic 56]
1i
[Graphic 57]
3ia
83
9 [Graphic 58]
1j
[Graphic 59]
3ja
93
10 [Graphic 60]
1k
[Graphic 61]
3ka
35
11 [Graphic 62]
1l
[Graphic 63]
3la
0
12 [Graphic 64]
1m
[Graphic 65]
3ma
0
13 [Graphic 66]
1n
[Graphic 67]
3na
0

aReaction conditions: 1 (2.5 mmol, 5 equiv), 2a (0.5 mmol), LiHMDS (1 M in toluene, 0.75 mL, 1.5 equiv), toluene (5 mL), 0 °C to rt, 9 h. bIsolated yield. Mes = 2,4,6-trimethylphenyl. OTs = 4-toluenesulfonate.

To demonstrate the practical utility of this methodology, treatment of 3aa with 20 mol % TsOH·H2O in DCE at 80 °C resulted in N-phenylnaphthalen-1-ylamine (4) in 93% yield [23], which was widely used in dye-sensitized solar cells [24], hole transport materials [25,26] and organic light-emitting diodes (OLEDs, Scheme 2a) [27]. In another similar reaction with 3am, a novel N-phenylamine derivative 5 was synthesized in 75% yield (Scheme 2b), whose structure was determined by 2D-NMR analyses (see Supporting Information File 1). Furthermore, as a unique electron donor, the novel compound 5 may have potential applications in photosensitive dyes and OLEDs [28,29]. Interestingly, the bridged-ring compound 6 could be easily obtained in 63% yield with palladium on carbon catalyst under hydrogen atmosphere at room temperature (Scheme 3).

[1860-5397-14-23-i2]

Scheme 2: Formation of N-phenylamine derivatives 4 and 5 via ring opening reactions.

[1860-5397-14-23-i3]

Scheme 3: Preparation of product 6 by hydrogenation.

Conclusion

In summary, we have demonstrated a Diels–Alder cycloaddition of N-arylpyrroles by using diaryliodonium salts under mild conditions. The synthetic method was extended to a wide range of substrates. As such, various bridged-ring amines were prepared in moderate to excellent yields of 35–96%. Additionally, the resulting products could be easily converted to N-phenylamine derivatives and hydrogenated products in good yields. Further investigations on the application of this transformation are underway in our laboratory.

Supporting Information

Supporting Information File 1: Experimental procedures and characterization data of all products, copies of 1H, 13C, 19F NMR and HRMS spectra of all compounds.
Format: PDF Size: 4.4 MB Download

Acknowledgements

The work was supported by the National Nature Science Foundation of China (NSFC 21472213, 21272069), National Key Program (2016YFA0200302, Study on application and preparation of aroma nanocomposites), the Fundamental Research Funds for the Central Universities and Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences.

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