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

Article abstract of DOI:10.3762/bjoc.14.23

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.

Full text of DOI:10.3762/bjoc.14.23

Diels–Alder cycloadditions of N-arylpyrroles via aryne
intermediates using diaryliodonium salts
Huangguan Chen1, Jianwei Han*1,2 and Limin Wang*1
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 354–363.
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 and 2Shanghai–Hong Kong Joint Laboratory in Chemical
Synthesis, Shanghai Institute of Organic Chemistry, The Chinese
Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
doi:10.3762/bjoc.14.23
Received: 08 December 2017
Accepted: 26 January 2018
Published: 06 February 2018
This article is part of the Thematic Series "Hypervalent iodine chemistry in
organic synthesis".
Email:
Jianwei Han* - jianweihan@ecust.edu.cn; Limin Wang* -
wanglimin@ecust.edu.cn
Guest Editor: T. Wirth
* Corresponding author
© 2018 Chen et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
benzyne; cycloaddition; diaryliodonium salts; N-phenylamine; pyrrole
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 excel-
lent 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.
Introduction
Pyrrole is a very useful heterocyclic substrate to produce struc- (Scheme 1a) [6]. Later in 2013, Xue and Xiao et al. developed a
tural attributes of valuable chemicals, functional materials and method of photoredox catalysis in the presence of [Ru(bpy)3]2+
pharmaceuticals [1-5]. Recently, arylation of pyrrole deriva- with visible light for the coupling reaction of arenes with unpro-
tives with diaryliodonium salts for pyrrole–aryl coupling prod- tected or N-substituted pyrroles, pyrrole substrates were well
ucts is generating tremendous academic interest in organic syn- tolerated with N-methyl and N-phenyl groups (Scheme 1a) [7].
thesis. In 2012, the Zhang and Yu group reported that sodium Ackermann et al. employed a 2,5-dimethylpyrrole derivative as
hydroxide promoted direct arylation of unprotected pyrroles substrate to deliver double arylated products at 3,4-positions of
with diaryliodonium salts at the temperature of 80 °C, the cou- the pyrrole ring (Scheme 1b) [8]. Recently, the research group
pling products were obtained in moderate to good yields of Kita documented an oxidative biaryl coupling for pyrroles
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Beilstein J. Org. Chem. 2018, 14, 354–363.
Scheme 1: Arylations of pyrrole derivatives with diaryliodonium salts.
using a hypervalent iodine reagent and a stabilizer for pyrrolyl- Results and Discussion
iodonium intermediates (Scheme 1c) [9]. The reactions readily We initially started the cycloaddition reaction of 1-phenylpyr-
provided a variety of desired coupling products in good yields. role (1a) using phenyl(mesityl)iodonium tosylate (2a) as
In general, the mechanism of these arylations was postulated by benzyne precursor. To our delight, with LiHMDS as the base in
generating aryl radicals with diaryiodonium salts in the litera- toluene, the Diels–Alder adduct 3aa was obtained in 23% yield
ture.
at room temperature (Table 1, entry 1). However, when the
reaction temperature was increased to 100 oC or the solvent was
In 1995, Kitamura prepared phenyl[o-(trimethylsilyl)phenyl]io- changed to THF, we found a slight decrease in the yield of 3aa
donium triflate which could be used as an efficient benzyne pre- (Table 1, entries 2 and 3). Interestingly, the reaction stoichiome-
cursor in trapping furans [10]. Surprisingly, the research groups try of 1a and 2a had a significant influence on the yield of 3aa,
of Stuart [11,12] and Wang [13] independently discovered in which was similar to Stuart’s work [11,12] (Table 1, entry 4–8).
2016 that simple diaryliodonium salts can generate benzynes Further examinations of bases did not lead to better results
under severe basic conditions, the resulted benzynes were (Table 1, entries 9–14). We then chose LiHMDS as the optimal
allowed to undergo cycloaddition reaction with furan or N-aryl- base for the reaction. The reaction yield could be improved to
ation of secondary amides and amines. Due to the easy accessi- 85% when an excess amount of LiHMDS was used (Table 1,
bility of the diaryliodonium salts, this kind of benzyne precur- entries 15–17). However, a screening of reaction temperature,
sor is attracting extensive attention [14-16]. Also as a five- solvent, and reaction time did not improve the yield of 3aa
membered heterocyclic ring, the cycloaddition reaction of (Table 1, entries 18–21).
N-substituted pyrroles is much less than that of furan [17-21].
As a matter of fact, the Diels–Alder adduct formation of With the optimal reaction conditions in hand, various
pyrroles with benzyne has been postulated in 1965 as transient aryl(mesityl)iodonium salts 2 were examined. As shown in
products under thermal conditions to afford arylamines [22]. Table 2, an extensive range of substituted aryl(mesityl)iodoni-
Inspired by the pioneering work of Stuart and Wang [12,13], um salts, bearing a wide variety of substituent groups, could
herein we reported the usage of diaryliodonium salts as aryne react with 1a to afford the corresponding cycloaddition adducts
precursor for Diels–Alder cycloadditions of N-arylpyrroles 3. It was observed that the reaction gave the desired products
(Scheme 1d).
3ab and 3ac in moderate yields of 63% and 57% when iodoni-
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Beilstein J. Org. Chem. 2018, 14, 354–363.
Table 1: Optimization of reaction conditions.a
entry
1a/2a (equiv)
base (equiv)
solvent
3aa (%)b
1
1:1.2
1:1.2
1:1.2
1:3
3:1
4:1
5:1
6:1
5:1
5:1
5:1
5:1
5:1
5:1
5:1
5:1
5:1
5:1
5:1
5:1
5:1
LiHMDS (1.2)
LiHMDS (1.2)
LiHMDS (1.2)
LiHMDS (3)
LiHMDS (1)
LiHMDS (1)
LiHMDS (1)
LiHMDS (1)
KHMDS (1.5)
KOt-Bu (1)
toluene
toluene
THF
23
22
20
40
59
73
80
74
68
60
39
65
40
n. r.
79
85
74
70
73
n. r.
73
2c
3
4
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
5
6
7
8
9
10
11
12
13
14
15
16
17
18d
19
20
21e
NaNH2 (1)
KOt-Bu (2)
NaOMe (2)
NaH (2)
LiHMDS (1.2)
LiHMDS (1.5)
LiHMDS (2)
LiHMDS (1.5)
LiHMDS (1.5)
LiHMDS (1.5)
LiHMDS (1.5)
MeCN
toluene
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.
um salts 2 have electron-donating groups in the para-position of To further probe the scope of this reaction, a wide range of
the aryl moiety, such as methyl groups and tert-butyl groups 1-arylpyrroles 1 was employed in the reaction under the stan-
(Table 2, entries 2 and 3). For those bearing electron-with- dard conditions. Generally, the conditions proved to be effi-
drawing groups, such as halogens (F, Cl, Br), cyano, nitro, tri- cient for this Diels–Alder cycloaddition. As shown in Table 3,
fluoromethyl, and trifluoromethoxy groups, the corresponding the electronic properties of aryl substituents had a little influ-
products 3ad–3aj were obtained in good to excellent yields of ence on the reaction outcome. For example, 1-phenylpyrrole
67–96% (Table 2, entries 4–10). It was found that the reactions with electron-donating groups (Me, t-Bu, OMe) gave 3ba–3da
underwent smoothly to give the products 3ak, 3al in good in good yields of 62–83% (Table 3, entries 1–3). Meanwhile,
yields of 89% and 82%, respectively, when there was a phenyl 1-phenylpyrrole with electron-withdrawing groups (F, Cl, Br,
group on the para- or ortho-positions of the aryl moiety for CF3, OCF3, CN) also gave the corresponding products 3ea–3ja
diaryliodonium salts (Table 2, entries 11 and 12). Analogous to in good to excellent yields of 71–93% (Table 3, entry 4–9).
previous work [11,12], when 2m and 2n were employed, the However, when R was biphenyl, the desired product 3ka was
cycloaddition regioselectively afforded 3am and 3an in only obtained in moderate yield of 35%, probably due to the
good yields of 80% and 71%, respectively (Table 2, entries poor solubility of the starting materials (Table 3, entry 10). In
13 and 14). Of note, substituents at the ortho-position contrast, when N-substituents (R) were Ts, Boc, Bn or methyl,
on the aryl moiety with 2, regardless of their electronic proper- no desired product was detected by thin layer chromatography
ties, had a negative effect on the reactivity (Table 2, entries (TLC) experiments (Table 3, entries 11–13). Interestingly, the
15–19).
method of Lautens works with an N-Boc pyrrole [21].
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Beilstein J. Org. Chem. 2018, 14, 354–363.
Table 2: Scope of diaryliodonium salts 2.a
entry
aryl(mesityl)iodonium salts
product
yield (%)b
1
85
2a
2b
3aa
3ab
3ac
3ad
3ae
3af
2
3
4
5
6
7
63
57
77
87
96
71
2c
2d
2e
2f
2g
3ag
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Table 2: Scope of diaryliodonium salts 2.a (continued)
8
67
77
88
89
2h
3ah
3ai
9
2i
10
2j
3aj
11
2k
3ak
12
82
2l
3al
13
80
71
2m
3am
3an
14
2n
15
78
2o
3ao
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Beilstein J. Org. Chem. 2018, 14, 354–363.
Table 2: Scope of diaryliodonium salts 2.a (continued)
16
60
2p
3ap
17
48
2q
3aq
3ar
3as
18
62
58
2r
19
2s
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.
Table 3: Scope of N-substituted pyrroles 1.a
entry
R
product
yield (%)b
1
77
1b
3ba
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Table 3: Scope of N-substituted pyrroles 1.a (continued)
2
83
1c
3ca
3
62
1d
3da
3ea
3fa
4
82
1e
5
81
1f
6
71
90
83
360
1g
3ga
3ha
3ia
7
1h
8
1i

Beilstein J. Org. Chem. 2018, 14, 354–363.
Table 3: Scope of N-substituted pyrroles 1.a (continued)
9
93
1j
3ja
10
35
1k
3ka
11
0
0
0
1l
3la
12
1m
3ma
13
1n
3na
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, treat- bon catalyst under hydrogen atmosphere at room temperature
ment of 3aa with 20 mol % TsOH·H2O in DCE at 80 °C (Scheme 3).
resulted in N-phenylnaphthalen-1-ylamine (4) in 93% yield
[23], which was widely used in dye-sensitized solar cells [24], Conclusion
hole transport materials [25,26] and organic light-emitting In summary, we have demonstrated a Diels–Alder cycloaddi-
diodes (OLEDs, Scheme 2a) [27]. In another similar reaction tion of N-arylpyrroles by using diaryliodonium salts under mild
with 3am, a novel N-phenylamine derivative 5 was synthesized conditions. The synthetic method was extended to a wide range
in 75% yield (Scheme 2b), whose structure was determined by of substrates. As such, various bridged-ring amines were pre-
2D-NMR analyses (see Supporting Information File 1). Further- pared in moderate to excellent yields of 35–96%. Additionally,
more, as a unique electron donor, the novel compound 5 the resulting products could be easily converted to N-phenyl-
may have potential applications in photosensitive dyes and amine derivatives and hydrogenated products in good yields.
OLEDs [28,29]. Interestingly, the bridged-ring compound 6 Further investigations on the application of this transformation
could be easily obtained in 63% yield with palladium on car- are underway in our laboratory.
361

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