A fluorous ethylenediamine promoted direct C-H arylation of unactivated arenes with aryl halides

Article abstract of DOI:10.1016/j.jfluchem.2016.05.011

A novel and recyclable fluorous ethylenediamine was prepared. Together with potassium tert-butoxide, the fluorous ethylenediamine showed a good activity in promoting the coupling of aryl halides with benzene derivatives without the aid of transition-metal catalysts. Furthermore, a chain homolytic aromatic substitution mechanism was proposed in this paper.

Full text of DOI:10.1016/j.jfluchem.2016.05.011

Accepted Manuscript
Title: A fluorous ethylenediamine promoted direct C-H
arylation of unactivated arenes with aryl halides
Author: Yi-Wei Zhu Yi-Xin Shi
PII:
S0022-1139(16)30127-0
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2016.05.011
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24-5-2016
25-5-2016
Please cite thisarticle as: Yi-Wei Zhu, Yi-XinShi, A fluorous ethylenediamine promoted
direct C-H arylation of unactivated arenes with aryl halides, Journal of Fluorine
Chemistry http://dx.doi.org/10.1016/j.jfluchem.2016.05.011
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A fluorous ethylenediamine promoted direct C-H arylation
of unactivated arenes with aryl halides
Yi-Wei Zhu*, Yi-Xin Shi
School of Biology and Chemical Engineering, Anhui Polytechnic University, Wuhu,
Anhui 24100, People’s Republic of China
*Corresponding author. Fax: +86-553-2871254; Tel.: +86-553-2871254; E-mail:
yiwei.zhu@ahpu.edu.cn
1

Graphical Abstract
A novel and recyclable fluorous ethylenediamine was prepared. Together with potassium
tert-butoxide, the fluorous ethylenediamine showed a good activity in promoting the coupling of
aryl halides with benzene derivatives without the aid of transition-metal catalysts.
Highlights
・A novel and recyclable fluorous ethylenediamine was prepared.
・The organocatalyst could promote the coupling without the aid of transition metal.
・A chain homolytic aromatic substitution mechanism was proposed
Abstract
A novel and recyclable fluorous ethylenediamine was prepared. Together with
potassium tert-butoxide, the fluorous ethylenediamine showed a good activity in
promoting the coupling of aryl halides with benzene derivatives without the aid of
transition-metal catalysts. Furthermore, a chain homolytic aromatic substitution
mechanism was proposed in this paper.
Keywords: Fluorous ethylenediamine; Organocatalysis; Coupling; Transition metal
free; Green chemistry; Homolytic aromatic substitution.
1. Introduction
As is known to all, biaryl compounds are essential substructures in a variety of natural
2

products, drugs (Scheme 1), and ligands for cross-coupling reactions [1,2]. Among
various synthetic strategies, the recent emergence of transition metal catalyzed direct
arylation of aromatic C-H bonds provides a valuable and efficient alternative to the
conventional cross-coupling approach for the synthesis of biaryl compounds [3-7].
While mainstream developments are still focusing on transition metal
catalyzed/mediated processes, radical chemistry offers a valuable alternative to
transition metal based arylations. Years ago, there have been reports about syntheses
of biaryl compounds by using homolytic aromatic substitution (HAS) mediated by
Bu3SnH/2,2’-azobisisobutyronitrile (AIBN) or (Me3Si)3SiH [8-17]. Recently, an
attractive alternative to the C-H arylation of arenes by using base-promoted HAS
reactions appeared, and it avoids the use of tin, silicon reagents or any transition
metals. These transition-metal-free reactions involving the direct C-H arylation of
unactivated arenes through radical anion intermediates and utilizing organomolecules
[14-23]. These reactions have opened the door to a new approach to HAS (Scheme 2)
[24-37]. Very recently, our group became interested in single-electron transfer (SET)
systems, also inspired by idea of fluorous ponytail tag, by trial and error, we found a
novel fluorous ethylenediamine could smoothly promote the direct C-H arylation of
unactivated arenes with aryl halides through a chain HAS mechanism. To the best of
our knowledge, there is no example using any effective fluorous source to promote
the direct arylation of unactivated aromatic C-H bonds.
2. Results and discussion
Initially, we prepared a fluoruos ethylenediamine (L) with perfluorohexyl iodide and
ethylenediamine as initial components [38-40], the synthetic route showed in Scheme
3, this fluorous ethylenediamine has 3 CH2 spacers which show some
electron-donating character.
The coupling between 4-iodotoluene (1a) and unactivated benzene (2a) was selected
as model reaction for our investigations (Table 1). Treatment of 4-iodotoluene (1a, 1
equiv.) with KOt-Bu (5 equiv.) and the fluorous ethylenediamine L (3 equiv.) in
benzene (2a, 6 mL) at 120 oC for 24 h gave 4-methylbiphenyl (3a) in an encouraging
3

72% yield (Table 1, entry 5) [41]. The use of reduced amounts of ligand L resulted in
lower yields within the same reaction period (Table 1, entries 1 and 2), and we
obtained similar results if the reaction was conducted at lower temperature (Table 1,
entries 3 and 4). However, the ligand loading employed in the model reaction is
higher than that in some previous reports, maybe the fluorous ponytail affects (e.g.
solubility or structure). No coupling product was obtained in the reaction without
adding any ligand or using any base (Table 1, entries 6 and 7). By using benzene as
the solvent, L as ligand, reactions with the use of other bases, including K2CO3,
NaOt-Bu, KOH, and LiOt-Bu, were explored. Bases weaker than KOt-Bu were found
to be much less effective, and no coupling product was formed in these cases (Table 1,
entries 8-11). Interestingly, GC-MS analysis of the crude reaction mixture (Table 1,
entry 5) revealed the formation of biphenyl, but it was afforded in a very low yield.
The substract scope of the reaction promoted by the KOt-Bu/fluorous
ethylenediamine under the optimal conditions described above was explored
next. Several electronically and structurally diverse aryl iodides were
investigated. In general, aryl iodides of various electronic character reacted
with benzene to give desired products in moderate to high yields (Table 2,
entries 1, 4-14). Yields for the direct arylation of unactivated benzene with
electron-rich aryl iodides containing methyl, methoxy, and phenyl groups
(Table 2, entries 4-8) were moderate to good and higher than the yield obtained
with an electron-deficient substrate such as 4-iodobenzonitrile (Table 2, entry
13). The couplings of iodobenzene, bromobenzene, and chlorobenzene with
benzene were also studied (Table 2, entries 1-3), and it was found that
iodobenzene delivered 3b in good yield, bromobenzene afforded a low yield of
the product, and chlorobenzene gave almost none of the desired coupling
product. This might be because homolysis of the aryl C-Cl bond is more
difficult than that of the aryl C-I bond.
Subsequently, 1,4-diiodobenzene was employed as the substrate, and the reaction
generated p-terphenyl (3h) in 55% yield (Table 2, entry 9). Upon using
1-chloro-4-iodobenzene and 1-bromo-4-iodobenzene as substrates under the same
4

reaction conditions, 3h was obtained in 51 and 55% yield, respectively (Table 2,
entries 10 and 11). Other unactivated arenes were also examined (Table 2, entries
14-16); the results show that regioisomeric mixtures with high ortho ratios were
obtained. It was reported that in the HAS mechanism, if an aryl radical adds to an
arene with transfer of a hydrogen radical, substituents on benzene (no matter if they
are electron-donating or electron-withdrawing) accelerate the addition of the aryl
radical, especially to the ortho position.
In order to gather further insight into this direct arylation of benzene, two typical
radical scavengers, 2,2,6,6-tetramethylpiperidine N-oxide (TEMPO) and
1,1-diphenylethylene were employed in the model reaction (Scheme 4). Authentically,
the reactions were completely shut off. These results demonstrate that such a coupling
involves a radical reaction mechanism.
A plausible mechanism is shown in Scheme 5, such couplings go through a radical
pathway. As for the fluorous ligand, some reports support its role as precursors of
organic electron donor [42-44]. Aryl halide radical anion 4 is generated from aryl
halide 1a through a SET process with the assistance of fluorous ethylenediamine
L/KOt-Bu. Radical anion 4 is transformed into aryl radical 5, then radical 5 adds to
benzene to give cyclohexadienyl radical 6. In HAS reactions with aryl radicals, this
addition step, which gives relatively stable 6, is considered to be fast and irreversible.
Next, with the deprotonation of KOt-Bu, radical anion 7 is generated. A radical chain
transfer then occurs between 7 and 1a to form coupling product 3a with the
regeneration of radical anion 4.
3. Conclusions
In conclusion, we disclosed the direct C-H arylation of unactivated benzene
derivatives with aryl halides with the aid of recoverable fluorous ethylenediamine L
and potassium tert-butoxide. Reactions occurred through a base-promoted homolytic
aromatic substitution process and involved aryl radicals and aryl radical anions as
intermediates. Further studies on the mechanism and application to other reactions are
currently underway in our laboratory.
5

4. Experimental
4.1 General remarks
All of the reagents and solvents are commercially available and were used without
1
further purification. H NMR 13C NMR and 19F NMR were recorded on a Bruker
Avance 500 MHz or 300 MHz analyzer using tetramethylsilane (TMS) as the internal
standard. GC analyses were performed on an Agilent 7890A instrument (Column:
Agilent 19091J-413: 30 m ×320 mm × 0.25 mm, carrier gas: N2, Injector: 300 oC, FID
o
o
detection detector: initial temperature 80 C, temperature program: 15 C/min, final
temperature 325 oC. H2 30 mL/min, air 400 mL/min, N2 25 mL/min). GC-MS spectra
were taken on Trace DSQ (Finnigan). Mass spectra were recorded on a Saturn
2000GC/MS instrument. All the biaryl products are known compounds and were
identified by comparing of their physical and spectra data with those reported in the
literature.
4.2 General procedure for direct arylation of benzene with aryl halides:
A reaction tube was charged with KOt-Bu (280.0 mg, 2.5 mmol) at room temperature,
and then, 4-iodotoluene (109.0 mg, 0.5 mmol), fluorous ethylenediamine L (1170.0
mg, 1.5 mmol) and benzene (6.0 mL) were added. The resulting mixture was stirred at
120 oC for 24 h in this sealed tube equipped with a Teflon plug. After cooling to room
temperature, (the fluorous ligand can be recovered by extraction with
perfluorotoluene 5 mL × 3, 91% recovery yield ) the reaction mixture was quenched
and extracted with ethyl acetate (10 mL × 3). The organic layers were combined, dried
over Na2SO4 and concentrated under reduced pressure, and then purified by silica gel
chromatograph (petroleum ether) to yield the desired product as a white solid (52.9
mg, 63% yield).
N1,N2-bis(4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluorononyl)ethane-1,2-diamine (L) : 1H
13
NMR (500 MHz, CDCl3) δ: 2.73 (t, J = 10 Hz 8H), 2.16 (m, 4H), 1.79 (m, 4H); C
NMR (125 MHz, CDCl3) δ: 120.84-106.18 (m), 49.14 (s), 48.69 (s) , 28.67 (b) , 20.88
(b); 19F NMR δ: -80.85 (6F), -114.36 (4F), -121.99 (4F), -122.96 (4F), -123.56 (4F),
-126.21 (4F); MS (ESI+) m/z 781.11 (M+H).
6

Acknowledgments
This work was supported by the Key Project of Anhui Provincial Education
Department (KJ2014A014) and startup fund from AHPU (2014YQQ011).
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9

Scheme 1. Biaryl compounds with biological activity.
Scheme 2. Approaches for direct arylation reactions.
10

Scheme 3. Synthetic route of fluoruos ethylenediamine L.
Scheme 4. Radical trapping experiments.
Scheme 5. Possible mechanism of this reaction.
11

Table 1. Optimization of arylation reaction conditions.a
Ligand
Yield
(%)b
15
Entry
Base
T (oC)
(equiv.)
L (1)
L (2)
L (3)
L (3)
L (3)c
-
1
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
-
80
2
80
28
3
80
47
4
100
120
120
120
120
120
120
120
59
5
72 (63)
Trace
Trace
Trace
Trace
Trace
Trace
6
7
L (3)
L (3)
L (3)
L (3)
L (3)
8
K2CO3
NaOt-Bu
LiOt-Bu
KOH
9
10
11
b
aReaction conditions: 1a (0.5 mmol), base (5 equiv.), 2a (6.0 mL), 24 h. GC yield
(internal standard method); value in parentheses indicates the yield of the isolated
c
product. The fluorous ethylenediamine L could be easily recovered by phase
separation using perfluorotoluene (C7F8) with excellent purity (99%) and good
recover yield (91%).
12

Table 2. Direct arylation of arenes with aryl halides.a
Entry
1
Aryl halides
Arene
Product
3b
3b
3b
3e
Yieldb (%)
70 (62)
11
Ph-I (1b)
Benzene (2a)
2
Ph-Br (1c)
2a
3
Ph-Cl (1d)
2a
Trace
70 (64)
72 (63)
53
4
4-MeOC6H4-I (1e)
4-MeC6H4-I (1a)
3-MeC6H4-I (1f)
2-MeC6H4-I (1g)
4-PhC6H4-I (1h)
4-IC6H4-I (1i)
4-BrC6H4-I (1j)
4-ClC6H4-I (1k)
4-FC6H4-I (1l)
4-NCC6H4-I (1m)
4-MeC6H4-I (1a)
4-MeC6H4-I (1a)
4-MeC6H4-I (1a)
2a
5
2a
3a
6
2a
3f
7
2a
3g
19
8
2a
3h
3h
3h
3h
3l
58 (55)
55 (52)
51 (43)
55 (49)
51 (48)
50 (46)
33
9
2a
10
11
12
13
14c
15c
16c
2a
2a
2a
2a
3m
3r
Mesitylene
p-Xylene
Toluene
3s
61
3t
31d
o
aStandard reaction conditions: 1a (0.5 mmol), KOt-Bu (5 equiv.), L (3 equiv.), arene (6.0 mL), 120 C,
c
24 h. bGC yield based on 1 (internal standard method); values in parentheses indicate isolate yield. 1a
(0.5 mmol), KOt-Bu (6 equiv.), L (4 equiv.), arenes (100 equiv.), 130 oC, 48 h. dRatio of 2,4'-/3,4'-/4,4'-
= 76/11/13.
13