Urea-based organocatalyst catalyzed direct C–H bond arylations of unactivated arenes

Article abstract of DOI:10.1016/j.catcom.2018.04.008

A simple 1,3-diethylurea was demonstrated to catalyze transition-metal-free arylations of unactivated aromatic C–H bonds with aryl iodides in the presence of t-BuOK. A broad range of aryl iodides with different arenes could couple in moderate to excellent yields. The mechanistic experiment results indicated that the radical is involved in this transformation.

Full text of DOI:10.1016/j.catcom.2018.04.008

Accepted Manuscript
Urea-based organocatalyst catalyzed direct C-H bond arylations
of unactivated arenes
Huaiqing Zhao, Xiangwen Xu, Wei Wu, Wei Zhang, Yunxian
Zhang
PII:
S1566-7367(18)30138-9
doi:10.1016/j.catcom.2018.04.008
CATCOM 5381
DOI:
Reference:
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Catalysis Communications
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Accepted date:
27 February 2018
7 April 2018
9 April 2018
Please cite this article as: Huaiqing Zhao, Xiangwen Xu, Wei Wu, Wei Zhang, Yunxian
Zhang , Urea-based organocatalyst catalyzed direct C-H bond arylations of unactivated
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ACCEPTED MANUSCRIPT
Urea-based organocatalyst catalyzed direct C-H bond arylations of unactivated arenes
*
Huaiqing Zhao , Xiangwen Xu, Wei Wu, Wei Zhang and Yunxian Zhang
Key Laboratory of Interfacial Reaction & Sensing Analysis in Universities of
Shandong, School of Chemistry and Chemical Engineering, University of Jinan, Jinan,
Shandong, 250022, P. R. China
E-mail: chm_zhaohq@ujn.edu.cn
Abstract

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A simple 1,3-diethylurea was demonstrated to catalyze transition-metal-free arylations
of unactivated aromatic C−H bonds with aryl iodides in the presence of t-BuOK. A
broad range of aryl iodides with different arenes could couple in moderate to excellent
yields. The mechanistic experiment results indicated that the radical is involved in this
transformation.
Keywords: 1,3-Diethylurea, Transition-metal-free, Arylation, Organocatalyst
1
. Introduction
Direct C−H arylation is an important and efficient strategy to constructing

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biaryl moiety which is a ubiquitous scaffold in the synthesis of natural products,
pharmaceuticals, agrochemicals and functional materials (Figure 1 Valsartan (I)
and liquid-crystalline NCB807 (II)) [1-4]. Exploring efficient methods to directly
synthesize the privileged biaryl structures has been a topic of great importance in
organic synthesis and attracted more and more attentions from chemists. Over the
past decades, transition-metal-catalyzed C−H arylation has provided a vital
solution to construct biaryl moieties.[5-7] Despite making more progress, these
methods usually require the precious transition metals as catalysts and often lead
to undesired side-products and transition metal impurities in final products. As a
green and friendly alternative to transition-metal catalysts, organocatalysts have
come into insight of synthetic chemists, offering a strategic protocol to assemble
various biaryl molecules. [8-10] Until now various organic compounds such as
N,N′-dimethylethane-1,2-diamine,[11] phenanthroline,[12] N-Methylanilines,[13]
imidazolium salt [14] and amino acid [15] have successfully been utilized to
promote the cross-coupling between aryl halides and unactivated arenes. And
there are some elegant works accomplished to elucidate the mechanism of this
transformation. [16-18] Organocatalysts promoted C−H arylation has widely been
comprehended as the base-promoted homolytic aromatic substitution (BHAS)
reaction. In this transformation, organocatalysts generally interact with t-BuOK or
t-BuONa to trigger the aryl radicals via the single-electron transfer (SET) that
subsequently undergo the direct arylation of unactivated arenes.[11-18]
Figure 1. Valsartan (I) and liquid-crystalline NCB807 (II)
Urea serves an important role in the metabolism of nitrogen-containing
compounds by animals and humankinds, and also plays a vital role in chemistry.
As a traditional example of urea application in chemistry, it is a raw material for

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the manufacture of two main types of materials: urea-formaldehyde resins and
urea-melamine-formaldehyde.[19] In organic chemistry, it has emerged as
asymmetric catalyst executing through hydrogen-bond interactions.[20- 23] Until
now there has been no related work reported utilizing urea catalyzed C−H
arylations. We have developed the macrocylic and acyclic folded pyridone-based
compounds catalyzed C−H arylations of arenes.[24, 25] These catalysts were
constituted with the formation of amide bond. The related research revealed that
the structural molecules could be deprotonated to afford the corresponding organic
electron donors in the presence of t-BuOK. Based on this consideration, we
believe that urea possessing the similar amide substructure and the ability to
forming organic electron donors could also catalyze C−H bond arylation under
similar conditions.
With the consideration in mind, we selected the cross-coupling reaction
between 4-iodoanisole (1a) and benzene (2a) as a model reaction for assessing the
catalytic capacity of various urea-based catalysts using the simple conditions
involving t-BuOK (3 equiv.) as a base at 120 °C for 24 h. Firstly, a control
experiment was carried out in the absence of organocatalysts and generated the
desired cross-coupling product with only 3% isolated yield (Table 1, entry 1).
Then a series of urea-based molecules bearing different substitutes (Scheme 1,
U1-U7) was respectively utilized to the system as a catalyst and consistently
afforded the arylation product 3a (entries 2-8). A loading 5 mol % of
1
,3-diethylurea (U6) comparing with other urea could furnish a higher yield of 76%
(entry 7). These results indicated that urea-based molecules are efficient to the
C−H bond arylation under this condition. Subsequently, increasing the amount of
catalysts to 10 mol % in this system could result in higher yields (entries 9-15).
We found that all organocatalysts could improve the yield of 3a and U6 could
afford a better yield of 94% (entry 14). We assigned this simple and commercial
urea structure U6 as a catalyst and then investigated the effects of reaction
temperature and base on the catalytic system. The experimental results indicated
that this reaction using U6 as a catalyst is sensitive to temperature (entries 16, 17).

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Other strong bases were examined and only t-BuOK was efficacious in C-H bond
arylations under this system (entries 19-21).
Table 1.
Optimization of arylation conditions.
a
o
Entry
Cat. (equiv)
-
Base (equiv)
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (2.5)
t-BuONa (3.0)
NaOH (3.0)
Temp. ( C)
Yield (%)
1
2
3
4
5
6
7
8
9
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
130
100
120
120
120
120
3
U1 (0.05)
U2 (0.05)
U3 (0.05)
U4 (0.05)
U5 (0.05)
U6 (0.05)
U7 (0.05)
U1 (0.1)
U2 (0.1)
U3 (0.1)
U4 (0.1)
U5 (0.1)
U6 (0.1)
U7 (0.1)
U6 (0.1)
U6 (0.1)
U6 (0.1)
U6 (0.1)
U6 (0.1)
U6 (0.1)
8
10
33
35
70
76
55
59
41
57
57
84
94
76
88
12
86
0
1
1
1
1
1
1
1
1
1
1
2
2
0
1
2
3
4
5
6
7
8
9
0
0
1
KOH (3.0)
0
a
Reaction conditions: 4-iodoanisole (0.2 mmol), benzene (2 mL), base and catalyst
in a sealed Schlenk tube, 24 h, N , isolated yield.
2

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Scheme 1. Cross-coupling reaction of 4-iodoanisole and benzene; structures of ureas
(U1-U7).
With the optimized conditions in hand (Table 1, entry 14), we surveyed a series of
aryl halides to evaluate the efficacy of the established protocol using U6 as a catalyst.
As summarized in Table 2, aryl iodides bearing the electron-donating group such as a
methoxyl group at different positions afforded the cross-coupling products with yields
ranging from 51% to 94% (Table 2, entries 1-3). Notably, in the case of 3-iodoanisole
1
b, a lower yield of the corresponding product was found, no matter which conditions
was modified (entry 2). In order to explore what the reaction yielded in this catalytic
system, the crude products of 3-iodoanisole coupled with benzenes were analyzed and
a byproduct of tert-butoxy-3-methoxybenzene was detected by the aid of
GC-Mass.[17] To our delight, unsubstituted iodobenzene proved to be a highly
reactive partner and smoothly underwent in an excellent yield (entry 4). Iodobenzenes
installing one or two methyl groups at different positions could also furnish the
desired products with good yields (entries 5-7). The coupled arylation products was
also generated from 4-fluoroiodobenzene, meanwhile, a small amount of p-terphenyl
was formed under this catalytic system (Table 2, entry 8). It was notable that
1
4
-chloro-4-iodobenzene as a partner delivered p-terphenyl as a main product (entry 9).
-Iodobenzonitrile bearing an electron-withdrawing group produced the
corresponding arylation product in only 42% yield (entry 10), a side-product of
-tert-butoxybenzonitrile was observed in this reaction. [17] Heterocyclic iodides
were utilized to this transformation and afforded the desired products in moderate to
4

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good yields (entries 11-14). At first, iodopyridines used as substrates furnished the
desired products with lower yields and provided pyridine as a side-product under
o
optimized conditions. Then we found that reducing the reaction temperature to 110 C
could achieve the better yields (entries 12-14). However, the 3-iodo- and
4
-iodopyridines still produced the corresponding products with moderate yields
entries 13, 14). The reason may be that the intermediate radical generated from
-iodopyridine would be stabilized by a neighboring nitrogen atom to achieve the
(
2
good reaction. But this effect does not exist in 3-iodo- and 4-iodopyridines.[15]
Disappointingly, bromo/chlorobenzene could not react with benzene under established
conditions (entries 15, 16).
Table 2
a
Direct arylation reactions of benzene with aryl halides.

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a
Reaction conditions: Ar-I (0.2 mmol), benzene (2 mL), t-BuOK (3 equiv.), U6 (10

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o
mol%) in a sealed Schlenk tube, 24 h, N2, 120 C, isolated yield.
b
c
d
1
2
5 mol% U6 was used.
4% p-terphenyl was isolated.
o
Reaction temperature: 110 C.
The urea-based catalytic approach for C−H bond arylation was further applied to
various arenes. According to the previous reported results, increasing the reaction
temperature and time could improve the reactivity of arenes in this
transformamtion.[12] In view of the reactivity of different arenes, we adjusted the
reaction temperature and obtained the better results. As depicted in Table 3, arenes
bearing either electron-donating or -withdrawing groups such as methyl, methoxy and
cyano substituents could react with 4-iodoanisole and furnish a mixture of
regioisomers in which the ratio of ortho-isomers is always dominated (Table 3, entries
1
-4). Notably, electron-deficient heteroarenes could smoothly occur with good yields
under the catalytic system (entries 5, 6). Satisfactorily, apart from the arylation
reactions of 4-iodoanisole, the Mizoroki-Heck-type reaction between 4-iodoanisole
and styrene was successfully carried out to generate corresponding product 3u in 74%
isolated yield by employing U6 as a catalyst (entry 7).
Table 3
a
Coupling reactions of 4-iodoanisole with arenes and styene.

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a
Reaction conditions: 1a (0.2 mmol), arenes (2 mL), t-BuOK (3 equiv.), U6 (10
o
mol %) in a sealed Schlenk tube, 24 h, N2, 150 C, isolated yield.
b
c
d
e
Ratio of products determined by NMR analysis.
o
Reaction temperature: 120 C.
o
Reaction temperature: 130 C.
Reaction conditions: 1a (0.2 mmol), styrene (5 equiv.), t-BuOK (3 equiv.), U6 (10
o
mol %), DMF (2 mL) in a sealed Schlenk tube, 120 C, 2 h, N2, isolated yield.
In order to comprehend the mechanism of U6 catalyzed C−H arylation reaction,
several related experiments were carried out. Addition of one equivalent of TEMPO
(2,2,6,6-tetramethylpiperidine-1-oxyl), a well-known radical scavenger into this
catalytic system completely shut down the reaction, no desired product was
observed. The experiment results demonstrated that U6 catalyzed C−H arylation
reaction involving a radical process. A kinetic isotope experiment involving a
mixture of benzene and D6-benzene reacting with 1a were conducted. The kinetic
isotope effect of 1.05 clearly indicated that the cleavage of the aromatic C–H bond

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is not the rate-determining step in the arylation reaction.
Based on the above experiments and the related reports published previously, [8,
11-18, 26-29] the U6 catalyzed arylation was proposed to undergo a radical process
as shown in Scheme 2. In this catalytic cycle, urea U6 firstly reacts with potassium
tert-butoxide to deliver the organic electron donor. Then aryl halide receives one
electron from the organic electron donor intermediate to produce aryl radical anion
I, and subsequently the cleavage of C−I bond forms the aryl radical II. The
generated aryl radical adds to benzene to yield an intermediate cyclohexadienyl
radical which is deprotonated by potassium tert-butoxide to furnish the biaryl
radical anion. This species transfers one electron to another aryl halide molecule,
propagating the catalytic cycle, and simultaneously liberating biaryl product.
Scheme 2. A proposed Catalytic Cycle.
2
. General procedure for the arylation of arenes.
Aryl iodides (0.2 mmol) t-BuOK (0.6 mmol, 3.0 equiv), and U6 (0.02 mmol, 10
mol %) were added in dried Schlenk tubes. Benzene (2 mL) were added into tubes
by syringe. The septum-sealed tube was evacuated and refilled with nitrogen three
times. The mixture was stirred under a nitrogen atmosphere in sealed Schlenk tubes
at 120 °C for 24 h. The reaction was cooled down to room temperature. The mixture
was filtered through a short plug of silica gel, washed with a copious amount of
ethyl acetate. The combined organic phase was concentrated under vacuum. The
product was purified through flash column chromatography on 300 -400 mesh silica
gel with hexane/ethyl acetate as eluent. Solvent was removed under vacuum to give

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the pure product.
3
. Conclusion
In summary, we here demonstrate a simple 1,3-diethylurea organocatalyst for the
construction of various biaryls using direct arylation of unactivated arenes with
aromatic halides in the presence of potassium tert-butoxide. This approach is
applicable to a range of aromatic iodides with different arenes with 10% loading of
U6 in moderate to good yields. The significant advantage of this new methodology
lies in the simple structure and easy source of the urea organocatalyst and the
broadening scope of urea’s application. We hope that urea-based organocatalyst
may be utilized to synthesize pharmaceutically important biaryl scaffold in the
foreseeable future.
Acknowledgements
Financial support from Shandong Provincial Natural Science Foundation, China
(ZR2016JL009), National Natural Science Foundation of China (21302184) and
University of Jinan is greatly appreciated.
Appendix A. Supplementary data
Available: Experimental procedures and characterization data for all compounds.
Supplementary data associated with this article can be found in the online version, at
https:
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Graphical abstract
Table of Contents Entry
A 1,3-diethylurea catalyzed transition-metal-free arylations of unactivated aromatic
C−H bonds with aryl iodides in the presence of t-BuOK.

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Highlights



A 1,3-Diethylurea was first utilized to catalyze C−H arylation of unactivated
arenes.
A broad range of aryl iodides with arenes could couple using 1,3-diethylurea as a
catalyst.
The mechanistic experiments indicated that the radical is involved in this
transformation.