Metal-free arylation of benzene and pyridine promoted by amino-linked nitrogen heterocyclic carbenes

Article abstract of DOI:10.1039/c2cc32519e

An amino-linked nitrogen heterocyclic carbene (amino-NHC), 1-tBu, has been shown to mediate carbon-carbon coupling through the direct C-H functionalization of benzene and pyridine in the absence of a metal catalyst. Using EPR, the first spectroscopic evidence corroborating the single electron transfer mechanism for the metal-free carbon-carbon coupling manifold, as reported by others, is introduced.

Full text of DOI:10.1039/c2cc32519e

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2012, 48, 6702–6704
www.rsc.org/chemcomm
COMMUNICATION
Metal-free arylation of benzene and pyridine promoted by amino-linked
nitrogen heterocyclic carbenesw
Wen-Ching Chen,a Yu-Chen Hsu,ab Wei-Chun Shih,a Ching-Yu Lee,ac Wen-Han Chuang,ad
Yi-Fang Tsai,a Peter Ping-Yu Chen*e and Tiow-Gan Ong*a
Received 8th April 2012, Accepted 8th May 2012
DOI: 10.1039/c2cc32519e
An amino-linked nitrogen heterocyclic carbene (amino-NHC),
1-tBu, has been shown to mediate carbon–carbon coupling through
the direct C–H functionalization of benzene and pyridine in the
absence of a metal catalyst. Using EPR, the first spectroscopic
evidence corroborating the single electron transfer mechanism for
the metal-free carbon–carbon coupling manifold, as reported by
others, is introduced.
be beneficial towards initiating exploration of other catalytic
manifolds, as the steric, electronic and structural features of
NHCs may be modified with ease for reaction diversification.
Herein, we wish to report an amino-linked nitrogen heterocyclic
carbene (amino-NHC), 1-tBu,11 that mediates a carbon–carbon
coupling manifold through the direct C–H functionalization of
benzene and pyridine.
The direct arylation of benzene with 4-iodotoluene, 2a, was
selected as a starting point for our investigations (Scheme 1),
using 20 mol% amino-NHC in the presence of 3 equiv. KOtBu
at 80 1C. The desired cross-coupling product, 3a, was obtained
in good yield (78%) with 1-tBu, but lower yield (11%) with the
pyridine NHC derivative, Py-IMes. Monitoring the reaction
mixture closely by NMR spectroscopy revealed that 1-tBu
remained intact after the catalytic reaction. Moreover, a
similarly good catalytic yield could also be achieved using
the much more robust imidazolium salt 1-tBu-Im without
preparing the moisture-sensitive free carbene.
Organocatalysts offer an economical and greener platform for
mediating organic transformations as they exclude the use of
highly toxic and expensive metallic catalysts.1 Recent break-
throughs led by Kwong–Lei,2 Shirakawa–Hayashi,3 Shi,4 Itami,5
Jiang,6 and Li–Jiang7 have propelled organic catalysis into the
realm of aryl–aryl cross-coupling via C–H bond functionalization
of arenes,8 an area that has been predominantly monopolized by
transition-metal chemistry for decades. As a result, numerous
reports related to metal-free cross-coupling manifolds have
gradually appeared, demonstrating rich opportunities and
hidden potentials for synthetic utility. Yet, the exact formalism
with regards to the claim of ‘‘organocatalytic C–H bond
activation reaction’’ remains debatable due to the lack of direct
experimental evidence. Nonetheless, it is broadly accepted that
the coupling process is initiated by base-promoted homolytic
radical aromatic substitution (HAS).9
Prior to investigating the cross-coupling arylation reactions,
several control experiments were completed to remove the
possibility that metal impurities may be responsible for the
coupling reaction. First, the quality of KOtBu, obtained from
several commercially available sources, does not affect the rate
of reaction to a great extent. We also took the extreme step of
running the experiments in new glassware with ultra-pure
KOtBu, produced via sublimation, to reproducibly confirm
this methodology. Spiking the reaction with 10 mol% of
transition-metal salts, such as Fe(OAc)2, PdCl2 and CuBr, only
diminished the efficiency of the process, further demonstrating the
metal-free conditions. The importance of the NHC structure was
N-Heterocyclic carbenes (NHCs) have proven to be efficient
metal-free catalysts for a wide variety of key organic reactions
through Lewis acid–base-interactions.10 In this context, the
use of NHCs as organic catalysts for aryl–aryl cross-coupling
reactions via HAS constitutes an almost unexplored field.
Thus, expanding such a proof of concept using NHCs would
a Institute of Chemistry, Academia Sinica, Nangang, Taipei, Taiwan,
Republic of China. E-mail: tgong@chem.sinica.edu.tw
b Institute of Organic and Polymeric Materials, National Taipei
University of Technology, Taipei, Taiwan,
Republic of China
c Taipei Municipal University of Education, Taiwan,
Republic of China
d Department of Chemistry, Tamkang University, Taiwan,
Republic of China
e Department of Chemistry, National Chung Hsing University,
Taiwan, Republic of China
w Electronic supplementary information (ESI) available: Syntheses of
3 and 4 with characterization data. EPR spectrum of the mixture 5 and
18-crown-6 in toluene. See DOI: 10.1039/c2cc32519e
Scheme 1 Optimization of direct arylation of benzene. The reaction was
performed under a nitrogen atmosphere using 2a (0.5 mmol), base
(1.5 mmol) and benzene (4 mL) in a sealed tube. Yield determined by GC.
c
6702 Chem. Commun., 2012, 48, 6702–6704
This journal is The Royal Society of Chemistry 2012

View Article Online
Table 1 Amino-NHC-catalyzed direct arylation of benzene with
various Ar–Ia
Table 2 Imidazolium salt-catalyzed direct arylation of pyridine with
various Ar–Ia
Yieldb (%)
(o/m/p)c
Entry
Ar-group
Product 3
Yieldb (%)
Entry
Ar-group
Product 4
1
2
3
4
5
6
7
8
9
10
4-MeC6H4
3-MeC6H4
2-MeC6H4
4-MeOC6H4
3-MeOC6H4
2-MeOC6H4
4-CNC6H4
3-Pyridyl
2a
2b
2c
2d
2e
2f
2g
2h
2i
3a
3b
3c
3d
3e
3f
3g
3h
3i
73
54
1
2
3
4
5
6
7
8
4-MeC6H4
3-MeC6H4
2-MeC6H4
4-MeOC6H4
3-MeOC6H4
2-MeOC6H4
4-CNC6H4
3-Pyridyl
2a
2b
2c
2d
2e
2f
2g
2h
2i
4a
4b
4c
4d
4e
4f
4g
4h
4i
84
78
40d
87
70
60d
53
50
46
67
33e
77
(2.5/2.1/1)
(2.8/2.3/1)
(2.5/1.4/1)
(3.4/2.8/1)
(3.4/2.7/1)
(2.4/2.7/1)
—
(3.2/1.9/1)
(2.3/1.5/1)
(3.1/2.2/1)
(3/3/1)
39c
75d
62d
50c
59
47d
44
2-Pyridyl
1-Naphthyl
9
2-Pyridyl
2j
3j
41 (45e)
10
11
12
1-Naphthyl
4-CF3C6H4
4-FC6H4
2j
2k
2l
4j
4k
4l
a
The reaction was carried out under a nitrogen atmosphere using 2
(0.5 mmol), KOtBu (1.5 mmol) and benzene (4 mL) in a sealed tube.
(3.2/3.1/1)
b
c
Isolated yield based on 2. Reaction time was 24 h. Reaction time
d
a
The reaction was carried out under a nitrogen atmosphere using 2
(0.5 mmol), NaOtBu (1.5 mmol) and pyridine (4 mL) in a sealed tube.
was 3 h. KHMDS was used instead of KOtBu.
e
b
c
d
Isolated yield based on 2. Determined by 1H NMR. Reaction
e
time was 24 h. Reaction time was 48 h.
also probed early-on. Replacement of 1-tBu with monodentate
NHCs, namely IMes and IPr, furnished only disappointing
outcomes, illustrating the importance of the two binding sites
within the architectural framework in this process.12
furnished a satisfactory yield, yet low yields were observed for the
CF3 derivative, 2k, (entry 11). Finally, naphthyl and 3-pyridyl
iodides also underwent a smooth transformation to give
coupling products 4j and 4h. Amongst these organic-mediated
cross-coupling reactions via aryl C–H bond activation, there
exists to date only one report involving the coupling of
pyridine with aryl iodide using KOtBu in DMF solvent, albeit
producing lower yields.5
With the optimized conditions in hand, additional aryl
iodide-derived substrates were also examined in order to
expand the generality of this arylation (Table 1). Good yields
of the coupling products were observed for electron-rich aryl
iodides 4-iodotoluene, 2a, (entry 1) and 4-iodoanisole, 2d,
(entry 4) (B75% yield). As expected, the more sterically
demanding ortho substrates 2-iodotoluene, 2c, (entry 3) and
2-iodoanisole, 2f, (entry 6) gave slightly lower yields of coupling
products, in the range of 50%. Aryl iodides containing electron-
withdrawing groups, such as 4-iodobenzonitrile, 2g, also partici-
pated smoothly in the catalytic reaction, producing an average
yield of 59% (entry 7). However, diminishing yields were witnessed
for 3-pyridyl (47%), 2-pyridyl (44%) and 1-naphthyl (41%)
derivatives (entries 8–10), suggesting sensitivity toward strong
deactivators. In general, the overall catalytic efficiency of benzene
cross-coupling mediated by amino-NHCs is somewhat lower than
previous reports using phenanthroline derivatives,2–7 but we have
established the viability of the NHC concept for the first time in
this process.
In order to understand the role played by amino-NHC in
these reactions, several experiments were performed. First,
competition experiments revealed small kinetic isotope effects
(KIE) for benzene (1.05) as well as pyridine (1.22–1.67)
(Scheme 2), indicating that the C–H bond-breaking step is
not the rate-limiting step of the reaction. More importantly,
heating the model reaction of benzene or pyridine in the
presence of 1 equiv. of TEMPO, a radical scavenger, completely
halts the reactivity. These results demonstrate that radical
intermediates are involved in such a reaction.
To further verify our assumption regarding radical generation
by amino-NHCs, a solution of freshly prepared potassium tert-
butoxide was mixed stoichiometrically with amino-NHC 1-tBu in
toluene at room temperature, and a dark red solution was
observed after one day. Electron paramagnetic resonance (EPR)
analysis of the reaction mixture showed a very broad signal
(Fig. 1, green dotted line), implying the production of a radical,
In view of the importance of heterocyclic rings as a common
motif in organic molecules, we turned our attention toward
pyridine in order to broaden the applicability of our method.
In the optimization process for the cross-coupling of pyridine
(see Table 1, ESIw), 1-tBu-Im (84–85%) was found to be more
effective than 1-tBu (80%) and NaOtBu was found to possess
same effect as its potassium counterpart. However, the statistically
expected 2 : 2 : 1 isomeric ratio o:m:p suggests little to no regio-
selectivity. The scope of the reaction was then expanded using
various aryl iodide derivatives (Table 2). Coupling products were
observed for electron-rich para and meta-substituted aryl iodides
bearing methoxy and methyl groups with an average B80% yield
(see entries 1–2 and 4–5). On the other hand, slightly diminished
conversion was witnessed for ortho substrates (entries 3 and 6).
Electron-withdrawing groups, such as 4-iodobenzonitrile, 2g,
(53%, entry 7) and 1-fluoro-4-iodobenzene, 2l, (77%, entry 12),
Scheme 2 KIE experiments.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 6702–6704 6703

View Article Online
subsequently transforms to the transient aryl radical 8; (2)
benzene reacts with the aryl radical 8 to generate the cyclo
hexadienyl radical 9; and (3) subsequent coupling of 7 and 9 occurs
to afford the biaryl. Metal tert-butoxides are known to behave as
single electron donors in many cases, such as towards alkyl halides,
ketones and polyaromatic substrates.15 It is quite clear that the
presence of amino-NHC 1-tBu is essential to promote or assist
KOtBu in generating the radical species 7, which is more likely to
be a cation radical species. Nonetheless, the identity of 7 remains to
be ascertained by detailed mechanistic studies.
In summary, an amino-linked nitrogen heterocyclic carbene
(amino-NHC) 1-tBu was shown to mediate the carbon–carbon
coupling of benzene and pyridine through direct C–H functio-
nalization in the absence of a metal catalyst. We have
also disclosed the first spectroscopic evidence corroborating
the metal-free carbon–carbon coupling mechanism via single
electron transfer, as reported by others. Ongoing work seeks to
further explore the mechanistic aspect and the utility of the
amino-NHC manifold for the development of new metal-free
organic catalysts for C–H functionalization.
Fig. 1 Room-temperature EPR spectrum of a solution containing
equivalent amounts of 1-tBu, KOtBu and crown ether (black) dissolved
in toluene and the best-fit simulated spectrum (red) of a radical anion
with giso = 2.0031, AH = 2.1, 7.1, 8.6 G, and AN = 2.9, 3.2 G.
Notes and references
1 (a) A. Dondoni and A. Massi, Angew. Chem., Int. Ed., 2008,
47, 4638; (b) A. Grossmann and D. Enders, Angew. Chem., Int.
Ed., 2012, 51, 314; (c) S. Schenker, A. Zamfir, M. Freund and
S. B. Tsogoeva, Eur. J. Org. Chem., 2011, 2209; (d) C. Grondal,
M. Jeanty and D. Enders, Nat. Chem., 2010, 2, 167; (e) S. Bertelsen
and K. A. Jørgensen, Chem. Soc. Rev., 2009, 38, 2178.
2 W. Liu, H. Cao, H. Zhang, H. Zhang, K. H. Chung, C. He, H. Wang,
F. Y. Kwong and A. Lei, J. Am. Chem. Soc., 2010, 132, 16737.
3 E. Shirakawa, K. Itoh, T. Higashino and T. Hayashi, J. Am. Chem.
Soc., 2010, 132, 15537.
4 C.-L. Sun, H. Li, D.-G. Yu, M. Yu, X. Zhou, X.-Y. Lu, K. Huang,
S.-F. Zheng, B.-J. Li and Z.-J. Shi, Nat. Chem., 2010, 2, 1044.
5 S. Yanagisawa, K. Ueda, T. Taniguchi and K. Itami, Org. Lett.,
2008, 10, 4673.
6 Y. Qiu, Y. Liu, K. Yang, W. Hong, Z. Li, Z. Wang, Z. Yao and
S. Jiang, Org. Lett., 2011, 13, 3556.
Scheme 3 Plausible mechanism.
portrayed as 7 in Scheme 3. Unfortunately, the signal is too broad
to make any meaningful interpretation on the nature of the
radical species. Subsequently, crown-ether was added to lessen
the quadrupole effect derived from the potassium ion, with the
aim of resolving the line broadening of the signal and the
complication of the EPR spectrum (dark, straight line). Fig. 1
displays the EPR signal with a distinct splitting at g B 2.0031.
The corresponding simulation, highlighted by the red spectrum,
was obtained with the involvement of three proton nuclei and two
nitrogen nuclei in hyperfine coupling interactions. The simulated
hyperfine coupling constants are 7.1, 8.6 and 2.1 G for the protons,
and 2.9 and 3.2 G for the nitrogen atoms. This result rationally
infers that an unpaired spin is located within the NHC-imidazole
ring coupled with its two ethylene H atoms, the distant methylene
H atom and two nitrogen atoms. Performing the reaction with
phenyl iodide and using the solution of 7 in catalytic amounts
generated the aryl–aryl coupling product in good yield, implying
that 7 is an intermediate radical species in the catalytic cycle. To
our knowledge, this data represents the first spectroscopic evidence
corroborating a metal-free carbon–carbon coupling manifold via a
single-electron transfer mechanism and confirming the formation
of NHC-derived radical intermediates, 7.13 Interestingly, the
Arnold group has isolated and observed a similar NHC radical
via potassium reduction.14
7 H. Liu, B. Yin, Z. Gao, Y. Li and H. Jiang, Chem. Commun., 2012,
48, 2033.
8 (a) O. Vakuliuk, B. Koszarna and D. T. Gryko, Adv. Synth. Catal.,
2011, 353, 925; (b) C.-L. Sun, Y.-F. Gu, W.-P. Huang and
Z.-J. Shi, Chem. Commun., 2011, 47, 9813; (c) M. Rueping,
M. Leiendecker, A. Das, T. Poisson and L. Bui, Chem. Commun.,
2011, 47, 10629; (d) G.-P. Yong, W.-L. She, Y.-M. Zhang and
Y.-Z. Li, Chem. Commun., 2011, 47, 11766; (e) D. S. Roman,
Y. Takahashi and A. B. Charette, Org. Lett., 2011, 13, 3242.
9 A. Studer and D. P. Curran, Angew. Chem., Int. Ed., 2011,
50, 5018.
10 (a) A. T. Biju, N. Kuhl and F. Glorius, Acc. Chem. Res., 2011,
44, 1182; (b) D. Enders, O. Niemeier and A. Henseler, Chem. Rev.,
2007, 107, 5606; (c) V. Nair, S. Vellalath and B. P. Babu, Chem.
Soc. Rev., 2008, 37, 2691.
11 (a) C.-Y. Li, Y.-Y. Kuo, J.-H. Tsai, G. P. A. Yap and T.-G. Ong,
Chem.–Asian J., 2011, 6, 1520; (b) W.-C. Shih, C.-H. Wang, Y.-T.
Chang, G. P. A. Yap and T.-G. Ong, Organometallics, 2009, 28, 1060.
12 Based upon reviewer’s suggestion, we replaced 1-tBu with its amine
precursor, 2-(tert-butylamino)ethanol and found 35% yield of
coupling product.
13 Literatures for EPR studies with metal-free coupling using hyper-
valent iodine: (a) Y. Kita, H. Tohma, K. Hatanaka, T. Takada,
S. Fujita, S. Mitoh, H. Sakurai and S. Oka, J. Am. Chem. Soc., 1994,
116, 3684; (b) Y. Kita, T. Takada and H. Tohma, Pure Appl. Chem.,
1996, 68, 627; (c) T. Dohi, M. Ito, N. Yamaoka, K. Morimoto,
H. Fujioka and Y. Kita, Angew. Chem., Int. Ed., 2010, 49, 3334.
14 P. L. Arnold and S. T. Liddle, Organometallics, 2006, 25, 1485.
15 (a) E. C. Ashby, A. B. Goel and R. N. DePriest, J. Org. Chem.,
1981, 46, 2429; (b) E. C. Ashby and J. N. Argyropoulos, J. Org.
Chem., 1986, 51, 3593.
On the basis of experimental evidence and literature
precedents,3,9 we propose that the preliminary NHC-mediated
cross-coupling mechanism proceeds through the following
steps, as shown in Scheme 3: (1) a single-electron transfer
from the KOtBu-amino-NHC adduct 5 to the aryl iodide gives
a new NHC radical cation 7 and the radical anion 6, which
c
6704 Chem. Commun., 2012, 48, 6702–6704
This journal is The Royal Society of Chemistry 2012