Robust acenaphthoimidazolylidene palladium complexes: Highly efficient catalysts for suzuki-miyaura couplings with sterically hindered substrates

Article abstract of DOI:10.1021/ol3019665

Robust acenaphthoimidazolylidene palladium complexes have been demonstrated as highly efficient and general catalysts for the sterically hindered Suzuki-Miyaura cross-coupling reactions in excellent yields even with low catalyst loadings under mild reaction conditions. The high catalytic activity of these complexes highlights that, besides the "flexible steric bulky" concept, σ-donor properties of the NHC ligands are also crucial to accelerate the transformations.

Full text of DOI:10.1021/ol3019665

ORGANIC
LETTERS
2012
Vol. 14, No. 16
4250–4253
Robust Acenaphthoimidazolylidene
Palladium Complexes: Highly Efficient
Catalysts for SuzukiꢀMiyaura Couplings
with Sterically Hindered Substrates
Tao Tu,* Zheming Sun, Weiwei Fang, Mizhi Xu, and Yunfei Zhou
Department of Chemistry, Fudan University, 220 Handan Road, 200433,
Shanghai, China
taotu@fudan.edu.cn
Received July 16, 2012
ABSTRACT
Robust acenaphthoimidazolylidene palladium complexes have been demonstrated as highly efficient and general catalysts for the sterically
hindered SuzukiꢀMiyaura cross-coupling reactions in excellent yields even with low catalyst loadings under mild reaction conditions. The high
catalytic activity of these complexes highlights that, besides the “flexible steric bulky” concept, σ-donor properties of the NHC ligands are also
crucial to accelerate the transformations.
Sterically hindered biaryls are vital substructures found
in various biologically active compounds,1 functional
materials,2 and many useful ligands (such as Buchwald’s
biaryl-based monophosphines 1aꢀc, Figure 1).3 There-
fore, considerable attention has been focused toward the
field of sterically congested biaryl synthesis. Although,
SuzukiꢀMiyaura coupling reactions constitute one of the
most powerful, attractive, and practical protocols for CꢀC
bond formation,4 the transformation with sterically de-
manding boronic acids and aryl halides to construct di-,
tri-, and even tetra-ortho-substituted biaryls remains an
extremely challenging task, especially under mild reaction
conditions.5
(1) (a) Bringmann, G.; Gulder, T.; Gulder, T. A. M.; Breuning, M.
Chem. Rev. 2011, 111, 563. (b) Kozlowski, M. C.; Morgan, B. J.; Linton,
E. C. Chem. Soc. Rev. 2009, 38, 3193. (c) Bringmann, G.; Gunther, G.;
Ochse, M.; Schupp, O.; Tasler, S. In Progress in the Chemistry of Organic
Natural Products; Herz, W., Falk, H., Kirby, G. W., Moore, R. E., Tamm, C.,
Eds.; Springer: New York, 2001; Vol. 82.
(2) (a) Pu, L. Acc. Chem. Res. 2012, 45, 150. (b) Lightowler, S.; Hird,
M. Chem. Mater. 2005, 17, 5538. (c) Kertesz, M.; Choi, C. H; Yang, S.
Chem. Rev. 2005, 105, 3448.
(3) (a) Martin, R; Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461. (b)
Surry, D. S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 6338.
(4) (a) Suzuki, A. Angew. Chem., Int. Ed. 2011, 50, 6722. (b) Modern
Arylation Methods; Ackermann, L., Ed.; Wiley-VCH: Weinheim, 2009. (c)
Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; de Meijere, A.,
Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004.
Figure 1. A selection of ligands and complexes applied in
Pd-catalyzed sterically hindered cross-coupling reactions.
€
Inspired by recent advances in the development of novel
catalysts, research efforts have focused on coupling reactions
with sterically hindered substrates. A variety of palladium
catalysts derived from sterically congested monodentate
(5) (a) Valente, C.; C-alimsiz, S.; Hoi, K. H.; Mallik, D.; Sayah, M.;
Organ, M. G. Angew. Chem., Int. Ed. 2012, 51, 3314. (b) McGlacken,
G. P.; Bateman, L. M. Chem. Soc. Rev. 2009, 38, 2447.
r
10.1021/ol3019665
Published on Web 08/03/2012
2012 American Chemical Society

phosphines have been designed and prepared for this pur-
pose, and some of them demonstrated a broad substrate scope
and good functional group tolerance.3a,6 Furthermore, N-
heterocyclic carbenes (NHCs) represent a class of environ-
mentally friendly ligands and have exhibited promising po-
tential in these transformations.5a,7 In general, the steric and
electronic properties of ligands play a crucial role in enhanc-
ing the coupling efficiency. Influenced by the “flexible steric
bulky” concept proposed by Glorius and co-workers,8 cur-
rently, a number of research groups have focused on increas-
ing catalytic activity by using the bulkier NHC ligands. For
example, among NHC palladium complexes 2 developed by
Organ and co-workers, the i-Pent carbene complex exhibited
higher activity than its i-Pr analogues.7c,9 However, much less
attention has been given to the variation of the electronic
properties of NHC ligands to accelerate the coupling process.
Furthermore, the existing protocols are still hampered: (1) a
high catalyst loading (usually 2ꢀ10 mol %) is required to
achieve a reasonable conversion; (2) some ligand syntheses
are often time-consuming; (3) the general catalyst, which has
the ability to satisfy the diverse requirements of the coupling
reactions with various substrates, is still under investigation.
During our recent research on the synthesis of metal
complexes and their potential applications in catalysis and
soft matter aspects,10,11 we found that ylidenes derived from
benzimidazolium or other π-extended imidazolium salts
show better catalytic activity than their imidazolium ana-
logues, which may arise from their stronger σ-donor and
weaker π-acceptor properties. Therefore, a novel robust
palladium NHC complex 3a was recently synthesized from
commercially available starting materials by our group
and revealed high catalytic activity in the amination of
(hetero)aryl chlorides.11a Herein, we now extend this study
and explore the catalytic potential of this new type of catalysts
3aꢀc toward sterically hindered biaryl coupling reactions.
To evaluate the efficiency of Pd-NHC complexes 3aꢀc
in highly sterically congested aryl formation reactions,
2-methoxynapthalene bromide and 2,6-dimethylphenyl
boronic acid were selected as substrates to optimize the
reaction conditions (Table 1). To our delight, with only
0.5 mol % of 3a, the tetra-ortho-substituted biaryl 4a was
formed almost in a quantitative yield when the reaction
was carried with t-BuOK and dioxane at 80 °C within 24 h
(Table 1, entry 1). However, when less bulky catalysts 3b
and 3c were applied, very unsatisfying results were ob-
served (Table 1, entries 2 and 3). In general, 4 A molecular
sieves (M.S.) are required in the coupling reactions in order
to avoid phenol formation.12 However, there is no differ-
ence the yields with or without 4 A M.S. even when
t-BuOK and t-BuOH were applied with 3a. Further in-
creasing the catalyst loading to 1 mol % resulted in a
similar isolated yield (96% vs 97%, Table 1, entries 4ꢀ5).
When toluene was utilized, the coupling process still works
well and a 95% yield was obtained(Table 1, entry 6). When
other organic solvents were screened, however, no desired
product could be detected (see the Supporting Information).
In addition, only a 70% isolated yield was observed when
t-BuONa was applied instead of its potassium analogue.
Therefore, other potassium bases were selected for further
optimization. The strong base KOH afforded a moderate
yield, whereas weak bases such as K2CO3 and K3PO4 even
suppressed the transformation (Table 1, entries 8, 9, and 11).
By varying bases to Cs2CO3 or CsF, or using xylene instead of
dioxane, 75%, 55%, and 42% yields were observed (Table 1,
entries 10, 12, and 13), respectively. Additionally, no reac-
tions occurred when selected organic bases were tested (see
the Supporting Information). In contrast to the blank test,
upon decreasing the catalyst loading to 0.1 or 0.05 mol %,
94% and 77% yields were still obtained (Table 1, entries
14ꢀ16), which further confirmed the catalyst efficiency.
As illustrated in Scheme 1, PdꢀNHC complex 3a ex-
hibits high catalytic activity to form sterically hindered
di-, tri-, and tetra-ortho-substituted biaryls. Even with a
0.5 mol % catalyst loading, the protocol well tolerated a
number of substituted arylboronic acids to form tetra-
ortho-substituted biaryl products in good to quantitative
yields (4ꢀ6). The electronic properties of the ortho-sub-
stituted groups affected the coupling process slightly more
strongly than the additional substituted groups in the
para-position of arylboronic acids (4b and 6aꢀb vs 5aꢀc);
in the later case all substrates result in similar excellent
yields (5aꢀc, 98ꢀ>99%). When Cs2CO3 and t-BuOH
(6) Selected recent publications: (a) To, S. C.; Kwong, F. Y. Chem.
Commun. 2011, 5079. (b) Tang, W.; Capacci, A. G.; Wei, X.; Li, W.;
White, A.; Patel, N. D.; Savoie, J.; Gao, J. J.; Rodriguez, S.; Qu, B.;
Haddad, N.; Lu, B. Z.; Krishnamurthy, D.; Yee, N. K.; Senanayake,
C. H. Angew. Chem., Int. Ed. 2010, 49, 5879. (c) Bolliger, J. L.; Frech,
C. M. Chem.;Eur. J. 2010, 16, 4075. (d) So, C. M.; Chow, W. K.; Choy,
P. Y.; Lau, C. P.; Kwong, F. Y. Chem.;Eur. J. 2010, 16, 7996.
(e) Ackermann, L.; Potukuchi, H. K.; Althammer, A.; Born, R.; Mayer,
P. Org. Lett. 2010, 12, 1004. (f) Hoshi, T.; Nakazawa, T.; Saitoh, I.;
Mori, A.; Suzuki, T.; Sakai, J; Hagiwara, H. Org. Lett. 2008, 10, 2063.
(7) Selected recent publications: (a) Wu, L.; Drinkel, E.; Gaggia, F.;
Capolicchio, S.; Linden, A.; Falivene, L.; Cavallo, L.; Dorta, R.
Chem.;Eur. J. 2011, 17, 12886. (b) Schmidt, A.; Rahimi, A. Chem.
Commun. 2010, 2995. (c) Organ, M. G.; C-alimsiz, S.; Sayah, M.; Hoi,
K. H.; Lough, A. J. Angew. Chem., Int. Ed. 2009, 48, 2383. (d) Luan, X.;
Mariz, R.; Gatti, M.; Costabile, C.; Poater, A.; Cavallo, L.; Linden, A.;
ꢀ
´
z-Gonzalez, S.;
Dorta, R. J. Am. Chem. Soc. 2008, 130, 6848. (e) Dı
Marion, N.; Nolan, S. P. Chem. Rev. 2009, 109, 3612.
(8) Altenhoff, G.; Goddard, R.; Lehmann, C. W.; Glorius, F. J. Am.
Chem. Soc. 2004, 126, 15195.
(9) (a) Sayah, M.; Organ, M. G. Chem.;Eur. J. 2011, 17, 11719.
(b) Hoi, K. H.; C-alimsiz, S.; Froese, R. D. J.; Hopkinson, A. C; Organ,
M. G. Chem.;Eur. J. 2011, 17, 3086. (c) C-alimsiz, S.; Organ, M. G.
Chem. Commun. 2011, 5181. (d) Nasielski, J.; Hadei, N.; Achonduh, G.;
Kantchev, E. A.; O’Brien, B. C. J.; Lough, A.; Organ, M. G. Chem.;
Eur. J. 2010, 16, 10844.
€
(10) (a) Tu, T.; Fang, W.; Bao, X.; Li, X.; Dotz, K. H. Angew. Chem., Int.
Ed. 2011, 50, 6601. (b) Tu, T.; Bao, X.; Assenmacher, W.; Peterlik, H.;
€
Daniels, J.; Dotz, K. H. Chem.;Eur. J. 2009, 15, 1853. (c) Tu, T.;
€
Assenmacher, W.; Peterlik, H.; Schnakenburg, G.; Dotz, K. H. Angew.
Chem., Int. Ed. 2008, 47, 7127. (d) Tu, T.; Assenmacher, W.; Peterlik, H.;
Weisbarth, R.; Nieger, M.; Dotz,K.H.Angew. Chem., Int. Ed. 2007, 46, 6368.
(12) Anderson, K. W.; Ikawa, T.; Tundel, R. E.; Buchwald, S. L.
J. Am. Chem. Soc. 2006, 128, 10694.
€
(11) (a) Tu, T.; Fang, W.; Jian, J. Chem. Commun. 2011, 12358. (b)
Wang, Z.; Feng, X.; Fang, W.; Tu, T. Synlett 2011, 951. (c) Tu, T.; Feng,
X.; Wang, Z.; Liu, X. Dalton Trans. 2010, 10598. (d) Tu, T.; Mao, H.;
(13) Bellina, F.; Carpita, A.; Rossi, R. Synthesis 2004, 2419.
(14) (a) Baudoin, O.; Gueritte, F. In Studies in Natural Product
Chemistry; Rahman, A.-U., Ed.; Elsevier: Amsterdam, 2003; Vol. 29, pp
€
Herbert, C.; Xu, M.; Dotz, K. H. Chem. Commun. 2010, 7796. (e) Tu, T.;
€
€
Malineni, J.; Bao, X.; Dotz, K. H. Adv. Synth. Catal. 2009, 351, 1029.
355ꢀ418; (b) Nicolaou, K. C.; Boddy, C. N. C.; Brase, S.; Winssinger, N.
€
(f) Tu, T.; Malineni, J.; Dotz, K. H. Adv. Synth. Catal. 2008, 350, 1791.
Angew. Chem., Int. Ed. 1999, 38, 2096.
Org. Lett., Vol. 14, No. 16, 2012
4251

Table 1. Optimization of the Sterically Encumbered Suzukiꢀ
Miyaura Couplings with PdꢀNHC Complexes 3aꢀca
Scheme 1. Sterically Encumbered SuzukiꢀMiyaura Couplings
with Various Arylboronic Acidsa
entry
[cat.] (mol %)
base
solvent
yield (%)b
1
3a: 0.5
3b: 0.5
3c: 0.5
3a: 0.5
3a: 1
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuONa
KOH
dioxane
dioxane
dioxane
t-BuOH
t-BuOH
toluene
dioxane
dioxane
dioxane
dioxane
dioxane
xylene
>99
5
2
3
0
4
96/96c
97
5
6
3a: 1
95
7
3a: 1
70
8
3a: 1
77
9
3a: 1
K2CO3
Cs2CO3
K3PO4
K3PO4
CsF
NR
75
10
11
12
13
14
15
16
3a: 1
3a: 1
NR
42
3a: 1
3a: 1
dioxane
dioxane
dioxane
dioxane
55
a 0.5 mmol scale at 80 °C for 24 h. b Isolated yield. c With Cs2CO3 and
t-BuOH. dWith CsF and t-BuOH.
3a: 0.1
3a: 0.05
ꢀ
t-BuOK
t-BuOK
t-BuOK
94
77
NR
a Reactions were carried out at 80 °C in 2 mL of solvent for 24 h
with bromoarene (0.5 mmol), aryl boronic acid (1 mmol), and base
(1.5 mmol). b Isolated yield. c With 4 A M.S.
Scheme 2. Sterically Encumbered SuzukiꢀMiyaura Couplings
with Various Aryl Boromidesa
were applied, the protocol was also successfully extended
to produce the tri-ortho-substituted biaryls.6a,14 Again, the
electronic properties of the ortho-substituted group influ-
enced the coupling transformation, and the boronic acids
with an electron-donating group resulted in higher yields
(7aꢀb vs 7c). Identical yields were observed with 8 and 9,
when bulky (1,10-biphenyl)-2-ylboronic acid and naphtha-
len-1-ylboronic acid were applied. Furthermore, less steri-
cally hindered phenyl and heterocyclic arylboronic acids
were also well accommodated to synthesize di-ortho-sub-
stituted heterocyclic biaryls even with a 0.5 mol % catalyst
loading (10ꢀ12).
Delighted by the high efficiency and tolerance of Pd-
NHC 3a presented in the sterically hindered coupling
reactions with various (hetero-)aryl boronic acids, we
turned our attention to study the protocol accommodation
ability for a broad range of aryl and heteroaryl bromides;
the results are compiled in Scheme 2. With the standard
reaction conditions, the relative positions, electronic prop-
erties, and bulkiness of the functional groups were well
tolerated, and almost all di-, tri-, and tetra-ortho-substi-
tuted biaryls (13ꢀ21) were formed in quantitative yields
(91ꢀ>99%), even with heteroaryl substrates possessing
strong coordination abilities, which further demonstrated
the powerful applicability of complex 3a.
a 0.5 mmol scale at 80 °C for 24 h. b Isolated yield.
(hetero)biaryls in good to quantitative yields (22ꢀ24,
Scheme 3). Due to polyarylbenzenes having played a
crucial role in organic optical and electronic sensors,16
synthesizing them is still regarded as an intriguing task
especially by one-pot multiple couplings. Dicoupled cou-
pling reactions were performed, and products (25ꢀ27)
were isolated in excellent yields (93ꢀ99%) without mono-
coupled adducts. Particularly, the protocol successfully
To our delight, regardless of the electronic effects and
bulkiness of the functional groups, sluggish chloroarenes15
reacted with various arylboronic acids efficiently to
afford the desired di-, tri-, and tetra-ortho-substituted
(16) (a) Vyas, V. S.; Rathore, R. Chem. Commun. 2010, 46, 1065. (b)
€
€
Mahler, C.; Muller, U.; Muller, W. M.; Enkelmann; Moon, V. C.;
€
Brunklaus, G.; Zimmermann, H.; Hoger, S. Chem. Commun. 2008, 4816.
(c) Goel, A.; Singh, F. V.; Dixit, M.; Verma, D.; Raghunandan, R.;
Maulik, P. R. Chem.;Asian J. 2007, 2, 239. (d) Sergeyev, S.; Pisula, W.;
Geerts, Y. H. Chem. Soc. Rev. 2007, 36, 1902.
(15) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176.
4252
Org. Lett., Vol. 14, No. 16, 2012

quantitative yields. To our delight, in the synthesis of
Lamotrigine analogue 34, two chloro-substituted groups
are well tolerated.
Scheme 3. Sterically Encumbered SuzukiꢀMiyaura Couplings
with Various Aryl Chloridesa
Table 2. Functionalized Molecules Synthesized by Suzukiꢀ
Miyarua Coupling Reactions Using PdꢀNHC Complex 3aa
a 0.5 mmol scale at 80 °C for 24 h. b Isolated yield.
c
a 0.5 mmol scale at 80 °C for 24 h. bIsolated yield. With CsF and
toluene. dWith K3PO4 and xylene. With Cs2CO3 and t-BuOH. With
CsF and toluene at 80 °C for 6 days or assisted with microwave
irradiation at 110 °C for 60 min.
e
f
In summary, our newly developed robust acenaphthoi-
midazolylidene palladium complexes have been demon-
strated as highly efficient and general catalysts for the
SuzukiꢀMiyaura cross-coupling of sterically hindered
(hetero)aryl bromides/chlorides with various aryl boronic
acids to form di-, tri-, and tetra-ortho-substituted (hetero)-
biaryls in excellent yields under mild reaction conditions.
Furthermore, the protocol was successfully extended not
only to prepare polyarylbenzenes from sterically hindered
and unreactive polychloroarenes but also to construct
various useful functional molecules. In contrast to its im-
idazolylidene analogues 2aꢀc, the high activity of Pdꢀ
NHC 3a exhibited even with a low catalyst loading re-
vealed that, besides the “flexible steric bulky” environment
around the catalytic center, σ-donor properties of the
ligands are also crucial in order to increase the activity of
the catalyst.
accommodated free hydroxyl and amino groups without
additional protection procedures. And this concept was
readily extended to triple and quadruple couplings to
produce the corresponding polyarylbenzenes (28ꢀ29) in
excellent isolated yields (91ꢀ96%). As precursors of
hexabenzocoronene (HBC) derivatives, hexaphenyl-ben-
zene (HPB, 30) and its analogues have wide application in
synthetic chemistry and material sciences.17 To the best of
our knowledge, there is only one coupling example with
perbromobenzene resulting in a very low yield.18 How-
ever, even with a lower catalyst loading, our protocol
successfully produced HPB (30) in a 61% yield. More-
over, the transformation can dramatically be expedited
by microwave irradiation.
With potential application in the synthesis of functional
materials such as HPB, we further extended this protocol
to construct other di-, tri-, and tetra-ortho-substituted fun-
ctional molecules such as useful ligands (31ꢀ32, Table 2,
entries 1ꢀ2) and biologically active compounds (33ꢀ35,
Table 2, entries 3ꢀ5), which all resulted in good to
Acknowledgment. Financial support from the National
Natural Science Foundation of China (No. 21172045 and
20902011), Shanghai Shuguang Program (11SG04), the
Changjiang Scholars and Innovative Research Team in
University (IRT1117), the Shanghai Leading Academic
Discipline Project (B108), and Department of Chemistry,
Fudan University is gratefully acknowledged.
(17) (a) Hill, J. P.; Jin, W.; Kosaka, A.; Fukushima, T.; Ichihara, H.;
Shimomura, T.; Ito, K.; Hashizume, T.; Ishii, N.; Aida, T. Science 2004,
€
€
304, 1481. (b) Schmidt-Mende, L.; Fechtenkotter, A.; Mullen, K.;
Moons, E.; Friend, R. H.; MacKenzie, J. D. Science 2001, 293, 1119.
(c) Katz, H. E.; Lovinger, A. J.; Johnson, J.; Kloc, C.; Siegrist, T.; Li, W.;
Lin, Y. Y.; Dodabalapur, A. Nature 2000, 404, 478. (d) Martin, R. E.;
Diederich, F. Angew. Chem., Int. Ed. 1999, 38, 1350.
Supporting Information Available. Experimental details,
NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
ꢀ
ꢀ
(18) Mora, M.; Jimenez-Sanchidrian, C.; Ruiz, J. R. Appl. Organo-
metal. Chem. 2008, 22, 122.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 16, 2012
4253