Ether-imidazolium carbenes for Suzuki-Miyaura cross-coupling of heteroaryl chlorides with Aryl/heteroarylboron reagents

Article abstract of DOI:10.1021/ol4010189

Easily accessible and handled ether-imidazolium chlorides were developed as ligand precursors. The coupling reactions of heteroaryl chlorides with aryl/heteroarylboronic acids and esters were catalyzed by the palladium/ether-imidazolium chloride system with high substrate tolerance to give various heterobiaryls in good to excellent yields.

Full text of DOI:10.1021/ol4010189

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Ether-Imidazolium Carbenes for
SuzukiÀMiyaura Cross-Coupling
of Heteroaryl Chlorides with
Aryl/Heteroarylboron Reagents
Masami Kuriyama,* Seira Matsuo, Mina Shinozawa, and Osamu Onomura*
Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi,
Nagasaki 852-8521, Japan
mkuriyam@nagasaki-u.ac.jp; onomura@nagasaki-u.ac.jp
Received April 12, 2013
ABSTRACT
Easily accessible and handled ether-imidazolium chlorides were developed as ligand precursors. The coupling reactions of heteroaryl chlorides
with aryl/heteroarylboronic acids and esters were catalyzed by the palladium/ether-imidazolium chloride system with high substrate tolerance to
give various heterobiaryls in good to excellent yields.
Heterobiaryls are known as ubiquitous and significant
structures in naturally occurring and biologically active
compounds.1 SuzukiÀMiyaura coupling has been widely
utilized to construct this class of compounds due to the
advantageous features of organoboronic acids and their
derivatives, such as low toxicity, easy manipulation, and
ready availability.2,3 In particular, the coupling of hetero-
aryl chlorides with heteroarylboron reagents remains a
quite important but challenging task on the grounds of
lower reactivity of chlorides and detrimental influences of
heterocyclic motifs on catalytic activity,4,5 though several
efficient palladiumÀphosphine catalysts for this type of
transformation have been reported.6
N-Heterocyclic carbenes (NHCs) have been focused on
as useful ligands for transition metals because of their
strong σ-electron-donating ability that allows formation of
active and stable catalysts in addition to flexible access to
their varying precursors.7 These basic properties hold the
promise of producing practically superior ligands bearing
beneficial effects on catalytic performance. Although the
development of PdÀNHC catalysts for challenging SuzukiÀ
Miyaura reactions has been actively pursued,8,9 examples
of the heterobiaryl synthesis from heteroaryl chlorides and
(1) Recent examples of biheteroaryl motifs: (a) Liu, Q.; Wang, J.;
Kang, S. A.; Thoreen, C. C.; Hur, W.; Ahmed, T.; Sabatini, D. M.; Gray,
N. S. J. Med. Chem. 2011, 54, 1473–1480. (b) Mandal, D.; Yamaguchi,
A. D.; Yamaguchi, J.; Kenichiro Itami, K. J. Am. Chem. Soc. 2011, 133,
€
19660–19663. (c) Beaulieu, P. L.; Bos, M.; Cordingley, M. G.; Chabot,
C.; Fazal, G.; Garneau, M.; Gillard, J. R.; Jolicoeur, E.; LaPlante, S.;
McKercher, G.; Poirier, M.; Poupart, M.-A.; Tsantrizos, Y. S.; Duan, J.;
Kukolj, G. J. Med. Chem. 2012, 55, 7650–7666. (d) Burckhardt, T.;
Harms, K.; Koert, U. Org. Lett. 2012, 14, 4674–4677.
(2) For reviews of SuzukiÀMiyaura cross-coupling, see: (a) Miyaura,
N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483. (b) Molander, G. A.;
Canturk, B. Angew. Chem., Int. Ed. 2009, 48, 9240–9261.
(3) Cyclic triolborate: (a) Yamamoto, Y.; Takizawa, M.; Yu, X.-Q.;
Miyaura, N. Angew. Chem., Int. Ed. 2008, 47, 928–931. MIDA ester: (b)
Knapp, D. M.; Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2009, 131,
6961–6963. Triisopropyl borate: (c) Oberli, M. A.; Buchwald, S. L. Org.
Lett. 2012, 14, 4606–4609.
(4) (a) Zhao, D.; You, J.; Hu, C. Chem.;Eur. J. 2011, 17, 5466–5492.
(b) Ge, S.; Hartwig, J. F. Angew. Chem., Int. Ed. 2012, 51, 12837–12841.
(5) Chlorides are known as ideal coupling partners in terms of cost
and diversity: Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41,
4176–4211.
(6) (a) Kudo, N.; Perseghini, M.; Fu, G. C. Angew. Chem., Int. Ed.
2006, 45, 1282–1284. (b) Billingsley, K. L.; Anderson, K. W.; Buchwald,
S. L. Angew. Chem., Int. Ed. 2006, 45, 3484–3488. (c) Guram, A. S.;
Wang, X.; Bunel, E. E.; Faul, M. M.; Larsen, R. D.; Martinelli, M. J.
J. Org. Chem. 2007, 72, 5104–5112. (d) Fleckenstein, C. A.; Plenio, H.
Chem.;Eur. J. 2008, 14, 4267–4279. (e) Molander, G. A.; Canturk, B.;
Kennedy, L. E. J. Org. Chem. 2009, 74, 973–980. (f) Kinzel, T.; Zhang,
Y.; Buchwald, S. L. J. Am. Chem. Soc. 2010, 132, 14073–14075.
(7) (a) Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1290–1309.
(b) Benhamou, L.; Chardon, E.; Lavigne, G.; Bellemin-Laponnaz, S.;
ꢀ
Cesar, V. Chem. Rev. 2011, 111, 2705–2733.
r
10.1021/ol4010189
XXXX American Chemical Society

heteroarylboron reagentsare very few, and effective NHCs
forthiskind ofcross-coupling are still desired.10 Herein, we
describe the coupling of heteroaryl chlorides with aryl/
heteroarylboronic acids and esters catalyzed by the
palladium/ether-imidazolium chloride system.
Scheme 1. Synthesis of Ether-Imidazolium Chlorides
The ether-imidazolium chlorides (2b and 2dÀe) were
simply prepared as ligand precursors in two steps from
inexpensive reagents (Scheme 1). The one-pot synthesis of
imidazoles (1b and 1dÀe) was carried out as the first step,
leading to good yields.11 The subsequent benzylation of
imidazoles gave the desired products in high yields. Other
ligand precursors were prepared in the same manner.12
These ether-imidazolium chlorides were crystalline solids
stable enough to handle and store exposed to air.
To evaluate the effects of ether-imidazolium chlorides,
the coupling of 4-chloroanisole (3a) with phenylboronic
acid (4a) using 1 mol % of catalysts (Pd/L = 1/2) formed
in situ from carbene precursors 2aÀi and palladium(II)
acetate was conducted at 80 °C (Table 1, entries 1À9).13
The ether-imidazolium chloride with methyl groups at
the 4- and 5-position led to high catalytic performance
though the coupling with precursor 2a gave 4-methoxy-
biphenyl (5aa) in moderate yield (entries 1 and 2). The
extremely low result was obtained in the case of using the
bulkier precursor bearing the 2,4,6-triisopropylbenzyl group
(entry 3).
Table 1. Effects of Ether-Imidazolium Chlorides in
SuzukiÀMiyaura Couplinga
Whereas the ether-imidazolium chlorides with the phe-
nyl or isopropyl group on the oxygen afforded a 94% yield,
entry
substrate
NHC HCl
Pd
yield (%)b
(8) For examples of effective monodentate NHCs in the coupling
with aryl/heteroaryl chlorides, see: (a) Zhang, C.; Huang, J.; Trudell,
3
1
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
3b
3b
3b
3b
2a
2b
2c
2d
2e
2f
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
[Pd(allyl)Cl]2
PdCl2
49
€
M. L.; Nolan, S. P. J. Org. Chem. 1999, 64, 3804–3805. (b) Gstottmayr,
€
C. W. K.; Bohm, V. P. W.; Herdtweck, E.; Grosche, M.; Herrmann,
2
88
W. A. Angew. Chem., Int. Ed. 2002, 41, 1363–1365. (c) Navarro, O.;
Kelly, R. A., III; Nolan, S. P. J. Am. Chem. Soc. 2003, 125, 16194–16195.
(d) Song, C.; Ma, Y.; Chai, Q.; Ma, C.; Jiangb, W.; Andrus, M. B.
3
2
4
94
€
5
94
Tetrahedron 2005, 61, 7438–7446. (e) Ozdemir, I.; Demir, S.; C-etinkaya,
B. Tetrahedron 2005, 61, 9791–9798. (f) Luan, X.; Mariz, R.; Gatti, M.;
Costabile, C.; Poater, A.; Cavallo, L.; Linden, A.; Dorta, R. J. Am.
6
trace
7
2g
2h
2i
0
€
Chem. Soc. 2008, 130, 6848–6858. (g) Wurtz, S.; Glorius, F. Acc. Chem.
8
4
Res. 2008, 41, 1523–1533. (h) Jin, Z.; Guo, S.-X.; Gu, X.-P.; Qiu, L.-L.;
Song, H.-B.; Jian-Xin Fang, J.-X. Adv. Synth. Catal. 2009, 351, 1575–
1585. (i) Wu, L.; Drinkel, E.; Gaggia, F.; Capolicchio, S.; Linden, A.;
Falivene, L.; Cavallo, L.; Dorta, R. Chem.;Eur. J. 2011, 17, 12886–
12890. (j) Valente, C.; C-alimsiz, S.; Hoi, K. H.; Mallik, D.; Sayah, M.;
Organ, M. G. Angew. Chem., Int. Ed. 2012, 51, 3314–3332. (k) Chartoire,
A.; Lesieur, M.; Falivene, L.; Slawin, A. M. Z.; Cavallo, L.; Cazin,
C. S. J.; Nolan, S. P. Chem.;Eur. J. 2012, 18, 4517–4521. (l) Tu, T.; Sun,
Z.; Fang, W.; Xu, M.; Zhou, Y. Org. Lett. 2012, 14, 4250–4253.
(9) For examples of effective bidentate NHCs in the coupling with
aryl/heteroaryl chlorides, see: (a) Zhang, C.; Trudell, M. L. Tetrahedron
Lett. 2000, 41, 595–598. (b) Liao, C.-Y.; Chan, K.-T.; Tu, C.-Y.; Chang,
Y.-W.; Hu, C.-H.; Lee, H. M. Chem.;Eur. J. 2009, 15, 405–417. (c)
Schmidt, A.; Rahimi, A. Chem. Commun. 2010, 2995–2997. (d) Kumar,
M. R.; Park, K.; Lee, S. Adv. Synth. Catal. 2010, 352, 3255–3266.
(10) Examples: (a) O’Brien, C. J.; Kantchev, E. A. B.; Valente, C.;
Hadei, N.; Chass, G. A.; Lough, A.; Hopkinson, A. C.; Organ, M. G.
Chem.;Eur. J. 2006, 12, 4743–4748. (b) Organ, M. G.; C-alimsiz, S.;
Sayah, M.; Hoi, K. H.; Lough, A. J. Angew. Chem., Int. Ed. 2009, 48,
2383–2387. (c) Peh, G.-R.; Kantchev, E. A. B.; Er, J.-C.; Ying, J. Y.
Chem.;Eur. J. 2010, 16, 4010–4017. (d) Liu, T.; Zhao, X.; Shen, Q.; Lu,
L. Tetrahedron 2012, 68, 6535–6547.
9
0
10
11
12
13
14
15
16
17c
2b
2d
2e
2d
2d
2d
2d
2d
3
94(99)d
91
90(98)d
14
6
Pd2(dba)3
Pd(dba)2
Pd(OAc)2
0
4
a Reaction conditions: 3 (1 mmol), 4a (1.5 mmol), 2 (2 mol %), Pd
(1 mol %), Cs2CO3 (2 mmol), dioxane (2 mL), 80 °C, 18 h. b Isolated
yield. c Pd/2d = 1/1 (Pd: 1 mol %). d 90 °C.
the reaction with the precursor bearing the thioether group
hardly proceeded (entries 4À6). The carbene precursors
without an ether group and with a methoxy group at the
para-position did not show beneficial effects (entries 7À9),
(11) The procedure was modified on the basis of Orru’s report:
Gelens, E.; De Kanter, F. J. J.; Schmitz, R. F.; Sliedregt, L. A. J. M.;
Van Steen, B, J.; Kruse, C. G.; Leurs, R.; Groen, M. B.; Orru, R. V. A.
Molecular Diversity 2006, 10, 17–22.
(12) The full details of carbene precursor synthesis were included in
the Supporting Information.
(13) The precatalysts were prepared in situ by heating, and then the
coupling reactions were carried out. See Supporting Information.
(14) The ether group could serve as a hemilabile donor: (a) Slone,
C. S.; Weinberger, D. A.; Mirkin, C. A. Prog. Inorg. Chem. 1999, 48,
233–350. (b) Weng, Z.; Teo, S.; Hor, T. S. A. Acc. Chem. Res. 2007, 40,
676–684. (c) Kwong, F. Y.; Chan, A. S. C. Synlett 2008, 1440–1448.
B
Org. Lett., Vol. XX, No. XX, XXXX

which proved that an ether moiety at the ortho-position
was necessary for high catalytic activity.14 In the coupling
with 3-chloropyridine (3b), ether-imidazolium chlorides
(2b and 2dÀe) were examined, and 2d was found to be a
superior ligand precursor while a significant decrease in
yield was observed in the reaction with 2b (entries 10À12).
Screening of Pd sources revealed that an allylpalladium(II)
chloride dimer as well as palladium(II) acetate were
suitable (entries 11 and 13À16). The catalyst formed from
2d and Pd(OAc)2 in a 1:1 molar ratio led to a 4% yield
(entry 17).
Scheme 3. SuzukiÀMiyaura Coupling with Ether-Imidazolium
CarbeneÀPalladium Complexes
Furthermore, complex 7e was converted with AgSbF6
into the cationic complex 9 (Scheme 4), whose structure
was confirmed by X-ray crystallography (Figure 1).15 In
this cationic complex 9, the PdÀarene interaction was
observed, which could stabilize catalysts and contribute
to the improvement of catalyst activity and lifetime.16 The
cross-coupling using complexes 7e and 9 also proceeded
efficiently without problems (Scheme 3).
Scheme 2. Synthesis of Ether-Imidazolium CarbeneÀPalladium
Complexes and X-ray Crystal Structures of 7dÀe and 8
Scheme 4. Synthesis of Cationic Complex 9
Figure 1. X-ray crystal structure of 9. NHC with no PdÀarenÀe
interaction is displayed in a wireframe model, and two SbF6
are omitted for simplicity.
To acquire more information on the catalysts, the 1:2 and 1:1
molar ratio complexes of Pd/2 were prepared via the Ag-NHC
complexes (Scheme 2). Complexes 6À8 were obtained
quantitatively, and the structures of 7and 8were determined
by X-ray crystallographic analysis. The reaction with 8 in
addition to that with 7d gave desired product 5ba in excellent
yields (Scheme 3). These results suggested that the second
precursor 2d for Pd could play a key role in the formation of
stable precatalysts, whereas one precursor 2d in a complex
catalyst was essential to achieve high catalytic performance.
Investigation of heterobiaryl synthesis was conducted
with 1 mol % of the palladium/ether-imidazolium chloride
system (Scheme 5). Initially, a series of heteroaryl chlorides
were examined using phenylboronic acid as a coupling
partner. Neither the electronic influence of substituents
(15) The single crystals of cationic complex prepared from 7d could
not be obtained despite careful screening of recrystallization conditions.
(16) Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461–
1473 and references therein.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 5. Coupling of Heteroaryl Chlorides with Arylboronic
Acids Using Ether-Imidazolium Chloridea
Scheme 6. Coupling of Heteroaryl Chlorides with Heteroaryl-
boronic Acids and Esters Using Ether-Imidazolium Chloridea
a Reaction conditions: 3 (1 mmol), 4 (1.5 mmol), 2d (2 mol %), Pd
(1 mol %), Cs2CO3 (2 mmol), dioxane (2 mL), 90 °C, 18 h. b PhB(OH)2
(2 mmol) was used. c [Pd(allyl)Cl]2 (0.5 mol %) was used. d 100 °C.
(5caÀda) nor steric hindrance (5eaÀfa) led to a significant
decrease in yield. The substrates bearing a heteroatom
adjacent to the reactive site also proved to be good reaction
partners (5gaÀha). Then, the influence of arylboronic
acids was investigated in the reactions with 3-chloropyr-
idine and its derivative. The sterically hindered reagent
reacted smoothly to afford the desired products in high
yields (5bb and 5eb). The coupling with arylboronic acids
bearing electron-donating and -withdrawing groups also
proceeded with sufficient efficiency (5bcÀbf).
a Reaction conditions: 3 (1 mmol), 4 (1.5 mmol), 2d (2 mol %), Pd
b
(1 mol %), Cs2CO3 (2 mmol), dioxane (2 mL), 90 °C, 18 h. Pinacol
boronate ester (1.5 mmol) was used. c 100 °C. d Pd(OAc)2 (1 mol %) was
used. e Pinacol boronate ester (2 mmol) was used. f H2O (0.2mL) wasadded.
In summary, the palladium/ether-imidazolium chloride
system achieved high catalytic performance and substrate
tolerance in the coupling reactions of heteroaryl chlorides
with aryl/heteroarylboron reagents. The carbene precursor
was prepared from inexpensive reagents in two steps and
obtained as crystalline solids stable enough to handle and
store under air. Investigation of the effects of ligand struc-
tures and the PdÀNHC complexes suggested that the ether
moiety as a ligand and PdÀarene interaction could play key
roles for catalytic activity. For the development of new
catalytic reactions, tuning of this catalyst system is currently
under investigation in our research group.
The cross-coupling of heteroaryl chlorides with hetero-
arylboron reagents was examined with 1 mol % catalyst
loading (Scheme 6). High catalytic activity was observed in
the synthesis of biheteroaryls from sterically hindered
4-chloroquinoline and a variety of heteroarylboronic acids
and esters bearing quinoline, indole, furan, and thiophene
moieties (5fgÀfk). A series of 3-chloropyridine derivatives
with fluoro, methoxy, and amino groups showed good
reactivity in the presence of heteroaryl coupling partners
(5cl, 5dg, and 5ii).17 In the coupling with 2-chloroquino-
line, this catalytic system tolerated an indole NH group
(5gm) as well as nitrogen-, oxygen-, and sulfur-containing
heteroaromatic rings (5ggÀgh and 5gjÀgk), leading to
high yields. The 2-chlorothiophene derivative reacted suf-
ficiently with heteroarylboronic acids bearing carbazole
and thiophene units (5hl and 5hk).
Acknowledgment. This research was supported by
MEXT and JSPS KAKENHI (23105539 and 24590012),
the Research Grant for Pharmaceutical Sciences from
Takeda Science Foundation, and the Research Support
Grant for Young Scientists from Nagasaki University.
Supporting Information Available. Full experimental
1
details, a cif file, and H and 13C NMR spectra. This
(17) Instead of 2d, IMes HCl (2 mol %), IPr HCl (2 mol %), and
3
3
SIPr HCl (2 mol %) were examined in the synthesis of 5ii with the same
material is available free of charge via the Internet at
http://pubs.acs.org.
3
reaction conditions, leading to 18%, 28%, and 2% yields, respectively.
The reactions with [Pd(IPr)(allyl)Cl] (1 mol %) and [Pd-PEPPSI-IPr]
(1 mol %) in place of 2d and [Pd(allyl)Cl]2 gave 5ii in 22% and 18%
yields, respectively.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX