Ruthenium-catalyzed ortho-selective aromatic c-h borylation of 2-arylpyridines with pinacolborane

Article abstract of DOI:10.1002/cctc.201500110

The ruthenium-catalyzed dehydrogenative borylation of 2-arylpyridines with pinacolborane took place at ortho-positions of the benzene ring. Density functional theory calculations and kinetic isotope effect experiments suggest that the catalytic cycle should involve oxidative addition of the C-H bond, the rate-determining σ-bond metathesis of pinacolborane with the ruthenium hydride complex, and reductive elimination of the C-B bond. A ruthenium for C-H borylation: The ruthenium-catalyzed dehydrogenative borylation of 2-arylpyridines with pinacolborane took place at ortho-positions of the benzene ring.

Full text of DOI:10.1002/cctc.201500110

DOI: 10.1002/cctc.201500110
Communications
Ruthenium-Catalyzed Ortho-Selective Aromatic CÀH
Borylation of 2-Arylpyridines with Pinacolborane
Shinsuke Okada, Takeshi Namikoshi, Shinji Watanabe, and Miki Murata*[a]
The ruthenium-catalyzed dehydrogenative borylation of 2-aryl-
pyridines with pinacolborane took place at ortho-positions of
the benzene ring. Density functional theory calculations and ki-
netic isotope effect experiments suggest that the catalytic
cycle should involve oxidative addition of the CÀH bond, the
rate-determining s-bond metathesis of pinacolborane with the
ruthenium hydride complex, and reductive elimination of the
CÀB bond.
related CÀH functionalization, there is only one report about
ruthenium catalysts to affect the direct CÀH borylation.[5]
Herein, we wish to report on an alternative approach using
pinacolborane (1) as a boron source for the ruthenium-cata-
lyzed CÀH borylation of 2-arylpyridines.
To evaluate potential ruthenium catalysts for this transforma-
tion, we investigated the CÀH borylation of 2-phenylpyridine
(3a). The results are summarized in Table 1. When 3a was
treated with an excess amount of pinacolborane (1, 3 equiv) in
the presence of 2 mol% of [RuH2(CO)(PPh3)3] in THF at 1508C
for 16 h, a full conversion of 3a was observed (entry 1). The re-
action was completely ortho-regioselective affording mono-
borylated 4a and diborylated 5a. Analysis of the 11B NMR spec-
tra indicated that, as expected, 4a has the tetrahedral boron–
nitrogen interaction in the solution state.[6h,7c] Alternatively, the
11B NMR signal of 5a was observed at 21.8 ppm, which is the
middle value of trigonal and tetrahedral boron atom. The pres-
ence of only one signal for the boron atoms of 5a can be ex-
plained by a dynamic behavior that involves rapid coordina-
tion and dissociation of the boron and nitrogen atoms. In con-
trast to Nolan’s report,[5] several attempts at the selective for-
mation of monoborylated 4a, including using lower reaction
temperatures or lower quantities of 1, were unsuccessful, prob-
ably because the higher temperature would be sufficient to
As arylboronates are an important class of organometallics,
which can be widely used as versatile building blocks in
modern organic synthesis, the development of transition
metal-catalyzed aryl CÀB bond-forming reactions has sustained
ongoing interest.[1] From an environmental and economic
point of view, there is no doubt that the direct borylation of
ubiquitous CÀH bonds of aromatic hydrocarbons is an ultimate
goal in this area.[2] Numerous catalyst systems, most of which
were rhodium and iridium complexes, have been proposed for
utilization in the CÀH borylation of arenes with pinacolborane
(4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 1) or bis(pinacolato)di-
boron (4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi-1,3,2-dioxaborolane,
2) as a boron source. In contrast, an example of such transfor-
mation using ruthenium catalysts is rare. In 2006, the
[Cp*RuCl2]2-catalyzed CÀH borylation of alkanes with bis(pina-
colato)diboron (2) has been reported by Hartwig’s group; how-
ever, benzene was not the suitable substrate under these con-
ditions.[3] Although the ruthenium-catalyzed CÀH borylation of
indoles with pinacolborane (1) has been achieved by Tatsumi,
Oestreich, and co-workers, the borylation of other substrates
has not been disclosed.[4] Very recently, Nolan and co-workers
have described an efficient ruthenium catalyst for the CÀH bor-
ylation of 2-arylpyridines with bis(pinacolato)diboron (2).[5]
During the past few years, considerable attention has been
devoted to the ortho-selective CÀH borylation of arenes bear-
ing various oxygen and nitrogen functionalities as directing
groups.[2,5–7] The pioneer studies that introduced the concept
of chelation-assisted catalytic CÀH functionalization relied on
ruthenium catalysts.[8] For example, the ruthenium-catalyzed
CÀH silylation of arenes bearing ortho-directing groups has
been reported.[9] Despite the success of ruthenium catalysts for
Table 1. Optimization of Ru-catalyzed borylation of 2-phenylpyridine (3a)
with pinacolborane (1).[a]
Entry
Catalyst
Solvent
Yield[b] [%]
5a
4a
1
[RuH2(CO)(PPh3)3]
[RuH2(CO)(PPh3)3]
[RuH2(CO)(PPh3)3]
Ru3(CO)12
[Ru(cod)(cot)]
[Cp*RuCl]4
[RuCl2(p-cymene)]2
[RuH2(CO)(PPh3)3]
[RuH2(CO)(PPh3)3]
[RuH2(CO)(PPh3)3]
THF
THF
THF
THF
THF
THF
THF
toluene
cyclohexane
THF
6
47
40
42
15
23
13
41
22
6
94
43
18
31
39
18
59
18
42
93
2[c]
3[d]
4
5
6
7
8
9
10[e]
[a] S. Okada, Dr. T. Namikoshi, Prof. Dr. S. Watanabe, Prof. Dr. M. Murata
Department of Materials Science and Engineering
Kitami Institute of Technology
165 Koen-Cho, Kitami, Hokkaido 090-8507 (Japan)
Fax: (+81)157-26-4973
E-mail: muratamk@mail.kitami-it.ac.jp
[a] Reaction conditions:
1 (0.75 mmol), 3a (0.25 mmol), Ru catalyst
(2 mol% Ru atom), and solvent (0.5 mL), 1508C, 16 h. [b] GC yields are
based on 3a. [c] At 1208C. [d] 1 (0.30 mmol) was used. [e] 2 (0.38 mmol)
was used instead of 1.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cctc.201500110.
ChemCatChem 2015, 7, 1531 – 1534
1531
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communications
promote the equilibrium of BÀN interaction (entries 2 and 3).
Although several ruthenium complexes, including Ru3(CO)12,
[Ru(cod)(cot)], [Cp*RuCl]4, and [RuCl2(p-cymene)]2, showed
some catalytic activity for the CÀH borylation (entries 4–7),
[RuH2(CO)(PPh3)3] was the catalyst of choice. Different reaction
media were subsequently investigated, and THF proved to be
the best solvent (entries 1, 8, and 9). Thus, the optimized reac-
tion conditions utilized [RuH2(CO)(PPh3)3] in THF. Under the
condition, bis(pinacolato)diboron (2) also participated in the
CÀH borylation (entry 10).[5]
normal trigonal boron atom of 4e was characterized by
11B NMR analysis. Furthermore, the pyrazol ring can also func-
tion as a directing group (entry 6).
To gain mechanistic insights into the ruthenium-catalyzed
CÀH borylation, we conducted some preliminary isotope ex-
periments with pinacolborane (1). Comparison of the observed
pseudo-first-order rate constants for individual experiments
with 3a and a deuterated substrate 3a-[D5] yielded a kinetic
isotope effect of 3.2 (Scheme 1a). However, when the reaction
The results obtained with some other substrates 3, giving ar-
ylboronates 4 or 5 similarly as above, are listed in Table 2. The
Table 2. Ru-catalyzed Borylation of 3 with Pinacolborane (1).[a]
Entry
3
Product
Yield[b] [%]
1
87
2
68
65
3[c]
Scheme 1. Isotope experiments to reveal the catalytic cycle.
4
5
82
79
of 3a-[D5] was taken to 62% conversion, 1H NMR spectra of
the recovered starting material 3a-[D5] showed that partial
H/D exchange occurred at the ortho positions of the phenyl
ring (Scheme 1b). This result indicates that the CÀH bond acti-
vation step is an equilibrium process. Next, the unreacted 3a
was recovered at 87% conversion (Scheme 1c). The 13C ratio of
each carbon in the recovered 3a to the same carbon in
a virgin 3a was measured by Singleton’s NMR technique at
natural abundance, but no significant carbon isotope effect
was observed.[10,11] These results suggest that neither the CÀH
bond activation step nor the CÀB bond formation step would
be the rate-determining for the present CÀH borylation.
[a] Reaction conditions: 1 (0.75 mmol), 3 (0.25 mmol), [RuH2(CO)(PPh3)3]
(2 mol%), and THF (0.5 mL), 1508C, 16 h. [b] Isolated yield. [c] At 1008C.
reaction of 3b, bearing only one ortho CÀH bond on the aro-
matic ring, afforded the corresponding 4b as the sole product
(entry 1). In the case of 3c, the 11B NMR signals of the dibory-
lated product 5c were observed at 9.4 and 30.5 ppm (entry 2).
The stronger boron–nitrogen interaction than 5a should arise
from the electron-withdrawing group on the aromatic ring.
The monoborylation of 2-phenyl-b-picoline (3d) was achieved
selectively at 1008C to give the corresponding 4d (entry 3),
whereas the reaction at 1508C resulted in a 1:1 mixture of 4d
and diborylated product. The borylation of benzo[h]quinoline
(3e) selectively occurred at the 10-position (entry 4). The
The present CÀH borylation was then addressed computa-
tionally by density functional theory (DFT) calculations. We
have adopted the reaction of phenylmethanimine with HB(eg)
(1,3,2-dioxaborolane) as a model reaction, and the PPh3 ligand
of [RuH2(CO)(PPh3)3] was replaced by PH3 in the computed
structures.[12] The energy profile of a proposed catalytic cycle is
depicted in Figure 1. On the basis of the theoretical study by
Morokuma and co-workers on the ruthenium-catalyzed addi-
ChemCatChem 2015, 7, 1531 – 1534
www.chemcatchem.org
1532
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communications
Figure 1. Reaction pathways with calculated relative free energies (kcalmolÀ1).
tion of arenes to alkenes, a chelation of the substrate to an
active ruthenium(0) species “Ru(CO)(PH3)2” followed by oxida-
tive addition of the ortho CÀH bond would take place through
a transition state TS6À7 to form an intermediate 7.[13] The acti-
vation barrier for the CÀH bond activation step is very low.
A ligand substitution reaction includes dissociation of the
PH3 ligand and coordination of HB(eg) forming a s-borane
ruthenium 9. The s-complex-assisted metathesis (s-CAM) with
the RuÀH bond takes place through a transition state TS9À10 to
form an aryl boryl ruthenium 10.[14] During the hydrogen disso-
ciation step from 10 to 11, the RuÀC bond moves from the
trans to the cis position to the boron atom due to the strong
trans influence.[15] After the coordination of PH3, the CÀB re-
ductive elimination through a transition state TS12À13 takes
place to give a ruthenium(0) complex 13, which contains a co-
ordinated product. An associative ligand exchange between
the product and the substrate would regenerate 6.
mechanism, and reductive elimination of the CÀB bond. The s-
CAM between the RuÀH and BÀH bonds of 9 is the rate-deter-
mining step of the catalytic cycle. Further studies, including
the expansion of substrate scope as well as detailed kinetic
studies, are currently underway.
Experimental Section
General Procedure: [RuH2(CO)(PPh3)3] (4.6 mg, 5.0 mmol) was
placed in a resealable Schlenk tube. The tube was evacuated and
backfilled with nitrogen, and then charged with THF (0.5 mL), the
2-arylpyridines (2, 0.25 mmol), and pinacolborane (1; 108 mL,
0.75 mmol). The reaction mixture was then stirred at 1508C for
16 h. The resulting mixture was allowed to cool to room tempera-
ture, diluted with toluene, washed with brine, and dried over
Na2SO4. The solvent was removed under reduced pressure, and the
residue was purified by Kugelrohr distillation to afford the desired
product 3.
As shown in Figure 1, the transition state for the s-CAM
TS9À10 is the highest point on the free energy profile of the
catalytic cycle.[16] The rate-determining s-CAM involving RuÀH
(or RuÀD) bond cleavage would be agreement with the deute-
rium kinetic isotope effect as shown in Scheme 1a.[17] Further-
more, it is possible that H2 also coordinates with 8 to yield a s-
hydrogen ruthenium 9’. The s-CAM of 9’ results in an ex-
change between dihydrogen and hydride ligands. This transi-
tion state TS9’À10’, which would achieve the H/D scrambling as
Keywords: boranes · CÀH activation · density functional
calculations · isotope effects · ruthenium
[1] See, for example: Boronic Acids. Preparation, Applications in Organic Syn-
thesis and Medicine (Ed.: D. G. Hall), Wiley-VCH, Weinheim, 2005.
[2] For reviews on the catalytic CÀH borylation, see: a) I. A. I. Mkhalid, J. H.
Barnard, T. B. Marder, J. M. Murphy, J. F. Hartwig, Chem. Rev. 2010, 110,
890–931; b) J. F. Hartwig, Chem. Soc. Rev. 2011, 40, 1992–2002; c) J. F.
Hartwig, Acc. Chem. Res. 2012, 45, 864–873; d) A. Ros, R. Fernandez,
J. M. Lassaletta, Chem. Soc. Rev. 2014, 43, 3229–3243.
shown in Scheme 1b, is lower in energy than TS9À10
.
In conclusion, [RuH2(CO)(PPh3)3] was found to catalyze the
ortho-selective borylation of 2-arylpyridines 3 with pinacolbor-
ane (1). Theoretical calculations suggest that the catalytic cycle
involves oxidative addition of the CÀH bond of 3, the forma-
tion of the boryl ruthenium intermediate 10 through a s-CAM
[3] J. M. Murphy, J. D. Lawrence, K. Kawamura, C. Incarvito, J. F. Hartwig, J.
Am. Chem. Soc. 2006, 128, 13684–13685.
[4] T. Stahl, K. Muther, Y. Ohki, K. Tatsumi, M. Oestreich, J. Am. Chem. Soc.
2013, 135, 10978–10981.
[5] J. A. Fernµndez-Salas, S. Manzini, L. Piola, A. M. Z. Slawin, S. P. Nolan,
Chem. Commun. 2014, 50, 6782–6784.
ChemCatChem 2015, 7, 1531 – 1534
www.chemcatchem.org
1533
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communications
[6] Ir-catalyzed, functional group-directed CÀH borylations: a) T. A. Boebel,
J. F. Hartwig, J. Am. Chem. Soc. 2008, 130, 7534–7535; b) S. Kawamorita,
H. Ohmiya, K. Hara, A. Fukuoka, M. Sawamura, J. Am. Chem. Soc. 2009,
131, 5058–5059; c) T. Ishiyama, H. Isou, T. Kikuchi, N. Miyaura, Chem.
Commun. 2010, 46, 159–161; d) S. Kawamorita, H. Ohmiya, M. Sawa-
mura, J. Org. Chem. 2010, 75, 3855–3858; e) D. W. Robbins, T. A. Boebel,
J. F. Hartwig, J. Am. Chem. Soc. 2010, 132, 4068–4069; f) K. Yamazaki, S.
Kawamorita, H. Ohmiya, M. Sawamura, Org. Lett. 2010, 12, 3978–3981;
g) H. Itoh, T. Kikuchi, T. Ishiyama, N. Miyaura, Chem. Lett. 2011, 40,
1007–1008; h) A. Ros, B. Estepa, R. López-Rodríguez, E. lvarez, R.
Fernµndez, J. M. Lassaletta, Angew. Chem. Int. Ed. 2011, 50, 11724–
11728; Angew. Chem. 2011, 123, 11928–11932; i) C. W. Liskey, J. F. Hart-
wig, J. Am. Chem. Soc. 2012, 134, 12422–12425; j) R. López-Rodríguez,
A. Ros, R. Fernµndez, J. M. Lassaletta, J. Org. Chem. 2012, 77, 9915–
9920; k) A. J. Roering, L. V. A. Hale, P. A. Squier, M. A. Ringgold, E. R. Wie-
derspan, T. B. Clark, Org. Lett. 2012, 14, 3558–3561; l) A. Ros, R. López-
Rodríguez, B. Estepa, E. lvarez, R. Fernµndez, J. M. Lassaletta, J. Am.
Chem. Soc. 2012, 134, 4573–4576; m) S. H. Cho, J. F. Hartwig, J. Am.
Chem. Soc. 2013, 135, 8157–8160; n) T. Mita, Y. Ikeda, K. Michigami, Y.
Sato, Chem. Commun. 2013, 49, 5601–5603; o) I. Sasaki, H. Doi, T. Hashi-
moto, T. Kikuchi, H. Ito, T. Ishiyama, Chem. Commun. 2013, 49, 7546–
7548; p) I. Sasaki, T. Amou, H. Ito, T. Ishiyama, Org. Biomol. Chem. 2014,
12, 2041–2044; q) B. Ghaffari, S. M. Preshlock, D. L. Plattner, R. J. Staples,
P. E. Maligres, S. W. Krska, R. E. Maleczka, M. R. Smith, J. Am. Chem. Soc.
2014, 136, 14345–14348; r) K. M. Crawford, T. R. Ramseyer, C. J. A. Daley,
T. B. Clark, Angew. Chem. Int. Ed. 2014, 53, 7589–7593; Angew. Chem.
2014, 126, 7719–7723.
Chatani, S. Murai, Chem. Lett. 2002, 31, 396–397; c) F. Kakiuchi, M. Mat-
sumoto, K. Tsuchiya, K. Igi, T. Hayamizu, N. Chatani, S. Murai, J. Organo-
met. Chem. 2003, 686, 134–144; d) H. Ihara, M. Suginome, J. Am. Chem.
Soc. 2009, 131, 7502–7503; e) T. Sakurai, Y. Matsuoka, T. Hanataka, N.
Fukuyama, T. Namikoshi, S. Watanabe, M. Murata, Chem. Lett. 2012, 41,
374–376.
[10] a) D. A. Singleton, A. A. Thomas, J. Am. Chem. Soc. 1995, 117, 9357–
9358; b) D. E. Frantz, D. A. Singleton, J. P. Snyder, J. Am. Chem. Soc.
1997, 119, 3383–3384.
[11] The 13C kinetic isotope effect in Ru-catalyzed CÀH functionalizations:
a) F. Kakiuchi, H. Ohtaki, M. Sonoda, N. Chatani, S. Murai, Chem. Lett.
2001, 30, 918–919; b) C. S. Yi, D. W. Lee, Organometallics 2009, 28,
4266–4268; c) K.-H. Kwon, D. W. Lee, C. S. Yi, Organometallics 2010, 29,
5748–5750; d) C. S. Yi, D. W. Lee, Organometallics 2010, 29, 1883–1885;
e) D.-H. Lee, K.-H. Kwon, C. S. Yi, J. Am. Chem. Soc. 2012, 134, 7325–
7328.
[12] See Supporting Information for the reaction pathway with B2(eg)2.
[13] a) T. Matsubara, N. Koga, D. G. Musaev, K. Morokuma, J. Am. Chem. Soc.
1998, 120, 12692–12693; b) T. Matsubara, N. Koga, D. G. Musaev, K. Mo-
rokuma, Organometallics 2000, 19, 2318–2329.
[14] For a review on the s-complex-assisted metathesis, see: R. N. Perutz, S.
Sabo-Etienne, Angew. Chem. Int. Ed. 2007, 46, 2578–2592; Angew.
Chem. 2007, 119, 2630–2645.
[15] a) G. Sivignon, P. Fleurat-Lessard, J.-M. Onno, F. Volatron, Inorg. Chem.
2002, 41, 6656–6661; b) K. C. Lam, W. H. Lam, Z. Lin, T. B. Marder, N. C.
Norman, Inorg. Chem. 2004, 43, 2541–2547; c) H. Braunschweig, P. Bren-
ner, A. Muller, K. Radacki, D. Rais, K. Uttinger, Chem. Eur. J. 2007, 13,
7171–7176.
[16] Figure 1 shows the B3LYP energy profile. The energy profile using the
M06 functional is given in the Supporting Information.
[17] As suggested by a reviewer, kinetic studies with deuterated pinacolbor-
ane DB(pin)would be more convincing to determine the rate-limiting
step. These experiments will be undertaken in the near future.
[7] Rh-catalyzed, functional group-directed CÀH borylations: a) S. Kawa-
morita, T. Miyazaki, H. Ohmiya, T. Iwai, M. Sawamura, J. Am. Chem. Soc.
2011, 133, 19310–19313; b) S. Kawamorita, T. Miyazaki, T. Iwai, H.
Ohmiya, M. Sawamura, J. Am. Chem. Soc. 2012, 134, 12924–12927;
c) E. C. Keske, B. D. Moore, O. V. Zenkina, R. Wang, G. Schatte, C. M.
Crudden, Chem. Commun. 2014, 50, 9883–9886.
[8] For reviews on the ruthenium-catalyzed CÀH bond functionalizations,
see: a) F. Kakiuchi, S. Murai, Acc. Chem. Res. 2002, 35, 826–834; b) F. Ka-
kiuchi, N. Chatani, Adv. Synth. Catal. 2003, 345, 1077–1101; c) F. Kakiu-
chi, T. Kochi, Synthesis 2008, 3013–3039; d) P. B. Arockiam, C. Bruneau,
P. H. Dixneuf, Chem. Rev. 2012, 112, 5879–5918.
Received: February 5, 2015
Revised: March 18, 2015
[9] a) F. Kakiuchi, K. Igi, M. Matsumoto, N. Chatani, S. Murai, Chem. Lett.
2001, 30, 422–423; b) F. Kakiuchi, K. Igi, M. Matsumoto, T. Hayamizu, N.
Published online on April 20, 2015
ChemCatChem 2015, 7, 1531 – 1534
www.chemcatchem.org
1534
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Copyright of ChemCatChem is the property of Wiley-Blackwell and its content may not be
copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.