Palladium-catalyzed ortho-selective C-H borylation of 2-phenylpyridine and its derivatives at room temperature

Article abstract of DOI:10.1002/anie.201210328

Boron delivery: C-H borylation at the ortho-position of aromatic compounds is promoted by the treatment of 2-phenylpyridine, or its derivatives, with 9-borabicyclo[3.3.1]nonane in the presence of a palladium catalyst. This reaction proceeds at room temperature and can be conducted without the palladium catalyst at higher temperatures. In both cases, the regioselectivity is controlled by Lewis acid-base interaction between the boron and nitrogen atoms. Copyright

Full text of DOI:10.1002/anie.201210328

Angewandte
Chemie
DOI: 10.1002/anie.201210328
Borylation Reactions
À
Palladium-Catalyzed ortho-Selective C H Borylation of 2-
Phenylpyridine and Its Derivatives at Room Temperature**
Yoichiro Kuninobu,* Takashi Iwanaga, Tetsuya Omura, and Kazuhiko Takai*
À
À
Direct C H bond transformations have received much
converted into a reactive species for C H activation upon
treatment with a transition metal (Scheme 1b). Until recently,
it was difficult to promote transition-metal-catalyzed ortho-
attention as ideal and highly efficient methods for the
synthesis of useful organic compounds. However, several
difficulties remain, in particular the issue of regioselectivity.
To solve this problem, directing groups bearing the unshared
electron pair of a heteroatom have been used, resulting in
À
selective C H borylation, but several examples of such
transformations have appeared in the last one or two years.[4,5]
À
In C H borylation, pinacolborane and bis(pinacolate)di-
boron are usually employed as substrates.[6] Therefore, we
initially investigated the reactions between 2-phenylpyridine
(1a) and various borane reagents in the presence of a catalytic
amount of several transition metal compounds. However, the
desired reaction did not occur at all.[7–9] The reason for the low
reactivity was thought to be that the Lewis acidity of the
borane reagents was not enough to promote the Lewis acid–
base interaction between the pyridyl group of 1a and the
boron atom of pinacolborane or bis(pinacolate)diboron.
Consequently, 9-borabicyclo[3.3.1]nonane (9-BBN, 2a) was
selected as a promising substrate, because 9-BBN has higher
Lewis acidity than pinacolborane and bis(pinacolate)diboron.
Treatment of 2-phenylpyridine (1a) with 9-BBN (2a) in the
presence of a catalytic amount of a palladium salt, Pd(OAc)2,
in 1,2-dichloroethane at 258C for 24 h gave ortho-borylated
2-phenylpyridine 3a in 87% yield [Eq. (1)].[10–14] To verify the
À
dramatic development of the chemistry of C H bond trans-
formations over the last few decades.[1] The directing group
usually acts as a Lewis base to coordinate a transition metal,
and thus, the metal center comes close to an appropriate site
À
À
(a C H bond) for the reaction, and subsequent C H
activation occurs (Scheme 1a). Herein, we report the ortho-
À
Scheme 1. C H bond functionalization. a) Using the coordination of
a directing group to a metal center. b) By Lewis acid–base interaction.
DG=directing group, LB=Lewis basic heteroatom, [M]=metal cata-
lyst.
À
selective borylation of aromatic C H bonds with a palladium
catalyst using the interaction between a Lewis basic nitrogen
and Lewis acidic boron atoms.[2,3] This is a new concept for the
directing group; the group also has an electron pair, but
coordinates to a Lewis acidic main-group metal, and a boron
atom that also bears a hydrogen atom, which is then
existence of the Lewis acid–base interaction, the following
experiment was carried out: a mixture of 2-phenylpyridine
(1a) and 9-BBN (2a) in CD2Cl2 was stirred at 258C for 24 h,
and 11B NMR analysis of the reaction mixture was then
conducted. As a result, a new signal was observed at 0.3 ppm
(vs. 27.7 ppm for 2a), which is consistent with signals observed
for boranes coordinated to pyridine derivatives.[15] This result
indicates that the borylation reaction proceeded, supported
by Lewis acid–base interaction. Moreover, the reaction
proceeded even in the absence of the palladium catalyst at
higher temperature (1358C, 73%). In this reaction, other
regioisomers were not formed to the limits of detection by
1H NMR. This also supports the existence of a Lewis acid–
base interaction between the boron and nitrogen atoms.
Product 3a exhibited a light blue fluorescence in CDCl3
solution and a reddish purple to blue fluorescence as a solid
[*] Prof. Dr. Y. Kuninobu,[+] T. Iwanaga, T. Omura, Prof. Dr. K. Takai
Division of Chemistry and Biotechnology, Graduate School of
Natural Science and Technology, Okayama University
3-1-1 Tsushimanaka, Kita-ku, Okayama 700-8530 (Japan)
E-mail: kuninobu@mol.f.u-tokyo.ac.jp
ktakai@cc.okayama-u.ac.jp
[+] Present address: Graduate School of Pharmaceutical Sciences
The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku
Tokyo 113-0033 (Japan)
[**] This work was partially supported by the Ministry of Education,
Culture, Sports, Science, and Technology of Japan.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201210328.
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under UV irradiation (254 nm).[16,17] The result in Eq. (1)
shows that the directing group, a pyridyl group, acts not only
moiety when 2-(1-naphthalenyl)pyridine (1e) was employed
as a substrate (Table 1, entry 4). In the case of 2-(2-naph-
thalenyl)pyridine (1 f), there are two possible reaction sites.
However, the borylation reaction occurred only at the
a-position of the naphthalene skeleton (Table 1, entry 5).
Treatment of benzo[h]quinoline (1g) with 9-BBN (2a)
provided the corresponding borylated product 3g in low
yield (Table 1, entry 6). 2-Phenylpyridine having a methyl
group on the pyridyl group, 1h, also gave ortho-borylated
2-phenylpyridine 3h in 89% yield (Table 1, entry 7). Another
directing group, a pyrazolyl group, was effective for the
borylation, providing the corresponding borylated product 3i
was in 97% yield (Table 1, entry 8). 2-Phenyl-4,5-dihydroox-
azole (1j) also provided the borylated product 3j in low yield
(Table 1, entry 9). In the case of reactions at 1358C without
any catalysts, the yields of the borylated products tended to be
similar to the palladium-catalyzed reactions.[18] The reaction
did not proceed using 2-phenylpyrimidine, 2,6-diphenylpyr-
idine, 2-benzylpyridine, ketimine, benzophenone, methyl
benzoate, or trans-azobenzene.
À
to bring the reactive species close to the C H bond, but also
as a useful component for fluorescence.
Next, we investigated the scope and limitations of
aromatic compounds with an sp2 nitrogen atom. 2-Phenyl-
pyridine with an electron-donating group at the para-position
of the benzene ring, 1b, produced ortho-borylated 2-phenyl-
pyridine 3b in 83% yield in the presence of a palladium
catalyst, Pd(OAc)2 (Table 1, entry 1). The yield of the ortho-
Table 1: Reactions between several N-heteroaromatic compounds 1 and
9-BBN (2a).[a]
Entry
1
3
Yield [%][b]
Although there is no direct evidence for the reaction
mechanism, we propose the mechanism for the palladium-
catalyzed ortho-selective borylation shown in Scheme 2a.
1
2
3
1b: R1 =4-MeO
1c: R1 =4-CF3
1d: R1 =2-Me
83 (69)
41 (0)
93 (59)
4
5
6
1e
1 f
1g
1h
77 (68)
50[c] (52)
19 (0)
7
8
9
89 (69)
97 (0)
27 (0)
Scheme 2. Proposed mechanism for the formation of ortho-borylated
2-phenylpyridines.
[a] 2a (0.70 equiv). [b] Yields shown are for reactions using Pd(OAc)2
(3.0 mol%) at 258C. Data given in parentheses are for reactions
conducted at 1358C without catalyst. [c] Reaction conducted at 508C.
Step a1) Lewis acid–base interaction between a boron atom
of 9-BBN (2a) and a nitrogen atom of 2-phenylpyridine 1.
À
Step a2) Oxidative addition of a B H bond to palladium(0)
borylated product decreased when 2-phenylpyridine 1c,
which bears an electron-withdrawing group, was used as
a substrate (Table 1, entry 2). The reaction was not inhibited
by a methyl group at the 2-position, and the desired product
3d was afforded in 93% yield (Table 1, entry 3). The
(the oxidation state of the palladium atom is II).[19,20]
À
Step a3) C H bond activation by the elimination of H2
(s-bond metathesis). Step a4) Reductive elimination to give
3 and regenerate the palladium(0) species. In step a2, the
palladium(0) species, which is formed by the reduction of
Pd(OAc)2 with 9-BBN, is likely the active catalytic species
À
borylation also proceeded at the C H bond of a naphthyl
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À
because black precipitates, presumably palladium black, were
observed.
will provide useful insight into transformations through C H
bond activation.
For borylation without the palladium catalyst, we propose
another reaction mechanism (Scheme 2b). As the reactivity
decreases under light shielding, the borylation reaction likely Experimental Section
Typical procedure for the palladium-catalyzed synthesis of ortho-
occurs via a radical process. The metal-free process was
completely inhibited by radical inhibitors such as 2,2,6,6-
tetramethylpiperidine 1-oxyl (TEMPO) and galvinoxyl, lead-
ing to the recovery of 89% and 99% of 2-phenylpyridine
(1a), respectively. These results also support the radical
pathway. The proposed reaction mechanism is as follows:
Step b1) Lewis acid–base interaction between a boron atom
of 9-BBN (2a) and a nitrogen atom of 2-phenylpyridine 1.
Step b2) Formation of a boryl radical by the elimination of
a hydrogen radical.[21] Step b3) Intramolecular addition. Step
b4) Elimination of a hydrogen radical (the hydrogen radical
is combined with that formed from another hydrogen radical
to generate H2) to give product 3.
borylated product 3a: A mixture of 2-phenylpyridine (1a, 77.6 mg,
0.500 mmol), 9-BBN dimer (2a, 85.4 mg, 0.35 mmol), and Pd(OAc)2
(3.4 mg, 0.015 mmol) in 1,2-dichloroethane (1.0 mL) was stirred at
258C for 24 h under an argon atmosphere. After purification by silica
gel column chromatography (n-hexane/benzene = 5:1), 2-[2-(9-
borabicyclo[3.3.1]-9-nonyl)phenyl]pyridine (3a) was isolated in
87% yield (60.0 mg).
Received: December 28, 2012
Revised: February 19, 2013
Published online: March 19, 2013
Keywords: borylation · Lewis acid · Lewis base · palladium ·
.
regioselectivity
This reaction also proceeded well on a gram scale
[Eq. (2)]. As a result, 1.5 g of the borylated product 3a was
obtained (88% yield).[22]
[1] There have been several reviews on transition metal-catalyzed
À
C H bond transformations using directing groups; see: a) F.
Kakiuchi, S. Murai, Top. Organomet. Chem. 1999, 3, 47; b) Y.
Guari, S. Sabo-Etienne, B. Chaudret, Eur. J. Inorg. Chem. 1999,
1047; c) G. Dyker, Angew. Chem. 1999, 111, 1808; Angew. Chem.
Int. Ed. 1999, 38, 1698; d) F. Kakiuchi, T. Kochi, Synthesis 2008,
3013; e) R. Jazzar, J. Hitce, A. Renaudat, J. Sofack-Kreutzer, O.
Baudoin, Chem. Eur. J. 2010, 16, 2654; f) T. W. Lyons, M. S.
Sanford, Chem. Rev. 2010, 110, 1147.
[2] We have recently reported transition-metal-catalyzed introduc-
À
tion of heteroatoms into aromatic compounds by aromatic C H
bond activation; see: a) T. Ureshino, T. Yoshida, Y. Kuninobu,
K. Takai, J. Am. Chem. Soc. 2010, 132, 14324; b) Y. Kuninobu, T.
Yoshida, K. Takai, J. Org. Chem. 2011, 76, 7370.
The desired product 5 was not formed upon treatment of
2,3-diphenylpyrazine (4) with 9-BBN (2a) in the presence of
a catalytic amount of a palladium salt, Pd(OAc)2; instead,
a complex mixture was generated. However, when the
catalyst was changed to a rhenium complex, [{ReBr(CO)3-
(thf)}2], the double borylation reaction proceeded at both
ortho-positions and the corresponding product 5 was obtained
in 51% yield [Eq. (3)].[23,24]
[3] For recent examples of transition metal-catalyzed introduction
À
of heteroatoms into aromatic compounds via aromatic C H
bond activation, see: a) Handbook of C-H Transformations
(Ed.: G. Dyker), Wiley-VCH, Weinheim, 2005; see also,
Ref. [1f].
[4] There have been several reports on the borylation of aromatic
À
C H bonds. However, the reactions usually occur at the meta-
and para-positions of the substrates. The regioselectivity is
controlled by steric effects; see: a) J.-Y. Cho, M. K. Tse, D.
Holmes, R. E. Maleczka, Jr., M. R. Smith III, Science 2002, 295,
305; b) T. Ishiyama, J. Takagi, K. Ishida, N. Miyaura, N. R.
Anastasi, J. F. Hartwig, J. Am. Chem. Soc. 2002, 124, 390; c) T.
Ishiyama, J. Takagi, J. F. Hartwig, N. Miyaura, Angew. Chem.
2002, 114, 3182; Angew. Chem. Int. Ed. 2002, 41, 3056. For recent
reviews, see: d) J. F. Hartwig, Chem. Soc. Rev. 2011, 40, 1992;
e) I. A. I. Mkhalid, J. H. Barnard, T. B. Marder, J. M. Murphy,
J. F. Hartwig, Chem. Rev. 2010, 110, 890.
[5] Quite recently, ortho-selective borylation of aromatic com-
À
pounds by C H bond activation has been reported; see: a) T. A.
In summary, we have succeeded in the palladium-cata-
lyzed regioselective borylation of 2-phenylpyridine deriva-
tives. This reaction proceeded even at room temperature. The
regioselectivity arises from Lewis acid–base interaction
between the nitrogen and boron atoms. Using this method,
the borylated product can be obtained on a gram scale. As the
ortho-borylated 2-phenylpyridines exhibit fluorescence under
UV irradiation, the products will be useful as functional
materials. In addition, the p-conjugated systems could be
expanded by double borylation. We hope that this reaction
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J.-Q. Yu, J. Am. Chem. Soc. 2012, 134, 134; i) A. Ros, R. Lꢀpez-
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Angew. Chem. 2006, 118, 3242; Angew. Chem. Int. Ed. 2006, 45,
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Chem. Soc. 2009, 131, 14549; for a review, see: d) A. Loudet, K.
Burgess, Chem. Rev. 2007, 107, 4891; see also Ref. [12].
[17] 3a turned pink in color under UV light irradiation. After the
color changed, the fluorescence of 3a nearly disappeared.
However, after recrystallization, 3a turned white in color and
the fluorescence returned. The reason for this is not clear.
[18] In the case of substrate 1c, the coupling reaction between the
electron-poor aromatic ring and electron-deficient boryl radical
is expected to be difficult. On the other hand, when 1g, 1i, and 1j
were employed as substrates, the distances between the carbon
atom of the substrates and boron atom of 9-BBN in the Lewis
acid–base complexes are longer than those of complexes
between 2-phenylpyridine derivatives and 9-BBN.
[6] The hydroborane reagents were limited to only pinacolborane
and bis(pinacolate)diboron. For several reviews, see: a) T.
Ishiyama, N. Miyaura, Handbook of C-H Transformations,
Vol. 1 (Ed.: G. Dyker, Wiley-VCH, Weinheim, 2005, pp. 126 –
131; b) T. Ishiyama, J. Synth. Org. Chem. Jpn. 2005, 63, 440.
[7] Pinacolborane in CH2ClCH2Cl at 1358C for 24 h gave no
reaction with 5 mol% of: [Re2(CO)10], [ReBr(CO)5],
[{ReBr(CO)3(thf)}2], [RhCl(PPh3)3], [{IrCl(cod)}2], or Pd-
(OAc)2.
[8] Bis(pinacolate)diboron in CH2ClCH2Cl at 1358C for 24 h gave
no reaction with 5 mol% of: [Re2(CO)10], [ReBr(CO)5],
[{ReBr(CO)3(thf)}2], [RhCl(PPh3)3], [{IrCl(cod)}2], or Pd-
(OAc)2.
À
[19] For an example of oxidative addition of a B H bond to
a palladium center, see: D. E. Kadlecek, P. J. Carroll, L. G.
Sneddon, J. Am. Chem. Soc. 2000, 122, 10868.
[9] Catecholborane in CH2ClCH2Cl at 1358C for 24 h gave no
reaction with 5 mol% of: [Re2(CO)10], [ReBr(CO)5],
[{ReBr(CO)3(thf)}2], [RhCl(PPh3)3], [{IrCl(cod)}2], or Pd-
(OAc)2.
[10] CCDC 926839 (3a) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif. For details, see the Supporting
Information.
[11] Yields from metal catalyst (5.0 mol%) screening with 2a
(0.50 equiv) in toluene at 1358C for 24 h: [Mn2(CO)10], trace;
[MnBr(CO)5], trace; [Re2(CO)10], 0%; [ReBe(CO)5], 15%;
[{ReBr(CO)3(thf)}2], 63%; [RhCl(PPh3)3], 9%; [{IrCl(cod)}2],
59%; Pd/C, 0%; [Pd2(dba)3], 97%; [Pd(PPh3)4], 8%; Pd(OAc)2,
65%; [PdCl2(NCPh)2], 50%; [PdCl2(PPh3)2], 19%; [PdBr2-
(PPh3)2], 76%. Under the conditions in Table 1: [Pd2(dba)3],
76%; [Pd(PPh3)4], 0%.
[20] The 11B NMR signal of a mixture of pyridine and 9-BBN was
observed at 1.4 ppm. In contrast, a signal was observed at
5.7 ppm in the measurement of a mixture of pyridine, 9-BBN,
and palladium catalyst. These results show that another species
was formed upon addition of the palladium catalyst, one with
a chemical shift suitable for a metal-boron-nitrogen species (see:
A. Zech, M. F. Haddow, H. Othman, G. R. Owen, Organo-
metallics 2012, 31, 6753). Therefore, it can be suggested that
Lewis acid – base interaction between nitrogen and boron atoms
remains after Step a2.
[21] For an example of the formation of a borane radical species from
9-BBN, see: V. T. Perchyonok, C. H. Schiesser, Tetrahedron Lett.
1998, 39, 5437.
[22] The palladium-catalyzed cross-coupling reaction between the
borylated product 3a and 1-iodododecane did not proceed; see:
T. Ishiyama, S. Abe, N. Miyaura, A. Suzuki, Chem. Lett. 1992,
691).
[12] Yields from solvent screening with 2 (0.50 equiv) and Pd(OAc)2
(5.0 mol%) at 1358C for 24 h: octane, 32%; toluene, 65%; 1,2-
dichloroethane, 67%; dioxane, 42%; acetonitrile, 0%; neat,
92%.
[13] For the synthesis of pyridine-borane complexes by electrophilic
aromatic borylation, see: N. Ishida, T. Moriya, T. Goya, M.
Murakami, J. Org. Chem. 2010, 75, 8709.
[14] Although the borylation reaction did not proceed using di-
siamylborane, dicyclohexylborane (2b) gave the desired bory-
lated product 3k in 3% or 4% yield, respectively, in the presence
of Pd(OAc)2 (5.0 mol%) or [ReBr(CO)3(thf)]2 (2.5 mol%) in
1,2-dichloroethane at 1358C for 24 h.
[15] C. K. Narula, H. Nçth, Inorg. Chem. 1985, 24, 2532. The
existence of a Lewis acid – base interaction between a boron
atom of 9-BBN (2a) and the pyridine moiety of 1 is also
supported by the 11B NMR chemical shift of a mixture of 1a and
2a (0.3 ppm), which is similar to that of product 3a (3.4 ppm).
[16] There have been several reports on aza-p-conjugated frame-
works containing an intramolecular boron–nitrogen coordina-
[23] Yields from a metal catalyst screen: [Re2(CO)10], 13%;
[ReBr(CO)5], 26%; [MnBr(CO)5], 0%; [{IrCl(cod)}2], 14%;
Pd(OAc)2, 0%.
[24] The reaction in Eq. (4) did not proceed without the rhenium
catalyst. The possible mechanism for the rhenium-catalyzed
double borylation must be the similar to that of palladium-
catalyzed borylation; that is: Step a1) Lewis acid–base interac-
tion between a boron atom of 9-BBN (2) and a nitrogen atom of
À
2-phenylpyridine 1. Step a2) Oxidative addition of a B H bond
to a rhenium(I) atom (the oxidation state of the rhenium atom is
À
III). Step a3) C H bond activation by the elimination of H2
(s-bond metathesis). Step a4) Reductive elimination to give 3
and regenerate the rhenium(I) species. The electron density of
pyrazine is lower than that of pyridine, and the Lewis acid–base
interaction must be weaker owing to the lower basicity of the
pyrazine moiety. Therefore, heating at 1358C was necessary to
promote the reaction.
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