Catalytic borylation of o-xylene and heteroarenes via C-H activation

Article abstract of DOI:10.1016/S1381-1169(03)00470-9

Iridium and rhodium complexes catalyze the borylation of xylene and different heteroarenes using pinacolborane via C-H activation. Various five-membered heterocycles such as thiophene, pyrrole, thionaphthene, and indole derivatives yield the borylated pro

Full text of DOI:10.1016/S1381-1169(03)00470-9

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Journal of Molecular Catalysis A: Chemical 207 (2004) 21–25
Catalytic borylation of o-xylene and heteroarenes
via C–H activation
Kristin Mertins, Alexander Zapf, Matthias Beller∗
Leibniz-Institut für Organische Katalyse an der Universität Rostock e. V., Buchbinderstrasse 5-6, 18055 Rostock, Germany
Received 16 May 2003; received in revised form 16 June 2003; accepted 16 June 2003
Abstract
Iridium and rhodium complexes catalyze the borylation of xylene and different heteroarenes using pinacolborane via C–H activation. Various
five-membered heterocycles such as thiophene, pyrrole, thionaphthene, and indole derivatives yield the borylated products in moderate to
good yields. In general, the reactions proceed with high selectivity to give borylation ortho to the heteroatom.
© 2003 Elsevier B.V. All rights reserved.
Keywords: Boronates; Borylation; C–H activation; Iridium; Rhodium
1. Introduction
rylation of unsubstituted hydrocarbons [10]. Fundamental
studies on hydrocarbon activation by Cp∗M(PMe3)(H)2 (M:
Ir, Rh) were described by Bergman [11] and Jones [12]. The
direct borylation of non-activated C–H bonds was first de-
scribed using alkanes. Initial stoichiometric reactions devel-
oped by Bergmann [13] were soon followed up by catalytic
protocols reported by Hartwig and coworkers [14]. Hartwig
also developed a photochemical borylation of non-activated
hydrocarbons using catalytic amounts of metal complexes
[15]. In 1999, the first thermally induced metal-catalyzed re-
action of a borane and an arene has been reported by Smith
and coworkers [16]. Recently, Hartwig and coworkers have
described the borylation of halogenated arenes even at room
temperature [17]. Most reports on catalytic borylations use
the substrate as solvent [18]. Nevertheless, in some cases cy-
clohexane [19] or octane [20] served as an inert solvent for
borylation of arenes. Due to the importance of heteroarenes
as part of pharmaceuticals and agrochemicals [21] we be-
came interested in the direct borylation of heteroarenes.
When we started our investigations mid of 2002 the catalytic
borylation of heteroaromatic substrates has been known just
for 2,6-dimethylpyridine [16b], 2,6-dichloropyridine [22]
and 1-triisopropylsilyl-pyrrole as substrates [19]. Parallel
to our work, Miyaura and coworkers have described the
borylation of different heteroarenes using diboranes in the
presence of [Ir(COD)Cl]2 and 4,4ꢀ-di-t-butyl-2,2ꢀ-bipyridine
at 80–100 ◦C to give the corresponding heteroarylboronates
[20].
The versatility of organoboron compounds in organic
chemistry renders them attractive targets for synthesis. For
example, palladium- and nickel-catalyzed cross-coupling
reactions of boronic acids with aryl halides have become the
most important method for the synthesis of biaryls (Suzuki
reaction) [1]. In addition to their role in cross-coupling re-
actions, boronic acids and esters are used for the preparation
of amines [2], alcohols [3], and olefins [4]. Traditionally,
arylboronic acids are prepared by reacting aryl Grignard
[5] or lithium [6] reagents with trialkylborates, followed by
hydrolytic work up. More recently, Miyaura and coworkers
[7] and Masuda and coworkers [8] have synthesized aryl-
boronates by Pd-catalyzed coupling of (di)borane reagents
and arenes substituted by a leaving group. Clearly, from
an environmental point of view, the selective borylation of
arenes as depicted in Scheme 1 is a more attractive goal.
While the catalytic functionalization of inert C–H bonds
remains one of the major challenges in synthetic organic
chemistry [9], recently important progress has been made
in the direct borylation of C–H bonds.
Theoretical estimation of B–H and B–C bond enthalpies
gave conviction in organoborane synthesis via direct bo-
∗
Corresponding author. Tel.: +49-381-466930;
fax: +49-381-4669324.
E-mail address: matthias.beller@ifok.uni-rostock.de (M. Beller).
1381-1169/$ – see front matter © 2003 Elsevier B.V. All rights reserved.
doi:10.1016/S1381-1169(03)00470-9

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K. Mertins et al. / Journal of Molecular Catalysis A: Chemical 207 (2004) 21–25
double borylated products were observed. On the other
hand, benzylic activation of o-xylene became the main re-
action pathway for Rh-catalysts. Shimada et al. found a
similar strong preference for benzylic functionalization of
toluene by Rh-catalysts [18b]. Surprisingly, we found that
Cp∗RhCl2 resulted in a predominant arene activation reac-
tion. Best yields of borylated products were obtained using
Rh(COD)acac in the presence of 1 eq. of bpy giving 67% 4,4,
5,5-tetramethyl-2-(o-tolylmethyl)-1,3,2-dioxaborolane (3a)
and [Ir(COD)Cl]2 in the presence of 8 eq. of bpy, resulting in
69% 4,4,5,5-tetramethyl-2-(3,4-dimethylphenyl)-1,3,2-di-
oxaborolane (2a).
Catalyst
- H2
H
B(OR)2
H
+
B(OR)2
Scheme 1. Borylation of benzene.
2. Results and discussion
In order to become familiar with the methodology we
started our investigation on the influence of the metal pre-
cursors and additional P- and N-donor ligands using the
reaction of o-xylene with pinacolborane at different re-
action conditions (Scheme 2). As catalyst precursors, we
chose 15 commercially available metal complexes selected
from the transition metals Ir, Rh, Ru and Pd. Product yields
were determined by GC analysis of the crude reaction mix-
tures. Selected results from approximately 100 experiments
are summarized in Table 1. Among the various complexes
[Ir(COD)Cl]2 and Rh(COD)acac gave the best results at
80 ◦C.
In general, all catalysts containing TMEDA, sparteine,
PPh3, or PCy3 were found to be ineffective in the model
reaction. In agreement with previous literature selective
borylation of sp2 C–H bonds was observed in the pres-
ence of Ir complexes and 2,2ꢀ-bipyridine (bpy). No acti-
vation of the position 3 occurred, the 4-borylated isomer
being the major product for steric reasons. In no case,
The combination of ruthenium(II)acetylacetonate, dich-
loro(p-cymene)ruthenium(II) and dichloro(1,5-cycloocta-
diene)ruthenium(II), respectively, with bpy did not catalyze
the borylation reaction at all.
In analogy to the functionalization of o-xylene we
attempted the coupling of pinacolborane and several
heterocycles catalyzed by [Ir(COD)Cl]2/2bpy at 80 ◦C
(Table 2). Here, we studied initially the reaction of sev-
eral N-heterocycles. Typically, 2 mmol pinacolborane were
reacted with an excess of 60 mmol N-heteroarene in the
presence of 0.015 mmol [Ir(COD)Cl]2 (1.5 mol% Ir) and
0.03 mmol (1.5 mol%) bpy. While pyrrole gave the corres-
ponding o-borylated product in 42% yield, N-methylpyrrole
gave only 3% of the desired product. Indoles proved to
be more reactive leading to the o-borylated products in
O
O
B
O
B
H
O
O
+
B
1.5 mol % catalyst / bpy
80 ˚C, 6 h
O
(3a)
(2a)
(1a)
Scheme 2. Borylation of o-xylene.
Table 1
Influence of several catalysts and ligands on the borylation of o-xylene
Entry
Catalyst
Ligand
Conversion (%)a
Yield 2a (%)a
Yield 3a (%)a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
[Ir(COD)Cl]2
[Ir(COD)Cl]2
[Ir(COD)Cl]2
[Ir(COD)Cl]2
[Ir(COD)Cl]2
[Ir(COD)Cl]2
[Cp∗RhCl2]2
[Rh(COD)Cl]2
Rh(COD)acac
Rh2(OAc)4
[PindophosRh(COD)][BF4]b
[PindophosRh(COD)][BF4]b
[Rh(COD)2][BF4]
[Rh(COD)2][BF4]
2bpy
4PCy3
4PPh3
2sparteine
2TMEDA
8bpy
2bpy
2bpy
1bpy
2bpy
–
100
86
96
100
55
100
100
100
100
100
27
67
0
0
3
6
69
28
4
3
3
1
0
0
1
0
0
2
59
67
39
0
0
0
0
0
1bpy
–
1bpy
72
11
65
0
0
16
a
GC yield and conversion based on pinacolborane.
Pindophos: 2,3-O,N-bis(diphenylphosphino)-1-(4-indolyloxy)-2-hydroxy-3-isopropylamino propane.
b

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K. Mertins et al. / Journal of Molecular Catalysis A: Chemical 207 (2004) 21–25
23
Table 2
Borylation of different heterocycles
Entry
Educt 1
Product 2
Yield 2b–o (%)a
Entry
6
Educt 1
Product 2
Yield 2b–o (%)a
1
1b
42
1h
0
2
1c
3
7
1i
1
3
4
1d
1e
1f
89
45
53
8
9
1j
1k
1l
88
61
4
5
10
a
GC yield based on pinacolborane.
ous catalytic borylation of other heteroarenes used more
expensive diboranes as borylation reagent. Our results
demonstrate that similar reactions can be performed with
various heteroarenes using less expensive pinacolborane
in the presence of a reduced catalyst amount. In general,
the catalytic borylation using Ir catalysts proceeds with
high selectivity for position 2 of electron-rich N- and S-
heteroarenes.
O
B
H
O
O
B
S
1.5 mol % [Ir(COD)Cl]2 / 2 bpy
S
O
80 ˚C, 6 h
(2j)
(1j)
Scheme 3. Borylation of thiophene.
45–89% (Table 2, entries 3–5). Other N-heterocycles such as
pyrazine or pyridine did not react to an appreciable amount.
The reaction of pinacolborane with thiophene (Scheme 3)
and benzothiophene resulted in 88 and 61% of the monobo-
rylated products 2j and 2k, respectively (Table 2, entries 8
and 9). In all reactions, the borylation occurred at position
2 regioselectively (>95%). Only in case of N-methylindole,
significant amounts of another isomer were observed. Here,
besides the 2-borylated product (45%) the 3-substituted
isomer is obtained in 36% yield.
4. Experimental
All experiments were carried out under an argon atmo-
1
sphere. H and 13C NMR spectra were recorded in CDCl3
solutions using a Bruker ARX 400 FT Spectrometer (1H:
400.1 MHz, 13C: 100.6 MHz). Chemical shifts are given
in ppm and refer to residual solvent as internal standard.
Gas chromatography was performed on a Hewlett Packard
HP6890 chromatograph with a HP5 column. The products
were purified on silica gel 60, 230–400 mesh.
A flask containing 2 mmol pinacolborane, 1.5 mol% cata-
lyst, and 1.5 mol% ligand was charged with 60 mmol arene
or heteroarene. The solution was stirred at 80 ◦C for 6 h. The
solvent was then removed under vacuum at room tempera-
ture and the residue was chromatographed over silica gel,
eluting with CH2Cl2, to yield the analytically pure product.
3. Conclusions
We have shown for the first time that selective catalytic
borylation of substituted indoles can be achieved. Previ-

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24
K. Mertins et al. / Journal of Molecular Catalysis A: Chemical 207 (2004) 21–25
4.1. 4,4,5,5-Tetramethyl-2-(3,4-dimethylphenyl)-1,3,2-
4.6. 2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-
dioxaborolane (2a)
thiophene (2j)
1H NMR (CDCl3, 25 ◦C, 400.1 MHz) δ: 1.25 (s, 12H),
2.18 (s, 3H), 2.19 (s, 3H), 7.05–7.07 (d, J = 7.3 Hz, 1H),
7.46–7.48 (d, J = 7.3 Hz, 1H), 7.5 (s, 1H); 13C NMR
(CDCl3, 25 ◦C, 100.6 MHz) δ: 19.9, 20.5, 25.3, 84.0, 129.6,
132.9, 136.3, 136.4, 140.6. Anal. Calcd. for C14H21BO2: C,
72.44; H, 9.12; B, 4.66; O, 13.79. Found: C, 72.65; H, 9.05;
B, 4.49; O, 13.62.
1H NMR (CDCl3, 25 ◦C, 400.1 MHz) δ: 1.39 (s, 12H),
7.23 (dd, J = 3.6, 4.8 Hz, 1H), 7.68 (dd, J = 0.9, 4.6 Hz,
1H), 7.70 (dd, J = 0.9, 3.4 Hz, 1H); 13C NMR (CDCl3,
25 ◦C, 100.6 MHz) δ: 25.2, 84.5, 128.6, 132.8, 137.6; IR (ν):
724, 856, 1142, 1521 cm−1. Anal. Calcd. for C10H15BO2S:
C, 57.17; H, 7.20; S, 15.26. Found: C, 57.42; H, 6.96; S,
15.45.
4.7. 2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-
benzothiophene (2k)
4.2. 2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-
pyrrole (2b)
1H NMR (CDCl3, 25 ◦C, 400.1 MHz) δ: 1.39 (s, 12H),
7.37 (m, 2H), 7.89 (m, 3H); 13C NMR (CDCl3, 25 ◦C,
100.6 MHz) δ: 25.4, 84.9, 123.0, 124.5, 124.8, 125.7, 134.9,
140.9, 144.1; IR (KBr) ν: 664, 752, 1137, 1523 cm−1. Anal.
Calcd. for C14H17BO2S: C, 64.63; H, 6.59; S, 12.33. Found:
C, 64.89; H, 6.69; S, 12.12.
1H NMR (CDCl3, 25 ◦C, 400.1 MHz) δ: 1.35 (s, 12H),
6.33 (dt, J = 2.4, 3.4 Hz, 1H), 6.88 (ddd, J = 1.2, 2.4,
3.6 Hz, 1H), 7.03 (dt, J = 1.4, 2.6 Hz, 1H), 8.80 (br, 1H);
13C NMR (CDCl3, 25 ◦C, 100.6 MHz) δ: 25.2, 84.0, 110.1,
120.4, 123.1; IR (ν): 746, 1142, 1559, 3354 cm−1. Anal.
Calcd. for C10H16BNO2: C, 62.22; H, 8.35; N, 7.26. Found:
C, 62.01; H, 8.14; N, 7.04.
4.8. 4,4,5,5-Tetramethyl-2-(o-tolylmethyl)-1,3,2-
dioxaborolane (3a)
4.3. 2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-
indole (2d)
1H NMR (CDCl3, 25 ◦C, 400.1 MHz) δ: 1.15 (s, 12H),
2.18 (s, 2H), 2.19 (s, 3H), 7.02 (m, 4H); 13C NMR (CDCl3,
25 ◦C, 100.6 MHz) δ: 20.5, 25.2, 83.8, 125.6, 126.3, 129.9,
130.2, 136.3, 137.9. Anal. Calcd. for C14H21BO2: C, 72.44;
H, 9.12; B, 4.66; O, 13.79. Found: C, 72.56; H, 9.10; B,
4.56; O, 13.65.
1H NMR (CDCl3, 25 ◦C, 400.1 MHz) δ: 1.38 (s, 12H),
7.11 (m, 2H), 7.26 (m, 1H), 7.39 (dd, J = 0.8, 8.3 Hz, 1H),
7.68 (dd, J = 0.8, 7.9 Hz, 1H), 8.58 (br, 1H); 13C NMR
(CDCl3, 25 ◦C, 100.6 MHz) δ: 25.4, 84.7, 111.8, 114.4,
120.3, 122.2, 124.2, 128.8, 138.7; IR (ν): 706, 852, 1137,
1539, 3415 cm−1. Anal. Calcd. for C14H18BNO2: C, 69.17;
H, 7.46; N, 5.76. Found: C, 69.24; H, 7.32; N, 5.71.
Acknowledgements
This work was funded by the BMBF (“Nachhaltige
Aromatenchemie”) and the state of Mecklenburg-Western
Pomerania. Dr. W. Baumann (IfOK) is thanked for
help with assigning the regioisomeric boranes via NMR
techniques.
4.4. 2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-
N-methylindole (2e)
1H NMR (CDCl3, 25 ◦C, 400.1 MHz) δ: 1.35 (s, 12H),
3.95 (s, 3H), 7.07 (m, 1H), 7.14 (s, 1H), 7.25 (m, 1H), 7.33
(d, J = 7.8 Hz, 1H), 7.65 (d, J = 7.9 Hz, 1H); 13C NMR
(CDCl3, 25 ◦C, 100.6 MHz) δ: 25.3, 32.7, 84.2, 101.4, 110.2,
114.7, 119.8, 122.1, 123.7, 128.4, 140.6; IR (ν): 689, 735,
1140, 1524 cm−1. Anal. Calcd. for C15H20BNO2: C, 70.06;
H, 7.84; N, 5.45. Found: C, 69.85; H, 7.73; N, 5.66.
References
[1] (a) N. Miyaura, A. Suzuki, Chem. Rev. 95 (1995) 2457;
(b) A. Suzuki, in: F. Diederich, P.J. Stang (Eds.), Metal-catalyzed
Cross-coupling Reactions, Wiley-VCH, Weinheim, 1997, p. 49;
(c) H. Geissler, in: M. Beller, C. Bolm (Eds.), Transition Metals for
Organic Synthesis, vol. 1, Wiley-VCH, Weinheim, 1998, p. 158;
(d) A. Suzuki, J. Organomet. Chem. 576 (1999) 147;
(e) A.F. Littke, G.C. Fu, Angew. Chem. 114 (2002) 4350;
A.F. Littke, G.C. Fu, Angew. Chem. Int. Ed. 41 (2002) 4176;
(f) A. Zapf, A. Ehrentraut, M. Beller, Angew. Chem. 112 (2000)
4315;
4.5. 2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-
5-methoxyindole (2f)
1H NMR (CDCl3, 25 ◦C, 400.1 MHz) δ: 1.37 (s, 12H),
3.86 (s, 3H), 6.93 (dd, J = 2.4, 8.9 Hz, 1H), 7.05 (d, J =
1.2 Hz, 1H), 7.10 (d, J = 2.4 Hz, 1H), 7.29 (d, J = 8.9 Hz,
1H), 8.52 (br, 1H); 13C NMR (CDCl3, 25 ◦C, 100.6 MHz)
δ: 25.4, 53.9, 84.5, 102.5, 112.4, 113.8, 115.3, 129.0, 134.1,
154.6; IR (ν): 835, 1138, 1120, 1537, 3377 cm−1. Anal.
Calcd. for C15H20BNO3: C, 65.96; H, 7.38; N, 5.13. Found:
C, 65.90; H, 7.12; N, 5.30.
A. Zapf, A. Ehrentraut, M. Beller, Angew. Chem. Int. Ed. 39 (2000)
4153;
(g) M. Gómez Andreu, A. Zapf, M. Beller, Chem. Commun. (2000)
2475.
[2] G.W. Kabalka, K. Sastry, G.W. McCollum, H. Yoshioka, J. Org.
Chem. 46 (1981) 4296.