Iridium-catalysed borylation of sterically hindered C(sp3)-H bonds: Remarkable rate acceleration by a catalytic amount of potassium tert-butoxide

Article abstract of DOI:10.1039/c4cc01262c

The C(sp³)-H bonds located on the methyl groups of an isopropyl group participate in iridium-catalysed C-H borylation with bis(pinacolato) diboron via a significant rate acceleration caused by a catalytic amount of t-BuOK. the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc01262c

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Iridium-catalysed borylation of sterically hindered
C(sp3)–H bonds: remarkable rate acceleration by
a catalytic amount of potassium tert-butoxide†
Cite this: Chem. Commun., 2014,
50, 6333
Received 18th February 2014,
Accepted 16th March 2014
Toshimichi Ohmura,* Takeru Torigoe and Michinori Suginome*
DOI: 10.1039/c4cc01262c
www.rsc.org/chemcomm
The C(sp3)–H bonds located on the methyl groups of an isopropyl of more powerful catalyst systems is highly desirable to broaden the
group participate in iridium-catalysed C–H borylation with bis- substrate scope considerably.
(pinacolato)diboron via a significant rate acceleration caused by a
catalytic amount of t-BuOK.
We have recently reported the iridium-catalysed C(sp3)–H
borylation of organosilicon compounds.9 The efficient borylation at
the methyl group of alkyltrimethylsilanes9b indicated the potential
Alkylboron compounds are versatile intermediates in the syn- reactivity of C(sp3)–H bonds that are located at sterically hindered
thesis of aliphatic compounds via carbon–carbon and carbon– positions. We focused our attention on substrates having isopropyl
heteroatom bond-formation at the boron-bound carbon atoms.1 groups, which have never been reported to participate in catalytic
In addition to their application in organic synthesis, the mole- C(sp3)–H borylation efficiently.10 Herein, we describe an efficient
cular function of alkylboron compounds has been explored catalytic system for the C(sp3)–H borylation of aliphatic substrates
greatly, as exemplified by the bioactivity of a-aminoalkylboronic that do not bear strong directing groups. A remarkable rate
acids.2 The preparation of alkylboron compounds has mainly acceleration of the borylation was achieved by a catalytic
relied on the hydroboration of alkenes,1a,3 together with the amount of basic additives such as t-BuOK.
reactions of alkylmagnesium and alkyllithium reagents with
The reaction of diisobutyl ether (1a, 4 equiv.) with bis(pinacolato)-
boron electrophiles.4,5 Recently, the transition-metal-catalyzed diboron (2, 1 equiv.) was carried out at 110 1C in the presence of
conversion of C(sp3)–H bonds into C(sp3)–B bonds has been [Ir(OMe)(cod)]2 (4 mol%, 8 mol% Ir) and 3,4,7,8-tetramethyl-
developed as an alternative and more efficient route to alkylboron phenanthroline (Me4phen, 8 mol%) without an additional solvent
compounds.6–8 This catalytic C(sp3)–H borylation has an advan- (entry 1, Table 1). The borylated product 3a was formed only in 11%
tage over conventional methods in that it allows the conversion of yield after 20 h, indicating that the sterically demanding 1a is an
unfunctionalized inert alkane derivatives. However, this boryl- unreactive substrate, even with the Ir–Me4phen catalyst, which has
ation is rather sensitive to steric hindrance. Indeed, C(sp3)–H been reported as an effective catalyst for C(sp3)–H borylation.6b,d,f,9
bonds that can be borylated with high efficiency have been limited To achieve the borylation of 1a, we tested the reaction in the
to the sterically less-hindered methyl on alkyl termini of acyclic presence of t-BuOK, which has been reported by Eliseeva and Scott
substrates6b,7a–f,h,i or methylene units in cyclic substrates.6b,d,7j–l as an effective additive in the multiple borylation of C(sp2)–H bonds
Hartwig and co-workers have reported the C(sp3)–H borylation in aromatic compounds.11 In that report, the role of t-BuOK was
of the sterically hindered methyl side chain of polypropylene,7g supposed to be the improvement of the iridium complex structure
which needs extremely high reaction temperatures (185–200 1C). via the deprotonation of the ligand.11 We found remarkable accel-
Although C(sp3)–H borylation of methylene groups in 2-alkyl- eration of the C(sp3)–H borylation of 1a when the reaction was
pyridines6c,e,g,7m and 2-(hydrosilyl)alkylbenzenes6f,h has been carried out in the presence of a catalytic amount of t-BuOK (2 mol%),
achieved under relatively mild conditions, the reaction requires which led to the formation of the alkylboronic ester 3a in high yield
directing groups such as 2-pyridyl and hydrosilyl groups. For (entry 6). It should be noted that the effect was highly sensitive to the
further utilization of catalytic C(sp3)–H borylation, the development amount of t-BuOK. This acceleration was not observed with 12 or
8 mol% catalyst loading (Ir : t-BuOK = 1 : 1.5–1, entries 2 and 3),
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of
whereas efficient borylation took place in the presence of less than 6
Engineering, Kyoto University, Katsura, Nishikyo-ku, Kyoto 615-8510, Japan.
mol% catalyst loading (Ir : t-BuOK = 1 : 0.75–0.125) (entries 4–7).
E-mail: ohmura@sbchem.kyoto-u.ac.jp, suginome@sbchem.kyoto-u.ac.jp;
Me4phen is an essential ligand for the t-BuOK-accelerated C(sp3)–H
Fax: +81-75-383-2722; Tel: +81-75-383-2723
borylation: other phenanthroline ligands, such as 4,7-dimethyl-
phenanthroline (4,7-Me2phen, entry 8) and phenanthroline
† Electronic supplementary information (ESI) available: Experimental details and
characterization data of the products. See DOI: 10.1039/c4cc01262c
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Table 1 Effect of additives and ligands in iridium-catalysed borylation of 1aa
Table 2 Iridium-catalysed C(sp3)–H borylation with or without t-BuOKa
Yieldb
Yieldc
without with
Ir cat. t-BuOK t-BuOK
Entry Substrate
1d
Product
(mol%) (%)
(%)
6
8
6
10
15
13
96 (71)
Entry
Additive (mol%)
Ligand
Yieldb (%)
1
2
3
4
5
6
7
8
—
Me4phen
Me4phen
Me4phen
Me4phen
Me4phen
Me4phen
Me4phen
4,7-Me2phen
phen
11
0
4
56
t-BuOK (12)
t-BuOK (8)
t-BuOK (6)
t-BuOK (4)
t-BuOK (2)
t-BuOK (1)
t-BuOK (2)
t-BuOK (2)
t-BuOK (2)
t-BuOK (2)
NaOMe (2)
Cs2CO3 (2)
CsOHꢀH2O (2)
CsF (2)
2
3
73 (63)
88 (75)
68
88 (77)c
80
1
9
Trace
Trace
Trace
74
59
58
10
11
12
13
14
15
4,40-Me2bpy
dtbpy
Me4phen
Me4phen
Me4phen
Me4phen
4d
4
6
87
109e (88)
87 (81)g
56
a
1a (2.0 mmol), 2 (0.50 mmol), [Ir(OMe)(cod)]2 (0.020 mmol), a ligand
(0.040 mmol), and an additive (0–0.060 mmol) were stirred at 110 1C for
b
c
5d
35f
20 h. GC yield based on 2. Isolated yield in 1.0 mmol scale reaction.
(phen, entry 9), showed no or much lower catalytic activities. It is also
noted that 4,40-dimethyl-2,20-bipyridine (4,40-Me2bpy), which has
been reported as an effective ligand in C(sp2)–H borylation under
the Ir/t-BuOK catalyst system,11 was completely ineffective for the
C(sp3)–H borylation (entry 10). No reaction took place with 4,40-di-
tert-butyl-2,20-bipyridine (dtbpy, entry 11). In addition to t-BuOK,
other bases, such as NaOMe, Cs2CO3, CsOHꢀH2O, and CsF, pro-
moted the borylation efficiently (entries 12–15).12 These results
indicate the possibility of activation of 2 by the additives,13 although
Scott’s proposal where the additives change the structure of the
iridium complex can not be ruled out.11 The reaction with pinacol-
borane [HB(pin)] instead of 2 under the conditions used for entry 6
resulted in the formation of 3a in low yield (2%). This result indicates
that HB(pin), which was formed as a by-product in the reaction of 1a
with 2, hardly participated in the C(sp3)–H borylation of 1a.
The aliphatic substrates 1b–1k were subjected to the Ir/Me4phen-
catalyzed C(sp3)–H borylation at 110 1C with or without a catalytic
amount of t-BuOK (Ir : t-BuOK = 1 : 0.25) (Table 2).14 Diisopropyl
ether (1b) and diisopentyl ether (1c), which showed low reactivity in
the absence of t-BuOK (10–15% yields), underwent C–H borylation
at the isopropyl and isopentyl termini, giving the borylalkyl ethers
3b and 3c in high yields (entries 1 and 2). The Ir/t-BuOK catalyst
system was also effective for the borylation of a sterically less-
hindered di-n-butyl ether (1d) (entry 3). Although the rhenium-
and rhodium-catalysed C(sp3)–H borylation of 1d has been reported
by Hartwig and co-workers,7a,b the present iridium-catalysed
method is more advantageous in avoiding irradiation or high
temperature reaction conditions. Although C3 borylation of
6
7
8
17
69 (64)
8
17
26
86h (85)
8
9
10
71 (67)
10
10
10
8
45 (42)
42 (38)
10d
a
1 (4.0 mmol), 2 (1.0 mmol), [Ir(OMe)(cod)]2 (0.020–0.050 mmol),
Me4phen (Ir : Me4phen = 1: 1), and t-BuOK (Ir : t-BuOK = 1 : 0 or 1 : 0.25)
b
c
were stirred at 110 1C for 20 h. GC yield based on 2. GC yield based on
2 and isolated yield in parentheses. 1 (6.0 mmol) was used. HB(pin)
d
e
formed as a byproduct also participated in the C–H borylation.
f
g
A mixture of 3f and 3f0 (92 : 8). A mixture of 3f and 3f0 (92 : 8).
Diborylated product (5%, GC) was also formed (see ESI).
h
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tetrahydrofuran (1e) took place efficiently without t-BuOK as catalyst system, sterically hindered C(sp3)–H bonds in the iso-
expected by a precedent,6b appreciable acceleration was observed in propyl group could be converted to C(sp3)–B bonds efficiently.
the presence of t-BuOK (entry 4). Substantial improvement by
This work is supported by Grant-in-Aid for Scientific
t-BuOK was achieved in the borylation of tetrahydropyran (1f), which Research on Innovative Areas ‘‘Molecular Activation Directed
showed moderate reactivity under t-BuOK-free conditions (entry 5). Toward Straightforward Synthesis (No. 23105520)’’ from MEXT
The reaction gave a mixture of the 3-boryl- and 4-boryltetra- and ACT-C FS from JST.
hydropyrans 3f and 3f0 in a ratio of 92 : 8. In addition to the ethers
1a–1c, the borylation was applicable to sterically hindered triiso-
Notes and references
butylamine (1g) to afford 3g in good yield (entry 6). The reaction
1 (a) A. Pelter, K. Smith and H. C. Brown, Boron Reagents, Academic Press,
with t-BuOK was also effective in the borylation of the unfunction-
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alized hydrocarbons 1h–1k (entries 7–10). In the borylation of 1,3,5-
triisopropylbenzene (1h), the C(sp3)–H on the isopropyl group
reacted selectively over the C(sp2)–H on the aromatic ring, giving
3h in high yield (entry 7). 2,4-Dimethylpentane (1i) gave a branched
alkylboronate 3i more efficiently under the t-BuOK-modified condi-
tions (entry 8). The borylation of isooctane (1j) took place selectively
at the less-branched terminus to afford 3j in moderate yield
probably because of the high steric demand of the tert-butyl group
(entry 9). The Ir/t-BuOK catalyst system was effective even for the
borylation of cyclohexane (1k), which has been achieved only by the
(Z6-mesitylene)Ir[B(pin)]3/Me4phen catalyst at 140 1C.6b
(c) D. S. Matteson, in Boronic Acids, ed. D. Hall, Wiley-VCH, 2005, p. 305;
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The Ir/t-BuOK catalyst system could be applied to the gram-
scale synthesis of 3a (eqn (1)). The borylation of 1a took place
efficiently on a larger scale to give 1.9 g of 3a (74%).
(1)
We also found that [IrCl(cod)]2, which is more stable and less
expensive than [Ir(OMe)(cod)]2, serves as a catalyst precursor for the
C(sp3)–H borylation in the presence of t-BuOK. Use of the chloride
with t-BuOK with the ratio of 1 : 1.25 resulted in comparable catalyst
efficiency in the C–H borylation of 1e (see ESI†).
7 For Re-, Rh-, Pd-, and Ru-catalysed C(sp3)–H borylation, see: (a) H. Chen
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The present new C(sp3)–H borylation allows the use of inert,
unfunctionalized organic feedstocks as new starting materials
for organic synthesis. The borylation products were successfully
used in Suzuki–Miyaura coupling1d and one-carbon homologation
reactions1c (eqn (2) and (3)).
´
N. Miyaura, Chem. Lett., 2001, 1082; (e) Y. Kondo, D. Garcıa-Cuadrado,
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K. J. Szabo, J. Org. Chem., 2009, 74, 7715; (m) S. Kawamorita, T. Miyazaki,
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(3)
10 It has been reported that the branched termini of 2-methylbutane
and 2-methylheptane undergo the C–H borylation, although the
borylation at the non-branched termini proceeds much faster. See
ref. 7a, b, and i.
11 M. N. Eliseeva and L. T. Scott, J. Am. Chem. Soc., 2012, 134, 15169.
12 Effectiveness of these additives has been reported also in the C(sp2)–H
borylation of aromatic rings. See ref. 11.
In conclusion, we have established an efficient iridium catalyst
system for the borylation of C(sp3)–H bonds. Significant improve-
ment of catalyst efficiency was achieved via the use of a catalytic
amount of t-BuOK with a Ir/Me4phen catalyst. Using the iridium
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13 For catalytic activation of the B–B bond of 2 by Lewis basic compounds,
see: (a) K. Lee, A. R. Zhugralin and A. H. Hoveyda, J. Am. Chem. Soc.,
was charged with [Ir(OMe)(cod)]2 (0.020–0.050 mmol), Me4phen
(0.040–0.10 mmol, Ir : Me4phen = 1 : 1), t-BuOK (0.01–0.025 mmol,
Ir : t-BuOK = 1 : 0.25), 2 (254 mg, 1.0 mmol), and 1 (4.0 or 6.0 mmol).
The tube was sealed by the stopcock and was taken out from the
glove box. The mixture was stirred at 110 1C by a heating magnetic
stirrer with an aluminum heating block (hole size: 21 mm diameter ꢁ
33 mm depth). After 20 h, the mixture was cooled to room tempera-
ture and undecane (39 mg, 0.25 mmol, internal standard) was added.
The resulting mixture was analyzed by GC to determine the yield of
the borylated products. After removal of the volatiles including
HB(pin) under reduced pressure, the crude product was purified
by column chromatography on silica gel and/or bulb-to-bulb dis-
tillation. Caution: HB(pin) is readily decomposed by protic com-
pounds such as water and generates hydrogen gas. The collected
volatile materials during the concentration process should be
treated carefully with MeOH to convert HB(pin) into MeOB(pin)
before throw them away.
´
´
2009, 131, 7253; (b) A. Bonet, H. Gulyas and E. Fernandez, Angew.
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´
´
H. Gulyas and E. Fernandez, Angew. Chem., Int. Ed., 2011, 50, 7158;
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Apperley, M. S. Cheung, Z. Lin and T. B. Marder, J. Org. Chem.,
2012, 77, 785. For stoichiometric activation of 2 by t-BuOK, see:
(e) C. Kleeberg, L. Dang, Z. Lin and T. B. Marder, Angew. Chem., Int.
Ed., 2009, 48, 5350. For activation of the B–B bond by forming sp3 boron
center, see: ( f ) M. Gao, S. B. Thorpe, C. Kleeberg, C. Slebodnick,
T. B. Marder and W. L. Santos, J. Org. Chem., 2011, 76, 3997. For a
´
´
´
review, see: (g) J. Cid, H. Gulyas, J. J. Carbo and E. Fernandez, Chem.
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14 General procedure for the C(sp3)–H borylation of 1 with t-BuOK:
In a glove box, a glass tube (outside diameter: 20 mm) having
PTFE stopcock (J. Young), equipped with a magnetic stirring bar,
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