Site-Selective Aliphatic C?H Silylation of 2-Alkyloxazolines Catalyzed by Ruthenium Complexes

Article abstract of DOI:10.1002/cctc.201600312

The Ru-catalyzed dehydrogenative silylation of 2-alkyloxazolines with 1,1,1,3,5,5,5-heptamethyltrisiloxane took place site-selectively at methyl C(sp³)?H bonds located γ to the nitrogen atom of the oxazolyl groups. Pyridine and pyrazole rings could also be used as a directing group. A catalytic mechanism based upon successive σ-bond metathesis is proposed.

Full text of DOI:10.1002/cctc.201600312

DOI: 10.1002/cctc.201600312
Communications
Site-Selective Aliphatic CÀH Silylation of 2-Alkyloxazolines
Catalyzed by Ruthenium Complexes
Kazumasa Kon, Hiroyuki Suzuki, Kosuke Takada, Yoshihito Kohari, Takeshi Namikoshi,
[a]
Shinji Watanabe, and Miki Murata*
The Ru-catalyzed dehydrogenative silylation of 2-alkyloxazo-
lines with 1,1,1,3,5,5,5-heptamethyltrisiloxane took place site-
activations by a-position atoms. During the preparation of this
3
manuscript, the C(sp )ÀH silylation of 2-ethylpyridines with
3
selectively at methyl C(sp )ÀH bonds located g to the nitrogen
Et SiH was published; however, the a-position amino group
3
[5]
atom of the oxazolyl groups. Pyridine and pyrazole rings could
also be used as a directing group. A catalytic mechanism
based upon successive s-bond metathesis is proposed.
was not tolerated.
Recently, Hartwig’s group and our group
[6]
[7–9]
have reported
2
that HSi(OSiMe ) Me (1) participated in the C(sp )ÀH silylation
3
2
of aromatic compounds. In previous studies, 1 was often
a more efficient silylating reagent than other common silanes
As organosilicon compounds are an important class of organo-
metallics for modern organic synthesis, the development of
transition-metal-catalyzed CÀSi bond-forming reactions has
triggered ongoing interest. Over the past few years, considera-
ble attention has been devoted to the functional-group-
directed silylation of CÀH bonds through nearby heteroatom
such as Et SiH. During the course of our studies on Ru-cata-
3
lyzed functional-group-directed CÀH silylation, we expanded
the nitrogen-directed silylation protocol to unactivated methyl
3
C(sp )ÀH bonds. Herein, we wish to report a site-selective
3
C(sp )ÀH silylation of nitrogen-containing compounds 2, such
as 2-alkyloxazolines and 2-alkylpyrideines, with 1 as a silylating
reagent.
[
1]
coordination to the metal center of the catalyst. Despite the
2
success of the aromatic C(sp )ÀH silylation, examples of the in-
At the outset of our studies, we tested various reaction con-
3
3
termolecular silylation of aliphatic C(sp )ÀH bonds, to our
ditions for the Ru-catalyzed C(sp )ÀH silylation of 2-ethyl-4,4-di-
knowledge,
are
still
rare
to
date
(Scheme 1).
methyl-2-oxazoline (2a) (Table 1). When 2a was treated with
four equivalents of HSi(OSiMe ) Me (1) in the presence of
3
2
1
.25 mol% of [Cp*RuCl] (5 mol% of Ru atom; Cp*=1,2,3,4,5-
4
pentamethylcyclopentadiene) in cyclohexane at 1808C for
[
a]
Table 1. Optimization of catalytic CÀH silylation of 2a.
3
Scheme 1. Comparison of previous chelate-assisted C(sp )ÀH silylations with
current work.
[
b]
Entry Hydrosilane
Catalyst
Solvent
Yield [%]
1
2
3
4
5
6
7
8
9
1
11
12
13
14
15
1
1
1
1
1
1
1
1
1
1
1
[Cp*RuCl]
[Cp*RuCl]
4
4
cyclohexane 99
cyclohexane 51
cyclohexane 87
cyclohexane 75
cyclohexane 44
cyclohexane 36
[
c]
3
Since the pioneering work on benzylic C(sp )ÀH silylation by
[Cp*RuCl2]2
RuCl ·nH
[RuCl (p-cymene)]
[
2]
3
Kakiuchi and co-workers, the C(sp )ÀH silylation of methyl-
3
2
O
[
3]
[4]
2
2
boranes and that of methylamines have been reported by
Ru
[Cp*RhCl
[Cp*IrCl2]2
3
(CO)12
3
others. That is, the examples of directed C(sp )ÀH silylation
2
]
2
cyclohexane
cyclohexane
THF
DMF
toluene
cyclohexane
cyclohexane
cyclohexane
cyclohexane
5
2
59
20
24
9
have hitherto been limited to cases where there are additional
[Cp*RuCl]
[Cp*RuCl]
[Cp*RuCl]
4
0
4
4
4
4
4
4
[
a] K. Kon, H. Suzuki, K. Takada, Dr. Y. Kohari, Dr. T. Namikoshi,
Prof. Dr. S. Watanabe, Prof. Dr. M. Murata
Department of Materials Science and Engineering
Kitami Institute of Technology
Et
(Me
(EtO)
Me ClSiH
3
SiH
SiO)Me
SiH
[Cp*RuCl]
3
2
SiH [Cp*RuCl]
[Cp*RuCl]
3
0
0
3
1
65 Koen-Cho, Kitami, Hokkaido 090-8507 (Japan)
[Cp*RuCl]
2
Fax: (+81)157-26-4973
E-mail: muratamk@mail.kitami-it.ac.jp
[
a] Reaction conditions: hydrosilane (1.0 mmol), 2a (0.25 mmol), Ru cata-
lyst (5 mol% Ru atom), and solvent (0.5 mL), 1808C, 24 h. [b] GC yields
based on 2a. [c] 1 (0.38 mmol) was used.
Supporting information for this article can be found under http://
dx.doi.org/10.1002/cctc.201600312.
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2
4 h, a quantitative yield of monosilylated product 3a was ob-
[
a]
Table 2. Scope of Ru-catalyzed silylation of 2 with 1.
tained (entry 1). This transformation was found to be com-
3
pletely site-selective; that is, it occurred only at the C(sp )ÀH
bond located g to the nitrogen atom of the oxazolyl group.
Under these conditions, the desired silylation competed with
the dehydrogenative dimerization of 1, resulting in contamina-
tion by a considerable amount of HSi[CH SiMe(OSiMe ) ]-
2
3 2
[
9,10]
(OSiMe ) (4).
Furthermore, a control experiment without
3
2
[
b]
Entry
1
Substrate 2
Product 3
Yield [%]
2
a afforded 4 in moderate yield (Scheme 2). Therefore, an
excess amount of 1 was necessary for full conversion of 2a
into 3a (Table 1, entry 2).
2b
2c
3b
3c
58
2
84
11
Scheme 2. Dehydrogenative dimerization of 1.
3
c’
Although
several
ruthenium complexes, including
[
Cp*RuCl ] , RuCl ·nH O, [RuCl (p-cymene)] , and Ru (CO) ,
2
2
3
2
2
2
3
12
showed moderate to good catalytic activity for the
3
4
2d
2e
3d
70
0
3
C(sp )ÀH silylation (entries 3–6), [Cp*RuCl] was the best cata-
4
lyst. In contrast, neither [Cp*RhCl ] nor [Cp*IrCl ] was effective
2
2
2 2
for this reaction (entries 7 and 8). Different reaction media
were subsequently investigated (entries 9–11), and cyclohex-
ane proved to be the solvent of choice. The present study
demonstrates that 1 is an efficient silylating reagent for the
3
C(sp )ÀH silylation; however, in place of 1, the use of Et SiH in-
3
5
6
2 f
0
duced a drastic lowering of the reactivity (entry 12) and that of
(
Me SiO)Me SiH led to complex mixtures (entry 13). Further-
3 2
more, no reaction with (EtO) SiH or with Me ClSiH occurred,
3
2
presumably because of disproportionation of the silanes (en-
tries 14 and 15). As shown in Table 1, the present success prob-
ably relies on the use of 1. We believe that not only the ther-
mal stability resulting from the steric bulk of the SiMe(OSiMe3)2
2g
2h
3g
85
group, but also the electronic effect of the two OSiMe groups
3
3
7
8
3h
3i
89
68
on the silicon atom play an important role in the C(sp )ÀH sily-
lation. Thus, the optimized reaction conditions utilized four
equivalents of 1 and 1.25 mol% of [Cp*RuCl] in cyclohexane.
4
2i
1
With the optimal reaction conditions in hand, we investi-
gated a series of nitrogen-containing substrates 2 for the pres-
ent transformation (Table 2). As a whole, the desired prod-
ucts 3 were contaminated with considerable amounts of 4, but
their isolation was very easy. The monosilylation of 2-(tert-
butyl)-4,4-dimethyl-2-oxazoline (2b) took place selectively to
give the corresponding 3b (entry 1), whereas the reaction of
[
a] Reaction conditions:
(1.0 mmol),
2
(0.25 mmol), [Cp*RuCl]
4
(3.1 mmol), and cyclohexane (0.5 mL), 1808C, 24 h. [b] GC yield.
Nitrogen-containing heteroaromatic rings also appeared to
be suitable directing groups. It is noteworthy that not only
2-dimethylaminopyridine (2g) but also 2-ethylpyridine (2h) un-
2
-isopropyl-4,4-dimethyl-2-oxazoline (2c) resulted in a mixture
of monosilylated 3c and disilylated 3c’ (entry 2). The reaction
of 2-(sec-butyl)-4,4-dimethyl-2-oxazoline (2d) was completely
site-selective, affording monosilylated 3d (entry 3). In this case,
no silylation was observed at the g-methylene group. Addition-
ally, 2e as well as 2 f did not undergo silylation owing to the
absence of methyl CÀH bonds at the suitable position (en-
tries 4 and 5).
3
derwent the C(sp )ÀH silylation at the g-position to the pyri-
dine nitrogen atom (entries 6 and 7). In contrast to the case of
2c (entry 2), for 2b (entry 1) and 2g (entry 6) we did not ob-
served any disilylation, although there is no clear explanation
for these selectivities at present. Previous protocols did not
[4,5]
allow for the silylation of both substrates 2g and 2h.
Fur-
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thermore, the site-selective silylation of 1-ethylpyrazole (2i)
proceeded in the same fashion (entry 8).
recovered 2h to the same carbon in a virgin sample was mea-
13
sured by using quantitative C NMR spectroscopy. The change
in isotopic composition in each position was determined rela-
tive to the methylene carbon. As shown in Scheme 5, the only
appreciable carbon isotope effect was observed at the terminal
To demonstrate the synthetic utility of the nitrogen-directed
3
C(sp )ÀH silylation with 1, we then tried to conduct Fleming–
Tamao oxidation of the product 3 derived from this method
[
11]
13
(Scheme 3).
Treatment of 3h (1 equiv.) with aq. H O2
methyl position. The C enhancement from the virgin 2h indi-
2
(
10 equiv.) in the presence of KHF (2.5 equiv.) in MeOH/THF at
cates a primary kinetic isotope effect at the methyl carbon.
Therefore, it is suggested that the CÀSi bond formation step is
the rate-determining step for the present silylation of 2, as the
CÀH bond cleavage step was not rate-limiting.
2
5
08C was found to lead to the corresponding alcohol 5.
3
Finally, the present C(sp )ÀH silylation was computationally
addressed by density functional theory (DFT) calculations. We
have adopted the reaction of 2-(sec-butyl)-2-oxazoline (2j) with
HSiMe as a model reaction, and the Cp* ligand was replaced
3
[14]
Scheme 3. Fleming–Tamao oxidation of 3.
by Cp (cyclopentadiene) in the computed structures.
The
calculated energy profile for a proposed catalytic cycle is de-
picted in Figure 1. Based on the previous report, we postulated
that the reaction pathway involves the formation of a
Next, to gain mechanistic insights into the present Ru-cata-
lyzed silylation, we conducted some preliminary isotope
experiments. When the reaction of 2d with deuterotriethylsi-
[15]
ruthenium(II) hydride complex 6. The first step of the methyl
3
2
C(sp )ÀH silylation is the coordination of both the N(sp ) atom
3
lane (Et SiD) was carried out under the standard conditions,
and methyl C(sp )ÀH bond of 2j to the ruthenium center of 6
3
only a trace amount of silylated product was detected by GC
(red line in Figure 1). An alkyl ruthenium species (8) is formed
through the s-complex-assisted metathesis (s-CAM) between
1
analysis (Scheme 4). H NMR spectra of the recovered starting
[
16]
material 2d showed that partial H/D exchange occurred at the
g-positions to the nitrogen atom of the oxazolyl group. Inter-
estingly, incorporation of D was observed at both the methyl
and methylene positions. This result indicates that the site-
the RuÀH bond and CÀH bond via transition state TS7-8. The
next step is a ligand substitution reaction, involving dissocia-
tion of the H ligand and coordination of HSiMe . Subsequent
2
3
s-CAM between the RuÀC bond and the SiÀH bond takes
place through transition state TS9 to give a ruthenium
3
selective C(sp )ÀH bond activation step is a rapid equilibrium
-10
process. The present result is consistent with the previous
hydride complex 10, which contains coordinated 3j. Finally, an
associative ligand exchange between the product 3j and 2j
would regenerate 7.
[
5]
report by You.
3
The methylene C(sp )ÀH silylation through the analogy
mechanism has also been investigated (blue line in Figure 1).
As shown in Figure 1, both CÀH bond activation steps are ex-
tremely facile. The experimental results shown in Scheme 4
also indicate that our calculated results are reasonable. In con-
trast, the CÀSi bond forming steps have high energy barriers,
indicating that these steps should greatly contribute to deter-
[17]
mining the product. Based on the energetic span concept,
the effective activation energy of the subsequent cycle for the
3
Scheme 4. Deuterium-labeling experiments with Et SiD.
3
À1
methyl C(sp )ÀH silylation is predicted to be 35.9 kcalmol .
Comparing the energetics of the CÀSi bond forming step, we
3
Then, the carbon isotope effect of the C(sp )ÀH silylation
3
was determined by Singleton’s NMR technique at natural
estimate that the methyl C(sp )ÀH silylation is more favorable
[
12,13]
3
abundance (see the Supporting Information).
of 2h was taken to 88% conversion, and the unreacted 2h
The reaction
than the methylene C(sp )ÀH silylation, which is in good agree-
ment with the experimental results presented here.
13
was recovered (Scheme 5). The C ratio of each carbon in the
Furthermore, we have speculated that the dehydrogenative
dimerization of 1 (Scheme 2) involves b-hydrogen elimination
[10]
from silyl complexes as a key step. To evaluate this hypothe-
sis, preliminary DFT calculations on the dimerization of HSiMe3
were performed (see the Supporting Information). As the effec-
À1
tive activation energy is predicted to be 34.0 kcalmol , it
3
would be reasonable that the desired C(sp )ÀH silylation of 2
competes with the dehydrogenative dimerization of 1.
In conclusion, we have successfully demonstrated the
3
Ru-catalyzed nitrogen-directed silylation of methyl C(sp )ÀH
bonds by using 1,1,1,3,5,5,5-heptamethyltrisiloxane (1). DFT cal-
culations and preliminary isotopic studies support a catalytic
1
2
13
Scheme 5. Measurement of C/ C ratio of unreacted 2h.
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Figure 1. Calculated energy profile for Ru-catalyzed silylation of methyl (red line) and methylene (blue line) C(sp )ÀH bonds.
cycle involving rapid CÀH bond activation followed by the
rate-determining CÀSi bond formation. Further studies, includ-
ing the expansion of substrate scope as well as detailed mech-
anistic studies, are currently underway in our group.
[10] P. I. Djurovich, A. R. Dolich, D. H. Berry, J. Chem. Soc. Chem. Commun.
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358; b) D. E. Frantz, D. A. Singleton, J. P. Snyder, J. Am. Chem. Soc.
997, 119, 3383–3384.
9
1
1
3
Keywords: CÀH activation · density functional calculations ·
isotope effects · ruthenium catalysis · silanes
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Received: March 18, 2016
Revised: April 19, 2016
Published online on && &&, 0000
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K. Kon, H. Suzuki, K. Takada, Y. Kohari,
T. Namikoshi, S. Watanabe, M. Murata*
&& – &&
Site-Selective Aliphatic CÀH Silylation
of 2-Alkyloxazolines Catalyzed by
Ruthenium Complexes
3
3
Chelate-assisted C(sp )ÀH bond activa-
tively at methyl C(sp )ÀH bonds located
tion: The dehydrogenative silylation of
g to the nitrogen atom of the oxazolyl
2-alkyloxazolines with 1,1,1,3,5,5,5-hep-
groups.
tamethyltrisiloxane took place site-selec-
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