Palladium-catalyzed direct C-H silylation and germanylation of benzamides and carboxamides

Article abstract of DOI:10.1021/ol500519y

A palladium-catalyzed regioselective activation of C(sp²)-H and C(sp³)-H bonds of benzamides and carboxamides, followed by coupling with disilanes to afford organosilanes in moderate to high yields, with the aid of 8-aminoquinoline as a directing group, is reported. Catalytic C(sp ²)-H germanylation of benzamides also proceeds under the same palladium catalysis. The reaction tolerates a wide variety of functional groups and is scalable without yield reduction. The bidentate directing group is readily removed and recovered by the reaction with a hydrazine, with concominant generation of an acyl hydrazide.

Full text of DOI:10.1021/ol500519y

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Direct C−H Silylation and Germanylation of
Benzamides and Carboxamides
Kyalo Stephen Kanyiva,† Yoichiro Kuninobu,*,†,‡ and Motomu Kanai*,†,‡
†Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
‡ERATO, Japan Science and Technology Agency (JST), Kanai Life Science Catalysis Project, 7-3-1 Hongo, Bunkyo-ku, Tokyo
113-0033, Japan
S
* Supporting Information
ABSTRACT: A palladium-catalyzed regioselective activation of
C(sp2)−H and C(sp3)−H bonds of benzamides and carboxamides,
followed by coupling with disilanes to afford organosilanes in
moderate to high yields, with the aid of 8-aminoquinoline as a
directing group, is reported. Catalytic C(sp2)−H germanylation of
benzamides also proceeds under the same palladium catalysis. The
reaction tolerates a wide variety of functional groups and is scalable
without yield reduction. The bidentate directing group is readily
removed and recovered by the reaction with a hydrazine, with
concominant generation of an acyl hydrazide.
rganosilicon compounds are valuable synthetic intermedi-
ates in a variety of organic reactions1 and have various
been made in this field which allow for silylation of aromatic,5
vinylic,6 allylic,7 and aliphatic8 C−H bonds using transition
metals such as Sc, Ru, Rh, Ir, and Pt as catalysts. Despite their
extensive uses in a variety of organic reactions, palladium
catalysts have not been used for the direct silylation of
unactivated C(sp3)−H bonds.
Inspired by recent works on the use of a quinolylamide
bidentate directing group9 to facilitate catalytic functionalizations
of C−H bonds, we have developed a palladium-catalyzed direct
silylation reaction of nonacidic C−H bonds of benzamide and
carboxamide derivatives. Our strategy was successfully extended
to germanylation of benzamides. Moreover, the bidentate
directing group was readily removed and recovered by the
reaction with a hydrazine, with concomitant generation of an acyl
hydrazide.
O
potential uses in materials science.2 In addition, recently there
have been a growing number of interesting reports in the
literature on the application of organosilicon compounds as
therapeutically relevant molecules such as amsilarotene, sila-
dimetracrine, a sila-analogue of tetrahydroisoquinoline, silapro-
line, and TMS-alanine in medicinal chemistry (Figure 1).3
Our initial optimization focused on the effects of oxidants to
the silylation reaction of N-(8-quinolinyl)benzamide (1a, 0.200
mmol) with hexamethyldisilane (2a, 1.00 mmol) in the presence
of Pd(OAc)2 (10 mol %) in 1,4-dioxane (1.0 mL) as a solvent at
130 °C for 24 h (Table 1). Although only a trace amount of
product 3aa was observed by GC-MS without an oxidant (entry
1), the desired product was obtained in 53% yield when 1,4-
benzoquinone was used (entry 2). Further screening revealed
that silver oxidants are superior (entries 3−10), and the yield of
the desired product increased to 70% GC yield when Ag2CO3
was employed (entry 6). In order to further improve the yield, we
turned our attention to additives (entries 11−16) and found that
the use of calcium sulfate improved the yield to 70% (75% GC
yield) after isolation using flash column chromatography on silica
gel (entry 14).10 Although 20% of starting material 1a was
Figure 1. Examples of silicon-containing molecules of medicinal
interests.
Consequently, development of new methods for efficient
strategic installation of silyl groups into organic compounds is
of significant importance in organic chemistry. Compared to the
conventional methods for silylation reactions, synthesis of
organosilanes through direct C−H bond functionalization is
attractive from the viewpoints of atom economy, efficiency, and
environmental benignity.4 Several innovative contributions have
Received: February 18, 2014
Published: March 19, 2014
© 2014 American Chemical Society
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dx.doi.org/10.1021/ol500519y | Org. Lett. 2014, 16, 1968−1971

Organic Letters
Letter
a
Table 1. Optimization Studies
Scheme 1. Palladium-Catalyzed C(sp2)−H Silylation of
a
Various Benzamides (1) with Disilanes (2)
b
entry
oxidant
additive
yield of 3aa (%)
1
none
−
−
−
−
−
−
−
−
−
−
2
2
1,4-benzoquinone
AgOAc
53
63
9
3
4
AgOTf
5
Ag2O
42
70
46
2
6
Ag2CO3
Ag3PO4
7
8
CuCO3
9
Cu(OAc)2
Na2S2O8
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
57
1
10
11
12
13
14
15
16
c
MS 3A
68
71
8
c
MS 4A
c
MS 5A
d
CaSO4
MgSO4
Na2SO4
CaSO4
75 (70)
40
25
43
e
17
a
Reaction conditions: 1a (0.200 mmol), 2a (1.00 mmol), Pd(OAc)2
(10 mol %), oxidant (0.400 mmol), additive (0.400 mmol), 1,4-
b
dioxane (1.0 mL), 130 °C, 24 h. Determined by GC-MS using
c
d
e
undecane as an internal standard. 60 mg. Isolated yield. 150 °C.
recovered in this case, further efforts to increase the yield were
not successful. Increasing the temperature to 150 °C resulted in a
lower yield of 3aa (entry 17).
With the optimized conditions in hand, the scope of the
reaction with benzamides was examined using hexamethyl-
disilane (2a) as the silylation partner (Scheme 1). Overall, the
desired silylated products were successfully obtained from a wide
range of substrates in moderate to high yields (up to 83%) with
excellent ortho-regioselectivity and selectivity for monosilylated
products (>95%). Under the optimized conditions, 2-, 3-, and 4-
methyl-substituted N-(8-quinolinyl)benzamides gave the desired
aryl silanes 3ba, 3ca, and 3da in 80%, 73%, and 54% yields,
respectively. Although these substrates have benzylic C−H
bonds with smaller bond dissociation energies than aromatic
C(sp2)−H bonds, their silylation proceeded exclusively at the
aromatic C−H bond.8a Various functional groups on the phenyl
ring of benzamides were tolerable in this reaction, including
benzyloxy (3ea), methoxy (3fa), and silyloxy (3ga) groups.
Electron-withdrawing groups such as fluoro (3ha), acetoxy (3ia),
trifluoromethyl (3ja), methoxycarbonyl (3ka), acetyl (3la), and
sulfonyl (3ma) groups were also tolerated. In the case of 2-
methoxycarbonyl substituent-containing 1k, in situ intramolec-
ular nucleophilic attack of the nitrogen atom in the amide moiety
to the methoxycarbonyl group and elimination of methanol
resulted in formation of phthalimide 3k′a. 1-Naphthalene
carboxamide was regioselectively silylated at the 2-position in
62% yield (3na). The value of this method was further
demonstrated by the successful silylation of heterocycles such
as thiophene (3oa) and benzofuran (3pa), albeit in moderate
yields. Next, we sought to investigate the scope of the
organosilicon sources. Compared to 2a, (Me2BnSi)2 (2b) and
(Me2PhSi)2 (2c) were less reactive, affording 3ab and 3ac,
a
Reaction conditions: benzamide (0.200 mmol), 2a (1.00 mmol),
Pd(OAc)2 (10 mol %), Ag2CO3 (0.400 mmol), CaSO4 (0.400 mmol),
1,4-dioxane (1.0 mL), 130 °C. Het(Ar) = heteroaryl or aryl group, Q =
8-quinolinyl.
respectively. No desired product was observed when (ClMe2Si)2,
HSiMe3, and HSiEt3 were used as organosilicon sources. Despite
the low yield, the formation of 3ab using this method is
noteworthy because it can be used in Fleming−Tamao
oxidation.5j
Although we have not yet investigated the mechanism of this
silylation reaction in detail, we propose a catalytic cycle initiated
by activation of the ortho-C−H bond of a benzamide by
Pd(OAc)2 to form intermediate A (Scheme 2). The following σ
bond metathesis between intermediate A and disilane 2a and N-
to-O silicon migration will generate intermediate B. Subsequent
C−Si reductive elimination would afford Pd(0) species and
intermediate C, which provides the desired product 3aa after
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dx.doi.org/10.1021/ol500519y | Org. Lett. 2014, 16, 1968−1971

Organic Letters
Letter
The present silylation strategy can be effectively extended to
germanylation of benzamides (Scheme 5). Thus, under the same
Scheme 2. A Plausible Mechanism for the Palladium-
Catalyzed C−H Silylation
Scheme 5. Palladium-Catalyzed C(sp2)−H Germanylation of
a
Benzamides with Hexamethyldigermane
hydrolysis. Oxidation of the Pd(0) species by Ag2CO3
regenerates Pd(OAc)2. Calcium sulfate possibly traps H2O
generated by the reaction of the Pd(0) species with Ag2CO3 and
AcOH. An alternative mechanism involving transmetalation11
also could be conceivable.12
In order to demonstrate the efficiency and practicality of this
catalytic process, we conducted the reaction on a gram scale
using 1.02 g of 1j (3.23 mmol) with 2a (Scheme 3), which
provided 3ja in 68% yield (851 mg).
a
Reaction conditions: benzamide (0.200 mmol), Me6Ge2 (1.0 mmol),
Pd(OAc)2 (10 mol %), Ag2CO3 (0.400 mmol), CaSO4 (0.400 mmol),
1,4-dioxane (1.0 mL), 130 °C. (Het)Ar = heteroaryl or aryl group, Q =
8-quinolinyl.
Scheme 3. Gram-Scale Silylation of 1j with 2a
palladium catalysis conditions, germanylated compounds 4ba,
4fa, 4k′a, and 4oa were obtained in moderate to high yield. To
the best of our knowledge, this is the first example of transition-
metal-catalyzed germanylation of C−H bonds to provide
arylgermanes, which have been demonstrated to be useful
synthetic intermediates.14
In contrast to transition-metal-catalyzed C(sp2)−H silylation
reactions, C(sp3)−H silylation reactions are rare.8 To this end,
we examined whether the present silylation is applicable to
aliphatic C(sp3)−H bonds. Initial application of the reaction
conditions to 1q with hexamethyldisilane (2a) gave less than
10% of the desired product 3qa. After further optimization, we
found that the use of N,N-dimethylformamide (DMF) as an
additive resulted in an increase in reaction yield to 35% (Scheme
6).15 Disilylated product 3′qa was also formed in 5% yield. Under
the same conditions, silylation of 1r and 1s also proceeded.
Although the yield is moderate, this study presents the first
example of intermolecular C(sp3)−H silylation at the internal
positions of alkyl chains. The unreacted starting materials could
be recovered quantitatively.
The 8-quinolinylamino group in 3aa can be readily removed
and recovered in good yield as shown in Scheme 4. Activation of
Scheme 4. Directing Group Removal: Synthesis of Acyl
Hydrazide
In summary, we have demonstrated a palladium-catalyzed
regioselective activation of C(sp2)−H and C(sp3)−H bonds of
benzamides and carboxamides, followed by coupling with
disilanes to afford organosilanes in moderate to high yields,
with the aid of 8-aminoquinoline as a directing group. Catalytic
germanylation also proceeded smoothly under the same reaction
conditions. The reaction tolerated a wide variety of functional
groups and was scalable without yield reduction. Moreover, the
bidentate directing group was readily removed and recovered by
the reaction with a hydrazine, with concomitant generation of an
acyl hydrazide. This study gives the first example of transition-
metal-catalyzed germanylation of C(sp2)−H bonds and
intermolecular C(sp3)−H silylation at the internal positions of
alkyl chains. Further C(sp3)−H bond functionalizations based
on detailed mechanistic studies are in progress in our laboratory.
the secondary amide moiety of 3aa with a Boc group,9j followed
by the reaction with hydrazine monohydrate under microwave
irradiation, afforded N-acyl hydrazide 6 and Boc-protected
quinolylamine 7 in 71% and 60% (based on the recovered
starting material of 40%) yield, respectively.13
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dx.doi.org/10.1021/ol500519y | Org. Lett. 2014, 16, 1968−1971

Organic Letters
Letter
Scheme 6. Preliminary Extension to C(sp3)−H Silylation of
Carboxamides with Hexamethyldisilane (2a)
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ASSOCIATED CONTENT
* Supporting Information
General experimental procedure and characterization data for
silylation and germanylation products. This material is available
free of charge via the Internet at http://pubs.acs.org.
■
S
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: kuninobu@mol.f.u-tokyo.ac.jp.
*E-mail: kanai@mol.f.u-ac.tokyo.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported in part by ERATO from JST (for M.K.
and Y.K.) and JSPS research fellowship for K.S.K.
■
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