Palladium-catalyzed direct intermolecular silylation of remote unactivated C(sp3)-H bonds

Article abstract of DOI:10.1039/c6cc07885k

An efficient and convenient method has been developed to achieve direct silylation of unactivated remote primary or secondary C(sp³)-H bonds to form C-Si bonds with hexamethyldisilane (HMDS). This method highlights the emerging strategy to transform unactivated methyl or methylene into versatile functional groups in organic synthesis and provides a new method to construct functionalized C-Si bonds for synthetic chemistry.

Full text of DOI:10.1039/c6cc07885k

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Palladium-Catalyzed Direct Intermolecular Silylation of Remote
Unactivated C(sp3)−H Bonds
Jin-Long Pan,a Quan-Zhe Li,a Ting-Yu Zhang,a Si-Hua Hou, a Jun-Cheng Kangc and Shu-Yu Zhang*a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
new reaction conditions to achieve an efficient and practical
silylation of unreactive C(sp3)−H bonds.6c In continuing efforts
and interests to develop efficient and selective functional-
izations of unactivated C(sp3)–H bonds and their applications
in the synthesis of natural products,7 herein, we disclosed a
palladium-catalyzed bidentate-chelation assistant remote
intermolecular unactivated direct primary or secondary C(sp3)–
H silylation protocol.
An efficient and convenient method has been developed to
achieve direct silylation of unactivated remote primary or
secondary C(sp3)−H bonds to form C–Si bonds with
hexamethyldisilane (HMDS). This method highlights the emerging
strategy to transform unactivated methyl or methylene into
versatile functional groups in organic synthesis and provides a
new method to construct functionalized C–Si bond for the
synthetic chemistry.
Pr evious wor k
Organosilane compounds play a crucial role and widely used in
organic synthesis (Hiyama reactions, Hosomi-Sakurai-type
allylation, and etc.), materials science, and pharmaceutical
compounds.1 The development of an efficient and novel C–Si
bond forming method as an intensively investigated field has
been focused in synthetic chemistry.2 In the past decades,
transition-metal-catalyzed the direct selectively conversion of
an unactivated C–H bond to the corresponding C–Si bond is
one of the most attractive synthetic approach since it was
known as efficient, convenient and atom-economical.3
Significant advances have been made in this field using Ru, Rh,
Ir, Sc and Pt.4 However, direct palladium-catalyzed
functionalization of intermolecular unactivated aliphatic
C(sp3)−H silylation reaction still remains a great challenge in
synthetic chemistry.5
(Q)
R
O
R
O
Pd(OAc)2/Me3Si–SiMe3
A)
Me3Si
NHQ
H
N
Ag2CO3 (2 equiv)
DMF, 130 °C, 35 h
H
N
three C(sp3)–H sily lation examples
17, 35, and 39% yield
N(iPr)2
O
NHDG
Pd(OAc)2/Me3Si–SiMe3
(DG)
O
Me3Si
HN
AgOAc (3 equiv)
CO2Me
B)
K
3PO4 (1.5 equiv)
H
Toluene, 140 °C, 48 h
CO2Me
two unactivated C(sp3)–H sily lation examples
21 and 49% yield
T his wor k
R
O
R1
O
Pd(OAc)2/Me3Si–SiMe3
Me3Si
NHQ
C)
H
NHQ
BQ (4 equiv)/ 4Å MS (30mg)
R2
26 examples
up to 88% yield
R2
DMA, 110 °C, 12 h
Scheme 1 Palladium-Catalyzed Direct Intermolecular Silylation
of Unactivated C(sp3)−H bond
Since the seminal work by Kuninobo and Kanai laboratory in
2014, only two papers were reported that the unactivated
C(sp3)−H bond could be silylation under palladium/Ag2CO3
catalysis system (Scheme 1A)6a or palladium/AgOAc catalysis
system (Scheme 1B).6b Although this silylation was limited to
few examples and low efficiency, it has become highly valuable
and has established the foundation for the development of
Elegant by palladium-catalyzed N, N-bidentate directing
group in the functionalization of unactivated methyl and
methylene C(sp3)–H bonds,8 and the results previously
reported,6a our initial attempt in the intermolecular silylation
started with the model aliphatic amide substrate 1a using 8-
aminoquinoline as the auxiliary to
react
with
hexamethyldisilane (HMDS) (Table 1). It provided promising
results showing the feasibility of this reaction. After an initial
screening of the oxidants in toluene (Table 1, entries 1–5), we
found that the oxidant was essential for the silylation of 1a
.
The desired silylation product 2a was obtained in 17% yield by
using catalytic amounts of Pd(OAc)2 and 2 equiv. of Ag2CO3 as
oxidant (entry 4). To our delight, non-metal oxidant 1,4-
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benzoquinone (BQ) seemed to be better than previously two β
-primary C(sp3)–H methyl groups were present in the
reported silver oxidant improving the yield of the desired C–H substrate, a monoselective silylated product 2c was obtained
silylation to 28% (entry 5). A detailed screening of various in 75% yield and only trace diselective silylated product was
solvents have revealed that the reaction could be improved detected. Furthermore, a high region-preference and the β-
into a higher conversion to obtain the 59% yield when the C(sp3)‒H bonds reactivity of methyl group prior over
DMA was used as the solvent (entry 10), but there still was a methylene group were demonstrated and only the primary
few amount of 1a which was recovered. Replacing BQ with silylated products 2d and 2e were obtained in 78% and 79%
other quinone oxidants, such as 2-methyl-1,4-benzoquinone, yield, respectively. The reaction system could be applied to a
1,4-naphtho-quinone, and anthrax-quinone (
3
–
8
) afforded 2a variety of
β
in lower yields. Moreover, we found that O2 has an inhibitory carboxamides and the silylated products 2f
-methylene C(sp3)‒H bonds of linear aliphatic
2n were given in
‒
effect on the reaction system (entries 11 and 12) and that moderate yields (Table 2B). Especially the more sterically
varying the temperature (entries 13 and 14) could not increase demanding substrates 1h (6-aminocaproic acid derivative) and
the yield of 2a. In order to promote the circulation of 1i (oleic acid derivative) can still give the yield of 48% for 2h
palladium catalyst, a further study on a series of additives was and 40% for 2i. The
surveyed (entries 15‒19). Interestingly, adding of 4 Å MS
seemed significantly improving the desired C–H silylation
reaction (entry 19). After the amounts of oxidant and HMDS
were examined, finally, the optimized reaction conditions were
Pd(OAc)2 (10 mol %), BQ (4 equiv), HMDS (10 equiv) and 4 Å
β-methylene
Table 2 Scope of carboxamide substratesa,b
MS (30 mg) in DMA (1 mL) at 110 °C for 12 h (entry 20).
Table 1 Optimization of the Pd-catalyzed silylationa
Entry
Additives (equiv)/atmosphere
Solvent
T(oC)
Yield b (%)
1
2
3
4
5
6
7
8
9
HMDS (5), Ar
Toluene
Toluene
Toluene
Toluene
Toluene
MeCN
tꢀBuOH
DMSO
DMF
110
110
110
110
110
110
110
110
110
110
110
110
<2
<2
5
17
28
6
14
5
50
59
47
31
PhI(OAc)2 (2), HMDS (5), Ar
Cu(OAc)2 (2), HMDS (5), Ar
Ag2CO3 (2), HMDS (5), Ar
BQ (2), HMDS (5), Ar
BQ (2), HMDS (5), Ar
BQ (2), HMDS (5), Ar
BQ (2), HMDS (5), Ar
BQ (2), HMDS (5), Ar
BQ (2), HMDS (5), Ar
BQ (2), HMDS (5), air
BQ (2), HMDS (5), O2
10
11
12
DMA
DMA
DMA
13
BQ (2), HMDS (5), Ar
DMA
90
39
14
15
16
17
18
19
BQ (2), HMDS (5), Ar
DMA
DMA
DMA
DMA
DMA
DMA
130
110
110
110
110
110
57
12
28
65
35
70
BQ (2), HMDS (5), PPh3 (0.3), Ar
BQ (2), HMDS (5), (BnO)2PO2H(0.3), Ar
BQ (2), HMDS (5), Li2CO3 (2), Ar
BQ (2), HMDS (5), H2O(2), Ar
BQ (2), HMDS (5), 4 Å MS (30 mg), Ar
20
BQ (4), HMDS (10), 4 Å MS (30 mg),Ar
DMA
110
79 (56)c
O
O
O
O
O
O
Cl
O
O
O
O
O
O
5, < 2%
6, < 2%
8, < 2%
3, 39%
4, 52%
7, 6%
a All screening reactions were carried out in a 10 mL glass vial with a
PTFE-lined cap on a 0.2 mmol scale. b Yields are based on GC-MS
analysis of the reaction mixture. c Isolated yield in parentheses.
a
Reaction conditions:
1 (0.2 mmol), Me3Si–SiMe3 (2 mmol),
Pd(OAc)2 (10 mol %), BQ (0.8 mmol), and 4 Å MS (30 mg) in DMA
(1.0 mL) at 110 °C under Ar for 12 hours. b Yields were based on
c
d
isolated products. X-Ray structure of 2j (see ESI). BQ (0.4 mmol)
With an optimized set of conditions in hand, we then
probed the substrate scope of carboxamides in order to survey
and Me3Si–SiMe3 (1.0 mmol) were used.
the generality of this reaction. As shown in Table 2A, the β-
primary C(sp3)‒H silylation has given 44%–79% yield. When
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C(sp3)‒H bonds of three- to six- membered cyclic alkane amide 10a was successfully obtained starting from
carboxamides afforded the bisilylated products in 45%‒53% protected Ala 9a in excellent yield. Next, we examined some
yield (Table 2C, 2o 2r). The relative configuration of 2p was natural or unnatural -amino acids Bur, Leu and Phe. As
determined by X-Ray crystallographic analysis (Figure 1, see expected, the desired
-methylene C(sp3)–H silylated products
ESI†). In contrast, the cycloheptanone carboxamide substrate, 10b 10d were obtained in moderate to good yield with high
N-Phth-
-
α
β
–
showing a similarity to the linear aliphatic carboxamide diasterelectivity under standard reaction conditions. The
substrates, prefered to give the monosilylated product 2s in experiments indicated that the diasterelectivity of the
64% yield. Interestingly, adamantane derivative 1t achieved a corresponding silylated products could be improved by the
desired monoselective silylated product 2t on the challenging steric hindrance of R3. Additionally, when
N
-Phth-protected
-methylene C(sp3)–H bonds in 13% yield. Val or Ile amides were used as the substrates, the γ-
This method provides a possible protocol to direct access to monoselective silylation of methyl C(sp3)–H 10e and 10f could
and rigid aliphatic
β
1,2-disubstituted diamondoids.9
be obtained in moderate yield and high diasterelectivity.
On the basis of the above results and the reported
literatures,5,6,11 a plausible proposal can be put forward in
Scheme 2, although the details of the mechanism of this
silylation reaction remain to be elucidated. Firstly, the amide
1a with Pd(OAc)2 generated 11 ligated by
N, N-bidentate
directing group. Moreover, a five-membered palladacycle 12
was formed via a concerted metalation-deprotonation process
(CMD), followed by the transmetalation to give the 13 or 13’
,
which proceeded the reductive elimination to give the desired
products 2a. In fact, the byproduct 14 was detected in the
reaction mixture. Finally, the Pd(0) was reoxidized to Pd(II) by
BQ to complete the palladium catalytic cycle.
Figure 1 X-Ray structure of 2p
.
Silicon-containing α-amino acids as unnatural amino acids
provide a useful insight into the biosciences and medicines due
O
O
HO
OH
oxidantion
O
H
+ 2 AcOH
Pd(0)
to their unique properties.10 We then turned our attention to
N
H
N-Phth-protected amino acids substrates. As shown in table 3,
we are delighted to find that the silylated product TMS-alanine
N
Pd(OAc)2
O
1a
N
H
N
SiMe3
2a
O
H
Table 3 Scope of α-amino acids substratesa,b
reductive
elimination
HO
OSiMe3
N
14
N
Pd
O
O
11
Me3Si–SiMe3 (10 equiv)
Pd(OAc)2 (10 mol %)
BQ (4 equiv)
O
SiMe3
R3
HO
OH
+ AcOH
C–H activation
O
H
R3
4 Å MS (30 mg)
QHN
Me3SiO
QHN
O
N
NPhth
10
NPhth
DMA, 110 °C, Ar, 12 h
N
N
or
Pd
9
O
N
Pd
N
SiMe3
+ AcOH
Me3Si
SiMe3
N
Pd
13
13'
12
Me3Si–SiMe3
O
O
O
Scheme 2 Proposed reaction mechanism.
PhthN
PhthN
PhthN
NHQ
NHQ
SiMe
NHQ
SiMe3
SiMe3
βꢀTMSꢀAla
10a, 88%
βꢀTMSꢀBur
10b, 81%, d.r. ~ 5:1
βꢀTMSꢀLeu
10c, 32%, d.r. > 15:1
In consequence of recent interesting reports and the
application of organosilicon compounds as therapeutically
relevant molecules such as silaproline and TMS-alanine in
medicinal chemistry,12 the synthetic applications and the
O
O
O
PhthN
PhthN
NHQ
PhthN
NHQ
NHQ
SiMe3
SiMe3
SiMe3
Ph
removal of the directing group were further investigated.
N-
βꢀTMSꢀPhe
10d, 23%, d.r. > 15:1
γꢀTMSꢀVal
10e, 45%, d.r. > 15:1
γꢀTMSꢀIle
10fc, 45%, d.r. > 15:1
Phth-protected TMS-alanine amide 10a was synthesized
successfully in gram-scale in 80% isolated yield under Pd-
catalysed system. The auxiliary directing-group 8-
a
Reaction conditions:
9 (0.2 mmol), Me3Si–SiMe3 (2 mmol),
Pd(OAc)2 (10 mol %), BQ (0.8 mmol), and 4 Å MS (30 mg) in
b
DMA (1.0 mL) at 110 °C under Ar for 12 hours. Yields were
based on isolated products. c X-Ray structure of 10f (see ESI).
aminoquinoline was then removed in BF3
to give β-silylated
—OEt2/MeOH system
α
-amino acid methyl ester 15 in 86% yield.13
This strategy offers a simple and unique method for synthesis
of bioactive multi-substituted primary or secondary β-silylated
α-amino acid analogues, which might have a wide biological
activity and medicinal applications.
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483, 70; (d) Y. Kuninobu, T. Nakahara, H. Takeshima and K.
Takai, Org. Lett., 2013, 15, 426; (e) N. Ghavtadze, F. S.
Melkonyan, A. V. Gulevich, C. Huang and V. Gevorgyan, Nat.
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,
Takeshima, H. Morita, Y. Kuninobu and K. Takai, J. Org.
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6
(a) T. Mita, K. Michigami and Y. Sato, Chem.-Asian J., 2013, 8,
2970; (b) W. Li, X. Huang and J. You, Org. Lett., 2016, 18, 666.
(a) K. S. Kanyiva, Y. Kuninobu and M. Kanai, Org. Lett., 2014,
16, 1968; (b) C. Chen, M. Guan, J. Zhang, Z. Wen and Y. Zhao,
Org. Lett., 2015, 17, 3646; (c) While this manuscript was
submitted under review, a similar and elegant C(sp3)-H
silylation work using
a Pd/Ag2CO3 system by Prof. Shi
appeared: Y.-J. Liu, Y.-H. Liu, Z.-Z. Zhang, S.-Y. Yan, K. Chen,
B.-F. Shi, Angew. Chem., Int. Ed., 2016, DIO:
10.1002/anie.201607766.
Scheme 3 Synthetic utilities and removal of the auxiliary
7
8
(a) S.-Y. Zhang, G. He, Y. Zhao, K. Wright, W. A. Nack and G.
Chen, G. J. Am. Chem. Soc., 2012, 134, 7313; (b) S.-Y. Zhang,
G. He, W. A. Nack, Y. Zhao, Q. Li and G. Chen, J. Am. Chem.
Soc., 2013, 135, 2124; (c) S.-Y. Zhang, Q. Li, G. He, W. A.
Nack, and G. Chen, J. Am. Chem. Soc., 2013, 135, 12135; (d)
S.-Y. Zhang, Q. Li, G. He, W. A. Nack and G. Chen, J. Am.
Chem. Soc., 2015, 137, 531.
The pioneering work using 8-aminoquinoline as N, N-
bidentate directing group, see: V. G. Zaitsev, D. Shabashov,
and O. Daugulis, J. Am. Chem. Soc., 2005, 127, 13154. The
recent reviews, see: (a) M. Corbet, and F. De Campo, Angew.
Chem., Int. Ed., 2013, 52, 9896; (b) G. Rouquet and N.
Chatani, Angew. Chem., Int. Ed., 2013, 52, 11726; (c) O.
In summary, we have developed a direct intermolecular
silylation method to functionalize the β-methyl or methylene
C(sp3)–H bonds of 8-aminoquinoline-protected aliphatic
amides with HMDS. A broad range of substrates proved to be
well tolerable. This protocol provided an alternatively
convenient and simple strategy for the efficient access to
structurally C–Si bond. The directing group can be easily
removed under simple conditions to give an efficient and
straightforward strategy for the synthesis of β-silylated
α-
Daugulis, J. Roane and L. D. Tran, Acc. Chem. Res., 2015, 48
,
amino acid analogues. Further mechanistic and asymmetric
studies and applications of this C–H silylation methodology in
the synthesis of complex organosilane compounds are
currently under investigation.
1053; (d) G. He, B. Wang, W. A. Nack and G. Chen, Acc.
Chem. Res., 2016, 49, 635.
M. Larrosa, S. Heiles, J. Becker, B. Spengler and R. Hrdina,
Adv. Synth. Catal., 2016, 358, 2163.
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Soc. Rev., 2009, 38, 1002; (b) E. Rémond, C. Martin, J.
Martinez and F. Cavelier, Chem. Rev., 2016, DOI:
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12 M. Iwasaki, Y. Tsuchiya, K. Makajima and Y. Nishihara, Org.
Lett., 2014, 16, 4920.
This work was supported by the “Thousand Youth Talents
Plan” and startup fund from Shanghai Jiao Tong University. We
thank Prof. Gong Chen for helpful suggestions and comments
on this manuscript.
13 L. D. Tran, O. Daugulis, Angew. Chem., Int. Ed., 2012, 51
5188.
,
Notes and references
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2
3
4
(a) E. W. Colvin, Silicon Reagents in Organic Synthesis,
Academic Press, London, 1988; (b) Z. Rappoport and Y.
Apeloig, Chemistry of Organosilicon Compounds, Wiley-VCH,
New York, 2001; (c) E. G. Rochow, Silicon and Silicones,
Springer-Verlag, New York, 1987.
For recent reviews about C-H silylation, see: (a) Y. Yang and
C. Wang, Sci. China Chem., 2015, 58, 1266; (b) R. Sharma, R.
Kumar, I. Kumar, B. Singh and U. Sharma, Synthesis, 2015,
47, 2347; (c) C. Cheng and J. F. Hartwig, Chem. Rev., 2015,
115, 8946.
For recent selected examples, see: (a) J. Oyamada, M.
Nishiura and Z. Hou, Angew. Chem., Int. Ed., 2011, 50, 10720;
(b) T. Sakurai, Y. Matsuoka, T. Hanataka, N. Fukuyama, T.
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4 | J. Name., 2012, 00, 1-3
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