Copper-Catalyzed Silylation of C(sp3)-H Bonds Adjacent to Amide Nitrogen Atoms

Article abstract of DOI:10.1021/acs.orglett.8b01698

A copper-catalyzed C-Si bond formation between N-halogenated amides and Si-B reagents is described. This oxidative coupling enables the silylation of C(sp³)-H bonds α to an amide nitrogen atom. The utility of the new method is demonstrated for

Full text of DOI:10.1021/acs.orglett.8b01698

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Copper-Catalyzed Silylation of C(sp3)−H Bonds Adjacent to Amide
Nitrogen Atoms
Jian-Jun Feng and Martin Oestreich*
Institut fur Chemie, Technische Universitat Berlin, Strasse des 17. Juni 115, 10623 Berlin, Germany
̈
̈
S
* Supporting Information
ABSTRACT: A copper-catalyzed C−Si bond formation
between N-halogenated amides and Si−B reagents is described.
This oxidative coupling enables the silylation of C(sp3)−H
bonds α to an amide nitrogen atom. The utility of the new
method is demonstrated for sulfonamides, and N-chlorination
with tBuOCl and C−H silylation employing CuSCN/4,4′-
dimethoxy-2,2′-bipyridine as catalyst can be performed without
purification of the N−Cl intermediate.
atalytic oxidative functionalization of C(sp3)−H bonds
Scheme 1. Catalytic Approaches to α-Silylated Amines and
a
C
adjacent to the nitrogen atom of amines is an important
way of diversifying their substitution pattern.1 While C−C
bond formation in this position is now relatively well
established,1 the related installation of heteroatoms α to the
nitrogen atom is less developed.2 To the best of our
knowledge, there is no report on the formation of a C−Si
bond by this strategy. Aside from the conventional preparation
of α-silylated amines from amides by directed metalation−
electrophilic silylation,3 there are just a few catalytic
approaches known.4,5 Mita and Sato recently disclosed a
rhodium-catalyzed dehydrogenative coupling of mainly Me2N
groups and Et3SiH directed by a pyridin-2-yl donor; further
substitution at the methyl group is detrimental (Scheme 1A).4
Similar observations were made by Zeng and co-workers in
their [1,5]-hydrogen atom transfer strategy starting from ortho-
fluorinated benzamides with different alkyl groups attached to
the nitrogen atom (Scheme 1B).5 We therefore targeted an
oxidative procedure that would convert those C(sp3)−H into
C(sp3)−Si bonds without the structural bias of the
aforementioned examples (Scheme 1C). Our approach is
intended to complement the existing methods for the catalytic
preparation of α-silylated amines,6 particularly the addition of
silicon nucleophiles to imines7 and carbon nucleophiles to
silylated imines,8 respectively.9,10
Amides by Silylation of α-C(sp3)−H Bonds
a
PG = protective group.
Our plan was to make use of copper/bipyridine catalysts11
and alkoxide-mediated activation of the Si−B bond12,13 in Si−
B reagents14 (Scheme 1C). To avoid the use of oxidants in the
presence of Si−B reagents,15 we decided to transform the
amine substrates into the readily available16 N-chlorinated
derivatives. The N−Cl linkage could serve as a traceless
activating group in the coupling of the C(sp3)−H bond α to
the nitrogen atom by engaging in single electron transfer
(SET) processes.17 To demonstrate the feasibility of our
proposal, we began with the optimization of the reaction using
N-chlorosulfonamide 1a as the model substrate and Me2PhSi−
Bpin14a as the silicon source (Table 1). After screening of
various reaction parameters, we found that the desired bond
formation occurred with CuSCN/4,4′-dimethoxy-2,2′-bipyr-
idine as catalyst and LiOMe as alkoxide base in CH3CN at
room temperature; the α-silylated amide 2a was obtained in
78% NMR yield along with 22% NMR yield of amide 3a
resulting from hydrodechlorination at the nitrogen atom (entry
1; see the Supporting Information for the complete set of
optimization data). Control experiments showed that both the
copper salt and the alkoxide are essential (entries 2 and 3). Of
note, when CuSCN was not employed, 42% NMR yield of
hydrodechlorinated 3a as well as a similar amount of the
Received: May 30, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01698
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
withdrawing Tf group did not lead to C−Si bond formation
(entries 6 and 7). Aside from sulfonamides, phosphinamide 1h
and benzoylamide 1i are also suitable substrates (entries 8 and
9).
Table 1. Selected Examples of the Optimization of the
a
C(sp3)−H Silylation
Before examining the substrate scope with Ts as protective
group, we tested silicon pronucleophiles other than Me2PhSi−
Bpin in the model reaction. MePh2Si−Bpin14a led to a
comparable result (70% versus 77% yield, see the Supporting
Information for characterization data and NMR spectra) while
Et3Si−Bpin14b did not react;15 degradation of 1a to 3a (65%)
and 4a (35%) was detected. The substrate scope is
summarized in Table 3. The reaction of sulfonamides 5a−
b
b
yield of yield of
entry
1
variation
2a (%)
3a (%)
Table 3. Scope of Copper-Catalyzed Silylation of C(sp3)−H
none
w/o CuSCN
w/o LiOMe
78
15
0
60
76
67
33
22
42
94
40
23
33
48
62
a
c
Bonds Adjacent to an Amide Nitrogen Atom
2
3
d
4
5
6
7
8
w/o 4,4′-(OMe)2bpy
1,4-dioxane/DMF (9:1) instead of MeCN
1,4-dioxane instead of MeCN
DMF instead of MeCN
THF instead of MeCN
37
a
b
All reactions performed on a 0.10 mmol scale. NMR yield with
c
CH2Br2 as an internal standard. 43% NMR yield of the 4a observed.
d
5% NMR yield of 4a observed.
corresponding aldimine 4a were produced (entry 2); more-
over, the formation of the α-silylated amide 2a in 15% NMR
yield suggests that LiOMe alone is able to mediate the Si−B
bond activation and the subsequent silyl transfer onto 4a.18
The combination of CuSCN and 4,4’-(OMe)2bpy is crucial to
secure high yield (entry 4). The solvent also had substantial
effect on the product distribution but no improvement over
acetonitrile was seen (entries 5−8).
With the optimized conditions in hand, we evaluated
different protecting groups on the nitrogen atom (Table 2).
It was found that the electronic situation of the sulfonamide
had a significant impact on the reaction outcome. Electron-rich
1a, 1b, and 1d afforded relatively better results than electron-
deficient 1c and 1e (entries 1−5). Ms-protected 1f furnished
2f in moderate yield whereas 1g bearing a strongly electron-
a
b
All reactions performed on a 0.20 mmol scale. Isolated yield after
c
a
flash chromatography on silica gel. Performed in 1,4-dioxane/DMF
(9:1) instead of MeCN for better solubility.
Table 2. Assessment of Different Amides
11a bearing various benzyl groups with substituents in the
para, meta, and ortho positions proceeded smoothly, and the
corresponding α-silylated amines 16a−22a were obtained in
moderate yields (entries 1−7). In general, substrates with
electron-withdrawing substituents on the aryl moiety showed
lower yields than those bearing an electron-donating group
(entry 1 versus 4). The phenyl unit in 1a could be replaced by
an α-naphthyl (12a → 23a, entry 8) and a heteroaryl group
(13a → 24a, entry 9), still maintaining decent yields. However,
the yield dropped to 29% for R1 = alkyl (14a → 25a, entry 10).
Conversely, fully substituted 15a with R1 = Ph and R2 = Me
yielded α-silylated amine 26a with a “quaternary” carbon atom
in acceptable yield (entry 11).
As mentioned above, the N-chlorosulfonamides are easily
accessible from the corresponding sulfonamides by oxidation
with tBuOCl,17c e.g., 3a → 1a (Scheme 2). This procedure is
in fact compatible with the formal C−H silylation, and the α-
silylated amine 2a was isolated in 70% yield after subjecting
crude 1a to the standard protocol (Scheme 2).
b
entry
amide
PG
amine
yield (%)
1
2
3
1a
1b
1c
1d
1e
1f
1g
1h
1i
Ts
2a
2b
2c
2d
2e
2f
2g
2h
2i
77
80
50
80
72
66
0
p-MeOPhSO2
p-NO2PhSO2
o-MePhSO2
o-BrPhSO2
MeSO2
CF3SO2
Ph2P(O)
Bz
c
4
5
6
7
8
9
78
60
a
b
All reactions performed on a 0.20 mmol scale. Isolated yield after
flash chromatography on silica gel. Performed in 1,4-dioxane/DMF
c
(9:1) instead of MeCN for better solubility.
B
DOI: 10.1021/acs.orglett.8b01698
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
method allows for the silylation C(sp3)−H bonds adjacent to
amide nitrogen atoms at room temperature. The starting
material, that is, the N-halogenated amide, can be prepared in
situ and used without further purification in the subsequent
copper-catalyzed silylation.
Scheme 2. Procedure on Larger Scale without Purification
of the N-Chlorosulfonamide
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01698.
To gain preliminary insight into the reaction mechanism,
specifically the formation of the imine 4a, we performed two
control experiments (Scheme 3). The reaction of 1a in the
Experimental procedures and spectral data for all new
compounds (PDF)
Scheme 3. Control Experiments
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: martin.oestreich@tu-berlin.de.
ORCID
Jian-Jun Feng: 0000-0002-6094-3268
Martin Oestreich: 0000-0002-1487-9218
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
J.-J.F. gratefully acknowledges the Alexander von Humboldt
Foundation for a postdoctoral fellowship (2017−2019). M.O.
is indebted to the Einstein Foundation (Berlin) for an
endowed professorship.
absence of the Si−B reagent did form imine 4a in 64% NMR
yield along with amine 3a in 25% NMR yield (top). Treatment
of 4a with the standard setup then gave α-silylated amine 2a in
85% NMR yield (bottom).7a
On the basis of these control experiments and previous
experimental observations, we believe that the catalysis
proceeds through the imine (gray box, Scheme 4) that, in
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DOI: 10.1021/acs.orglett.8b01698
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DOI: 10.1021/acs.orglett.8b01698
Org. Lett. XXXX, XXX, XXX−XXX