Formal Carbene C-H Bond Insertion in the Cu(I)-Catalyzed Reaction of Bis(trimethylsilyl)diazomethane with Benzoxazoles and Oxazoles

Article abstract of DOI:10.1021/acs.orglett.9b00391

A Cu(I)-catalyzed cross-coupling reaction of bis(trimethylsilyl)diazomethane and benzoxazoles/oxazoles is reported. A wide range of functional groups can be tolerated in this transformation. This reaction provides a new method to directly introduce a 1,1-bis(trimethylsilyl)methyl group into heteroaromatic C-H bonds. Subsequent transformations of 1,1-bis(trimethylsilyl)-methylated heteroaromatic compounds are also presented.

Full text of DOI:10.1021/acs.orglett.9b00391

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Formal Carbene C−H Bond Insertion in the Cu(I)-Catalyzed Reaction
of Bis(trimethylsilyl)diazomethane with Benzoxazoles and Oxazoles
†
†
†
†
,†,‡
Shuai Wang, Shuai Xu, Cheng Yang, Hanli Sun, and Jianbo Wang*
†Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of Bioorganic Chemistry and Molecular
Engineering of Ministry of Education, College of Chemistry, Peking University, Beijing 100871, China
‡
State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
*
S Supporting Information
ABSTRACT: A Cu(I)-catalyzed cross-coupling reaction of
bis(trimethylsilyl)diazomethane and benzoxazoles/oxazoles is
reported. A wide range of functional groups can be tolerated in
this transformation. This reaction provides a new method to
directly introduce a 1,1-bis(trimethylsilyl)methyl group into
heteroaromatic C−H bonds. Subsequent transformations of
1
,1-bis(trimethylsilyl)-methylated heteroaromatic compounds are also presented.
rganosilicon compounds play an important part in organic
require introduction of two silyl groups in more than one step.
O
chemistry owing to their wide applications in organic
To the best of our knowledge, the method for the direct
introduction of a gem-disilyl unit into aromatic C−H bonds has
not been explored.
On the other hand, transition-metal-catalyzed cross-coupling
reactions of metal carbene precursors have recently emerged as a
1
synthesis. Geminal disilyl compounds represent a special type
of organosilicon compounds because of their unique structure
2
and reactivity. For example, geminal disilyl compounds can
react as bicarbanion precursors and take part in the construction
2
b−e
9,10
of CC bonds in Peterson reactions
and other functional
In addition, geminal disilyl com-
pounds can also undergo reactions with only one of the two silyl
powerful tool for the construction of C−C and C−X bonds.
2c,f
group transformations.
In this context, we have previously developed an efficient
method for the direct heteroaromatic C−H functionalization
through Cu(I)-catalyzed reaction of heteroaromatic compounds
and N-tosylhydrazones. To further expand this type of Cu(I)
carbene migratory insertion process, we have conceived using
bis(trimethylsilyl)diazomethane 1 to access bis(trimethylsilyl)-
methylated heteroaromatic compounds (Scheme 1c). Bis-
(trimethylsilyl)diazomethane 1 was synthesized previously by
2g−k
groups, with the other one remaining in the products.
10a
Traditional synthesis of the gem-disilyl unit requires stepwise
deprotonative silylation under strong basic conditions (Scheme
2
e,3
1
a).
In recent years, several transition-metal-catalyzed
Scheme 1. Synthesis of gem-Disilyl Compounds
11
Barton and Hoekman. However, it shows higher stability and
different reactivity compared with that of other diazo
compounds, such as (trimethylsilyl)diazomethane
(
TMSCHN ), and the synthetic applications of this compound
2
12,13
have not been explored until very recently.
Herein, we
demonstrate that bis(trimethylsilyl)diazomethane undergoes
efficient coupling with heteroarenes in the presence of a Cu(I)
catalyst, affording the corresponding bis(trimethylsilyl)-methy-
lated heteroaromatic compounds in moderate to good yields.
In the initial investigation, we examined the reactivity of
various Cu(I) catalysts by using 5-methylbenzoxazole 2a as the
model substrate (Table 1, entries 1−3). The desired product 3a
was isolated in 21% yield with CuI as the catalyst and dioxane as
the solvent at 110 °C (entry 1). When the ratio of 1 and 2a was
changed to 2:1, the yield of 3a could be increased to 71% (entry
4
). The reaction temperature was found to have a notable effect
processes were developed for the synthesis of these compounds,
4
on the reaction. Reactions at 100 and 120 °C led to diminished
yields (entries 5 and 6). By further screening the solvents, it was
including Kumada cross-coupling reactions (Scheme 1b),
5
,6
carbene insertion reactions of Si−H and Si−Si bonds,
7
hydrosilylation of unsaturated bonds, and rearrangement
reactions. However, the methods to synthesize geminal disilyl
8
Received: January 30, 2019
compounds are still limited, and most of the known methods
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00391
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions
b
t
c
entry
ratio (1/2a)
cat. (mol %)
solvent
LiO Bu (x equiv)
T (°C)
yield (%)
1
2
3
4
5
6
7
8
1:1
1:1
1:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
CuI (20)
CuCl (20)
CuBr (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
Rh (OAc) (1)
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
1
1
1
1
1
1
1
1.5
1.8
1.5
0
0
1.5
1.5
110
110
110
110
100
120
110
110
110
110
110
110
110
110
21
trace
20
71
40
43
75
85
84
89
0
9
c
1
1
1
1
1
0
1
2
3
4
c
c
c
c
0
0
17
2
4
Pd(OAc) (5)
2
CuBr (20)
2
a
t
Reaction conditions: bis(trimethylsilyl)diazomethane 1 (0.1 mmol), 2a (0.1 mmol), CuI (0.02 mmol), LiO Bu (0.1 mmol), solvent (1.0 mL) for 8
b
c
h. Isolated yield. The reaction was carried out at 0.2 mmol scale.
proven that the reaction with toluene afforded the optimal result
Scheme 2. Substrate Scope of Benzoxazoles and
Benzothiazoles
a
(
entry 7). The choice of base also had a great influence on the
reaction. Several organic and inorganic bases were tested, and
t
the use of LiO Bu gave the best result (see Supporting
Information). The yield of 3a could be increased to 85% when
the loading of base was increased to 1.5 equiv, but a further
increase of the base loading had no obvious benefit (entries 8
and 9). Finally, under the optimized conditions, the reaction at
the 0.2 mmol scale afforded the desired product in 89% isolated
yield. Several control experiments were also carried out (entries
1
1−14). No desired product was observed without the addition
of base. The reaction with Rh(II) and Pd(II) catalysts did not
give product 3a (entries 12 and 13), whereas the reaction with
2
0 mol % of CuBr afforded 3a in 17% yield (entry 14).
With the optimized conditions in hand, we then explored the
2
substrate scope of this reaction (Scheme 2). For benzoxazoles,
both electron-donating and electron-withdrawing group,
including alkyl (3a, 3d, 3h, 3j, 3l), halogen (3c, 3f, 3i, 3k),
methoxyl (3g), and phenyl (3e), were well-tolerated and gave
the corresponding products in moderate to good yields.
However, substrates with a strong electron-withdrawing group
failed to afford the corresponding products under standard
conditions (3p, 3q). Substituent groups at different positions
showed similar reactivity (3a and 3h, 3f and 3k). We also tested
the reactivity of benzothiazole derivatives for this reaction, and
the corresponding products can be obtained in moderate to
good yields under modified conditions (3m−o).
a
Reaction conditions: bis(trimethylsilyl)diazomethane 1 (0.4 mmol),
t
2
a−o (0.2 mmol), CuI (0.04 mmol), LiO Bu (0.3 mmol), toluene
b
t
(
1.0 mL), 110 °C for 8 h. 120 °C, LiO Bu (0.4 mmol). All yields
refer to the isolated products.
We then expanded the substrate scope of the substituted
oxazoles (Scheme 3). For 5-aryl-substituted oxazoles, both
electron-donating and electron-withdrawing groups on the 5-
aryl moiety were well-tolerated (5a−h). In addition to the
substituted aryl group on the 5-position, naphthyl, furyl, and
thienyl groups were also tolerated (5l−n). However, 5-pyridyl
oxazole did not work for this reaction (5o). We also examined
the reactivity of several 4-substituted oxazoles and obtained
similar results as the corresponding 5-substituted substrates
To gain further insight into the mechanism of this reaction, we
have carried out kinetic isotope effects (KIE) and deuterium
labeling experiments (Scheme 4). The result showed that the
reaction had a delay time of about 5 min, and no significant
primary kinetic isotope effects were observed in parallel kinetic
experiments (Scheme 4a), which indicated that the deprotona-
tion process should not be involved in the rate-limiting step.
When the reaction was carried out with isotopically labeled
substrate d-2b, obvious H/D exchange was observed (Scheme
(5i−k). To our disappointment, the alkyl-substituted oxazole
did not work for this transformation (5p).
4b). Quenching the reaction with D O led to a slight decrease of
2
B
DOI: 10.1021/acs.orglett.9b00391
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 3. Substrate Scope of Oxazoles
reaction mixture. This result also suggested the substantial high
acidity of 3b/d-3b.
It has been reasoned that the current reaction does not follow
14
the mechanism of classic carbene C−H bond insertion for the
following reasons: (1) in the absence of base, no formal insertion
product was formed (Table 1, entry 11); (2) carbene insertion
did not occur in the presence of Rh(II) catalyst (Table 1, entry
1
2); (3) the target C−H bond of benzoxazole or oxazole is
electron-deficient, which is typically less reactive in classic
carbene C−H insertions. Thus, based on the experimental
results and our previous report, a mechanistic rationale is
proposed in Scheme 5. The reaction is initiated by the
10
Scheme 5. Proposed Reaction Mechanism
a
Reaction conditions: bis(trimethylsilyl)diazomethane 1 (0.4 mmol),
a−p (0.2 mmol), CuI (0.04 mmol), LiO Bu (0.3 mmol), toluene
t
4
(
1.0 mL), 110 °C for 8 h. All yields refer to the isolated products.
Scheme 4. KIE and Deuterium Labeling Experiments
deprotonation of the relatively acidic C−H bond of the oxazole
t
substrate 4 with LiO Bu, which is followed by transmetalation to
the Cu(I) catalyst to generate oxazolyl Cu(I) species A.
Intermediate A then reacts with the diazo substrate 1 to form
a Cu(I) carbene species B. Subsequently, migratory insertion
occurs to give Cu(I) intermediate C, followed by protonation to
give the gem-disilylated product 5 and regenerate the Cu(I)
catalyst.
To demonstrate the practical application of this method, the
Cu(I)-catalyzed cross-coupling reaction was carried out at gram
scale (Scheme 6). The corresponding geminal disilyl com-
pounds 3a and 3b could be successfully obtained, albeit in
slightly diminished yields.
Scheme 6. Gram-Scale Synthesis
Furthermore, to explore the synthetic application of the
geminal disilyl compounds obtained from the Cu(I)-catalyzed
cross-coupling reaction of bis(trimethylsilyl)diazomethane and
benzoxazoles, we have attempted further transformations of
these compounds (Scheme 7). The geminal disilyl compounds
(3d, 3e, 3f) could be easily transformed into the corresponding
methylated products (6d, 6e, 6f) under mild conditions
the loss of deuterium in the product. Further treatment of
deuterium-labeled d-3b with silica gel also led to the decrease of
deuterium-labeled ratio. The loss of deuterium may be the result
of the weak acidity of the geminal disilyl product. When the
reaction of non-deuterium-labeled substrate 2b was quenched
with D O, the product was partially deuterium-labeled, which
2
15
indicated that the product 3b was partially deprotonated in the
(Scheme 7a). Finally, the geminal disilyl compounds 3a and
C
DOI: 10.1021/acs.orglett.9b00391
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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(
1
(
7
coupling of bis(trimethylsilyl)diazomethane and benzoxazoles/
oxazoles via a metal carbene migratory insertion process. This
reaction provides a new method to directly introduce 1,1-
bis(trimethylsilyl)methyl group into heteroaromatic C−H
bonds. By using this cross-coupling reaction, a series of 1,1-
bis(trimethylsilyl)-methylated heteroaromatic compounds have
been successfully synthesized in moderate to good yields from
easily available materials. The reaction uses readily available and
inexpensive CuI as the catalyst and tolerates a wide range of
functional groups. We thus expect this bis(trimethylsilyl)-
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ASSOCIATED CONTENT
Supporting Information
(10) (a) Zhao, X.; Wu, G.; Zhang, Y.; Wang, J. J. Am. Chem. Soc. 2011,
■
*
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133, 3296−3299. (b) Xu, S.; Wu, G.; Ye, F.; Wang, X.; Li, H.; Zhao, X.;
Zhang, Y.; Wang, J. Angew. Chem., Int. Ed. 2015, 54, 4669−4672.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b00391.
(
11) Barton, T. J.; Hoekman, S. K. J. Am. Chem. Soc. 1980, 102, 1584−
1591.
1
13
Experiment details, spectra data, and copies of H and C
NMR spectra for all products (PDF)
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Chem. Soc. 2012, 134, 17757−17768.
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AUTHOR INFORMATION
Corresponding Author
■
*
(
(
(
E-mail: wangjb@pku.edu.cn.
ORCID
1
2
Jianbo Wang: 0000-0002-0092-0937
Notes
2011, 40, 1857−1869. (e) Lu, H.; Zhang, X. P. Chem. Soc. Rev. 2011,
4
0, 1899−1909.
(
15) For a recent report on methylation of aromatic compounds, see:
The authors declare no competing financial interest.
He, Z.-T.; Li, H.; Haydl, A. M.; Whiteker, G. T.; Hartwig, J. F. J. Am.
Chem. Soc. 2018, 140, 17197−17202.
ACKNOWLEDGMENTS
This project was supported by 973 program (2015CB856600)
and NSFC (21871010).
■
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DOI: 10.1021/acs.orglett.9b00391
Org. Lett. XXXX, XXX, XXX−XXX