Palladium-Catalyzed C(sp3)-H Nitrooxylation with tert-Butyl Nitrite and Molecular Oxygen

Article abstract of DOI:10.1021/acs.orglett.0c03794

Herein, we report a Pd(II)-catalyzed nitrooxylation of unactivated methyl C(sp3)-H bonds using commercial available and easily manageable tert-butyl nitrite as the precursor of ONO2 radical under aerobic conditions. Environmentally benign molecular oxygen is used to initiate the generation of active radical reactant; it is also used as the terminal oxidant. A broad range of nitrooxylated aliphatic carboxamides were prepared in moderate to good yields under mild conditions.

Full text of DOI:10.1021/acs.orglett.0c03794

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Letter
Palladium-Catalyzed C(sp3)−H Nitrooxylation with tert-Butyl Nitrite
and Molecular Oxygen
Bo Li,∇ Ye-Qiang Han,∇ Xu Yang, and Bing-Feng Shi*
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ABSTRACT: Herein, we report a Pd(II)-catalyzed nitrooxylation of
unactivated methyl C(sp3)−H bonds using commercial available and
easily manageable tert-butyl nitrite as the precursor of ONO2 radical
under aerobic conditions. Environmentally benign molecular oxygen is
used to initiate the generation of active radical reactant; it is also used as
the terminal oxidant. A broad range of nitrooxylated aliphatic carboxamides were prepared in moderate to good yields under mild
conditions.
rganic nitrate esters are an important class of
compounds, which are used for the treatment of vascular
Scheme 1. Development of C(sp3)−H Nitrooxylation
O
aliments and are widely present in pharmaceutical and
bioactive compounds (Figure 1).1 In addition, the nitrooxy
Figure 1. Commercial drugs containing nitrooxy group.
group can be transformed to C−N, C−O, and C−C functional
groups.2 Traditionally, esterification of alcohols with nitric acid
was used to prepare organic nitrates.3 However, this approach
has several drawbacks, including hazardous reaction proce-
dures, poor functional group tolerance, and harsh reaction
conditions. Alternative strategies have been developed to
access these compounds. In 2011, the Inoue group achieved
the C−H nitrooxylation at benzylic positions by employing the
N-hydroxyphthalimide (NHPI) catalyst and cerium(IV)
ammonium nitrate (CAN) reagent (Scheme 1a).4 In 2016,
Kanai and co-workers reported an aerobic C(sp3)−H nitro-
oxylation based on an N-hydroxyamide-derived directing
activator (DA), albeit with low yields (27%−46%) and poor
chemoselectivity with overoxidation (Scheme 1b).5 Therefore,
although these early efforts of radical involved C(sp3)−H
nitrooxylation strategies demonstrated the potential of direct
transformation of C(sp3)−H bonds into the nitrooxy group,
the development of efficient methods for the C(sp3)−H
nitrooxylation under mild conditions using simple and readily
available nitrooxylation reagents is still highly desirable.
generally using stoichiometric organic or inorganic oxidants,
such as PhI(OAc)2, K2S2O8, BQ, and others.6,7 However, the
use of stoichiometric oxidants led to the generation of
undesired byproducts, poor atom economy, and high cost.
With respect to green chemistry, oxygen is regarded as a clean
and inexpensive oxidant in organic synthesis.8 Thus, the
development of Pd-catalyzed C(sp3)−H oxygenation using
oxygen as the oxidant is highly demanding. Many elegant
works have been reported on the use of oxygen as the sole
oxidant; however, most of them were limited to the PdII/Pd0
Received: November 15, 2020
In recent years, Pd-catalyzed C(sp3)−H functionalization
has become a powerful and versatile strategy to construct C−O
and C−N bonds.6 Among several catalytic cycles, those
involving high-valent palladium, such as Pd(III) and Pd(IV),
are major pathways that have been broadly employed,
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catalytic cycle pathway.8,9 Recently, elegant works on Pd-
catalyzed aerobic oxidative formation of C−O, C−N, and C−
C bonds through reductive elimination from high-valent
palladium species have been reported.10 In 2015, the Jiao
group reported the aerobic oxidation of PdII to PdIV using
simple and commercially available tert-butyl nitrite (TBN) as
the radical precursors to achieve the direct C(sp2)−H nitration
(Scheme 1c).10g Mechanistic studies revealed that TBN
decomposed to the NO radical, which could be directly
oxidized to the NO2 radical by O2. The in-situ-generated NO2
radical enabled the facile C(sp2)−H nitration.10g However,
TBN has never been used as the source of the ONO2 radical to
enable the more challenging nitrooxylation reaction. Herein,
we report that the readily available and easy-to-handle TBN
could act as the precursor of ONO2 radical to give the C(sp3)−
H nitrooxylation products.11 Environmentally benign molec-
ular oxygen is used as the terminal oxidant and reactant.
Notably, this is the first example of using TBN as ONO2
radical precursor in C−H activation reaction.
detected in the absence of Pd catalyst under standard
conditions or higher temperature (Table 1, entries 12 and
13), suggesting that the Pd catalyst was crucial to the reaction.
With the optimized reaction conditions in hand, the
efficiency and practicality of the strategy was further proved
by the compatibility with a range of aliphatic carboxamides
(Scheme 2). Aliphatic carboxamides bearing α-tertiary carbons
a
Scheme 2. Scope of Aliphatic Carboxamides
We performed our investigations using 1a bearing a strong
bidentate 2-pyridinylisopropyl (PIP) directing group12,13 as the
model substrate under O2 atmosphere (Table 1). When the
a
Table 1. Optimization of Reaction Conditions
b
entry
additive
solvent
temperature, t (°C)
yield (%)
1
2
3
4
5
6
7
8
9
−
−
−
−
−
−
−
toluene
MeCN
dioxane
DCE
THF
t-BuOH
PhCl
toluene
toluene
toluene
toluene
toluene
toluene
100
100
100
100
100
100
100
100
100
80
38
trace
15
20
trace
trace
22
54
58
70
c
TBAI
TBAOAc
TBAOAc
TBAOAc
TBAOAc
TBAOAc
10
11
c
60
60
100
70 (66)
d
12
d
0
0
13
a
Reaction conditions: 1a (0.2 mmol), TBN (2.0 euqiv), Pd(OAc)2
(10 mol %), additive (0.1 equiv) in 2 mL solvent at temperature t
b
(°C) under O2 for 24 h. 1H NMR yield using CH2Br2 as internal
c
d
a
standard. Isolated yield. No Pd(OAc)2.
Reaction conditions: 1 (0.2 mmol), TBN (2.0 equiv), Pd(OAc)2 (10
mol %), TBAOAc (0.1 equiv) in toluene (2.0 mL) under O2 at 60 °C
b
c
for 24 h. At 45 °C. At 80 °C. The ellipsoids drawn at 30%
reaction was conducted in toluene at 100 °C, the desired
product 2a was obtained in 33% yield (Table 1, entry 1). A
thorough screening of various solvents showed that toluene
was the optimal solvent for this transformation (Table 1,
entries 2−7). Notably, the yield could be significantly
improved when using quaternary ammonium salts as additives
(Table 1, entries 8 and 9). The use of 0.1 equiv of TBAOAc as
an additive gave the desired product 2a in 58% yield (Table 1,
entry 9). The addition of TBAOAc might provide extra acetate
to promote the acetate-mediated concerted metalation-
deprotonation (CMD)-type C−H cleavage. Lowering the
reaction temperature led to improved yield (Table 1, entries
9−11) and nitrooxylation product 2a was obtained in 66%
isolated yield when the reaction was conducted at 60 °C
(Table 1, entry 11). As a control, no desired product was
probability level.
with different alkyl chains were compatible, giving the desired
products in moderate to good yields (40%−87% yield, 2a−2f).
Carboxamide 1e with trifluoromethyl group at the β-position
was also tolerated well and gave the product 2e in 67% yield.
Notably, aliphatic carboxamides with more sterically hindered
α-quaternary carbons were still compatible to this reaction
protocol and gave the nitrooxylation products in good yields,
albeit with a mixture of mononitrooxylation (m) and
dinitrooxylation (d) (2g, 66%, m:d = 2.3:1; 2h, 63%, m:d =
3.5:1). Carboxamide 1i bearing a benzyl ether also reacted
smoothly, giving 2i in 58% yield. A broad range of electron-
donating and electron-withdrawing substituents on the
B
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aromatic ring were tolerated well (51%−75% yield, 2j−2q). In
addition, carboxamides bearing a pyridyl group and an
electron-rich naphthyl group also reacted well, giving the
corresponding products 2r (70%) and 2s (70%) when the
reaction temperature was increased to 80 °C. Note that the N-
phthaloyl protected alanine 1t was also compatible with the
reaction, affording the corresponding product 2t in 59% yield
without any racemization (99% ee). The structure of the
nitrooxylation product 2a was determined by X-ray crystallo-
graphic analysis.
Scheme 4. Proposed Mechanism
To gain more insight into the mechanism, a range of
experiments were conducted. The kinetic isotope effect (KIE)
experiments were conducted and a KIE value of kH/kD = 2.36
was obtained (Scheme 3a), indicating that the C−H cleavage
Scheme 3. Mechanistic Studies
through a Pd-mediated radical pathway involving a PdII/IV
catalytic cycle.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03794.
Experimental details and spectral data for all new
compounds (PDF)
Accession Codes
CCDC 2021467 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
step is likely the rate-determining step of the reaction pathway.
The addition of 1,1-diphenylethylene or 2,6-di-tert-butyl-4-
methylphenol as a radical quencher inhibited the reaction
completely (Scheme 3b), indicating that a radical process
might be involved. We then performed the reaction under the
18O2 atmosphere; the mass of the product 2a-[18O] shows that
18O was incorporated into the product (Scheme 3c; see
Section 2.3 in the Supporting Information for details).
AUTHOR INFORMATION
Corresponding Author
■
Bing-Feng Shi − Department of Chemistry, Zhejiang
University, Hangzhou 310027, People’s Republic of China;
orcid.org/0000-0003-0375-955X; Email: bfshi@
zju.edu.cn
Based on the above studies and previous reports,10g,11
a
plausible mechanism for the Pd(II)-catalyzed aerobic oxidation
of unactived C(sp3)−H bonds is presented (Scheme 4).
Coordination of 1a with palladium acetate is followed by a
rate-determining C−H activation step to form palladacycle A.
Meanwhile, TBN could decompose to generate the NO
radical, which could be oxidized to ONO2 radical B by
O2.10g,11 Oxidation of palladacycle A with ONO2 radical B
gives high-valent Pd(IV) complex C. The C−O bond
formation through reductive elimination then affords the
corresponding desired nitrooxylation product 2a, along with
the regeneration of Pd(OAc)2 by ligand exchange.
Authors
Bo Li − Department of Chemistry, Zhejiang University,
Hangzhou 310027, People’s Republic of China
Ye-Qiang Han − Department of Chemistry, Zhejiang
University, Hangzhou 310027, People’s Republic of China
Xu Yang − School of Biotechnology and Health Sciences, Wuyi
University, Jiangmen 529020, People’s Republic of China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03794
In summary, we have developed a Pd(II)-catalyzed nitro-
oxylation of unactivated C(sp3)−H bonds using commercial
available tert-butyl nitrite (TBN) as ONO2 radical precursor
for the first time. Oxygen is employed as oxygen source to
initiate the generation of active radical reactants and as the
terminal oxidant. The nitrooxylation reaction may proceed
Author Contributions
∇B.L. and Y.-Q.H. contributed equally.
Notes
The authors declare no competing financial interest.
C
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ACKNOWLEDGMENTS
■
Financial support from the NSFC (Nos. 21925109 and
21772170), and Outstanding Young Talents of Zhejiang
Province High-level Personnel of Special Support (No.
ZJWR0108) is gratefully acknowledged.
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