Nickel-Catalyzed Aminoxylation of Inert Aliphatic C(sp3)-H Bonds with Stable Nitroxyl Radicals under Air: One-Pot Route to α-Formyl Acid Derivatives

Article abstract of DOI:10.1021/acs.orglett.7b00479

Nickel-catalyzed aminoxylation of an unactivated C(sp³)-H bond with a stable nitroxyl radical has been accomplished for the first time to offer various N-alkoxyamine derivatives, which further enables a one-pot approach to α-formyl acid derivatives. The aminoxylation process reported also provides direct evidence for the oxidative addition of a cyclometallic intermediate with a free radical, which is helpful for the reaction-mechanism study in transition-metal-catalyzed functionalization of inert C(sp³)-H bonds.

Full text of DOI:10.1021/acs.orglett.7b00479

Letter
pubs.acs.org/OrgLett
Nickel-Catalyzed Aminoxylation of Inert Aliphatic C(sp3)−H Bonds
with Stable Nitroxyl Radicals under Air: One-Pot Route to α‑Formyl
Acid Derivatives
Chunxia Wang, Luoqiang Zhang, and Jingsong You*
Key Laboratory of Green Chemistry and Technology of Ministry of Education, College of Chemistry, Sichuan University, 29
Wangjiang Road, Chengdu 610064, P.R. China
S
* Supporting Information
ABSTRACT: Nickel-catalyzed aminoxylation of an unactivated C(sp3)−H bond
with a stable nitroxyl radical has been accomplished for the first time to offer various
N-alkoxyamine derivatives, which further enables a one-pot approach to α-formyl acid
derivatives. The aminoxylation process reported also provides direct evidence for the
oxidative addition of a cyclometallic intermediate with a free radical, which is helpful
for the reaction-mechanism study in transition-metal-catalyzed functionalization of
inert C(sp3)−H bonds.
tional precursors, have been widely applied in research and
development of materials and drugs.4,5 Although the past
decades have witnessed substantial progress in the development
of approaches for preparing N-alkoxyamines,6 the amino-
xylation of inert aliphatic C(sp3)−H bond has not yet been
implemented.
n recent years, tremendous efforts have been devoted to the
1−3 As an effective strategy
Iformation of alkyloxy compounds.
for the construction of these compounds, carbon−oxygen
bond-forming reactions involving transition-metal-catalyzed
unactivated C(sp3)−H activation have emerged and attracted
much attention in the organic chemistry community (Scheme
1, eq 1).3 N-Alkoxyamines, as effective fireproofing agents,
rheology modifiers, chiral building blocks and other polyfunc-
In the past few decades, significant progress has been made
in free-radical reactions. 2,2,6,6-Tetramethylpiperidin-1-oxyl
(TEMPO), a stable nitroxyl radical, has been used as radical
scavenger, nonmetallic catalyst, organic single electron oxidant,
and coupling partner.7 TEMPO displays various roles in these
reactions due to its unique physicochemical property. Recently,
the copper-catalyzed aminoxylation of reactive C(sp3)−H
bonds, such as those which are adjacent to N, O, ketone,
nitrile, ester, allylic, and aryl with TEMPO, was reported
(Scheme 1, eq 2).6f In this work, we demonstrate that
unactivated C(sp3)−H bonds enable the aminoxylation with a
stable nitroxyl radical to construct N-alkoxyamines by nickel-
catalyzed C(sp3)−H bond activation (Scheme 1, eq 3).
Despite significant progress in transition-metal-catalyzed
carbon−oxygen bond-forming reactions of C(sp3)−H bonds,
transition-metal-catalyzed directed functionalization of inert
C(sp3)−H bonds involving free radicals has been rarely
reported until now.8 In previous reports, carbon−oxygen
bond-forming reactions in the field of unactivated C(sp3)−H
activation have been developed mainly with palladium as the
catalyst.3 Considering that inexpensive and earth-abundant
first-row transition metals such as iron, copper, and nickel salts
have been widely used as the catalyst in the free-radical
reactions,9 these metals were thus employed to investigate this
type of aminoxylation of unreactive C(sp3)−H bonds.
Choosing the 8-aminoquinoline unit as a readily removable
bidentate directing group, we initiated our study with the
Scheme 1. Transition-Metal-Catalyzed C−O Bond-Forming
Reactions of C(sp3)−H Bonds
Received: February 16, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00479
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a,b
reaction of 2-ethyl-2-methyl-N-(quinolin-8-yl)butanamide 1a
with TEMPO (Scheme 2). Luckily, the desired cross-coupled
Scheme 3. Scope of Aliphatic Acid Derivatives
Scheme 2. Optimization of Reaction Conditions
product 3aa was obtained in toluene in 7% yield by using NiCl2
as the catalyst in the presence of 2.0 equiv of t-BuOLi as the
base (Table S1, entry 1). Other commercially available simple
metal salts, such as CoCl2, CuCl2, and CuCl, did not give any
desired product. Other bases such as t-BuONa, t-BuOK, K3PO4,
Li2CO3, Na2CO3, NaOAc, PhCOONa, CsF, DIPEA, and DBU
were screened, and no product was detected (Table S2). Next,
the effect of solvents was investigated (Table S3). DCE, DMF,
DMSO, and acetonitrile were incompatible in this reaction.
Benzonitrile could improve the yield to 21% (Table S3, entry
9). However, some undefined side reaction was observed when
PhCN was used as the solvent. Then a mixture of benzonitrile
and toluene (ca. 1:5 v/v) was used as the solvent, giving the
desired product in a similar yield (Table S3, entry 10).
Subsequently, various Ni(II) and Ni(0) species were examined
(Table S4), and Ni(OTf)2 was found to afford 3aa in 81% yield
at 120 °C for 6 h under air (Table S5, entry 8). Notably, the
aminoxylation occurred in 69% yield under an atmosphere of
nitrogen, indicating that, besides oxygen, TEMPO could also
serve as the oxidant (Table S5, entries 8, 12, and 13).
With the optimized conditions in hand, the substrate scope
of aliphatic amides using TEMPO as the aminoxyl source was
investigated. As summarized in Scheme 3, a series of 2,2-
disubstituted propanamides bearing linear or cyclic chains could
be transformed into the desired N-alkoxyamine products in
moderate to high yields. Substrates with functional groups such
as bromine, alkoxy, heteroaryl, trifluoromethyl, and alkenyl on
the alkane skeletons were compatible with this reaction.
However, no reactions were detected when the substrates
contained functional groups such as esters, benzyl ethers, and
ketones (for details, see the SI). Moreover, the disubstituted
products could be obtained under the standard conditions
when aliphatic amides with small steric hindrance were
employed (3ba′, 3ja′, and 3ka′). Furthermore, site selectivity
for the β-methyl group over the methylene group or γ- and δ-
methyl group was revealed even though the β-benzylic site
exists (3aa−ra). Notably, the trisubstituted product could not
be detected in this catalytic system probably due to steric
hindrance. 2-Benzyl-2-methyl-3-phenyl-N-(quinolin-8-yl)-
propanamide (1w) did not undergo the aminoxylation.
Next, substrate scope with respect to nitroxyl radicals was
explored (Scheme 4). The nitroxyl radicals with a reactive
functional group such as hydroxyl (2-a), keto carbonyl (2-b),
and amino (2-c) did not provide the desired cross-coupled
products. However, this catalytic system was tolerant of the
protected hydroxyl, keto carbonyl, and amino groups, delivering
the desired N-alkoxyamines. 2,2,6,6-Tetramethyl-4-
(phenylmethoxy)piperidinoxy compounds with an electron-
donating or electron-drawing group on the phenyl ring could
also be transformed into the desired products (3bh−bk). The
presence of a diethylphosphate group did not lead to the N-
alkoxyamine product (2-d).
a
Reaction conditions: 1 (0.25 mmol), 2a (2.0 equiv), Ni(OTf)2 (20
mol %), PhCN (4.0 equiv), and t-BuOLi (2.0 equiv) were stirred in
toluene (0.5 mL) at 120 °C for 6 h under an atmosphere of air.
b
c
d
e
Isolated yields. 12 h. 12 h, 140 °C. 1.5 mmol scale. Q = 8-
quinolinyl.
To gain insight into the reaction mechanism, deuterium-
labeling experiments were conducted (Scheme 5). When the
reaction was performed with D2O or CD3OD instead of
nitroxyl radicals, no methyl hydrogen in [dn]-1a was
deuterated, indicating that the primary C(sp3)−H bond
activation was an irreversible process. We then measured
both the parallel and intermolecular kinetic isotope effects
(KIEs). The observed KIE values indicated that C−H bond
cleavage might be related to the rate-determining step.10
Based on the above results and previous reports,11 a tentative
mechanism of aminoxylation is proposed in Scheme 6. Initially,
a bidentate chelation process of the amide A with the Ni(II)
species gives the Ni(II) complex B with the generation of HX,
which is trapped by t-BuOLi. Then the C−H bond in complex
B undergoes an irreversible cleavage to give the cyclometallic
intermediate C. The Ni(III) species D is generated via the
oxidative addition of the nickelacycle C with the nitroxyl
radical. The reductive elimination and protonation next occur
to deliver the desired product with generation of the Ni(I)
species (Scheme 6, path a). Finally, the Ni(I) species is oxidized
to the Ni(II) species by either the stable nitroxyl radical or
oxygen in air, fulfilling the catalytic cycle. It is noted that no
B
DOI: 10.1021/acs.orglett.7b00479
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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a,b
As important structural motifs, α-formyl acid derivatives are
widely found in pharmaceutical and natural product molecules
(Figure 1).12 To further extend the utility of this protocol, a
Scheme 4. Scope of Stable Nitroxyl Radicals
Figure 1. Selected pharmaceutical and natural product molecules
containing α-formyl acid derivatives.
one-pot route to α-formyl acid derivatives was put forward.
After the aminoxylation of the C(sp3)−H bond of aliphatic
amides, 2 equiv of m-CPBA was directly added in the same tube
to yield α-formyl acid derivatives.13 As shown in Scheme 7, a
range of α-formyl acid derivatives bearing alkoxy, phenyl, and
heteroaryl groups were obtained in acceptable yields.
a
Reaction conditions: 1a (0.25 mmol), 2 (2.0 equiv), Ni(OTf)2 (20
mol %), PhCN (4.0 equiv), and t-BuOLi (2.0 equiv) were stirred in
toluene (0.5 mL) at 120 °C for 6 h under an atmosphere of air.
a,b
Scheme 7. Synthesis of α-Formyl Acid Derivatives
b
c
d
Isolated yields. 24 h. 24 h, 140 °C. Q = 8-quinolinyl.
Scheme 5. Deuterium-Labeling Experiments
a
Reaction conditions: (1) 1 (0.25 mmol), 2a (2.0 equiv), Ni(OTf)2
(20 mol %), PhCN (4.0 equiv), and t-BuOLi (2.0 equiv) were stirred
in toluene (0.5 mL) at 120 °C for 6−12 h under an atmosphere of air;
(2) 0.5 mmol of m-CPBA and 10 mL of dichloromethane were added
in the same tube. The system was stirred for 10 min at room
b
c
temperature. Isolated yields. 1.5 mmol scale. Q = 8-quinolinyl.
Scheme 6. Plausible Mechanistic Pathway
The N-alkoxyamine product 3ma could be converted into
the corresponding carboxylic esters in the presence of BF3·Et2O
(Scheme S1). In addition, a β-hydroxyl amide 6-e could be
easily obtained by reduction of the α-formyl acid derivative 4-e
by use of NaBH4 (Scheme S2).
In summary, we have developed the nickel-catalyzed
aminoxylation of an unactivated C(sp3)−H bond with a stable
nitroxyl radical, affording various N-alkoxyamine derivatives.
This protocol can further provide a feasible synthetic approach
to α-formyl acid derivatives in one pot. This protocol also offers
direct evidence for an oxidative addition of a cyclometallic
intermediate with a free radical, which is helpful to the study of
the reaction mechanism in transition-metal-catalyzed function-
alization of inert C(sp3)−H bonds.8 Further studies related to a
radical-involved process are ongoing in our laboratory.
lactam product was detected in this catalytic system (Scheme 6,
path b).7e
C
DOI: 10.1021/acs.orglett.7b00479
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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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.7b00479.
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Detailed experimental procedures, characterization data,
1
and H and 13C NMR spectra of final products (PDF)
AUTHOR INFORMATION
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Corresponding Author
*E-mail: jsyou@scu.edu.cn.
ORCID
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Jingsong You: 0000-0002-0493-2388
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the financial support from the National NSF of
China (No 21432005).
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