Transition-metal-assisted radical/radical cross-coupling: A new strategy to the oxidative C(sp3)-H/N-H cross-coupling

Article abstract of DOI:10.1021/ol501485f

A transition-metal-assisted oxidative C(sp³)-H/N-H cross-coupling reaction of N-alkoxyamides with aliphatic hydrocarbons is described. During the reaction, nitrogen radicals were generated from the oxidation of N-alkoxyamides. Experiments and DFT calculations revealed that transition-metal catalyst could lower the reactivity of the generated nitrogen radical by the coordination of the transition metal, which allowed the selective radical/radical cross-coupling with the transient sp³ carbon radical to construct C(sp³) - N bonds. Various C(sp³)-H bonds could be transformed into C(sp³)-N bonds through this radical amidation strategy.

Full text of DOI:10.1021/ol501485f

Letter
pubs.acs.org/OrgLett
Transition-Metal-Assisted Radical/Radical Cross-Coupling: A New
Strategy to the Oxidative C(sp3)−H/N−H Cross-Coupling
Liangliang Zhou,†,§ Shan Tang,†,§ Xiaotian Qi,‡ Caitao Lin,† Kun Liu,† Chao Liu,† Yu Lan,*,‡
and Aiwen Lei*,†
†College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei 430072, P. R. China
‡School of Chemistry and Chemical Engineering, Chongqing University, Chongqing 400030, P. R. China
S
* Supporting Information
ABSTRACT: A transition-metal-assisted oxidative C(sp3)-H/N−H
cross-coupling reaction of N-alkoxyamides with aliphatic hydrocarbons
is described. During the reaction, nitrogen radicals were generated
from the oxidation of N-alkoxyamides. Experiments and DFT
calculations revealed that transition-metal catalyst could lower the
reactivity of the generated nitrogen radical by the coordination of the
transition metal, which allowed the selective radical/radical cross-
coupling with the transient sp3 carbon radical to construct C(sp3)−-N
bonds. Various C(sp3)−H bonds could be transformed into C(sp3)−N
bonds through this radical amidation strategy.
C−N bond formation is of great importance in organic synthesis
since nitrogen-containing compounds are found in numerous
biological, pharmaceutical, and material molecules.1 Over the
past few years, transition-metal-catalyzed C(sp2)−N bond
formation has been intensively studied.2 However, C(sp3)−H
bonds, which are naturally more abundant, still face great
challenges in C−N bond formation.3 This may be due to the
following two reasons: (1) β-hydride elimination would take
place for alkyl metal intermediates,4 (2) C(sp3)−N reductive
elimination is usually troublesome.5 Therefore, continuous
efforts have been made in this area.6 Among the processes
developed, radical processes have been receiving more and more
attention.6d,f,k,m,t Zhang et al. developed a significant improve-
ment in this area through metallo-radical-catalyzed radical
amidation. In these processes, azides were utilized as the source
of nitrogen radical to generate C(sp3)−N bonds.6n−s It is known
that the nitrogen radical could also be generated from the
oxidation of amides.7 We wonder whether a radical/radical cross-
coupling amidation strategy in C(sp3)−H/N−H oxidative
coupling could be developed to allow the C(sp3)−N bond
formation with more alternatives.
Generally, radicals with a single electron have a strong
tendency to form chemical bonds. However, selective bond
formation from radical intermediates was less developed
compared to ionic intermediates.8 Since single-electron-transfer
processes widely exist in chemical transformations, we believe
that direct coupling of two radicals would represent a powerful
approach for bond formations. Usually, the selective radical
couplings obey the persistent radical effect; only the radical
coupling between a persistent radical and a transient radical
would lead to a selective bond formation.9 It is difficult to realize
the selective bond formation between two reactive radicals,
which limits the application of this protocol in organic synthesis.
If methods could be developed to stabilize one of the reactive
radicals, it might provide a solution for the direct cross-coupling
between two transient radicals.
It has been demonstrated that transition-metal catalysts might
interact with radicals in many different ways, including direct
redox bond formation, coordination, and atom transfer, etc.10
Each of these processes may be reversible or irreversible.
Reversible interaction between transition metal and radicals
might play an important role in changing the reactivity of the
corresponding radicals to allow it to be utilized in many organic
transformations such as radical polymerization.11 The nature of
the transition-metal complexes could be considered as radical
stabilizer in those cases. Thus, we assume that we could take
advantage of this feature of transition metals to stabilize one of
the transient radicals to achieve selective radical coupling.
Herein, we describe a transition-metal-assisted oxidative radical/
radical coupling between nitrogen radical and carbon radical
(Scheme 1).
According to the previous reports, nitrogen radicals can be
easily generated from the oxidation of N-alkoxyamides by CAN,
metal oxides, or peroxides.12 At the same time, we found that the
α-alkoxyl carbon radical could be generated by heating the
mixture of THF with organic peroxides through hydrogen atom
Scheme 1. Transition-Metal-Assisted Radical/Radical
Oxidative Cross-Coupling
Received: May 22, 2014
© XXXX American Chemical Society
A
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Letter
abstraction.13 At first glance, we wondered whether the direct
radical/radical cross-coupling could take place between the
nitrogen radical and the transient sp3 carbon radicals to afford
C(sp3)−N bonds.9,14 Then the following reactions were carried
out to test our initial proposal. N-Methoxybenzamide (1a) was
heated in tetrahydrofuran (THF) at 120 °C in the presence of
peroxide compounds, such as dicumyl peroxide (DCP), tert-
butyl hydroperoxide (TBHP), and di-tert-butyl peroxide
(DTBP). Reactions did take place but only afforded the
C(sp3)−N bond formation product in low yields (Table 1,
Scheme 2. Intermolecular Competition Experiment between
THF and THF-d8
Table 1. Radical/Radical Oxidative Coupling for the C(sp3)−
Scheme 3. Decomposition of N-Alkoxyamides
a
N Bond Formation
b
c
entry
1
oxidant
additive
yield (%)
DCP
31
d
2
TBHP
DTBP
DTBP
DTBP
trace
39
3
4
5
Cu(acac)2
Ni(acac)2
72
93
a
TBHP as the oxidant was observed by Zhao and co-workers
recently.15 Therefore, from this point of view, we can say that the
nitrogen free radical did exist in this oxidative condition.16
To clarify the exact role of nickel in this reaction system,
density functional theory (DFT) calculations were carried out.
[B3LYP/6-31+G(d) method]17 The homocoupling energy of
nitrogen radical 1a-R is −13.6 kcal/mol (Scheme 4, eq 1).
The reaction was carried out in the presence of an oxidant (1.0
b
mmol) with 1a (0.50 mmol), 2a (3.0 mL), 120 °C, 20 h. Additive
(0.10 mmol). Yield determined by GC analysis with naphthalin as the
internal standard. TBHP (1.0 mmol, 5−6 M in decane).
c
d
entries 1−3). DTBP showed a slightly better result with low
conversion of the substrate (Table 1, entry 3). These initial
results showed that the radical/radical cross-coupling could
indeed be realized for C(sp3)−N bond formations in this
transformation, although the selectivity was still unsatisfactory.
This might be because both radicals are too reactive to achieve
the highly selective cross-coupling. As discussed previously,
transition metals could have some effect on the reactivity of
radicals. We then screened some transition metal salts as
additives to promote selectivity for cross-coupling. Delightfully,
transition-metal additives had a significant effect for improving
the reaction efficiency. Cu(acac)2 was effective for promoting the
selective cross-coupling with an increased yield (72%, Table 1,
entry 4), and Ni(acac)2 showed an excellent reactivity for
promoting the selectivity in this transformation. The cross-
coupling product 3aa was obtained in a 93% yield (Table 1, entry
5).
Scheme 4. Gibbs Free Energies for the Direct Radical
Coupling
To understand the metal effect in this system, the role of
Ni(acac)2 was studied. Since Ni catalyst might be involved in the
sp3 C−H activation step, experiments were done to get some
insight into the hydrogen abstraction process of THF. An
intermolecular competition experiment between THF and THF-
d8 was performed. As a result, the reaction exhibited nearly the
same isotopic effects both with and without the nickel catalyst
(Scheme 2, kH/kD values up to 4.0 and 3.8). This result indicated
that the hydrogen abstraction of THF was the key step in which
nickel did not play a role.
In order to get some evidence for the generation of the
nitrogen free radical, we conducted a reaction with DCE as the
only solvent. When 1a was applied, we got methyl benzoate (5a)
with DTBP as the oxidant (Scheme 3). According to the former
studies,12b the ester came from the decomposition of the
corresponding N′-benzoyl-N,N′-dimethoxybenzohydrazide (4a)
obtained from the homocoupling of nitrogen free radical (1a-R).
Similar result on the formation of nitrogen free radical with
Homocoupling of α-alkoxyl carbon-centered radical 2a-R is
more favorable since the transformation energy is −57.2 kcal/
mol (Scheme 4, eq 2). It means that both the nitrogen radical and
the carbon radical are reactive radicals, while the nitrogen radical
is relatively more stable than the carbon radical. These results
might explain why a certain amount of the radical/radical cross-
coupling product could be obtained according to the persistent
radical effect.9 DFT calculations agree with our assumption,
which shows a favorable energy of −45.0 kcal/mol (Scheme 4, eq
3).
The interaction of nickel catalyst with the substrates and the
radicals was then studied (see Scheme S4 in Supporting
Information for details). Only the interaction between the
nitrogen radical and Ni(acac)2 is exothermic (−1.4 kcal/mol)
and exhibits a slightly favorable process for this interaction
(Scheme 5). The small energy change means that the
coordination of the nitrogen radical to nickel exists as a quick
B
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Letter
Scheme S3 in the Supporting Information for the dynamics
calculations on the generation of both the nitrogen radical and
the carbon radical). Transition-metal additives such as nickel
coordinates with the generated nitrogen radical in an equilibrium
to increase the lifetime of the nitrogen radical. Thus, stabilized
nitrogen radical couples with the transient sp3 carbon radical to
result in the cross-coupling product in a highly selective manner
according to persistent radical effect.9,14
Scheme 5. Favorable Coordination between Ni(acac)2 and
Nitrogen Radical 1a-R
After the study on understanding the reaction mechanism, we
turned to explore other kinds of substrates in this C(sp3)−N
bond formation (Scheme 8). A variety of ethers, benzylic
equilibrium with a tendency toward the complexation side (1a-
R-I). Therefore, the generated complex could be considered as a
nitrogen radical pool. This interaction increases the lifetime of
the nitrogen radical, which makes it more closer to a persistent
radical. Thus, the radical coupling between nitrogen and sp3
carbon-centered radical can take place in a higher selectivity and
efficiency.
Scheme 8. Substrate Scope of the Radical/Radical Coupling
a
for the Formation of Various C(sp3)−N Bonds
Obviously, the C(sp3)−N bond formation process could
proceed though the direct interaction of 1a-R-I with α-alkoxyl
carbon radical 2a-R instead of direct radical coupling. As shown
in Scheme 6, the possibilities for the formation of Ni(IV) and
Scheme 6. Possible Reaction Pathway for 1a-R-I
a
The reactions were carried out with 1 (0.50 mmol), Ni(acac)2 (0.10
mmol) and DTBP (1.0 mmol), 2 (3.0 mL), 120 °C, 20 h. Yields
radical homolytic substitution of C−Ni bond were calculated.
The formation of Ni(IV) was unfavorable, which shows an
energy barrier of 27.3 kcal/mol (Scheme 6, eq 1). Thus, direct
reductive elimination from the metal center to form the C(sp3)−
N bond is a disadvantage. Moreover, homolytic substitution by
carbon-centered radical 2a-R with 1a-R-I complex showed a
−17.4 kcal/mol exothermic value (Scheme 6, eq 2), which is still
a less effective interaction pathway compared with the energy of
direct cross-coupling between radical 1a-R and 2a-R (Scheme 4,
eq 3).
On the basis of these assumptions and experimental results, a
plausible mechanism could be brought forward (Scheme 7).
First, homolysis of DTBP takes place under high temperature to
generate the tert-butoxyl radical.18 Then tert-butoxyl radicals
react with both THF and N-alkoxyamides, which afford an α-
alkoxyl carbon-centered radical and a nitrogen radical (see
b
shown in parentheses were obtained in the absence of nickel. 1 mL of
c
benzo[d][1,3]dioxole was used with 1 mL of 1,2-dichloroethane. 1
d
equiv of KBr was added. 1.5 mmol of DTBP was used.
hydrocarbons, and even simple alkanes were tested in this
transformation. Ether derivatives were suitable substrates in this
transformation. As for the reaction with THF, electron-donating
groups, electron-withdrawing groups, and halide groups at the
para position of phenyl ring were all tolerated and afforded the
coupling product in good yields (Scheme 8, 3ba−ea). Substrates
with other aromatic groups such as furan and naphthalene were
also suitable in this transformation (Scheme 8, 3fa, 3ga).
Aliphatic acyl alkoxylamine reacted with THF with low yield
(Scheme 8, 3ha). This might be because the substituents on the
N-alkoxyamides can affect the reactivity of the nitrogen
radical.7c,d Besides tetrohydrofuran, tetrahydropyran was tested
and afforded the desired products in a good yield (Scheme 8, 3ab,
3cb, and 3eb). When it came to the reaction with benzo[d]-
[1,3]dioxole, we obtained the desired product in 48% yield by
adding 1.0 mL of DCE to ensure solubility (Scheme 8, 3ac).
Subsequently, we also explored the reaction with other kinds of
carbon radicals. To our pleasure, benzylic C(sp3)−H bonds were
also suitable for the direct amidation (Scheme 8, 3ad). As for
cyclohexane, a low yield was obtained, which might due to the
mismatch between the nitrogen radical and the more reactive sp3
carbon radical (Scheme 8, 3ae).
Scheme 7. Transition-Metal-Assisted Radical/Radical Cross-
Coupling Mechanism
In conclusion, we have described a transition-metal-assisted
oxidative radical/radical cross-coupling reaction. In this trans-
C
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedure, characterization data, and copies of 1H,
13C, and 19F NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
(7) (a) Nicolaou, K. C.; Baran, P. S.; Zhong, Y. L.; Barluenga, S.; Hunt,
K. W.; Kranich, R.; Vega, J. A. J. Am. Chem. Soc. 2002, 124, 2233−2244.
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6994. (d) Chen, Q.; Shen, M.; Tang, Y.; Li, C. Org. Lett. 2005, 7, 1625−
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(f) Liwosz, T. W.; Chemler, S. R. Chem.Eur. J. 2013, 19, 12771−
12777.
*E-mail: lanyu@cqu.edu.cn.
*E-mail: aiwenlei@whu.edu.cn.
Author Contributions
§These authors contributed equally.
Notes
(8) (a) Hart, D. J. Science 1984, 223, 883−887. (b) Pintauer, T.;
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This work was supported by the 973 Program (2012CB725302),
the National Natural Science Foundation of China (21390400,
21025206, 21272180, 21302148, 21372266, and 51302327), the
Research Fund for the Doctoral Program of Higher Education of
China (20120141130002), and the Program for Changjiang
Scholars and Innovative Research Team in University
(IRT1030).
Radicals in Synthesis III; Heinrich, M., Gansauer, A., Eds.; Springer:
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Berlin, Heidelberg, 2012; Vol. 320, pp 191−322.
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