N-Methylanilines as Simple and Efficient Promoters for Radical-Type Cross-Coupling Reactions of Aryl Iodides

Article abstract of DOI:10.1002/chem.201604602

Activation of the carbon–halogen bonds in aryl halides is a key step in transition-metal-free cross-coupling reactions. In this paper, a new and efficient radical initiation system for the activation of iodoarenes to produce aryl radicals was discovered, which employs the combination of N-methylanilines and tBuOK. This radical initiation system is robust and versatile, enabling various types of aryl-radical-related reactions.

Full text of DOI:10.1002/chem.201604602

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Accepted Article
Title: N-Methylanilines as Simple and Efficient Promoters for Radical-
Type Cross-Coupling Reactions of Aryl Iodides
Authors: Huan Yang, Li Zhang, and Lei Jiao
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N-Methylanilines as Simple and Efficient Promoters for Radical-
Type Cross-Coupling Reactions of Aryl Iodides
Huan Yang, Li Zhang, and Lei Jiao*
Dedication
Abstract: Activation of the carbon-halogen bonds in aryl halides is a
key step in transition-metal-free cross-coupling reactions. In this
paper a new and efficient radical initiation system for the activation of
iodoarenes to produce aryl radicals was discovered, which employed
the combination of N-methylanilines and t-BuOK. This radical initiation
system is robust and versatile, enabling various types of aryl radical-
related reactions.
transfer. We recently investigated the radical initiation mechanism
of the 1,2-diamine/t-BuOK system using the model coupling
reaction of iodoarene 1a, and recognized that a mechanistic
network functions to initiate the chain reaction, where the ethylene
bridge in 1,2-diamine plays an important role (Scheme 1a).[9]
Cross-coupling reactions catalyzed by transition metals have
been studied for a long time and are widely employed in
laboratory and industry.[1,2] In these reactions, aryl halides are
among the most frequently used coupling components and the
activation of a carbon-halogen bond by transition metals lays the
foundation for the traditional cross-coupling chemistry. Very
recently, a series of cross-coupling reactions involving aryl
halides have been found to proceed under transition-metal-free
conditions,[3] in which the combination of a small molecule organic
additive and t-BuOK promotes the carbon-halogen bond cleavage
and carbon-carbon bond formation efficiently. Typical examples
include inter- and intramolecular aryl-aryl coupling,[4] aryl-olefin
coupling,[5] and aryl alkoxycarbonylation reactions.[6] These
reactions have attracted great interest due to their intriguing
reaction mechanism and promising synthetic potential.
These transition-metal-free cross-coupling reactions are
generally accepted to proceed through a radical chain mechanism
and the chain propagation process is regarded as the base-
promoted homolytic aromatic substitution (BHAS).[7] Compared
with chain propagation, the radical initiation mechanism in these
reactions is more complicated. Though challenging, it is important
to identify the role of the small molecule organic additives in the
activation of aryl halides,[8] not only to understand the molecular
basis for the radical initiation chemistry, but also to guide the
development of new and efficient promoter molecules for
synthetic use.[4j,o,8f] In this context, Murphy and co-workers have
systematically studied the radical initiation mechanism of these
reactions.[8a,b,f] A unified conclusion was that various organic
additives serve as precursors to electron donors, which then
initiate the radical process by electron transfer to aryl halide. Lei
and co-workers studied the 1,10-phenathroline/t-BuOK reaction
system,[8d] and found that the complexation between 1,10-
phenanthroline and t-BuOK was important for the electron
Scheme 1. Radical initiation mechanism of the 1,2-diamine/t-BuOK system and
control experiments leading to an unexpected result. HAT = hydrogen atom
transfer, PT = proton transfer, SET= single electron transfer.
Following this mechanistic interpretation, an interesting control
experiment would be to block the radical proliferation pathway by
breaking the ethylene bridge of 1,2-diamine to see whether the
initiation activity diminishes. Indeed, if the active promoter N,N’-
dimethyl-1,2-ethylenediamine (DMEDA) was replaced by N-
methylbenzylamine, which has only one half of the DMEDA
structure and a phenyl termini, dramatic decrease in activity was
observed (Scheme 1b). This indicates that the secondary amine
functionality is not sufficient for efficient radical initiation, in
agreement with the previous mechanism. However, rather
unexpectedly, N-methylaniline, in which a phenyl group is directly
attached to the secondary amine, exhibited comparable activity to
DMEDA. Further examination showed that N-alkylanilines with an
-hydrogen were all efficient promoters for this transformation
(Scheme 1b). This result prompted us to investigate the role of
such a simple small molecule in the radical initiation process, and
[*]
H. Yang, L. Zhang, Prof. Dr. L. Jiao
Center of Basic Molecular Science (CBMS)
Department of Chemistry, Tsinghua University
Beijing 100084 (China)
E-mail: Leijiao@mail.tsinghua.edu.cn
Supporting information for this article is given via a link at the end of
the document.
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led to the discovery of N-methylanilines as simple yet one of the
most efficient organic additives for the activation of aryl halides to
promote aryl-radical-related reactions.
phenyl-1,2-ethylenediamine
and
N,N’-diphenyl-1,2-
ethylenediamine, showed similar activity and air resistance to N-
methylaniline. However, when the methyl group in N-
methylaniline was replaced by a benzyl group, the activity
decreased dramatically. The above experimental results
confirmed that the N-methylaniline/t-BuOK system is highly
efficient and robust for the initiation of transition-metal-free
coupling reaction, and implied that this system must functions in
a quite different way from the 1,2-diamine/t-BuOK system.
The structure of this small molecule organic additive enabled
us to investigate the electronic effect on its radical initiation activity.
Initial rate experiments on the model reaction were conducted
with a series of N-methylanilines baring electronic substituents at
the para-positon. The electronic nature of N-methylaniline was
found to have a major impact on its activity: electron-donating
groups enhanced the activity, while electron-withdrawing groups
diminished activity (Figure 3). N-methyl-4-methoxyaniline (A2)
was figured out as the most suitable additive for synthetic
purposes, due to its relatively high activity and commercial
availability.
Figure 1. Kinetic profiles of aryl iodides 1a for the coupling reaction employing
DMEDA and PhNHCH3 as additives.
Figure 3. Comparison of the initial rates of N-methyl anilines with different
electronic substitutions.
Figure 2. Yields of the cross-coupling product 2a in the reaction between 1a
and benzene employing various additives under Ar (blue) and air (red)
atmosphere. Reaction conditions: 1a (0.5 mmol), organic additive (10 mol%), t-
BuOK (1.5 mmol), 4 mL benzene, 80 ºC for 20 h.
The synthetic utility of this new promoter was explored. It was
found that, in aryl-aryl cross-coupling reactions, aniline A2 as the
additive could promote the coupling of a wide range of aryl iodides
1 and benzene (Table 1). Both electron-rich and electron-deficient
aryl iodides underwent efficient couplings with benzene to give
the corresponding biaryls (2a-j) in good yields. Naphthyl iodide 1k
and heteroaryl iodide 1l also participated in the coupling reaction
smoothly to give the desired products in good yields. These
results demonstrated that the N-methylaniline/t-BuOK system is
indeed a unique and highly efficient system for the activation of
iodoarenes.
We first tried to figure out the difference between N-
methylaniline and DMEDA by reaction kinetics. The kinetic
profiles revealed that, the cross-coupling reaction promoted by
DMEDA exhibited a significant induction period,[9] while the
reaction promoted by N-methylaniline did not (Figure 1).
Meanwhile, an extensive survey on the activities of representative
organic additives for the same model reaction disclosed the
unique feature of N-methylaniline (Figure 2): it was superior to
many previously reported promoter molecules, including 1,2-
, , , and 1,10-
diamine[4a,h] alcohols[4e,j,5a] phenyl hydrazine[4i,j]
phenanthroline[4b,c,f,l,5b,c], making it among the most efficient
additive under 80 ºC. Remarkably, the activity of N-methylaniline
almost remained unchanged when the reaction was conducted
under air, while the DMEDA/t-BuOK system was completely
ineffective. Interestingly, when the aniline moiety was introduced
into the diamine backbone, the resulting molecules, N-methyl-N’-
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Table 1. Intermolecular aryl-aryl coupling reactions.[a]
employing N-methyl 4-methoxyaniline as the additive under
milder conditions compared with those reported previously.[4c,g]
The Heck-type reaction between aryl iodide 1a and styrene was
also successfully carried out to produce product 6a.[5a,d] Radical
dehalogenation of iodoarene 1h, a recently developed procedure
promoted by small organic molecules,[10] could also be achieved
by employing the N-methylaniline/t-BuOK system. Finally, radical
alkoxycarbonylation reaction of 1a could also be promoted by the
same additive to produce benzoate 7,[6] albeit in a lower yield. The
success of this additive in the above reactions rendered N-
methylaniline a versatile small molecule for promoting aryl-
radical-mediated reactions.
Preliminary mechanistic studies were performed to identify the
role of this simple molecule in the activation of aryl halides. First,
deprotonation of N-methylaniline by t-BuOK under the reaction
conditions was verified by 1H NMR and 1D-TOCSY spectroscopy
(see the Supporting Information), indicating that N-methylanilide
anion is the major species of the aniline in the reaction system.
Second, cyclic voltammetry (CV) experiments confirmed that the
N-methylanilide anions formed by treatment of anilines A4 and A2
with t-BuOK could act as an electron donor: N-methylanilide anion
and N-methyl 4-methoxyanilide anion exhibited oxidation waves
at -0.66 V and -0.93 V vs Fc+/0, respectively. Third, the model
reaction employing deuterated N-methylanilines showed no
significant kinetic isotope effect (KIE) and a minimum extent of
deuterium incorporation in product 3, implying that the C-H or N-
H bond cleavage by radical abstraction is not a significant
pathway in the initiation process, and the deprotonation steps are
not rate-limiting (Table 3).
[a] Reaction conditions: 1 (1 mmol), A2 (10 mol%), t-BuOK (3 equiv.), benzene
(8 mL), 80 °C for 20 h. Yields after column chromatography were reported.
Interestingly, in addition to intermolecular aryl-aryl coupling, N-
methylaniline is able to promote a series of radical-based
reactions requiring aryl radical formation from iodoarenes, though
previously there was no unified small molecule promoter for all
these reactions (Table 2). Intramolecular aryl-aryl coupling of
substrate 4 to afford cyclization product 5 was achieved by
Table 2. Various types of coupling reactions promoted by N-methylaniline additive
Applied conditions
Entry
1
Reaction
Literature
This work[a]
1,10-phenathroline (50 mol%),
100 C, 24 h, 62% yield;[4c]
or
A2 (50 mol%),
80 C, 20 h, 58 % yield.
2,6-bis(imino)pyridine (20 mol%)
160 C, 12 h, 75% yield.[4g]
EtOH (20 mol%),
A2 (20 mol%),
80 C, 2 h, 68 % yield
80 C, 2 h, 65% yield;[5a]
or
2
3
4
N,N’-dialkyldiketopiperazine (30
mol%), 130 C, 3 h, 36% yield.[5d]
MeOCH2CH2OCH2CH2OH (7 equiv.),
NaH (7 equiv.), O2, 1,4-dioxane,
rt, 24 h, >99% yield.[10]
A2 (50 mol%),
t-BuOK (3 equiv.), 1,4-dioxane,
80 C, 24 h, 85% yield.
1,10-phenathroline (40 mol%)
A2 (40 mol%),
90 C, 20 h, 44 % yield.
90 C, 24 h, 72% yield.[6]
[a] The yields of product 5, 6a, 2c was 54%, 43% and 52% under air atmosphere, respectively.
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expect this study to provide further understanding for the initiation
process in the cross-coupling reaction promoted by small organic
molecules, as well as to present a general and efficient radical
initiation system for this type of reactions.
Table 3. Kinetic isotope study
Acknowledgements
The National Natural Science Foundation of China (Grant No.
21390403) and the Thousand Talents Plan for Young
Professionals are acknowledged for financial support. The
technology platform of CBMS is acknowledged for providing
instrumentation.
Keywords: cross-coupling • N-methyl aniline • radical initiation •
electron donor • homolytic aromatic substitution
In light of the above experimental results, a plausible
mechanism for the activation of aryl halide by N-methylaniline was
proposed (Scheme 2). N-methyl aniline is first deprotonated by t-
BuOK to form N-methylanilide anion, which then acts as an
electron donor to transfer an electron to aryl iodide, facilitating the
formation of the aryl radical. The generated N-centered radical is
then deprotonated by t-BuOK to form a radical anion, which is also
an electron donor to initiate the radical process. N-
methylideneaniline is produced as the end-product of N-
methylanilene, which after work-up was converted to aniline and
could be detected by GC-MS. The observed electronic effect on
the activity of substituted N-methylanilines (Figure 3) supported
this radical initiation mechanism, as the substituents on the phenyl
ring influence the activity of the involved electron donors. It is
worth noting that the PhNHNH2/t-BuOK promoted cross-coupling
reactions were proposed to have a similar radical initiation
process.[4i] The present study demonstrates that the key structural
feature for a successful promoter molecule might be the ArNH
moiety but not the N-N bond.
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Scheme 2. Proposed radical initiation mechanism.
In conclusion, we have disclosed that N-methylanilines, which
are simple and easily available, could efficiently activate
iodoarenes in the presence of t-BuOK. This new and robust
radical initiation system could be employed in a series of aryl
radical related reactions, including inter-/intramolecular aryl-aryl
coupling, the Heck-type coupling, dehalogenation of iodoarenes,
and aryl alkoxycarbonylation reactions. Preliminary mechanistic
studies showed that single electron transfer from N-methylanilide
anion to the iodoarene was the key step in radical initiation. We
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