Heterocyclization Approach for Electrooxidative Coupling of Functional Primary Alkylamines with Aromatics

Article abstract of DOI:10.1021/jacs.5b06526

A new approach for electrooxidative coupling of aromatic compounds and primary alkylamines bearing a functional group such as a hydroxyl group and an amino group was developed. The key to the success of the transformation is heterocyclization of functional primary alkylamines. Treatment of primary alkylamines bearing a functional group with nitriles or their equivalents gives the corresponding heterocycles. The electrochemical oxidation of aromatic substrates in the presence of the heterocycles followed by chemical reaction under nonoxidative conditions gave the desired coupling products.

Full text of DOI:10.1021/jacs.5b06526

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Heterocyclization Approach for Electrooxidative Coupling of Func-
tional Primary Alkylamines with Aromatics
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Tatsuya Morofuji, Akihiro Shimizu, and Jun-ichi Yoshida*
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Nishikyo-
ku, Kyoto 615-8510
Supporting Information Placeholder
Also, nucleophilic functional groups bearing an acidic proton
ABSTRACT: A new approach for electrooxidative coupling of
such as such as OH and NHR groups might be problematic for the
aromatic compounds and primary alkylamines bearing a function-
electrooxidative reaction because of their undesired nucleophilic
al group such as a hydroxyl group and an amino group was devel-
attack on the radical cation of an aromatic compound.
oped. The key to the success of the transformation is heterocy-
clization of functional primary alkylamines. Treatment of primary
alkylamines bearing a functional group with nitriles or their
equivalents gives the corresponding heterocycles. The electro-
chemical oxidation of aromatic substrates in the presence of the
heterocycles followed by chemical reaction under non-oxidative
conditions gave the desired coupling products.
Amination of aromatic compounds serves as a straightforward and
useful route to aromatic amines which are often key components
of natural products, medicinal compounds, and functional materi-
Figure 1. Aromatic compounds bearing functional alkylamino
groups.
1
als. In particular, C−H amination of aromatic compounds is the
2
state of the art in amination reactions. A variety of methods have
3
4
been developed based on transition-metals, hypervalent iodines,
5
and radical species, and serve as powerful tools for synthesizing
nitrogen containing complex molecules. We have also developed
electrochemical C−H amination which enables direct introduc-
tion of nitrogen functionalities into electron-rich aromatic com-
pounds selectively. However, the introduction of primary alkyla-
As we have previously reported, heterocyclic compounds such as
8a
8b
8c
pyridine, N-mesylimidazole, and pyrimidine are effective as
nitrogen sources affording the electrooxidatively inactive cationic
intermediates, which can be subsequently converted to the corre-
sponding neutral nitrogen-containing products under non-
electrolytic conditions. Consequently, the overoxidation can be
avoided.
6,7
8
9
mino groups bearing a functional group still remains challenging,
although such structures serve as prominent structural motif in
various biologically and pharmaceutically active compounds as
In analogy, we envisaged that an initial heterocyclization of a
functional primary alklamine might solve the current challenge as
well (Scheme 2). Treatment of primary alkylamines bearing a
functional group with nitriles (RCN) or their equivalents gives the
1
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exemplified in Figure 1. We report here a new strategy for elec-
trooxidative coupling of aromatic compounds and primary alkyl-
amines bearing a functional group such as a hydroxyl group and
an amino group.
14
corresponding heterocycles. In particular, favorable 5-membered
The conventional approaches using electrochemical oxidation
suffer from the following problems: The direct use of alkylamines
should be unsuccessful because they are oxidized prior to aro-
and 6-membered ring formation takes place if the functional
group is attached at an appropriate position. In the presence of the
resulting heterocycles, aromatic substrates can be electrochemi-
cally oxidized to give their radical cations, which reacts with the
heterocycles to generate the corresponding cationic intermediates.
The cationic intermediates can be chemically converted to the
desired cross-coupling products under non-oxidative conditions.
1
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matic substrates (Scheme 1A). The use of N-protected alkyla-
mines could suppress such undesired oxidation because protecting
groups are usually electron-withdrawing (Scheme 1B). However,
the nucleophilitity of an N-protected alkylamine toward the radi-
cal cation of an aromatic compound would also be decreased in
such situations. Furthermore, even if the nucleophilic attack is
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Scheme 1. Conventional approaches to the introduction of
functional alkylamines using electrochemical oxidation
successful, overoxidation is inevitable because addition of the
1
3
amine to the aromatic ring will lower its oxidation potential.
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Table 1. Electrooxidative coupling of naphthalene with
various heterocycles
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The following points of this approach should be stressed: (1) the
formation of the heterocycles removes protons in the amino and
the functional groups, which might disturb the electrochemical
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reaction, (2) the oxidation potential of the heterocycles is higher
2
than those of the corresponding alkylamines because of the sp -
hybridization of nitrogen atoms, enabling selective oxidation of
aromatic substrates, (3) the hetereocycles have sufficient nucleo-
16
philicity toward the radical cations of aromatic compounds, and
(4) the resulting cationic intermediates, which can be stable
enough to accumulate, are not oxidized because of strong elec-
tron-withdrawing effect of a positive charge.
Scheme 2. Present approach for electrooxidative coupling
of functional primary alkylamines with aromatics
The electrochemical oxidation reactions were carried with 1 (0.2
mmol) and 0.6 mmol of 2 in a 0.3 M solution of LiClO in
CH CN at 0 ºC unless otherwise stated, and the resulting solution
4
3
was subjected to the chemical reaction: A, aq NaHCO
ylenediamine. 1.0 mmol of 2c was used.
3
; B, eth-
a
The scope of the aromatic substrates was examined using 2-
methyloxazoline (2a) as a coupling partner (Figure 2). In the reac-
tion with o-iodoanisole (1b), the alkylamino group was intro-
duced at the para position selectively without affecting the iodo
group (Figure 2, 3ba, 3ba’). In the case of p-iodoanisole (1c), the
alkylamino group was introduced at the ortho position selectively
We first examined the reaction of naphthalene (1a) (Eox=1.52 V,
+
vs. Ag/Ag ) with 2-methyloxazoline (2a) (Eox=1.73 V, vs.
+
Ag/Ag ) which can be derived from 2-hydroxylethylamine (Table
1, entry 1). The anodic oxidation led to the formation of a corre-
(
3ca, 3ca’). The reactions of anisoles bearing various functional
1
sponding cationic intermediate 4a, which was characterized by H
groups such as ester (1d), amide (1e), cyano (1f), and t-butyl (1g)
groups at the para position gave the corresponding amination
products without affecting such functionality (3da-3ga). In the
case of a phenol derivative which has two aromatic rings (1h), the
more electron-rich aromatic ring was selectively functionalized
without affecting the electron-deficient aromatic ring (3ha). Poly-
cyclic aromatic hydrocarbons such as phenanthrene (1i) and 9,9-
dimethylfluorene (1j) gave the corresponding amination products
3
NMR (See SI). Hydrolysis with aq NaHCO gave 1-(2-
acetoxylethylamino)naphthalene (3aa) in 75% yield. Furthermore,
treatment of the cationic intermediate with ethylenediamine gave
1
2
-(2-hydroxylethylamino)naphthalene (3aa’) in 79% yield (entry
). As shown in table 1, the present method is applicable to C−H
amination with various functionalized primary alkylamines. 2-
Hydroxy-2-phenylethylamine was also effective (entry 3). The use
of a 6-membered-ring heterocycle 2c which can be derived from
3-hydroxyl-1-propylamine also gave the amination product 3ad in
a good yield (entry 4). Heterocycles derived from ethylenediamine
3
ia and 3ja, respectively in good yields. Furthermore, heteroaro-
matic compounds such as indole and benzothiophene derivatives
k and 1l also gave the corresponding amination products 3ka
1
2
d and 1,3-diaminopropane 2e gave the corresponding amination
and 3la, respectively Small molecule drugs such as aniracetam
(1m) and fenofibrate (1n) gave the corresponding amination
products 3ma and 3na, respectively without affecting other func-
tional groups.
products in good yields (entries 5-7). Heterocycles derived from
cyclohexane-fused 3-hydroxyl-1-propylamine 2f (entry 8) and
long chain primary alkylamine bearing a hydroxyl group at 3-
position 2g (entry 9) gave the corresponding amination products
in good yields.
Regioselectivity of the amination can be predicted based on the
8
a,17
DFT calculations.
The alkylamines are introduced to the car-
bon bearing hydrogen with the largest coefficient of the lowest
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unoccupied molecular orbital (LUMO) of the radical cations of
the aromatic substrates (Figure 3).
It is also noteworthy that the hydroxyl group attached to the al-
kylamino group in the products can be used for further transfor-
mations. For example, after benzyl protection of the amino group,
the hydroxyl group was successfully converted to various func-
tional groups such as tosylate, azide, and cyano groups as shown
in Scheme 3.
Scheme 3. Transformation of the hydroxyl group in the
alkylamino group
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Chemical synthesis of mutagens is very important in confirming
their structures and evaluating their activity. To demonstrate the
utility of the present C−H amination method, we synthesized a
key intermediate 9 for the synthesis of a mutagen 10 isolated from
blue cotton-adsorbed materials in the Nikko River in Japan
1
8
(Scheme 4). The electrochemical oxidation of p-iodoanisole (1c)
in the presence of 2-methyloxazoline (2a) followed by the treat-
ment with ethylenediamine gave the corresponding amination
product 3ca’. The iodo group, which was not affected during the
electrolysis, was then successfully converted to -NHAc group
using a copper catalyst to give desired 9. The previous synthesis
Figure 2. Electrooxidative coupling of various aromatic and het-
eroaromatic compounds with 2-methyloxazoline. Aromatic sub-
strate 1 (0.2 mmol) was oxidized electrochemically in the pres-
18
of 9 reported in the literature requires 6 steps with the overall
ence of 0.6 mmol of 2a in a 0.3 M solution of LiClO
4 3
in CH CN
yield of only 7% because protection and deprotection steps are
necessary. In contrast, the present approach provides a short and
straightforward route to 9 with the overall yield of 51%.
at room temperature unless otherwise stated, and the resulting
a
solution was treated with aq NaHCO
3
.
1.0 mmol of 2-
methyloxazoline was used. 1.0 M solution of LiClO was used.
The reaction mixture obtained by the electrolysis was treated
b
4
c
d
e
with ethylenediamine. 0.2 M solution of Mg(ClO
4
)
2
was used.
Scheme 4. Synthesis of mutagen 10
f
0
.3 M solution of NaClO
4
was used. Electrolysis was carried out
at 50 ºC.
In summary, we have developed an effective method for C-H
amination of aromatic compounds with functionalized primary
alkylamines via heterocyclization based on the rational reaction
design. The method is highly chemoselective and provides a met-
al- and chemical-oxidant-free route to the N-alkylaniline deriva-
tives bearing oxygen and nitrogen functionalities in the alkyl
group, which can be used for further transformations.
Figure 3. The lowest unoccupied molecular orbitals (-LUMOs)
8
a
8a
8a
of radical cations of (a) 1a, (b) 1b, (c) 1c, (d) 1d, (e) 1e, (f)
f, (g) 1g, (h) 1h, (i) 1i, (j) 1j, (k) 1k, (l) 1l, (m) 1m, and (n) 1n
obtained by DFT calculations.
1
ASSOCIATED CONTENT
Supporting Information. Experimental procedures and spec-
troscopic data for new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
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Franke, R.; Waldvogel, S. R. Angew. Chem., Int. Ed. 2014, 53, 5210.
(e) Rosen, B. R.; Werner, E. W.; O’Brien, A. G.; Baran, P. S. J. Am.
Chem. Soc. 2014, 136, 5571. (f) Chen, J.; Yan, W. Q.; Lam, C. M.;
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8) (a) Morofuji, T.; Shimizu, A.; Yoshida, J. J. Am. Chem. Soc. 2013,
135, 5000. (b) Morofuji, T.; Shimizu, A.; Yoshida, J. J. Am. Chem.
Soc. 2014, 136, 4496. (c) Morofuji, T.; Shimizu, A.; Yoshida, J.
Chem. Eur. J. 2015, 21, 3211. (d) Waldvogel, S. R.; Möhle, S. An-
gew. Chem., Int. Ed. 2015, 54, 6398.
9) Elegant methods for introducing primary alkylamines to aromatic
compounds based on directed C−H activation were reported. (a) Shin,
K.; Baek, Y.; Chang, S. Angew. Chem., Int. Ed. 2013, 52, 8031. (b)
Ng, K. H.; Zhou, Z.; Yu, W. Y. Chem. Comm. 2013, 49, 7031. (c)
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AUTHOR INFORMATION
Corresponding Author
(
yoshida@sbchem.kyoto-u.ac.jp
ACKNOWLEDGMENT
We thank the Grant-in-Aid for Scientific Research for financial
support.
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