Organic Superbase t-Bu-P4 Catalyzes Amination of Methoxy(hetero)arenes

Article abstract of DOI:10.1021/acs.orglett.9b01805

We report that the organic superbase t-Bu-P4 efficiently catalyzes the amination of methoxy(hetero)arenes with amine nucleophiles such as aniline, indoline, and aminopyridine derivatives. This catalytic reaction is effective for the transformation of elec

Full text of DOI:10.1021/acs.orglett.9b01805

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Organic Superbase t‑Bu-P4 Catalyzes Amination of
Methoxy(hetero)arenes
Masanori Shigeno,* Kazutoshi Hayashi, Kanako Nozawa-Kumada, and Yoshinori Kondo*
Department of Biophysical Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Sendai 980-8578,
Japan
S
* Supporting Information
ABSTRACT: We report that the organic superbase t-Bu-P4
efficiently catalyzes the amination of methoxy(hetero)arenes
with amine nucleophiles such as aniline, indoline, and
aminopyridine derivatives. This catalytic reaction is effective
for the transformation of electron-deficient methoxyarenes
possessing diverse functionalities (carbonyl, cyano, nitro, and
halogen) as well as methoxyheteroarenes, including pyrazine,
quinoline, isoquinoline, and pyridine derivatives. Intramolec-
ular reactions provide six- and seven-membered ring cyclic amine products.
he development of amination reactions of aryl moieties
has been of significant importance in organic chemistry
T
because the obtained aromatic amines find widespread
application as biologically active molecules and functional
materials (dyes and electronic materials).1 The aminations of
(pseudo)haloarenes with readily available amine nucleophiles,
which furnish the corresponding products in a regioselective
manner, have largely contributed to this area. Common
examples of these reactions include Pd-catalyzed Hartwig−
Buchwald amination,2 Cu-catalyzed Ullmann-type amination,3
and nucleophilic aromatic substitution (SNAr).4 Recently,
aminations of less reactive methoxyarenes have attracted the
attention of organic chemists (Figure 1) because these
compounds are readily available and the direct transformation
of their robust C(sp2)−OMe bonds allows the renewal of
retrosynthesis and the late-stage functionalization. Tobisu,
Chatani, and coworkers demonstrated that a nickel catalyst
promotes the amination of methoxy(hetero)arenes with
dialkylamine and aniline derivatives in the presence of a
stoichiometric amount of NaO-t-Bu (Figure 1a).5 Nicewicz
and coworkers showed that the acridinium photocatalyst
facilitates the amination of methoxy(hetero)arenes with azoles
under 455 nm irradiation via a single-electron oxidation
pathway (Figure 1b).6 Biswas and coworkers reported that the
reactions of electron-rich methoxy(hetero)arenes with anilines
are catalyzed by triflic acid via an oxocarbenium intermediate
(Figure 1c).7 As an alternative approach, Brønsted-base-
mediated reactions were studied, which proceed through an
SNAr process, mechanistically different from the above-
mentioned reactions (Figure 1d). Thus these reactions are
expected to expand the substrate scope and improve the
functional group compatibility.8−11 In a pioneering study,
Wynberg and coworkers demonstrated that methoxyarenes are
aminated by dialkylamides prepared from dialkylamine and n-
BuLi.8 Subsequently, Chiba and coworkers carried out the
amination of methoxyarenes with dialkylamines by using a
Figure 1. Amination reactions of methoxy(hetero)arenes.
NaH−LiI composite,9a which was also applied to the
conversion of methoxypyridines.9b In these Brønsted-base-
mediated aminations, dialkylamines were used as nucleophiles,
but anilines were not employed because of their lower
nucleophilicity.12 In addition, a stoichiometric amount of the
base was required for the transformations.
Received: May 24, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01805
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Our group has studied catalytic transformations using the
phosphazene base t-Bu-P413−15 and recently reported that this
base promotes methoxy−alkoxy exchange reactions of
methoxy(hetero)arenes with alcohols.14a On the basis of the
studies, we herein found that t-Bu-P4 catalyzes the amination
of methoxy(hetero)arenes with amine nucleophiles. The
reaction proceeds smoothly with a variety of amines, including
aniline, indoline, and aminopyridine derivatives bearing
functional groups (methyl, methoxy, and halogens). This
system allows the use of electron-deficient methoxyarenes with
substituents such as carbonyl, cyano, nitro, and halogen groups
as well as methoxyheteroarenes such as pyradine, quinoline,
and isoquinoline derivatives. Note that in contrast with the
conventional aminations using (pseudo)haloarenes, the
proposed reaction generates only MeOH and not a
stoichiometric amount of inorganic waste. The detailed results
will be reported.
We commenced this study by investigating the reaction of
anisole 1a bearing a benzoyl substituent and N-methylaniline
2a (pKa = 29.5 in dimethyl sulfoxide16) (Table 1) in the
Table 1. Optimization of Reaction Conditions for
a
Amination of 1a and 2a
Figure 2. Scope of amines. aReactions were conducted on a 0.2 mmol
b
c
d
scale. Isolated yields. Reaction was conducted at 90 °C. Reaction
b
entry
deviation from standard conditions
3aa (%)
was conducted with t-Bu-P4 (30 mol %).
1
2
3
4
5
6
7
8
9
none
97
41
82
90
93
86
79
81
90
in the absence of 5 Å MS
3 Å MS instead of 5 Å MS
4 Å MS instead of 5 Å MS
cyclohexane as solvent
1,4-dioxane as solvent
10 mol % of t-Bu-P4
rt
Methylanilines 2b and 2c, bearing electron-donating methyl
and methoxy groups, afforded the products in 90 and 76%
yield, respectively. Halogen atoms (Cl and Br) on the phenyl
ring of the anilines were compatible with the reaction
conditions to provide 3ad and 3ae, respectively, in high
yield. The reaction of N-ethylaniline 2f also proceeded to
provide 3af in 60% yield. The reaction carried out with
indoline 2g as well as its derivatives 2h and 2i bearing methyl
and bromo substituents at the five-position gave the
corresponding aminated products in 87, 94, and 87% yield,
respectively. The use of the sterically hindered 2-methylindo-
line 2j led to the formation of 3aj in 95% yield. Reactions of 2-
and 3-(methylamino)pyridines 2k and 2l also proceeded to
give the corresponding products 3ak and 3al. When aniline 2m
(pKa = 30.6 in dimethyl sulfoxide16) and 4-methoxyaniline 2n
were used in the reactions, the desired products 3am and 3an
were formed in low yield of 15 and 12%, respectively.17,18
Then, aminations of a variety of methoxy(hetero)arenes
were performed with 2a and 2g (Figure 3). Aminations of 4-
cyanoanisole 1b and 4-nitroanisole 1c proceeded to furnish the
relevant products in 70 and 84% yield, respectively. Substrates
1d and 1e bearing halogen atoms (Cl and Br) also underwent
aminations with 2a and 2g to provide the products in 86 and
59% yield, respectively. The reaction of 1f possessing a pivaloyl
group proceeded to give 3fg in 89% yield. Anisole 1g, which
had a C(sp3)−H bond at the α-position of the carbonyl group,
also afforded the desired product 3gg in 89% yield. Substrate
1h bearing a 1-indanone scaffold furnished 3ha in 88% yield. 2-
Methoxynaphthalene 1i did not perform the amination, which
shows the requirement of an electron-withdrawing group on an
arene ring.19 Subsequently, the reactions of heteroarene
c
scale-up of the reaction
a
Standard conditions: 1a (0.20 mmol), 2a (0.40 mmol), t-Bu-P4
(0.04 mmol), 5 Å MS (100 mg), THF (0.7 mL), 60 °C, and 18 h.
Isolated yields. 1a (1.0 mmol), 2a (2.0 mmol), t-Bu-P4 (0.20
b
c
mmol), 5 Å MS (500 mg), THF (3.5 mL), 60 °C, and 18 h.
presence of t-Bu-P4 (pKBH = 28.0 in THF;13a pKBH = 30.3 in
dimethyl sulfoxide13b) (20 mol %), which afforded the desired
amination product 3aa in 41% yield (entry 2). The reaction
was then carried out with molecular sieves to trap the
generated MeOH, and the yield increased to 97% when using 5
Å MS (entries 1, 3, and 4). Solvent effects were also observed
in this reaction. Cyclohexane and 1,4-dioxane gave 3aa in high
yield of 93 and 86%, respectively (entries 5 and 6). Upon
decreasing the amount of t-Bu-P4 (10 mol %) or the reaction
temperature (room temperature), the product yield also
slightly decreased to 79 and 81%, respectively (entries 7 and
8). When the reaction was scaled up to 1.0 mmol, the product
was still obtained in a high yield of 90% (entry 9). When
Brønsted bases other than t-Bu-P4 were used, either the yield
of 3aa was poor or no product was formed, which indicated the
crucial role of t-Bu-P4 in this system (Table S1).
With the optimized conditions in hand, we next investigated
the scope of amines for this reaction (Figure 2). N-
B
DOI: 10.1021/acs.orglett.9b01805
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
and 4b without an electron-withdrawing group under the t-Bu-
P4 catalytic conditions led to the syntheses of six- and seven-
membered ring compounds 5a and 5b in 73 and 74% yield,
respectively.20
A plausible mechanism of this reaction is illustrated in Figure
5. t-Bu-P4 deprotonates amine 2 to give amide anion A.
Figure 5. Proposed mechanism of the catalytic amination by t-Bu-P4.
Subsequently, A takes part in the methoxy-amine exchange on
1 through an SNAr process to form 3 and B. Then, the reaction
of B and 2 occurs to regenerate A, with the formation of
MeOH, thus completing the catalytic cycle. In the intermediate
A, the amide anion part is a naked anion because of a huge soft
cation ([t-Bu-P4]+H, ∼500 Å3),21 which allows the high
reactivity compared with the cases of using other Brønsted
bases (Table S1).
In summary, t-Bu-P4 facilitated catalytic methoxy−amino
exchange reactions on (hetero)arenes. The catalytic system
efficiently triggered reactions on electron-deficient (hetero)-
arenes bearing various functionalities. In the aminations
reported by the groups of Wynberg et al.8 and Chiba et al.,9
electron-rich to neutral methoxyarenes were applicable, but not
in our reactions. However, our catalytic system has the benefit
of being able to employ aniline, indoline, and aminopyridine
derivatives as amine nucleophiles, which could not be used in
their systems.22 Intramolecular aminations were also per-
formed to prepare six- and seven-membered cyclic amines
without an electron-withdrawing group.
Figure 3. Scope of methoxy(hetero)arenes. aReactions were
conducted on a 0.2 mmol scale. bIsolated yields. cReaction was
conducted at room temperature. dReaction was conducted in
e
cyclohexane. Reaction was conducted at 90 °C.
substrates were attempted. 2-Methoxypyrazine 1j provided the
corresponding product 3ja in 71% yield. 2-Methoxyquinoline
1k and 6-bromo-2-methoxyquinoline 1l underwent the
aminations to give the products in good yield of 78 and
85%, respectively. The use of 2-methoxyisoquinoline 1m led to
the production of 3 mg in 92% yield. 2-Methoxypyridine
derivative 1n having an amide moiety was also converted into
the aminated product in 83% yield.
Next, an intramolecular version of this amination was carried
out to obtain cyclic amine products (Figure 4). The use of 4a
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.9b01805.
Effects of organic or inorganic bases (Table S1),
preparations of 1d, 1g, 1m, 4a, and 4b, experimental
procedures and spectra data for obtained products, and
1H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Figure 4. Intramolecular aminations. aReactions were conducted on a
0.2 mmol scale. Isolated yields. DMI (1,3-dimethyl-2-imidazolidi-
none) was used as a solvent.
b
c
*E-mail: mshigeno@m.tohoku.ac.jp (M.S.).
*E-mail: ykondo@m.tohoku.ac.jp (Y.K.).
C
DOI: 10.1021/acs.orglett.9b01805
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
ORCID
Letter
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Masanori Shigeno: 0000-0002-9640-8283
Kanako Nozawa-Kumada: 0000-0001-8054-5323
Notes
(12) As a related study, Zhao, Wang, and coworkers reported that
KHMDS (HMDS = hexamethyldisilazide) mediates amination
reactions of 1-(methylthio)-2-naphthalenecarbonitriles with anilines.
See: (a) Wang, X.; Tang, Y.; Long, C.-Y.; Dong, W.-K.; Li, C.; Xu, X.;
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Lett. 2018, 20, 4267. Murakami, Yorimitsu, and coworkers showed
that Pd catalyzes aminations of aryl methy sufides with anilines in the
presence of KHMDS; see: (c) Sugahara, T.; Murakami, K.; Yorimitsu,
H.; Osuka, A. Angew. Chem., Int. Ed. 2014, 53, 9329. (d) Pratap, R.;
Yorimitsu, H. Synthesis 2019, 51, 2705.
(13) (a) Schwesinger, R.; Schlemper, H. Angew. Chem., Int. Ed. Engl.
1987, 26, 1167. (b) Schwesinger, R.; Schlemper, H.; Hasenfratz, C.;
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M.; Boele, J.; Fritz, H.; Putzas, D.; Rotter, H. W.; Bordwell, F. G.;
Satish, A. V.; Ji, G.-Z.; Peters, E.-M.; Peters, K.; von Schnering, H. G.;
Walz, L. Liebigs Ann. 1996, 1996, 1055.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by JSPS KAKENHI grant
number 19H03346 (Y.K.), JSPS KAKENHI grant number
17K15419 (M.S.), JSPS KAKENHI grant number 19K06967
(M.S.), the Grant for Basic Science Research Projects from
The Sumitomo Foundation (M.S.), the Yamaguchi Educa-
tional and Scholarship Foundation (M.S.), the NIPPON
SHOKUBAI Award in Synthetic Organic Chemistry, Japan
(M.S.), and also the Platform Project for Supporting Drug
Discovery and Life Science Research funded by Japan Agency
for Medical Research and Development (AMED) (M.S., K.N.-
K., and Y.K.).
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(17) The acidity of the N−H bond of diarylamine 3am is higher
than that of 2m. Thus, in the reaction, t-Bu-P4 deprotonates 3am over
2m to form a stable and low nucleophilic diarylamide anion, because
of which the amination with 2m is considered to be inhibited. Indeed,
when the reaction of 1a and 2a (pKa = 29.5 in dimethyl sulfoxide16)
was carried out in the presence of diphenylamine (pKa = 24.95 in
dimethyl sulfoxide16), only a small amount of product 3aa was formed
(Scheme S1).
(18) Reactions of dialkylamines (pyrrolidine and morpholine) were
also conducted; however, no amination products were obtained
(results not shown).
(19) 4-Methoxybiphenyl was also examined as a substrate, however,
which did not give the amination product (results not shown).
(20) When the reaction of 4b was conducted in dioxane at 120 °C,
5b was formed in a low NMR yield of 10%.
(21) (a) Mamdani, H. T.; Hartley, R. C. Tetrahedron Lett. 2000, 41,
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DOI: 10.1021/acs.orglett.9b01805
Org. Lett. XXXX, XXX, XXX−XXX