Synthesis of meta-substituted anilines via copper-catalyzed [1,3]-methoxy rearrangement

Article abstract of DOI:10.1021/acs.orglett.0c01009

meta-Substituted anilines were efficiently synthesized via copper-catalyzed [1,3]-methoxy rearrangement of N-methoxyanilines followed by Michael addition of nucleophiles to the in situ generated ortho-quinol imine. The present reaction exhibits excellent

Full text of DOI:10.1021/acs.orglett.0c01009

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Letter
Synthesis of meta-Substituted Anilines via Copper-Catalyzed [1,3]-
Methoxy Rearrangement
Itaru Nakamura,* Hiroki Tashiro, Yasuhiro Ishida, and Masahiro Terada
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sı Supporting Information
ABSTRACT: meta-Substituted anilines were efficiently synthe-
sized via copper-catalyzed [1,3]-methoxy rearrangement of N-
methoxyanilines followed by Michael addition of nucleophiles to
the in situ generated ortho-quinol imine. The present reaction
exhibits excellent applicability of para-substituents, such as vinyl,
methylthio, ester, and bromo, and carbon nucleophiles, such as
1
,3,5-trimethoxybenzene, N-methylindole, and dimethyl malonate.
Thus, the present rearrangement can resolve problems stemming from oxidation reactions, such as the use of stoichiometric amounts
of oxidants and low compatibility of electron-withdrawing groups.
niline derivatives have been utilized for a wide variety of
Scheme 1. Synthesis of meta-Substituted Anilines
A
purposes, such as pharmaceuticals, agrochemicals, dyes,
1
and organic electronic devices. Therefore, it has been of great
importance to develop synthetic methods for functionalized
anilines in order to impart desired biological and physical
properties. In particular, due to inherent ortho- and para-
preference of anilines in electrophilic substitution reactions,
effective and selective preparation for meta-substituted anilines
are still a fundamental challenge in the synthetic community.
Although protocols from nitrobenzenes including electrophilic
substitution followed by reduction of the nitro group have
been conventionally utilized for meta-substituted aniline
synthesis (Scheme 1a), the process severely suffered from
harsh conditions and narrow scope of substituents on the
aniline ring because the strong electron-withdrawing nitro
group significantly decelerates the electrophilic substitution
reactions. Transition-metal-catalyzed cross-coupling reactions
2
of meta-haloanilines and Buchwald−Hartwig amination of
meta-haloarenes have been practically employed as an efficient
tool to prepare meta-substituted anilines under mild conditions
(
Scheme 1b). However, these processes often face the similar
selectivity issue since meta-substituted substrates are prepre-
pared typically through electrophilic substitution. Accordingly,
the development of a reaction system, namely, other than
protocols involving electrophilic substitution reactions is highly
desirable. Transition-metal-catalyzed direct meta-C−H func-
tionalization reactions of anilines have been recently gathering
3
,4
much attention for this purpose (Scheme 1c), realizing
various functionalization reactions, such as arylation, boryla-
tion, alkylation, chlorination, and olefination, using well-
designed ligands and directing groups. However, this state-
of-the-art methodology still has some drawbacks, such as
overfunctionalization due to equal reactivity between the two
meta positions and low efficiency in the reactions of the para-
substituted anilines presumably due to the steric repulsion
Received: March 19, 2020
©
XXXX American Chemical Society
https://dx.doi.org/10.1021/acs.orglett.0c01009
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
between the neighboring para-substituent and the metal
catalyst bound at the meta position in the arylmetal
intermediate. Here we demonstrate the new approach to
meta-substituted aniline derivatives by the Cu-catalyzed
cascade reaction between N-methoxyanilines 1 having an
electron-donating group (EDG) at the ortho position and
carbon nucleophiles 2 (Scheme 1d), which can overcome the
aforementioned problems.
(see Supporting Information) with catalytic amounts of
IPrCuBr [IPr: N,N’-bis(2,6-diisopropylphenyl)-imidazol-2-yli-
dene, 10 mol %] and AgSbF (10 mol %) in chlorobenzene
6
(
1.0 M) at 80 °C (Table 1, entry 1). The reaction was
completed within 20 h, affording the corresponding 5-arylated
aniline 3aa in 91% isolated yield. It should be noted that only
a
That is to say, we have recently disclosed that the [1,3]-
alkoxy rearrangement of N-alkoxyanilines was efficiently
promoted by cationic copper catalysts ligated to an N-
heterocyclic carbene (NHC) ligand with high functional
Table 1. Scope of the Nucleophile 2
5
group compatibility (Scheme 2, route a). Moreover,
Scheme 2. Synthesis of meta-Substituted Anilines 3 through
Cu-Catalyzed [1,3]-Methoxy Rearrangement from N-
Methoxyanilines 1
substrates 1 having electron-donating alkyl and aryl groups at
the ortho position of the N-methoxyanilines underwent a
domino rearrangement of the methoxy group and the ortho-
substituent, leading to 3-substituted 2-anisidines (Scheme 2,
6
route a to b). Our experimental studies firmly proved that the
ortho-quinol imine intermediate A was efficiently generated
through copper-catalyzed [1,3]-rearrangement of the methoxy
group to the ortho position bound to the electron-donating
group. Accordingly, we envisioned that catalytically generated
ortho-quinol imine A would serve as a Michael acceptor to
react with suitable nucleophiles, leading to meta-monosub-
stituted anilines (Scheme 2, route a to c); since the quinol
imine A generates just one time from the starting material 1 in
the catalytic cycle, the process is essentially free from
overreaction. It should be mentioned that Michael addition
7
8
7,8a−g
to ortho- and para-quinol imines, which are preprepared
8h
9
or catalytically generated through oxidation of anilines, has
been studied for a long time (Scheme 2, route a′ to c).
However, the synthetic value of this approach has been
severely discounted because the process requires stoichio-
metric amounts of strong oxidants and therefore inevitably
suffers from incompatibility of oxidant-sensitive functional
groups as well as electron-withdrawing groups (EWGs). Thus,
the catalytic methoxy rearrangement (Scheme 2, route a),
which is the key step of the present cascade process, would
overcome intrinsic problems stemming from the oxidation
process.
a
The reactions of 1 (0.2 mmol) and 2 (0.4 mmol) were carried out in
the presence of IPrCuBr (10 mol %) and AgSbF
(10 mol %) in PhCl
6
b
c
(
0.2 mL) at 80 °C for 20−35 h. Isolated yields. Yield for gram-scale
11 d e
reaction.
yield.
6ae was obtained in 8% yield. 6ag was obtained in 8%
The meta-selective functionalization of aniline derivatives
was realized when a mixture of N-methoxy-2-methylaniline 1a,
in which the nitrogen atom was protected by a benzylox-
ycarbonyl (Cbz) group, and 1,3,5-trimethoxybenzene 2a (2
equiv) was treated under the optimized reaction conditions
B
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Letter
trace amounts of 4a and 5a, which were derived from the
domino [1,3]/[1,2] rearrangement and [1,3]-methoxy rear-
rangement to the unsubstituted ortho position, respectively,
were observed as byproducts. The reaction was applicable to
Table 2. Scope of the Substituent at the ortho and para
a
Positions of N-Methoxyanilines 1
2
various sp -carbon nucleophiles, such as electron-rich arenes
(
2a and 2b), 2-methylfuran (2c), 3-methoxythiophene (2d),
and N-methylindoles (2e−i) (entries 2−9). 2-Methylfuran 2c
reacted with 1a at the 5 position of the furan ring, affording a
entry
1
R1
R2
2
3 (%)
b
4
:1 mixture of the 2,5-disubstituted aniline 3ac and 2,3-
disubstituted aniline 3ac′ (entry 3). It should be noted that the
1
2
3
4
5
6
7
8
1b
1c
1d
1e
1e
1f
1g
1g
1g
1g
1h
1h
1i
p-MeOC H4
H
H
H
H
H
H
Me
Me
Me
Me
Et
Et
F
F
F
Cl
Cl
Br
CO Me
SMe
vinyl
2a
2a
2a
2a
2e
2a
2a
2c
2e
2k
2a
2e
2a
2k
2a
2a
2k
2a
2a
2a
2a
3ba (53)
3ca (55)
3da (88)
6
reactions employing strong indole nucleophiles, such as 2e and
2-furyl
cyclopropyl
Et
Et
MeO
Me
Me
Me
Me
Et
Et
Me
Me
Et
Me
Me
Me
Me
2
g, with 1a were accompanied by formation of small amounts
c
(
ca. 8%) of 6ae and 6ag, respectively, which were derived from
3ea (56)
3ee (61)
3fa (86)
3ga (74)
3gc (84)
3ge (82)
d
addition to the para position, as byproducts (entries 5 and 7).
Notably, a difluoroboron β-diketonate 2j, which often
10
exhibited rich photophysical properties, underwent arylation
at the central diketone moiety by the present reaction,
affording 3aj in an acceptable yield (entry 10). Moreover, an
9
3
sp -carbon nucleophile, such as dimethyl malonate 2k, was
10
11
12
13
14
15
16
17
3gk (74)
3ha (13)
3he (58)
3ia (82)
3ik (60)
e
f
employed as an efficient nucleophile to furnish the arylated
malonate 3ak in good yield (entry 11). Notably, the gram-scale
reaction of 1a and 2a effectively afforded the desired product
11
3aa in good yield.
1i
1j
g
Next, the substituent effect on the N-methoxyaniline 1 was
3ja (82)
3ka (82)
3kk (61)
3la (60)
examined (Table 2 and Scheme 3). Not only methyl (1a) but
also p-anisyl (1b), 2-furyl (1c), cyclopropyl (1d), and ethyl
groups (1e) were employed as electron-donating substituents
at the ortho position of the N-methoxyaniline 1 (Table 2,
entries 1−4). In addition, a methoxy group (1f) was tolerated
as the ortho substituent (entry 6). Moreover, various functional
groups were tolerated at the para position such as methylthio
1k
1k
1l
1m
1n
1o
18
h
1
2
2
9
0
1
3ma (56)
3na (61)
3oa (51)
2
Me
Me
a
The reactions of 1 (0.2 mmol) and 2 (0.4 mmol) were carried out in
the presence of IPrCuBr (10 mol %) and AgSbF (10 mol %) in PhCl
0.2 mL) at 80 °C for 13−24 h. Isolated yields. 4e was obtained in
2% yield. 4e and 6ee were obtained in 6% and 11% yield,
(1n, entry 20) and vinyl (1o, entry 21) groups, which are labile
6
b
c
(
2
under typical oxidation conditions, as well as chloro (1k,
entries 16−17) and methoxycarbonyl (1m, entry 18), which
decelerate oxidation reactions, in the present rearrangement−
Michael addition cascade. In addition, the present reaction
showed high compatibility of reactive functional groups, such
as bromo (1l, Table 2, entry 18) and iodo (2g, Table 1, entry
d
e
respectively. f 4h and 5h were obtained in 25% and 43% yields,
respectively. 5h and 6he′ were obtained in 10% and 12% yields,
g
h
respectively. 5j was obtained in 5% yield. 118 h.
a
Scheme 3. Scope of the N-Methoxyaniline 1
7
) groups. It should be noted the substrates having an ethyl
group at the ortho position, such as 1e and 1h, involved
formation of the undesired byproducts 4e and 4h, respectively,
due to the higher migrating ability of the ethyl group in the
reaction with 1,3,5-trimethoxybenzene 2a (Table 2, entries 4
and 11). However, the reactions using a stronger nucleophile,
such as N-methylindole 2e, gave the desired product 3ee and
3
he, respectively, with high product selectivities (entries 5 and
1
2). More interestingly, a fluoro group at the para position
(
1j) was effective to afford the desired product 3ja, in good
yield (entry 15). The 2,3- (1p) and 2,6-dimethyl-N-
methoxyaniline (1q) were converted to the desired products
a
The reactions of 1 (0.2 mmol) and 2a (0.4 mmol) were carried out
3
pa and 3qa, respectively, in good yields (Scheme 3).
in the presence of IPrCuBr (10 mol %) and AgSbF (10 mol %) in
PhCl (0.2 mL) at 80 °C for 15−24 h. Isolated yields.
6
Furthermore, the reaction between 2,4,6-trimethyl-N-methox-
yaniline 1r and 1,3,5-trimethoxybenzene 2a produced the
biaryl 3ra, in which four ortho positions were fully substituted,
in good yield. In addition, substrate 1s, in which the 5-position
was substituted by a methoxycarbonyl group, reacted with 2a
at the 3-position, affording 3sa′ in an acceptable yield.
6
130 °C in the absence of the copper catalyst (Scheme 4a).
Thus, we preheated 7q at 130 °C for 4 h to form the mixture
of 7q and 8q (ca. 6:4), which was then treated with 1,3,5-
trimethoxybenzene 2a (4 equiv) and the cationic copper
catalyst (Scheme 4b). To our delight, the one-pot reaction
afforded the corresponding product 3qa, albeit in low chemical
yield (29%). In contrast, when the mixture of 7q/8q and 2a
was heated without the cationic IPrCu catalyst, the desired
product 3qa was not obtained (Scheme 4c). These results
We experimentally proved the intermediacy of the ortho-
quinol imine intermediate A (Scheme 2) by using the dimer 7q
of a quinol imine, as illustrated in Scheme 4. We previously
reported that 7q, which was obtained by the reaction of the
2
,6-dimethyl-N-methoxyaniline 1q in the presence of cationic
IPrCu catalysts, was dissociated to the ortho-quinol imine 8q at
C
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Scheme 4. Intermediacy of ortho-Quinol Imine 8
(1 → 8 → 3) rather than undesired [1,3]/[1,2] rearrangement
1 → 8 → 4). These results clearly indicate that the generated
(
ortho-quinol imine 8 (Scheme 5) can serve as a useful synthetic
intermediate like ortho-quinols, which have been widely
13
utilized in organic synthesis.
In conclusion, we have developed novel approach to meta-
substituted anilines via a copper-catalyzed [1,3]-methoxy
rearrangement−Michael addition cascade. Since the N-
methoxy anilines are readily prepared from reduction of
commercially available nitroarenes with inexpensive zinc, the
present process efficiently synthesizes multiply substituted
anilines with a wide variety of functional groups at the meta
and other desirable positions in a unique and selective manner.
ASSOCIATED CONTENT
sı Supporting Information
■
*
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01009.
clearly indicate that the present transformation proceeds via
the ortho-quinol imine 8. Moreover, the cationic copper
catalyst plays a dual role to promote not only the former [1,3]-
methoxy rearrangement but also the latter Michael addition,
realizing efficient functionalization at the meta position.
A proposed mechanism for the present cascade reaction is
illustrated in Scheme 5. First, the cationic NHC copper catalyst
Experimental procedure and characterization data
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
Itaru Nakamura − Research and Analytical Center for Giant
Molecules, Graduate School of Science, Tohoku University,
Sendai 980-8578, Japan; orcid.org/0000-0002-1452-
Scheme 5. A Proposed Mechanism
5
989; Email: itaru-n@tohoku.ac.jp
Authors
Hiroki Tashiro − Department of Chemistry, Graduate School of
Science, Tohoku University, Sendai 980-8578, Japan
Yasuhiro Ishida − Department of Chemistry, Graduate School
of Science, Tohoku University, Sendai 980-8578, Japan
Masahiro Terada − Department of Chemistry, Graduate School
of Science, Tohoku University, Sendai 980-8578, Japan;
orcid.org/0000-0002-0554-8652
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01009
Notes
The authors declare no competing financial interest.
coordinates to the substrate 1 to form the chelate complex 9.
Then, the N−O bond would be ionically cleaved to form the
arylnitrenium intermediate 10, in which the positive charge is
developed on the benzene ring. The C−O bond formation
preferentially occurs at the more hindered ortho-position
because of stabilization of the process by the electron-donating
group, leading to the ortho-quinol imine 8. The copper catalyst
simultaneously coordinates to the imine nitrogen atom of the
key intermediate 8, facilitating Michael addition of the carbon
nucleophile 2 to the less hindered meta position. Finally,
elimination of methanol and proton transfer give the meta-
substituted aniline 3 while regenerating the cationic copper
catalyst. The fact that the reaction between N-methoxyaniline
ACKNOWLEDGMENTS
■
This work was supported by JSPS KAKENHI Grant Number
JP16H00996 in Precisely Designed Catalysts with Customized
Scaffolding and a Grant-in-Aid for Scientific Research on
Innovative Areas “Hybrid Catalysis for Enabling Molecular
Synthesis on Demand” (JP17H06447) from MEXT (Japan).
REFERENCES
■
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(
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(
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(
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E
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