Cationic N-Heterocyclic Carbene Copper-Catalyzed [1,3]-Alkoxy Rearrangement of N-Alkoxyanilines

Article abstract of DOI:10.1021/acs.orglett.7b01110

The [1,3]-alkoxy rearrangement reactions of N-alkoxyanilines were efficiently catalyzed by cationic N-heterocyclic carbene (NHC)-Cu catalysts in affording 2-alkoxyaniline derivatives in good to excellent yields with high functional group compatibility. For N-alkoxyanilines having an electron-withdrawing substituent at the meta-position, the alkoxy group selectively migrated to the more hindered ortho-position. In contrast, the alkoxy group migrated to the less hindered ortho-position for N-alkoxyanilines having an electron-donating substituent. Mechanistic studies suggest that the rearrangement reactions proceed via an intramolecular route.

Full text of DOI:10.1021/acs.orglett.7b01110

Letter
pubs.acs.org/OrgLett
Cationic N‑Heterocyclic Carbene Copper-Catalyzed [1,3]-Alkoxy
Rearrangement of N-Alkoxyanilines
Itaru Nakamura,*,† Takeru Jo,‡ Yasuhiro Ishida,‡ Hiroki Tashiro,‡ and Masahiro Terada†,‡
‡
†Research and Analytical Center for Giant Molecules, and Department of Chemistry, Graduate School of Science, Tohoku
University, Sendai 980-8578, Japan
S
* Supporting Information
ABSTRACT: The [1,3]-alkoxy rearrangement reactions of N-
alkoxyanilines were efficiently catalyzed by cationic N-
heterocyclic carbene (NHC)-Cu catalysts in affording 2-
alkoxyaniline derivatives in good to excellent yields with high
functional group compatibility. For N-alkoxyanilines having an
electron-withdrawing substituent at the meta-position, the alkoxy group selectively migrated to the more hindered ortho-position.
In contrast, the alkoxy group migrated to the less hindered ortho-position for N-alkoxyanilines having an electron-donating
substituent. Mechanistic studies suggest that the rearrangement reactions proceed via an intramolecular route.
earrangement reactions of N-arylhydroxylamine deriva-
tives have been extensively investigated and employed for
thermal [1,3]-rearrangement of electron-deficient trifluorome-
thoxy groups.6 Accordingly, we envisioned that a strongly Lewis
acidic transition metal would catalytically promote the [1,3]-
rearrangement of various N-alkoxyanilines via cleavage of the
N−O bond under mild reaction conditions, with compatibility
over a wide range of functional groups.7 Herein, we report on
the efficient [1,3]-alkoxy rearrangements of N-alkoxyanilines 1
using cationic Cu(I) catalysts coordinated by an N-heterocyclic
carbene (NHC) ligand to afford the corresponding ortho-
alkoxyaniline derivatives 2 in good to excellent yields (eq 1).
R
the syntheses of highly functionalized aniline derivatives
(Scheme 1).1 Rearrangements involving strong Brønsted acids
Scheme 1. Rearrangement of N-Arylhydroxylamine
Derivatives
We initially came across this catalytic rearrangement when N-
methoxy-N-(3,4,5-trimethoxybenzoyl)aniline 1a was treated
with a cationic NHC−Cu catalyst system;8 the reaction in
the presence of IPrCuBr [10 mol %, IPr: 1,3-(2,6-diisopropyl-
phenyl)imidazol-2-ylidene] and AgNTf2 [10 mol %, NTf2:
bis(triflyl)imidate] in chlorobenzene at 110 °C afforded the
corresponding 2-methoxyanilide 2a in 94% yield (Table 1,
entry 1). The use of IMes or PPh3 instead of IPr as ligands
resulted in lower yields, along with the formation of the
reduced anilide 3a as a byproduct (entries 2 and 3,
respectively). With regard to counterions other than NTf2
(entry 1), hexafluoroantimonate was found to be similarly
effective (entry 4), whereas perchlorate resulted in lower
efficiencies (see Supporting Information (SI)). In the absence
of Ag salts, the neutral IPrCuBr complex did not exhibit any
catalytic activities (entry 5). Complexes involving Cu(II) and
Co(II) exhibited lower catalytic activities (entries 6 and 7,
respectively), whereas the complexes of other metal salts such
affording 4-aminophenols are well-known as the Bamberger
rearrangement (Scheme 1a),2 while thermally induced
rearrangements of N-acyloxyaniline derivatives, which proceed
in a concerted [3,3]-manner, have been effectively utilized in
the synthesis of ortho-substituted aniline derivatives (Scheme
1b).3 Quite recently, we have disclosed rearrangements of an
N-alkoxycarbonyloxy group, in the presence of cationic Co
catalysts, which proceed in a concerted [1,3]-manner (Scheme
1c).4 These findings encouraged us to further explore the [1,3]-
rearrangements of the alkoxy group of N-alkoxyanilines,
synthesizing ortho-alkoxyanilines, which are frequently utilized
for pharmaceutical science (Scheme 1d). Kikugawa has
previously reported on the [1,3]-rearrangement of N-
methoxyanilines using stoichiometric amounts of a strong
Lewis acid, AlCl3,5 while Ngai has recently reported on the
Received: April 12, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01110
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions
Scheme 2. Scope of Cationic NHC Cu-Catalyzed [1,3]-
a
Alkoxy Rearrangement
b
b
catalyst (mol %)
t (h) 2a (%)
3a (%)
1
2
3
4
5
6
7
8
9
IPrCuBr (10), AgNTf2 (10)
IMesCuBr (10), AgNTf2 (10)
CuBr (10), PPh3 (10), AgNTf2 (10)
IPrCuBr (10), AgSbF6 (10)
IPrCuBr (10)
15
48
22
2
(94)
<1
10
23
<1
<1
19
20
<1
<1
<1
c
45
34
>99
d
48
12
24
48
14
12
<1
CuCl2 (10), IPr (10), AgNTf2 (10)
CoCl2 (10), AgSbF6 (20)
AgNTf2 (10)
65
35
<1
e
IPrCuBr (10), AgSbF6 (10)
IPrCuBr (10), AgSbF6 (10)
>99
(98)
ef
,
10
a
The reaction of 1a was carried out in the presence of catalysts in
b
chlorobenzene (0.8 mL) at 110 °C. Yields were determined using 1H
NMR with CH2Br2 as the internal standard. Isolated yields in
c
d
parentheses. 35% of 1a was recovered. 1a was quantitatively
e
f
recovered. At 80 °C. DCE (1,2-dichloroethane) was used instead of
chlorobenzene.
as Ag(I), Zn(II), Sc(III), and Fe(II) did not promote the
present reaction (see SI). Of note, the reaction proceeded at a
lower reaction temperature (80 °C, entry 9) to afford the
desired product 2a in an excellent yield. With regard to the
reaction solvent, the present reaction proceeded smoothly in
various solvents, such as chlorobenzene, toluene, 1,4-dioxane,
ethyl acetate (see SI), and particularly 1,2-dichloroethane
(DCE, entry 10). In contrast, the catalytic activities of the
Cu(I) complex were diminished using polar organic solvents
such as acetonitrile and DMF (see SI). It is noteworthy that the
formation of the corresponding para-methoxyaniline 4a was
not observed during these studies.
Next, using the optimized reaction conditions (Table 1, entry
10), the substitution effects at the N atom were examined, as
summarized in Scheme 2. Our studies show that the reaction
can tolerate various aroyl moieties as the N-protecting group of
aniline. In particular, electron-rich aromatic groups, such as a
3,4,5-trimethoxybenzoyl group, are more effective in promoting
the present rearrangement (2a versus 2e). The reaction was
also applicable for anilines with Cbz and Alloc as the N-
protecting group, to afford 2-methoxyanilines 2g and 2h,
respectively, in good yields. Furthermore, in addition to the
methoxy, ethoxy, and n-propoxy groups, a deprotectable
methoxymethoxy group also served as effective migrating
groups. For the Cu complex involving IMes instead of IPr as
the ligand, the reaction afforded 2-isopropoxyaniline 2l in an
acceptable yield. In the case of 2-(4-nitrobenzyloxy)aniline 2m,
the reaction resulted in the formation of reduced aniline 3a and
para-nitrobenzaldehyde (34%) as byproducts.9 Under the
optimized reaction conditions, a wide variety of 2-methoxyani-
line derivatives possessing functional groups such as ester (2n),
ketone (2o), trifluoromethyl (2p), chloro (2q), bromo (2r),
and iodo (2s) at the 4-position were obtained in excellent
yields. It is noteworthy that, in the case of an electron-donating
methyl group (1t), the reaction was significantly faster.
a
The reaction of 1 (0.4 mmol) was carried out in the presence of
IPrCuBr (10 mol %) and AgSbF6 (10 mol %) in DCE (0.8 mL) at 80
b
c
°C. Isolated yields. 26% of 3a was obtained. Yields were determined
d
using 1H NMR with CH2Br2 as the internal standard. IMesCuBr was
e
used as catalyst. 54% of 3a was obtained. 24% of 3a and 34% of p-
nitrobenzaldehyde were obtained. Ar′ = 3,4,5-(MeO)3C6H2.
donating groups, such as methoxy and fluoro, at the meta-
position favored the migration of the methoxy group to the less
hindered ortho-position (entries 1−3). Particularly, the bulky
TBSO group afforded 2,5-dioxyaniline 2u with excellent
selectivity (entry 1). In sharp contrast, electron-withdrawing
and less bulky functional groups, such as ester or keto groups,
favored the migration of the methoxy group to the more
hindered ortho-position (entries 5 and 6).10 Moreover,
substrates 1aa and 1ab which possess both an electron-
withdrawing ester and an electron-donating group at the two
meta-positions selectively afforded products 2aa′ and 2ab′,
The characteristic feature of the present reaction is the
selectivity in meta-substituted N-alkoxyanilines (1u−z), as
summarized in Table 2. That is, mesomerically electron-
B
DOI: 10.1021/acs.orglett.7b01110
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 2. Substitution Effect at the meta Position
b
c
d
e
1
R2
σp
A-value
t (h)
2
yield (%)
2:2′
f
1
2
3
4
5
6
1u
1v
1w
1x
1y
1z
TBSO
MeO
F
−0.27
−0.27
0.06
1.06
0.6
7
12
38
72
24
72
2u
2v
2w
2x
2y
2z
95
95
86
87
97
81
15:1
7.6:1
3.6:1
0.15
2.1
CF3
0.54
1:1.2
CO2Me
Ac
0.45
1.27
1.17
1:3.4
1:4.4
0.50
a
The reaction of 1 (0.4 mmol) was carried out in the presence of IPrCuBr (10 mol %) and AgSbF6 (10 mol %) in DCE (0.8 mL) at 80 °C.
b
c
d
Hammett constant for para-substitution (σp).11 A-value was conventionally utilized as an index for bulkiness of the functional group.12 Combined
e
f
yields of 2 and 2′. The ratio was determined by weight of isolated 2 and 2′. σp for OTMS.
respectively, that involve the migration to the ortho-position
adjacent to the ester group (eq 2). Thus, the present
transformation can allow for the effective and selective
preparation of aminophenol derivatives, in which amino,
alkoxy, or electron-withdrawing functional groups are sequen-
tially substituted on the benzene ring and are difficult to
selectively synthesize via conventional methods.
Scheme 4. A Plausible Mechanism
Crossover experiments were carried out using 1a and 1q-d3.
As shown in Scheme 3, the rearrangement afforded products 2a
Scheme 3. Crossover Experiments
charge on the aniline ring via delocalization. Next, the Lewis
basic alkoxy O atom attacks the ortho-position to form a C−O
bond, followed by the tautomerization to give product 2.
Although it is possible that the Cu atom oxidatively adds at the
ortho-position followed by tautomerization to afford an
arylcopper(III) intermediate (see SI),13 because the reactions
were promoted by not only Cu(I) but also Cu(II) and Co(II),
it is more likely that the Cu catalysts serve as the Lewis acid, as
illustrated in Scheme 4. The electron-donating methyl group at
the para-position probably accelerates the N−O bond cleavage
process from 5 to 6, which involves inducing the positive
charge on the aniline aromatic ring (Scheme 2, 2t). The 3,4,5-
trimethoxyphenyl group in the aroyl moiety also reduces the
electron-withdrawing ability of the carbonyl group, which is
necessary to form the chelated intermediate 5 (Scheme 2, 2a).
Because the mesomeric nature of the substituent at the meta-
position significantly affects the selectivity between the less- and
more-hindered ortho-position (Table 2), we believe that the
alkoxy oxygen would preferentially attack the more electrophilic
ortho-position, where the density of the π-electron was
and 2q-d3, respectively, which are derived from the starting
material; no crossover products were detected using HRMS. In
other words, the migration of the methoxy group proceeded in
an intramolecular manner. In addition, inter- and intra-
molecular kinetic isotope effects were not observed (see SI).
These results suggest that the cleavage of the C−H bond occurs
after the bond formation at the ortho-position.
As shown in Scheme 4, a plausible reaction mechanism based
on our experimental results can be proposed. First, the cationic
Cu catalyst coordinates to the carbonyl oxygen and the alkoxy
group to form chelate complex 5. Afterward, ionic cleavage of
the N−O bond leads to Cu alkoxide species 6, in which the Cu
atom is coordinated by the sp2 N, thus inducing a positive
C
DOI: 10.1021/acs.orglett.7b01110
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(8) (a) Díez-Gonzal
́
ez, S.; Scott, N. M.; Nolan, S. P. Organometallics
controlled by the meta substituent, during the transformation
from 6 to 7.14
2006, 25, 2355. (b) Díez-Gonzal
Petersen, J. L.; Nolan, S. P. Chem. - Eur. J. 2008, 14, 158. (c) Díez-
Gonzalez, S.; Nolan, S. P. Acc. Chem. Res. 2008, 41, 349. (d) Marion,
́
ez, S.; Stevens, E. D.; Scott, N. M.;
In conclusion, we have successfully developed a novel
approach for the synthesis of ortho-alkoxyaniline derivatives
featuring the use of cationic NHC−Cu(I) catalysts. Because the
2-alkoxyaniline structure is ubiquitous among biologically active
compounds, the present scheme can serve as a highly useful
step toward the preparation of such compounds under much
mild reaction conditions and for a wide range of functional
groups. Continued studies to investigate the scope of the
functional groups for the substrate and to understand the
unprecedented catalytic [1,3]-alkoxy rearrangement are cur-
rently underway in our laboratory.
́
R.; Sguerra, F.; Di Meo, F.; Sauvageot, E.; Lohier, J.-F.; Daniellou, R.;
Renaud, J.-L.; Linares, M.; Hamel, M.; Gaillard, S. Inorg. Chem. 2014,
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(9) The reaction of 1l-d7 having a deuterated isopropoxy group
afforded the ortho-deuterated byproduct 3a-d (80% D), clearly
indicating that the hydrogen source to form the reduced byproduct
3 is the migrating alkoxy group (see Supporting Information). The
byproduct 3 is probably formed through migration of the hydride at
the oxygen-bound carbon of the alkoxy group to the ortho-position in
6. However, it is alternatively possible that 3 is formed through a retro-
carbonyl ene reaction. Haidasz, E. A.; Shah, R.; Pratt, D. A. J. Am.
Chem. Soc. 2014, 136, 16643. Further mechanistic studies are
underway in our laboratory.
(10) Reactions of 1 which had a much less bulky and electron-
withdrawing cyano group and a potentially directing 2-pyridyl group,
respectively, resulted in recovery of the starting materials, presumably
due to deactivation of the cationic copper catalyst by the nitrogen
atom.
(11) Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165.
(12) (a) Winstein, B. S.; Holness, N. J. J. Am. Chem. Soc. 1955, 77,
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(14) Our preliminary calculations suggest that the meta-ester group
makes the more hindered ortho-position more positive in the
intermediate 6 while the methoxy group shows a reverse trend. See
SI. Further computational studies are underway in our laboratory.
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.7b01110.
General procedures, analytical data, NMR data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: itaru-n@m.tohoku.ac.jp.
ORCID
Itaru Nakamura: 0000-0002-1452-5989
Masahiro Terada: 0000-0002-0554-8652
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by JSPS KAKENHI Grant Number
JP16H00996 in Precisely Designed Catalysts with Customized
Scaffolding.
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DOI: 10.1021/acs.orglett.7b01110
Org. Lett. XXXX, XXX, XXX−XXX