Copper-Catalyzed Domino [1,3]/[1,2] Rearrangement for the Efficient Synthesis of Multisubstituted ortho-Anisidines

Article abstract of DOI:10.1021/jacs.8b03669

Multisubstituted ortho-anisidines were efficiently synthesized via cationic N-heterocyclic carbene-Cu-catalyzed domino rearrangement of N-methoxyanilines that possess an electron-donating functional group, such as an alkyl or an aryl group, at the ortho position. The reaction proceeded first through a [1,3]-rearrangement of the methoxy group to the ortho position bound to the electron-donating substituent, followed by a semipinacol type [1,2]-rearrangement of the electron-donating group from the ortho to the meta position. Mechanistic studies suggest that both rearrangement reactions are promoted by a cationic Cu catalyst.

Full text of DOI:10.1021/jacs.8b03669

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Communication
Copper-catalyzed Domino [1,3]/[1,2] Rearrangement for the
Efficient Synthesis of Multisubstituted ortho-Anisidines
Yasuhiro Ishida, Itaru Nakamura, and Masahiro Terada
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b03669 • Publication Date (Web): 19 Jun 2018
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Copper-catalyzed Domino [1,3]/[1,2] Rearrangement for the Efficient
Synthesis of Multisubstituted ortho-Anisidines
Yasuhiro Ishida,a Itaru Nakamura,*b and Masahiro Teradaa
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a Department of Chemistry, Graduate School of Science, Tohoku University, 980ꢀ8578, Japan
b Research and Analytical Center for Giant Molecules, Graduate School of Science, Tohoku University, 980ꢀ8578, Japan
Supporting Information Placeholder
and R1 groups. Herein, we report on the cationic NHCꢀCu cataꢀ
lyzed domino [1,3]/[1,2]ꢀrearrangement of Nꢀmethoxyanilines 1,
having an alkyl or aryl group at the ortho position, to afford the
corresponding 3ꢀsubstitutedꢀ2ꢀanisidines 2 in good to high yields
(Eq. 1).
ABSTRACT: Multisubstituted orthoꢀanisidines were efficiently
synthesized via cationic Nꢀheterocyclic carbeneꢀCuꢀcatalyzed
domino rearrangement of N-methoxyanilines that possess an elecꢀ
tronꢀdonating functional group, such as an alkyl or an aryl group,
at the ortho position. The reaction proceeded first through a [1,3]ꢀ
rearrangement of the methoxy group to the ortho position bound
to the electronꢀdonating substituent, followed by a semipinacol
type [1,2]ꢀrearrangement of the electronꢀdonating group from the
ortho to the meta position. Mechanistic studies suggest that both
rearrangement reactions are promoted by a cationic Cu catalyst.
Scheme 1. Cu-catalyzed Rearrangement of N-
Alkoxyanilines
Multisubstituted anilines, which are frequently encountered in
fields such as pharmaceutical and materials science,1 are typically
synthesized via electrophilic substitution of anilines or nitration of
aromatic compounds under strongly acidic conditions. Such
methods, however, suffer from both low ortho/para selectivity
and low reactivity due to electronꢀwithdrawing functional groups.
Recently, directed CꢀH functionalizations involving transition
metal catalysts have been extensively investigated as an efficient
and selective methodology to functionalize anilines under mild
reaction conditions.2 In spite of tremendous progress, however, it
remains a challenge to sequentially arrange more than three funcꢀ
tional groups on the aromatic ring in an efficient manner with
high functional group tolerance, since the efficiency and selectiviꢀ
ty of such intermolecular functionalization reactions are often
influenced by steric effects of the neighboring substituents.3 To
overcome the aforementioned problems, we propose a “domino
rearrangement reaction”, which features an initial rearrangement
reaction on the aromatic ring that subsequently induces a second
rearrangement (Scheme 1).4
Initially, 1a, which possesses a methyl group at the ortho position
and a paraꢀtrifluorobenzoyl group on the nitrogen atom, was
treated with catalytic amounts of IPrCuBr [IPr: N,N’ꢀbis(2,6ꢀ
diisopropylphenyl)ꢀimidazolꢀ2ꢀylidene] and AgBF4 in chlorobenꢀ
zene at 90 °C for 20 hours. The reaction afforded the correspondꢀ
ing 3ꢀmethylꢀ2ꢀanisidine derivative 2a in 63% yield, along with a
small amount of 3a (16%), which was derived from the [1,3]ꢀ
rearrangement on the nonꢀsubstituted ortho position (Table 1,
entry 1). Notably, the efficiency of the present domino reaction is
strongly affected by the Lewis acidity of the cationic NHCꢀCu
catalyst as well as the electronic nature of the functional group on
the nitrogen atom. Specifically, the use of the strongly electronꢀ
donating SIPr [SIPr: N,N’ꢀbis(2,6ꢀdiisopropylphenyl)ꢀ4,5ꢀ
dihydroimidazolꢀ2ꢀylidene] ligand, relative to the IPr ligand, reꢀ
sulted in significant deceleration of the reaction (entry 2). In conꢀ
trast, SIPr was highly effective in our previous [1,3]ꢀalkoxy rearꢀ
Recently, we have reported on the efficient [1,3]ꢀalkoxy rearꢀ
rangement of Nꢀalkoxyanilines that involve cationic Cu catalysts
ligated to an Nꢀheterocyclic carbene (NHC) ligand,5 to afford the
corresponding orthoꢀalkoxyanilines with high functional group
compatibility (Scheme 1a).6,7 Mechanistic studies suggest that the
reaction proceeds via CꢀO bond formation between the Cu alkoxꢀ
ide and the positively charged arenium moiety of intermediate A.
Accordingly, we envisioned that the [1,3]ꢀrearrangement of the
alkoxy group would preferentially occur at the substituted side
because of stabilization of positively charged ortho position with
the electronꢀdonating group (R1) (Scheme 1b). Consequently,
intermediate B’ would undergo
a
semipinacol [1,2]ꢀ
rearrangement8,9 of R1, which would be driven by the donation of
electrons from the migrated alkoxy group, to afford the orthoꢀ
anisidines with the sequential substitution of the amino, methoxy,
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rangement reactions.6 The use of lessꢀcoordinating anions such as
tetrafluoroborate and hexafluoroantimonate provided acceptable
results (entries and 3), whereas the use of
ier ethyl group instead of the smaller methyl group – such selecꢀ
tivity remains elusive via conventional intermolecular reactions.
Besides the N-methoxyanilines, the Nꢀpropyloxyaniline 1u was
employed as a substrate for the present reaction, affording 2u in a
moderate chemical yield mainly due to formation of considerable
amounts of the reduced aniline as byproduct.6 The exceptional
feature of our [1,3]ꢀalkoxy rearrangement was demonstrated by
the selective synthesis of the positional isomers trisubstituted
anilines 2v/2v” (Scheme 3). In the case of aniline 2v (Scheme
3a), the domino rearrangement of 3ꢀaminobenzoate 1v, which
possesses an orthoꢀmethyl group, resulted in migration of the
methoxy group and its insertion between the methyl and amino
groups. On the other hand, in the case of aniline 2v” (Scheme
3b), it was previously reported that the reaction of 4, which posꢀ
sesses a metaꢀmethyl group, proceeded with the migration of the
methoxy group to the ortho positions, with a strong preference to
be next to the electronꢀwithdrawing ester group, to afford alterꢀ
nate product 2v” as the major product. These results indicate that
the present domino rearrangement can serve as a complementary
method for direct [1,3]ꢀrearrangement towards the synthesis of
multisubstituted anilines. Due to the commercial availability of
nitroarenes, which serve as raw materials for the preparation of Nꢀ
methoxyanilines 1, our catalytic [1,3]ꢀrearrangement of Nꢀ
alkoxyanilines allows for unique and powerful synthetic routes to
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bis(trifluoromethanesulfonyl)imidate was ineffective (entry 4),
despite its effectiveness for [1,3]ꢀalkoxy rearrangements.6 The
presence of an electronꢀwithdrawing group on the nitrogen atom
seemed to accelerate the reaction (entry 5 versus 6). Accordingly,
the strongly electronꢀwithdrawing tosyl group resulted in the reacꢀ
tion of 1g that proceeded even at 50 °C (entry 11), whereas a benꢀ
zyl group was shown to interrupt the reaction (entry 12). Also,
while a bulky 2,4,6ꢀtrimethylbenzoyl group exhibited excellent
selectivity (entry 7), a readily deprotectable Cbz group gave the
desired group 2e with the best yield and high selectivity (entry 9).
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Table 1. Reaction Conditionsa
afford multisubstituted aminophenol derivatives.
It should be
Catalyst
2 (%)b
2a (63)
2a (13)c
3 (%)c
3a (16)
3a (3)
1 (%)c
<1
1
noted that products 2 can be readily separated from byproducts 3
(as shown in Scheme 2) using conventional silica gel column
chromatography.
Scheme 2. Cu-catalyzed Reaction of 1i-ua
1d
2d
3d
4d
5
IPrCuBr, AgBF4
SIPrCuCl, AgBF4
IPrCuBr, AgSbF6
IPrCuBr, AgNTf2
IPrCuBr, AgBF4
IPrCuBr, AgBF4
IPrCuBr, AgBF4
IPrCuBr, AgBF4
IPrCuBr, AgBF4
IPrCuBr, AgBF4
IPrCuBr, AgBF4
IPrCuBr, AgBF4
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
45
2a (58) c 3a (20)
<1
2a (18) c
2a (72)
2b (33)c
2c (76)
2d (51)
2e (86)
2f (63)
2g (82)
<1
3a (6)
3a (16)
<1
42
<1
6e
7f
<10
<1
<1
8
3d (25)
3e (8)
3f (6)
3g (11)
<1
<1
9
<1
10
11g
<1
<1
1g
1h
12
42
a
The reaction of 1 (0.4 mmol) was carried out in the presence of
NHCꢀCu halide (0.04 mmol) and a silver salt (0.04 mmol) in toluꢀ
ene (0.8 mL) at 90 °C for 20 h. b Isolated yield. c Determined by
1H NMR using dibromomethane as an internal standard. d Chloꢀ
g
robenzene was used as solvent. e For 36 h. f At 110 °C for 48 h.
At 50 °C for 1 h.
The scope of Nꢀmethoxyanilines for the present domino reaction
is summarized in Scheme 2. Substrates 1i and 1j, which possess a
simple alkyl group at the ortho position, were efficiently convertꢀ
ed to desired products 2i and 2j, respectively, in good yields. The
results show that the present reaction can tolerate alkoxy and
phthalimidyl groups as functional groups of the migrating alkyl
chain. A cyclopropyl group was preserved during the Cuꢀ
catalyzed reaction; byproducts that derive from the ring opening
of the cyclopropane moiety were not observed. Substrates 1n, 1o,
1p, and 1q, which possess a substituent at the para position, were
effectively converted to trisubstituted anilines 2n, 2o, 2p, and 2q
respectively, in acceptable yields, in which the four substituents
are positioned sequentially. It is important to note that electronꢀ
withdrawing ester and trifluoromethyl groups, and a reactive broꢀ
mo group are compatible in the present transformation. Our domꢀ
ino rearrangement reaction selectively afforded multisubstituted
aniline 2s, in which the methoxy group ended up next to the bulkꢀ
a The reaction of 1 (0.4 mmol) was carried out in the presence of
IPrCuBr (0.04 mmol) and AgBF4 (0.04 mmol) in toluene (0.8 mL)
b
c
at 90 °C for 20ꢀ24 hours. For 36 hours. Yield of 3 was less
than 10%. AgSbF6 was used, instead of AgBF4. e The reaction
d
was carried out using 20 mol % of IPrCuBr and 20 mol % of
AgBF4 at 110 °C for 48 hours. f For 48 hours. g Yield brsm; 27%
h
of 1q was recovered. For 18 hours. i NꢀBenzyloxycarbonylꢀ2ꢀ
methylaniline was obtained as byproduct (45%).
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the NHCꢀCu catalyst promoted not only the former [1,3]ꢀalkoxy
Scheme 3. Complementary Synthesis of Multisubstituted
Anisidines via [1,3]-Rearrangement
but also the latter [1,2]ꢀrearrangement. Indeed, when a cationic
NHCꢀCu catalyst was added to a mixture of 5z and 6z that was
obtained by preheating 5z at 130 °C for 4 hours, domino product
2z was obtained, albeit in a low yield (4%, Scheme 5c).12 In conꢀ
trast, the reaction of 5z without preheating, in the presence of a
Cu catalyst at 90 °C, resulted in merely the decomposition of 5z,
without any formation of 2z. These results clearly indicate that
the imine 6 is a reactive intermediate for the domino rearrangeꢀ
ment reaction (Scheme 1b), while the dimer 5 is an unfavorable
resting species.
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Scheme 5. Mechanistic Studies
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In order to determine if the key selectivity for [1,3]ꢀrearrangement
of the methoxy group to the sterically congested ortho position is
due to electronic preference as proposed in Scheme 1b or steric
repulsion between the ortho substituent and the protective group
on the nitrogen atom, domino rearrangement of substrates 1wꢀy,
which possess a bulkier aryl group than methyl group at the ortho
position, was examined. The reactions resulted in lowering prodꢀ
uct selectivity, affording 2wꢀy along with byproducts 3wꢀy that
are derived from migration of the methoxy group to the nonꢀ
substituted ortho position (Scheme 4), although 1e having a less
bulky methyl group was converted to 2e with higher selectivity
(Table 1, entry 9). In addition, it is noteworthy that the 2/3 ratio
was influenced by the electronic character of the aryl group; an
electronꢀdonating pꢀanisyl group at the ortho position preferentialꢀ
ly afforded the domino rearrangement product 2w over byproduct
3w. These results clearly indicate that the selective migration of
the methoxy group to the substituted ortho position is primarily
due to electronic characteristics rather than steric effect.
Based on the above experimental results, we can propose the
mechanism for the present domino reaction as shown in Scheme
6. First, the cationic NHCꢀCu catalyst coordinates to substrate 1
to form chelate complex 7. Next, the NꢀO bond is ionically
cleaved to form intermediate 8, followed by the formation of a Cꢀ
O bond, at the sterically hindered ortho position due to contribuꢀ
tions from canonical form 8’.13 Simultaneously, the Cu catalyst
would coordinate to the imine nitrogen atom of the resulting or-
thoꢀquinol imine intermediate 6,14 thus facilitate a semipinacolꢀ
type [1,2]ꢀrearrangement of substituent R1 from the ortho to the
meta position. Finally, rapid proton transfer would lead to prodꢀ
uct 2 while regenerating the cationic NHCꢀCu catalyst. The
strong electronꢀwithdrawing group on the nitrogen atom would
probably facilitate the [1,2]ꢀrearrangement process by lowering
the LUMO of the diene moiety in the rearranged intermediate 6.
The strong Lewis acidity of the NHCꢀCu catalyst due to the counꢀ
teranion employed is also essential for the latter [1,2]ꢀ
rearrangement.
Scheme 4. Domino Rearrangement of ortho-Aryl-N-
methoxyanilines 1w-y
Although our previous studies show that the [1,3]ꢀrearrangement
is not particularly sensitive to electronic characteristics,6 the preꢀ
sent study indicates that the domino [1,3]/[1,2]ꢀrearrangements
are highly influenced by both the Lewis acidity of the NHCꢀCu
catalyst and the electronꢀwithdrawing nature of the protective
group on the nitrogen atom (Table 1).6 To investigate the indiꢀ
vidual steps in the domino reaction, the rearrangement was carried
out using 2,6ꢀdimethylꢀNꢀmethoxyaniline 1z, which possesses an
electronꢀdonating paraꢀmethoxybenzoyl group,10 in the presence
of a silver salt (AgNTf2) that would decelerate the latter [1,2]ꢀ
rearrangement reaction, to effectively capture the reactive interꢀ
mediates. To our delight, the main product of the reaction was 5z
(Scheme 5a), which was regarded as the dimer of the expected
intermediate B’ (Scheme 1b).11 To further probe the mechanism
of the [1,2]ꢀrearrangement, dimer 5z was subsequently heated in
the absence of cationic NHCꢀCu catalysts, while monitoring the
Scheme 6. A Plausible Mechanism
1
process using H NMR. After 2 hours at 130 °C, the reaction
reached thermal equilibrium, and dimer 5z coꢀexisted with monꢀ
omer 6z at a 5z/6z ratio of roughly 6:4 (Scheme 5b, See SI). Furꢀ
thermore, it is noteworthy that heating of dimer 5z at 130 °C did
not result in domino rearrangement product 2z, thus implying that
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B.; Renaud, J.ꢀL.; Linares, M.; Hamel, M.; Costa, R. D.; Gaillard,
In summary, we have successfully developed a novel approach to
afford multisubstituted 2ꢀaminophenol derivatives from readily
accessible Nꢀmethoxyanilines via a catalytic domino rearrangeꢀ
ment reaction. Because 2ꢀaminophenols are frequently found in
biologically active compounds, the present synthetic scheme
would provide a useful and efficient step in the synthesis of these
molecular scaffolds. Recently, methoxyarenes have gained reꢀ
newed attention as substrates for crossꢀcoupling reactions,15 and
so we can expect that our method can greatly assist in the syntheꢀ
sis of multisubstituted anilines.
S. Designing ACS Appl. Mater. Interfaces 2016, 8, 14678; (d)
Elie, M.; Weber, M. D.; Di Meo, F.; Sguerra, F.; Lohier, J.ꢀF.;
Pansu, R. B.; Renaud, J.ꢀL.; Hamel, M.; Linares, M.; Costa, R.
D.; Gaillard, S. Chem. Eur. J. 2017, 23, 16328; The use of cationꢀ
ic NHCꢀCu as catalyst; (e) DíezꢀGonzález, S.; Scott, N. M.; Noꢀ
lan, S. P. Organometallics 2006, 25, 2355; (f) Cheng, L.ꢀJ.; Corꢀ
dier, C. J. Angew. Chem. Int. Ed. 2015, 54, 13734.
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6. Nakamura, I.; Jo, T.; Ishida, Y.; Tashiro, H.; Terada, M. Org. Lett.
2017, 19, 3059.
7. AlCl3ꢀmediated [1,3]ꢀrearrangement of Nꢀmethoxyanilines; (a)
Kikugawa, Y.; Shimada, M. J. Chem. Soc., Chem. Commun. 1989,
1450. The reaction of 1e in the presence of 2 equivalents of AlCl3
did not give 2e, indicating that the our cationic copper catalyst is
essential for the present domino [1,3]/[1,2] rearrangement.
Thermal [1,3]ꢀrearrangement of Nꢀtrifluoromethoxyanilines; (b)
Hojczyk, K. N.; Feng, P.; Zhan, C.; Ngai, M.ꢀY. Angew. Chem.
Int. Ed. 2014, 53, 14559.
8. Song, Z.ꢀL.; Fan, C.ꢀA.; Tu, Y.ꢀQ. Chem. Rev. 2011, 111, 7523.
9. (a) Kouznetsov, V. V.; Zubkov, F. I.; Nikitina, E. V.; Duarte, L.
D. A. Tetrahedron Lett. 2004, 45, 1981; (b) Zubkov, F. I.; Nikitiꢀ
na, E. V.; Kouznetsov, V. V.; Duarte, L. D. A. Eur. J. Org. Chem.
2004, 5064.
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ASSOCIATED CONTENT
Supporting Information
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The Supporting Information is available free of charge on the
ACS Publications website.
SI.pdf
AUTHOR INFORMATION
Corresponding Author
10. The reaction of 1z under the standard reaction conditions (Table 1,
entry 5) afforded 2z in 38% yield.
* Eꢀmail: itaruꢀn@tohoku.ac.jp
11. Dong, S.; Zhu, J.; Porco, Jr., J. A. J. Am. Chem. Soc. 2008, 130,
2738.
12. The reaction afforded considerable amounts of unidentified byꢀ
products along with 2z.
Author Contributions
The all authors contributed equally.
13. Although our proposed mechanism for [1,3]ꢀmethoxy rearrangeꢀ
ment based on Lewis acidic nature of the cationic Cu catalyst reaꢀ
sonably explains our experimental results, it is still possible that
NꢀO bond cleavage in [1,3]ꢀmethoxy rearrangement can be trigꢀ
gered by singleꢀelectron transfer from Cu(I) as well as oxidative
addition of Cu(I). Further mechanistic studies for the [1,3]ꢀ
alkoxy rearrangement are underway in our laboratory.
14. (a) Döpp, D.; Krüger, C.; Makedakis, G.; NourꢀelꢀDin, A. M.
Chem. Ber. 1985, 118, 510; (b) Miyata, O.; Kimura, Y.; Naito, T.
Chem. Commun. 1999, 2429; (c) Miyata, O.; Takeda, N.; Kimura,
Y.; Takemoto, Y.; Tohnai, N.; Miyata, M.; Naito, T. Tetrahedron
2006, 62, 3629; (d) Zhao, D.; Zhang, J.; Xie, Z. J. Am. Chem. Soc.
2015, 137, 13938.
15. Representative reports on metalꢀcatalyzed cross coupling of aroꢀ
matic methyl ethers; (a) Dankwardt, J. W.; Angew. Chem,. Int. Ed.
2004, 43, 2428; (b) Guan, B.ꢀT.; Xiang, S.ꢀK.; Wu, T.; Sun, Z.ꢀP.;
Wang, B.ꢀQ.; Zhao, K.ꢀQ.; Shi, Z.ꢀJ. Chem. Commun. 2008,
1437; (c) Tobisu, M.; Takahashi, T.; Morioka, T.; Chatani, N. J.
Am. Chem. Soc. 2016, 138, 6711.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work was supported by JSPS KAKENHI Grant Number
JP16H00996 in Precisely Designed Catalysts with Customized
Scaffolding.
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