Concerted [1,3]-Rearrangement in Cationic Cobalt-Catalyzed Reaction of O-(Alkoxycarbonyl)-N-arylhydroxylamines

Article abstract of DOI:10.1021/acs.orglett.7b00700

O-(Alkoxycarbonyl)-N-arylhydroxylamines were efficiently converted to 2-aminophenol derivatives by cationic cobalt catalysts at 30 °C. The results of ¹⁸O-labeling experiments suggested that rearrangement of the alkoxycarbonyl group from the aniline nitrogen to the ortho position proceeded in an unprecedented [1,3] manner.

Full text of DOI:10.1021/acs.orglett.7b00700

Letter
pubs.acs.org/OrgLett
Concerted [1,3]-Rearrangement in Cationic Cobalt-Catalyzed
Reaction of O‑(Alkoxycarbonyl)‑N‑arylhydroxylamines
Itaru Nakamura,*,† Mao Owada,‡ Takeru Jo,‡ and Masahiro Terada†,‡
‡
†Research and Analytical Center for Giant Molecules and Department of Chemistry, Graduate School of Science, Tohoku
University, Sendai 980-8578, Miyagi, Japan
S
* Supporting Information
ABSTRACT: O-(Alkoxycarbonyl)-N-arylhydroxylamines
were efficiently converted to 2-aminophenol derivatives by
cationic cobalt catalysts at 30 °C. The results of 18O-labeling
experiments suggested that rearrangement of the alkoxycar-
bonyl group from the aniline nitrogen to the ortho position
proceeded in an unprecedented [1,3] manner.
etal catalysts have enabled various kinds of organic
transformations to proceed under much milder
excellent catalytic activity for the reaction of 1a, which has
benzoyl and benzyloxycarbonyl (Cbz) groups on the nitrogen
and oxygen atoms, respectively, in 1,2-dichloroethane (DCE) at
30 °C, affording 2a in 82% yield (eq 1).4 According to previous
works,1 in order to determine whether the migration of the
CbzO group proceeded in a concerted [3,3] manner (Scheme
2a, mode A)8 as in a thermally induced reaction,1c,d or via
M
conditions with higher functional group compatibility. The
effectiveness of metal-catalyzed transformation is often due to a
change of the reaction pathway driven by suitable complexation
of the metal catalyst with the substrate. Here, we show that
such a change of the reaction mode by metal catalysts occurred
in the classical rearrangement reaction of O-acyl-N-arylhydrox-
ylamines 1 to O-acylated 2-aminophenol 2 (Scheme 1).1,2 That
Scheme 2. 18O-Labeling Experiments
Scheme 1. Rearrangement of O-Acyl-N-arylhydroxylamines
is, the focused rearrangement reaction of 1 has been extensively
investigated to proceed typically under elevated temperature
(>140 °C) or microwave irradiation in a concerted [3,3]
manner (Scheme 1a). In this paper, we report that the pathway
of the well-known rearrangement reaction was dramatically
switched to an unprecedented [1,3] manner by using cationic
cobalt catalysts, which proceeded at 30 °C, efficiently affording
a wide repertoire of the 2-aminophenol derivatives 2, which
have been frequently utilized in pharmaceutical chemistry
(Scheme 1b).3
Initially, the screening of the metal catalysts for the reaction
of 1 disclosed that the cationic metal species such as Co2+,
Cu2+, and Zn2+ afforded the desired 2-aminophenol derivative 2
(see Supporting Information). In particular, the combination of
CoCl2 (10 mol %) and AgSbF6 (20 mol %) exhibited an
heterolytic cleavage of the N−O bond1b by the Lewis acid
(mode B),5 we conducted 18O-labeling experiments using
1a-18O with an oxygen-18 content at the hydroxylamine moiety
of 62%.6,7 To our surprise, the cobalt-catalyzed reaction
followed by hydrogenolysis of the migrated Cbz group afforded
the aminophenol 3a-18O with 18O content at the phenolic
oxygen of 64%. The complete retention of the labeled 18O
Received: March 9, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00700
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a,b
strongly indicated that the rearrangement of the benzylox-
ycarbonyloxy group did not proceed in a [3,3] manner or
through ionic N−O bond cleavage but exclusively in an
unprecedented [1,3] manner (Scheme 2a, mode C).9,10 Indeed,
the thermally induced reaction of 1a-18O (23% 18O) in the
absence of the cobalt catalyst in xylene at 140 °C1g followed by
hydrogenative deprotection afforded 3a with an 18O content at
the phenolic oxygen of less than 2%, indicating that the
thermally induced reaction of 1a proceeded in a concerted
[3,3] manner (Scheme 2b).
Scheme 3. Substrate Scope
Various alkoxycarbonyloxy groups, such as CbzO (1a),
methoxycarbonyloxy (1b), and AllocO (1c) groups showed
good migrating abilities (eq 1 and Table 1, entries 1 and 2),
a
Table 1. Substitution Effect at the Hydroxylamine Moiety
b
entry
1
R1
R2
time (h)
2
yield (%)
c
1
1b
1c
1d
1e
1f
OMe
O-allyl
Ph
Bz
3
2
2b
2c
75
2
Bz
75
<1
<1
3
Bz
120
120
6
4
Me
Bz
c
5
OMe
OMe
OMe
OMe
OMe
OMe
OMe
Boc
Alloc
Cbz
CO2Me
2f
2g
2h
2i
64
6
1g
1h
1i
4
45
64
7
5
c
8
4
72
c
9
1j
p-MeOC6H4C(O)
p-F3CC6H4C(O)
Ac
2
2j
60
a
10
11
1k
1l
24
120
2k
2l
61
44
The reactions of 1 (0.4 mmol) were conducted in the presence of 10
mol % of CoCl2 and 20 mol % of AgSbF6 in DCE (1.6 mL) at 30 °C.
b
c
Isolated yield. 1H NMR yield using dibromomethane as an internal
a
The reactions of 1 (0.4 mmol) were conducted in the presence of 10
mol % CoCl2 and 20 mol % of AgSbF6 in DCE (1.6 mL) at 30 °C.
d
standard. See the SI for details. Yield brsm (41% of 1v was
recovered). Yield brsm (28% of 1v’ was recovered). Yield brsm (34%
of 1w‘ was recovered). Combined yield of the two regioisomers.
e
f
b
c
Isolated yield. 1H NMR yield using dibromomethane as an internal
g
standard.
whereas, in sharp contrast, substrates 1d and 1e, which have an
acyl group on the oxygen atom of the hydroxylamine moiety,
did not undergo the rearrangement under the present reaction
conditions and decomposed (entries 3 and 4). On the other
hand, various acyl groups, such as acetyl and benzoyl, and
alkoxycarbonyl groups, such as Boc, Alloc, and Cbz, were
tolerated as the protecting group of the nitrogen atom under
the optimized reaction conditions (entries 5−11), as
summarized in Table 1. It is noteworthy that the reaction of
1j having an electron-rich p-methoxybenzoyl group proceeded
much faster than that of 1k having an electron-deficient p-
(trifluoromethyl)benzoyl group (entries 9 and 10). The
reaction of substrates having a substituent at the ortho position,
such as methyl group, did not give the desired product.
The reaction was applicable for synthesizing a wide repertory
of multisubstituted aminophenol derivatives (2m−aa), as
summarized in Scheme 3. In particular, highly reactive
functional groups, such as bromo, iodo, and alkynyl groups,
were compatible in the present rearrangement reaction to
afford the desired products 2q, 2r, and 2s in good yields.
Moreover, products 2o, 2p, and 2t having electron-withdrawing
functional groups on the aromatic ring, which are generally less
efficiently synthesized through electrophilic substitution re-
actions, were obtained in good yields. Notably, our catalytic
conditions successfully promoted the rearrangement of 1v′ and
1w′, having a 4-(trifluoromethyl)phenyl and 3,5-difluorophenyl
group, respectively, by using a p-nitrobenzyloxycarbonyl group
in place of Cbz.11,12 Thus, the present method is potentially
useful for the synthesis of 2-aminophenols having highly
electron-withdrawing functional groups, which are inaccessible
by thermal [3,3]-rearrangement reactions. The reaction of
meta-substituted substrates 1x−aa afforded c.a. 1:1 mixtures of
the 5- and 3-substituted 2-aminophenols, regardless of the
character of the substituent.
In order to gain further insight into the mechanism of the
unprecedented [1,3]-rearrangement reaction, first crossover
experiments using equally reactive substrates 1a and 1p were
conducted. The reaction of the mixture under the standard
reaction conditions gave only products 2a and 2p derived from
the starting materials; no crossover products were observed by
B
DOI: 10.1021/acs.orglett.7b00700
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
1974, 3, 671. (d) Oae, S.; Sakurai, T. Tetrahedron 1976, 32, 2289.
(e) Ohta, T.; Shudo, K.; Okamoto, T. Tetrahedron Lett. 1978, 19,
1983. (f) Porzelle, A.; Woodrow, M. D.; Tomkinson, N. C. O. Eur. J.
Org. Chem. 2008, 2008, 5135. (g) Porzelle, A.; Woodrow, M. D.;
Tomkinson, N. C. O. Org. Lett. 2010, 12, 812.
HRMS (Scheme 4). This result strongly indicates that
migration of the alkoxycarbonyloxy group takes place intra-
Scheme 4. Crossover Experiment
(2) Photorearrangement of O-acyl-N-arylhydroxylamines: (a) Sakurai,
T.; Nakamura, M.; Hakii, T.; Inoue, H. Bull. Chem. Soc. Jpn. 1992, 65,
2789. (b) Kaneko, T.; Kubo, K.; Sakurai, T. Tetrahedron Lett. 1997, 38,
4779.
(3) (a) Sum, P. E.; Petersen, P. Bioorg. Med. Chem. Lett. 1999, 9,
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Tanaka, K. Inflammation Res. 2002, 51, 188. (c) Ahmad, R.; Kookana,
R. S.; Alston, A. M.; Skjemstad, J. O. Environ. Sci. Technol. 2001, 35,
878.
(4) For details of the optimization of reaction conditions, see the
Supporting Information.
(5) For a review, see: Tabolin, A. A.; Ioffe, S. L. Chem. Rev. 2014,
114, 5426.
(6) 1a-18O was prepared from nitrobenzene-18O. Rajendran, G.;
Santini, R. E.; Van Etten, R. L. J. Am. Chem. Soc. 1987, 109, 4357.
Deprotection of the Cbz group of 1a-18O under basic conditions
afforded the corresponding N-hydroxylamine with an oxygen-18
content of 65%, unambiguously indicating that the oxygen-18 in
1a-18O exists at the hydroxylamine moiety. See the Supporting
Information.
(7) The percentage of oxygen-18 content was determined by the
intensity of the mass spectrum.
(8) Metal-catalyzed [3,3] rearrangement involving N−O bond
cleavage: Wu, Q.; Yan, D.; Chen, Y.; Wang, T.; Xiong, F.; Wei, W.;
Lu, Y.; Sun, W.-Y.; Li, J. J.; Zhao, J. Nature Commun. 2017,
DOI: 10.1038/ncomms14227.
(9) Oae, S.; Kitao, T.; Kitaoka, Y. Tetrahedron 1963, 19, 827.
(10) Review for 1,3-rearrangement: (a) Nasveschuk, C. G.; Rovis, T.
Org. Biomol. Chem. 2008, 6, 240. Oxygen [1,3]-sigmatropic
rearrangement: (b) Hou, S.; Li, X.; Xu, J. J. Org. Chem. 2012, 77,
10856. Cu-mediated [1,3] nitrogen rearrangement: (c) Wada, N.;
Kaneko, K.; Ukaji, Y.; Inomata, K. Chem. Lett. 2011, 40, 440.
(11) The thermal reaction of 1v and 1v′ in xylene at reflux resulted in
decomposition of the starting materials, while that of 1w′ gave 2w′ in
29% yield. The reaction of 1v′ at 60 °C gave 2v′ in low chemical yield
(26%) due to competitive decomposition of the starting material 1v′.
(12) (a) Gutschke, D.; Heesing, A.; Heuschkel, U. Tetrahedron Lett.
1979, 20, 1363. (b) Gassman, P. G.; Granrud, J. E. J. Am. Chem. Soc.
1984, 106, 1498.
(13) Our preliminary attempts to find transition state(s) for the
cationic Co-catalyzed [1,3]-rearrangement were unsuccessful, ob-
viously due to convergent failure of “naked cationic cobalt” species.
Therefore, it is necessary to develop ligand-coordinated metal catalysts
for the present reaction in order to carry out further computational
studies to understand the details of the unprecedented [1,3]-
rearrangement. Such studies are currently underway in our laboratory.
molecularly. In addition, intra- and intermolecular isotope
effects were not observed, suggesting that the C−H bond
cleavage occurs after C−O bond formation at the ortho position
(see the SI). At the present stage, we speculate that cationic
cobalt catalyst functions as a Lewis acid not only to lower the
LUMO of the migrating alkoxycarbonyloxy group12 but also to
change the geometry of the transition state from [3,3] to [1,3],
allowing the rearrangement to proceed at 30 °C with high
functional group compatibility.13
In conclusion, we have discovered the unprecedented [1,3]-
rearrangement of N-(alkoxycarbonyl)-N-arylhydroxylamines by
using cationic cobalt catalysts, synthesizing useful 2-amino-
phenol derivatives in an efficient manner under mild reaction
conditions. Further mechanistic studies are currently 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.7b00700.
Experimental procedures as well as full spectroscopic
data for all new compounds (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 No.
JP16H00996 in Precisely Designed Catalysts with Customized
Scaffolding. We thank Prof. Ilya D. Gridnev for valuable
discussions on the mechanistic investigations.
REFERENCES
■
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DOI: 10.1021/acs.orglett.7b00700
Org. Lett. XXXX, XXX, XXX−XXX