2-aminophenols containing electron-withdrawing groups from N -Aryl hydroxylamines

Article abstract of DOI:10.1055/s-0030-1258546

Reaction of substituted N-aryl hydroxylamines with methanesulfonyl chloride, p-toluenesulfonyl chloride, or trifluoromethanesulfonic anhydride under basic conditions leads to the rearranged 2-aminophenols (45-94%). The overall reaction sequence can be per

Full text of DOI:10.1055/s-0030-1258546

LETTER
2471
2-Aminophenols Containing Electron-Withdrawing Groups from N-Aryl
Hydroxylamines
Hydroxylamine
R
e
c
arrangeme
h
nt im Porzelle,a Anthony W. J. Cooper,b Michael D. Woodrow,b Nicholas C. O. Tomkinson*a
a
School of Chemistry, Main Building, Cardiff University, Park Place, Cardiff, CF10 3AT, UK
E-mail: tomkinsonnc@cardiff.ac.uk
b
GlaxoSmithKline Medicines Research Centre, Stevenage, Hertfordshire, SG1 2NY, UK
Received 19 July 2010
In previous investigations a specific trend that emerged in
the rearrangement of O-functionalised N-aryl hydroxyl-
amines was increasing the electron-withdrawing nature of
the oxygen-substituent (i.e., R2 in compound 1), increased
Abstract: Reaction of substituted N-aryl hydroxylamines with
methanesulfonyl chloride, p-toluenesulfonyl chloride, or trifluo-
romethanesulfonic anhydride under basic conditions leads to the re-
arranged 2-aminophenols (45–94%). The overall reaction sequence
can be performed using polymer-supported sulfonyl chloride resin the propensity of rearrangement. Further work showed
allowing for the effective conversion of N-aryl hydroxylamines to
the 2-aminophenols without the need for chromatography.
that for a series of oxygen-substituents, the sulfonyl group
allowed for the most facile rearrangement. For example,
Key words: rearrangement, hydroxylamine, solid-phase synthesis,
2-aminophenol
for the substrates 3, 4, and 5 (Figure 2) rearrangement oc-
curred at 160 °C, 140 °C, and r.t.,2,6 respectively. With re-
gards the aromatic portion of the substrate, mechanistic
studies by Gassman have shown the dramatic effect of re-
2-Aminophenols are valuable precursors in the prepara- ducing electron density on the aromatic ring on decreasing
tion of heterocycles such as benzoxazoles,1 benzoxazol- the rate of rearrangement for a series of hydroxamic acid
ones,2 indoles,3 benzoxathiazole-2,2-dioxides,4 and derivatives.10 Combination of these two factors suggested
benzoxazepines5 amongst others, highlighting their im- that use of the sulfonyl group for the rearrangement of
portance in synthesis. As a consequence, simple and ef- electron-deficient substrates would provide the best op-
fective methods for their preparation are of great use in the portunity for success in the overall strategy.
preparation of pharmaceutically relevant compounds.
O
O
We recently described methods to prepare 2-
aminophenols6 and 2-aminoanilines7 through rearrange-
ment of N-aryl hydroxylamine derivatives which were
readily accessible from either aryl halides8 or nitroarenes.9
Throughout these investigations a specific challenge that
emerged was the rearrangement of electron-deficient N-
aryl hydroxylamines 1, such that we were unable to pre-
pare 2-aminophenols (or their derivatives) through this
strategy where the aromatic ring contained an electron-
withdrawing group (Figure 1). Within this report we de-
scribe a method to overcome these problems and have
found suitably protected electron-deficient N-aryl-O-sul-
fonyl hydroxylamines effectively undergo rearrangement
to give protected 2-aminophenol products.
O
O
O
OMe
O
Ph
MeO
N
S
MeO
N
MeO
N
O
O
O
O
3
4
5
r.t.
160 °C
140 °C
Figure 2 Effect of O-substitution on rearrangement temperature
Reassessment of the conditions reported for the rearrange-
ment of N-aryl hydroxylamines6 showed that, for unsub-
stituted aromatic rings, coupling/rearrangement occurred
at room temperature for both methanesulfonyl and tolu-
enesulfonyl chloride with the N-hydroxy carbamates ex-
amined giving the products in high yield (Table 1; entries
1–6; 78–94%). With electron-deficient substrates cou-
pling with the sulfonyl chloride occurred at room temper-
ature but, despite long reaction times, rearrangement did
not take place. Pleasingly, warming the reaction mixture
to 60 °C for two hours brought about rearrangement al-
lowing the product to be isolated in excellent yield. This
protocol was tolerant of a variety of functional groups in-
cluding nitrile, ester, ketone, chloride, alkyne, and bro-
mide with both Boc and methoxy carbamate nitrogen
protecting groups (entries 7–15; 82–94%). This simple
and highly effective strategy to access challenging tri- and
tetrasubstituted aromatic compounds bearing electron-
O
O
O
R2
R1
N
Y
X
R1
NH
conditions
X
R2
Y
EWG
EWG
O
1
2
X = N, O; Y = C
no rearrangement
Figure 1
SYNLETT 2010, No. 16, pp 2471–2473
x
x
.x
x
.2
0
1
0
Advanced online publication: 26.08.2010
DOI: 10.1055/s-0030-1258546; Art ID: D19110ST
© Georg Thieme Verlag Stuttgart · New York

2472
A. Porzelle et al.
LETTER
withdrawing substituents significantly expands the scope droxylamine precursor 6 at –78 °C then allowing the solu-
of the transformation and suggests the 2-aminophenol of tion to warm to room temperature gave the rearranged
choice can be prepared through this methodology.
products in 45–74% yield (Table 2). Although isolated
yields were lower than those with methanesulfonyl and
toluenesulfonyl chloride (Table 1) the products could be
isolated by chromatography and several of the challeng-
ing electron-deficient precursors were effective substrates
within the reaction (entries 1–4).
Table 1 Treatment of N-Aryl Hydroxylamines with Sulfonyl Chlo-
ridesa
O
O
R3SO2Cl,
Et3N, CHCl3
OH
H
R1O
N
R1O
N
R3
r.t., 30 min
or
O
Table 2 Formation of O-Trifluoromethane Sulfonate Productsa
S
r.t., 30 min
then 60 °C, 2 h
for R2 = EWG
O
O
O
O
OH
H
R2
6
R2
7–21
R1O
N
R1O
N
Tf2O
DMAP, Et3N
OTf
–78 °C, 30 min
Entry
1c
R1
R2
H
R3
Product Yield (%)b
Me
Me
Tol
Me
Tol
Me
Tol
Tol
Tol
Tol
Me
Tol
Tol
Tol
7
78
86
88
81
94
89
88
85
82
94
91
85
84
88
84e
R2
6
R2
22–25
2c
Me
H
8
Entry
R1
R2
Product
22
Yield (%)b
3c
t-Bu
t-Bu
Bn
H
9
1
2
3
4
Me
Cl
51
45
55
74
4c
H
10
11
12
13
14
15
16
17
18
19
20
21
Me
Br
23
5c
H
t-Bu
t-Bu
CO2Et
CN
24
6c
Bn
H
25
7d
t-Bu
t-Bu
t-Bu
t-Bu
Me
CN
CO2Et
Ac
Cl
a All reactions performed in CH2Cl2 (0.18 M).
b Isolated yield.
8d
9d
10d
11d
12d
13d
14d
15d
Having established effective conditions for the prepara-
tion of electron-deficient N-protected 2-aminophenols,
we sought to develop the work further by the use of a
‘catch-and-release’ strategy using a polymer-supported
sulfonyl chloride resin. Standard conditions are outlined
in Table 3. Treatment of N-protected N-aryl hydroxyl-
amine 6 with commercially available sulfonyl chloride
resin in THF at room temperature for 30 minutes followed
by heating at 60 °C for two hours gave the polymer-
supported rearranged product which could be thoroughly
washed. Suspension of the residue in methanol and treat-
ment with sodium hydroxide solution (2 M) at reflux for
two hours gave the products 27–32 (44–56%; >82% puri-
ty LC-MS). This simple and standard protocol should
have good applicability in the preparation of arrays of 2-
aminophenols as key heterocyclic building blocks.
C2H
Cl
Me
Me
Br
Me
2-Me-4-Cl Me
3-Br Me
Me
a All reactions performed in CHCl3 (0.25 M).
b Isolated yield.
c Reaction conducted at r.t. for 30 min.
d Reaction conducted at r.t. for 30 min then 60 °C for 2 h.
e Isolated as an inseparable mixture of isomers in a 30:70 ratio (1,2,6-
isomer/1,2,4-isomer).
Along with providing access to N-protected 2-aminophe-
nols as heterocyclic building blocks, the O-sulfonyl phe-
nol products (e.g., 7) represent potential partners for
transition-metal-catalysed couplings.11 Of the O-sulfonyl
substrates reported to be effective in these reactions, the
O-trifluoromethanesulfonate functionality readily under-
goes oxidative addition and has the broadest applicabili-
ty.12 We therefore examined reaction of N-aryl
hydroxylamines 6 with trifluoromethanesulfonic anhy-
dride to determine if this would also undergo a similar re-
arrangement to that described above (Table 1). Reaction
at room temperature (as above) or 0 °C proved difficult to
control. However, addition of the anhydride to the hy-
In summary, we have described a simple and effective
method for the preparation of both electron-rich and elec-
tron-deficient 2-aminophenols by reaction of protected
N-aryl hydroxylamines with sulfonyl chlorides. Use of
polymer-supported sulfonyl chloride resin provides the
specific advantage of giving the products through a stan-
dard protocol without the need for chromatography. Giv-
en the mild conditions required for rearrangement and the
ready availability of N-aryl hydroxylamines we believe
this strategy will have application in the preparation of a
variety of biologically significant heterocycles in drug
discovery campaigns.
Synlett 2010, No. 16, 2471–2473 © Thieme Stuttgart · New York

LETTER
Hydroxylamine Rearrangement
2473
Rearrangement Using Supported Sulfonyl Chloride
Table 3 Catch-and-Release Strategy for Rearrangement
To a suspension of polymer-bound sulfonyl chloride (1 g, 1.5 mmol,
Sigma Aldrich #498211) in THF (6 mL) was added Et3N (0.23 mL,
2 mmol), followed by hydroxylamine (1 mmol) in THF (2 mL). The
mixture was stirred for 30 min at r.t. and 2 h at 60 °C. The mixture
was filtered and the residue washed with Et2O. The residue was sus-
pended in MeOH (8 mL) and NaOH (2 mL, 2 M) was added, and
the mixture was heated to reflux for 2 h. The reaction mixture was
filtered and washed with Et2O. The filtrate was analysed by LC-MS.
The organic layer was washed with H2O and evaporated to give the
2-aminophenols in moderate yield.
O
O
1. Et3N,
THF, r.t.
OH
H
O
O
R1O
N
R1O
N
S
+
Cl
OH
2. NaOH,
MeOH, Δ
R2
6
R2
26
27–32
Entry R1
R2
Product Yield (%)a Purity (%)b
1
2
3
4
5
6
t-Bu
t-Bu
CN
CO2Me
Ac
27
28
29
30
31
32
47
44c
52
48
56
54
82
87
88
91
97
95
Acknowledgment
The authors thank the EPSRC and GlaxoSmithKline for financial
support and EPSRC Mass Spectrometry Service, Swansea for high-
resolution spectra.
t-Bu
t-Bu
t-Bu
Me
Cl
References and Notes
Me
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(2) Porzelle, A.; Woodrow, M. D.; Tomkinson, N. C. O. Org.
Lett. 2010, 12, 812.
Br
a Isolated yield.
b Determined by LC-MS.
c Conducting hydrolysis in EtOH gave the ethyl ester (35%).
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Rearrangement of Methanesulfonates and Toluenesulfonates13
The N-protected N-phenyl hydroxylamine (1.0 mmol) was dis-
solved in CHCl3 (4 mL) and Et3N (0.28 mL, 2 mmol) was added fol-
lowed by the addition of the sulfonyl chloride (1.1 mmol) at 0 °C.
The ice bath was removed and the reaction mixture allowed to stir
at r.t. If rearrangement precursor remained after 30 min the reaction
was heated to 60 °C for 2 h. The crude mixture was directly subject-
ed to column chromatography to obtain the rearrangement products.
(9) Porzelle, A.; Woodrow, M. D.; Tomkinson, N. C. O. Synlett
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(10) Gassman, P. G.; Granrud, J. E. J. Am. Chem. Soc. 1984, 106,
Rearrangements of Trifluoromethanesulfonates13
The N-protected N-phenyl hydroxylamine (0.72 mmol) was dis-
solved in CH2Cl2 (4 mL), Et3N (0.28 mL, 2 mmol), and a catalytic
amount of DMAP were added followed by the slow addition of tri-
fluoromethanesulfonic anhydride (0.17 mL, 1.0 mmol) at –78 °C.
Stirring was continued at –78 °C for 30 min then the reaction mix-
ture was allowed to warm to r.t. On completion, the mixture was di-
luted with CH2Cl2 (10 mL), washed with NaHCO3 solution and
brine (10 mL each). The solvent was evaporated and the crude prod-
uct further purified by column chromatography on silica to give the
rearrangement product.
1498.
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(13) All rearrangement products were characterised by 1H NMR,
13C NMR, LRMS, and HRMS.
Synlett 2010, No. 16, 2471–2473 © Thieme Stuttgart · New York