Rearrangement of differentially protected N-arylhydroxylamines

Article abstract of DOI:10.1002/ejoc.200800672

The rearrangement of a series of N,O-difunctionalised N-arylhydroxylamines to generate protected 2-aminophenols has been investigated. N-Boc-N-Aryl-O- acylhydroxylamines are stable, isolable compounds which rearrange smoothly at temperatures between 110 and 140°C. The corresponding N-Boc-N-aryl-O- sulfonylhydroxylamines were not isolated and rearrange to 1,2-difunctionalised aminophenols at room temperature in excellent yield. Deprotection of either the N- or O-substituents under standard conditions allows for further synthetic manipulation of either the aniline or phenol functionality. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800672

FULL PAPER
DOI: 10.1002/ejoc.200800672
Rearrangement of Differentially Protected N-Arylhydroxylamines
Achim Porzelle,[a] Michael D. Woodrow,[b] and Nicholas C. O. Tomkinson*[a]
Keywords: Rearrangement / Hydroxylamine / Aromatic substitution
The rearrangement of a series of N,O-difunctionalised N-ar- perature in excellent yield. Deprotection of either the N- or
ylhydroxylamines to generate protected 2-aminophenols has
been investigated. N-Boc-N-Aryl-O-acylhydroxylamines are
stable, isolable compounds which rearrange smoothly at tem-
peratures between 110 and 140 °C. The corresponding N-
Boc-N-aryl-O-sulfonylhydroxylamines were not isolated and
rearrange to 1,2-difunctionalised aminophenols at room tem-
O-substituents under standard conditions allows for further
synthetic manipulation of either the aniline or phenol func-
tionality.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
through a concerted pericyclic process. These overall reac-
tions provide a simple and easily accessible method with
which to functionalise anilines at the ortho position. The
use of these versatile rearrangements is currently limited by
the resulting amide or sulfonamide on the aniline nitrogen
of the products 4–6, where harsh reaction conditions would
be required to unmask the aniline functionality. Having re-
cently developed a simple method for the preparation of
differentially protected N-arylhydroxylamines through a
modified Ullman coupling,[11] we sought to investigate the
scope and limitations of subsequent rearrangements that
employ synthetically versatile nitrogen protecting groups,
providing an important extension to existing technology.
Within this paper, we describe a method for the conversion
of N-arylhydroxylamines to differentially protected 2-ami-
Introduction
The controlled functionalisation and elaboration of aro-
matic compounds is of major importance in synthetic re-
search.[1] Of particular interest is the introduction of new
carbon–heteroatom bonds. In this context, robust transi-
tion-metal-mediated methodology allows access to high-
value aromatic and heteroaromatic products of great use in
pharmaceutical, agrochemical and natural product re-
search.[2] Much of the fundamental technology developed
for the construction of carbon–heteroatom bonds involves
the activation of aryl halides or triflates with precious metal
catalysts.[3] In recent years, considerable research efforts
into C–H activation/functionalisation, has provided impor-
tant contributions to the arsenal of methods available to
the synthetic chemist.[4] Although efficient and practical,
the majority of these processes rely on activation of the sub-
strate with transition metals.[5] The development of method-
ology which allows for the formal metal-free[6] activation
of aromatic rings would significantly augment the available
methods and provide a valuable synthetic alternative.
In 1957 Horner described the synthesis and thermal re-
arrangement of N-aryl-N,O-diacylhydroxylamine 1 to pro-
vide protected 2-aminophenol 4 (Scheme 1).[7] Subsequent
mechanistic studies have shown these reactions proceed via
either a [3,3]-sigmatropic rearrangement process or an ion-
pair mechanism depending upon the reaction conditions
adopted.[8] In contrast, the related rearrangement of N-aryl-
N-sulfonyl-O-acylhydroxylamines 2 to give 5[9] and N-aryl-
N-acyl-O-sulfonylhydroxylamines 3 to the 2-functionalised
products 6[10] have been shown to proceed exclusively
[a] School of Chemistry, Main Building, Cardiff University,
Park Place, Cardiff, CF10 3AT, UK
E-mail: tomkinsonnc@cardiff.ac.uk
[b] ImmunoInflammation Centre of Excellence for Drug Discov-
ery, GlaxoSmithKline Medicines Research Centre,
Stevenage, Hertfordshire, SG1 2NY, UK
Scheme 1. Rearrangements of N-arylhydroxylamines.
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A. Porzelle, M. D. Woodrow, N. C. O. Tomkinson
FULL PAPER
nophenols, examine the regiochemical outcome of the re- Table 1. Rearrangement of O-acylhydroxylamines.
arrangement using non-symmetrical substrates, and report
methods for the selective deprotection of both the nitrogen
and oxygen substituents.
Results and Discussion
Entry
R1
R2
Product Solvent[a]
Yield[b]
Conversion of N-Boc-N-phenylhydroxylamine (7)[12] to
the corresponding O-acyl and O-carbonate derivatives pro-
ceeded smoothly under standard conditions to deliver a
series of rearrangement precursors 8–12 (76–94%)
(Scheme 2). Each of these compounds (8–12) was bench
stable and showed no indication of rearrangement/decom-
position at room temperature over the course of this investi-
gation.
1
2
3
4
5
6
7
8
OtBu
OtBu
OtBu
OtBu
OtBu
OtBu
OtBu
OtBu
OtBu
OMe
OMe
4-NO2-C6H4
4-NO2-C6H4
Ph
13
13
14
14
15
15
16
16
17
18
18
toluene
p-xylene
toluene
p-xylene
toluene
p-xylene
toluene
p-xylene
toluene
toluene
p-xylene
45% (92%)[c]
75%
30% (82%)[c]
55%
Ph
4-OMe-C6H4
4-OMe-C6H4
OMe
OMe
OtBu
0%
33%
37%[d]
62%
9
10
11
0%[e]
OMe
OMe
40% (90)[c]
65%
[a] Toluene: 110 °C, 48 h; xylene: 140 °C, 24 h. [b] Isolated yield.
[c] Yield based on recovered starting material. [d] Conversion by
1H NMR. [e] Loss of O-carbonate group.
Our initial results (Table 1) suggested that increasing the
electron-withdrawing ability of the oxygen substituent (and/
or decreasing that of the nitrogen) lowered the activation
barrier of rearrangement. We therefore examined the intro-
duction of a sulfonyl group on the hydroxylamine oxygen
with the hope of facilitating the overall rearrangement pro-
cess further in agreement with previous reports of this class
of transformation (Table 2).[10] To our delight, treatment of
the N-protected hydroxylamines 7 and 20–22[13] with one
equivalent of methanesulfonyl chloride and triethylamine at
room temperature for 30 min led directly to the rearranged
products 23–26 in 78–94% isolated yield (Entries 1–4), pro-
viding significantly improved reaction conditions for the se-
quence. Both carbamate (Entries 1 and 2) and sulfonamide
(Entries 3 and 4) were well tolerated on the hydroxylamine
nitrogen without compromise in reactivity. The protocol
was equally effective for the one-pot O-tosylation/re-
arrangement (Entries 5 and 6), with the reactions reaching
Scheme 2. Preparation of rearrangement precursors.
In previous reports, rearrangement of N-aryl-N-acyl-O-
acylhydroxylamines (e.g. 1) was performed at temperatures
in the range 150–200 °C.[7] Rationalising that decreasing the
electron-withdrawing ability of the nitrogen protecting
group would facilitate rearrangement we examined the reac-
tion of 8–12 at lower temperatures than those reported, the
results of which are collected in Table 1. Rearrangement of
8 proceeded effectively, but slowly at temperatures as low as
110 °C (Table 1, Entry 1) (45%, 48 h) along with recovered
starting material (47%). Raising the temperature to 140 °C
(refluxing p-xylene, 24 h) resulted in complete consumption
of starting material giving 13 in a pleasing 75% isolated
yield (Entry 2). This trend was reflected with both the O-
benzoyl 9 (Entries 3 and 4) and O-4-methoxybenzoyl 10
(Entries 5 and 6) substrates, suggesting that refluxing xylene
provide the most effective conditions for this transforma-
tion. Reducing the electron withdrawing ability of the oxy-
gen substituent to a carbonate reduced the propensity of
these substrates to undergo rearrangement, however, the ex-
pected products could be isolated using refluxing xylene as
the reaction medium (Entries 8 and 11). It is worth noting
that use of polar solvents such as DMF resulted in complex
reaction mixtures, mainly due to loss of carbamate, carbon-
ate, and ester functionalities. Additionally, little benefit was
gained by carrying out these reactions under microwave ir-
radiation (300 W, 140 °C, 3 h), with the desired products
being isolated in similar yields.
Table 2. Rearrangements with sulfonyl chlorides.
Entry
R1
R2
Product
Yield[a]
1
2
3
4
5
6
Boc (7)
Cbz (20)
pTs (21)
Ms (22)
Boc (7)
Cbz (20)
Me
Me
Me
Me
pTol
pTol
23
24
25
26
27
28
78%
94%
85%
93%
71%
89%
[a] Isolated yield.
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Rearrangement of Differentially Protected N-Arylhydroxylamines
completion within 1 h at room temperature. In each of these the two possible regioisomers 38 and 39 (83%) in a 55:45
reactions, no indication of the proposed hydroxylamine in- ratio (1H NMR) as an inseparable mixture. Cleavage of the
termediate was detected, suggesting the rearrangement of phenolic esters (KOH, DMF/H2O, 80 °C, 3 h) allowed for
N-protected N-aryl-O-sulfonylhydroxylamines is rapid.
simple separation of the isomeric products 49 (42%) and 50
Having established effective conditions for the rearrange- (52%) by column chromatography (Scheme 3). In contrast
ment of N-protected O-acyl and O-sulfonylhydroxylamines to all other rearrangements undertaken, both the 1,2- and
we examined a series of substituted N-arylhydroxylamines 1,4-aminophenol derivatives 40 and 41 were obtained from
to gain further insight into the effects of substitution on the 2-methyl-substituted aromatic 35 in a 54:46 ratio (1H
the aromatic ring on the facility of rearrangement and the NMR) (Entry 3). Once again, the isomeric products could
regiochemical outcome with non-symmetrical substrates readily be separated by solvolysis of the esters (NaOMe,
(Table 3 and Table 4). The substituted N-Boc-N-phenylhy- MeOH, ∆, 3 h) to give the phenols 51 (52%) and 52 (42%).
droxylamines 29–32 were initially O-functionalised with 4- Introduction of an electron withdrawing trifluoromethyl
nitrobenzoyl chloride to give stable rearrangement precur- group on the aromatic substrate (Entry 4) resulted in de-
sors 33–36 (86–97%). Heating each of these precursors con- composition of starting material when heating in refluxing
taining an electron donating methyl group (140 °C, 24 h) xylene. Lowering the temperature to refluxing chloroform
gave the protected aminophenol products 37–41 in excellent (72 °C) or toluene (110 °C) resulted in isolation of starting
yield (83–90%) (Entries 1–3). Interestingly, rearrangement material after heating for 24 h. Overall, this suggests that
of the 3-methylhydroxylamine derivative 34 (Entry 2) gave electron deficiency in the aromatic ring disfavours re-
arrangement and electron-rich aromatic substrates readily
undergo rearrangement.
Table 3. Acyl rearrangements with substituted arenes.
Entry
R
Product
Yield[a]
1
2
3
4
5
4-Me 33
3-Me 34
2-Me 35
3-CF3 36
3-CF3 36
37
90%
38 and 39
40 and 41
42
83%[b]
85%[b]
decomposition
42
0%[c]
[a] Isolated yield. [b] Product isolated as an inseparable ca. 1:1 mix-
ture of regioisomers. [c] Reaction carried out at 73 °C in CHCl3 or
110 °C in toluene for 24 h.
Table 4. Sulfonyl rearrangements with substituted arenes.
Scheme 3. Isomeric products from rearrangement of 34 and 35.
Rearrangement of the O-sulfonylhydroxylamines oc-
curred readily at ambient temperature with methyl-substi-
tuted aromatics (Table 4). Treatment of hydroxylamines 29–
31 with methanesulfonyl chloride under basic reaction con-
ditions gave the rearranged products 43–46 in 89–96% iso-
lated yield. Pleasingly, each of these was isolated as single
products directly after rearrangement. Difficulties were
once again encountered with the electron-deficient substrate
32 (Entry 4), however, this could be circumvented simply
by warming the reaction mixture to reflux in dichlorometh-
ane to give the rearranged products 47 (60%) and 48 (35%),
which could easily be separated by column chromatography
(Entry 5).
Entry
R
Product
Yield[a]
1
2
3
4
5
4-Me 29
3-Me 30
2-Me 31
3-CF3 32
3-CF3 32
43
89%
96%
44 and 45
46
92%
47
10%[b]
95%[c]
47 and 48
[a] Isolated yield. [b] Isolated yield along with 42% rearrangement
precursor. [c] Reaction carried out at 40 °C for 24 h, products iso-
lated in a 60:35 ratio.
Eur. J. Org. Chem. 2008, 5135–5143
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A. Porzelle, M. D. Woodrow, N. C. O. Tomkinson
FULL PAPER
the fraction with a boiling range of 40–60 °C. Flash chromatog-
raphy was carried out using Merck Kieselgel 60 H silica. Analytical
thin-layer chromatography was carried out using aluminium-
backed plates coated with Merck Kieselgel 60 GF254 that were
visualized under UV light (at 254 and/or 360 nm). Nuclear mag-
netic resonance (NMR) spectra were recorded in CDCl3 at 18 °C
unless stated otherwise and are reported in ppm; J values were
recorded in Hz and multiplicities were expressed by the usual con-
ventions. High-resolution mass spectra were obtained courtesy of
the EPSRC Mass Spectrometry Service, Swansea using the ioniza-
Selective removal of either the nitrogen or the oxygen
protecting groups of the rearranged products proceeded
smoothly under standard conditions to unmask these im-
portant functionalities for further synthetic manipulation,
revealing the potential of this methodology (Scheme 4).
Treatment of 27 with trifluoroacetic acid (0 °C, 1 h) pro-
vided the aniline 53 (89%). Hydrolysis of the 4-nitrobenzo-
ate 13 and methyl carbonate 16 with potassium hydroxide
(DMF, 80 °C, 2 h) gave phenol 54 (90 and 86%, respec-
tively). In addition, it was also possible to remove the sulfon- tion methods specified. ES refers to electron spray ionization, CI
refers to chemical ionization (ammonia) and EI refers to electron
ionization. In vacuo refers to evaporation at reduced pressure using
a rotary evaporator and diaphragm pump, followed by the removal
of trace volatiles using a vacuum (oil) pump.
ate ester in the presence of the N-Boc-aniline under solvo-
lytic conditions (NaOMe, MeOH, ∆, 6 h; 72%), suggesting
that each of the rearranged products described in this inves-
tigation can easily be selectively deprotected.
N-Arylhydroxylamines were obtained by Zn/NH4Cl reduction of
the corresponding nitrobenzenes following literature procedures.[14]
General Procedure for the Rearrangement of O-Acylhydroxylamines:
N-Boc-N-Phenyl-O-acylhydroxylamines (0.3 mmol) were dissolved
in toluene or p-xylene (3 mL) and heated to reflux for 48 h (tolu-
ene) or 24 h (xylene). After cooling, the crude mixtures were di-
rectly subjected to column chromatography (gradient petroleum
ether/ethyl acetate, 8:1 to 3:1) to obtain the rearrangement prod-
ucts.
General Procedure for the Rearrangement of O-Sulfonylhydroxyl-
amines: N-Boc-N-Phenylhydroxylamines (0.5 mmol) was dissolved
in dichloromethane (2 mL) and NEt3 (0.14 mL, 1 mmol) was added
followed by the addition of methanesulfonyl chloride (0.04 mL,
0.51 mmol) at 0 °C. The ice bath was removed and the reaction
mixture stirred at room temperature. After 30 min the crude mix-
ture was directly subjected to column chromatography (gradient
petroleum ether/ethyl acetate, 3:1 to 1:1) to obtain the rearrange-
ment products.
N-Boc-N-Phenyl-O-(4-nitrobenzoyl)hydroxylamine
(8):
NEt3
(300 mg, 3 mmol) and a catalytic amount of DMAP (10 mg) was
added to a solution of 7 (316 mg, 1.51 mmol) in THF (5 mL) and
the reaction mixture was cooled to 0 °C. 4-Nitrobenzoyl chloride
(287 mg, 1.55 mmol) was added and the resulting solution was
stirred for 1 h at 0 °C and 2 h at room temperature. The reaction
mixture was diluted with diethyl ether (20 mL) and washed with
saturated NaHCO3 (10 mL), water (10 mL) and brine (10 mL). The
organic phase was dried with (MgSO4) and the volatiles removed
under reduced pressure. The crude product was purified by column
chromatography on silica eluting with petroleum ether/ethyl acetate
(3:1) to give the title compound 8 (500 mg, 94%) as pale yellow oil;
Rf = 0.63 (petroleum ether/ethyl acetate, 3:1). 1H NMR (400 MHz,
CDCl3): δ = 8.35–8.28 (m, 4 H), 7.51–7.49 (m, 2 H), 7.41–7.37 (m,
2 H), 7.29–7.26 (m, 1 H), 1.49 (s, 9 H) ppm. 13C NMR (62.5 MHz,
CDCl3): δ = 162.8 (s), 152.1 (s), 152.0 (s), 140.2 (s), 132.9 (s), 131.1
(d), 128.9 (d), 127.4 (d), 124.2 (d), 123.8 (d), 83.7 (s), 28.1 (q) ppm.
Scheme 4. Selective deprotection of rearranged products.
Conclusions
In summary, we have described the preparation and ther-
mal rearrangement of a series of differentially protected N-
arylhydroxylamines. N-Boc-N-Aryl-O-acylhydroxylamines
were found to be stable, isolable compounds, which re-
arranged smoothly at temperatures between 110 and
140 °C. The corresponding N-Boc-N-aryl-O-sulfonylhy-
droxylamines were not isolated and rearranged to the 1,2-
difunctionalised phenols at room temperature. Deprotec-
tion of either the N- or O-substituents under standard con-
ditions allows for further synthetic manipulation of either
the aniline or the phenol functionalities. Substitution of the
aromatic ring with electron donating substituents was toler-
ated, however, electron-withdrawing substituents signifi-
cantly inhibit rearrangement. Application of this methodol-
ogy in the preparation of drug-like molecules is currently
underway.
HRMS (ES) found 376.1501 [M
C18H22N3O6 376.1509.
+
NH4]·+; calculated for
N-Boc-N-Phenyl-O-benzoylhydroxylamine (9): NEt3 (100 mg,
1 mmol) was added to a solution of 7 (100 mg, 0.48 mmol) in THF
(5 mL) and the reaction mixture was cooled to 0 °C. Benzoyl chlo-
ride (70 mg, 0.5 mmol) was added and the resulting solution was
stirred for 1 h at 0 °C and 2 h at room temperature. The reaction
mixture was diluted with diethyl ether (20 mL) and washed with
saturated NaHCO3 (10 mL), water (10 mL) and brine (10 mL). The
organic phase was dried with (MgSO4) and the volatiles removed
under reduced pressure. The crude product was purified by column
Experimental Section
General Information: Commercially available solvents and reagents
were used without further purification. Petroleum ether refers to
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Eur. J. Org. Chem. 2008, 5135–5143

Rearrangement of Differentially Protected N-Arylhydroxylamines
chromatography on silica eluting with petroleum ether/ethyl acetate
(3:1) to give the title compound 9 (115 mg, 76%) as colourless oil;
Rf = 0.52 (petroleum ether/ethyl acetate, 3:1). 1H NMR (400 MHz,
CDCl3): δ = 8.15 (d, J = 7.5 Hz, 2 H), 7.68–7.65 (m, 1 H), 7.55–
7.48 (m, 4 H), 7.43–7.37 (m, 2 H), 7.22–7.17 (m, 1 H), 1.52 (s, 9
H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = 164.5 (s), 152.1 (s),
140.4 (s), 134.3 (s), 130.6 (d), 130.0 (d), 128.9 (d), 128.7 (d), 126.5
(d), 123.3 (d), 83.2 (s), 28.2 (q) ppm. HRMS (ES) found 331.1645
[M + NH4]·+; calculated for C18H23N2O4 331.1658.
N-(Methoxycarbonyl)-N-phenyl-O-(methoxycarbonyl)hydroxyl-
amine: To a solution of N-phenylhydroxylamine (110 mg, 1 mmol)
in THF (10 mL) was added NEt3 (300 mg, 3 mmol) and the mix-
ture was cooled to 0 °C. Methyl chloroformate (200 mg, 2.1 mmol)
was added and the reaction mixture was stirred for 1 h at 0 °C. The
reaction mixture was diluted with diethyl ether (30 mL) and washed
with saturated NaHCO3 (20 mL), water (20 mL) and brine
(20 mL). The organic phase was dried with (MgSO4) and the vola-
tiles removed under reduced pressure. The crude product was puri-
fied by column chromatography on silica eluting with petroleum
ether/ethyl acetate (3:1) to give the title compound (182 mg, 81%)
as yellow oil; Rf = 0.35 (petroleum ether/ethyl acetate, 3:1). 1H
NMR (400 MHz, CDCl3): δ = 7.50–7.47 (m, 2 H), 7.44–7.39 (m, 2
H), 7.34–7.28 (m, 1 H), 3.94 (s, 3 H), 3.87 (s, 3 H) ppm. 13C NMR
(62.5 MHz, CDCl3): δ = 154.7 (s), 154.0 (s), 139.3 (s), 129.0 (d),
127.8 (d), 124.2 (d), 56.4 (q), 54.0 (q) ppm. HRMS (ES) found
226.0706 [M + H]·+; calculated for C10H12NO5 226.0715.
N-Boc-N-Phenyl-O-(4-methoxybenzoyl)hydroxylamine (10): NEt3
(100 mg, 1 mmol) was added to a solution of 7 (100 mg, 0.48 mmol)
in THF (2 mL) and the mixture was cooled to 0 °C. 4-Methoxyben-
zoyl chloride (85 mg, 0.5 mmol) was added and the reaction mix-
ture was stirred for 1 h at 0 °C and 2 h at room temperature. The
reaction mixture was diluted with diethyl ether (10 mL) and washed
with saturated NaHCO3 (10 mL), water (10 mL) and brine
(10 mL). The organic phase was dried with (MgSO4) and the vola-
tiles removed under reduced pressure. The crude product was puri-
fied by column chromatography on silica eluting with petroleum
ether/ethyl acetate (3:1) to give the title compound 10 (140 mg,
79%) as colourless oil; Rf = 0.47 (petroleum ether/ethyl acetate,
2-(Boc-Amino)phenyl 4-Nitrobenzoate (13): White solid (62 mg,
75%); m.p. 40–42 °C; Rf = 0.46 (petroleum ether/ethyl acetate, 3:1).
1H NMR (400 MHz, CDCl3): δ = 8.42–8.37 (m, 4 H), 8.00 (br. d,
J = 8.0 Hz, 1 H), 7.31–7.26 (m, 1 H), 7.22–7.19 (m, 1 H), 7.16–
7.12 (m, 1 H), 6.44 (br. s, 1 H), 1.46 (s, 9 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 162.8 (s), 152.5 (s), 151.1 (s), 140.3 (s),
134.4 (s), 131.5 (d), 130.3 (s), 127.0 (d), 124.0 (d), 123.9 (d), 122.1
(d), 122.0 (d), 81.1 (s), 28.2 (q) ppm. HRMS (ES) found 376.1501
[M + NH4]·+; calculated for C18H22N3O6 376.1509.
1
3:1). H NMR (400 MHz, CDCl3): δ = 8.10 (d, J = 8.9 Hz, 2 H),
7.52 (d, J = 8.2 Hz, 2 H), 7.35 (dd, J = 8.2 Hz, 2 H), 7.20 (t, J =
8.2 Hz, 1 H), 6.95 (d, J = 8.9 Hz, 2 H) 1.50 (s, 9 H) ppm. 13C NMR
(62.5 MHz, CDCl3): δ = 164.3 (s), 164.1 (s), 152.2 (s), 140.5 (s),
132.2 (d), 128.7 (d), 126.3 (d), 123.0 (d), 119.5 (s), 114.0 (d), 83.0
(s), 55.5 (q), 28.2 (q) ppm. HRMS (ES) found 361.1759
[M + NH4]·+; calculated for C19H25N2O5 361.1763.
2-(Boc-Amino)phenyl Benzoate (14): White solid (63 mg, 55%); m.p.
1
67–69 °C; Rf = 0.55 (petroleum ether/ethyl acetate, 3:1). H NMR
(400 MHz, CDCl3): δ = 8.24 (m, 2 H), 8.10 (br. s, 1 H), 7.71–7.69
(m, 1 H), 7.58–7.54 (m, 2 H), 7.28–7.23 (m, 1 H), 7.20–7.17 (m, 1
H), 7.12–7.08 (m, 1 H), 6.54 (br. s, 1 H), 1.48 (s, 9 H) ppm. 13C
NMR (62.5 MHz, CDCl3): δ = 164.5 (s), 152.4 (s), 140.2 (s), 134.0
(d), 130.7 (s), 130.3 (d), 129.1 (s), 128.8 (d), 126.5 (d), 123.4 (d),
122.2 (d), 121.2 (d), 80.9 (s), 28.3 (q) ppm. HRMS (ES) found
331.1645 [M + NH4]·+; calculated for C18H23N2O4 331.1658.
N-Boc-N-Phenyl-O-Boc-hydroxylamine (11):
A solution of 7
(200 mg, 0.96 mmol) in THF (10 mL) was cooled to 0 °C and
Boc2O (240 mg, 1.1 mmol) was added. The reaction mixture was
stirred for 5 h at room temperature, diluted with diethyl ether
(30 mL) and washed with saturated NaHCO3 (20 mL), water
(20 mL) and brine (20 mL). The organic phase was dried with
(MgSO4) and the volatiles removed under reduced pressure. The
crude product was purified by column chromatography on silica
eluting with petroleum ether/ethyl acetate (3:1) to give the product
11 (243 mg, 82%) as colourless oil; Rf = 0.66 (petroleum ether/ethyl
acetate, 3:1). 1H NMR (400 MHz, CDCl3): δ = 7.46–7.44 (m, 2 H),
7.37–7.33 (m, 2 H), 7.23–7.19 (m, 1 H), 1.53 (s, 9 H), 1.52 (s, 9 H)
ppm. 13C NMR (125 MHz, CDCl3): δ = 152.2 (s), 152.0 (s), 146.8
(s), 128.8 (d), 126.4 (d), 122.9 (d), 85.3 (s), 83.1 (s), 28.1 (q), 27.6
(q) ppm. HRMS (ES) found 327.1917 [M + NH4]·+; calculated for
C16H27N2O5 327.1920.
2-(Boc-Amino)phenyl 4-Methoxybenzoate (15): Yellow oil (30 mg,
33%); Rf = 0.50 (petroleum ether/ethyl acetate, 3:1). 1H NMR
(400 MHz, CDCl3): δ = 8.19 (d, J = 10.9 Hz, 2 H), 8.17 (br. s, 1
H), 7.26–7.22 (m, 1 H), 7.17–7.15 (m, 1 H), 7.10–7.01 (m, 1 H),
6.98–6.95 (d, J = 10.9 Hz, 2 H), 6.55 (br. s, 1 H), 3.92 (s, 3 H), 1.48
(s, 9 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = 164.3 (s), 164.2
(s), 152.6 (s), 140.5 (s), 132.5 (d), 130.8 (s), 126.3 (d), 123.3 (d),
122.2 (d), 121.3 (s), 121.0 (d), 114.1 (d), 80.8 (s), 55.6 (q), 28.3
(q) ppm. HRMS (ES) found 361.1759 [M + NH4]·+; calculated for
C19H25N2O5 361.1763.
N-Boc-N-Phenyl-O-(methoxycarbonyl)hydroxylamine (12): NEt3
(72 mg, 0.72 mmol) was added to a solution of 7 (100 mg,
0.48 mmol) in THF (2 mL) and the mixture was cooled to 0 °C.
Methyl chloroformate (50 mg, 0.53 mmol) was added and the reac-
tion mixture was stirred for 1 h at 0 °C. The reaction mixture was
diluted with diethyl ether (10 mL) and washed with satd. NaHCO3
(10 mL), water (10 mL) and brine (10 mL). The organic phase was
dried with (MgSO4) and the volatiles removed under reduced pres-
sure. The crude product was purified by column chromatography
on silica eluting with petroleum ether/ethyl acetate (3:1) to give
the title compound 12 (117 mg, 91%) as colourless oil; Rf = 0.55
2-(Boc-Amino)phenyl Methyl Carbonate (16): Colourless oil (48 mg,
62%); Rf = 0.40 (petroleum ether/ethyl acetate, 3:1). 1H NMR
(400 MHz, CDCl3): δ = 8.01 (br. s, 1 H), 7.26–7.19 (m, 2 H), 7.05–
7.01 (m, 1 H), 6.69 (br. s, 1 H), 3.94 (s, 3 H), 1.52 (s, 9 H) ppm.
13C NMR (62.5 MHz, CDCl3): δ = 153.6 (s), 152.3 (s), 140.0 (s),
130.2 (s), 126.6 (d), 122.9 (d), 121.3 (d), 120.4 (d), 81.0 (s), 55.7
(q), 28.3 (q) ppm. HRMS (ES) found 285.1456 [M + NH4]·+; calcu-
lated for C13H21N2O5 285.1450.
2-[(Methoxycarbonyl)amino]phenyl Methyl Carbonate (18): Colour-
less oil (98 mg, 65%); Rf = 0.40 (petroleum ether/ethyl acetate, 3:1).
1H NMR (400 MHz, CDCl3): δ = 8.14 (br. s, 1 H), 7.32–7.26 (m,
1
(petroleum ether/ethyl acetate, 3:1). H NMR (400 MHz, CDCl3):
δ = 7.45–7.42 (m, 2 H), 7.39–7.34 (m, 2 H), 7.25–7.22 (m, 1 H), 2 H), 7.14–7.10 (m, 1 H), 6.95 (br. s, 1 H), 3.98 (s, 3 H), 3.84 (s, 3
3.90 (s, 3 H), 1.51 (s, 9 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ
= 154.8 (s), 152.1 (s), 140.0 (s), 128.7 (d), 127.0 (d), 123.6 (d), 83.5
(s), 56.1 (q), 28.1 (q) ppm. HRMS (ES) found 285.1456
[M + NH4]·+; calculated for C13H21N2O5 285.1450.
H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = 153.7 (s), 153.4 (s),
140.1 (s), 129.8 (d), 126.6 (d), 123.5 (d), 121.4 (d), 120.6 (s), 55.7
(q), 52.5 (q) ppm. HRMS (ES) found 226.0706 [M + H]·+; calcu-
lated for C10H12NO5 226.0715.
Eur. J. Org. Chem. 2008, 5135–5143
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5139

A. Porzelle, M. D. Woodrow, N. C. O. Tomkinson
FULL PAPER
2-(Boc-Amino)phenyl Methanesulfonate (23): White solid (150 mg,
78%); m.p. 63–65 °C; Rf = 0.33 (petroleum ether/ethyl acetate, 3:1).
1H NMR (400 MHz, CDCl3): δ = 8.10 (d, J = 8.1 Hz, 1 H), 7.30–
7.26 (m, 2 H), 7.07–7.01 (m, 2 H), 3.20 (s, 3 H), 1.52 (s, 9 H) ppm.
petroleum ether/ethyl acetate (3:1) to give the product 29 (189 mg,
85%) as a white solid; m.p. 82–84 °C; Rf = 0.41 (petroleum ether/
ethyl acetate, 3:1). H NMR (400 MHz, CDCl3): δ = 7.32 (d, J =
1
8.5 Hz, 2 H), 7.14 (d, J = 8.5 Hz, 2 H), 2.34 (s, 3 H), 1.49 (s, 9 H)
13C NMR (62.5 MHz, CDCl3): δ = 152.5 (s), 138.3 (s), 131.6 (s), ppm. 13C NMR (62.5 MHz, CDCl3): δ = 154.5 (s), 138.4 (s), 135.1
128.0 (d), 123.5 (d), 122.3 (d), 121.8 (d), 81.3 (s), 37.7 (q), 28.3
(q) ppm. HRMS (ES) found 305.1165 [M + NH4]·+; calculated for
C12H21N2O5S 305.1171.
(s), 129.0 (d), 121.9 (d), 83.1 (s), 28.3 (q), 20.9 (q) ppm. HRMS (ES)
found 224.1284 [M + H]·+; calculated for C12H18NO3 224.1281.
N-Boc-N-(4-Methylphenyl)-O-(4-nitrobenzoyl)hydroxylamine (33):
Waxy pale yellow solid (165 mg, 89%); Rf = 0.56 (petroleum ether/
ethyl acetate, 3:1). 1H NMR (400 MHz, CDCl3): δ = 8.33–8.26 (m,
4 H), 7.39 (d, J = 8.4 Hz, 2 H), 7.19 (d, J = 8.4 Hz, 2 H), 2.35 (s,
3 H), 1.51 (s, 9 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = 162.9
(s), 152.4 (s), 151.1 (s), 137.8 (s), 137.7 (s), 133.1 (s), 131.1 (d),
129.5 (d), 124.9 (d), 123.7 (d), 83.5 (s), 28.1 (q), 21.0 (q) ppm.
2-(Cbz-Amino)phenyl Methanesulfonate (24): White solid (112 mg,
94%); m.p. 65–66 °C; Rf = 0.28 (petroleum ether/ethyl acetate, 3:1).
1H NMR (400 MHz, CDCl3): δ = 8.13 (br. d, J = 4.0 Hz, 1 H),
7.43–7.28 (m, 8 H), 7.09–7.07 (m, 1 H), 5.21 (s, 2 H), 3.15 (s, 3 H)
ppm. 13C NMR (62.5 MHz, CDCl3): δ = 153.2 (s), 138.4 (s), 135.9
(s), 131.2 (s), 128.6 (d), 128.4 (d), 128.4 (d), 128.1 (d), 124.1 (d),
122.5 (d), 122.0 (d), 67.4 (t), 37.9 (q) ppm. HRMS (ES) found
322.0741 [M + H]·+; calculated for C15H16NO5S 322.0749.
HRMS (ES) found 390.1679 [M
C19H24N3O6 390.1665.
+
NH4]·+; calculated for
2-[(4-Tolylsulfonyl)amino]phenyl Methanesulfonate (25): White solid
(87 mg, 85%); m.p. 112–115 °C; Rf = 0.19 (petroleum ether/ethyl
acetate, 3:1). 1H NMR (400 MHz, CDCl3): δ = 7.76 (d, J = 8.3 Hz,
2 H), 7.64 (d, J = 8.2 Hz, 1 H), 7.39 (br. s, 1 H), 7.32–7.26 (m, 4
H), 7.20–7.15 (m, 1 H), 3.19 (s, 3 H), 2.43 (s, 3 H) ppm. 13C NMR
(62.5 MHz, CDCl3): δ = 144.2 (s), 139.8 (s), 136.5 (s), 130.0 (s),
129.7 (d), 128.2 (d), 127.3 (d), 125.9 (d), 123.7 (d), 123.0 (d), 38.0
(q), 21.5 (q) ppm. HRMS (ES) found 342.0482 [M + H]·+; calcu-
lated for C14H16NO5S2 342.0470.
2-(Boc-Amino)-5-methylphenyl 4-Nitrobenzoate (37): Pale yellow oil
(68 mg, 90%); Rf = 0.58 (petroleum ether/ethyl acetate, 3:1). 1H
NMR (400 MHz, CDCl3): δ = 8.40–8.35 (m, 4 H), 7.81 (br. d, J =
4.0 Hz), 7.09–7.07 (m, 1 H), 7.01 (br. s, 1 H), 6.32 (br. s, 1 H), 2.34
(s, 3 H), 1.44 (s, 9 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ =
162.9 (s),152.7 (s), 151.1 (s), 140.8 (s), 134.5 (s), 131.4 (d), 127.6
(d), 127.5 (s), 123.8 (d), 122.7 (d), 122.5 (d), 80.9 (s), 28.3 (q), 20.8
(q) ppm. HRMS (ES) found 390.1679 [M + NH4]·+; calculated for
C19H24N3O6 390.1665.
2-[(Methylsulfonyl)amino]phenyl Methanesulfonate (26): White solid
39 mg, (93%); m.p. 102–103 °C; Rf = 0.12 (petroleum ether/ethyl
acetate, 3:1). 1H NMR (400 MHz, CDCl3): δ = 7.74–7.71 (m, 1 H),
7.37–7.34 (m, 2 H), 7.26–7.21 (m, 1 H), 7.08 (br. s, 1 H), 3.33 (s, 3
H), 3.06 (s, 3 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = 139.2
(s), 130.4 (s), 128.7 (d), 126.1 (d), 123.6 (d), 123.0 (d), 40.1 (q), 38.3
(q) ppm. HRMS (ES) found 283.0420 [M + NH4]·+; calculated for
C8H15N2O5S2 283.0422.
N-Boc-N-(3-Methylphenyl)hydroxylamine (30): A solution of N-(3-
methylphenyl)hydroxylamine (123 mg, 1 mmol) in THF (10 mL)
was cooled to –78 °C and a precooled solution of Boc2O (240 mg,
1.1 mmol) in THF (10 mL) was added. The reaction mixture was
warmed slowly to room temperature overnight, diluted with diethyl
ether (40 mL) and washed with satd. NaHCO3 (20 mL), water
(20 mL) and brine (20 mL). The organic phase was dried (MgSO4)
and the volatiles removed under reduced pressure. The crude prod-
uct was purified by column chromatography on silica eluting with
petroleum ether/ethyl acetate (3:1) to give 30 (194 mg, 87%) as a
pale yellow solid; m.p. 63–65 °C; Rf = 0.45 (petroleum ether/ethyl
acetate, 3:1). 1H NMR (400 MHz, CDCl3): δ = 7.32 (br. s, 1 H),
7.26–7.21 (m, 2 H), 6.99 (br. d, J = 8 Hz, 1 H); 2.38 (s, 3 H), 1.52
(s, 9 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = 154.5 (s), 140.9
(s), 138.2 (s), 128.1 (d), 126.0 (d), 122.3 (d), 118.9 (d), 83.2 (s), 28.3
(q), 21.5 (q) ppm. HRMS (EI) found 223.1209 [M]·+; calculated for
C12H17NO3 223.1208.
2-(Boc-Amino)phenyl 4-Toluenesulfonate (27): White solid (130 mg,
71%); m.p. 79–80 °C; Rf = 0.52 (petroleum ether/ethyl acetate, 3:1).
1H NMR (400 MHz, CDCl3): δ = 8.00 (br. d, J = 8.1 Hz, 1 H),
7.69 (d, J = 8.3 Hz, 2 H), 7.30 (d, J = 8.3 Hz, 2 H), 7.20–7.16 (m,
1 H), 6.99–6.97 (m, 1 H), 6.93–6.89 (m, 1 H), 6.71 (br. s, 1 H), 2.43
(s, 3 H), 1.47 (s, 9 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ =
152.1 (s), 146.0 (s), 138.2 (s), 131.9 (s), 131.6 (s), 130.0 (d), 128.5
(d), 127.7 (d), 122.8 (d), 122.6 (d), 120.6 (d), 80.8 (s), 28.2 (q),
21.8 (q) ppm. HRMS (ES) found 363.1126 [M]·+; calculated for
C18H21NO5S 363.1140.
N-Boc-N-(3-Methylphenyl)-O-(4-nitrobenzoyl)hydroxylamine (34):
Pale yellow oil (172 mg, 96%); Rf = 0.53 (petroleum ether/ethyl
acetate, 3:1). 1H NMR (400 MHz, CDCl3): δ = 8.32–8.25 (m, 4 H),
7.31 (br. s, 1 H), 7.26–7.22 (m, 2 H), 7.07 (br. d, J = 4.0 Hz, 1 H),
2.34 (s, 3 H), 1.47 (s, 9 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ
= 162.9 (s), 152.2 (s), 151.1 (s), 139.9 (s), 138.9 (s), 132.9 (s), 131.2
(d), 128.8 (d), 128.3 (d), 124.9 (d), 123.8 (d), 121.3 (d), 83.6 (s),
28.1 (q), 21.4 (q) ppm. HRMS (ES) found 390.1664 [M + NH4]·+;
calculated for C19H24N3O6 390.1665.
2-(Cbz-Amino)phenyl 4-Toluenesulfonate (28): Pale yellow oil
(141 mg, 89%); Rf = 0.28 (petroleum ether/ethyl acetate, 3:1). 1H
NMR (400 MHz, CDCl3): δ = 8.01 (br. s, 1 H), 7.69 (d, J = 8.3 Hz,
1 H), 7.44–7.35 (m, 4 H), 7.26–7.20 (m, 4 H), 7.04–6.95 (m, 4 H),
5.14 (s, 2 H), 2.39 (s, 3 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ
= 152.8 (s), 146.0 (s), 138.7 (s), 135.9 (s), 131.9 (s), 131.1 (s), 129.9
(d), 128.6 (d), 128.5 (d), 128.4 (d), 128.2 (d), 127.8 (d), 123.5 (d),
122.7 (d), 121.0 (d), 67.1 (t), 21.7 (q) ppm. HRMS (ES) found
398.1074 [M + H]·+; calculated for C21H20NO5S 398.1062.
2-(Boc-Amino)-4-methylphenyl 4-Nitrobenzoate (38) and 2-(Boc-
Amino)-6-methylphenyl 4-Nitrobenzoate (39): Mixture of regioiso-
mers, isomer 38 (1,2,4-trisubstituted), isomer 39 (1,2,6-trisubsti-
tuted). White solid (85 mg, 83%); Rf = 0.50 (petroleum ether/ethyl
acetate, 3:1). 1H NMR (400 MHz, CDCl3): δ = 8.44–8.35 (m, 8 H),
7.85–7.80 (br. m, 2 H, o-CH), 7.19 (t, J = 7.9 Hz, 1 H), 7.07 (d, J
= 8.2 Hz, 1 H), 7.00 (d, J = 7.2 Hz, 1 H), 6.93 (d, J = 7.2 Hz, 1
H), 6.43 (br. s, 1 H, NH), 6.37 (br. s, 1 H, NH), 2.37 (s, 3 H), 2.17
(s, 3 H), 1.46 (s, 9 H), 1.44 (s, 9 H) ppm. 13C NMR (62.5 MHz,
CDCl3): δ = 163.0 (s), 162.4 (s), 152.6 (s), 152.5 (s), 151.2 (s), 151.1
N-Boc-N-(4-Methylphenyl)hydroxylamine (29): A solution of 4-
methyl-N-phenylhydroxylamine (123 mg, 1 mmol) in THF (10 mL)
was cooled to –78 °C and a precooled solution of Boc2O (240 mg,
1.1 mmol) in THF (10 mL) was added. The reaction mixture was
warmed slowly to room temperature overnight, diluted with diethyl
ether (40 mL) and washed with saturated NaHCO3 (20 mL), water
(20 mL) and brine (20 mL). The organic phase was dried (MgSO4)
and the volatiles removed under reduced pressure. The crude prod-
uct was purified by column chromatography on silica eluting with
5140
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5135–5143

Rearrangement of Differentially Protected N-Arylhydroxylamines
(s), 139.5 (s), 138.0 (s), 137.1 (s), 134.5 (s), 134.0 (s), 131.6 (d), 131. N-Boc-N-(3-Trifluoromethylphenyl)-O-(4-nitrobenzoyl)hydroxyl-
5 (d), 130.6 (s), 129.8 (s), 126.8 (d), 126.0 (d), 124.5 (d), 124.0 (d),
123.9 (d), 122.3 (d), 121.7 (d), 119.9 (d), 81.1 (s), 28 (m, 2 C),
21.3 (q), 16.6 (q) ppm. HRMS (ES) found 390.1664 [M + NH4]·+;
calculated for C19H24N3O6 390.1665.
amine (36): Colourless oil (183 mg, 86%); Rf = 0.51 (petroleum
ether/ethyl acetate, 3:1). 1H NMR (400 MHz, CDCl3): δ = 8.38–
8.30 (m, 4 H), 7.78 (s, 1 H), 7.69–7.66 (m, 1 H), 7.51–7.50 (m, 2
H), 1.50 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 163.1 (s),
151.7 (s), 151.6 (s), 140.9 (s), 132.8 (s), 132.0 (s), 131.7 (d), 129.9
(d), 126.1 (d), 123.8 (d), 123.0 (q, CF3) 122.6 (s), 120.2 9 (d), 80.5
(s), 28.5 (q) ppm. HRMS (ES) found 444.1374 [M + NH4]·+; calcu-
lated for C19H21O6N3F3 444.1377.
N-Boc-N-(2-Methylphenyl)hydroxylamine (31): A solution of N-(2-
methylphenyl)hydroxylamine (123 mg, 1 mmol) in THF (10 mL)
was cooled to –78 °C and a precooled solution of Boc2O (240 mg,
1.1 mmol) in THF (10 mL) was added. The reaction mixture was
warmed slowly to room temperature overnight, diluted with diethyl
ether (40 mL) and washed with saturated NaHCO3 (20 mL), water
(20 mL) and brine (20 mL). The organic phase was dried (MgSO4)
and the volatiles removed under reduced pressure. The crude prod-
uct was purified by column chromatography on silica eluting with
petroleum ether/ethyl acetate (3:1) to give 31 (176 mg, 79%) as a
pale yellow solid; m.p. 60–62 °C; Rf = 0.38 (petroleum ether/ethyl
acetate, 3:1). 1H NMR (400 MHz, CDCl3): δ = 7.32–7.29 (m, 1 H),
7.23–7.19 (m, 3 H), 2.33 (s, 3 H), 1.45 (s, 9 H) ppm. 13C NMR
(62.5 MHz, CDCl3): δ = 156.0 (s), 139.8 (s), 135.9 (s), 130.6 (d),
128.3 (d), 127.1 (d), 126.3 (d), 82.3 (s), 28.3 (q), 17.8 (q) ppm.
HRMS (APCI) found 223.1205 [M]·+; calculated for C12H17NO3
223.1208.
2-(Boc-Amino)-5-methylphenyl Methanesulfonate (43): White solid
(134 mg, 89%); m.p. 104–106 °C; Rf = 0.44 (petroleum ether/ethyl
acetate, 3:1). 1H NMR (400 MHz, CDCl3): δ = 7.91 (d, J = 4.0 Hz,
1 H), 7.09–7.07 (m, 2 H), 6.88 (br. s, 1 H), 3.18 (s, 3 H), 2.31 (s, 3
H), 1.50 (s, 9 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = 152.7
(s), 138.5 (s), 134.0 (s), 128.8 (s), 128.6 (d), 122.7 (d), 122.1 (d), 81.0
(s), 37.7 (q), 28.3 (q), 20.6 (q) ppm. HRMS (ES) found 319.1321 [M
+ NH4]·+; calculated for C13H23N2O5 319.1328.
2-(Boc-Amino)-4-methylphenyl Methanesulfonate (44): Pale yellow
waxy solid (73 mg, 48%); Rf = 0.39 (petroleum ether/ethyl acetate,
3:1). 1H NMR (400 MHz, CDCl3): δ = 7.93 (s, 1 H), 7.18–7.14 (m,
1 H), 6.95–6.92 (m, 1 H), 6.85 (br. d, J = 8.0 Hz, 1 H), 3.18 (s, 3
H), 2.34 (s, 3 H), 1.51 (s, 9 H) ppm. 13C NMR (62.5 MHz, CDCl3):
δ = 152.6 (s), 138.2 (s), 132.1 (s), 131.1 (s), 127.5 (d), 124.1 (d),
122.0 (d), 81.2 (s), 37.5 (q), 28.3 (q), 21.4 (q) ppm. HRMS (ES)
N-Boc-N-(2-Methylphenyl)-O-(4-nitrobenzoyl)hydroxylamine (35):
Pale yellow oil (185 mg, 97%); Rf = 0.48 (petroleum ether/ethyl
acetate, 3:1). 1H NMR (400 MHz, CDCl3): δ = 8.32–8.23 (m, 4 H),
7.31 (br. d, J = 8.0 Hz, 1 H), 7.30–7.24 (m, 3 H), 2.48 (s, 3 H), 1.47
(s, 9 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = 162.6 (s), 153.1
(s), 151.0 (s), 138.7 (s), 137.3 (s), 133.2 (s), 131.1 (d), 131.0 (d),
129.5 (d), 128.4 (d), 126.7 (d), 123.8 (d), 83.3 (s), 28.1 (q), 17.8
(q) ppm. HRMS (ES) found 373.1397 [M + H]·+; calculated for
C19H21N2O6 373.1394.
found 319.1335 [M
319.1328.
+
NH4]·+; calculated for C13H23N2O5S
2-(Boc-Amino)-6-methylphenyl Methanesulfonate (45): Colourless
oil (72 mg, 48%); Rf = 0.39 (petroleum ether/ethyl acetate, 3:1). 1H
NMR (400 MHz, CDCl3): δ = 7.85 (br. d, J = 8.0 Hz, 1 H), 7.30
(br. s, 1 H), 6.95–6.92 (m, 1 H), 6.88–6.85 (m, 1 H), 3.32 (s, 3 H),
2.34 (s, 3 H), 1.52 (s, 9 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ
= 152.8 (s), 138.2 (s), 136.1 (s), 131.9 (s), 125.9 (d), 122.1 (d), 120.0
(d), 80.9 (s), 38.7 (q), 28.3 (q), 17.2 (q) ppm. HRMS (ES) found
319.1335 [M + NH4]·+; calculated for C13H23N2O5S 319.1328.
2-(Boc-Amino)-3-methylphenyl 4-Nitrobenzoate (40) and 4-(Boc-
Amino)-3-methylphenyl 4-Nitrobenzoate (41): Mixture of isomers;
1
white solid (85 mg, 85%). H NMR (400 MHz, CDCl3): δ = 8.30–
8.25 (m, 8 H) 7.85 (br. d, J = 9.4 Hz, 1 H), 7.23 (t, J = 7.8 Hz, 1
H), 7.18–7.16 (m, 1 H), 7.12–7.10 (m, 1 H), 7.07–7.04 (m, 2 H),
6.28 (br. s, 1 H), 5.84 (br. s, 1 H), 2.33 (s, 3 H), 2.27 (s, 3 H), 1.53
(s, 9 H), 1.34 (s, 9 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ =
163.5 (s), 162.9 (s), 153.1 (s), 150.9 (s), 150.9 (s), 146.8 (s), 146.1
(s), 135.1 (s), 134.8 (s), 134.6 (s), 131.4 (d), 131.2 (d), 129.1 (d),
127.9 (d), 123.7 (d), 123.7 (d), 123.0 (d), 120.1 (d), 119.4 (d), 80.8
(s), 80.4 (s), 28.3 (q), 28.1 (q), 18.1 (q), 17.9 (q) ppm. HRMS (ES)
found 390.1663 [M + NH4]·+; calculated for C19H24N3O6 390.1665.
4-(Boc-Amino)-3-methylphenyl Methanesulfonate (46): Colourless
liquid (139 mg, 92%); Rf = 0.29 (petroleum ether/ethyl acetate, 3:1).
1H NMR (400 MHz, CDCl3): δ = 7.87 (br. d, J = 8 Hz, 1 H), 7.09–
7.07 (m, 2 H), 6.30 (br. s, 1 H), 3.10 (s, 3 H), 2.25 (s, 3 H), 1.52 (s,
9 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = 152.9 (s), 144.7 (s),
135.7 (s), 129.0 (s), 123.8 (d), 121.9 (d), 120.0 (d), 81.0 (s), 37.1 (q),
28.3 (q), 17.8 (q) ppm. HRMS (ES) found 324.0875 [M + Na]·+;
calculated for C13H19NO5NaS 324.0882.
2-(Boc-Amino)-4-trifluoromethylphenyl Methanesulfonate (47):
N-Boc-N-(3-Trifluoromethylphenyl)hydroxylamine (32): A solution
of N-(3-trifluoromethylphenyl)hydroxylamine (177 mg, 1 mmol) in
THF (10 mL) was cooled to –78 °C and a precooled solution of
Boc2O (240 mg, 1.1 mmol) in THF (10 mL) was added. The reac-
tion mixture was warmed slowly to room temperature overnight,
diluted with diethyl ether (40 mL) and washed with saturated
NaHCO3 (20 mL), water (20 mL) and brine (20 mL). The organic
phase was dried (MgSO4) and the volatiles removed under reduced
pressure. The crude product was purified by column chromatog-
raphy on silica eluting with petroleum ether/ethyl acetate (3:1) to
give 32 (188 mg, 68%) as a white solid; m.p. 67–68 °C; Rf = 0.46
White solid (130 mg, 65%); m.p. 77–78 °C; Rf = 0.55 (petroleum
1
ether/ethyl acetate, 3:1). H NMR (400 MHz, CDCl3): δ = 8.42 (d,
J = 8.0 Hz, 1 H), 7.66 (br. s, 1 H), 7.37–7.32 (m, 2 H), 3.39 (s, 3
H), 1.52 (s, 9 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = 152.4
(s), 135.2 (s), 134.4 (s), 127.7 (s), 125.2 (d), 123.9 (q, J = 15.7 Hz,
CF3), 123.8 (d), 120.9 (q, J = 5.0 Hz), 81.5 (s), 39.2 (q), 28.2 (q)
ppm. HRMS (ES) found 373.1031 [M + NH4]·+; calculated for
C13H20N2O5F3S 373.1045.
2-(Boc-Amino)-6-trifluoromethylphenyl Methanesulfonate (48):
Colourless oil (53 mg, 30%); Rf = 0.29 (petroleum ether/ethyl ace-
1
1
(petroleum ether/ethyl acetate, 3:1). H NMR (400 MHz, CDCl3):
tate, 3:1). H NMR (400 MHz, CDCl3): δ = 8.52 (br. s, 1 H), 7.42
δ = 7.77 (s, 1 H), 7.67 (br. d, J = 8.0 Hz, 1 H), 7.45 (dd, J = 8.0 Hz,
(d, J = 8.5 Hz, 1 H), 7.32–7.30 (m, 1 H), 7.08 (br. s, 1 H), 3.27 (s,
1 H), 7.39–7.37 (m, 1 H), 1.52 (s, 9 H) ppm. 13C NMR (62.5 MHz, 3 H), 1.52 (s, 9 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = 152.1
CDCl3): δ = 153.9 (s), 141.2 (s), 131.0 (CF3), 128.9 (d), 123.4 (d), (s), 144.4 (s), 139.6 (s), 130.3 (q, J = 33.0 Hz, CF3), 124.5 (s), 122.7
121.3 (d), 121.2 (d), 117.6 (s), 84.5 (s), 28.2 (q) ppm. HRMS (ES)
found 295.1267 [M + NH4]·+; calculated for C12H18F3N2O3
295.1264.
(d), 120.0 (m), 118.3 (d), 82.1 (s), 38.3 (q), 28.2 (q) ppm. HRMS
(ES) found 373.1037 [M + NH4]·+; calculated for C13H20N2O5F3S
373.1045.
Eur. J. Org. Chem. 2008, 5135–5143
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5141

A. Porzelle, M. D. Woodrow, N. C. O. Tomkinson
FULL PAPER
2-(Boc-Amino)-4-methylphenol (49): Colourless oil (25 mg, 42%);
Rf = 0.49 (petroleum ether/ethyl acetate, 3:1). 1H NMR (400 MHz,
CDCl3): δ = 7.78 (br. s, 1 H), 6.91 (s, 1 H), 6.87–6.82 (m, 2 H),
6.60 (br. s, 1 H), 2.24 (s, 3 H), 1.52 (s, 9 H) ppm. HRMS (EI) found
223.1208 [M]·+; calculated for C12H17NO3 223.1208.
(20 mL) and water (10 mL). The organic layer was washed with
HCl (1 , 5 mL) water (10 mL) and brine (10 mL). The organic
layer was concentrated and the crude product purified by column
chromatography (petroleum ether/ethyl acetate, 3:1) to give the title
compound 54 (145 mg, 86%).
N-Boc-2-Aminophenol (54): Compound 23 (50 mg, 0.17 mmol) was
dissolved in MeOH (4 mL) and NaOMe (5 mg) was added. The
mixture was heated to reflux for 6 h after which time it was cooled,
evaporated and diluted with diethyl ether (10 mL). The organic
layer was washed with HCl (1 , 5 mL), water (10 mL) and brine
(10 mL). The organic layer was concentrated and the product was
isolated by column chromatography (petroleum ether/ethyl acetate,
3:1) to give the title compound 54 (26 mg, 72%).
2-(Boc-Amino)-6-methylphenol (50): Colourless oil (31 mg, 52%);
Rf = 0.53 (petroleum ether/ethyl acetate, 3:1). 1H NMR (400 MHz,
CDCl3): δ = 8.13 (br. s, 1 H), 6.94 (d, J = 7.5 Hz, 1 H), 6.85 (d, J
= 7.5 Hz, 1 H), 6.75 (dd, J = 7.5, 7.5 Hz, 1 H), 6.57 (br. s, 1 H),
2.28 (s, 3 H), 1.53 (s, 9 H) ppm. HRMS (EI) found 223.1201
[M]·+; calculated for C12H17NO3 223.1208.
2-(Boc-Amino)-3-methylphenol (51): Colourless oil (31 mg, 52%);
Rf = 0.36 (petroleum ether/ethyl acetate, 3:1). 1H NMR (400 MHz,
CDCl3): δ = 8.12 (br. s, 1 H), 7.02 (dd, J = 7.8, 7.8 Hz, 1 H), 6.89
(d, J = 7.8 Hz, 1 H), 6.76 (d, J = 7.8 Hz, 1 H), 6.24 (br. s, 1 H),
2.26 (s, 3 H), 1.52 (s, 9 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ
= 154.7 (s), 153.6 (s), 132.2 (s), 128.2 (s), 125.9 (d), 117.3 (d), 113.5
(d), 80.5 (s), 28.4 (q), 17.8 (q) ppm. HRMS (EI) found 223.1201
[M]·+; calculated for C12H17NO3 223.1208.
Acknowledgments
The authors thank the Engineering and Physical Sciences Research
Council (EPSRC) and GlaxoSmithKline for financial support and
the Mass Spectrometry Service, Swansea for high-resolution
spectra.
4-(Boc-Amino)-3-methylphenol (52): White solid (25 mg, 42%); m.p.
1
42–43 °C; Rf = 0.20 (petroleum ether/ethyl acetate, 3:1). H NMR
(400 MHz, CDCl3): δ = 7.21 (br. d, J = 5.5 Hz, 1 H), 6.53–6.49 (m,
2 H), 6.08 (br. s, 2 H), 2.13 (s, 3 H), 1.51 (s, 9 H) ppm. 13C NMR
(62.5 MHz, CDCl3): δ = 154.4 (s), 149.8 (s), 129.7 (s), 125.5 (d),
122.8 (s), 122.5 (d), 121.4 (d), 81.3 (s), 27.3 (q), 17.2 (q) ppm.
HRMS (EI) found 223.1208 [M]·+; calculated for C12H17NO3
223.1208.
[1] a) A. Arora, Aromatic Organic Chemistry, Discovery Publishing
House, India, 2008; b) J. D. Hepworth, D. R. Waring, J. M.
Waring, Aromatic Chemistry, Royal Society of Chemistry,
Cambridge, 2002.
[2] Transition metals in organic synthesis (Eds: M. Beller, C. Bolm),
Wiley-VCH, Weinheim, 2004.
[3] For selected reviews of Pd-mediated methods see: a) M. C. Wil-
lis, Angew. Chem. Int. Ed. 2007, 46, 3402–3404; b) B. Schlu-
mmer, U. Schloz, Adv. Synth. Catal. 2004, 346, 1599–1626; c)
J. F. Hartwig in Handbook of Organopalladium Chemistry for
Organic Synthesis, vol. 1 (Ed.: E. I. Negishi), Wiley-Intersci-
ence, New York, 2002, p. 1051–1097; d) A. R. Muci, S. L.
Buchwald, Top. Curr. Chem. 2002, 219, 131–209; e) D. Prim,
J.-M. Campagne, D. Joseph, B. Andrioletti, Tetrahedron 2002,
58, 2041–2075. For selected reviews of Cu mediated methods
see: f) I. P. Beletskaya, A. V. Cheprakov, Coord. Chem. Rev.
2004, 248, 2337–2364; g) K. Kunz, U. Scholz, D. Ganzer, Syn-
lett 2003, 2428–2439; h) S. V. Ley, A. W. Thomas, Angew.
Chem. Int. Ed. 2003, 42, 5400–5449.
2-Aminophenyl 4-Toluenesulfonate (53):[15] Compound 27 (45 mg,
0.12 mmol) was dissolved in dichloromethane (2 mL) and cooled
to 0 °C. TFA (0.2 mL) was added via syringe and the resulting solu-
tion was warmed to room temperature over 2 h. The reaction mix-
ture was diluted with dichloromethane (10 mL) and washed with
NaHCO3, water (10 mL) and brine (10 mL). The organic layer was
evaporated and the crude product purified by column chromatog-
raphy on silica to give the title compound (29 mg, 89%) as a brown
waxy solid; Rf = 0.22 (petroleum ether/ethyl acetate, 3:1). 1H NMR
(400 MHz, CDCl3): δ = 7.78 (d, J = 8.9 Hz, 2 H), 7.33 (d, J =
8.9 Hz, 2 H), 7.02 (ddd, J = 8.0, 8.0, 1.3 Hz, 1 H), 6.78 (dd, J =
6.8, 1.4 Hz, 1 H), 6.72 (dd, J = 6.8, 1.4 Hz, 1 H), 6.60 (ddd, J =
8.0, 8.0, 1.3 Hz, 1 H), 3.6 (br. s, 2 H), 2.46 (s, 3 H) ppm. 13C NMR
(62.5 MHz, CDCl3): δ = 145.5 (s), 139.7 (s), 137.0 (s), 132.8 (s),
129.8 (d), 128.5 (d), 127.8 (d), 122.9 (d), 118.3 (d), 117.2 (d), 21.7
(q) ppm.
[4] For recent reviews in the area see: a) B.-J. Li, S.-D. Yang, Z.-J.
Shi, Synlett 2008, 947–957; b) I. J. S. Fairlamb, Ann. Rep. Prog.
Chem. Sect. B 2007, 103, 68–89; c) K. Godula, D. Sames, Sci-
ence 2006, 312, 67–72.
[5] For selected recent advances in this area see: a) J. Norinder, A.
Matsumoto, N. Yoshikai, E. Nakamura, J. Am. Chem. Soc.
2008, 130, 5858–5859; b) D. R. Stuart, K. Fagnou, Science
2007, 316, 1172–1175; c) K. L. Hull, M. S. Sanford, J. Am.
Chem. Soc. 2007, 129, 11904–11905.
N-Boc-2-Aminophenol (54):[16] Compound 13 (80 mg, 0.22 mmol)
was dissolved in DMF (6 mL) and KOH (1 , 2 mL) was added.
The mixture was heated to 80 °C for 2 h, diluted with ethyl acetate
(20 mL) and water (10 mL). The organic layer was washed with
HCl (1 , 5 mL), water (10 mL) and brine (10 mL). The organic
layer was concentrated and the crude product was purified by col-
umn chromatography (petroleum ether/ethyl acetate, 3:1) to give
the title compound 54 as a colourless oil (42 mg, 90%); Rf = 0.46
[6] a) Enantioslective Organocatalysis: Reaction and Experimental
Procedures (Ed.: P. I. Dalko), Wiley-VCH, Weinheim, 2007; b)
A. Berkessel, H. Grøger, Asymmetric Organocatalysis, Wiley-
VCH, Weinheim, 2004.
[7] L. Horner, H. Steppan, Justus Liebigs Ann. Chem. 1957, 606,
1
(petroleum ether/ethyl acetate, 3:1). H NMR (400 MHz, CDCl3):
24–47.
δ = 8.16 (br. s, 1 H), 7.09 (br. d, J = 8.8 Hz, 1 H), 7.06–7.01 (m, 1
H), 6.97–6.95 (m, 1 H), 6.88–6.83 (m, 1 H), 6.69 (br. s, 1 H), 1.51
(s, 9 H) ppm. 13C NMR (62.5 MHz, CDCl3): δ = 155.0 (s), 147.5
(s), 125.6 (s), 125.6 (d), 121.4 (d), 120.8 (d), 118.8 (d), 82.1 (s), 28.3
(q) ppm.
[8] A. Bassoli, G. Di Gregorio, G. Galliani, M. Riboldi, B. Rin-
done, S. Tollari, F. Chioccara, Bull. Chem. Soc. Fr. 1988, 293–
297.
[9] S. Oae, T. Sakurai, H. Kimura, S. Kozuka, Chem. Lett. 1974,
671–674.
[10] D. Gutschke, A. Heesing, U. Heuschkel, Tetrahedron Lett.
1979, 16, 1363–1364.
[11] K. L. Jones, A. Porzelle, A. Hall, M. D. Woodrow, N. C. O.
Tomkinson, Org. Lett. 2008, 10, 797–800.
N-Boc-2-Aminophenol (54): Compound 16 (215 mg, 0.81 mmol)
was dissolved in DMF (6 mL) and KOH (1 , 2 mL) was added.
The mixture was heated to 80 °C for 2 h, diluted with ethyl acetate
5142
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5135–5143

Rearrangement of Differentially Protected N-Arylhydroxylamines
[12] T. Sheradsky, E. Nov, J. Chem. Soc. Perkin Trans. 1 1980, 2781–
2786.
[15]
N. K. Downer-Riley, Y. A. Jackson, Tetrahedron 2007, 63,
10276–10281.
[13] For the preparation of 20 see: E. Boyland, R. Nery, J. Chem.
Soc., C. 1966, 346–350; for the preparation of 21 and 22 see:
J. D. Birchall, C. Glidewell, J. Chem. Soc., Dalton Trans. 1978,
604–607.
[16] R. Varala, S. Nuvula, S. R. Adapa, J. Org. Chem. 2006, 71,
8283–8286.
Received: July 8, 2008
Published Online: September 16, 2008
[14] D. A. Evans, H.-J. Song, K. R. Fandrick, Org. Lett. 2006, 8,
3351–3354.
Eur. J. Org. Chem. 2008, 5135–5143
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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