Photoredox Synthesis of Arylhydroxylamines from Carboxylic Acids and Nitrosoarenes

Article abstract of DOI:10.1055/s-0036-1591744

Hydroxylamines are found in biologically active compounds and serve as building blocks for the preparation of nitrogen-containing molecules. Here the direct conversion of carboxylic acids into the corresponding alkylhydroxylamines using organo-photoredox catalysis is reported. The process relies in the generation of alkyl radicals via photoinduced oxidation-decarboxylation and their following reaction with nitrosoarenes. We have successfully applied this method to the late-stage modification of complex and biologically active acids and applied it in novel radical cascade processes.

Full text of DOI:10.1055/s-0036-1591744

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–J
paper
A
en
J. Davies et al.
Paper
Synthesis
Photoredox Synthesis of Arylhydroxylamines from Carboxylic
Acids and Nitrosoarenes
Jacob Daviesa
Me Me
Me Me
Lucrezia Angelinia
Mohammed A. Alkhalifahb
Laia Malet Sanzc
Mes-acridinium
perchlorate (cat.)
Cs2CO3
O
N
OH
Me
Me
H
CO2H
+
Me
Me
H
N
blue LEDs
Ph
Nadeem S. Sheikh*b
Ph
H
H
Me
H
H
Me
Daniele Leonori*a
0
0
0
0
0-
0
0
2
7-
6
9
2
4-
5
0
4
21 examples
up to 90% yield
HO
HO
Me Me
from carboxylic acid
Me Me
to hydroxylamine
a School of Chemistry, University of Manchester, Oxford Road,
Manchester M13 9PL, UK
daniele.leonori@manchester.ac.uk
b Department of Chemistry, Faculty of Science, King Faisal
University, P.O. Box 380, Al-Ahsa 3192, Saudi Arabia
nsheikh@kfu.edu.sa
c Eli Lilly and Company Limited, Erl Wood Manor, Windlesham,
Surrey GU20 6PH, UK
Published as part of the Bürgenstock Special Section 2017 Future
Stars in Organic Chemistry
Received: 03.11.2017
Accepted after revision: 01.12.2017
Published online: 02.01.2018
A) Biologically relevant hydroxylamines and their derivatives
Me
CO2H
DOI: 10.1055/s-0036-1591744; Art ID: ss-2017-z0715-op
Me
O
HO
N
Abstract Hydroxylamines are found in biologically active compounds
and serve as building blocks for the preparation of nitrogen-containing
molecules. Here the direct conversion of carboxylic acids into the corre-
sponding alkylhydroxylamines using organo-photoredox catalysis is re-
ported. The process relies in the generation of alkyl radicals via photoin-
duced oxidation-decarboxylation and their following reaction with
nitrosoarenes. We have successfully applied this method to the late-
stage modification of complex and biologically active acids and applied
it in novel radical cascade processes.
Me
H
N
CONH2
N
N
H3N
S
Me
N
O
S
SO3
O
zileuton
antiasthma
aztreonam
antibiotic
B) Ionic processes using nitrosoarenes as electrophiles
O
N
O
N
OH
N
Nu–
Nu–
+
via
Key words hydroxylamines, radical addition, nitrosoarenes, late-
stage functionalization, radical cascade, photoredox
R
R
Nu
R
R–Li
OM
NR2
OH
R–MgX
R–ZnX
allyl–B(pin)
Hydroxylamines and their derivatives are a privileged
class of compounds with applications spanning from active
pharmaceutical ingredients and agrochemicals to versatile
building blocks for the synthesis of complex molecules
(Scheme 1, A).1 Despite this relevance, their preparation can
still be troublesome and the development of novel strate-
gies able to selectively introduce the hydroxylamine func-
tionality on structurally complex molecules under mild re-
action conditions is a relevant goal.
Nu–
:
R
R1
NHC
Ar
R1
R2
R2
C) Recent radical reactions using nitrosoarenes
O
O
N
O
O
OH
N
N
O
OH
N
R2
Cu(II)
R
Br
S
R
R
R2
F3C
ONa
F3C
R
Cu(II)
R1
R1
D) This work: Oxidative synthesis of hydroxylamines
Visible-light photoredox catalysis is now an established
and powerful technique to perform single-electron transfer
(SET)2 reactions under mild conditions.3 In particular, the
ability of harvesting carboxylic acids for the generation of
sp3-C-radicals by oxidative decarboxylation has enabled the
development of many C–C and C–X (X = F, N3, S…) bond-
forming processes.4
Owing to our ongoing interest in the preparation of
hydroxylamine derivatives as nitrogen-radical precursors,5
we wondered if a visible-light-mediated protocol for their
O
O
O
N
OH
via
R
+
N
N
R1
R
OH
R1
R
R1
Scheme 1 Relevance of hydroxylamines, previous ionic and radical ap-
proaches using nitrosoarenes, and this work
direct assembly from simple feedstock chemicals could be
developed. In particular, we were interested in the possibil-
ity of using carboxylic acids as source of sp3-C-radicals and
to exploit them in the reaction with nitrosoarenes.6 Such an
approach would be complementary to the more established
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

B
J. Davies et al.
Paper
Synthesis
ionic pathways where nitrosoarenes are used as electrophiles
in conjunction with organometallic reagents,7 enolates,8 and
enamine9/NHC10-based catalytic systems (Scheme 1, B).11
Furthermore, the preparation of hydroxylamines via radical
addition onto nitrosoarenes has been considerably over-
looked and only few protocols are available.12 Most notably,
de Alaniz13 and Selander14 have recently developed Cu(II)-
catalyzed protocols for the coupling of nitrosoarenes with rad-
ical deriving from α-bromocarbonyls and sodium triflinate,
respectively (Scheme 1, C).
In this paper, we describe the development of the first
approach for the generation of hydroxylamines from readily
available carboxylic acids and its use in the functionalization
of complex and biologically active molecules (Scheme 1, D).
At the outset, we envisioned a catalytic cycle starting
with the visible-light-promoted excitation of a photo-
catalyst and the following oxidative SET decarboxylation of
acid A upon in situ deprotonation A → B (Scheme 2, A).4
This step would deliver the C-radical C that would react
with a nitrosoarene D forging the required C–N bond and
delivering the persistent nitroxyl radical E.15 At this point,
we speculated that the final hydroxylamine G could be ob-
tained by reductive SET of E with the reduced photoredox
catalyst (to give F) and protonation.
In order to obtain information regarding the feasibility
of our proposed process, preliminary DFT studies were con-
ducted (Scheme 2, B). We were in fact concerned about the
potential addition of the C-radical at both the N (path a – to
give E) and the O atom (path b – to give H) of the nitroso-
arene, an issue frequently encountered in ionic process-
es.7a,8c We started by characterizing nitrosobenzene I in
terms of electron donor properties by calculating its adia-
batic ionization potential (IP), electron affinity (EA), and ab-
solute electronegativity (χDB).16 These values are in line with
I being a competent radical acceptor. The preferred site of
radical attack was then assessed by calculating the N and O
atom Mulliken spin densities (MSDs) in the triplet state
(ππ*).16 According to this study, I should display a slight
A) Proposed catalytic cycle
H+
OH
N
O
N
R1
R
R1
R
PC
G
F
SET
O
N
R
R1
PC•–
*PC
E
persistent
radical
SET
– CO2
O
O
base
R
CO2H
R
CO2
R
R
N
N
R1
R1
D
A
B
C
B) DFT studies [UB3LYP]
b
a
R1
R
O
N
N
O
N
R
a
b
O
R1
R
R1
E
H
O (0.82)
N (0.89)
IP (eV)
EA (eV) : 1.4
χ (eV) : 4.8
: 8.1
MSD
ω
+rc (eV) : 0.34
Ph
I
J
b
a
O
N
N
Ph
O
N
a
b
O
Ph
)
Ph
I
J
K
L
ΔG° (kcal mol–1
)
ΔG‡ (kcal mol–1
d(C–N/O) (Å)
δTS
a
b
–26.7
–29.7
8.5
9.4
3.86
3.18
–0.08
–0.01
Scheme 2 Proposed photoredox cycle and computational studies on the reaction of nitrosobenzene I with the adamantyl radical J
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

C
J. Davies et al.
Paper
Synthesis
preference for the reaction at the N-atom owing to its high-
er MSD. Further support for this reactivity was obtained
upon determination of the activation parameters for the re-
action of I with the adamantyl radical J (nucleophilic radi-
cal; ω+rc = 0.34).17 According to our study both radical path-
ways (a: attack at the N-atom and b: attack at the O-atom)
are very exergonic but there is a slight preference for path
a, which would support our proposed process.16 The very
low |δTS| values also indicate that these radical additions are
not influenced very much by polar effects in the transition
state and should be predominantly enthalpy controlled.18
To assess our working hypothesis, the reaction of ada-
mantane carboxylic acid (1a) and nitrosobenzene was in-
vestigated using various photoredox catalysts (Figure 1) and
bases in CH2Cl2 (0.05 M) at room temperature. As illustrated
in Table 1, we were pleased to find out that using mesityl
acridinium perchlorate 2a (Fukuzumi’s acridinium,
E*1/2 = +2.06 V vs SCE)19 as the photoredox catalyst and Cs2-
CO3 as the base under blue LEDs irradiation, the product 3a
was obtained in good yield (Table 1, entry 1). We then
changed the stoichiometry of the reaction (entries 2–4) and
found out that a slight excess of nitrosobenzene (2.0 equiv
with respect to 1a) was optimum, providing 3a in 90% yield
(entry 3). Other bases were evaluated and while K2CO3 gave
3a in a useful 62% yield (entry 5); 2,6-lutidine was not com-
patible and completely suppressed the reactivity (entry 6).
We also tried to run the reaction under more concentrated
conditions (entries 7 and 8) but this was detrimental. Other
photocatalysts 2b–d were screened but they generally pro-
vided 3a in considerably lower efficiency (if any) (entries 9–
11). Lastly, control experiments confirmed the requirement
for base, light, and 2a (entries 12–14).
Table 1 Optimization of the Visible Light-Mediated Synthesis of
Hydroxylamine 3a from Carboxylic Acid 1a
Ph–N=O
photocatalyst (5 mol%)
base (1.0 equiv)
CO2H
OH
N
CH2Cl2, rt, 1 h
blue LEDs
Ph
1a
3a
Entry
PCa
1a/PhNO
Base
[M]
Yield (%)
1
2
2a
2a
2a
2a
2a
2a
2a
2a
2b
2cb
2dc
2a
2a
–
1:1
1:1.1
1:2
2:1
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
0.05
0.05
0.05
0.05
0.05
0.05
0.1
58
72
90
70
62
–
3
4
5
6
2,6-lutidine
7
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
50
36
75
–
8
0.2
9
0.05
0.05
0.05
0.05
0.05
0.05
10
11
12
13b
14
–
–
–
–
a Photoredox catalyst.
b 1,2,3,5-Tetrakis(carbazol-9-yl)-4,6-dicyanobenzene.
c [Ir{dF(CF3)ppy}2(dtbpy)]PF6 {[4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine-
N1,N1′]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridi-
um(III) hexafluorophosphate}.
d The reaction was carried out in the dark.
we evaluated the use of functionalized nitrosoarenes in
conjunction with adamantine carboxylic acid (1a) and
found them compatible. Both electron-rich 3j and ortho-
substituted 3k derivatives reacted well. Substrates contain-
ing an electron-withdrawing CF3-group 3l could also be
employed, albeit in lower yield.
Mes
2a: X = ClO4
2b: X = BF4
2c: 4CzIPN
2d: [(Ir(df(CF3)ppy)2)dtbpy](PF6)
N
X
Me
Figure 1 Photoredox catalysts used
We were particularly keen in showcasing the utility of
the methodology by using high-value and structurally com-
plex carboxylic acids in order to provide access to the corre-
sponding hydroxylamines. As reported in Scheme 3, this
approach was successfully used to modify the blockbuster
drug gemfibrozil (1j → 3m), which is used to lower lipid
levels. Furthermore, we were able to selectively introduce
the hydroxylamine functionality on the core of the highly
complex hepatoprotective oleanoic acid (1k → 3n) and the
antiulcer drug enoxolone (1l → 3o). Overall, these examples
show that the methodology can be used as a late-stage
modification techniques, which tolerates redox active func-
tionalities such as electron rich aromatics (which could un-
dergo SET oxidation), enones (which can be photo-excited
upon visible-light irradiation as demonstrated by Lectka)20
as well as free hydroxyl groups.
With the optimized reaction conditions in hand, the
scope of the process using nitrosobenzene and a series of
structurally different carboxylic acids was evaluated
(Scheme 3). In general, tertiary carboxylic acids worked
well and provided the desired hydroxylamines 3b–g in
good yields. This approach tolerated several functional
groups like alkyl halides, terminal olefins, carbamates and
was effective for accessing C-3 and C-4 aminopiperidines,
which are a frequent structural motif in many commercial-
ly available drugs (e.g., the antidiabetic alogliptin and the
opioid analgesic sufentanil). Secondary carboxylic acids
were tried next but unfortunately the use of a secondary
mono-benzylic 3h and a primary alkylic 3i was not possi-
ble, thus representing the limitation of the strategy. Lastly,
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

D
J. Davies et al.
Paper
Synthesis
We then decided to evaluate if this radical decarboxyl-
ative process could be part of a cascade sequence leading to
the concomitant formation of two C–N bond across an ole-
fin. We have recently developed a divergent photoredox
imino-functionalization strategy for the assembly of poly-
functionalized pyrroline-based heterocycles.5b Specifically,
we envisaged a cascade process starting with the SET oxida-
tion-fragmentation of the oxime M (Scheme 4). This would
deliver an iminyl radical O (M → N → O) that would undergo
fast 5-exo-trig cyclization resulting in the C-radical P. At
this point, radical attack onto the nitrosoarene and SET re-
duction and protonation of the persistent nitroxyl radical Q
would enable the formation of R. Also in this case, we have
evaluated the key radical reaction between nitrosobenzene
I and the Ph-dimethyl-substituted C-radical S (to give T) by
DFT and found it feasible.16
R3-N=O (2.0 equiv)
R1 R2
CO2H
R1 R2
2a (5 mol%), Cs2CO3 (1.0 equiv)
R3
R
CH2Cl2 (0.05 M), rt,1 h
R
N
blue LEDs
1a–l
(1.0 equiv)
OH
3a–o
Me Me
Me OH
Ph OH
N
OH
N
OH
OH
N
N
Cl
N
Ph
Ph
Ph
Ph
Ph
3a
90%
3b
64%
3c
71%
3d
90%
3e
54%
Me OH
N
OH
N
Me OH
OH
Ph
Ph
N
N
Ph
N
Ph
N
Ph
Ph
Boc
Me
3h
traces
Boc
3f
56%
3g
82%
3i
traces
OH
OH
OH
N
N
N
Me
CF3
OMe
3j
59%
3k
55%
3l
39%
Late-Stage Modification of Bioactive Molecules
Me Me
Me CO2H
Me
Me
H
Me
O
O
Me
Me
H
CO2H
Me
Me
Me
Me
CO2H
H
H
Me
H
H
Me
HO
HO
Me Me
Me Me
gemfibrozil (1j)
oleanoic acid (1k)
enoxolone (1l)
lipid lowering drug
hepatoprotective
antiulcer
HO
Me
Me Me
Me
N
Ph
Me
O
Me
O
OH
Me
Me
H
N
Me
Me
H
Me
Me
Ph
H
H
Me
H
H
Me
HO
N
HO
Ph
OH
Me Me
Me Me
3m
68%
3n
35%
3o
77%, dr 5:1
Scheme 3 Scope of the process for the synthesis of hydroxylamines 3
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

E
J. Davies et al.
Paper
Synthesis
O
Me
Me
Me
CO2H
Me
O
O
– e–
SET
– H+
O
R2
N
R2
N
R2
– CO2
N
– acetone
R
R1
R
R1
R
R1
M
O
N
5-exo-trig
O
R2
R2
OH
O
R1
R1
R1
+ e–
SET
+ H+
N
N
R2
N
R3
R3
R3
N
N
N
R
R
R
R
Q
P
O
Me
Me
Me
Me
N
O
N
Ph
ΔG‡ (kcal mol–1
)
)
: 9.8
: –19.5
N
N
ΔGº (kcal mol–1
Ph
I
Ph
Ph
S
T
Scheme 4 Proposed cascade for the imino-hydroxylamination of olefins via iminyl radicals and preliminary DFT studies
The implementation of this strategy was assessed using
the oxime 6a, which was prepared by condensation of the
ketone 4 with commercially available 2-(aminooxy)-2-
methylpropanoic acid (5) on a gram-scale (Scheme 5).
Other nitrosoarenes were compatible with the process
as shown by the formation of products 7a–h in good to
moderate yields. Also in this case, the use of highly electron
poor nitrosoarene 7i as well as the trapping primary C-rad-
icals (e.g., following cyclization onto a terminal olefin 7j)
was not possible representing the limit of the strategy.
Overall, this cascade process generates molecules contain-
Me Me
HCl·H2N
Me
Me
O
CO2H
CO2H
5
(1.1 equiv)
NaOAc (2.2 equiv)
O
O
Me
N
Me
MeOH, reflux
quant.
gram-scale
Ph
Me
Ph
Me
Table 2 Optimization of the Imino-Hydroxylamination Cascade Using
Oxime 6a
4
6a
Scheme 5 Preparation of oxime 6a from ketone 5
Me
Me
OH
Me
Me
Ph–N=O
2a (5 mol%), Cs2CO3 (1.0 equiv)
CO2H
N
Ph
As illustrated in Table 2, we were pleased to find out
that by irradiating (blue LEDs) a solution of 6a and nitroso-
benzene (1:2) using 2a as the photoredox catalyst, Cs2CO3
as the base in CH2Cl2 (0.1 M), the product 7a was obtained
in 48% (Table 2, entry 1). In this case however, increasing
the amount of nitrosobenzene with respect to 6a was detri-
mental (entries 2 and 3) and eventually a ratio of 1:1.1 (en-
try 4) and a reaction concentration of 0.05 M were identi-
fied to be optimum for this transformation (entry 5). Also in
this case control experiments confirmed the requirement
for base, 2a, and blue LEDs for irradiation (entries 6–8).
With this optimized conditions in hand, other iminyl
radical precursors were tested (Scheme 6). We were able to
engage substrate containing pyridine 6b and ester 6c func-
tionalities giving access to pyrrolines 7b and 7c that can be
used for the preparation of nicotine and proline analogues.
Interestingly, in this case we were able to engage a second-
ary α-ester radical 7d in the cascade cyclization-functional-
ization reaction.
O
N
Me
N
CH2Cl2, rt, 1 h
blue LEDs
Ph
Me
Ph
6a
7a
Entry
6a/PhNO
[M]
Yield (%)
1
1:2
0.1
48
26
16
53
60
67
–
2
1:3
0.1
3
1:4
0.1
4
1:2
0.05
0.05
0.05
0.05
0.05
0.05
5
1:1.1
1:1.1
1:1.1
1:1.1
1:1.1
6
7a
8b
9c
–
–
a The reaction was run in the dark.
b The reaction was run without 2a.
c The reaction was run without Cs2CO3.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

F
J. Davies et al.
Paper
Synthesis
Hydroxylamines 3a–o; General Procedure 1 (GP1)
R2
OH
Me
R3–N=O (1.1 equiv)
2a (5 mol%), Cs2CO3 (1.0 equiv)
CO2H
A dry tube equipped with a stirring bar was charged with the carbox-
ylic acid 1a–l (0.2 mmol, 1.0 equiv), 2a (4.0 mg, 10 μmol, 5 mol%),
Cs2CO3 (66 mg, 0.1 mmol, 1.0 equiv), and the requisite nitrosoarene
(0.4 mmol, 2.0 equiv). The tube was capped with a Supelco aluminum
crimp seal with septum (PTFE/butyl) and it was evacuated and re-
filled with N2(3 ×). CH2Cl2 (anhydrous and degassed by bubbling
through with N2 for 20 min; 4.0 mL) was added. The N2 inlet was then
removed and the cap sealed with parafilm. The mixture was stirred at
r.t. for 1 h in front of blue LEDs. The tube was opened to air and the
mixture was diluted with CH2Cl2 (5 mL) and brine (5 mL). The layers
were separated and the aqueous layer was extracted with CH2Cl2
(3 × 5 mL). The combined organic layers were dried (MgSO4), filtered,
and evaporated. Purification by column chromatography on silica gel
gave 3a–o.
R1
Me
N
R3
O
N
R2
N
CH2Cl2, rt, 1 h
blue LEDs
R
R1
R
7a–i
6a–e
OH
OH
Me
Me
OH
Me
Me
OH
Me
Me
MeO2C
N
N
N
N
N
Ph
Ph
Ph
Ph
N
N
N
Ph
MeO2C
Ph
7a
67%
7b
51%
7c
36%
7d
N
45%, dr 3:2
OH
OH
OH
Me
Me
Me
Me
Me
Me
N
N
N
N-[(3s,5s,7s)-Adamantan-1-yl]-N-phenylhydroxylamine (3a)
CF3
N
N
N
Following GP1, 1-adamantanecarboxylic acid (1a; 36 mg, 0.2 mmol)
gave 3a (44 mg, 90%) as a brown solid, purified by column chromatog-
raphy (CH2Cl2).
Ph
OMe Ph
Cl Ph
7e
56%
7f
70%
7g
36%
IR (film): 2905, 2850, 1595, 1486, 1451, 1357, 1306, 1209, 1209,
1103, 1074 cm–1
.
OH
OH
OH
Me
Me
Me
Me
Me
N
N
N
1H NMR (CDCl3, 400 MHz): δ = 7.21 (4 H, dt, J = 15.4, 7.7 Hz), 7.10 (1
H, t, J = 7.0 Hz), 6.58 (1 H, br s), 2.04 (2 H, br s), 1.77–1.71 (6 H, d,
J = 2.0 Hz), 1.57 (6 H, q, J = 12.0 Hz).
13C NMR (CDCl3, 101 MHz): δ = 147.9, 127.3, 125.1, 124.9, 60.5, 38.5,
36.5, 29.4.
Ph
N
N
N
Ph
Ph
NO2
Ph
7h
55%
7i
–
7j
–
Scheme 6 Scope of the process for the synthesis of hydroxylamines 7
MS (EI): m/z = 227 (MH – OH), 170, 135, 107.
HRMS (ASAP): m/z [M + H]+ calcd for C16H22NO: 244.1696; found:
244.1691.
ing two nitrogen functionalities, imine and hydroxyl-
amines, which can be orthogonally functionalized and fur-
ther modified.
In conclusion we have developed a photoredox decar-
boxylative approach for the formation of hydroxylamines
and demonstrated its application in late-stage functional-
izations and radical imino-hydroxylamination cascades.
N-(1-Methylcyclohexyl)-N-phenylhydroxylamine (3b)
Following GP1, 1-methyl-1-cyclohexanecarboxylic acid (1b; 28 mg,
0.2 mmol) gave 3b (26 mg, 64%) as a brown solid, purified by column
chromatography (pentane/CH2Cl2 1:1).
IR (film): 2925, 2857, 2361, 1596, 1487, 1449, 1372, 1120, 1028 cm–1
1H NMR (CDCl3, 400 MHz): δ = 7.33 (2 H, br d, J = 7.8 Hz), 7.28 (2 H, t,
J = 7.8 Hz), 7.17 (1 H, t, J = 7.1 Hz), 1.73–1.65 (3 H, m), 1.58–1.51 (3 H,
m), 1.42–1.27 (4 H, m), 1.09 (3 H, s).
.
13C NMR (CDCl3, 126 MHz): δ = 128.6, 127.4, 125.8, 124.3, 34.4, 29.4,
25.44, 22.3, 17.5.
MS (EI): m/z = 205 [M]+, 189, 146, 109.
HRMS (HESI): m/z [M + H]+ calcd for C13H20NO: 206.1539; found:
All required fine chemicals were used directly without purification,
unless stated otherwise. All air and moisture sensitive reactions were
carried out under N2 atmosphere using standard Schlenk manifold
technique. 1H and 13C NMR spectra (abbreviations: M = major; m =
minor) were acquired at various field strengths as indicated and were
referenced to CHCl3(7.27 and 77.0 ppm for 1H and 13C, respectively).
High-resolution mass spectra were obtained using a JEOL JMS-700
spectrometer or a Fissions VG Trio 2000 quadrupole mass spectrome-
ter. Spectra were obtained using electron impact ionization (EI) and
chemical ionization (CI) techniques, or positive electrospray (ES). IR
spectra were recorded using a JASCO FT/IR 410 spectrophotometer or
using an ATI Mattson Genesis Seris FTIR spectrometer as evaporated
films or liquid films. Flash column chromatography was performed
using Merck Silica Gel 60 (40–63 μm). All the reactions were conduct-
ed in CEM 10 mL glass microwave tube using the EvoluChem Pho-
toRedOx Box.
206.1540.
N-Phenyl-N-(1-phenylcyclohexyl)hydroxylamine (3c)
Following GP1, 1-phenylcyclohexane-1-carboxylic acid (1c; 41 mg,
0.2 mmol) gave 3c (38 mg, 71%) as an orange solid, purified by col-
umn chromatography (pentane/CH2Cl2 1:1).
IR (film): 2929, 2861, 1593, 1484, 1456, 1447, 1204, 1152, 1037 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 7.32–7.11 (5 H, m), 7.15–6.99 (3 H, m),
6.71 (2 H, d, J = 7.6 Hz), 5.98 (1 H, br s), 2.41 (2 H, d, J = 12.6 Hz), 1.90
(2 H, t, J = 11.7 Hz), 1.66 (2 H, d, J = 9.5 Hz), 1.49 (1 H, d, J = 4.7 Hz),
1.39–1.12 (3 H, m).
13C NMR (CDCl3, 101 MHz): δ = 148.6, 138.0, 129.1, 127.5, 127.1,
126.9, 125.1, 124.9, 68.1, 33.4, 26.1, 22.7.
The syntheses of the precursor ketones and oximes 6a–e are de-
scribed in the Supporting Information.
MS (EI): m/z = 267 [MH – OH], 251, 208, 182, 159.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

G
J. Davies et al.
Paper
Synthesis
HRMS (HESI): m/z [M + H]+ calcd for C18H22NO: 268.1696; found:
tert-Butyl 4-[Hydroxy(phenyl)amino]-4-methylpiperidine-1-
268.1699.
carboxylate (3g)
Following GP1, 1-N-Boc-4-methylpiperidine-4-carboxylic acid (1g;
49 mg, 0.2 mmol) gave 3g (50 mg, 82%) as a brown oil, purified by
column chromatography (CH2Cl2 → CH2Cl2/MeOH 99:1.)
N-[(1r,3s,5R,7S)-3-Chloroadamantan-1-yl]-N-phenylhydroxyl-
amine (3d)
Following GP1, 3-chloroadamantane-1-carboxylic acid (1d; 43 mg,
0.2 mmol) gave 3d (50 mg, 90%) as a brown solid, purified by column
chromatography (pentane/CH2Cl2 1:1).
IR (film): 3390, 2973, 2929, 1692, 1669, 1596, 1486, 1425, 1391,
1366, 1348, 1279, 1262, 1245, 1153, 1125, 1092, 1026 cm–1
.
1H NMR (CDCl3, 400 MHz): δ (rotamers) = 7.31–7.21 (4 H, m), 7.19–
7.11 (1 H, m), 3.78 (2 H, br s), 3.18–3.04 (2 H, m), 1.94–1.74 (2 H, m,),
1.57–1.37 (11 H, m), 1.09 (3 H, s).
IR (film): 2913, 2859, 1595, 1487, 1450, 1349, 1328, 1303, 1204,
1154, 1074 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 7.25 (2 H, t, J = 7.5 Hz), 7.17 (2 H, d,
J = 7.7 Hz), 7.13 (1 H, t, J = 7.2 Hz), 6.93 (1 H, br s), 2.21 (1 H, br s), 1.97
(4 H, q, J = 12.0 Hz), 1.72 (2 H, d, J = 11.7 Hz), 1.68 (2 H, q, J = 11.7 Hz),
1.58–1.37 (2 H, m).
13C NMR (CDCl3, 101 MHz): δ = 147.4, 127.7, 125.7, 124.8, 68.5, 63.4,
47.8, 46.7, 37.2, 34.5, 31.5.
13C NMR (CDCl3, 101 MHz): δ (rotamers) = 154.9, 148.6, 127.7, 125.5,
124.8, 79.4, 61.2, 34.8, 31.0, 28.5, 17.3.
MS (EI): m/z = 290 [MH – OH]+, 233, 189, 141.
HRMS (HESI): m/z [M + H]+ calcd for C17H27N2O3: 307.2016; found:
307.2018.
MS (EI): m/z = 261 [MH – OH], 227 (MH – OH – Cl), 204, 170, 133.
HRMS (HESI): m/z [M + H]+ calcd for C16H21NO: 278.1306; found:
N-[(3s,5s,7s)-Adamantan-1-yl]-N-(4-methoxyphenyl)hydroxyl-
amine (3j)
278.1304.
Following GP1, 1-adamantanecarboxylic acid (1a; 36 mg, 0.2 mmol)
gave 3j (32 mg, 59%) as a red solid, purified by column chromatogra-
phy (CH2Cl2 → CH2Cl2/MeOH 99.5:0.5).
N-(2-Methylbut-3-en-2-yl)-N-phenylhydroxylamine (3e)
Following GP1, 2,2-dimethylpent-4-enoic acid (1e; 26 mg, 0.2 mmol)
gave 3e (21 mg, 54%) as an orange solid, purified by column chroma-
tography (CH2Cl2).
IR (film): 2905, 2850, 1502, 1454, 1298, 1245, 1210, 1182, 1106, 1034
cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 7.11 (2 H, d, J = 8.2 Hz), 6.78 (2 H, d,
J = 8.2 Hz), 3.82 (3 H, s), 2.05 (3 H, s), 1.74 (6 H, s), 1.59 (6 H, q, J = 12.1
Hz).
IR (film): 3070, 2976, 2933, 1639, 1596, 1487, 1450, 1382, 1362,
1260, 1230, 1206, 1151, 1077, 1027 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 7.31–7.23 (4 H, m), 7.19–7.08 (1 H, m),
5.93 (1 H ddt, J = 15.8, 10.9, 7.4 Hz), 5.79 (1 H, br s), 5.08 (1 H, d, J = 1.4
Hz), 5.07–4.99 (1 H, m), 2.34 (2 H, d, J = 7.3 Hz), 1.08 (6 H, s).
13C NMR (CDCl3, 101 MHz): δ = 149.2, 135.6, 127.6, 125.2, 124.8,
117.2, 63.0, 43.6, 23.2.
13C NMR (CDCl3, 101 MHz): δ = 156.3, 140.1, 125.3, 111.8, 59.6, 54.7,
44.7, 37.8, 35.8, 35.34 30.0, 28.7.
MS (EI): m/z = 257 (MH – OH), 242 (M – OMe), 214, 200, 163, 135.
HRMS (ASAP): m/z [M]+ calcd for C17H23NO2: 273.1723; found:
273.1726.
MS (EI): m/z = 190 [M]+, 150, 133, 109.
HRMS (HESI): m/z [M + Na]+ calcd for C12H17NONa: 213.1124; found:
N-[(3s,5s,7s)-Adamantan-1-yl]-N-(o-tolyl)hydroxylamine (3k)
213.1125.
Following GP1, 1-adamantanecarboxylic acid (1a; 36 mg, 0.2 mmol)
gave 3k (28 mg, 55%) as a red solid, purified by column chromatogra-
phy (pentane/CH2Cl2 3:1 → 1:1).
tert-Butyl 3-[Hydroxy(phenyl)amino]-3-methylpiperidine-1-
carboxylate (3f)
IR (film): 2905, 2850, 1487, 1452, 1356, 1307, 1103, 1080 cm–1
.
Following GP1, 1-N-Boc-3-methylpiperidine-3-carboxylic acid (1f; 49
mg, 0.2 mmol) gave 3f (34 mg, 56%) as a brown solid, purified by col-
umn chromatography (CH2Cl2).
1H NMR (CDCl3, 400 MHz): δ = 7.48 (1 H, d, J = 8.0 Hz), 7.18 (1 H, t,
J = 7.5 Hz), 7.14 (1 H, d, J = 7.3 Hz), 7.08 (1 H, t, J = 7.3 Hz), 5.11 (1 H, br
s), 2.32 (3 H, s), 2.06 (3 H, s, br), 1.83 (6 H, br s).
IR (film): 3350, 2975, 2359, 1692, 1661, 1597, 1488, 1453, 1425,
13C NMR (CDCl3, 101 MHz): δ = 147.1, 135.1, 130.1, 127.0, 125.6,
125.3, 61.5, 38.2, 36.7, 29.5, 19.1.
1392, 1365, 1284, 1161, 1087 cm–1
.
1H NMR (CDCl3, 400 MHz): δ (rotamers) = 7.26 (4 H, m), 7.15 (1 H s),
7.12–7.07 (1 H, m), 4.35 (0.8 H, d, J = 13.8 Hz), 4.02 (0.8 H d, J = 12.9
Hz), 3.78–3.70 (0.2 H, m), 3.57 (0.2 H, br s), 3.32–3.17 (0.4 H, m), 2.88
(0.8 H, t, J = 12.2 Hz), 2.65 (0.8 H, d, J = 13.9 Hz), 2.15 (0.8 H, q, J = 12.2
Hz), 1.93 (0.2 H, br s), 1.68 (1.2 H, d, J = 13.3 Hz), 1.47 (9 H, s), 1.43–
1.28 (2 H, m), 0.94 (3 H, m).
13C NMR (CDCl3, 101 MHz): δ (rotamers) = 157.2 (M), 154.9 (m), 149.3
(M), 148.8 (m), 127.8 (M + m), 125.4 (m), 125.0 (M), 124.5 (m), 124.4
(M), 80.2 (M + m), 61.6 (m), 61.1 (M), 53.1 (M + m), 46.3 (M), 44.3 (m),
34.9 (M), 34.4 (m), 28.6 (M + m), 21.7 (M), 21.6 (m), 17.3 (M), 16.7
(m).
MS (EI): m/z = 257 [M]+, 241, 184, 135.
HRMS (ASAP): m/z [M + H]+ calcd for C17H24NO: 258.1852; found:
258.1845.
N-[(3s,5s,7s)-Adamantan-1-yl]-N-[3-(trifluoromethyl)phenyl]-
hydroxylamine (3l)
Following GP1, 1-adamantanecarboxylic acid (1a; 36 mg, 0.2 mmol)
gave 3l (24 mg, 39%) as an orange solid, purified by column chroma-
tography (pentane/CH2Cl2 2:1 → 1:1).
IR (film): 2907, 2853, 1439, 1325, 1306, 1164, 1068, 1123, 1094, 1068
cm–1
.
MS (EI): m/z = 290 [MH – OH], 217, 190, 160, 132.
1H NMR (CDCl3, 400 MHz): δ = 7.41 (1 H, s), 7.30 (4 H, m), 6.55 (1 H, br
s), 2.08 (3 H, br s), 1.75 (6 H, s), 1.63 (3 H, d, J = 11.6 Hz), 1.55 (3 H, d,
J = 11.5 Hz).
HRMS (HESI): m/z [M + H]+ calcd for C17H27N2O3: 307.2016; found:
307.2016.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

H
J. Davies et al.
Paper
Synthesis
13C NMR (CDCl3, 101 MHz): δ = 148.5, 129.8 (q, J = 31.9, 31.3 Hz),
127.9, 127.7, 124.0 (q, J = 273.1 Hz), 121.7, 121.4, 60.8, 38.4, 36.4,
29.3.
19F NMR (CDCl3, 376 MHz): δ = –62.5.
MS (EI): m/z = 311 [M]+, 295, 275, 238, 135.
1H NMR (CDCl3, 400 MHz): δ (diastereomers) = 7.24 (4 H, m), 7.13 (1
H, t, J = 6.9 Hz), 5.63 (0.2 H, d), 5.55 (0.8 H, s), 3.23 (1 H, dd, J = 10.6,
5.6 Hz), 2.79 (1 H, dt, J = 13.5, 3.5 Hz), 2.16–1.98 (2 H, m), 1.86–1.72 (2
H, m), 1.74–1.55 (8 H, m), 1.49–1.32 (5 H, m), 1.33 (3 H, s), 1.12 (7 H,
m), 1.09 (3 H, s), 1.01 (3 H, s), 0.95 (2 H, m), 0.86–0.68 (6 H, m).
13C NMR (CDCl3, 126 MHz): δ (diastereomers) = 199.8 (m), 199.7 (M),
169.8 (m), 168.8 (M), 149.4 (m), 147.7 (M), 127.8 (M), 127.7 (m),
127.3 (m), 127.1 (M), 125.0 (M), 124.4 (M + m), 123.5 (m), 78.3 (m),
78.2 (M), 63.3 (M), 61.8 (m), 61.6 (m), 61.2 (M), 54.5 (m), 54.4 (M),
47.4 (M), 45.8 (m), 44.8 (M + m), 42.9 (m), 42.7 (M), 41.4 (m), 39.3
(M), 38.7 (M + m), 38.6 (M + m), 36.6 (M + m), 36.3 (M), 35.4 (m), 32.5
(m), 32.3 (M), 32.2 (M + m), 31.7 (M), 31.2 (m), 29.1 (M), 28.1 (m),
27.8 (M + m), 27.7 (M + m), 27.6 (M + m), 26.8 (M), 26.4 (m), 26.0 (m),
25.8 (M), 22.9 (M), 22.8 (m), 18.2 (M), 17.0 (M + m), 16.4 (m), 15.8 (M
+ m), 15.1 (M + m).
HRMS (ASAP): m/z [M + H]+ calcd for C17H21F3NO: 312.1570; found:
312.1566.
N-[5-(2,5-Dimethylphenoxy)-2-methylpentan-2-yl]-N-phenyl-
hydroxylamine (3m)
Following GP1, gemfibrozil (1j; 50 mg, 0.2 mmol) gave 3m (42 mg,
68%) as a brown solid, purified by column chromatography (CH2Cl2).
IR (film): 2923, 1615, 1585, 1508, 1486, 1451, 1413, 1384, 1361,
1284, 1264, 1208, 1156, 1129, 1077, 1046, 1002 cm–1
.
MS (EI): m/z = 515 (M – OH2), 424 (M–H – NOHPh), 257, 216, 175,
135, 91.
HRMS (ASAP): m/z [M + H]+ calcd for C35H52NO3: 534.3942; found:
534.3949.
1H NMR (CDCl3, 400 MHz): δ = 7.26–7.21 (4 H, m), 7.15–7.07 (1 H, m),
7.00 (1 H, d, J = 7.4 Hz), 6.66 (1 H, d, J = 7.4 Hz), 6.60 (1 H, br s), 3.86 (2
H, t, J = 6.3 Hz), 2.32 (3 H, s), 2.16 (3 H, s), 1.95–1.77 (2 H, m), 1.78–
1.62 (2 H, m), 1.08 (6 H, s).
13C NMR (CDCl3, 101 MHz): δ = 157.0, 149.3, 136.4, 130.3, 127.6,
125.1, 124.7, 123.5, 120.6, 112.1, 68.3, 62.8, 35.6, 24.5, 23.0, 21.4,
15.8.
Hydroxylamines 7; General Procedure 2 (GP2)
A dry tube equipped with a stirring bar was charged with the carbox-
ylic acid 6a–d (0.1 mmol, 1.0 equiv), 2a (2.0 mg, 5 μmol, 5 mol%), Cs2-
CO3 (33 mg, 0.1 mmol, 1.0 equiv), and the requisite nitrosoarene (0.11
mmol, 1.1 equiv). The tube was capped with a Supelco aluminum
crimp seal with septum (PTFE/butyl) and it was evacuated and re-
filled with N2(3 ×). CH2Cl2 (anhydrous and degassed by bubbling
through with N2 for 20 min) (2.0 mL) was added. The N2 inlet was
then removed and the cap sealed with parafilm. The mixture was
stirred at r.t. for 1 h in front of blue LEDs. The tube was opened to air
and the mixture was diluted with CH2Cl2 (5 mL) and brine (5 mL). The
layers were separated and the aqueous layer was extracted with
CH2Cl2 (3 × 5 mL). The combined organic layers were dried (MgSO4),
filtered, and evaporated. Purification by column chromatography on
silica gel gave 7a–h.
MS (EI): m/z = 296 [M – OH], 282, 204, 160, 135.
HRMS (HESI): m/z [M + Na]+ calcd for C20H26NO2Na : 335.1856; found:
335.1860.
N-[(4aS,6aS,6bR,8aS,12aS,12bR,14bS)-2,2,6a,6b,9,9,12a-Hep-
tamethyl-1,3,4,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octa-
decahydropicen-4a(2H)-yl)-N-phenylhydroxylamine (3n)
Following GP1, oleanoic acid (1k; 91 mg, 0.2 mmol) gave 3n (36 mg,
35%) as a red solid, purified by column chromatography (CH2Cl2).
IR (film): 2945, 1486, 1463, 1386, 1364, 1263, 1028 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 7.42–7.33 (2 H, d, J = 7.7 Hz), 7.26 (2 H,
t, J = 7.7 Hz), 7.08 (1 H, t, J = 7.3 Hz), 5.21 (1 H, t, J = 3.4 Hz), 4.76 (1 H,
br s), 3.32–3.13 (1 H, m), 2.49 (1 H, d, J = 13.0 Hz), 2.26–2.15 (1 H, m),
2.16–2.04 (1 H, m), 2.05–1.88 (2 H, m), 1.82–1.69 (2 H, m), 1.68–1.54
(7 H, m), 1.53–1.46 (2 H, m), 1.45–1.40 (2 H, m), 1.39–1.29 (2 H, m),
1.28–1.24 (2 H, m), 1.21 (3 H, s), 1.17–1.09 (2 H, m), 1.05 (3 H, s), 1.02
(3 H, s), 0.96 (3 H, s), 0.83 (3 H, s), 0.81 (3 H, s), 0.62 (3 H, s).
13C NMR (CDCl3, 101 MHz): δ = 149.6, 146.2, 127.5, 124.3, 124.2,
122.5, 79.1, 65.4, 55.3, 53.5, 48.3, 48.0, 43.0, 42.0, 39.6, 38.8, 38.4,
37.2, 37.1, 35.4, 32.6, 32.8, 30.8, 28.3, 27.3, 26.6, 26.4, 24.4, 23.9, 23.7,
23.6, 18.4, 17.6, 15.7, 15.3.
N-Phenyl-N-[2-(5-phenyl-3,4-dihydro-2H-pyrrol-2-yl)propan-2-
yl]hydroxylamine (7a)
Following GP2, 6a (58 mg, 0.2 mmol) gave 7a (39 mg, 67%) as a brown
solid, purified by column chromatography (CH2Cl2 → CH2Cl2/MeOH
99.8:0.2).
IR (film): 3212, 2978, 1618, 1596, 1576, 1486, 1448, 1342, 1168, 1063
cm–1
.
1H NMR (CDCl3, 101 MHz): δ = 7.89 (2 H, dd, J = 8.0, 1.4 Hz), 7.49–7.39
(5 H, m), 7.30 (2 H, t, J = 7.9 Hz), 7.13 (1 H, t, J = 7.3 Hz), 4.37 (1 H, t,
J = 8.2 Hz), 3.04 (1 H, dddd, J = 16.8, 10.3, 3.0, 2.5 Hz), 2.83 (1 H, dtd,
J = 11.6, 9.5, 2.3 Hz), 2.07 (1 H, dddd, J = 11.3, 9.8, 8.0, 3.3 Hz), 1.85–
1.74 (1 H, (m), 1.27 (3 H, s), 1.11 (3 H, s).
MS (EI): m/z = 410, 406, 395, 392.
HRMS (HESI): m/z [M + H]+ calcd for C35H54NO2: 520.4149; found:
520.4157.
13C NMR (CDCl3, 101 MHz): δ = 173.3, 149.2, 133.5, 131.2, 128.7,
129.0, 127.8, 125.2, 125.0, 78.6, 65.1, 34.1, 25.4, 25.1, 18.2.
(2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-Hydroxy-2-[hydroxy
(phenyl)amino]-2,4a,6a,6b,9,9,12a-heptamethyl-
1,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,14b-octadecahydropi-
cen-13(2H)-one (3o)
MS (EI): m/z = 278 (MH – OH), 170, 144, 134, 77.
HRMS (APCI): m/z [M + H]+ calcd for C19H22N2O: 294.1727; found:
Following GP1, enoxolone (glycyrrhetinic acid, 1l; 91 mg, 0.2 mmol)
gave 3o (82 mg, 77%) as an orange solid, purified by column chroma-
tography (CH2Cl2 → CH2Cl2/MeOH 98:2); dr = 5:1.
294.1725.
N-Phenyl-N-{2-[5-(pyridin-3-yl)-3,4-dihydro-2H-pyrrol-2-yl]-
IR (film): 3351, 2927, 1651, 1486, 1455, 1386, 1260, 1206, 1112, 1037
propan-2-yl}hydroxylamine (7b)
cm–1
.
Following GP2, 6b (29 mg, 0.1 mmol) gave 7b (15 mg, 51%) as a brown
oil, purified by column chromatography (CH2Cl2 → CH2Cl2/MeOH
99.5:0.5).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

I
J. Davies et al.
Paper
Synthesis
IR (film): 2979, 1620, 1594, 1485, 1413, 1377, 1358, 1342, 1168,
1071, 1026 cm–1
IR (film): 3285, 2970, 1615, 1502, 1463, 1447, 1342, 1296, 1245,
.
1160, 1033 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 9.00 (1 H, d, J = 2.2 Hz), 8.70 (1 H, dd,
J = 4.8, 1.7 Hz), 8.25 (1 H, dt, J = 7.9, 2.0 Hz), 7.41–7.35 (3 H, m), 7.33–
7.24 (2 H, m), 7.15–7.10 (1 H, m), 4.43 (1 H, tt, J = 8.2, 2.4 Hz), 3.05 (1
H, dddd, J = 17.3, 10.4, 3.5, 2.3 Hz), 2.93–2.79 (1 H, m), 2.11 (1 H,
dddd, J = 13.2, 9.8, 8.0, 3.5 Hz), 1.87 (1 H, ddt, J = 13.1, 10.3, 8.6 Hz),
1.24 (3 H, s), 1.08 (3 H, s).
1H NMR (CDCl3, 400 MHz): δ = 7.91 (2 H, d, J = 6.8 Hz), 7.52–7.44 (3 H,
m), 7.37 (2 H, d, J = 8.8 Hz), 6.86 (2 H, d, J = 8.8 Hz), 4.41 (1 H, t, J = 8.1
Hz), 3.82 (3 H, s), 3.06 (1 H, ddt, J = 16.4, 10.4, 2.8 Hz), 2.92–2.79 (1 H,
m), 2.15–2.03 (1 H, m), 1.90–1.73 (1 H, m), 1.26 (3 H, s), 1.08 (3 H, s).
13C NMR (CDCl3, 101 MHz): δ = 173.3, 157.1, 142.0, 133.5, 131.1,
128.6, 128.0, 126.5, 113.0, 78.5, 65.1, 55.5, 34.2, 25.3, 24.7, 18.0.
13C NMR (CDCl3, 101 MHz): δ = 171.1, 151.8, 149.3, 149.1, 135.0,
129.4, 127.8, 125.1, 125.1, 123.6, 79.0, 65.3, 34.2, 25.1, 23.9, 18.3.
MS (EI): m/z = 308 (MH – OH), 265, 164, 115, 91.
HRMS (ASAP): m/z [M]+ calcd for C20H24N2O2: 324.1832; found:
324.1836.
MS (EI): m/z = 279 (MH – OH), 236, 171, 147, 134, 118, 91, 77.
HRMS (ASAP): m/z [M + H]+ calcd for C18H22N3O: 296.1757; found:
296.1758.
N-(4-Chlorophenyl)-N-[2-(5-phenyl-3,4-dihydro-2H-pyrrol-2-
yl)propan-2-yl]hydroxylamine (7f)
Methyl 2-{2-[Hydroxy(phenyl)amino]propan-2-yl}-3,4-dihydro-
2H-pyrrole-5-carboxylate (7c)
Following GP2, 6a (29 mg, 0.1 mmol) gave 7f (23 mg, 70%) as a brown
oil, purified by column chromatography (CH2Cl2 → CH2Cl2/MeOH
99.5:0.5).
Following GP2, 6c (54 mg, 0.2 mmol) gave 7c (20 mg, 36%) as a brown
oil, purified by column chromatography (CH2Cl2 → CH2Cl2/MeOH
99.5:0.5).
IR (film): 2952, 1723, 1596, 1488, 1439, 1325, 1243, 1167, 1111 cm–1
1H NMR (CDCl3, 400 MHz): δ = 7.29 (4 H, m), 7.13 (1 H, t, J = 6.7 Hz),
6.45 (1 H, br s), 4.55 (1 H, tt, J = 8.2, 2.8 Hz), 3.88 (3 H, s), 2.92 (1 H,
ddt, J = 17.7, 10.4, 3.4 Hz), 2.83–2.69 (1 H, m), 2.10–2.00 (1 H, m), 1.94
(1 H, dq, J = 13.4, 8.6 Hz), 1.23 (3 H, s), 0.96 (3 H, s).
IR (film): 3184, 2977, 1618, 1576, 1482, 1448, 1379, 1360, 1343,
1169, 1090, 1011 cm–1
.
.
1H NMR (CDCl3, 400 MHz): δ = 9.27 (1 H, br s), 7.87 (2 H, d, J = 7.4 Hz),
7.46 (3 H, m), 7.33 (2 H, d, J = 8.6 Hz), 7.25 (2 H, d, J = 8.7 Hz), 4.33 (1
H, t, J = 6.8 Hz), 3.09–2.99 (1 H, m), 2.84 (1 H, m), 2.12–2.03 (1 H, m),
1.84–1.72 (1 H, m), 1.22 (3 H, s), 1.10 (3 H, s).
13C NMR (CDCl3, 101 MHz): δ = 173.7, 147.9, 133.4, 131.4, 130.2,
128.8, 128.1, 127.9, 126.5, 78.7 (br), 65.3, 34.2 (br), 25.4, 25.0, 18.0.
13C NMR (CDCl3, 101 MHz): δ = 167.8, 163.2, 149.0, 127.8, 125.3,
125.1, 124.0, 80.5, 65.5, 52.8, 35.6, 24.3, 21.5, 19.2.
MS (EI): m/z = 312 (MH – OH), 269, 169, 145, 91.
MS (EI): m/z = 260 (MH – OH), 185, 134, 77.
HRMS (ASAP): m/z [M + H]+ calcd for C15H21N2O3: 277.1547; found:
HRMS (HESI): m/z [M + Na]+ calcd for C19H21ClN2ONa: 351.1235;
found: 351.1241.
277.1547.
N-[2-(5-Phenyl-3,4-dihydro-2H-pyrrol-2-yl)propan-2-yl]-N-[3-
Methyl 2-[Hydroxy(phenyl)amino]-2-(5-phenyl-3,4-dihydro-2H-
(trifluoromethyl)phenyl]hydroxylamine (7g)
pyrrol-2-yl)acetate (7d)
Following GP2, 6a (29 mg, 0.1 mmol) gave 7g (13 mg, 36%) as a brown
Following GP2, 6d (34 mg, 0.2 mmol) gave 7d (29 mg, 45%) as a brown
oil, purified by column chromatography (CH2Cl2 → CH2Cl2/MeOH
99.5:0.5); dr = 3:2.
oil, purified by column chromatography (CH2Cl2).
IR (film): 2979, 1616, 1576, 1439, 1381, 1362, 1326, 1281, 1163,
1119, 1095, 1068 cm–1
.
IR (film): 3059, 2950, 1737, 1614, 1597, 1578, 1520, 1489, 1447,
1H NMR (CDCl3, 400 MHz): δ = 7.88 (2 H, d, J = 7.4 Hz), 7.65 (1 H, s),
7.57 (1 H, d, J = 7.4 Hz), 7.47 (3 H, m), 7.39 (2 H, m), 4.34 (1 H, br s),
3.11–3.01 (1 H, m), 2.86 (1 H, m), 2.15–2.06 (1 H, m), 1.79 (1 H, m),
1.23 (3 H, s), 1.13 (3 H, s).
13C NMR (CDCl3, 101 MHz): δ = 173.9, 145.0, 133.3, 131.5, 130.3 (q,
J = 32.1 Hz), 128.8, 128.4, 128.2, 128.1, 124.3 (q, J = 272.7 Hz), 121.8
(q, J = 3.8 Hz), 121.6 (q, J = 3.7 Hz), 79.0, 65.6, 34.3, 25.3, 24.8, 17.8.
1434, 1342, 1259, 1197, 1155 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 7.85–7.79 (2 H, m), 7.48–7.36 (4 H, m),
7.32–7.27 (1 H, m), 7.14 (0.8 H, d, J = 7.9 Hz), 7.09 (1.2 H, d, J = 7.8 Hz),
7.00–6.87 (1 H, m), 4.97–4.88 (1 H, m), 4.48 (0.6 H, d, J = 6.4 Hz), 4.33
(0.4 H, d, J = 7.4 Hz), 3.72 (1.2 H, s), 3.71 (1.8 H, s), 3.11 (1 H, dddd,
J = 19.8, 10.2, 4.2, 2.2 Hz), 3.03–2.92 (1 H, m), 2.40–2.31 (1 H, m),
2.09–1.96 (1 H, m).
13C NMR (CDCl3, 101 MHz): δ = 174.7 (M), 174.3 (m), 171.8 (m), 171.1
(M), 151.2 (M), 150.9 (m), 134.0 (m), 133.8 (M), 130.9 (M), 130.8 (m),
129.0 (m), 128.8 (M), 128.5 (M), 128.4 (m), 127.9 (M), 127.9 (m),
121.8 (m), 121.5 (M), 115.3 (M + m), 72.9 (m), 72.2 (M), 71.6 (M), 70.7
(m), 52.1 (M), 52.0 (m), 35.4 (M), 35.0 (m), 26.7 (M), 26.5 (m).
19F NMR (CDCl3, 376 MHz): δ = –63.9.
MS (EI): m/z = 346 (MH – OH), 345, 327, 202, 186, 145, 91.
HRMS (ASAP): m/z [M + H]+ calcd for C20H22F3N2O: 363.1679; found:
363.1679.
N-[2-(5-Phenyl-3,4-dihydro-2H-pyrrol-2-yl)propan-2-yl]-N-
(o-tolyl)hydroxylamine (7h)
MS (EI): m/z = 308 (MH – OH), 249, 145, 104, 77.
HRMS (APCI): m/z [M + H]+ calcd for C19H21N2O3: 325.1547; found:
325.1534.
Following GP2, 6a (29 mg, 0.1 mmol) gave 7h (17 mg, 55%) as a brown
solid, purified by column chromatography (CH2Cl2 → CH2Cl2/MeOH
99.5:0.5).
N-(4-Methoxyphenyl)-N-[2-(5-phenyl-3,4-dihydro-2H-pyrrol-2-
yl)propan-2-yl]hydroxylamine (7e)
IR (film): 2979, 1616, 1576, 1487, 1447, 1376, 1342, 1168, 1063, 1027
cm–1
.
Following GP2, 6a (29 mg, 0.1 mmol) gave 7e (18 mg, 56%) as a brown
oil, purified by column chromatography (CH2Cl2 → CH2Cl2/MeOH
99.5:0.5).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J

J
J. Davies et al.
Paper
Synthesis
1H NMR (CDCl3, 400 MHz): δ = 7.89 (2 H, d, J = 6.9 Hz), 7.70 (1 H, d,
J = 7.9 Hz), 7.45 (3 H, m), 7.19 (2 H, d, J = 8.1 Hz), 7.10 (1 H, t, J = 7.3
Hz), 4.62 (1 H, t, J = 8.1 Hz), 3.06 (1 H, ddt, J = 16.2, 10.2, 2.7 Hz), 2.95–
2.85 (1 H, m), 2.45 (3 H, s), 2.20–2.06 (1 H, m), 1.93–1.81 (1 H, m),
1.27 (3 H, s), 0.95 (3 H, s).
13C NMR (CDCl3, 101 MHz): δ = 173.2, 147.9, 135.7, 133.7, 131.0,
130.3, 128.6, 128.0, 126.7, 125.7, 80.1 (br), 66.2, 34.4, 25.2, 22.4, 19.2,
17.1 (br).
Chem. Int. Ed. 2017, 56, 13361. (c) Davies, J.; Svejstrup, T. D.;
Reina, D. F.; Sheikh, N. S.; Leonori, D. J. Am. Chem. Soc. 2016, 138,
8092. (d) Davies, J.; Booth, S. G.; Essafi, S.; Dryfe, R. W. A.;
Leonori, D. Angew. Chem. Int. Ed. 2015, 54, 14017.
(6) (a) Yamamoto, H.; Kawasaki, M. Bull. Chem. Soc. Jpn. 2007, 80,
595. (b) Yamamoto, H.; Momiyama, N. Chem. Commun. 2005, 7
3514. (c) Zuman, P.; Shah, B. Chem. Rev. 1994, 94, 1621.
(7) (a) Kanegawa, S.; Karasawa, S.; Maeyama, M.; Nakano, M.; Koga,
N. J. Am. Chem. Soc. 2008, 130, 3079. (b) Forrester, A. R.;
Fullerton, J. D.; McConnachie, G. J. Chem. Soc., Perkin Trans. 1
1983, 1759. (c) Dhayalan, V.; Sämann, C.; Knochel, P. Chem.
Commun 2015, 51, 3239. (d) Li, Y.; Chakrabarty, S.; Studer, A.
Angew. Chem. Int. Ed. 2015, 54, 3587.
MS (EI): m/z = 292 (MH – OH), 186, 148, 115, 91.
HRMS (ASAP): m/z [M + H]+ calcd for C20H24N2O: 308.1883; found:
308.1887.
(8) (a) Momiyama, N.; Yamamoto, H. Org. Lett. 2002, 4, 3579.
(b) Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc. 2003, 125,
6038. (c) Payette, J. N.; Yamamoto, H. J. Am. Chem. Soc. 2008,
130, 12276. (d) Yanagisawa, A.; Izumib, Y.; Takeshita, S. Synlett
2009, 716. (e) Yanagisawa, A.; Takeshita, S.; Izumi, Y.; Yoshida,
K. J. Am. Chem. Soc. 2010, 132, 5328.
Funding Information
D.L. thanks the European Union for a Career Integration Grant
(PCIG13-GA-2013-631556) and EPSRC for
a
research grant
(EP/P004997/1).
E
u
or
p
e
a
n
Unoin
o
f
r
a
C
a
erer
n
I
et
g
oriatn
Grant
P(
C
G
I
1
3-GA-2
0
1
3-6
3
1
5
5
6
E)
P
S
R
C
E(
P
P/
0
0
4
9
9
7
1/
)
(9) (a) Bøgevig, A.; Sundén, H.; Córdova, A. Angew. Chem. Int. Ed.
2004, 43, 1109. (b) Kano, T.; Ueda, M.; Takai, J.; Maruoka, K.
J. Am. Chem. Soc. 2006, 128, 6046. (c) Palomo, C.; Vera, S.; Velilla,
I.; Mielgo, A.; Gómez-Bengoa, E. Angew. Chem. Int. Ed. 2007, 46,
8054. (d) Shen, K.; Liu, X.; Wang, G.; Lin, L.; Feng, X. Angew.
Chem. Int. Ed. 2011, 50, 4684.
Acknowledgment
L. A. thanks Eli Lilly for a Ph.D. CASE Award. M. A. A. and N. S. S. thank
the Department of Chemistry, King Faisal University, Saudi Arabia for
the support.
(10) Wong, F. T.; Patra, P. K.; Seayad, J.; Zhang, Y.; Ying, J. Y. Org. Lett.
2008, 10, 2333.
(11) Ayhan, P.; Demir, A. S. Adv. Synth. Catal. 2011, 353, 624.
(12) (a) Gingras, B. A.; Water, W. A. J. Chem. Soc. 1954, 1920.
(b) Inamoto, N.; Simamura, O. J. Org. Chem. 1958, 23, 408.
(c) Hosogai, T.; Inamoto, N.; Okazaki, R. J. Chem. Soc., Chem.
Commun. 1971, 3399. (d) Corey, E. J.; Gross, A. W. J. Org. Chem.
1985, 50, 5391. (e) Gui, J.; Pan, C.-M.; Jin, Y.; Qin, T.; Lo, J. C.; Lee,
B. J.; Spergel, S. H.; Mertzman, M. E.; Pitts, W. J.; Cruz, T. E. L.;
Schmidt, M. A.; Darvatkar, N.; Natarajan, S. R.; Baran, P. S.
Science 2015, 348, 886.
(13) (a) Fisher, D. J.; Shaum, J. B.; Mills, C. L.; Read de Alaniz, J. Org.
Lett. 2016, 18, 5074. (b) Fisher, D. J.; Burnett, G. L.; Velasco, R.;
Read de Alaniz, J. J. Am. Chem. Soc. 2015, 137, 11614.
(14) van der Werf, A.; Hribersek, M.; Selander, N. Org. Lett. 2017, 19,
2374.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591744.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
References
(1) (a) The Chemistry of Hydroxylamines, Oximes and Hydroxamic
Acids; Rappoport, Z.; Liebman, J. F., Eds.; Wiley: Chichester,
2008. (b) Ashani, Y.; Silman, I. Hydroxylamines and Oximes: Bio-
logical Properties and Potential Uses as Therapeutic Agents, In
The Chemistry of Hydroxylamines, Oximes and Hydroxamic Acids;
Rappoport, Z.; Liebman, J. F., Eds.; Wiley: Chichester, 2008,
Chap. 13. (c) Race, N. J.; Hazelden, I. R.; Faulkner, A.; Bower, J. F.
Chem. Sci. 2017, 8, 5248. (d) Gao, H.; Zhou, Z.; Kwon, D.-H.;
Coombs, J.; Jones, S.; Behnke, N. E.; Ess, D. H.; Kürti, L. Nat. Chem.
2017, 9, 681.
(15) Studer, A. Chem. Eur. J. 2001, 7, 1159.
(16) See SI for more information.
(17) Vleeschouwer, F. D.; Speybroeck, V. V.; Waroquier, M.;
Geerlings, P.; Proft, F. D. Org. Lett. 2007, 9, 2721.
(18) (a) Weber, M.; Fischer, H. Helv. Chim. Acta 1998, 81, 770.
(b) Wong, M. W.; Pross, A.; Radom, L. J. Am. Chem. Soc. 1994,
116, 6284.
(19) (a) Nicewicz, D. A.; Nguyen, T. M. ACS Catal. 2014, 4, 355.
(b) Margrey, K. A.; Nicewicz, D. A. Acc. Chem. Res. 2016, 49,
1997. (c) Fukuzumi, S.; Ohkubo, K. Org. Biomol. Chem. 2014, 12,
6059.
(20) (a) Pitts, D. D.; Ghorbani, C. R.; Harry, S. A.; Capilato, J. N.;
Siegler, M. A.; Lectka, T. Chem. Sci. 2017, 8, 6918. (b) Pitts, C. R.;
Bume, D. D.; Harry, S. A.; Siegler, M. A.; Lectka, T. J. Am. Chem.
Soc. 2017, 139, 2208.
(2) Studer, A.; Curran, D. P. Angew. Chem. Int. Ed. 2015, 55, 58.
(3) (a) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev.
2013, 113, 5322. (b) Skubi, K. L.; Blum, T. R.; Yoon, T. P. Chem.
Rev. 2016, 116, 10035. (c) Romero, N. A.; Nicewicz, D. A. Chem.
Rev. 2016, 116, 10075. (d) Hopkinson, M. N.; Sahoo, B.; Li, J.-L.;
Glorius, F. Chem. Eur. J. 2014, 20, 3874.
(4) Xuan, J.; Zhang, Z.-G.; Xiao, W.-J. Angew. Chem. Int. Ed. 2015, 54,
15632.
(5) (a) Reina, D. F.; Duncey, E. M.; Morcillo, S. P.; Svejstrup, T. D.;
Popescu, M. V.; Douglas, J. J.; Sheikh, N. S.; Leonori, D. Eur. J. Org.
Chem. 2017, 2108. (b) Davies, J.; Sheikh, N. S.; Leonori, D. Angew.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–J