Reductive cyclizations of nitroarenes to hydroxamic acids by visible light photoredox catalysis

Article abstract of DOI:10.1055/s-0033-1338419

We have developed a photocatalytic reduction of nitroarenes as an efficient, chemoselective route to biologically important N-phenyl hydroxamic acid scaffolds. Optimal conditions call for 2.5 mol% of a ruthenium photocatalyst, visible light irradiation, and a dihydropyridine terminal reductant. Because of the mild nature of the visible light activation, functional groups that might be sensitive to other non-photochemical reduction methods are easily tolerated. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1338419

SPECIAL TOPIC
▌2699
sRpeecidal utopcictive Cyclizations of Nitroarenes to Hydroxamic Acids by Visible Light
Photoredox Catalysis
Photocatalytic Hydroxamic Acid Synthesis
Megan A. Cismesia, Michael A. Ischay, Tehshik P. Yoon*
Department of Chemistry, University of Wisconsin–Madison, 1101 University Avenue, Madison, WI 53706, USA
Fax +1(608)2654534; E-mail: tyoon@chem.wisc.edu
Received: 01.03.2013; Accepted: 17.03.2013
4 e–
reduction
Abstract: We have developed a photocatalytic reduction of ni-
troarenes as an efficient, chemoselective route to biologically im-
portant N-phenyl hydroxamic acid scaffolds. Optimal conditions
call for 2.5 mol% of a ruthenium photocatalyst, visible light irradi-
ation, and a dihydropyridine terminal reductant. Because of the mild
nature of the visible light activation, functional groups that might be
sensitive to other non-photochemical reduction methods are easily
tolerated.
CO2Me
CO2Me
NO2
1
NHOH
2
cyclization
hydroxamic acids
antimicrobial,
anticancer,
antipsychotic activity
Key words: electron transfer, heterocycles, hydroxamic acids, pho-
tochemistry, reduction
N
O
OH
3
Scheme 1 Preparation of hydroxamic acids by reduction and cycli-
zation of nitroarenes
Hydroxamic acids are high-affinity chelating ligands for a
wide range of metal cations.1 Many hydroxamic acid con-
taining secondary metabolites are produced naturally, and
they have important biological roles in a variety of con-
texts including microbial iron metabolism and endoge-
nous chemical defense in plants.2 In medicinal chemistry,
cyclic hydroxamic acids have been reported to possess an-
timicrobial and antifungal activity and have also been in-
vestigated as potential treatments for conditions ranging
from cancer to schizophrenia.3
properties of Ru(bpy)32+ and related transition-metal chro-
mophores in the visible light regime.7 Our efforts have led
to a wide range of cycloaddition reactions that are initiat-
ed by photocatalytic oxidation or reduction of alkenes;8
related efforts in other groups investigating photocatalytic
redox reactions of amines, arenes, and alkyl halides have
resulted in the development of a remarkable diversity of
synthetically useful transformations.9 As part of our ongo-
ing efforts to broaden the scope of reactions amenable to
visible light photocatalysis, we became interested in de-
signing a selective photocatalytic four-electron reduction
of nitroarenes to afford hydroxamic acids.
The most common strategies for the synthesis of cyclic
hydroxamic acids involve reduction of nitroarenes to the
corresponding hydroxylamines followed by intramolecu-
lar cyclization with a tethered acyl moiety (Scheme 1). A
variety of methods to achieve this transformation have
been reported, including those using stoichiometric zinc
or tin4 as well as palladium-5 or platinum-catalyzed6 par-
tial reduction. Many of these methods can be somewhat
problematic. First, the stoichiometric processes can gen-
erate metal-containing byproducts that complicate the iso-
lation and purification of these strong chelators. Second,
the strongly reducing conditions used in many of these re-
actions can be incompatible with sensitive, easily reduced
functional groups such as aryl halides. Finally, a signifi-
cant challenge in this approach to the synthesis of hy-
droxamic acids is to achieve selective four-electron
reduction of the nitroarene to the desired hydroxamic acid
without competitive six-electron reduction to the fully re-
duced quinolinone.
2+
The use of Ru(bpy)3 as a photocatalyst for the exhaus-
tive six-electron reduction of nitrobenzene to aniline has
been previously reported using hydrazine as the terminal
reductant.10 Similarly, the photocatalytic four-electron re-
duction of nitroalkenes to oximes has been accomplished
using EDTA as the terminal reductant.11 To the best of our
knowledge, the photocatalytic four-electron reduction of
nitrobenzene to a hydroxylamine or hydroxamic acid has
not previously been described.
Table 1 summarizes optimization and control experiments
for the photocatalytic reductive cyclization of nitroarene 1
to hydroxamic acid 3. We began by applying conditions
reported by Stephenson for reductive dehalogenation
reactions9b to this reduction. However, when 1 was irradi-
ated in the presence of formic acid, N,N-diisopropylethyl-
amine, and 2.5 mol% Ru(bpy)32+, we observed none of the
expected hydroxamic acid 3 and only a trace of the inter-
mediate hydroxylamine 2 (entry 1). In a screen of alter-
nate terminal reductants, we observed that while Hantzsch
ester 4 provided only a trace of reduction products (entry
2), the related diketone 5 resulted in good conversion of 1
Over the last several years, our laboratory, along with sev-
eral others, has been investigating the design of syntheti-
cally useful new reactions that exploit the photochemical
SYNTHESIS 2013, 45, 2699–2705
Advanced online publication: 24.04.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338419; Art ID: SS-2013-C0176-ST
© Georg Thieme Verlag Stuttgart · New York

2700
M. A. Cismesia et al.
SPECIAL TOPIC
into a mixture of hydroxylamine 2 and hydroxamic acid 3 However, treatment of the unpurified reaction mixture
(entry 3). We speculated that the Brønsted acid could be with di-tert-butyl dicarbonate and triethylamine resulted
responsible for the cyclization of 2 to 3; indeed, in the ab- in the formation of a protected hydroxamic acid that could
sence of an exogenous Brønsted acid additive, we ob- be easily purified by standard chromatographic meth-
served exclusive formation of 2 without any obvious ods.4c
change in the rate of the photoreduction process (entry 4).
Using these optimized conditions for production and pro-
The use of stronger acids, on the other hand, increased the
tection of hydroxamic acids, we conducted an exploration
yield of 3 (entries 5–7). Optimal results were obtained us-
of the scope of this process (Table 2). The reaction proved
ing camphorsulfonic acid, and we found that the stoichio-
to be relatively insensitive to electronic perturbation at
metry of this acid could be lowered to 0.1 equivalents
C7; both electron-donating and electron-withdrawing
without affecting the yield of the reaction (entry 8). Final-
substituents at this position provide similarly good yields
ly, control experiments verified the photocatalytic nature
of hydroxamic acids (entries 1–6). Importantly, we ob-
2+
of this reaction; in the absence of either Ru(bpy)3 or
served no reduction of potentially reducible functional
light, we observed no significant formation of 3 (entries 9
groups such as aryl bromides or nitriles (entries 5 and 6).
The identity of the C6 substituent had a more dramatic ef-
and 10).
fect. While electron-withdrawing groups at this position
had little impact (entry 7), the methoxy-substituted sub-
strate cleanly underwent over-reduction to the quinoli-
Table 1 Optimization Studies for Photocatalytic Hydroxamic Acid
Synthesis
EtO2C
CO2Et
MeOC
COMe
none. A similar effect of electron-donating substituents
was reported by McAllister,4c who proposed that the ac-
cessibility of an iminoquinone intermediate could be re-
sponsible for the ease of subsequent over-reduction
(Scheme 2). Changes to the tethering moiety were also
tolerated (entries 9–11), although either introducing a to-
syl-protected nitrogen (entry 10) or reducing the length of
the tether by one carbon (entry 11) resulted in slower cy-
clizations that necessitated stoichiometric acid. Finally,
N
H
4
N
H
5
2
Ru(bpy)3Cl2
(2.5 mol%)
visible light
+
CO2Me
reductant
NO2
(2.1 equiv)
N
O
1
acid, DMF, 16 h
OH
3
Table 2 Scope Studies for Hydroxamic Acid Synthesis
Entrya
Product
Yieldb (%)
Entry
Reductant Acid (equiv)
Yielda (%)
2
3
1
2
3
4
5
6
R = H
83
77
85
81
72
76
R = OMe
R = Me
R = CF3
R = CN
R = Br
1
2
i-Pr2NEt
HCO2H (1)
HCO2H (1)
HCO2H (1)
none
<5
0
0
4
5
5
5
5
5
5
5
5
<5
20
0
R
R
N
O
O
OBoc
3
50
71
52
0
4
7
8
R = F
R = OMe
79
0c
5
AcOH (1)
TFA (1)
25
84
89
88
<5
0
N
6
OBoc
X
N
7
CSA (1)
0
9
X = O
X = NTs
78
53
8
CSA (0.1)
CSA (0.1)
CSA (0.1)
0
10d
O
9b
10c
0
OBoc
0
O
11d
12d
64
58
N
a Yield determined by 1H NMR analysis.
OBoc
b Reaction conducted in the absence of Ru(bpy)3Cl2.
c Reaction conducted in the dark.
NHAc
N
O
On larger scales, isolation of pure hydroxamic acid 3
could easily be accomplished in good yields by recrystal-
lization. Chromatographic isolation of this material, how-
ever, proved to be more challenging; the mass recovery
was low, and the eluted product was deeply colored,
which we attributed to the ability of this strongly chelating
compound to leach metallic impurities from the silica gel.
OBoc
a Reactions conducted using Ru(bpy)3Cl2 (2.5 mol%), 5 (2.1 equiv),
CSA (0.1 equiv), unless otherwise noted.
b Values represent the averaged isolated yields from two reproducible
experiments.
c Quinolinone 10 was isolated in 54% yield (Scheme 2).
d Reaction conducted using Ru(bpy)3Cl2 (2.5 mol%), CSA (1 equiv).
Synthesis 2013, 45, 2699–2705
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Photocatalytic Hydroxamic Acid Synthesis
2701
these conditions tolerated an α-acetamido substituent (en- Thus, the easily handled O-Boc hydroxamic acid can be
try 12), which provided access to a privileged scaffold re- converted into these useful scaffolds with good efficiency.
ported to possess a range of biological properties.12
In conclusion, we have developed a mild photocatalytic
method for the reduction and cyclization of nitroarenes to
hydroxamic acids. This method provides access to a class
+ 4 e–
+ 4 H+
MeO
CO2Me
of biologically relevant scaffolds that should possess util-
ity in drug discovery efforts. In the context of our ongoing
studies of visible light induced organic reactions, this
study is significant because it shows that synthetically
useful transformations can be initiated by photoreduction
of nitroarenes. These results raise intriguing questions
concerning the precise mechanism of this process, includ-
ing the effect of the terminal reductant both of the effec-
tiveness of the reduction and the selectivity between four-
electron and six-electron reduction. Studies to further in-
terrogate this reaction and design new transformations ini-
tiated by reduction of nitro organics are subjects of
continuing interest in our laboratory.
NO2
– H2O
6
MeO
CO2Me
MeO+
CO2Me
+ H+
NH
OH
– H2O
NH
8
7
+ 2 e–
+ H+
MeO
MeO
CO2Me
N
O
NH2
H
9
10 54%
Scheme 2 Origin of over-reduction of 6
DMF, Et3N, and i-Pr2NEt were purified by distillation from CaH2
prior to use. Dihydropyridines 4 and 5 were prepared using known
methods.15 The syntheses of the nitroarene substrates are described
in the Supporting Information. All other reagents were purchased
from commercial sources and used without further purification.
Chromatography was performed with Purasil 60Å silica gel (230–
400 mesh). 1H and 13C NMR data for all previously uncharacterized
compounds were obtained using Varian Inova-500 spectrometers
and are referenced to TMS (δ = 0.00) and CDCl3 (δ = 77), respec-
tively. IR spectral data were obtained using a Bruker Vector 22
spectrometer (thin film, NaCl on NaCl). Melting points were ob-
tained using a Mel-Temp II (Laboratory Devices, Inc., USA) melt-
ing point apparatus. Mass spectrometry was performed with a
Micromass LCT (electrospray ionization, time-of-flight analyzer).
N-Hydroxyindoles have also received considerable atten-
tion as potential pharmacophores, and the methods for
their synthesis have been similar to those used for the
preparation of hydroxamic acids.13 Thus, we examined
the photocatalytic reduction of 11 under conditions iden-
tical to those optimized for reduction of 1. Indeed, hy-
droxyindole 12 could be isolated in 88% yield without O-
protection (Equation 1).
O
Ru(bpy)3Cl2
(2.5 mol%)
Ph
Photochemical Reactions; General Procedure
Ph
N
5, CSA, DMF
A soln of the appropriate nitroarene (1 equiv), Ru(bpy)3Cl2·6 H2O
(0.025 equiv), CSA (0.10 or 1.0 equiv), and dihydropyridine 5 (2.1,
3.0, or 4.0 equiv) in DMF (0.1 M) was placed in a sealed 25-mL
Schlenk flask. The soln was degassed using three freeze–pump–
thaw cycles and then irradiated using a household 20-W compact
fluorescent light bulb. After 16 h, the reaction was diluted with
EtOAc, then washed with 1 M HCl (2 ×). The aqueous phases were
OH
12 88%
NO2
11
Equation 1 Preparation of N-hydroxyindoles
Finally, the Boc protecting group can be cleaved in good
yield using previously reported conditions (Scheme 3).14 extracted with EtOAc, and the organic phases were combined and
washed with brine (1 ×), dried (MgSO4), and concentrated in vacuo.
Treatment of 13 with trifluoroacetic acid in dichlorometh-
ane reveals the unprotected hydroxamic acid 3 in 83%
yield. Alternatively, the N–O bond of 13 can be cleaved
with iron powder to afford quinolinone 14 in 86% yield.
A soln of Boc2O (1.1 or 2.2 equiv), Et3N (5.0 equiv), and THF (0.05
M) was added. After 2–24 h, the mixture was concentrated in vacuo
and purified by column chromatography.
tert-Butyl[2-Oxo-3,4-dihydroquinolin-1(2H)-yl]Carbonate(13,
Table 2, Entry 1)
Experiment 1: Methyl 3-(2-nitrophenyl)propanoate (105 mg, 0.500
mmol), Ru(bpy)3Cl2·6 H2O (9.3 mg, 0.012 mmol), 5 (204 mg, 1.05
mmol), CSA (11.3 mg, 0.0486 mmol), DMF (5 mL, 0.1 M), Boc2O
(123 mg, 0.562 mmol), Et3N (0.35 mL, 2.5 mmol), and THF (10
mL, 0.05 M). Purification by column chromatography (hexanes–
EtOAc, 8:1) yielded 13 (111 mg, 0.42 mmol, 84%) as a white solid.
TFA, CH2Cl2
N
O
OH
3 83%
N
O
OBoc
13
Experiment 2: Methyl 3-(2-nitrophenyl)propanoate (105 mg, 0.500
mmol), Ru(bpy)3Cl2·6 H2O (9.5 mg, 0.013 mmol), 5 (203 mg, 1.05
mmol), CSA (11.8 mg, 0.0508 mmol), DMF (5 mL, 0.1 M), Boc2O
(122 mg, 0.559 mmol), Et3N (0.35 mL, 2.5 mmol), and THF (10
mL, 0.05 M) yielded 13 (106 mg, 0.40 mmol, 81%).
Fe, AcOH
EtOH, 80 °C
N
H
O
14 86%
Mp 112.6–116.4 °C.
IR (thin film, NaCl): 2983, 1792, 1701, 1247 cm–1.
Scheme 3 Manipulation of N-Boc hydroxamic acids
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2699–2705

2702
M. A. Cismesia et al.
SPECIAL TOPIC
1H NMR (500 MHz, CDCl3): δ = 7.28–7.22 (m, 1 H), 7.18 (dd, J =
7.5, 1.1 Hz, 1 H), 7.05 (td, J = 7.5, 1.2 Hz, 1 H), 6.99 (dd, J = 8.0,
1.1 Hz, 1 H), 3.02–2.98 (m, 2 H), 2.80 (t, J = 7.4 Hz, 2 H), 1.57 (s,
9 H).
DMF (5 mL, 0.1 M), Boc2O (120 mg, 0.550 mmol), Et3N (0.35 mL,
2.5 mmol), and THF (10 mL, 0.05 M). Purification by column chro-
matography (5:1 hexanes–EtOAc) yielded the product (139 mg,
0.42 mmol, 82%) as a white solid.
13C NMR (126 MHz, CDCl3): δ = 164.6, 150.7, 138.3, 127.7, 127.7,
123.9, 123.9, 111.7, 86.4, 31.4, 27.5, 24.8.
HRMS (ESI): m/z [M + Na]+ calcd for C14H17NNaO4: 288.1050;
found: 288.1050.
Experiment 2: Methyl 3-[2-nitro-4-(trifluoromethyl)phenyl]pro-
panoate (139 mg, 0.501 mmol), Ru(bpy)3Cl2·6H2O (9.4 mg, 0.013
mmol), 5 (204.2 mg, 1.06 mmol), CSA (11.6 mg, 0.0499 mmol),
DMF (5 mL, 0.1 M), Boc2O (122 mg, 0.559 mmol), Et3N (0.35 mL,
2.5 mmol), and THF (10 mL, 0.05 M) yielded the product (132 mg,
0.40 mmol, 79%).
tert-Butyl [7-Methoxy-2-oxo-3,4-dihydroquinolin-1(2H)-yl]
Carbonate (Table 2, Entry 2)
Mp 70.0–73.8 °C.
IR (thin film, NaCl): 2986, 1794, 1716, 1335, 1248 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.35–7.29 (m, 2 H), 7.23–7.18 (m,
1 H), 3.12–3.03 (m, 2 H), 2.83 (t, J = 7.4 Hz, 2 H), 1.58 (s, 9 H).
13C NMR (126 MHz, CDCl3): δ = 164.3, 150.3, 138.8, 130.3 (q, J =
32.9 Hz), 128.2, 127.6, 123.8 (q, J = 272.2 Hz), 120.6 (q, J = 3.8
Hz), 108.7 (q, J = 3.9 Hz), 87.1, 30.8, 27.4, 24.7.
Experiment 1: Methyl 3-(4-methoxy-2-nitrophenyl)propanoate
(117 mg, 0.490 mmol), Ru(bpy)3Cl2·6 H2O (9.1 mg, 0.012 mmol),
5 (203 mg, 1.05 mmol), CSA (11.8 mg, 0.0508 mmol), DMF (5 mL,
0.1 M), Boc2O (124 mg, 0.569 mmol), Et3N (0.35 mL, 2.5 mmol),
and THF (10 mL, 0.05 M). Purification by column chromatography
(hexanes–EtOAc, 5:1) yielded the product (109 mg, 0.37 mmol,
74%) as a white solid.
Experiment 2: Methyl 3-(4-methoxy-2-nitrophenyl)propanoate
(120 mg, 0.500 mmol), Ru(bpy)3Cl2·6 H2O (9.3 mg, 0.012 mmol),
5 (202 mg, 1.05 mmol), CSA (11.7 mg, 0.0504 mmol), DMF (5 mL,
0.1 M), Boc2O (123 mg, 0.564 mmol), Et3N (0.35 mL, 2.5 mmol),
and THF (10 mL, 0.05 M) yielded the product (117 mg, 0.40 mmol,
80%).
HRMS (ESI): m/z [M + Na]+ calcd for C15H16F3NNaO4: 354.0924;
found: 354.0932.
tert-Butyl [7-Cyano-2-oxo-3,4-dihydroquinolin-1(2H)-yl] Car-
bonate (Table 2, Entry 5)
Experiment 1: Methyl 3-(4-cyano-2-nitrophenyl)propanoate (118
mg, 0.503 mmol), Ru(bpy)3Cl2·6H2O (9.6 mg, 0.013 mmol), 5 (204
mg, 1.06 mmol), CSA (11.6 mg, 0.0499 mmol), DMF (5 mL, 0.1
M), Boc2O (121 mg, 0.554 mmol), Et3N (0.35 mL, 2.5 mmol), and
THF (10 mL, 0.05 M). Purification by column chromatography
(hexanes–EtOAc, 2:1) yielded the product (102 mg, 0.35 mmol,
70%) as a white solid.
Mp 73.4–74.5 °C.
IR (thin film, NaCl): 2983, 1793, 1713, 1248 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.08 (d, J = 8.0 Hz, 1 H), 6.61–
6.50 (m, 2 H), 3.78 (s, 3 H), 2.97–2.85 (m, 2 H), 2.76 (t, J = 7.3 Hz,
2 H), 1.57 (s, 9 H).
13C NMR (126 MHz, CDCl3): δ = 164.7, 159.3, 150.5, 139.1, 128.5,
115.9, 108.2, 98.8, 86.4, 55.4, 31.6, 27.5, 23.9.
HRMS (ESI): m/z [M + Na]+ calcd for C15H19NNaO5: 316.1156;
found: 316.1151.
Experiment 2: Methyl 3-(4-cyano-2-nitrophenyl)propanoate (117
mg, 0.501 mmol), Ru(bpy)3Cl2·6 H2O (9.7 mg, 0.013 mmol), 5 (204
mg, 1.06 mmol), CSA (11.9 mg, 0.0512 mmol), DMF (5 mL, 0.1
M), Boc2O (123 mg, 0.565 mmol), Et3N (0.35 mL, 2.5 mmol), and
THF (10 mL, 0.05 M) yielded the product (105 mg, 0.36 mmol,
73%).
tert-Butyl [7-Methyl-2-oxo-3,4-dihydroquinolin-1(2H)-yl] Car-
bonate (Table 2, Entry 3)
Mp 199.4–200.2 °C.
IR (thin film, NaCl): 2984, 2231, 1794, 1717, 1249 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.36 (dd, J = 7.7, 1.4 Hz, 1 H),
7.31 (dd, J = 7.7, 1.0 Hz, 1 H), 7.24 (d, J = 1.3 Hz, 1 H), 3.14–3.02
(m, 2 H), 2.83 (t, J = 7.4 Hz, 2 H), 1.59 (s, 9 H).
Experiment 1: Methyl 3-(4-methyl-2-nitrophenyl)propanoate (108
mg, 0.485 mmol), Ru(bpy)3Cl2·6 H2O (9.1 mg, 0.012 mmol), 5 (203
mg, 1.05 mmol), CSA (11.8 mg, 0.0508 mmol), DMF (5 mL, 0.1
M), Boc2O (124 mg, 0.569 mmol), Et3N (0.35 mL, 2.5 mmol), and
THF (10 mL, 0.05 M). Purification by column chromatography
(hexanes–EtOAc, 5:1) yielded the product (118 mg, 0.42 mmol,
87%) as a white solid.
13C NMR (126 MHz, CDCl3): δ = 163.9, 150.3, 139.2, 129.1, 128.7,
127.6, 118.2, 114.7, 111.8, 87.4, 30.5, 27.5, 25.0.
Experiment 2: Methyl 3-(4-methyl-2-nitrophenyl)propanoate (111
mg, 0.499 mmol), Ru(bpy)3Cl2·6 H2O (9.7 mg, 0.013 mmol), 5 (203
mg, 1.05 mmol), CSA (11.6 mg, 0.0499 mmol), DMF (5 mL, 0.1
M), Boc2O (123 mg, 0.564 mmol), Et3N (0.35 mL, 2.5 mmol), and
THF (10 mL, 0.05 M) yielded the product (115 mg, 0.42 mmol,
83%).
HRMS (ESI): m/z [M + NH4]+ calcd for C15H20N3O4: 306.1449;
found: 306.1447.
tert-Butyl [7-Bromo-2-oxo-3,4-dihydroquinolin-1(2H)-yl] Car-
bonate (Table 2, Entry 6)
Experiment 1: Methyl 3-(4-bromo-2-nitrophenyl)propanoate (145
mg, 0.503 mmol), Ru(bpy)3Cl2·6 H2O (9.7 mg, 0.013 mmol), 5 (205
mg, 1.06 mmol), CSA (12.2 mg, 0.0525 mmol), DMF (5 mL, 0.1
M), Boc2O (121 mg, 0.554 mmol), Et3N (0.35 mL, 2.5 mmol), and
THF (10 mL, 0.05 M). Purification by column chromatography
(hexanes–EtOAc, 6:1) yielded the product (125 mg, 0.36 mmol,
72%) as a white solid.
Mp 96.4–97.0 °C.
IR (thin film, NaCl): 3092, 2959, 1733, 1204 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.05 (d, J = 7.5 Hz, 1 H), 6.84 (d,
J = 7.5 Hz, 1 H), 6.79 (s, 1 H), 3.01–2.86 (m, 2 H), 2.75 (t, J = 7.3
Hz, 2 H), 2.33 (s, 3 H), 1.57 (s, 9 H).
13C NMR (126 MHz, CDCl3): δ = 164.6, 150.6, 138.0, 137.5, 127.5,
124.4, 120.8, 112.3, 86.3, 31.5, 27.4, 24.3, 21.3.
HRMS (ESI): m/z [M + NH4]+ calcd for C15H23N2O4:295.1653;
found: 295.1664.
Experiment 2: Methyl 3-(4-bromo-2-nitrophenyl)propanoate (145
mg, 0.504 mmol), Ru(bpy)3Cl2·6 H2O (9.5 mg, 0.013 mmol), 5 (204
mg, 1.06 mmol), CSA (12.5 mg, 0.0538 mmol), DMF (5 mL, 0.1
M), Boc2O (122 mg, 0.560 mmol), Et3N (0.35 mL, 2.5 mmol), and
THF (10 mL, 0.05 M) yielded the product (137 mg, 0.40 mmol,
79%).
tert-Butyl [2-Oxo-7-(trifluoromethyl)-3,4-dihydroquinolin-
1(2H)-yl] Carbonate (Table 2, Entry 4)
Experiment 1: Methyl 3-[2-nitro-4-(trifluoromethyl)phenyl]pro-
panoate (141 mg, 0.507 mmol), Ru(bpy)3Cl2·6H2O (9.7 mg, 0.013
mmol), 5 (204 mg, 1.06 mmol), CSA (11.8 mg, 0.0508 mmol),
Mp 108.2–109.7 °C.
IR (thin film, NaCl): 2982, 1793, 1716, 1247 cm–1.
Synthesis 2013, 45, 2699–2705
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Photocatalytic Hydroxamic Acid Synthesis
2703
1H NMR (500 MHz, CDCl3): δ = 7.18 (dd, J = 7.9, 1.9 Hz, 1 H),
7.14 (d, J = 1.9 Hz, 1 H), 7.05 (d, J = 7.9 Hz, 1 H), 3.03–2.89 (m, 2
H), 2.78 (t, J = 6.8 Hz, 2 H), 1.58 (s, 9 H).
13C NMR (126 MHz, CDCl3): δ = 164.4, 150.4, 139.4, 129.1, 126.7,
122.8, 121.1, 115.0, 86.9, 31.1, 27.5, 24.4.
HRMS (ESI): m/z [M + NH4]+ calcd for C14H20BrN2O4: 359.0601;
found: 359.0597.
HRMS (ESI): m/z [M + Na]+ calcd for C13H15NO5Na: 288.0843;
found: 288.0842.
tert-Butyl [2-Oxo-4-tosyl-3,4-dihydroquinoxalin-1(2H)-yl)]
Carbonate (Table 2, Entry 10)
Experiment 1: Following general procedure without aqueous work-
up before protection. After protection was complete, the mixture
was diluted with EtOAc and washed with H2O (2 ×) and brine (1 ×).
Methyl 2-[4-methyl-N-(2-nitrophenyl)phenylsulfonamido]acetate
(182 mg, 0.499 mmol), Ru(bpy)3Cl2·6 H2O (9.4 mg, 0.013 mmol),
5 (290 mg, 1.50 mmol), CSA (116 mg, 0.498 mmol), DMF (5 mL,
0.1 M), 242 mg (1.11 mmol) Boc2O, Et3N (0.35 mL, 2.5 mmol), and
THF (10 mL, 0.05 M). Purification by column chromatography
(hexanes–EtOAc, 9:1) yielded the product (109 mg, 0.26 mmol,
52%) as a white solid.
tert-Butyl [6-Fluoro-2-oxo-3,4-dihydroquinolin-1(2H)-yl] Car-
bonate (Table 2, Entry 7)
Experiment 1: Methyl 3-(5-fluoro-2-nitrophenyl)propanoate (114
mg, 0.500 mmol), Ru(bpy)3Cl2·6 H2O (9.5 mg, 0.013 mmol), 5 (204
mg, 1.06 mmol), CSA (11.7 mg, 0.0504 mmol), DMF (5 mL, 0.1
M), Boc2O (124 mg, 0.566 mmol), Et3N (0.35 mL, 2.5 mmol), and
THF (10 mL, 0.05 M). Purification by column chromatography
(hexanes–EtOAc, 6:1) yielded the product (109 mg, 0.39 mmol,
78%) as a white solid.
Experiment 2: Methyl 2-[4-methyl-N-(2-nitrophenyl)phenylsulfon-
amido]acetate (182 mg, 0.500 mmol), Ru(bpy)3Cl2·6 H2O (9.4 mg,
0.013 mmol), 5 (289 mg, 1.50 mmol), CSA (116 mg, 0.500 mmol),
DMF (5 mL, 0.1 M), Boc2O (237 mg, 1.09 mmol), Et3N (0.35 mL,
2.5 mmol), and THF (10 mL, 0.05 M) yielded the product (112 mg,
0.27 mmol, 53%).
Experiment 2: Methyl 3-(5-fluoro-2-nitrophenyl)propanoate (114
mg, 0.502 mmol), Ru(bpy)3Cl2·6 H2O (9.4 mg, 0.013 mmol), 5 (205
mg, 1.06 mmol), CSA (12.2 mg, 0.0525 mmol), DMF (5 mL, 0.1
M), Boc2O (121 mg, 0.554 mmol), Et3N (0.35 mL, 2.5 mmol), and
THF (10 mL, 0.05 M) yielded the product (112 mg, 0.40 mmol,
79%).
Mp 117.2–117.8 °C.
IR (thin film, NaCl): 2983, 1798, 1721, 1361, 1248 cm–1.
Mp 94.6–95.4 °C.
IR (thin film, NaCl): 2984, 1793, 1707, 1248 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.78 (dd, J = 8.0, 1.4 Hz, 1 H),
7.35 (d, J = 8.3 Hz, 2 H), 7.29 (td, J = 7.8, 1.4 Hz, 1 H), 7.20 (td, J =
7.8, 1.4 Hz, 1 H), 7.16 (d, J = 8.4 Hz, 2 H), 6.76 (dd, J = 8.1, 1.4 Hz,
1 H), 4.56 (app s, 2 H), 2.36 (s, 3 H), 1.51 (s, 9 H).
13C NMR (126 MHz, CDCl3): δ = 160.1, 149.6, 144.7, 133.8, 132.8,
129.8, 128.1, 127.6, 126.9, 124.4, 124.0, 112.0, 87.1, 49.6, 27.4,
21.6.
1H NMR (500 MHz, CDCl3): δ = 6.98–6.89 (m, 3 H), 3.08–2.90 (m,
2 H), 2.79 (t, J = 7.4 Hz, 2 H), 1.57 (s, 9 H).
13C NMR (126 MHz, CDCl3): δ = 164.2, 159.1 (d, J = 243.6 Hz),
150.6, 134.6 (d, J = 2.6 Hz), 126.1 (d, J = 7.8 Hz), 114.9 (d, J = 23.6
Hz), 114.1 (d, J = 23.0 Hz), 113.2 (d, J = 8.3 Hz), 86.6, 31.2, 27.5,
24.9 (d, J = 1.2 Hz).
HRMS (ESI): m/z [M + NH4]+ calcd for C20H26N3O6S: 436.1537;
found: 437.1555.
HRMS (ESI): m/z [M + NH4]+ calcd for C14H20FN2O4: 299.1402;
found: 299.1415.
tert-Butyl (2-Oxoindolin-1-yl) Carbonate (Table 2, Entry 11)
Experiment 1: Following general procedure without aqueous work-
up before protection. After protection was complete, the mixture
was diluted with EtOAc and washed with H2O (2 ×) and brine (1 ×).
Methyl 2-(2-nitrophenyl)acetate (97.3 mg, 0.499 mmol),
Ru(bpy)3Cl2·6H2O (9.3 mg, 0.012 mmol), 5 (291 mg, 1.50 mmol),
CSA (117 mg, 0.503 mmol), DMF (5 mL, 0.1 M), Boc2O (241 mg,
1.11 mmol), Et3N (0.35 mL, 2.5 mmol), and THF (10 mL, 0.05 M).
Purification by column chromatography (hexanes–EtOAc, 4:1)
yielded the product (76.9 mg, 0.31 mmol, 62%) as a white solid.
6-Methoxy-2-oxo-3,4-dihydroquinolin-1(2H)-yl (10, Table 2,
Entry 8)
Following general procedure, but without protection after aqueous
workup. Methyl 3-(5-methoxy-2-nitrophenyl)propanoate (121 mg,
0.506 mmol), Ru(bpy)3Cl2·6 H2O (9.7 mg, 0.013 mmol), 5 (388 mg,
1.96 mmol), CSA (113 mg, 0.486 mmol), DMF (5 mL, 0.1 M). Pu-
rification by column chromatography (hexanes–EtOAc, 1:1 + 0.5%
Et3N) yielded 10 (60.2 mg, 0.27 mmol, 54%) as a white solid. All
spectra data were consistent with reported values.16
Experiment 2: Methyl 2-(2-nitrophenyl)acetate (97.0 mg, 0.497
mmol), Ru(bpy)3Cl2·6 H2O (9.7 mg, 0.013 mmol), 5 (290 mg, 1.50
mmol), CSA (116 mg, 0.500 mmol), DMF (5 mL, 0.1 M), Boc2O
(240 mg, 1.10 mmol), Et3N (0.35 mL, 2.5 mmol), and THF (10 mL,
0.05 M) yielded the product (81.9 mg, 0.33 mmol, 66%).
tert-Butyl [3-Oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl] Carbonate
(Table 2, Entry 9)
Experiment 1: Methyl 2-(2-nitrophenoxy)acetate (106 mg, 0.502
mmol), Ru(bpy)3Cl2·6 H2O (9.5 mg, 0.013 mmol), 5 (203 mg,
1.05 mmol), CSA (11.3 mg, 0.0486 mmol), DMF (5 mL, 0.1 M),
Boc2O (122 mg, 0.559 mmol), Et3N (0.35 mL, 2.5 mmol), and THF
(10 mL, 0.05 M). Purification by column chromatography (hex-
anes–EtOAc, 5:1) yielded the product (98.0 mg, 0.37 mmol, 74%)
as a white solid.
Mp 88.1–89.4 °C.
IR (thin film, NaCl): 2984, 1796, 1743, 1247 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.29 (td, J = 7.7, 1.0 Hz, 1 H), 7.25
(d, J = 7.6 Hz, 1 H), 7.08 (td, J = 7.6, 1.0 Hz, 1 H), 6.85 (d, J = 7.8
Hz, 1 H), 3.60 (s, 2 H), 1.57 (s, 9 H).
13C NMR (126 MHz, CDCl3): δ = 169.1, 150.2, 141.2, 128.1, 124.9,
123.3, 120.1, 107.2, 87.1, 33.6, 27.4.
HRMS (ESI): m/z [M + Na]+ calcd for C13H15NO4Na: 272.0894;
found: 272.0889.
Experiment 2: Methyl 2-(2-nitrophenoxy)acetate (106 mg, 0.501
mmol), Ru(bpy)3Cl2·6 H2O (9.3 mg, 0.012 mmol), 5 (203 mg,
1.05 mmol), CSA (11.9 mg, 0.0512 mmol), DMF (5 mL, 0.1 M),
Boc2O (122 mg, 0.559 mmol), Et3N (0.35 mL, 2.5 mmol), and THF
(10 mL, 0.05 M) yielded the product (107 mg, 0.41 mmol, 81%).
Mp 89.1–90.5 °C.
IR (thin film, NaCl): 2979, 1700, 1685, 1244 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.14–6.85 (m, 4 H), 4.76 (s, 2 H),
tert-Butyl 3-Acetamido-2-oxo-3,4-dihydroquinolin-1(2H)-yl
Carbonate (Table 2, Entry 12)
Experiment 1: Following general procedure without aqueous work-
up before protection. After protection is complete, the mixture is di-
luted with EtOAc and washed with H2O (2 ×) and brine (1 ×). Ethyl
2-acetamido-3-(2-nitrophenyl)propanoate (140 mg, 0.500 mmol),
Ru(bpy)3Cl2·6 H2O (9.7 mg, 0.013 mmol), 5 (290 mg, 1.50 mmol),
1.58 (s, 9 H).
13C NMR (126 MHz, CDCl3): δ = 159.4, 149.9, 143.5, 127.8, 124.8,
122.9, 116.9, 112.1, 87.2, 68.2, 27.4.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2699–2705

2704
M. A. Cismesia et al.
SPECIAL TOPIC
CSA (116 mg, 0.501 mmol), DMF (5 mL, 0.1 M), Boc2O (240 mg,
1.10 mmol), Et3N (0.35 mL, 2.5 mmol), and THF (10 mL, 0.05 M).
Purification by column chromatography (hexanes–EtOAc, 3:1 to
0:1) yielded the product (92.2 mg, 0.29 mmol, 58%) as a white sol-
id.
Acknowledgment
M.A.C. is grateful for a graduate fellowship from the NSF. Funding
for this project was provided by the NIH (GM095666) and the Sloan
Foundation.
Experiment 2: Ethyl 2-acetamido-3-(2-nitrophenyl)propanoate
(141 mg, 0.503 mmol), Ru(bpy)3Cl2·6H2O (9.9 mg, 0.013 mmol), 5
(290 mg, 1.50 mmol), CSA (117 mg, 0.502 mmol), DMF (5 mL, 0.1
M), Boc2O (246 mg, 1.12 mmol), Et3N (0.35 mL, 2.5 mmol), and
THF (10 mL, 0.05 M) yielded the product (94.8 mg, 0.29 mmol,
58%).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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References
Mp 112.6–113.9 °C.
IR (thin film, NaCl): 3308, 2984, 1795, 1715, 1246 cm–1.
(1) Kurzak, B.; Kozłowski, H.; Farkas, E. Coord. Chem. Rev.
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1H NMR (500 MHz, CDCl3): δ = 7.29 (t, J = 7.8 Hz, 1 H), 7.24 (d,
J = 7.5 Hz, 1 H), 7.11 (td, J = 7.5, 1.1 Hz, 1 H), 7.10–6.82 (m, 1 H),
6.61 (d, J = 5.5 Hz, 1 H), 4.78 (dt, J = 14.1, 5.8 Hz, 1 H), 3.51 (dd,
J = 15.1, 6.0 Hz, 1 H), 3.01–2.85 (m, 1 H), 2.08 (s, 3 H), 1.56 (s, 9
H).
13C NMR (126 MHz, CDCl3): δ = 170.3, 163.9, 150.3, 128.5, 128.1,
124.8, 112.7, 86.9, 65.8, 49.5, 31.7, 27.4, 23.1, 15.2.
(2) (a) Weisburger, J. H.; Weisburger, E. K. Pharmacol. Rev.
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48, 9785. (b) Yoon, T. P.; Ischay, M. A.; Du, J. Nat. Chem.
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HRMS (ESI): m/z [M + NH4]+ calcd for C16H24N3O5: 338.1711;
found: 338.1718.
2-Phenyl-1H-indol-1-ol (12)
Experiment 1: Following general procedure, but without protection
after aqueous workup. 2-(2-Nitrophenyl)-1-phenylethanone
(11,121 mg, 0.500 mmol), Ru(bpy)3Cl2·6 H2O (10.0 mg, 0.013
mmol), 5 (205 mg, 1.06 mmol), CSA (11.6 mg, 0.0499 mmol),
DMF (5 mL, 0.1 M). Purification by column chromatography (hex-
anes–EtOAc, 20:1) yielded 13 (94.3 mg, 0.45 mmol, 90%) as a
white solid.
Experiment 2: 2-(2-Nitrophenyl)-1-phenylethanone (11, 122 mg,
0.505 mmol), Ru(bpy)3Cl2·6 H2O (9.2 mg, 0.012 mmol), 5 (205 mg,
1.06 mmol), CSA (11.7 mg, 0.0504 mmol), DMF (5 mL, 0.1 M)
yielded the product (90.2 mg, 0.43 mmol, 85%).
Mp 149.1–150.3 °C.
IR (thin film, NaCl): 3277, 3053, 2923, 2520, 1532 cm–1.
1H NMR (500 MHz, DMSO-d6): δ = 11.17 (s, 1 H), 7.88 (d, J = 7.3
Hz, 2 H), 7.54 (d, J = 7.9 Hz, 1 H), 7.49 (t, J = 7.7 Hz, 2 H), 7.44 (d,
J = 8.1 Hz, 1 H), 7.38 (t, J = 7.4 Hz, 1 H), 7.18 (t, J = 7.5 Hz, 1 H),
7.05 (t, J = 7.4 Hz, 1 H), 6.63 (s, 1 H).
(9) For leading examples from other groups, see: (a) Nicewicz,
D. A.; MacMillan, D. W. C. Science (Washington, D.C.)
2008, 322, 77. (b) Narayanam, J. M. R.; Tucker, J. W.;
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13C NMR (126 MHz, DMSO-d6): δ = 136.9, 135.5, 130.9, 128.6,
127.7, 123.0, 121.8, 120.2, 119.7, 108.8, 96.2.
HRMS (ESI): m/z [M + H]+ calcd for C14H12NO: 210.0914; found:
210.0919.
1-Hydroxy-3,4-dihydroquinolin-2(1H)-one (3)
A round-bottom flask was charged with 13 (100 mg, 0.380 mmol),
CH2Cl2 (7.5 mL, 0.05 M), and TFA (7.5 mL, 0.05 M). The mixture
was stirred for 1 h and then diluted with CH2Cl2 (50 mL) and poured
into H2O (50 mL). The mixture was washed with CH2Cl2 (2 × 50
mL). The organic layers were combined, dried (MgSO4), and con-
centrated in vacuo. Purification by recrystallization (Et2O) yielded
3 (51.7 mg, 0.317 mmol, 83%) as a tan solid. All spectra data were
consistent with reported values.17
(11) Tomioka, H.; Ueda, K.; Ohi, H.; Izawa, Y. Chem. Lett. 1986,
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3,4-Dihydroquinolin-2(1H)-one (14)
A 2-dram vial was charged with 13 (100 mg, 0.380 mmol), Fe metal
(41.9 mg, 0.776 mmol), EtOH (1.0 mL, 0.4 M), and AcOH (1.0 mL,
0.4 M). The mixture was heated to 80 °C for 1.5 h and then cooled
r.t. Sat. Na2CO3 soln was added, and the mixture was extracted with
Et2O (3 × 50 mL). The organic layers were combined, dried
(MgSO4), and concentrated in vacuo. Purification by recrystalliza-
tion (Et2O) yielded 14 (48.0 mg, 0.326 mmol, 86%) as a white solid.
All spectra data were consistent with reported values.18
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Synthesis 2013, 45, 2699–2705
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Photocatalytic Hydroxamic Acid Synthesis
2705
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2010.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2699–2705