Facile access to amides and hydroxamic acids directly from nitroarenes

Article abstract of DOI:10.1039/c4ob01155d

A new method for synthesis of amides and hydroxamic acids from nitroarenes and aldehydes is described. The MnO₂ catalyzed thermal deoxygenation of nitrobenzene resulted in formation of a reactive nitroso intermediate which on reaction with aldehydes provided amides and hydroxamic acids. The thermal neat reaction in the presence of 0.01 mmol KOH predominantly led to formation of hydroxamic acid whereas reaction in the presence of 1 mmol acetic acid produced amides as the only product. the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob01155d

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
PAPER
Facile access to amides and hydroxamic acids
directly from nitroarenes†‡
Cite this: Org. Biomol. Chem., 2014,
12, 6465
Shreyans K. Jain,a,b K. A. Aravinda Kumar,c Sandip B. Bharate*b,c and
Ram A. Vishwakarma*a,b,c
A new method for synthesis of amides and hydroxamic acids from nitroarenes and aldehydes is described.
The MnO2 catalyzed thermal deoxygenation of nitrobenzene resulted in formation of a reactive nitroso
intermediate which on reaction with aldehydes provided amides and hydroxamic acids. The thermal neat
reaction in the presence of 0.01 mmol KOH predominantly led to formation of hydroxamic acid whereas
reaction in the presence of 1 mmol acetic acid produced amides as the only product.
Received 4th June 2014,
Accepted 30th June 2014
DOI: 10.1039/c4ob01155d
www.rsc.org/obc
In the present article, we report a MnO2 catalyzed amide
bond formation directly from aldehydes and nitroarenes
Introduction
An amide bond constitutes a fundamental functional unit of (Fig. 1). Our protocol could also be optimized for synthesis of
biochemistry and is the most common C–N bond present in N-hydroxamic acids, which are pharmacologically important26
proteins, synthetic polymers, natural products, pharmaceutical and are considered as bioisosters of carboxylic acids.27
drugs, agrochemicals, perfumes, flavors and many industrial
products.1 Therefore the synthesis of the amide bond con-
tinues to be important in organic chemistry.2 A number of
Results and discussion
elegant and commercially viable methods have been dis-
covered,3 including the most widely used acylation of amines
In one of our study on oxidation of a methyl group of chro-
by the activated carboxylic acids.3b,4 In addition, several new
mone alkaloid rohitukine by an in situ generated nitroso inter-
mediate from nitrobenzene, we observed the formation of
methods have been reported over the time including: (a)
aminocarbonylation of aryl halides,5 (b) transition-metal
hydroxamic acids and amides as byproducts (section S1 of
ESI‡). Exploring this reaction further, we discovered that nitro-
mediated coupling of amines and alcohols through dehydro-
genation,6 and oxime rearrangement,7 (c) N-heterocyclic
benzene on reaction with benzaldehdye in the presence of
carbene mediated activation of aldehydes8 and α-hydroxye-
MnO2 produces the corresponding amide and hydroxamic acid
nones;9 (d) aldehyde oxidation using metal catalysts3c,10 such
products in excellent yield. Considering the importance of this
as Pd,11 Cu,12 Ru,13 and lanthanide;14 and (e) amidation using
observation, we decided to explore the scope of this reaction in
acyl surrogate from nitriles,15 alkenes,16 thioacids or thioe-
greater detail.
sters,17 alkynes,18 acyl and aminyl radicals.19 Other than this,
The study was initiated with a preliminary reaction of
4-chlorobenzaldehyde 3a with nitrobenzene 4a in the presence
amidation has been reported through Mn catalyzed C–C bond
cleavage20 and the Staudinger reaction.21 The nitro22 and
of 25 mol% MnO2 in an inert and neat medium for 48 h,
nitroso23 groups have also been utilized as a nitrogen source
which led to the formation of a mixture of two products in
for amide synthesis.23,24 Recently MnO2 catalyzed amide bond
45% yield (Table 1, entry 3). Analysis by NMR and LCMS of the
formation from nitriles has been reported.25
product mixture confirmed these two products as amide 1a
and hydroxamic acid 2a formed in the ratio of 50 : 50 (section
S3a in ESI‡). The formation of hydroxamic acid 2a indicated
aNatural Product Chemistry Division, CSIR-Indian Institute of Integrative Medicine,
Canal Road, Jammu-180001, India
bAcademy of Scientific and Innovative Research (AcSIR), CSIR-Indian Institute of
Integrative Medicine, Canal Road, Jammu-180001, India
cMedicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal
Road, Jammu-180001, India. E-mail: ram@iiim.res.in, sbharate@iiim.res.in;
Fax: +91-191-2569333; Tel: +91-191-2569111
†IIIM Publication number IIIM/1645/2014.
‡Electronic supplementary information (ESI) available: NMR spectra of all new
compounds. See DOI: 10.1039/c4ob01155d
Fig. 1 MnO2-catalyzed amide bond formation.
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 6465–6469 | 6465

View Article Online
Paper
Organic & Biomolecular Chemistry
Table 1 Optimization of reaction conditions
Entry
Catal. (mol%)
Additive (mmol)
Solvent
Temp (°C)
Time (h)
Yielda (%) (1a + 2a)
Ratiob of 1a : 2a
1
2
3
4
5
6
7
8
None
None
None
None
None
None
None
None
None
None
None
None
KOH (0.01)
KOH (0.01)
KOH (0.01)
AcOH (1)
AcOH (1)
AcOH (1)
None
None
None
CHCl3
THF
Dioxane
Toluene
Xylene
None
None
None
None
None
150
25
120
60
48
48
48
48
48
48
48
48
48
48
48
48
48
48
12
48
50
0
0
0
0
MnO2 (25)
MnO2 (25)
MnO2 (25)
MnO2 (25)
MnO2 (25)
MnO2 (25)
MnO2 (25)
MnO2 (10)
MnO2 (20)
MnO2 (30)
MnO2 (25)
MnO2 (25)e
MnO2 (25)f
MnO2 (25)
MnO2 (25)
MnO2 (25)
45
10
20
20
35
35
20
30
45
55
70
79
90
30
20
50 : 50
nd
nd
nd
nd
nd
nd
nd
nd
44 : 56
30 : 70
48 : 52
100 : 0
100 : 0
100 : 0
c
70
100
120
120
120
120
120
120
120
120
60
9
10
11
12
13d
14
15d
16
17
THF
CHCl3
g
g
CH2Cl2
25
60
MeOHh
a The combined yield (1a + 2a) is an isolated yield. b Individual ratios of 1a and 2a were determined by LCMS (see section S3 of ESI). c Similar
results were observed with CH2Cl2 and CCl4. d The bold entry 13 indicates optimized reaction conditions for synthesis of hydroxamic acids; and
bold entry 15 is optimized condition for synthesis of amides. e The catalyst was added portion-wise (3 batches). f 3a, 4a, MnO2 and KOH were
mixed in THF under sonication, followed by complete evaporation of the solvent. The remaining residue was heated at 120 °C for 48 h. g Similar
results were observed when THF or dioxane was used. h Similar results were observed with EtOH.
that the reaction involved in situ reduction of the nitro group and the ratio of amide–hydroxamic acid was changed to
to the nitroso group.
30 : 70. The reaction condition described in the entry 13
Next, the optimization experiments (solvent and tempera- (without solvent) was found optimal (70%) for the synthesis of
ture) were carried out to improve the yield of the amide 1a amides and hydroxamic acids, which were isolated in the ratio
(Table 1) using the aldehyde 3a and nitrobenzene 4a. Under of 3 : 7. In the next set of experiments, the substrates 3a and
neat conditions, the product was not obtained at room temp- 4a, the catalyst (MnO2) and the additive (KOH) were all mixed
erature (entry 2); however, 45% yield was obtained at 120 °C in THF by sonication followed by the evaporation of the
(entry 3). Then, we investigated the effect of the solvent in this solvent. The remaining residue when heated at 120 °C for 48 h
reaction. It was noticed that the solvent played an important led to 79% yield (entry 14) of the product mixture of amide
role, as methanol, ethanol, DMF and DMSO were found to and hydroxamate. Interestingly, in a further experiment, when
interfere with the reaction. However, when CH2Cl2, CHCl3 and the reaction was performed in CHCl3 in the presence of acetic
CCl4 were used as solvents at their reflux temperatures, both acid (entry 15) at a reflux temperature, the corresponding
the products (1a and 2a) were formed albeit in poor yield amide was obtained as the only product in 90% yield.
(entry 4). The yields got marginally improved when high
The scope of this reaction was then investigated under opti-
boiling point solvents (dioxane, toluene and xylene) were used mized reaction conditions (entry 15 of Table 1). The substi-
(entries 6–8). The catalyst loading of 25 mol% was found to be tution of aldehydes with various groups was well tolerated
suitable (entries 3 and 9–11). The reaction in a closed airtight (Table 2, entries 1–12). The heterocyclic aldehyde also partici-
vessel either failed to give the product or led to very poor pated well in this reaction (entry 9). In the case of nitroarenes,
yields, possibly due to the presence of gaseous side products the reaction worked well with nitrobenzene as well as with
(mainly H2O and CO2) in the reaction vessel, which are produced heterocyclic nitrene (entry 12). All our attempts with aliphatic
during the initial reduction of the nitro group to the nitroso nitro compounds failed to get desirable amides, possibly due
group, as explained in the Mars–van Kravelen mechanism.28 to the reactive nitroso getting stabilized through isomerization
KOH has been reported to enhance the conversion of nitro to with available α-hydrogen of RCH2NO to the corresponding
nitroso.29 The addition of KOH (0.01 mmol) to the reaction oxime RCHvNOH and thus restricting the desired reaction
mixture, significantly promoted the yield of the products (entry (entry 15). It was also observed that O-iodo-nitrobenzene (4m)
12) with the ratio of 1a : 2a as 44 : 56. Moreover, we also observed and o-bromo-nitrobenzene (4n) failed to produce desired
that the sequence of the addition of the catalyst MnO2 impacted amides in practical yields (7–8%; Table 2), perhaps due to the
the yield, as the addition of catalyst in portions was beneficial formation of the azodioxy dimer side product (section S2
(entry 13 vs. 12), where the overall yield improved up to 70% of ESI‡).
6466 | Org. Biomol. Chem., 2014, 12, 6465–6469
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
Table 2 Scope of the reactiona
machines. LC-ESI-MS/MS analysis was carried out on an
Agilent Triple-Quad LC-MS/MS system (model 6410).
General method of synthesis of amides 1a–1n (Table 1,
entry 15)
To the mixture of MnO2 (25 mol%, added in 3 portions), alde-
hyde (1 equiv.) and acetic acid (1 equiv.) was added nitroben-
zene (1.2 equiv.) in chloroform and the reaction mixture was
heated at 60 °C for 12 hours under a nitrogen atmosphere.
Reaction was monitored by TLC and MS analysis. After com-
pletion of the reaction (usually 12 h), the reaction mixture was
filtered, concentrated and partitioned into ethyl acetate and
water. The organic layer was dried over anhydrous sodium sul-
phate and concentrated. Purification on silica gel column
chromatography gave amides 1a–n in 8–90% yield.
Entry
R1
R2
Product
Yieldb
1
2
3
4
5
6
7
8
–Ph (4-Cl)
–Ph
–Ph
–Ph
–Ph
–Ph
–Ph
–Ph
–Ph
–Ph
–Ph
–Ph
–Ph
2-Pyridinyl
–Ph (2-I)
–Ph (2-Br)
1-Propanyl
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
90
85
88
79
76
86
85
76
78
76
84
76
7c
–Ph (2,6-di-Cl)
–Ph (2,4,5-tri-OMe)
–Ph (3-Br, 4-F)
–Ph (4-F)
–Ph (3,5-di-OMe)
–Ph (2-Cl)
5-Me-pyrazin-2-yl
–Ph (2-Me)
–Ph (3-OH, 4-OMe)
–Ph (2,4,5-OMe)
–Ph (3,4,5-OMe)
–Ph
9
10
11
12
13
14
15
4-Chloro-N-phenylbenzamide (1a). Yield: 78%; white
1
needles; H NMR (CDCl3, 400 MHz): δ 7.84–7.81 (m, 2H), 7.75
(s, NH), 7.65 (d, J = 8.2 Hz, 2H), 7.63 (m, 2H), 7.48 (t, J =
7.2 Hz, 2H), 7.39 (t, J = 7.3 Hz, 2H), 7.18 (t, J = 7.2 Hz, 1H);
ESIMS: m/z 232.0 [M + H]+; HRMS: m/z 232.0511 [M + H]+ calcd
for C13H11ClNO+ (232.0523).24
8c
–Ph
0d
a Reagents and conditions (optimized condition, entry 15 from
Table 1): aldehyde (3, 1 mmol), nitro compound (4, 1.2 mmol), MnO2
(25 mol%), AcOH (1 mmol) in chloroform, refluxed at 60 °C for 12 h.
b Isolated yield of amides. c Corresponding dimeric azodioxy was a
major side product. d Corresponding oxime was isolated as a major
product.
N-Phenylbenzamide (1b). Yield: 70%; white crystals; 1H
NMR (CDCl3, 400 MHz): δ 7.89–7.87 (m, 2H), 7.19 (s, NH), 7.65
(d, J = 8.2 Hz, 2H), 7.56–7.48 (m, 5H), 7.39 (t, 2H, J = 8.0 Hz),
7.16 (t, 1H, J = 8 Hz); 13C NMR (CDCl3, 100 MHz): 168, 139.9,
136.3, 132.9, 129.8, 129.6, 128.6, 125.6, 122.3. ESIMS: m/z
We are investigating the mechanism of this important new 198.0 [M + H]+; HRMS: m/z 198.0921 [M + H]+ calcd for
reaction to prepare amides and hydroxamic acids, and will C13H12NO+ (198.0913).24
report in due course.
2,6-Dichloro-N-phenylbenzamide (1c). Yield: 71%; white
1
needles; H NMR (CDCl3, 400 MHz): δ 7.65 (m, 2H), 7.48–7.26
(m, 6H), 7.22 (m, 1H); 13C NMR (CDCl3, 100 MHz): δ 162.4,
137.1, 135.9, 132.4, 130.9, 129.1, 128.1, 125.2, 120.3; ESIMS:
m/z 266.0 [M + H]+; HRMS: m/z 266.0121 [M + H]+ calcd for
Conclusion
In summary, we have reported a new Mn-oxide catalyzed C13H10Cl2NO+ (266.0134).30
method for synthesis of amides and hydroxamic acids from
2,4,5-Trimethoxy-N-phenylbenzamide (1d). Yield: 68%; crys-
nitroarenes. The reaction opens up new opportunities to dis- talline solid; 1H NMR (CDCl3, 400 MHz): δ 9.85 (s, 1H), 7.83 (s,
cover nitroarene-based methodologies for practical appli- 1H), 7.67 (d, 2H, J = 8.0 Hz), 7.36 (t, 2H, J = 8.0 Hz), 7.12 (t, 1H,
cations in medicinal and industrial chemistry for synthesis of J = 8.0 Hz), 4.06 (s, 3H), 3.97 (s, 3H), 3.93 (s, 3H); 13C NMR
amides and hydroxamic acids.
(CDCl3, 100 MHz): δ 163, 153.4, 153.2, 143.7, 136.6, 128.9, 123.9,
120.9, 114.0, 113.5, 96.9, 57.1, 56.3, 56.2; ESIMS: m/z 288.1
[M + H]+; HRMS: m/z 288.1221 [M + H]+ calcd for C16H18NO4
+
(288.1230).31
Experimental section
General information
3-Bromo-4-fluoro-N-phenylbenzamide (1e). Yield: 76%;
white solid; 1H NMR (CDCl3, 400 MHz): δ 8.10 (d, 1H, J =
All chemicals were obtained from Sigma-Aldrich Company and 8.0 Hz), 7.82 (m, 1H), 7.71 (s, 1H), 7.62 (s, 2H, J = 8.0 Hz), 7.39
1
used as received. The H and 13C NMR spectra were recorded (t, 2H, J = 8.0 Hz), 7.20 (m, 2H); 13C NMR (CDCl3, 100 MHz):
on Bruker-Avance DPX FT-NMR 500 and 400 MHz instruments. δ 163, 159.9, 137.4, 132.4, 129.1, 128.1, 125.0, 120.3, 116.9,
Chemical data for protons are reported in parts per million 109.8, 56.2; ESIMS: m/z 293.9 [M + H]+; HRMS: m/z 293.9922
(ppm) downfield from tetramethylsilane and are referenced to [M + H]+ calcd for C13H10BrFNO+ (293.9924).
the residual proton in the NMR solvent (CDCl3, 7.26 ppm).
4-Fluoro-N-phenylbenzamide (1f). Yield: 76%; white solid;
Carbon nuclear magnetic resonance spectra (13C NMR) were 1H NMR (CDCl3, 400 MHz): δ 10.40 (s, 1H, NH), 8.04 (m, 2H,
recorded at 125 or 100 MHz; chemical data for carbon are J = 8 Hz), 7.76 (d, 2H, J = 8 Hz), 7.36 (m, 4H), 7.11 (t, 1H, J =
reported in parts per million (ppm, δ scale) downfield from 8 Hz); 13C NMR (CDCl3, 100 MHz): δ 166.4, 164.5, 163.0, 137.3,
tetramethylsilane and are referenced to the carbon resonance 131.1, 129.4, 129.3, 129.1, 124.7, 120.2, 116.0, 115.8; ESIMS:
of the solvent (CDCl3, 77 ppm). ESI-MS and HRMS spectra m/z 216.2 [M + H]+; HRMS: m/z 216.0822 [M + H]+ calcd for
were recorded on Agilent 1100 LC-QTOF and HRMS-6540-UHD C13H11FNO+ (216.0819).24
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 6465–6469 | 6467

View Article Online
Paper
Organic & Biomolecular Chemistry
3,5-Dimethoxy-N-phenylbenzamide (1g). Yield: 70%; white 8.0 Hz, 2H), 7.18 (t, J = 8.0 Hz, 1H); 13C NMR (CDCl3,
solid; 1H NMR (CDCl3, 400 MHz): δ 7.81 (s, 1H, NH), 7.65–7.61 125 MHz): δ 150.51, 138.54, 137.40, 133.21, 129.17, 129.09,
(m, 3H), 7.41–7.35 (m, 3H), 6.94–6.88 (m, 3H); 13C NMR 128.40, 124.82, 120.21; ESIMS: m/z 248.3 [M + H]+; HRMS: m/z
(CDCl3, 100 MHz): δ 171.0, 153.7, 148.7, 129.0, 124.6, 124.4, 248.0462 [M + H]+ calcd for C13H11ClNO2+ (248.0473).
121.7, 120.1, 119.4, 112.3, 110.3, 56.0; ESIMS: m/z 258.1
+
[M + H]+; HRMS: m/z 258.1111 [M + H]+ calcd for C15H16NO3
(258.1124).32
Acknowledgements
2-Chloro-N-phenylbenzamide (1h). Yield: 72%; white solid;
1H NMR (CDCl3, 400 MHz): δ 7.8 (s, NH), 7.77 (1H, dd, J = 4.0,
Authors thank Analytical Department, IIIM for NMR and MS
8.0 Hz), 7.66 (2H, dd, J = 4.0, 8.0 Hz), 7.47–7.38 (m, 5H), 7.18
analysis of our compounds. This work was supported by the
(1H, t, J = 4.0 Hz); 13C NMR (CDCl3, 100 MHz): δ 168.2, 139.6,
Department of Biotechnology (Government of India) funding
138.1, 132.2, 132.0, 131.0, 129.9, 128.2, 125.2, 121.5. ESIMS:
GAP-1140 (grant no. BT/PR/10546/NDB/52/172/2008).
m/z 232.6 [M + H]+; HRMS: m/z 232.0511 [M + H]+ calcd for
C13H11ClNO+ (232.0523).33
5-Methyl-N-phenylpyrazine-2-carboxamide (1i). Yield: 72%;
1
white crystals; H NMR (CDCl3, 400 MHz): δ 9.96 (s, 1H), 9.38
(s, 1H), 8.45 (s, 1H), 7.76 (d, 2H, J = 8.0 Hz), 7.40 (t, 2H, J =
Notes and references
8.0 Hz), 7.18 (t, 1H, J = 8.0 Hz); 13C NMR (CDCl3, 100 MHz):
δ 161.2, 157.2, 143.7, 142.0, 141.7, 137.4, 129.1, 124.6, 119.7,
21.9; ESIMS: m/z 214.0 [M + H]+; HRMS: m/z 214.0951 [M + H]+
calcd for C12H12N3O+ (214.0975).
2-Methyl-N-phenylbenzamide (1j). Yield: 55%; white crys-
tals; 1H NMR (CDCl3, 400 MHz): δ 7.68 (s, NH), 7.59 (d, J =
4.0 Hz, 2H), 7.37 (d, 1H, J = 4.0 Hz), 7.33 (t, J = 8.0 Hz, 3H),
7.24–7.11 (m, 3H), 2.5 (s, 3H); 13C NMR (CDCl3, 100 MHz):
δ 168, 138, 136.4, 131.2, 130.2, 129.1, 126.6, 125.8, 124.5,
119.9, 19.8; ESIMS: m/z 212.2 [M + H]+; HRMS: m/z 212.1039
calcd for C14H14NO+ (212.1069).24
3-Hydroxy-4-methoxy-N-phenylbenzamide (1k). Yield: 71%;
crystalline solid; 1H NMR (CDCl3, 400 MHz): δ 10.0 (s, 1H,
OH), 9.30 (s, 1H, NH), 7.75 (d, J = 8.0 Hz, 2H), 7.46 (d, 1H, J =
12.0 Hz), 7.41 (s, 1H), 7.33 (t, J = 8.0 Hz, 2H), 7.05 (m, 2H),
3.85 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 167.2, 151.8, 150.9,
146.2, 145.9, 138.5, 128.3, 127.3, 127.0, 120.9, 119.5, 114.3,
110.4, 55.1; ESIMS: m/z 244.0 [M + H]+; HRMS: m/z 244.0977
[M + H]+ calcd for C14H14NO3+ (244.0968).
1 V. R. Pattabiraman and J. W. Bode, Nature, 2011, 480,
471–479.
2 D. J. C. Constable, P. J. Dunn, J. D. Hayler, G. R. Humphrey,
J. L. Leazer, R. J. Linderman, K. Lorenz, J. Manley,
B. A. Pearlman, A. Wells, A. Zaksh and T. Y. Zhang, Green
Chem., 2007, 9, 411–420.
3 (a) J. M. Humphrey and A. R. Chamberlin, Chem. Rev.,
1997, 97, 2243–2266; (b) E. Valeur and M. Bradley, Chem.
Soc. Rev., 2009, 38, 606–631; (c) C. Allen and J. Williams,
Chem. Soc. Rev., 2011, 40, 3405–3415.
4 (a) R. M. Al-Zoubi, O. Marion and D. G. Hall, Angew. Chem.,
Int. Ed., 2008, 47, 2876–2879; (b) H. Charville, D. Jackson,
G. Hodges and A. Whiting, Chem. Commun., 2010, 46,
1813–1823.
5 (a) Y.-S. Lin and H. Alper, Angew. Chem., Int. Ed., 2001, 40,
779–781; (b) B. Roberts, D. Liptrot, L. Alcaraz, T. Luker and
M. Stocks, Org. Lett., 2010, 12, 4280–4283; (c) X.-F. Wu,
H. Neumann and M. Beller, Chem. – Eur. J., 2010, 16, 9750–
9753; (d) K. Hosoi, K. Nozaki and T. Hiyama, Org. Lett.,
2002, 4, 2849–2851; (e) H. Jiang, B. Liu, Y. Li, A. Wang and
H. Huang, Org. Lett., 2011, 13, 1028–1031.
6 (a) C. Gunanathan, Y. Ben-David and D. Milstein, Science,
2007, 317, 790–792; (b) A. J. A. Watson, A. C. Maxwell and
J. M. J. Williams, Org. Lett., 2009, 11, 2667–2670;
(c) L. U. Nordstrom, H. Vogt and R. Madsen, J. Am. Chem.
Soc., 2008, 130, 17672–17673; (d) K.-i. Fujita, Y. Takahashi,
M. Owaki, K. Yamamoto and R. Yamaguchi, Org. Lett.,
2004, 6, 2785–2788; (e) Z. Theo, N. Jean-Valere and
G. Hansjorg, Angew. Chem., Int. Ed., 2009, 121, 567–571;
(f) K.-i. Shimizu, K. Ohshima and A. Satsuma, Chem. – Eur.
J., 2009, 15, 9977–9980; (g) S. Muthaiah, S. Ghosh, J.-E. Jee,
C. Chen, J. Zhang and S. Hong, J. Org. Chem., 2010, 75,
3002–3006.
2,4,5-Trimethoxy-N-(pyridin-2-yl)benzamide
(1l). Yield:
55%; white needles; 1H NMR (CDCl3, 400 MHz): δ 8.82 (s, NH),
8.42 (1H, d, J = 4.0 Hz), 8.31 (m, 1H), 7.8 (m, 1H), 7.19–7.14
(m, 3H); 13C NMR (CDCl3, 100 MHz): δ 166.6, 153.2, 151.7,
139.3, 119.8, 114.9, 107.4, 60.9, 56.3; ESIMS: m/z 289.3
+
[M + H]+; HRMS: m/z 289.1152 [M + H]+ calcd for C15H17N2O4
(289.1182).
General method of synthesis of hydroxamic acids (Table 1,
entry 13)
To the mixture of MnO2 (25 mol%, added in 3 portions), alde-
hyde (1 equiv.) and KOH (0.01 mmol; added portion-wise in
3 batches) was added nitrobenzene (1.2 equiv.) and the reac-
tion mixture was heated at 120 °C under a nitrogen atmos-
phere for 48 h. The purification using silica gel column
chromatography gave amides and hydroxamic acids in a
30 : 70 ratio.
4-Chloro-N-hydroxy-N-phenylbenzamide (2a). White solid;
1H NMR (CDCl3, 400 MHz): δ 7.84 (d, J = 12.0 Hz, 2H), 7.75 (s),
7.64 (d, J = 8.2 Hz, 2H), 7.50 (d, J = 12.0 Hz, 2H), 7.40 (t, J =
7 N. Owston, A. Parker and J. Williams, Org. Lett., 2007, 9,
73–75.
8 (a) J. W. Bode and S. Sohn, J. Am. Chem. Soc., 2007, 129,
13798–13799; (b) P.-C. Chiang, Y. Kim and J. Bode, Chem.
Commun., 2009, 4566–4568; (c) H. Vora and T. Rovis, J. Am.
Chem. Soc., 2007, 129, 13796–13797.
6468 | Org. Biomol. Chem., 2014, 12, 6465–6469
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
9 P.-C. Chiang, Y. Kim and J. W. Bode, Chem. Commun., 2009, 19 Z. Liu, J. Zhang, S. Chen, E. Shi, Y. Xu and X. Wan, Angew.
4566–4568. Chem., Int. Ed., 2012, 51, 3231–3235.
10 (a) K. Ekoue-Kovi and C. Wolf, Chem. – Eur. J., 2008, 14, 20 K. Yoichiro, U. Tadamasa, K. Atsushi and T. Kazuhiko,
6302–6315; (b) T. Annegret, R. Ivo and B. Matthias, Angew. Chem., Int. Ed., 2011, 123, 10590–10592.
Eur. J. Org. Chem., 2001, 525–528; (c) D. J. Cardin, 21 E. Saxon and C. Bertozzi, Science, 2000, 287, 2007–2010.
B. Cetinkaya and M. F. Lappert, Chem. Rev., 1972, 72, 22 A. Bhattacharya, V. C. Purohit, V. Suarez, R. Tichkule,
545–574.
G. Parmer and F. Rinaldi, Tetrahedron Lett., 2006, 47, 1861–
1864.
23 F. T. Wong, P. K. Patra, J. Seayad, Y. Zhang and J. Y. Ying,
Org. Lett., 2008, 10, 2333–2336.
11 Y. Tamaru, Y. Yamada and Z.-i. Yoshida, Synthesis, 1983,
474–476.
12 (a) M. Pilo, A. Porcheddu and L. De Luca, Org. Biomol.
Chem., 2013, 11, 8241–8246; (b) J. W. Chang, T. Ton, 24 F. Xiao, Y. Liu, C. Tang and G.-J. Deng, Org. Lett., 2012, 14,
S. Tania, P. Taylor and P. Chan, Chem. Commun., 2010, 46,
922–924.
13 J. W. W. Chang and P. W. H. Chan, Angew. Chem., Int. Ed.,
2008, 47, 1138–1140.
984–987.
25 C. Battilocchio, J. M. Hawkins and S. V. Ley, Org. Lett.,
2014, 16, 1060–1063.
26 D. Walkinshaw and X. Yang, Curr. Oncol., 2008, 15, 237–243.
14 (a) J. Li, F. Xu, Y. Zhang and Q. Shen, J. Org. Chem., 2009, 27 L. M. Lima and E. J. Barreiro, Curr. Med. Chem., 2005, 12,
74, 2575–2577; (b) S. Seo and T. Marks, Org. Lett., 2008, 10,
317–319.
15 S. Murahashi, T. Naota and E. Saito, J. Am. Chem. Soc.,
1986, 108, 7846–7847.
16 A. Yamamoto, Y. Kayaki, K. Nagayama and I. Shimizu,
Synlett, 2000, 925–937.
17 (a) P. Dawson, T. Muir, I. Clark-Lewis and S. Kent, Science,
23–49.
28 C. Doornkamp and V. Ponec, J. Mol. Catal. A: Chem., 2000,
162, 19–32.
29 A. Maltha, M. Muhler and V. Ponec, Appl. Catal., A, 1994,
115, 69–84.
30 M. Colombo, S. Bossolo and A. Aramini, J. Comb. Chem.,
2009, 11, 335–337.
1994, 266, 776–779; (b) N. Shangguan, S. Katukojvala, 31 N. K. Downer and Y. A. Jackson, Org. Biomol. Chem., 2004,
R. Greenberg and L. Williams, J. Am. Chem. Soc., 2003, 125,
7754–7755.
18 W.-K. Chan, C.-M. Ho, M.-K. Wong and C.-M. Che, J. Am.
Chem. Soc., 2006, 128, 14796–14797.
2, 3039–3043.
32 C. Cheng, G. Sun, J. Wan and C. Sun, Synlett, 2009, 2663–
2668.
33 S. J. Balkrishna and S. Kumar, Synthesis, 2012, 1417–1426.
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 6465–6469 | 6469