Ethyl 2-cyano-2-(4-nitrophenylsulfonyloxyimino)acetate-mediated lossen rearrangement: Single-pot racemization-free synthesis of hydroxamic acids and ureas from carboxylic acids

Article abstract of DOI:10.1021/jo4026429

Ethyl 2-cyano-2-(4-nitrophenylsulfonyloxyimino)acetate (4-NBsOXY) mediated Lossen rearrangement and its application for the synthesis of ureas is demonstrated. Required hydroxamic acids for the Lossen rearrangements were synthesized from carboxylic acids using the same reagent. Finally, reaction of an amine with the produced isocyanate resulted in urea. Good yields without racemization were achieved under milder and simpler reaction conditions. Reactions are compatible with common N-protecting groups, such as Boc, Fmoc, Cbz, and benzyl, as well as various OH protecting groups, such as ^tBu and Bzl. Conversion from carboxylic acid to urea is achieved in one pot. Most importantly, byproducts Oxyma [ethyl 2-cyano-2-(hydroxyimino)acetate] and 4-nitrobenzenesulfonic acid can be recovered easily and can be recycled to prepare the reagent. Thus, the method is environmentally friendly and cost-effective.

Full text of DOI:10.1021/jo4026429

Article
pubs.acs.org/joc
Ethyl 2‑Cyano-2-(4-nitrophenylsulfonyloxyimino)acetate-Mediated
Lossen Rearrangement: Single-Pot Racemization-Free Synthesis of
Hydroxamic Acids and Ureas from Carboxylic Acids
Kishore Thalluri, Srinivasa Rao Manne, Dharm Dev, and Bhubaneswar Mandal*
Department of Chemistry Indian Institute of Technology Guwahati, Guwahati 781039, India
S
* Supporting Information
A B S T R A C T : E t h y l
2 - c y a n o - 2 - ( 4 -
nitrophenylsulfonyloxyimino)acetate (4-NBsOXY) mediated
Lossen rearrangement and its application for the synthesis of
ureas is demonstrated. Required hydroxamic acids for the
Lossen rearrangements were synthesized from carboxylic acids
using the same reagent. Finally, reaction of an amine with the
produced isocyanate resulted in urea. Good yields without racemization were achieved under milder and simpler reaction
conditions. Reactions are compatible with common N-protecting groups, such as Boc, Fmoc, Cbz, and benzyl, as well as various
t
OH protecting groups, such as Bu and Bzl. Conversion from carboxylic acid to urea is achieved in one pot. Most importantly,
byproducts Oxyma [ethyl 2-cyano-2-(hydroxyimino)acetate] and 4-nitrobenzenesulfonic acid can be recovered easily and can be
recycled to prepare the reagent. Thus, the method is environmentally friendly and cost-effective.
On the other hand, hydroxamic acids were prepared by the
reaction of carboxylic acid or N-protected amino acids with
hydroxylamine hydrochloride in the presence of alkyl
chloroformate,14 cyanuric chloride,25 TFFH (tetramethylfluor-
oformamidinium hexafluorophosphate),26 coupling reagents,27
and other important methods.28 They also can be prepared
from esters using KCN29 and from N-acyloxazolidinone using
samarium triflate.30 The major drawback of these methods is
the usage of toxic reagents and harsh reaction conditions. These
methods also cause racemization and are hence not applicable
to amino acids. Thus, simpler and more efficient methods for
preparation of hydroxamic acids from N-protected amino acids
are still needed.
Here we describe an alternative method for synthesizing
racemization-free hydroxamic acids at ambient conditions
without using any acid chlorides or strong bases. We also
have extended the same methodology for conversion of the
hydroxamic acid, which was prepared in the first step, to ureas
via Lossen rearrangement using the same coupling reagent.
Finally, a one-pot protocol for the whole conversion is
described.
INTRODUCTION
■
The urea linkages and hydroxamic acids have interesting
applications in medicinal chemistry1 and in structural
chemistry.2 Many urea based compounds are potentially used
in pharmaceutical industry. For example, unsymmetrically
substituted ureas are potential inhibitors of HIV-1 protease,3
microbial alkaline protease,4 and several other classes of
enzymes.5 They have important application in dye chemistry
as well. Similarly, hydroxamic acids exhibit a wide range of
biological activities such as antihypertensive drugs, antibacte-
rial,6 inhibitors of various metalloproteases,7 inhibition of
peptide deformylase (PDF),8 and orally active human
epidermal growth factor receptor-2 sheddase inhibitor for the
treatment of cancer.9 Some hydroxamates are known as highly
potent tumor necrosis factor converting enzyme inhibitors
(TACE, ADAM17)10 and strong bidentate metal ion
chelators.11
Numerous synthetic methods for the synthesis of ureas have
been developed. Urea and its derivatives were synthesized via
azide, isocynate, or carbamate intermediates. Several coupling
reagents have been used in the last two decades such as CDI
(N,N-carbonyldiimidazole),12 N,N-disuccinimidocarbonate,13
EDC (1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide)/
DMAP (N,N-dimethylpyridin-4-amine),14 1,1-carbonylbisben-
zotriazole,15 and PPh3−CCl4−TEA system.16 Some other
methods involve Me3SiCl,17 cyanuric chloride,18 bromodime-
thylsulfonium bromide (BDMS),19 Zr(IV) catalyst,20 β-
elimination of haloform,21 Zn(OTf)2,22 N,O-bis-
(ethoxycarbonyl)hydroxylamine,23 and N-(tert-butyloxycarbon-
yl)-O-methanesulfonylhydroxamic acid.24 However, a major
disadvantage of most of the coupling reagents invented to date
is the generation of undesired byproducts and chemical waste
as well as racemization.
RESULTS AND DISCUSSION
■
Ethyl 2-cyano-2-(4-nitrophenylsulfonyloxyimino)acetate (4-
NBsOXY, I) (Figure 1) was used as a new coupling reagent
for preparation of hydroxamic acids and a new reagent for
Lossen rearrangement to convert the obtained hydroxamic
acids to urea. Compound I can be easily prepared by the
reaction of Oxyma and sulfonyl chloride in the presence of
Received: November 30, 2013
© XXXX American Chemical Society
A
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acid (2p), were observed in the HPLC profile of 2p, whereas a
single peak at 3.24 min, corresponding to the single
enantiomer, was noted at the HPLC profile of L-Boc-
phenylalanine hydroxamic acid (2o) (Figure 2). Thus, there
was no detectable racemization for the preparation of
hydroxamic acids using the present reagent.
A possible reaction mechanism is shown in Figure 3 and
Scheme 1. At first, the active Oxyma ester of carboxylic acid
(III) may form via transient intermediate II. Intermediate III
Figure 1. Ethyl 2-cyano-2-(4-nitrophenylsulfonyloxyimino)acetate (I,
4-NBsOXY) and Oxyma (ethyl 2-cyano-2-(hydroxyimino)acetate).
1
could be isolated and characterized by H and 13C NMR and
HRMS (see the Experimental Section and the Supporting
Information, Figure S113−115). In a second step, hydroxyl-
amine hydrochloride reacts with III to produce the desired
hydroxamic acid. DMAP may act as an acyl-transfer catalyst as
known for Steglich esterification.34 We commenced the
reaction using benzoic acid and 4-NBsOXY in the presence
of DIPEA/DMAP and recorded the C13 NMR in CDCl3 in an
NMR tube. At the initial stage, the peak for the carbonyl carbon
(a) of benzoic acid was noted at δ172.8 ppm as well as the
carbonyl carbon (b) and the aromatic carbon at para position
(c) of 4-NBsOXY was noted at 155.5 and 151.9 ppm,
respectively. At 30 min, four new peaks replaced those; two
peaks at 160.4 and 156.7 ppm (d and e) correspond to
intermediate III and the other two peaks at 151.7 and 148.0
ppm (f and g) correspond to the byproduct 4-nitro-
benzenesulfonic acid. Hydroxylamine hydrochloride was then
added. NMR was checked after 90 min of the addition of
hydroxylamine hydrochloride. The peaks d and e shifted to
164.7 ppm (h), 158.7 ppm (i), which correspond to 2a and the
byproduct, Oxyma, respectively. Intermediate III was isolated
and characterized with various spectroscopic techniques. These
observations clearly support the proposed mechanism as
DIPEA using a reported protocol.31 This reagent is stable at
room temperature and can be stored for long periods of time.
Oxyma was largely used as a racemization suppressant in
peptide synthesis.32
Hydroxamic acids were prepared by preactivation of the
carboxylic acids with I (1 equiv) in the presence of DIPEA and
a catalytic amount of DMAP (N,N-dimethylpyridin-4-amine)
(0.1 mol %) at room temperature, for 30 min in anhydrous
THF, followed by the addition of hydroxylamine hydrochloride
in DMF with DIPEA (1.5 equiv). It required 2 h for complete
conversion at room temperature as monitored by TLC.33
For optimization, we screened a variety of bases, e.g., DIPEA,
NMM (N-methylmorpholine), Et3N, and DABCO (1,4-
diazabicyclo[2.2.2]octane), using the reaction between benzoic
acid and hydroxylamine hydrochloride (Table 1). We found
DIPEA and a catalytic amount of DMAP (0.1 mol %) afforded
higher yields. DMAP may act as an acyl-transfer catalyst as
known for Steglich esterification.34
a
Table 1. Optimization of the Reaction Conditions
1
depicted in Figure 3. Time-dependent HNMR experiments
(Supporting Information, Figure S152−161) also confirm that.
However, the possibility of direct conversion of intermediate II
to the hydroxamic acid 2a cannot be obviated. In our method,
most probably, the reaction proceeds via intermediate III, as (a)
we could isolate III and (b) we are adding hydroxyl amine
hydrochloride after formation of III (30 min). A plausible
pathway explaining the involvement of DMAP is also proposed
on the basis of the existing literature (Scheme 1).34
Finally, urea was prepared via Lossen rearrangement of
hydroxamic acids into the corresponding isocyanate by the
reaction of I (1 equiv) in the presence of DIPEA. Stirring was
continued at 0 °C for 90 min followed by the addition of amine
to the reaction mixture at room temperature. The reaction was
completed within 4 h.
b
entry
base (1 mmol)
DMAP (mmol %)
0.1
yield (%)
1
2
3
4
5
6
DIPEA
DIPEA
NMM
NMM
Et3N
82
61
73
52
50
30
0.1
0.1
0.1
DABCO
a
Reaction conditions: substrate 1a (122 mg, 1 mmol), 4-NBsOXY
(327 mg, 1 mmol.), DMAP (12.2 mg, mmol), DIPEA (322.5 mg, 2.5
mmol), hydroxylamine hydrochloride (103.5 mg, 1.5 mmol), and THF
(2 mL), at room temperature, time of the reaction fixed to 2.5 h.
b
Isolated yield.
We screened various solvents using the reaction between
benzhydroxamic acid (1 mmol) and benzylamine (1 mmol)
(Table 3). THF was found to be the best solvent. Use of
CHCl3, CH3CN, ethyl acetate, acetone, and DMF also gave
good results. Starting material 2a completely disappeared in all
solvents other than water. In the case of water, 74% (82 mg) of
the starting material (2a) was recovered.
We synthesized various ureas (Table 4) to explore the scope
of this method under the above optimized reaction condition.
The reaction works with aliphatic, aromatic, and long-chain
containing hydroxamic acids with good yields (70−92%).
Yields of the products were good even when aniline (3a 3e, and
3q) or a secondary amine (3d) was used as a nucleophile.
Selectivity of the reaction was checked with ethanol amines
(3f); selective attachment of the amino group was noted in this
Under these optimized conditions, this methodology was
applied to a wide variety of carboxylic acids that included
aromatic, aliphatic, and long-chain carboxylic acids (Table 2).
This methodology was also successfully applied to amino acids
with excellent yield. The reactions were compatible with
common N-protecting groups, e.g., Bn (entry 6), Cbz (entries 7
and 8), Fmoc (entries 9−14), and Boc (entries 15−17).
We investigated the racemization probability of the current
protocol by comparison of the HPLC profile of DL-Boc-
phenylalanine hydroxamic acid (2p) and L-Boc-phenylalanine
hydroxamic acid (2o) (chiral column, 5 μm, 2.1× 150 mm,
isocratic gradient of 10% 2-propanol in hexane, 20 min). Two
peaks with retention times of 3.06 and 3.81 min, corresponding
to the two enantiomers of DL-Boc-phenylalanine hydroxamic
B
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a
Table 2. Wide Scope of the Synthesis of Hydroxamic Acid Using I
a
Isolated yield. Reaction condition was similar to that mentioned in Table 1.
Figure 2. HPLC profile diagrams of products 2o and 2p.
case. A few drops of water were necessary for solubility of free
glycine (3g), and 81% yield was obtained.
excellent (70 to 90%) in all cases including the sterically
hindered amino acids, e.g., leucine, valine, phenylalanine, and
phenylglycine. All the products were characterized using H
and 13C NMR, HRMS, and IR. The product 3g was
characterized using XRD data also (Supporting Information,
Figure S181).
1
This methodology was compatible with common amine
protecting groups, such as Boc, Fmoc, Cbz, and benzyl, as well
as various side-chain alcohol protecting groups of amino acids,
t
such as Bu and Bzl. The yields were found to be good to
C
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Table 3. Synthesis of Ureas from Hydroxamic Acids Using I
a
in Various Solvents
entry
solvent
isolated yield (%)
1
2
3
4
5
6
7
CHCI3
CH3CN
THF
87
85
91
87
82
80
20
EtOAc
acetone
DMF
H2O
a
Reaction conditions: substrate 2a (137 mg, 1 mmol), 4-NBsOXY
(327 mg, 1 mmol), DIPEA (193.5 mg, 1.5 mmol), amine (107 mg, 1
mmol), and solvent (2 mL), temperature (first 90 min at 0 °C and
then 4 h at room temparaure), total reaction time 5.5 h.
at 151.4 and 148.1 ppm (5 and 6) correspond to 4-nitro
benzenesulfonic acid. Finally, one new peak appeared at 155.7
ppm (7) after the addition of cyclohexyl amine, which
corresponds to the carbonyl carbon of urea. These observations
support the proposed mechanism depicted in Figure 4.
Finally, we achieved a one-pot synthesis of ureas from
carboxylic acids using I and obtained up to 71% yield. The one-
pot protocol requires 2 equiv of I: 1 equiv for activation of
carboxylic acid into Oxyma ester (III) which converts into
hydroxamic acid followed by the addition of hydroxylamine
hydrochloride and a further 1 equiv of I for conversion of
hydroxamic acid into urea via isocynate (Lossen rearrange-
ment). The scope of the one-pot protocol was investigated with
a variety of N-protected amino acids. All of the amino acids,
even with bulky side chains, produced good yields (Table 5).
We determined racemization in our method of urea synthesis
from carboxylic acid using the reaction starting from DL-Boc-
phenylalanine (3s) and L-Boc-phenylalanine (3r). In both cases,
the methyl ester of phenylglycine was used as nucleophile.
Analytical HPLC profiles of products 3r and 3s (symmetry C8,
5 μm, 3.0 × 150 mm analytical column, CH3CN in H2O with
0.1% formic acid, linear gradient from 0 to 100% CH3CN in
H2O up to 10 min, then 10 to 20 min 100% CH3CN) were
compared. Two peaks with retention times of 10.73 and 11.17
min, which correspond to the two diastereomers present in the
product, appeared in the HPLC profile of 3s. On the other
hand, a single peak at 10.89 min was observed in the HPLC
profile of 3r, which corresponds to the single stereoisomeric
product (Figure 5). This implies the current method does not
cause any racemization. The singlet at δ 3.71 ppm for methoxy
proton of 3r and two singlets at δ 3.70 ppm and δ 3.68 ppm for
the same of 3s in 1H NMR confirm that (Figure 5). Many other
Figure 3. Plausible reaction mechanism for the synthesis of
hydroxamic acids by I as noticed using C13 NMR experiments.
Scheme 1. Plausible Mechanism for the Involvement of
DMAP33
A possible reaction mechanism is shown in Figure 4. At first,
substrate 2a reacts with I and an active O-sulfonylated
intermediate (IV) forms at 0 °C. In the second step, IV
undergoes Lossen rearrangement to isocynate V, which was
1
characterized by H and 13C NMR and HRMS (Supporting
1
Information, Figures S116−118). Finally, nucleophilic amine
reacts with V to produce urea 3a. To identify the intermediate,
we performed the reaction between hydroxamic acid and 4-
NBsOXY in the presence of DIPEA in an NMR tube using
CDCl3 as a solvent, and 13C NMR was recorded at the specified
time interval. Initially, three peaks were present, one at 166.8
ppm (1) corresponding to the carbonyl carbon of the
hydroxamic acid (2a) and the other two peaks at 155.5 and
151.9 ppm (2 and 3) corresponding to the carbonyl carbons of
4-NBsOXY. At 90 min, the peaks 1, 2, and 3 were replaced by
4, 5, and 6, respectively. The peak at 162.2 ppm (4)
corresponds to the carbonyl carbon of Oxyma, and the peaks
peaks in H and 13C NMR also support that.
Stepwise conversion of the Fmoc-L-Ala-OH to hydroxamic
acid and that to urea (with methyl ester of leucine) was
performed by 4-nitrobenzenesulfonyl chloride, it worked as
expected (yield ∼50%). However, the one-pot protocol for the
same synthesis with 4-nitrobenzenesulfonyl chloride decreased
the yield to 30%. Moreover, 1.5% racemization (Supporting
Information, Figure S138) was observed. On the other hand,
use of I gave 61% yield for the same reaction under the same
conditions without detectable racemization (Supporting
Information, Figure S131). Thus, use of I is better than that
of the 4-nitrobenzenesulfonyl chloride.
D
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a
Table 4. Wide Scope of the Synthesis of Ureas Using I
a
Isolated yield; the products were characterized by NMR, ESI-MS, and IR; all amino acids were L-amino acids except 13, which had a DL
configuration.
From the avaliable litearature we found only one report for
one-pot conversion of carboxylic acids into urea that uses
carbonyl diimidazole.12 However, that reaction needs 60 °C
temperature and does not ensure retention of chiral integrity.
On the other hand, our method works at room temperature
and retains chiral integrity. Most importantly, byproducts
generated in our method, Oxyma and 4-nitrobenzenesulfonic
acid, were easily recovered by simple acid−base workup or a
column chromatographic separation after acid wash of the
reaction mixture. Chlorination of the recovered 4-nitro-
benzenesulfonic acid with sulfonyl chloride at 60 °C in toluene
gave 4-nitrobenzenesulfonyl chloride, which was treated with
the recovered Oxyma in the presence of DIPEA to regenerate I.
NMR spectra of the recovered byproducts were as good as the
commercial sample (Supporting Information, Figure S173−
178). Characteristic spectra of the regenerated I and the
products synthesized using that were also identical with those
spectra of the products obtained using other batch of the
reagent I. Thus, this is the first report of a racemization free
one-pot synthesis of urea from carboxylic with a recyclable
reagent.
CONCLUSIONS
■
In summary, we have developed an efficient method for the
racemization-free synthesis of ureas and hydroxamic acids
under milder reaction conditions utilizing ethyl 2-cyano-2-(4-
nitrophenylsulfonyloxyimino)acetate (4-NBsOXY) as a recy-
clable reagent. The reaction is compatible with common N-
protecting groups, such as, Boc, Fmoc, Cbz, benzyl, and various
side-chain alcohol protecting groups of amino acids including
tBu and OBzl. Mechanistic investigation suggests a Lossen
rearrangement mediated urea formation. We described a one-
pot synthesis protocol of ureas from carboxylic acids with
reasonable yields using 4-NBsOXY (I). Furthermore, the
byproduct, Oxyma and 4-nitrobenzenesulfonic acid, can be
recovered easily and reused for reagent preparation. This is the
first report of one-pot racemization-free synthesis of urea from
carboxylic acid, which is performed with a recyclable reagent.
E
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Table 5. One-Pot Synthesis of Ureas from Carboxylic Acids
a
with 4-NBsOXY (I)
Figure 4. Plausible reaction mechanism for synthesis of urea with 13C
NMR.
EXPERIMENTAL SECTION
■
General Information. All reagents were purchased from
commercial sources. All amino acids are L-amino acids except glycine
unless otherwise noted. NMR spectra were recorded on 600 and 400
MHz spectrometers using CDCl3 and CD3OD as solvent and
tetramethylsilane (TMS) as internal standard. Chemical shifts (δ)
are reported in ppm, and spin−spin coupling constants (J) are given in
hertz. Abbreviations to denote the multiplicity of a particular signal are
s (singlet), d (doublet), t (triplet), q (quartet), and m (multiplet).
High-resolution mass spectra were recorded on a Q-TOF ESI-MS
instrument and Q-TOF LC/MS system. Reactions were monitored
using thin-layer chromatography with silica gel G254. Purification of
the reaction products was carried out by column chromatography
using silica gel (60−120 mesh) using eluent EtOAc/hexane. Solvents
were removed under reduced pressure using a Buchi rotary evaporator.
HPLC analysis was carried out with a chiral column (5 μm, 2.1× 150
mm) and symmetry C8 (5 μm, 3.5 × 150 mm) column coupled to a
UV−visible detector, and HPLC grade solvents were used for HPLC
analysis. Melting points were determined using a dedicated melting
point measuring apparatus, and FT-IR spectra were recorded on a FT-
IR spectrometer. X-ray data were collected on a diffractometer
equipped with a CCDc area detector using Mo Kα radiation. The
structures were solved by direct methods using SHELLX-97
a
Reaction conditions: acid (1 mmol), hydroxamic acid (1.5 mmol), 4-
NBsOXY (2 mmol), amine (1 mmol), DMAP (0.1 mmol), and
DIPEA (3 mmol), temperature (at first 2.5 h at rt, 90 min at 0 °C, and
rt for 4 h). Isolated yield.
b
(Gottingen, Germany) software.
̈
General Procedure for the Synthesis of Ethyl 2-Cyano-2-(4-
nitrophenylsulfonyloxyimino)acetate (4-NBsOXY, I) from Sul-
fonyl Chloride and Oxyma. 4-Nitrobenzenesulfonyl chloride (1
mmol) was added to a stirred solution of Oxyma (1 mmol) and
DIPEA (1 mmol) in DCM (2 mL) under nitrogen at 0 °C. Then the
reaction mixture was stirred at room temperature for 2 h. The progress
of the reaction was monitored by TLC. After completion of the
reaction, the resulting solution was extracted with DCM (2 × 10 mL)
and 5% citric acid (2 × 5 mL), washed with brine (2 × 5 mL), and
dried over anhydrous CaCl2. It was then dried in vacuo and purified by
recrystallization using hexane. Characterization data including the
XRD structure are reported.31
General Procedure for the Synthesis of Hydroxamic Acids
2a−m. 4-NBsOXY (I, 1 mmol) was added to a stirred solution of
carboxylic acid (1 mmol), DIPEA (1 mmol), and DMAP (0.1 mmol)
in THF (2 mL) at room temperature. The reaction mixture was stirred
for 30 min followed by the addition of hydroxylamine hydrochloride in
DMF (0.5 mL) and DIPEA (1 5 mmol). The progress of the reaction
was monitored by TLC. After completion of the reaction, the reaction
mixture was concentrated using a rotary evaporator and then diluted
with 15 mL of ethyl acetate, washed with 5% HCl (2 × 10 mL), 5%
NaHCO3 (2 × 10 mL), and saturated NaCl solution (2 × 10 mL), and
dried over anhydrous Na2SO4. Evaporation of the organic layer gave a
residue that was purified on silica gel column chromatography using
hexane and ethyl acetate.
General Procedure for the Synthesis of Urea 3a−r. 4-
NBsOXY (1 mmol) was added to a stirred solution of hydroxamic acid
(1 mmol) and DIPEA (1.5 mmol) in THF (2 mL) at 0 °C. Then the
reaction mixture was stirred at the same temperature for 90 min
followed by the addition of amine (1 mmol) and stirring at room
temperature for more 4 h. The progress of the reaction was monitored
by TLC. After completion of the reaction, the reaction mixture was
concentrated using a rotary evaporator and then diluted with 15 mL of
ethyl acetate, washed with 5% HCl (2 × 10 mL), 5% NaHCO3 (2 × 10
mL), and saturated NaCl solution (2 × 10 mL), and dried over
anhydrous Na2SO4, and the evaporation of the solvent gave a residue
F
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1
Figure 5. HPLC profile diagrams and H NMR spectra of products 3r and 3s (Phe = phenylalanine, Phg = phenylglycine, L-Boc-Phe-Phg-OMe
indicates the urea prepared from L-Boc-Phe-OH and Phg-OMe; similarly, DL-Boc-Phe-Phg-OMe indicates the urea prepared from DL-Boc-Phe-OH
and Phg-OMe).
that was purified on silica gel column chromatography using hexane
and ethyl acetate.
Isocyanatobenzene (Intermediate V): colorless liquid (109 mg,
90%); 1H NMR (600 MHz, CDCl3) δ 7.37−7.36 (d, J = 7.8 Hz, 2H),
7.28−7.26 (t, J = 7.2 Hz, 2H), 7.03−7.01 (t, J = 7.8 Hz, 1H); 13C
NMR (150 MHz, CDCl3, few drops of CD3OD for solubility) δ 132.6,
128.7, 127.6, 127.0, 124.1; HRMS (ESI) m/z [M + H]+ calcd for
C7H6NO 120.0449, found 120.0456.
General Procedure for the Synthesis of Urea from
Carboxylic Acids (One-Pot Protocol). 4-NBsOXY (1 mmol) was
added to a stirred solution of carboxylic acid (1 mmol), DIPEA (1
mmol), and DMAP (0.1 mmol) in THF (2 mL) at room temperature.
Then the reaction mixture was stirred for 30 min followed by the
addition of hydroxylamine hydrochloride in DMF (0.5 mL) and
DIPEA (1.5 mmol) and stirred for more 2 h at room temperature. 4-
NBsOXY (1 mmol) and DIPEA (1 mmol) were added again to the
above reaction mixture at 0 °C and stirring continued for 90 min at the
same temperature followed by addition of amine (1 mmol) and
stirring at room temperature for further 4 h. The progress of the
reaction was monitored by TLC. After completion of the reaction, the
reaction mixture was concentrated using rotary evaporator and then
diluted with 15 mL of ethyl acetate, washed with 5% HCl (2 × 10
mL), 5% NaHCO3 (2 × 10 mL), and saturated NaCl solution (2 × 10
mL), and dried over anhydrous Na2SO4. The obtained residue that
was purified on silica gel column chromatography using hexane and
ethyl acetate
N-Hydroxybenzamide (2a):35 white solid (122 mg, 82%); mp
1
125−127 °C; H NMR (600 MHz, CDCl3) δ 7.72−7.71 (d, J = 7.8
Hz, 2H), 7.50−7.48 (t, J = 7.2 Hz, 1H), 7.41−7.38 (t, J = 7.8 Hz, 2H),
3.20 (br, 1H); 13C NMR (150 MHz, CDCl3, few drops of CD3OD for
solubility) δ 166.8, 131.9, 131.5, 128.6, 127.0; FT-IR (KBr) 3296,
3058, 2758, 1643, 1612, 1573, cm−1; HRMS (ESI) m/z [M + H]+
calcd for C7H8NO2 138.0555, found 138.0553.
N-Hydroxy-2-phenylacetamide (2b): white solid (119 mg, 79%);
mp 130−132 °C; 1H NMR (600 MHz, CDCl3) δ 7.34−7.24 (m, 5H),
3.49 (s, 2H), 2.30 (br, 1H); 13C NMR (150 MHz, CDCl3, few drops
of CD3OD for solubility) δ 169.36, 134.25, 126.3, 129.1, 128.7, 128.5,
127.2, 40.0; FT-IR (KBr) 3190, 3029, 2923, 1685, 1630, 1545 cm−1;
HRMS (ESI) m/z [M + H]+ calcd for C8H10NO2 152.0712, found
152.0718.
Bz-Oxyma (Intermediate III): white solid (226 mg, 92%); 1H NMR
(600 MHz, CDCl3) δ 8.20−8.18 (d, J = 7.8 Hz, 2H), 7.72−7.70 (t, J =
7.8 Hz, 1H), 7.56−7.53 (t, J = 7.8 Hz, 2H), 4.53−4.49 (q, J = 7.2 Hz,
2H), 1.45−1.43 (t, J = 7.2, 3H); 13C NMR (150 MHz, CDCl3) δ
160.8, 157.1, 135.3, 131.8, 130.7, 129.3, 125.9, 107.2, 64.7, 14.1;
HRMS (ESI) m/z [M + Na]+ calcd for C12H10N2O4Na 269.0538,
found 269.0555
N-Hydroxyfuran-2-carboxamide (2c): white solid (96 mg, 76%);
mp 122−123 °C; 1H NMR (400 MHz, CDCl3) δ 8.81 (br, 2H), 7.63−
7.62 (d, J = 7.2 Hz, 1H), 7.31−7.30 (d, J = 7.2 Hz, 1H), 6.54−6.53 (d,
J = 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 162.4, 147.0, 144.3,
119.3, 112.1 FT-IR (KBr) 3304, 3066, 2972, 1693, 1646, 1540 cm−1;
HRMS (ESI) m/z [M + H]+ calcd for C5H6NO3 128.0348, found
128.0348.
G
dx.doi.org/10.1021/jo4026429 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
N-Hydroxypicolinamide (2d): white solid (102 mg, 74%); mp
125−126 °C; H NMR (400 MHz, CDCl3) δ 10.5 (br, 2H), 8.48−
8.47 (d, J = 4.2 Hz, 1H), 8.07−8.06 (d, J = 7.8 Hz, 1H), 7.78−7.75 (m,
1H), 7.37−7.34 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 162.2,
149.5, 148.4, 137.6, 126.7, 122.5 FT-IR (KBr) 3324, 3166, 2961, 1683,
1626, 1550, cm−1; HRMS (ESI) m/z [M + H]+ calcd for C6H7N2O2
139.0508, found 139.0510.
170.3, 156.3, 143.6, 141.1, 127.6, 127.6, 124.9, 119.8, 66.9, 49.1, 46.9,
18.0; FT-IR (KBr) 3426, 3306, 2925, 1685, 1618, 1533 cm−1; HRMS
(ESI) m/z [M + H]+ calcd for C18H19N2O4 327.1345, found 327.1331.
(9H-Fluoren-9-yl)methyl (1-(hydroxyamino)-3-methyl-1-oxobu-
tan-2-yl)carbamate (2l): white solid (265 mg, 75%); mp 173−174
°C; 1H NMR (600 MHz, CDCl3, few drops of CD3OD for solubility)
δ 7.74−7.73(d, J = 7.2 Hz, 2H), 7.55−7.51 (d, J = 6.6 Hz, 2H), 7.38−
7.36 (t, J = 7.2 Hz, 2H), 7.29−7.27 (t, J = 7.8 Hz, 2H), 5.9 (br, 1H),
4.41−4.38 (d, J = 7.2 Hz, 2H), 4.33−4.30 (m, 1H), 4.18−4.16 (t, J =
7.2 Hz, 1H), 2.15−1.93 (m, 1H), 0.92−0.90 (d, J = 6.6 Hz, 3H),
0.89−0.87 (d, J = 6.6 Hz, 3H); 13C NMR (150 MHz, CDCl3, few
drops of CD3OD for solubility) δ 168.8, 156.8, 143.8, 141.3, 127.8,
127.1, 125.0, 120.0, 67.2, 58.3, 47.1, 30.9, 19.0, 18.4; FT-IR (KBr)
3305, 3208, 2925, 2467, 1686, 1647, 1536; HRMS (ESI) m/z [M +
H]+ calcd for C20H23N2O4 355.1658, found 355.1650.
1
N-Hydroxydodecanamide (2e): white solid (174 mg, 81%); mp
1
75−76 °C; H NMR (600 MHz, CDCl3) δ 2.46−2.44 (t, J = 7.8 Hz,
2H), 1.61−1.57 (m, 2H), 1.28−1.23 (m, 16H), 0.86−0.84 (t, J = 7.2
Hz, 3H); 13C NMR (150 MHz, CDCl3, few drops of CD3OD for
solubility) δ 171.7, 33.1, 32.0, 29.7, 29.6, 29.4, 29.4, 29.3, 25.6, 22.7,
14.1; FT-IR (KBr) 3258, 2915, 2847, 1663, 1623, 1469, 1423, 720, 649
cm−1; HRMS (ESI) m/z [M + H]+ calcd for C12H26NO2 216.1964,
found 216.1964.
(9H-Fluoren-9-yl)methyl (1-(hydroxyamino)-1-oxopropan-2-yl)-
N-(1-(hydroxyamino)-4-methyl-1-oxopentan-2-yl)benzamide
1
(methyl)carbamate (2m): white solid (262 mg, 77%); mp 160−161
(2f): white solid (202 mg, 81%); mp 122 °C; H NMR (600 MHz,
1
°C; H NMR (400 MHz, CDCl3) δ 7.69−7.67 (d, J = 7.6 Hz, 2H),
CDCl3, few drops of CD3OD for solubility) δ 7.76−7.75 (d, J = 7.8
Hz, 2H), 7.47−7.46 (t, J = 7.2 Hz, 1H), 7.38−7.37 (t, J = 5.4 Hz, 2H),
4.53−4.51 (m, 1H), 2.9 (br, 1H), 1.69−1.66 (m, 2H), 1.26−1.23 (m,
1H), 0.91−0.90 (d, J = 6 Hz, 3H), 0.88−0.87 (d, J = 6.6 Hz, 3H); 13C
NMR (150 MHz, CDCl3, few drops of CD3OD for solubility) δ 169.7,
168.2, 133.3, 131.8, 128.4, 128.1, 127.1, 126.8, 49.5, 40.9, 24.7, 22.4,
21.8; FT-IR (KBr) 3301, 2956, 2461, 1642, 1612, 1535, 1425, 866, 693
cm−1; HRMS (ESI) m/z [M + H]+ calcd for C13H19N2O3 251.1396,
found 251.1376.
7.48−7.46 (d, J = 7.6 Hz, 2H), 7.34−7.30 (t, J = 7.2 Hz, 2H), 7.25−
7.21 (t, J = 7.6 Hz, 2H), 4.61−4.59 (m, 1H), 4.36−4.34 (d, J = 6.6 Hz,
2H), 4.15−4.12 (t, J = 6.6 Hz, 1H), 2.72 (s, 3H), 1.26−1.25 (t, J = 7.6
Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 168.9, 157.0, 143.7, 141.3,
127.7, 127.1, 125.1, 120.0, 68.0, 51.8, 47.2, 29.7, 14.2; FT-IR (KBr)
3304, 3066, 2972, 1693, 1646, 1540 cm−1; HRMS (ESI) m/z [M +
Na]+ calcd for C19H20N2NaO4 363.1321, found 363.1320.
(9H-Fluoren-9-yl)methyl (1-(hydroxyamino)-2-methyl-1-oxopro-
pan-2-yl)carbamate (2n): white solid (255 mg, 75%); mp 172−174
Benzyl (2-(hydroxyamino)-2-oxoethyl)carbamate (2g): white
solid (174 mg, 78%); mp 119−121 °C; 1H NMR (600 MHz,
CDCl3) δ 7.44−7.17 (m, 5H), 5.16 (s, 2H), 3.95−3.94 (d, J = 5.4 Hz,
2H), 0.9 (br, 1H); 13C NMR (150 MHz, CDCl3, few drops of CD3OD
for solubility) δ 167.4, 157.2, 136.1, 128.5, 128.2, 128.0, 67.2, 41.9; FT-
IR (KBr) 3318, 2943, 1705, 1672, 1536, 770, 697 cm−1; HRMS (ESI)
m/z [M + H]+ calcd for C10H13N2O4 225.0875, found 225.0886.
Benzyl (2-(hydroxyamino)-2-oxo-1-phenylethyl)carbamate (2h):
1
°C; H NMR (600 MHz, CDCl3) δ 7.76−7.75 (d, J = 7.2 Hz, 2H),
7.58−7.57 (d, J = 7.2 Hz, 2H), 7.41−7.38 (t, J = 7.2 Hz, 2H), 7.33−
7.31 (t, J = 7.2 Hz, 2H), 4.43−4.42 (d, J = 6.6 Hz, 2H), 4.18−4.17 (t, J
= 6.6 Hz, 1H), 1.44 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 172.5,
155.6, 143.8, 141.4, 127.9, 127.2, 125.0, 120.1, 66.5, 55.6, 47.2, 25.3;
FT-IR (KBr) 3304, 3066, 2972, 1693, 1646, 1540, cm−1; HRMS (ESI)
m/z [M + Na]+ calcd for C19H20N2NaO4 363.1321, found 363.1324.
tert-Butyl (1-(hydroxyamino)-1-oxo-3-phenylpropan-2-yl)-
1
white solid (234 mg, 78%); mp 157−158 °C; H NMR (600 MHz,
1
carbamate (2o): white solid (224 mg, 80%); mp 135 °C; H NMR
CDCl3, few drops of CD3OD for solubility) δ 7.33−7.16 (m, 10H),
5.18 (s, 1H), 5.08 (s, 2H), 3.74 (br, 1H); 13C NMR (150 MHz,
CDCl3, few drops of CD3OD for solubility) δ 167.8, 156.1, 137.2,
136.0, 128.8, 128.7, 128.4, 128.3, 128.1, 127.9, 127.0, 126.8, 67.1, 56.1;
FT-IR (KBr) 3348, 3266, 2915, 1715, 1647, 1497, 751, 697 cm−1;
HRMS (ESI) m/z [M + H]+ calcd for C16H17N2O4 301.1188, found
301.1209.
(600 MHz, CDCl3) δ 7.30−7.29 (d, J = 6.6 Hz, 2H), 7.24−7.22 (d, J =
7.2 Hz, 1H), 7.14−7.13 (t, J = 7.2 Hz, 2H), 4.24−4.20 (m, 1H), 3.07−
3.0 (dd, J = 6.6 Hz, 1H), 2.97−2.94 (dd, J = 6.6 Hz, 1H), 2.03 (br,
1H), 1.40 (s, 9H); 13C NMR (150 MHz, CDCl3, few drops of CD3OD
for solubility) δ 168.9, 155.8, 136.4, 129.3, 128.5, 126.9, 80.4, 53.4,
38.7, 28.2; FT-IR (KBr) 3350, 3309, 2918, 2927, 1672, 1662, 1513
cm−1; HRMS (ESI) m/z [M + H]+ calcd for C14H21N2O4 281.1501,
found 281.1542.
(9H-Fluoren-9-yl)methyl (2-(hydroxyamino)-2-oxoethyl)-
1
carbamate (2i): white solid (249 mg, 80%); mp 127−128 °C; H
tert-Butyl (3-(benzyloxy)-1-(hydroxyamino)-1-oxobutan-2-yl)-
NMR (600 MHz, CDCl3) δ 7.76−7.75(d, J = 6.6 Hz, 2H), 7.58−7.57
(d, J = 6.6 Hz, 2H), 7.40−7.38 (t, J = 6.6 Hz, 2H), 7.32−7.30 (t, J =
5.4 Hz, 2H), 4.39−4.38 (d, J = 7.2 Hz, 2H), 4.19−4.16 (t, J = 6.6 Hz,
1H), 3.71−3.70 (d, J = 6 Hz, 2H), 3.37 (br, 1H); 13C NMR (150
MHz, CDCl3, few drops of CD3OD for solubility) δ 167.4, 157.3,
143.7,141.2, 127.7, 127.1, 125.0, 119.9, 67.2, 47.0, 41.9; FT-IR (KBr)
3342, 3259, 2922, 1695, 1667, 1551, 1281, 737, 698 cm−1; HRMS
(ESI) m/z [M + Na]+ calcd for C17H16N2O4Na 335.1008, found
335.0999.
1
carbamate (2q): white solid (259 mg, 80%); mp 168−169 °C; H
NMR (600 MHz, CDCl3) δ 7.35−7.28 (m, 5H), 5.4 (br, 1H) 4.57 (s,
2H), 4.52−4.50 (m, 1H), 4.30 (br, 1H), 4.11 (m, 1H), 1.42 (s, 9H),),
1.17−1.16 (d, J = 6 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 168.4,
156.0, 137.8, 128.6, 128.0, 80.6, 74.4, 71.8, 56.5, 28.4, 15.8; FT-IR
(KBr) 3331, 3260, 2983, 1679, 1637, 1525; HRMS (ESI) m/z [M +
Na]+ calcd for C16H24N2O5Na 347.1583, found 347.1584.
1,3-Diphenylurea (3a):36 white solid (176 mg, 83%); mp 225−226
°C; 1H NMR (400 MHz, CDCl3, few drops of CD3OD for solubility)
δ 7.90 (s, 2H), 7.33−7.31 (d, J = 7.6 Hz, 4H), 7.22−7.18 (t, J = 8 Hz,
4H), 6.96−6.92 (t, J = 7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3, few
drops of CD3OD for solubility) δ 152.7, 138.3, 129.0, 128.9, 123.0;
FT-IR (KBr) 3336, 2891, 2870, 1685, 1600, 1534 cm−1; HRMS (ESI)
m/z [M + H]+ calcd for C13H13N2O 213.1028, found 213.1018.
1-Benzyl-3-phenylurea (3b):37 white solid (205 mg, 91%); mp
(9H-Fluoren-9-yl)methyl (3-(hydroxyamino)-3-oxopropyl)-
1
carbamate (2j): white solid (264 mg, 81%); mp 170−171 °C; H
NMR (600 MHz, CDCl3) δ 7.66−7.65 (d, J = 7.2 Hz, 2H), 7.51−7.48
(d, J = 7.2 Hz, 2H), 7.31−7.28 (t, J = 7.2 Hz, 2H), 7.22−7.20 (t, J =
7.2 Hz, 2H), 4.26−4.25 (d, J = 6.6 Hz, 2H), 4.11−4.09 (t, J = 6.6 Hz,
1H), 3.67 (br, 1H), 3.30−3.28 (t, J = 6 Hz, 2H), 2.21−2.19 (t, J = 6
Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 168.6, 156.4, 143.8, 141.4,
127.8, 127.2, 125.2, 120.1, 67.4, 53.2, 47.2, 27.4; FT-IR (KBr) 3304,
3066, 2972, 1693, 1646, 1540 cm−1; HRMS (ESI) m/z [M + H]+ calcd
for C18H19N2O4 327.1345, found 327.1346.
1
173−174 °C; H NMR (400 MHz, CDCl3) δ 7.31−7.22 (m, 10H),
4.85 (br, 1H), 4.39−4.38 (d, J = 7.4 Hz, 4H); 13C NMR (100 MHz,
CDCl3) δ 156.6, 139.3, 137.6, 128.7, 128.5, 127.7, 127.6, 127.2, 122.7,
43.8; FT-IR (KBr) 3226, 2971, 2830, 1666, 1630, 1555; HRMS (ESI)
m/z [M + Na]+ calcd for C14H15N2O 227.1184, found 227.1185.
1-Cyclohexyl-3-phenylurea (3c):38 white solid (196 mg, 90%); mp
(9H-Fluoren-9-yl)methyl (1-(hydroxyamino)-1-oxopropan-2-yl)-
1
carbamate (2k): white solid (260 mg, 80%); mp 128−129 °C; H
NMR (600 MHz, CDCl3) δ 7.78−7.77 (d, J = 4.8 Hz, 2H), 7.61−7.59
(d, J = 7.8 Hz, 2H), 7.46−7.44 (t, J = 6 Hz, 2H), 7.31−7.29 (t, J = 7.8
Hz, 2H), 4.41−4.40 (d, J = 6.6 Hz, 2H), 4.31−4.27 (m, 1H), 4.12−
4.11 (t, J = 6.6 Hz, 1H), 2.5 (br, 1H), 1.39−1.38 (d, J = 6 Hz, 3H);
13C NMR (150 MHz, CDCl3, few drops of CD3OD for solubility) δ
1
168−169 °C; H NMR (600 MHz, CDCl3, few drops of CD3OD for
solubility) δ 7.31−7.26 (m, 4H), 7.07−7.06 (t, J = 6.8 Hz, 1H), 6.63
(s, 1H), 4.88−4.87 (d, J = 6.8 Hz, 1H), 3.65−3.62 (m, 1H), 1.96−1.94
(m, 2H); 1.69−1.67 (m, 2H), 1.59−1.57 (m, 1H), 1.38−1.34 (m, J =
H
dx.doi.org/10.1021/jo4026429 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
4.8 Hz, 2H), 1.17−1.14(m, 3H), 13C NMR (100 MHz, CDCl3, few
drops of CD3OD for solubility) δ 156.0, 139.4, 129.1, 122.9, 120.2,
48.9, 33.7, 25.7, 25.0; FT-IR (KBr) 3236, 2961, 2810, 1685,1620, 1585
cm−1; HRMS (ESI) m/z [M + H]+ calcd for C13H19N2O 219.1497,
found 219.1497.
N-Phenylpiperidine-1-carboxamide (3d): white solid (167 mg,
82%); mp 170−171 °C; 1H NMR (600 MHz, CDCl3) δ 7.50−7.48 (d,
J = 7.2 Hz, 2H), 7.35−7.34 (t, J = 7.2 Hz, 2H), 7.04−7.05 (t, J = 7.6
Hz, 1H), 3.40−3.34 (m, 4H), 2.6 (br, 1H), 1.45−1.41 (m, 6H); 13C
NMR (150 MHz, CDCl3, few drops of CD3OD for solubility) δ 156.7,
131.8, 131.6, 128.6, 127.0, 45.0, 28.4, 24.4; FT-IR (KBr) 3126, 2971,
2790, 1635, 1625, 1555 cm−1; HRMS (ESI) m/z [M + H]+ calcd for
C12H17N2O 205.1341, found 205.1333.
133.8, 131.7, 128.7, 128.6, 128.3, 127.2, 127.1, 57.5, 57.3, 52.3, 42.8,
24.8, 22.1, 22.0; FT-IR (KBr) 3365, 3317, 2956, 1744, 1660, 1637,
1567 cm−1; HRMS (ESI) m/z [M + Na]+ calcd for C22H27N3O4Na
420.1899, found 420.1896.
Methyl 2-(3-(1-benzamido-2-methylpropyl)ureido)-4-methylpen-
1
tanoate (3l): white solid (323 mg, 89%); mp 200 °C; H NMR (600
MHz, CDCl3) δ 8.09−8.07 (d, J = 7.8 Hz, 1H), 7.74−7.73 (d, J = 7.2
Hz, 2H), 7.43−7.28 (m, 3H), 4.88−4.86 (m, 1H), 4.28−4.25 (m, 1H),
3.65 (s, 3H), 2.18−2.16 (m, 1H), 1.65−1.50 (m, 2H), 1.28−1.24 (m,
1H), 0.96−0.95 (d, J = 6.6 Hz, 3H), 0.92−0.91 (d, J = 6.6 Hz, 3H),
0.86−0.84 (d, J = 6.6 Hz, 3H), 0.79−0.68 (d, J = 6.6 Hz, 3H); 13C
NMR (150 MHz, CDCl3) δ 174.7, 168.2, 158.2, 134.0, 131.7, 128.5,
127.4, 63.7, 52.0, 49.5, 41.2, 32.2, 28.3, 24.8, 22.9, 21.8, 19.0; FT-IR
(KBr) 3345, 2960, 1748, 1637, 1625, 1560 cm−1; HRMS (ESI) m/z
[M + H]+ calcd for C19H30N3O4 364.2236 found 364.2235.
1-(4-Cyanophenyl)-3-phenylurea (3e): white solid (175 mg, 74%);
1
mp 170−172 °C; H NMR (600 MHz, CDCl3) δ 7.85−7.83 (d, J =
Methyl 9-isobutyl-3,7-dioxo-1,5-diphenyl-2-oxa-4,6,8-triazade-
can-10-oate (3m): white solid (350 mg, 82%); mp 189−190 °C;
1H NMR (600 MHz, CDCl3) δ 7.43−7.21 (m, 5H), 6.27−6.26 (d, J =
7.8, 1H), 7.60−7.55 (m, 4H),, 7.40−7.38 (d, J = 7.6 Hz, 2H), 7.31−
7.27 (t, J = 7.8 Hz, 2H), 7.04−7.03 (d, J = 7.2 Hz, 1H); 13C NMR
(150 MHz, CDCl3) δ 152.8, 143.8, 138.4, 133.2, 128.7, 123.4, 119.6,
119.5, 118.4, 104.6; FT-IR (KBr) 3304, 3066, 2972, 1693, 1646, 1540,
cm−1; HRMS (ESI) m/z [M + H]+ calcd for C14H12N3O 238.0980,
found 238.0978.
6 Hz, 1H), 5.86−5.85 (br, 2H), 5.08 (s, 2H), 4.50−4.46 (m, 1H), 3.68
(s, 3H), 1.67−1.63 (m, 2H), 1.54−1.52 (m, 1H), 0.92−0.90 (d, J = 8.4
Hz, 3H), 0.89−0.88 (d, J = 8.4 Hz, 3H); 13C NMR (150 MHz,
CDCl3) δ 175.0, 157.3, 156.3, 136.2, 128.9, 128.7, 128.6, 128.2, 128.1,
127.4, 127.2, 126.0, 125.8, 67.1, 61.3, 52.2, 51.7, 49.7, 41.6, 24.9, 22.9,
22.0; FT-IR (KBr) 3299, 3034, 2958, 1726, 1689, 1636, 1571 cm−1;
HRMS (ESI) m/z [M + Na]+ calcd for C23H29N3O5Na 450.2005,
found 450.2006.
1-(2-Hydroxyethyl)-3-phenylurea (3f): white solid (163 mg, 91%);
mp 120−121 °C; 1H NMR (400 MHz, CDCl3) δ 7.83 (br, 1H), 7.27−
7.17 (m, 4H), 6.98−6.96 (t, J = 7.4 Hz, 1H), 5.9 (br, 1H), 3.58−3.55
(t, J = 5.2 Hz, 2H), 3.26−3.24 (t, J = 5.2 Hz, 2H); 13C NMR (100
MHz, CDCl3, few drops of CD3OD for solubility) δ 157.2, 139.2,
139.1, 128.8, 122.6, 119.5, 119.3, 61.7, 42.3; FT-IR (KBr) 3116, 2991,
2872, 1695, 1635, 1524 cm−1; HRMS (ESI) m/z [M + H]+ calcd for
C9H13N2O2 181.0977, found 181.0974.
Methyl 1-(9H-fluoren-9-yl)-9-isobutyl-5-methyl-3,7-dioxo-2-oxa-
4,6,8-triazadecan-10-oate (3n): white solid (362 mg, 80%); mp
1
201−203 °C; H NMR (600 MHz, CDCl3, few drops of CD3OD for
solubility) δ 7.77−7.76 (d, J = 7.2 Hz, 2H), 7.56−7.55 (d, J = 7.2 Hz,
4H); 7.41−7.39 (t, J = 7.4 Hz, 2H), 7.32−7.30 (t, J = 7.4 Hz, 2H),
5.55 (br, 1H), 5.22−5.20 (m, 1H), 4.41−4.35 (m, 3H), 4.24−4.20 (t, J
= 7.4 Hz, 1H), 3.73 (s, 3H), 1.63−1.43 (m, 6H), 0.95−0.94 (d, J = 6.6
Hz, 3H), 0.91−0.89 (d, J = 6.6 Hz, 3H); 13C NMR (150 MHz, CDCl3,
few drops of CD3OD for solubility) δ 174.8, 157.5, 156.6, 143.9, 141.3,
127.8, 127.2, 125.1, 120.0, 67.0, 55.9, 51.6, 49.5, 47.1, 41.6, 24.8, 22.9,
21.8, 21.2; FT-IR (KBr) 3294, 2955, 2926, 1730, 1694, 1637, 1573
cm−1; HRMS (ESI) m/z [M + Na]+ calcd for C25H31N3O5Na
476.2161, found 476.2159.
2-(3-Phenylureido)acetic acid (3g): white solid (161 mg, 81%); mp
1
96−97 °C; H NMR (400 MHz, CD3OD) δ 7.38−7.40 (d, J = 8 Hz,
2H), 7.21−7.19 (d, J = 8.4 Hz, 2H), 7.10−7.06 (t, J = 8 Hz, 2H),
6.84−6.80 (t, J = 7.6 Hz, 2H), 3.7 (s, 1H); 13C NMR (100 MHz,
CD3OD) δ 170.6, 158.3, 140.8, 129.9, 129.7, 128.5, 123.8, 120.5, 42.6;
FT-IR (KBr) 3216, 2951, 2892, 1772, 1665, 1645, 1544 cm−1; HRMS
(ESI) m/z [M − H]− calcd for C9H9N2O3 193.0613, found 193.0616.
1,3-Dibenzylurea (3h):39 white solid (211 mg, 88%); mp 172−173
°C; 1H NMR (400 MHz, CDCl3, few drops of CD3OD for solubility)
δ 7.32−7.22 (m, 10H), 6.82 (br, 2H), 4.37−4.36 (d, J = 7.4 Hz, 4H);
13C NMR (100 MHz, CDCl3, few drops of CD3OD for solubility) δ
161.5, 137.7, 128.7, 127.7, 127.0, 42.0; FT-IR (KBr) 3296, 3058, 2092,
1643, 1612, 1573 cm−1; HRMS (ESI) m/z [M + H]+ calcd for
C15H17N2O 241.1341, found 241.1336.
Methyl 1-(9H-fluoren-9-yl)-5-isopropyl-3,7-dioxo-9-phenyl-2-
oxa-4,6,8-triazadecan-10-oate (3o): white solid (396 mg, 79%);
1
mp 158−160 °C; H NMR (600 MHz, CDCl3, few drops of CD3OD
for solubility) δ 7.77−7.75 (d, J = 6.6 Hz, 2H), 7.63−7.62 (d, J = 7.8
Hz, 2H), 7.43−7.27 (m, 9H), 6.9 (br, 1H), 5.48−5.45 (m, 2H), 4.86
(m, 1H), 4.33−4.19 (m, 3H), 3.66 (s, 3H), 2.06−2.03 (m, 1H), 0.92−
0.89 (d, J = 7.2 Hz, 6H); 13C NMR (150 MHz, CDCl3, few drops of
CD3OD for solubility) δ 170.6, 155.0, 154.0, 142.5, 139.4, 136.3,
127.2, 126.6, 126.1, 125.6, 123.8, 118.4, 64.1, 62.0, 55.3, 50.7, 45.5,
31.0, 16.8; FT-IR (KBr) 3365, 3298, 2952, 1724, 1692, 1636, 1564
cm−1; HRMS (ESI) m/z [M + H]+ calcd for C29H32N3O5 502.2342,
found 502.2346.
Methyl 2-phenyl-2-(3-undecylureido)acetate (3i): white solid (334
1
mg, 92%); mp 78−80 °C; H NMR (600 MHz, CDCl3, few drops of
CD3OD for solubility) δ 7.32−7.27 (m, 5H), 5.42(s, 1H), 3.72 (s,
3H), 3.08−3.06 (t, J = 7.2 Hz, 2H), 1.58−1.53 (m, 2H), 1.44−1.39
(m, 2H), 1.25−1.18 (m, 14H), 0.84−0.82 (t, J = 7.2 Hz, 3H); 13C
NMR (150 MHz, CDCl3, few drops of CD3OD for solubility) δ 172.9,
158.1, 137.1, 128.8, 128.3, 127.3, 127.1, 57.2, 52.5, 40.1, 35.0, 31.9,
30.0, 29.5, 29.3, 26.8, 25.3, 22.6, 13.9; FT-IR (KBr) 3326, 2921, 2850,
1732, 1634, 1568 cm−1; HRMS (ESI) m/z [M + H]+ calcd for
C21H35N2O3 363.2648, found 363.2650.
Methyl 9-benzyl-1-(9H-fluoren-9-yl)-5,5-dimethyl-3,7-dioxo-2-
oxa-4,6,8-triazadecan-10-oate (3p): white solid (405 mg, 81%);
1
mp 180−182 °C; H NMR (400 MHz, CDCl3) δ 7.94−7.93 (d, J =
Methyl 2-(3-(1-benzamido-3-methylbutyl)ureido)propanoate
1
7.2 Hz, 2H), 7.82−7.80 (d, J = 7.8 Hz, 2H), 7.59−7.56 (t, J = 7.2 Hz,
3H), 7.51−7.45 (m, 5H), 7.36−7.34 (t, J = 7.2 Hz, 1H), 6.3 (s, 1H),
5.49−5.47 (d, J = 8.4 Hz, 1H), 4.85−4.80 (m,1H), 4.59−4.58 (d, J =
5.2 Hz, 2H), 4.41−4.39 (t, J = 6.4 Hz, 1H), 3.88 (s, 3H), 3.36−3.33
(dd, J = 6 Hz, 1H), 3.27−3.22 (dd, J = 6.4 Hz, 1H), 1.70 (s, 6H); 13C
NMR (100 MHz, CDCl3) δ 172.3, 155.1, 152.1, 143.6, 141.0, 135.9,
129.1, 128.3, 128.2, 127.5, 126.9, 126.8, 125.0, 119.7, 66.7, 60.3, 56.0,
52.0, 46.9, 38.0, 28.1; FT-IR (KBr) 3304, 3066, 2972, 1693, 1646,
1540 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C29H31N3NaO5
524.2161, found 524.2164
(3j): white solid (291 mg, 87%); mp 196−197 °C; H NMR (600
MHz, CDCl3) δ 7.76−7.75 (d, J = 7.2 Hz, 2H), 7.36−7.21 (m, 3H),
5.64 (br, 1H), 5.13 (m, 1H), 4.30−4.25 (m, 1H), 3.65 (s, 3H), 1.63−
1.59 (m, 2H), 1.36−1.25 (m, 3H), 0.85−0.84 (d, J = 5.4 Hz, 6H); 13C
NMR (150 MHz, CDCl3) δ 174.3, 167.5, 157.6, 134.0, 131.5, 128.9,
128.3, 127.4, 56.4, 52.0, 49.2, 43.6, 27.6, 22.2, 18.5; FT-IR (KBr) 3365,
3317, 2956, 1744, 1660, 1637, 1567 cm−1; HRMS (ESI) m/z [M +
H]+ calcd for C17H26N3O4 336.1923, found 336.1924.
Methyl 2-(3-(1-benzamido-3-methylbutyl)ureido)-2-phenylace-
1
tate (3k): white solid (357 mg, 90%); mp 202−203 °C; H NMR
(600 MHz, CDCl3, few drops of CD3OD for solubility) δ 7.80−7.80
(d, J = 7.8 Hz, 1H), 7.73−7.71(d, J = 7.2 Hz, 1H), 7.51−7.27(m, 8H),
5.42−5.40 (d, J = 7.2 Hz, 1H), 5.34−5.31 (m, 1H), 3.71 (s, 3H),
1.81−1.74 (m, 2H), 1.69−1.65 (m, 1H), 0.93−0.91 (d, J = 6.6 Hz,
3H), 0.90−0.89 (d, J = 6.6 Hz, 3H); 13C NMR (150 MHz, CDCl3, few
drops of CD3OD for solubility) δ 172.1, 168.4, 157.6, 136.7, 136.4,
Ethyl 4-(3-(1-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)-
amino)ethyl)ureido)benzoate (3q): white solid (360 mg, 74%); mp
174−175 °C; 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.92−7.90
(d, J = 7.2 Hz, 1H), 7.75−7.72 (d, J = 7.2 Hz, 3H), 7.59−7.25 (m,
8H), 5.60 (s, 1H), 5.30 (s, 1H), 4.41−4.33 (m, 4H), 4.21−4.18 (t, J =
6.6 Hz, 1H), 2.75 (s, 3H), 1.38−1.36 (t, J = 7.2 Hz, 3H), 1.19−1.17-
I
dx.doi.org/10.1021/jo4026429 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(t, J = 6.8 Hz, 3H) ; 13C NMR (100 MHz, CDCl3) δ 166.6, 158.9,
156.6, 143.7, 141.4, 139.4, 130.9, 127.9, 127.3, 125.2, 125.1, 124.4,
120.2, 118.3, 114.2, 67.8, 63.2, 60.9, 47.3, 31.7, 18.8, 14.5; FT-IR
(KBr) 3257, 2966, 2872, 1699, 1653, 1590 cm−1; HRMS (ESI) m/z
[M + H]+ calcd for C28H29N3NaO5 510.2005, found 510.2004
Methyl 6-benzyl-10,10-dimethyl-4,8-dioxo-2-phenyl-9-oxa-3,5,7-
triazaundecan-1-oate (3r): white solid (380 mg, 89%); mp 129−130
for financial support. K.T., S.R.M., and D.D. are thankful to
IITG for their fellowships.
REFERENCES
■
(1) (a) Kozikowski, A. P.; Zhang, J.; Nan, F.; Petukhov, P.;
Grajkowska, A. E.; Wroblewski, J. T.; Yamamoto, T.; Bzdega, T.;
Wroblewska, B.; Neale, J. H. J. Med. Chem. 2004, 47, 1729−1738.
(b) Flipo, M.; Beghyn, T.; Charton, J.; Leroux, A. V.; Deprez, P. B.;
Deprez-Poulain, R. Bioorg. Med. Chem. 2007, 15, 63−67.
(2) (a) Seebach, D.; Beck, A. K.; Bierbaum, D. J. Chem. Biodiversity.
2004, 1, 1111−1239. (b) Cheng, R. P.; Gellman, S. H.; De-Grado, W.
F. Chem. Rev. 2001, 101, 3219−3232. (c) Hill, D. J.; Mio, M. J.; Prince,
R. B.; Hughes, T. S.; Moore, J. S. A. Chem. Rev. 2001, 101, 3893−4012.
(d) Flipo, M.; Charton, J.; Hocine, A.; Dassonneville, S.; Deptez, B.;
Deprez-Poulain, R. J. Med. Chem. 2009, 52, 6790−6802. (e) Gellman,
S. H. Acc. Chem. Res. 1998, 31, 173−180.
1
°C; H NMR (600 MHz, CDCl3) δ 7.36−7.18 (m, 10H), 5.55 (br,
1H), 5.46−5.45 (d, J = 6 Hz, 1H), 5.32−5.31 (m, 1H), 3.71 (s, 3H),
3.07−3.03 (m, 2H), 1.32 (s, 9H), 13C NMR (150 MHz, CDCl3, few
drops of CD3OD for solubility) δ 171.7, 156.8, 155.5, 136.6, 136.3,
129.1, 128.6, 128.5, 128.2, 128.1, 126.9, 126.3, 79.5, 58.7, 57.0, 52.1,
40.2, 27.9 ; FT-IR (KBr) 3388, 3341, 3061, 2983, 1738, 1681, 1635,
1504 cm−1; HRMS (ESI) m/z [M + H]+ calcd for C23H30N3O5
428.2185, found 428.2193.
DL-Methyl 6-benzyl-10,10-dimethyl-4,8-dioxo-2-phenyl-9-oxa-
3,5,7-triazaundecan-1-oate (3s): white solid (380 mg, 88%); mp
1
129−130 °C; H NMR (600 MHz, CDCl3) δ 7.38−7.16 (m, 10H),
(3) Lam, P. Y.; Jadhav, P. K.; Eyermann, C. J.; Hodge, C. N.; Ru, Y.;
Bacheler, L. T.; Meek, J. L.; Otto, M. J.; Rayner, M. M.; Wong, Y. N.;
Chang, C. H.; Weber, P. C.; Jackson, D. A.; Sharpe, T. R. Science 1994,
263, 380−384.
(4) Broadbridge, R. J.; Sharma, R. P.; Akhtar, M. Chem. Commun.
1998, 1449−1450.
(5) Kozikowski, A. P.; Zhang, J.; Nan, F. P.; Petukhov, A.;
Grajkowska, E.; Wroblewski, J. T.; Yamamoto, T.; Bzdega, T.;
Wroblewska, B.; Neale, J. H. J. Med. Chem. 2004, 47, 1729−1738.
(6) (a) Weber, G. Cancer Res. 1983, 43, 3466−3492. (b) Miller, M. J.
Acc. Chem. Res. 1986, 19, 49−56. (c) Miller, M. J. Chem. Rev. 1989, 89,
1563−1579.
(7) (a) Flipo, M.; Beghyn, T.; Leroux, V.; Florent, I.; Deprez, B. P.;
Deprez-Poulain, R. F. J. Med. Chem. 2007, 50, 1322−1334. (b) Chen,
Y. F.; Lopex-Sanchez, M.; Savoy, D. N.; Billadieu, D. D.; Dow, G. S.;
Kozikowski, A. P. J. Med. Chem. 2008, 51, 3437−3448.
(8) (a) Boularot, A.; Giglione, C.; Petit, S.; Duroc, Y.; Alves de Sousa,
R.; Larue, V.; Cresteil, T.; Dardel, F.; Artaud, I.; Meinnel, T. J. Med.
Chem. 2007, 50, 10−20. (b) Capkova, K.; Yoneda, Y.; Dickerson, T. J.;
Janda, K. D. Bioorg. Med. Chem. Lett. 2007, 17, 6463.
(9) Yao, W.; Zhuo, J.; Burns, D. M.; Xu, M.; Zhang, C.; Li, Y. L.;
Qian, D. Q.; He, C.; Weng, L.; Shi, E.; Lin, Q.; Agrios, C.; Burn, T. C.;
Caulder, E.; Covington, M. B.; Fridman, J. S.; Friedman, S.; Katiyar,
K.; Hollis, G.; Li, Y.; Liu, C.; Liu, X.; Marando, C. A.; Newton, R.; Pan,
M.; Scherle, P.; Taylor, N.; Vaddi, K.; Wasserman, Z. R.; Wynn, R.;
Yeleswaram, S.; Jalluri, R.; Bower, M.; Zhou, B. B.; Metcalf, B. J. Med.
Chem. 2007, 50, 603−606.
(10) Zhu, Z.; Mazzola, R.; Sinning, L.; McKittrick, B.; Niu, X.;
Lundell, D.; Sun, J.; Orth, P.; Guo, Z.; Madison, V.; Ingram, R.; Beyer,
B. M. J. Med. Chem. 2008, 51, 725−736.
(11) (a) Whittaker, M.; Floyd, C. D.; Brown, P.; Gearing, H. J. A.
Chem. Rev. 1999, 99, 2735. (b) Cheng, M.; De, B.; Pikul, S.; Almstead,
N. G.; Natchus, M. G.; Anastasio, M. V.; McPhail, S. J.; Snider, C. E.;
Taiwo, Y. O.; Chen, L.; Dunaway, C. M.; Gu, F.; Dowty, M. E.;
Mieling, G. E.; Janusz, M. J.; Wang-Weigand, S. J. Med. Chem. 2000,
43, 369−380.
5.42−5.41 (d, J = 6 Hz, 1H), 5.09−5.05 (m, 1H), 3.70 (s, 3H), 3.68 (s,
3H), 3.08−3.05 (m, 2H), 2.84−2.81 (m, 2H), 1.39 (s, 9H), 1.34 (s,
9H); 13C NMR (150 MHz, CDCl3, few drops of CD3OD for
solubility) δ 172.3, 157.0, 155.9, 136.9, 129.4, 128.9, 128.8, 128.5,
127.3, 127.2, 126.7, 80.1, 60.3, 60.1, 57.6, 57.3, 52.7, 52.6, 40.4, 28.3,
28.2; FT-IR (KBr) 3388, 3341, 3061, 2983, 1738, 1681, 1635, 1504
cm−1; HRMS (ESI) m/z [M + H]+ calcd for C23H30N3O5 428.2185,
found 428.2193.
Methyl 6-(1-(benzyloxy)ethyl)-2,10,10-trimethyl-4,8-dioxo-9-oxa-
3,5,7-triazaundecan-1-oate (3t): white solid (347 mg, 85%); mp
1
140−142 °C; H NMR (600 MHz, CDCl3) δ 7.35−7.29 (m, 5H),
5.41−539 (m, 1H), 5.02 (br, 1H), 4.62−4.60 (d, J = 6 Hz, 2H), 4.44−
4.37 (m, 2H), 3.72 (s, 3H), 1.44 (s, 9H), 1.36−1.34 (d, J = 7.2 Hz,
3H), 1.21−1.20 (d, J = 6.6 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ
174.3, 156.8, 155.2, 137.7, 128.4, 127.8, 80.2, 71.0, 61.8, 52.1, 49.1,
27.8, 18.4, 15.8; FT-IR (KBr) 3327, 3030, 2979, 1733, 1688, 1641,
1569; HRMS (ESI) m/z [M + Na]+ calcd for C20H31N3O6Na
432.2111, found 432.2123.
Methyl 2-benzyl-6-(1-(benzyloxy)ethyl)-10,10-dimethyl-4,8-
dioxo-9-oxa-3,5,7-triazaundecan-1-oate (3u): white solid (397 mg,
1
82%); mp 157−159 °C; H NMR (600 MHz, CDCl3) δ 7.43−7.11
(m, 10H), 5.35 (br, 1H), 5.29−5.27 (m, 1H), 5.04 (br, 1H), 4.70−
4.68 (m, 1H), 4.63−4.61 (d, J = 6 Hz, 2H), 4.38−4.36 (d, J = 11.4 Hz,
1H), 3.62 (s, 3H), 3.11−3.07 (dd, J = 6.6 Hz, 1H), 3.03−3.0 (dd, J =
6.6 Hz, 1H), 1.40 (s, 9H), 1.22−1.21 (d, J = 6 Hz, 3H); 13C NMR
(150 MHz, CDCl3) δ 173.1, 156.6, 155.6, 137.8, 136.7, 129.3, 128.6,
128.4, 128.0, 126.8, 80.4, 76.3, 71.2, 62.2, 54.6, 52.0, 38.6, 28.4, 16.0;
FT-IR (KBr) 3326, 2981, 2933, 1723, 1666, 1627, 1527 cm−1; HRMS
(ESI) m/z [M + H]+ calcd for C26H36N3O6 486.2604, found 486.2602.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR and HRMS spectra of 2a−q, 3a−u, III, and
IV, data for racemization studies mechanistic data, and XRD
crystallographic data (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org
(12) (a) Dube, P.; Nathel, F. N.; Vetelino, M.; Couturier, M.;
Aboussafy, L. C.; Pichette, S.; Jorgensen, L. M.; Hardink, M. Org. Lett.
2009, 15, 5622−5625. (b) Zhang, X.; Rodrigues, J.; Evans, L.; Hinkle,
B.; Ballantyne, L.; Pena, M. J. Org. Chem. 1997, 62, 6420−6423.
(13) Takeda, K.; Akagi, Y.; Saiki, A.; Tsukahara, T.; Ogura, H.
Tetrahedron Lett. 1983, 24, 4569−4572.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: bmandal@iitg.ernet.in.
(14) Narendra, N.; Chennakrishnareddy, G.; Sureshbabu, V. V. Org.
Biomol. Chem. 2009, 7, 3520−3526.
Notes
The authors declare no competing financial interest.
(15) Katritzky, A. R.; Pleynet, D. P. M.; Yang, B. J. Org. Chem. 1997,
62, 4155−4158.
(16) Porwanski, S.; Menuel, S.; Marsura, X.; Marsura, A. Tetrahedron
Lett. 2004, 45, 5027−5029.
ACKNOWLEDGMENTS
■
We are grateful to the Central Instruments Facility (CIF) of
Indian Institute of Technology Guwahati for NMR and XRD
facilities and to the Department of Science & Technology, India
(FAST TRACK scheme, sanction no. SR/FT/CS-011/2008),
(17) Gastaldi, S.; Weinreb, M. S.; Stien, D. J. Org. Chem. 2000, 65,
3239−3230.
(18) Hamon, F.; Prie, G.; Lecornue, F.; Papot, S. Tetrahedron Lett.
2009, 50, 6800−6802.
J
dx.doi.org/10.1021/jo4026429 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(19) Yadav, D. K.; Yadav, A. K.; Srivastava, V. P.; Watal, G.; Yadav, L.
D. S. Tetrahedron Lett. 2012, 53, 2890−2893.
(20) Han, C.; Porco, A. J. Org. Lett. 2007, 9, 5717−5720.
(21) Braverman, S.; Cherkinsky, M.; Kedrova, L.; Reiselman, A.
Tetrahedron Lett. 1999, 40, 3235−3238.
(22) Lebel, H.; Leogane, O. Org. Lett. 2006, 8, 5717−5720.
(23) Anilkumar, R.; Chandrasekhar, S.; Sridhar, M. Tetrahedron Lett.
2000, 41, 5291−5293.
(24) Stafford, A. J.; Gonzales, S. S.; Barrett, G. D.; Suh, M. E.;
Feldman, L. P. J. Org. Chem. 1998, 63, 10040−10044.
(25) Giacomelli, G.; Porcheddu, A.; Salaris, M. Org. Lett. 2003, 5,
2715−2717.
(26) El-Faham, A.; Khattab, S. N.; Abdul-Ghani, M. ARKIVOC 2006,
xiii, 57−63.
(27) (a) Gissot, A.; Volonterio, A.; Zanda, M. J. Org. Chem. 2005, 70,
6925−6928. (b) Woo, S. C. J.; Fenster, E.; Dake, R. G. J. Org. Chem.
2004, 69, 8984−8986.
(28) (a) Fei, Z.; Kong, W.; Wang, H.; Peng, J.; Sun, F.; Yin, Y.;
Bajwa, J.; Jiang, X. Org. Process Res. Dev. 2012, 16, 1436−1441.
(b) Pirrung, C. M.; Chau, L. H. J. J. Org. Chem. 1995, 60, 8084−8085.
(c) Thouin, E.; Lubell, D. W. Tetrahedron Lett. 2000, 41, 457−460.
(d) Choi, J.; Park, G. J.; Pang, P. Y. Tetrahedron Lett. 2008, 49, 1103−
1106.
(29) Ho, C. Y.; Strobel, E.; Ralbovsky, J.; Galemmo, R. A., Jr. J. Org.
Chem. 2005, 70, 4873−4875.
(30) Sibi, M. P.; Hasegawa, H.; Ghorpade, S. R. Org. Lett. 2002, 4,
3343−3346.
(31) Nani Babu, P.; Dharm, D.; Shubhasmin, R.; Krishna, C. N.;
Bhubaneswar, M. Eur. J. Org. Chem. 2013, 2013, 2627−2633.
(32) El-Faham, A.; Subiros-Funosas, R.; Prohens, R.; Albericio, F.
Chem.Eur. J. 2009, 15, 9404−9416.
(33) In a separate experiment, we added hydroxylamine hydro-
chloride to the reaction mixture at 0 time (i.e., at the starting of the
reaction, without preactivation of acid). In that case, only 4-
nitrosulfonyl hydroxamic acid was formed (90%) within 30 min by
direct reaction of the hydroxyl amine to I; the product 2a was hardly
observed (Supporting Information, Figures S179−180).
(34) Neises, B.; Steglich, W. Angew. Chem., Int. Ed. Engl. I978, 17,
522−524.
(35) Porcheddu, A.; Giacomelli, G. J. Org. Chem. 2006, 71, 7057−
7059.
(36) Li, Q. X.; Wang, K. W.; Han, X. Y.; Zhang, C. Adv. Synth. Catal.
2010, 352, 2588−2598.
(37) Oh, K. H.; Park, E. J.; Sung, D. D.; Lee, I. J. Org. Chem. 2004,
69, 3150−3153.
(38) Vinogradova, V. E.; Fors, P. B.; Buchwald, L. S. J. Am. Chem. Soc.
2012, 134, 11132−11135.
(39) Gabriele, B.; Salerno, G.; Mancuso, R.; Costa, M. J. Org. Chem.
2004, 69, 4741−4750.
K
dx.doi.org/10.1021/jo4026429 | J. Org. Chem. XXXX, XXX, XXX−XXX