Copper(II)-Catalyzed Alkoxyhalogenation of Alkynyl Ureas and Amides as a Route to Haloalkylidene-Substituted Heterocycles

Article abstract of DOI:10.1021/acs.joc.5b01227

A highly effective synthesis of haloalkylidene-substituted heterocycles by copper(II)-catalyzed cyclization of alkynyl ureas and secondary amides has been developed. The reaction, which involves a catalytic amount of CuCl₂ and a stoichiometric

Full text of DOI:10.1021/acs.joc.5b01227

Article
pubs.acs.org/joc
Copper(II)-Catalyzed Alkoxyhalogenation of Alkynyl Ureas and
Amides as a Route to Haloalkylidene-Substituted Heterocycles
Silvia Gazzola,† Egle M. Beccalli,‡ Tea Borelli,† Carlo Castellano,§ Maria Assunta Chiacchio,∥
Daria Diamante,† and Gianluigi Broggini*,†
†Dipartimento di Scienza e Alta Tecnologia, Universita
̀
dell’Insubria, via Valleggio 11, 22100 Como, Italy
‡DISFARM, Sezione di Chimica Generale e Organica “A. Marchesini”, Universita
̀
degli Studi di Milano, via Venezian 21, 20133
Milano, Italy
§Dipartimento di Chimica, Universita
̀
degli Studi di Milano, via Golgi 19, 20133 Milano, Italy
∥Dipartimento di Scienze del Farmaco, Universita
̀
di Catania, Viale Andrea Doria 6, 95125 Catania, Italy
S
* Supporting Information
ABSTRACT: A highly effective synthesis of haloalkylidene-substituted
heterocycles by copper(II)-catalyzed cyclization of alkynyl ureas and
secondary amides has been developed. The reaction, which involves a
catalytic amount of CuCl2 and a stoichiometric amount of N-
halosuccinimide, occurs selectively through an alkoxyhalogenation
process. Alternatively, alkoxychlorination and alkoxybromination reac-
tions can be performed working solely with stoichiometric CuCl2 and
CuBr2, respectively.
propargyl amides in the presence of stoichiometric CuI and
INTRODUCTION
■
Selectfluor was described by Xu and co-workers.10
Intramolecular transition-metal-catalyzed alkoxylation of car-
bon−carbon multiple bonds represents one of the most
effective approaches to prepare oxygenated heterocycles,
which are important motifs in many biologically active
compounds.1 Processes leading to the generation of new
bonds in addition to the first-formed C−O bond have been
reported in the literature.2 While this approach is substantially
devoted to the functionalization of alkenes and allenes, related
reactions involving alkynes are somewhat limited.3 Among the
procedures of alkoxylation, transition-metal-catalyzed reactions
based on the use of secondary amides4 or ureas5 as nucleophiles
represent a useful tool to perform directly functionalized
oxygenated heterocycles.
On the basis of the picture emerging from the literature, as
part of our ongoing project on intramolecular transition-metal-
catalyzed amination and alkoxylation reactions involving C−H
and heteroatom−H functionalization,11 we tried to perform a
copper-catalyzed alkoxylation/halogenation of alkynyl ureas
and secondary amides to afford a range of haloalkylidene-
substituted heterocycles (Scheme 1). In principle, the
formation of an intramolecular bond with these substrates
Scheme 1. General Copper-Promoted Procedure for
Haloalkylidene-Substituted Heterocycles
The attractiveness of the copper catalysts stems from their
low cost and their tolerance toward many reactive functional
groups, and the reactions do not require rigorously anaerobic
and anhydrous conditions. These features strongly increased
the development of procedures for C−O6 and C−N7 bond
forming reactions. However, despite various kinds of
reactivities, the examples of copper-promoted exo-selective
intramolecular alkyne hydralkoxylation are rather restricted.8
Among these methods, a chlorocyclization of N-alkoxy-2-
alkynylbenzamides by CuCl2 and NCS, both in large excess
amounts, was reported as a synthetic protocol for isobenzofur-
an-1-one derivatives.9 Recently, the iodocyclization of terminal
Received: June 1, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b01227
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Table 1. Optimization of Copper-Promoted Alkoxychlorination Conditions of 4-Nitrophenyl Propargyl Urea 1a
a
entry
copper salt
additive (equiv)
solvent
time (h)
product (yield (%))
1
CuCl2 (1 equiv)
CuCl2 (0.5 equiv)
CuCl2 (1 equiv)
CuCl2 (5 mol %)
CuCl2 (10 mol %)
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
toluene
THF
2
2
2
5
5
8
8
6
3
3
3
6
2a (87)
2a (61)
2a (84)
2a (51)
2a (54)
2
3
K2CO3 (1)
NCS (1)
NCS (1)
NCS (1)
LiCl (2)
4
5
6
7
CuCl2 (10 mol %)
CuCl (1 equiv)
2a (3)
8
b
9
CuCl2 (5 mol %)
CuCl2 (5 mol %)
CuCl2 (5 mol %)
CuCl2 (5 mol %)
NCS (1)
NCS (1)
NCS (1)
2a (32)
2a (51)
10
11
12
c
DMF
NCS (1)
DCE
2a (18)
a
b
c
Unless otherwise noted, reactions were carried out at reflux. At 90 °C. At 110 °C.
can involve nitrogen and/or oxygen atoms.12 It is worth noting
that the cyclization, when achievable, arises selectively by
addition of the oxygen to the triple bond.
Table 2. Scope of Cu(II)-Catalyzed Alkoxychlorination of
Alkynyl Ureas
RESULTS AND DISCUSSION
■
The effectiveness of copper(II) salts in the alkoxyhalogenation
process was explored on 4-nitrophenyl propargyl urea 1a
(Table 1), which was initially reacted in the presence of CuCl2
(1 equiv) in acetonitrile at room temperature (entry 1).
Interestingly, the oxazole product 2a, arising from the 5-exo-dig
cyclization with the concurrent insertion of a chlorine atom,
was isolated in 87% yield. The E configuration of the carbon−
carbon double bond was assigned by comparison of the NMR
spectroscopic data with those reported in the literature for
analogous structures.13 When the amount of CuCl2 was split in
half (0.5 equiv), the same product was obtained in 61% yield
(entry 2). The use of stoichiometric CuCl2 in the presence of a
base such as K2CO3 did not improve the yield (entry 3). In
attempts to find conditions based on the use of CuCl2 solely as
catalyst, different additives were investigated as possible
chlorine sources. NCS was proven to be a fruitful additive
(entry 4). When the catalyst loading was increased from 5 to 10
mol %, no substantial improvement in yield was obtained (54%
vs 51%) (entry 5). CuCl2 was essential for the alkoxychlori-
nation process because 1a failed to react with NCS in its
absence (entry 6). The effect of LiCl as a possible alternative
source of chlorine was unsatisfactory (entry 7). Stoichiometric
CuCl employed as a copper salt without additives furnished
unreacted starting material (entry 8). Then, different conditions
were evaluated with 5 mol % of CuCl2 and stoichiometric NCS.
Finally, various combinations of solvent and temperature
(entries 9−12) did not provide 2a in higher yield.
product
entry urea
n
R
R′
R″
(yield (%))
1
1b
1c
1d
1e
1f
1
1
1
1
1
1
1
1
2
2
2
1
1
Me
Me
Me
Me
Me
Bn
Bn
Bn
Bn
Bn
Bn
Me
Me
C6H5
H
2b (64)
2c (82)
2d (12)
2e (98)
2f (75)
2g (98)
2h (71)
2i (85)
2j (28)
2k (56)
2l (77)
2n (41)
2o (37)
2
4-OMe-C6H4
4-Cl-C6H4
1-naphthyl
3,5-CF3-C6H3
C6H5
H
3
H
4
H
5
H
6
1g
1h
1i
H
7
4-NO2-C6H4
4-Cl-C6H4
C6H5
H
8
H
9
1j
H
10
11
12
13
1k
1l
4-NO2-C6H4
1-naphthyl
C6H5
H
H
1n
1o
C6H5
4-NO2-C6H4
4-OMe-C6H4
in good to excellent yields. The unsatisfactory outcome of
cyclization for urea 1d, which furnished a complex mixture of
tarry products also with use of stoichiometric CuCl2, was
unexpected and could not be ascribed to the presence of the
chlorine atom, as evidenced by the behavior of the analogous
urea 1i, which underwent the alkoxychlorination process in
85% yield. These conditions also provided 6-exo-dig-process, as
shown by the cyclization of the aryl butynyl ureas 1j−l that
furnished the 1,3-oxazine products, albeit in moderate yields
(Table 2, entries 9−11). The cyclization/chlorination reaction
was also achieved from the 1,2-disubstituted alkynes 1n,o, with
formation of the corresponding 5-(arylidene)oxazole deriva-
tives (Table 2, entries 12 and 13).
To define the scope of the alkoxychlorination reaction, we
further explored a range of substituted alkynyl ureas, choosing
the catalytic conditions of Table 1, entry 4 (i.e., 5 mol % of
CuCl2 with stoichiometric NCS). First, we investigated the aryl
propargyl ureas 1b−i, which were converted into the (E)-5-
(chloromethylidene)oxazole derivatives 2b−i (Table 2, entries
1−9). With the exception of the sole 4-chlorophenyl-
substituted oxazole 2d, the cyclization products were isolated
With the successful outcome of the direct alkoxychlorination
of alkynyl ureas, we subsequently examined the applicability of
B
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the procedure to prepare bromo- and iodoalkylidene hetero-
cycles. The reaction conditions, conveniently adjusted in term
of halogen source, worked well in bromo- and alkoxyiodination
processes of propargyl and butynyl ureas (Table 3). More
achieve chloro- and iodooxazole derivatives from aryl amides
bearing either electron-withdrawing or electron-donating
groups (5a,b,f) (Table 4). Among the propargyl amides of
Table 4. Alkoxyhalogenation Reactions of Secondary
(Hetero)aryl Alkynyl Amides
a
Table 3. Scope of Alkoxybromination and Alkoxyiodination
of Alkynyl Ureas
a
Reaction conditions: alkynyl amide (1 mmol), CuX2 (5 mol %), NXS
(1 mmol), room temperature, 12−24 h.
monohetero five-membered rings (5c−e), 2-furyl- and 2-(1-
methyl)pyrrolyl carboxyamides provided the alkoxyiodination
products in lower yields from mixtures enriched in tarry
products. Finally, α,α-disubstituted propargyl benzamides (5g)
also furnished the expected products, although chloro and iodo
substrates were isolated in different yields.
a
Reaction conditions: alkynyl urea (1 mmol), CuBr2 (1 mmol).
Reaction conditions: alkynyl urea (1 mmol), CuCl2 (5 mol %), NXS
b
To gain further insights into these reactions, some control
experiments were carried out in search of mechanistic evidence.
First, we investigated the reaction of the propargyl urea 1a in
the presence of catalytic CuCl2 and stoichiometric NCS in
acetonitrile at reflux under a nitrogen atmosphere (Scheme 2,
path A). The recovery of the unchanged starting material shows
that the presence of molecular oxygen is essential for the
outcome of the reaction, probably acting as an oxidant able to
renew the Cu(II) catalytic species. To fortify this hypothesis,
taking into account the behavior of copper(I) chloride which is
unable to promote any reaction, we repeated the experiment of
Table 1, entry 8, under a molecular oxygen atmosphere
(Scheme 2, path B). The reaction provided only compound 8,
albeit isolated in low yield, reasonably arising from the sole
intramolecular C−O bond formation, followed by an internal
isomerization of the carbon−carbon double bond. The addition
of NCS to catalytic CuCl under an oxygen atmosphere
gratifyingly provided the chloromethylidene product 2a in 49%
yield (Scheme 2, path C). The substitution of NCS with LiCl as
an additive led to the hydroalkoxylation/isomerization product
8 instead of the cyclization/chlorination compound 2a,
confirming the crucial role of NCS as a source of chlorine
(Scheme 2, path D). The different yields shown in paths B and
(1 mmol).
specifically, bromo derivatives 3 were proven to be achievable
either with stoichiometric CuBr2 or with a catalytic amount of
CuCl2 in the presence of a stoichiometric amount of NBS. On
the other hand, the treatment of alkynyl ureas with CuCl2 and
stoichiometric NIS provided the formation of the iodomethy-
lidene-substituted oxazole and 1,3-oxazine products 4.14 The
structure and E configuration of the alkoxyhalogenation
product was unambiguously confirmed by single-crystal X-ray
diffraction performed on compound 4i, which revealed the
presence of two independent molecules in the asymmetric unit
(see the Supporting Information, Figure S1).15
In view of the importance of vinyl halides as structural motifs,
we became interested in exploring other substrates toward
alkoxyhalogenation reactions. Using the reaction conditions
selected for the alkoxyhalogenation of the alkynyl ureas, the
process was performed starting from secondary propargyl
(hetero)aryl amides 5. Although alkoxybromination reactions
were unfruitful from a synthetic point of view due to the
difficult isolation of the product from complex reaction
mixtures, the outcome of the reactions was satisfactory to
C
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final product 2 and regenerating the copper catalyst. The
evolution of intermediate B could also proceed by a copper(III)
species that undergoes reductive elimination.17
Scheme 2. General Investigations in Search of Further
Insights into Copper-Promoted Alkoxyhalogenation
Reactions
CONCLUSIONS
■
In conclusion, we have developed a simple and efficient method
of alkoxyhalogenation of alkynyl ureas and secondary amides
with copper(II) salts, used in a stoichiometric amount or as a
catalyst in the presence of N-halosuccinimides. By exploitation
of the exocyclic haloalkylidene moiety, the resulting products
can undergo further functionalizations, for example by
transition-metal-catalyzed reactions, making them versatile
building blocks in organic synthesis. These conditions will be
tested with alkynyl carbamates and hydroxylamines to improve
their general applicability.
EXPERIMENTAL SECTION
■
General Information. Melting points are uncorrected. IR spectra
were recorded on a FT-IR spectrophotometer. Column chromatog-
raphy was performed on silica gel 60 (mesh size 63−200 μm). Nuclear
magnetic resonance spectra were recorded on a 200, 300, or 400 MHz
spectrometer for 1H NMR and a 100 MHz spectrometer for 13C
NMR. Chemical shifts (δ) for proton nuclear magnetic resonance (1H
NMR) spectra are reported in parts per million downfield relative to
the center line of the CDCl3 triplet at 7.26 ppm. Chemical shifts for
carbon nuclear magnetic resonance (13C NMR) spectra are reported in
parts per million downfield relative to the center line of the CDCl3
triplet at 77.23 ppm. The abbreviations s, d, t, and m stand for the
resonance multiplicities singlet, doublet, triplet, and multiplet,
respectively. 13C spectra are 1H decoupled, and multiplicities were
determined by the APT pulse sequence.
D could be attributed to a more effective outcome of the
cyclization step using a catalytic amount of CuCl.
On the basis of the experimental evidence, a plausible
mechanism to explain the alkoxyhalogenation reactions with
CuCl2 and N-halosuccinimide is shown in Scheme 3, taking the
General Procedure for the Preparation of Ureas 1a−i. To a
solution of the alkynyl amine (1 mmol) in THF (5 mL) was added the
suitable isocyanate (1 mmol) dropwise. The resulting mixture was
stirred at room temperature for 16 h, and then the solvent was
removed under reduced pressure; the crude product was pure enough
to be used in the subsequent step without further purification.
N′-Methyl-N-(4-nitrophenyl)-N′-propargylurea (1a). Pale yellow
solid (230 mg, 99%). Mp: 113 °C. νmax/cm−1: 1655 (CO). 1H
NMR (400 MHz, CDCl3): δ 2.35 (t, J = 2.4 Hz, 1H), 3.13 (s, 3H),
4.20 (d, J = 2.4 Hz, 2H), 7.05 (br s, 1H, missing after deuteration),
7.57 (ddd, J = 10.2, 5.1, 3.1 Hz, 2H), 8.14 (ddd, J = 10.2, 5.1, 3.1 Hz,
2H). 13C NMR (100 MHz, CDCl3): δ 34.5 (q), 38.2 (t), 73.2 (d), 78.3
(s), 118.7 (d), 125.0 (d), 142.7 (s), 145.1 (s), 154.2 (s). MS (%) ESI:
234 [M + H]+. Anal. Calcd for C11H11N3O3: C, 56.65; H, 4.75; N,
18.02. Found: C, 56.82; H, 4.98; N, 17.79.
Scheme 3. Proposed Mechanism of the Cu(II)-Catalyzed
Reaction
N′-Methyl-N-phenyl-N′-propargylurea (1b). White solid (175 mg,
1
93%). Mp: 88 °C. νmax/cm−1: 1680 (CO). H NMR (400 MHz,
CDCl3): δ 2.31 (t, J = 2.4 Hz, 1H), 3.07 (s, 3H), 4.17 (d, J = 2.4 Hz,
2H), 6.59 (br s, 1H, missing after deuteration), 7.04 (td, J = 7.7, 0.6
Hz, 1H), 7.28 (td, J = 7.7, 0.6 Hz, 2H), 7.37−7−39 (m, 2H). 13C
NMR (100 MHz, CDCl3): δ 34.2 (q), 37.9 (t), 72.6 (d), 78.9 (s),
120.1 (d), 123.3 (d), 128.8 (d), 138.8 (s), 155.3 (s). MS (%) ESI: 189
[M + H]+. Anal. Calcd for C11H12N2O: C, 70.19; H, 6.43; N, 14.88.
Found: C, 70.38; H, 6.21; N, 14.65.
N-(4-Methoxyphenyl)-N′-methyl-N′-propargylurea (1c). Light
brown solid (211 mg, 97%). Mp: 77 °C. νmax/cm−1: 1664 (CO).
1H NMR (400 MHz, CDCl3): δ 2.30 (t, J = 2.4 Hz, 1H), 3.06 (s, 3H),
3.78 (s, 3H), 4.18 (d, J = 2.4 Hz, 2H), 6.41 (br s, 1H, missing after
deuteration), 6.83 (d, J = 6.9 Hz, 2H), 7.27 (d, J = 6.9 Hz, 2H). 13C
NMR (100 MHz, CDCl3): δ 33.9 (q), 37.8 (t), 55.4 (q), 72.2 (d), 79.3
(s), 113.9 (d), 122.9 (d), 132.1 (s), 155.8 (s), 156.1 (s). MS (%) ESI:
219 [M + H]+. Anal. Calcd for C12H14N2O2: C, 66.04; H, 6.47; N,
12.84. Found: C, 66.19; H, 6.23; N, 13.10.
alkoxychlorination of the propargyl urea as an example. The
catalytic cycle would proceed through the vinyl copper
intermediate A, generated from an 5-exo-dig cyclization by
nucleophilic attack of the oxygen atom on the activated
carbon−carbon triple bond.7h,i,16 The subsequent deprotona-
tion of A forms the intermediate B, which is able to interact
with NCS, in the presence of HCl and oxygen, providing the
N-(4-Chlorophenyl)-N′-methyl-N′-propargylurea (1d). White
solid (217 mg, 98%). Mp: 105−106 °C. νmax/cm−1: 1651 (CO).
1H NMR (400 MHz, CDCl3): δ 2.33 (t, J = 2.5 Hz, 1H), 3.08 (s, 3H),
D
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4.18 (d, J = 2.5 Hz, 2H), 6.55 (br s, 1H, missing after deuteration),
7.23−7.26 (m, 2H), 7.32−7.34 (m, 2H). 13C NMR (100 MHz,
CDCl3): δ 34.3 (q), 38.0 (t), 72.7 (d), 78.7 (s), 121.2 (d), 128.3 (s),
128.8 (d), 137.4 (s), 154.9 (s). MS (%) ESI: 223 [M + H]+. Anal.
Calcd for C11H11ClN2O: C, 59.33; H, 4.98; N, 12.58. Found: C, 59.05;
H,5.17; N, 12.77.
N′-Methyl-N-(1-naphthyl)-N′-propargylurea (1e). White solid
(233 mg, 98%). Mp: 111−112 °C. νmax/cm−1: 1648 (CO). 1H
NMR (400 MHz, CDCl3): δ 2.38 (t, J = 2.4 Hz, 1H), 3.14 (s, 3H),
4.22 (d, J = 2.4 Hz, 2H), 6.89 (br s, 1H, missing after deuteration),
7.43−7.53 (m, 3H), 7.66 (d, J = 8.2 Hz, 1H), 7.73 (d, J = 7.4 Hz, 1H),
7.85−7.89 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 34.4 (q), 38.2
(t), 72.8 (d), 78.9 (s), 120.9 (d), 121.0 (d), 125.1 (d), 125.7 (d), 125.8
(d), 126.1 (d), 127.9 (s), 128.7 (d), 133.6 (s), 134.1 (s), 156.0 (s). MS
(%) ESI: 239 [M + H]+. Anal. Calcd for C15H14N2O: C, 75.61; H,
5.92; N, 11.76. Found: C, 75.46; H, 6.15; N, 11.56.
N-[3,5-Bis(trifluoromethyl)phenyl]-N′-methyl-N′-propargylurea
(1f). Colorless oil (304 mg, 94%). νmax/cm−1: 1662 (CO). 1H NMR
(400 MHz, CDCl3): δ 2.37 (t, J = 2.4 Hz, 1 H), 3.14 (s, 3H), 4.21 (d, J
= 2.4 Hz, 2H), 6.82 (br s, 1H, missing after deuteration), 7.53 (s, 1H),
7.90 (s, 2H). 13C NMR (100 MHz, CDCl3): δ 34.3 (q), 38.1 (t), 73.2
(d), 78.2 (s), 116.4 (d), 116.6 (d), 119.4 (d), 121.8 (s), 124.5 (s),
131.9 (s), 132.3 (s), 140.3 (s), 154.4 (s). MS (%) ESI: 325 [M + H]+.
Anal. Calcd for C13H10F6N2O: C, 48.16; H, 3.11; N, 8.64. Found: C,
48.29; H, 2.88; N, 8.85.
N′-Benzyl-N′-(butyn-4-yl)-N-(4-nitrophenyl)urea (1k). Pale yellow
1
oil (252 mg, 78%). νmax/cm−1: 1658 (CO). H NMR (400 MHz,
CDCl3): δ 2.14 (t, J = 2.6 Hz, 1H), 2.54 (dt, J = 6.4, 2.6 Hz, 2H), 3.62
(t, J = 6.4 Hz, 2H), 4.67 (s, 2H), 7.23 (br s, 1H, missing after
deuteration), 7.31−7.44 (m, 7H), 8.10 (d, J = 9.2 Hz, 2H). 13C NMR
(100 MHz, CDCl3): δ 18.5 (t), 47.0 (t), 51.4 (t), 71.1 (d), 82.0 (s),
118.4 (d), 124.9 (d), 127.0 (d), 128.1 (d), 129.2 (d), 136.6 (s), 142.4
(s), 145.4 (s), 154.8 (s). MS (%) ESI: 324 [M + H]+. Anal. Calcd for
C18H17N3O3: C, 66.86; H, 5.30; N, 12.90. Found: C, 67.07; H, 5.15;
N, 13.14.
N′-Benzyl-N′-(butyn-4-yl)-N-naphthylurea (1l). Colorless oil (207
mg, 63%). νmax/cm−1: 1667 (CO). 1H NMR (400 MHz, CDCl3): δ
2.09 (t, J = 2.6 Hz, 1H), 2.65 (dt, J = 2.6, 6.4 Hz, 2H), 3.76−3.80 (m,
2H), 4.79 (s, 2H), 6.80 (br s, 1H, missing after deuteration), 7.11 (d, J
= 8.1 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.39−7.49 (m, 7H), 7.60 (d, J
= 8.0 Hz, 1H), 7.78−7.81 (m, 2H). 13C NMR (100 MHz, CDCl3): δ
18.8 (t), 48.0 (t), 52.2 (t), 70.4 (d), 82.2 (s), 119.9 (d), 120.5 (d),
124.5 (d), 125.6 (d), 125.8 (d), 126.9 (d), 127.3 (s), 128.1 (d), 128.6
(d), 129.3 (d), 133.7 (s), 134.1 (s), 137.2 (s) 156.1 (s). MS (%) ESI:
329 [M + H]+. Anal. Calcd for C22H20N2O: C, 80.46; H, 6.14; N, 8.53.
Found: C,80.29; H, 6.21; N, 8.75.
N′-Benzyl-N′-(butyn-4-yl)-N-(2-methoxyphenyl)urea (1m). Color-
1
less oil (206 mg, 67%). νmax/cm−1: 1667 (CO). H NMR (400
MHz, CDCl3): δ 2.05 (t, J = 2.6 Hz, 1H), 2.57 (dt, J = 2.6, 6.5 Hz,
2H), 3.66 (s, 3H), 3.67 (t, J = 6.5 Hz, 2H), 4.67 (s, 2H), 6.77−6.80
(m, 1H), 6.90−6.95 (m, 2H), 7.17 (br s, 1H, missing after
deuteration), 7.26−7.41 (m, 5H), 8.15−8.18 (m, 1H). 13C NMR
(100 MHz, CDCl3): δ 18.6 (t), 47.5 (t), 51.9 (t), 55.6 (q), 70.2 (d),
81.8 (s), 109.8 (d), 109.9 (s), 119.0 (d), 119.7 (d), 121.1 (d), 122.0
(d), 122.8 (d), 126.9 (d), 127.7 (d), 128.9 (d), 137.1 (s), 147.7 (s),
155.2 (s). MS (%) ESI: 309 [M + H]+. Anal. Calcd for C19H20N2O2:
C, 74.00; H, 6.54; N, 9.08. Found: C, 74.17; H, 6.68; N, 8.87.
General Procedure for the Preparation of Ureas 1n,o. To a
solution of N-methylpropargylurea (1 mmol) in Et3N (12 mL) under a
N2 atmosphere were added Pd(PPh4) (0.05 mmol), CuI (0.1 mmol),
and Ar′I (1.2 mmol). The resulting mixture was stirred at room
temperature for 2 h and then heated to 60 °C for 3 h. The solvent was
removed under reduced pressure, and then the crude product was
filtered through a short pad of silica with AcOEt and the solvent was
removed under reduced pressure. The crude product was purified by
silica gel column chromatography.
N′-Benzyl-N-phenyl-N′-propargylurea (1g). White solid (92 mg,
35%). Eluent: petroleum ether/AcOEt 3:7. Mp: 68 °C. νmax/cm−1:
1
1639 (CO). H NMR (400 MHz, CDCl3): δ 2.36 (t, J = 1.9 Hz,
1H), 4.20 (d, J = 1.9 Hz, 2H), 4.67 (s, 2H), 6.61 (br s, 1H, missing
after deuteration), 6.98−7.07 (m, 1H), 7.21−7.46 (m, 9H). 13C NMR
(100 MHz, CDCl3): δ 36.7 (t), 50.7 (t), 73.1 (d), 79.0 (s), 119.9 (d),
123.3 (d), 127.4 (d), 127.9 (d), 128.9 (d), 129.1 (d), 136.8 (s), 138.8
(s), 155.4 (s). MS (%) ESI: 265 [M + H]+. Anal. Calcd for
C17H16N2O: C, 77.25; H, 6.10; N, 10.60. Found: C, 77.22; H, 6.24; N,
10.41.
N′-Benzyl-N-(4-nitrophenyl)-N′-propargylurea (1h). White solid
(294 mg, 95%). Mp: 72 °C. νmax/cm−1: 1647 (CO)1. 1H NMR (400
MHz, CDCl3): δ 2.41 (t, J = 2.4 Hz, 1H), 4.21 (d, J = 2.4 Hz, 2H),
4.68 (s, 2H), 7.08 (br s, 1H, missing after deuteration), 7.35−7.47 (m,
7H), 8.11 (d, J = 7.9 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 36.9
(t), 50.9 (t), 73.7 (d), 78.5 (s), 118.7 (d), 124.9 (d), 127.3 (d), 128.3
(d), 129.2 (d), 136.1 (s), 142.6 (s), 145.1 (s), 154.4 (s). MS (%) ESI:
310 [M + H]+. Anal. Calcd for C17H15N3O3: C, 66.01; H, 4.89; N,
13.58. Found: C, 65.84; H, 5.19; N, 13.46.
N′-Benzyl-N-(4-chlorophenyl)-N′-propargylurea (1i). Colorless oil
(292 mg, 98%). νmax/cm−1: 1663 (CO). 1H NMR (400 MHz,
CDCl3): δ 2.36 (t, J = 2.5 Hz, 1H), 4.14 (d, J = 2.5 Hz, 2H), 4.63 (s,
2H), 6.88 (br s, 1H, missing after deuteration), 7.20−7.41 (m, 9H).
13C NMR (100 MHz, CDCl3): δ 36.6 (t), 50.5 (t), 73.2 (d), 78.9 (s),
121.5 (d), 127.4 (d), 128.0 (d), 128.6 (s), 128.7 (d), 129.1 (d), 136.6
(s), 137.5 (s), 155.3 (s). MS (%) ESI: 299 [M + H]+. Anal. Calcd for
C17H15ClN2O: C, 68.34; H, 5.06; N, 9.38. Found: C, 68.46; H, 4.81;
N, 9.11.
General Procedure for the Preparation of Ureas 1j−m. To a
solution of N-benzylbutynylamine18 (1 mmol) in THF (5 mL) was
added the suitable isocyanate (1 mmol) dropwise. The resulting
mixture was stirred at room temperature for 16 h, and then the solvent
was removed under reduced pressure and the crude product was
purified by silica gel column chromatography (eluent: petroleum
ether/AcOEt 6/4).
N′-Benzyl-N′-(butyn-4-yl)-N-phenylurea (1j). Colorless oil (195
mg, 70%). νmax/cm−1: 1666 (CO). 1H NMR (400 MHz, CDCl3): δ
2.10 (t, J = 2.6 Hz, 1H), 2.53 (dt, J = 6.6, 2.6 Hz, 2H), 3.61 (t, J = 6.6
Hz, 2H), 4.67 (s, 2H), 6.69 (br s, 1H, missing after deuteration),
6.99−7.03 (m, 1H), 7.23−7.42 (m, 9H). 13C NMR (100 MHz,
CDCl3): δ 18.6 (t), 47.1 (t), 51.4 (t), 70.6 (d), 82.2 (s), 119.9 (d),
123.0 (d), 127.0 (d), 127.9 (d), 128.9 (d), 129.1 (d), 137.2 (s), 139.1
(s), 155.7 (s). MS (%) ESI: 279 [M + H]+. Anal. Calcd for
C18H18N2O: C, 77.67; H, 6.52; N, 10.06. Found: C, 77.83; H, 6.71; N,
9.86.
N′-Methyl-N′-(1-phenylpropyn-3-yl)-N-phenylurea (1n). Colorless
oil (108 mg, 41%). Eluent: petroleum ether/AcOEt 6/4. νmax/cm−1:
1
1637 (CO). H NMR (400 MHz, CDCl3): δ 3.13 (s, 3H), 4.41 (s,
2H), 6.70 (br s, 1H, missing after deuteration), 7.29−7.46 (m, 10H).
13C NMR (100 MHz, CDCl3): δ 34.3 (q), 38.8 (t), 84.4 (s), 84.4 (s),
119.1 (d), 120.3 (d), 120.5 (d), 122.2 (s), 122.6 (d), 122.9 (d), 128.4
(d), 128.5 (d), 128.7 (d), 131.8 (d), 132.0 (d), 139.2 (s), 155.6 (s).
MS (%) ESI: 265 [M + H]+. Anal. Calcd for C17H16N2O: C, 77.25; H,
6.10; N, 10.60. Found: C,77.37; H, 5.89; N, 10.69.
N′-Methyl-N′-[1-(4-methoxyphenyl)propyn-3-yl]-N-(4-
nitrophenyl)urea (1o). Pale orange oil (102 mg, 30%). Eluent:
petroleum ether/AcOEt 7/3. νmax/cm−1: 1629 (CO). 1H NMR
(400 MHz, CDCl3): δ 3.17 (s, 3H), 3.82 (s, 3H), 4.40 (s, 2H), 6.85 (d,
J = 8.8 Hz, 2H), 7.18 (br s, 1H, missing after deuteration), 7.37 (d, J =
8.8 Hz, 2H), 7.58 (d, J = 9.2 Hz, 2H), 8.15 (d, J = 9.2 Hz, 2H). 13C
NMR (100 MHz, CDCl3): δ 30.5 (q), 39.1 (t), 55.3 (q), 81.9 (s), 85.0
(s), 113.3 (d), 114.3 (s), 117.9 (d), 124.9 (d), 133.2 (d), 142.4 (s),
145.6 (s), 154.5 (s), 159.92 (s). MS (%) ESI: 340 [M + H]+. Anal.
Calcd for C18H17N3O4: C, 63.71; H, 5.05; N, 12.38. Found: C, 63.87;
H, 4.81; N, 12.21.
General Procedure for Stoichiometric Intramolecular Alkox-
yhalogenation of Alkynyl Ureas. A solution of alkynyl urea (1
mmol) and CuX2 (1 mmol) in MeCN (14 mL) was heated at reflux
for 6 h. The solvent was removed under reduced pressure, and the
crude product was purified by silica gel column chromatography.
(E)-5-(Chloromethylidene)-3-methyl-2-[(4-nitrophenyl)imino]-
oxazolidine (2a). Pale yellow oil (232 mg, 87%). Eluent: petroleum
1
ether/AcOEt 3/2. νmax/cm−1: 1662 (CN). H NMR (400 MHz,
CDCl3): δ 3.14 (s, 3H), 4.32 (d, J = 2.8 Hz, 2H), 6.00 (t, J = 2.8 Hz,
E
DOI: 10.1021/acs.joc.5b01227
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1H), 7.13 (d, J = 8.7 Hz, 2H), 8.14 (d, J = 8.7 Hz, 2H). 13C NMR (100
MHz, CDCl3): δ 31.7 (q), 49.8 (t), 96.7 (d), 123.7 (d), 124.6 (d),
142.8 (s), 147.3(s), 150.6 (s), 152.8 (s). MS (%) ESI: 268 [M + H]+.
Anal. Calcd for C11H10ClN3O3: C, 49.36; H, 3.77; N, 15.70. Found: C,
49.59; H, 3.54; N, 15.85.
NMR (100 MHz, CDCl3): δ 31.8 (q), 49.9 (t), 95.7 (d), 117.9 (d),
122.7 (d), 124.1 (d), 125.1 (d), 125.9 (d), 127.8 (d), 129.3 (s), 134.3
(s), 142.7 (s), 148.0 (s), 149.6 (s). MS (%) ESI: 273 [M + H]+. Anal.
Calcd for C15H13ClN2O: C, 66.06; H, 4.80; N, 10.27. Found: C, 65.87;
H, 5.11; N, 10.51.
(E)-2-[3,5-Bis(trifluoromethyl)phenylimino]-5-(chloromethyli-
dene)-3-methyloxazolidine (2f). Colorless oil (268 mg, 75%). Eluent:
petroleum ether/AcOEt 6/4. νmax/cm−1: 1668 (CN). 1H NMR
(400 MHz, CDCl3): δ 3.10 (s, 3H), 4.30 (d, J = 2.8 Hz, 2H), 5.99 (t, J
= 2.8 Hz, 1H), 7.50 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 31.9
(q), 50.2 (t), 97.9 (d), 116.6 (d), 123.3 (q, J = 271.3, Hz), 123.9 (d),
131.9 (q, J = 33.2 Hz), 145.9 (s), 147.0 (s), 151.7 (s). MS (%) ESI:
359 [M + H]+. Anal. Calcd for C13H9ClF6N2O: C,43.53; H, 2.53; N,
7.81. Found: C,43.76; H, 2.29; N, 7.99.
(E)-3-Benzyl-5-(chloromethylidene)-2-(phenylimino)oxazolidine
(2g). Colorless oil (292 mg, 98%). Eluent: petroleum ether/AcOEt 7/
3. νmax/cm−1: 1632 (CN). 1H NMR (400 MHz, CDCl3): δ 4.12 (d,
J = 2.9 MHz, 2H), 4.74 (br s, 2H), 5.91 (t, J = 2.9 Hz, 1H), 7.06−7.11
(m, 3H), 7.27−7.44 (m, 7H). 13C NMR (100 MHz, CDCl3): δ 47.2
(t), 48.8 (t), 96.3 (d), 119.9 (d), 123.3 (d), 123.7 (d), 128.1 (d), 128.4
(d), 128.9 (d), 145.3 (s), 148.1 (s), 149.9 (s), 171.1 (s). MS (%) ESI:
299 [M + H]+. Anal. Calcd for C17H15ClN2O: C, 68.34; H, 5.06; N,
9.38. Found: C, 68.58; H, 5.17; N, 9.21.
(E)-5-(Bromomethylidene)-3-methyl-2-[(4-nitrophenyl)imino]-
oxazolidine (3a). White solid (292 mg, 94%). Eluent: petroleum
1
ether/AcOEt 3/2. Mp: 210−211 °C. νmax/cm−1: 1658 (CN). H
NMR (400 MHz, CDCl3): δ 3.03 (s, 3H), 4.18 (d, J = 2.8 Hz, 2H),
5.90 (t, J = 2.8 Hz, 1H), 7.07 (d, J = 9.0 Hz, 2H), 8.07 (d, J = 9.0 Hz,
2H). 13C NMR (100 MHz, CDCl3): δ 31.7 (q), 51.1 (t), 83.3 (d),
123.7 (d), 124.6 (d), 142.7 (s), 148.1 (s), 150.4 (s), 153.2 (s). MS (%)
ESI: 312 [M + H]+. Anal. Calcd for C11H10BrN3O3: C, 42.33; H, 3.23;
N, 13.46. Found: C, 42.52; H, 3.47; N, 13.21.
(E)-5-(Bromomethylidene)-2-[(4-chlorophenyl)imino]-3-methyl-
oxazolidine (3d). Colorless oil (285 mg, 95%). Eluent: petroleum
1
ether/AcOEt 3/2. νmax/cm−1: 1653 (CN); H NMR (400 MHz,
CDCl3): δ 3.03 (s, 3H), 4.16 (d, J = 2.7 Hz, 2H), 5.86 (t, J = 2.7 Hz,
1H), 6.97 (d, J = 8.7 Hz, 2H), 7.21 (d, J = 8.7 Hz, 2H). 13C NMR (100
MHz, CDCl3): δ 31.7 (q), 51.1 (t), 82.5 (d), 124.7 (d), 127.6 (s),
128.6 (d), 144.8 (s), 148.5 (s), 149.9 (s). MS: m/z 300 (M+). Anal.
Calcd for C11H10BrClN2O: C, 43.81; H, 3.34; N, 9.29. Found: C,
43.90; H, 3.58; N, 9.55.
(E)-3-Benzyl-6-(bromomethylidene)-2-[(2-methoxyphenyl)-
imino]-2,3,4,5-tetrahydro-2H-1,3-oxazine (3m). Colorless oil (239
mg, 62%). Eluent: petroleum ether/AcOEt 7/3. νmax/cm−1: 1641
(E)-3-Benzyl-5-(chloromethylidene)-2-[(4-nitrophenyl)imino]-
oxazolidine (2h). Colorless oil (243 mg, 71%). Eluent: petroleum
1
ether/AcOEt 6/4. νmax/cm−1: 1590 (CN). H NMR (400 MHz,
1
(CN). H NMR (400 MHz, CDCl3): δ 2.74 (t, J = 5.7 Hz, 2H),
CDCl3): δ 4.16 (d, J = 2.9 Hz, 2H), 4.68 (s, 2H), 5.99 (t, J = 2.9 Hz,
1H), 7.17(d, J = 9.0 Hz, 2H), 7.35−7.44 (m, 5H), 8.15 (d, J = 9.0 Hz,
2H). 13C NMR (100 MHz, CDCl3): δ 47.1 (t), 48.7 (t), 97.0 (d),
123.8 (d), 124.7 (d), 124.9 (d), 125.1 (d), 128.3 (d), 128.6 (d), 135.0
(s), 142.8 (s), 147.5 (s), 150.3 (s), 153.0 (s). MS (%) ESI: 344 [M +
H]+. Anal. Calcd for C17H14ClN3O3: C, 59.40; H, 4.10; N, 12.22.
Found: C, 59.58; H, 3.78; N, 12.31.
3.32 (t, J = 5.7 Hz, 2H), 3.81 (s, 3H), 4.82 (br s, 2H), 5.77 (s, 1H),
6.82−7.08 (m, 3H), 7.30−7.45 (m, 6H). 13C NMR (CDCl3): δ 25.1
(t), 41.9 (t), 53.3 (t), 56.0 (q), 89.1 (d), 114.6 (d), 123.5 (d), 127.8
(d), 128.3 (d), 128.9 (d), 131.9 (s), 136.5 (s), 149.4 (s), 152.7 (s),
162.2 (s). MS (%) ESI: 387 [M + H]+. Anal. Calcd for C19H19BrN2O2:
C.58.93; H, 4.95; N, 7.23. Found: C, 59.19; H, 4.74; N, 7.49.
General Procedure for Catalytic Intramolecular Alkoxyhalo-
genation of Alkynyl Ureas. A solution of alkynyl urea (1 mmol),
CuCl2 (0.05 mmol), and the suitable NXS (1 mmol) in MeCN (14
mL) was heated at reflux for 6 h. The solvent was removed under
reduced pressure, and when required the crude product was purified
by silica gel column chromatography.
(E)-3-Benzyl-5-(chloromethylidene)-2-[(4-chlorophenyl)imino]-
oxazolidine (2i). Colorless oil (282 mg, 85%). Eluent: petroleum
1
ether/AcOEt 6/4. νmax/cm−1: 1669 (CN). H NMR (400 MHz,
CDCl3): δ 4.10 (d, J = 2.8 Hz, 2H), 4.63 (s, 2H), 5.92 (t, J = 2.8 Hz,
1H), 7.03 (d, J = 8.8 Hz, 2H), 7.24 (d, J = 8.8 Hz, 2H), 7.37−7.41 (m,
5H). 13C NMR (100 MHz, CDCl3): δ 47.1 (t), 48.7 (t), 96.1 (d),
124.7 (d), 127.7 (s), 128.8 (d), 128.9 (d), 129.1 (d), 129.2 (d); 135.5
(s). 144.8 (s), 148.0 (s), 149.3 (s). MS (%) ESI: 333 [M + H]+. Anal.
Calcd for C17H14Cl2N2O: C, 61.28; H, 4.23; N, 8.41. Found: C, 61.11;
H, 4.40; N, 8.69.
(E)-5-(Chloromethylidene)-3-methyl-2-(phenylimino)oxazolidine
(2b). Colorless oil (142 mg, 64%). Eluent: petroleum ether/AcOEt 7/
3. νmax/cm−1: 1643 (CN). 1H NMR (400 MHz, CDCl3): δ 3.01 (s,
3H), 4.17 (d, J = 2.8 Hz, 2H), 5.90 (t, J = 2.8 Hz, 1H), 7.03−7.09 (m,
3H), 7.29 (t, J = 7.7 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ31.6 (q),
49.7 (t), 95.7 (d), 122.7 (d), 123.3 (d), 128.6 (d), 146.3 (s), 148.2 (s),
149.5 (s). MS (%) ESI: 223 [M + H]+. Anal. Calcd for C11H11ClN2O:
C, 59.33; H, 4.98; N, 12.58. Found: C, 59.45; H, 5.29; N, 12.28.
(E)-5-(Chloromethylidene)-2-[(4-methoxyphenyl)imino]-3-meth-
yloxazolidine (2c). White solid (207 mg, 82%). Eluent: petroleum
(E)-3-Benzyl-6-(chloromethylidene)-2-(phenylimino)-2,3,4,5-tet-
rahydro-2H-1,3-oxazine (2j). Colorless oil (87 mg, 28%). Eluent:
petroleum ether/AcOEt 7/3. νmax/cm−1: 1641 (CN). 1H NMR
(400 MHz, CDCl3): δ 2.79 (td, J = 6.3, 1.5 Hz, 2H), 3.28 (t, J = 6.3
Hz, 2H), 4.82 (s, 2H), 5.88 (t, J = 1.5 Hz, 1H), 7.01−7.05 (m, 3H),
7.26−7.42 (m, 7H). 13C NMR (100 MHz, CDCl3): δ 23.4 (t), 41.8
(t), 53.3 (t), 101.6 (d), 122.4 (d), 123.6 (d), 127.7 (d), 128.2 (d),
128.4 (d), 128.5 (d), 128.7 (d), 136.7 (s), 140.9 (s), 146.2 (s), 148.9
(s). MS (%) ESI: 313 [M + H]+. Anal. Calcd for C18H17ClN2O: C,
69.12; H, 5.48; N, 8.96. Found: C, 69.31; H, 5.62; N, 8.65.
1
ether/AcOEt 6/4. Mp: 137 °C. νmax/cm−1: 1657 (CN). H NMR
(400 MHz, CDCl3): δ 3.01 (s, 3H), 3.76 (s, 3H), 4.19 (d, J = 2.8 Hz,
2H), 5.89 (t, J = 2.8 Hz, 1H), 6.82 (d, J = 8.0 Hz, 2H), 6.97 (d, J = 8.0
Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 31.8 (q), 49.8 (t), 55.4 (q),
95.5 (d), 113.9 (d), 124.1 (d), 139.2 (s), 148.1 (s), 149.3 (s), 155.3
(s). MS (%) ESI: 253 [M + H]+. Anal. Calcd for C12H13ClN2O2: C,
57.04; H, 5.19; N, 11.09. Found: C, 57.21; H, 4.99; N, 11.37.
(E)-5-(Chloromethylidene)-2-[(4-chlorophenyl)imino]-3-methyl-
oxazolidine (2d). White solid (30 mg, 12%). Eluent: petroleum ether/
(E)-3-Benzyl-6-(chloromethylidene)-2-[(4-nitrophenyl)imino]-
2,3,4,5-tetrahydro-2H-1,3-oxazine (2k). Colorless oil (199 mg, 56%).
1
Eluent: petroleum ether/AcOEt 7/3. νmax/cm−1: 1641 (CN). H
NMR (400 MHz, CDCl3): δ 2.84 (t, J = 6.1 Hz, 2H), 3.36 (t, J = 6.1
Hz, 2H), 4.84 (s, 2H), 5.94 (br s, 1H), 7.11 (d, J = 8.6 Hz, 2H), 7.34−
7.40 (m, 5H), 8.15 (d, J = 8.6 Hz, 2H). 13C NMR (100 MHz, CDCl3):
δ 22.9 (t), 42.0 (t), 53.7 (t), 102.6 (d), 123.9 (d), 124.6 (d), 128.0 (d),
128.1 (d), 128.9 (d), 135.9 (s), 142.5 (s), 145.1 (s), 147.1 (s), 148.3
(s). MS (%) ESI: 358 [M + H]+. Anal. Calcd for C18H16ClN3O3: C,
60.42; H, 4.51; N, 11.74. Found: C, 60.71; H, 4.29; N, 11.95.
1
AcOEt 7/3. Mp: 188 °C. νmax/cm−1: 1661 (CN). H NMR (400
MHz, CDCl3): δ 3.15 (s, 3H), 4.30 (d, J = 2.8 Hz, 2H), 5.97 (t, J = 2.8
Hz, 1H), 7.04 (d, J = 8.7 Hz, 2H), 7.22 (d, J = 8.7 Hz, 2H). 13C NMR
(100 MHz, CDCl3): δ 32.1 (q), 50.3 (t), 97.2 (d), 124.8 (d), 128.8
(d), 142.4 (s), 147.4 (s), 151.2 (s), 167.3 (s). MS (%) ESI: 257 [M +
H]+. Anal. Calcd for C11H10 Cl2N2O: C, 51.38; H, 3.92; N, 10.90.
Found: C, 51.60; H, 3.73; N, 11.15.
(E)-3-Benzyl-6-(chloromethylidene)-2-(naphthylimino)-2,3,4,5-
tetrahydro-2H-1,3-oxazine (2l). Colorless oil (278 mg, 77%). Eluent:
petroleum ether/AcOEt 6/4. νmax/cm−1: 1641 (CN). 1H NMR
(400 MHz, CDCl3): δ 2.81−2.85 (m, 2H), 3.37 (t, J = 6.2 Hz, 2H),
4.91 (s, 2H), 5.73 (s, 1H), 6.97 (d, J = 7.8 Hz, 1H), 7.33−7.58 (m,
9H), 7.95−8.08 (m, 1H), 8.12−8.24 (m, 1H). 13C NMR (100 MHz,
CDCl3): δ 23.3 (t), 42.2 (t), 53.6 (t), 101.6 (d), 113.8 (s), 117.9 (d),
(E)-5-(Chloromethylidene)-3-methyl-2-[(1-naphthyl)imino]-
oxazolidine (2e). Pale yellow oil (266 mg, 98%). Eluent: petroleum
1
ether/AcOEt 7/3. νmax/cm−1: 1668 (CN). H NMR (400 MHz,
CDCl3): δ 3.12 (s, 3H), 4.20 (d, J = 2.7 Hz, 2H), 5.85 (t, J = 2.7 Hz,
1H), 7.18 (d, J = 7.3 Hz, 1H), 7.43−7.51 (m, 3H), 7.59 (d, J = 8.2 Hz,
1H) 7.84 (dd, J = 6.4, 3.3 Hz, 1H), 7.25 (dd, J = 6.4, 3.3 Hz, 1H). 13C
F
DOI: 10.1021/acs.joc.5b01227
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The Journal of Organic Chemistry
Article
124.2 (d), 124.7 (d), 125.0 (s), 125.4 (d), 126.0 (d), 126.3 (d), 126.7
(d), 127.7 (d), 128.8 (d), 129.4 (s), 131.2 (s), 136.9 (s), 142.7 (s). MS
(%) ESI: 363 [M + H]+. Anal. Calcd for C22H19ClN2O: C, 72.82; H,
5.28; N, 7.72. Found: C, 72.98; H, 5.12; N, 8.05.
δ 3.08 (s, 3H), 4.05 (d, J = 2.6 Hz, 2H), 5.62 (t, J = 2.6 Hz, 1H), 7.23
(d, J = 8.2 Hz, 2H), 7.46−7.55 (m, 3H), 7.61 (d, J = 8.2 Hz, 2H)
7.87−7.89 (m, 1H), 8.30−8.33 (m, 1H). 13C NMR (100 MHz,
CDCl3): δ 31.7 (q), 49.4 (d), 53.5 (t), 118.0 (d), 122.7 (d), 124.2 (d),
125.1 (d), 125.9 (d), 126.0 (d), 127.8 (d), 129.4 (s), 134.3 (s), 142.7
(s), 150.2 (s), 150.7 (s). MS (%) ESI: 365 [M + H]+. Anal. Calcd for
C15H13IN2O: C, 49.47; H, 3.60; N, 7.69. Found: C, 49.22; H, 3.89; N,
7.83.
(Z)-5-[Chloro(phenyl)methylidene]-3-methyl-2-(phenylimino)-
oxazolidine (2n). Colorless oil (122 mg, 41%). Eluent: petroleum
1
ether/AcOEt 6/4. νmax/cm−1: 1668 (CN). H NMR (400 MHz,
CDCl3): δ 3.13 (s, 3H), 4.41 (s, 2H), 7.24−7.46 (m, 10H). 13C NMR
(100 MHz, CDCl3): δ 34.4 (q), 38.9 (t), 83.9 (s), 84.6 (s), 120.3 (d),
122.4 (s), 123.4 (d), 128.4 (d), 128.6 (d), 128.8 (d), 131.8 (d), 137.6
(s), 138.8 (s), 155.5 (s). MS (%) ESI: 299 [M + H]+. Anal. Calcd for
C17H15ClN2O: C, 68.34; H, 5.06; N, 9.38. Found: C, 68.19; H, 5.35;
N, 9.62.
(E)-3-Benzyl-2-[(chlorophenyl)imino]-5-(iodomethylidene)-
oxazolidine (4i). Colorless oil (334 mg, 79%). Eluent: petroleum
1
ether/AcOEt 4/1. νmax/cm−1: 1641 (CN); H NMR (400 MHz,
CDCl3): δ 3.99 (d, J = 2.7 Hz, 2H), 4.63 (s, 2H), 5.68 (t, J = 2.7 Hz,
1H), 7.06 (d, J = 8.7 Hz, 2H), 7.24−7.27 (m, 2H), 7.34−7.43 (m,
5H). 13C NMR (100 MHz, CDCl3): δ 48.7 (t), 49.6 (d), 50.7 (t),
124.8 (d), 128.1 (d), 128.2 (d), 128.6 (d), 128.9 (d), 127.7 (s), 135.6
(s) 144.8 (s), 149.9 (s), 150.6 (s). MS (%) ESI: 425 [M + H]+. Anal.
Calcd for C17H14ClIN2O: C, 48.08; H, 3.32; N, 6.60. Found: C, 47.76;
H, 3.57; N, 6.43.
(Z)-5-[Chloro(4-methoxyphenyl)methylidene]-3-methyl-2-[(4-
nitrophenyl)imino]oxazolidine (2o). White solid (138 mg, 37%).
1
Eluent: petroleum ether/AcOEt 7/3. νmax/cm−1: 1671 (CN). H
NMR (400 MHz, CDCl3): δ 3.19 (s, 3H), 3.84 (s, 3H), 4.51 (s, 2H),
6.86 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 8.8 Hz, 2H), 7.55 (d, J = 8.5 Hz,
2H), 8.13 (d, J = 8.5 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 31.8
(q), 52.1 (t), 55.4 (q), 111.2 (s), 113.7 (d), 123.7 (d), 124.6 (d), 128.6
(d), 139.9 (s), 142.8 (s),145.6 (s),151.5 (s),152.5 (s),159.7 (s). MS
(%) ESI: 374 [M + H]+. Anal. Calcd for C18H16ClN3O4: C, 57.84; H,
4.31; N, 11.24. Found: C, 57.99; H, 4.04; N, 11.47.
(E)-3-Benzyl-6-(iodomethylidene)-2-[(4-nitrophenyl)imino]-
2,3,4,5-tetrahydro-2H-1,3-oxazine (4k). Colorless oil (395 mg, 88%).
1
Eluent: petroleum ether/AcOEt 7/3. νmax/cm−1: 1641 (CN); H
NMR (400 MHz, CDCl3): δ 2.83 (t, J = 6.3 Hz, 2H), 3.32 (t, J = 6.3
Hz, 2H), 4.78 (s, 2H), 5.77 (s, 1H), 7.07 (dd, J = 7.0, 1.9 Hz, 2H),
7.33−7.39 (m, 5H), 8.13 (dd, J = 7.0, 1.9 Hz, 2H). 13C NMR (100
MHz, CDCl3): δ 27.3 (t), 42.3 (t), 53.4 (t), 58.2 (d), 123.9 (d), 124.5
(d), 127.9 (d), 128.1 (d), 128.8 (d), 136.2 (s), 142.1 (s), 146.6 (s),
150.9 (s), 154.0 (s). MS (%) ESI: 450 [M + H]+. Anal. Calcd for
C18H16IN3O3: C, 48.12; H, 3.59; N, 9.35. Found: C, 48.15; H, 3.90; N,
9.19.
(E)-5-(Bromomethylidene)-2-[3,5-bis(trifluoromethyl)-
phenylimino]-3-methyloxazolidine (3f). Colorless oil (297 mg, 74%).
1
Eluent: petroleum ether/AcOEt 7/3. νmax/cm−1: 1653 (CN); H
NMR (400 MHz, CDCl3): δ 3.08 (s, 3H), 4.24 (d, J = 2.7 Hz, 2H),
5.96 (t, J = 2.7 Hz, 1H), 7.47 (br s, 3H). 13C NMR (100 MHz,
CDCl3): δ 31.7 (q), 51.2 (t), 83.7 (d), 116.1 (d), 123.7 (d), 123.4 (q, J
= 270.8 Hz), 131.8 (q, J = 32.5 Hz), 147.2 (s), 147.8 (s), 151.2 (s).
MS (%) ESI: 403 [M + H]+. Anal. Calcd for C13H9BrF6N2O: C, 38.73;
H, 2.25; N, 6.95. Found: C, 38.43; H, 2.06; N, 7.13.
(E)-3-Benzyl-5-(iodomethylidene)-2-[(2-methoxyphenyl)imino]-
2,3,4,5-tetrahydro-2H-1,3-oxazine (4m). Colorless oil (234 mg,
54%). Eluent: petroleum ether/AcOEt 3/2. νmax/cm−1: 1653 (C
1
(E)-3-Benzyl-5-(bromomethylidene)-2-[(4-chlorophenyl)imino]-
N); H NMR (400 MHz, CDCl3): δ 2.76 (td, J = 6.3, 1.2 Hz, 2H),
oxazolidine (3i). Colorless oil (157 mg, 42%). Eluent: petroleum
3.27 (t, J = 6.3 Hz, 2H), 3.82 (s, 3H), 4.89 (br s, 2H), 5.64 (s, 1H),
6.87−6.92 (m, 2H), 7.02 (t, J = 7.1 Hz, 2H), 7.30−7.39 (m, 3H), 7.45
(d, J = 7.1 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 27.8 (t), 42.3 (t),
53.7 (t), 55.8 (q), 58.1 (d), 111.3 (d), 120.8 (d), 124.6 (d), 127.8 (d),
128.3 (d), 128.7 (d), 136.4 (s), 145.8 (s), 151.1 (s), 152.0 (s), 154.1
(s). MS (%) ESI: 435 [M + H]+. Anal. Calcd for C19H19IN2O2: C,
52.55; H, 4.41; N, 6.45. Found: C, 52.81; H, 4.59; N, 6.17.
General Procedure for Catalytic Intramolecular Alkoxy-
chlorination of Alkynyl Amides. A solution of alkynyl amide4b,c
(1 mmol), CuCl2 (0.05 mmol), and NCS (1 mmol) in MeCN (14
mL) was stirred at room temperature until all reagent disappeared
(12−24 h). The solvent was removed under reduced pressure, and the
crude product was purified by silica gel column chromatography.
(E)-5-(Chloromethylidene)-2-(4-nitrophenyl)-4,5-dihydrooxazole
(6a). Colorless oil (180 mg, 76%). Eluent: petroleum ether/AcOEt 3/
2. νmax/cm−1: 1661 (CN). 1H NMR (400 MHz, CDCl3): δ 4.81 (d,
J = 3.2 Hz, 2H), 6.13 (t, J = 3.2 Hz, 1H), 8.14−8.19 (m, 2H), 8.30−
8.34 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 58.2 (t), 95.8 (d),
123.8 (d), 129.2 (d), 131.4 (s), 131.9 (s), 149.9 (s), 162.0 (s). MS (%)
ESI: 239 [M + H]+. Anal. Calcd for C10H7ClN2O3: C, 50.33; H, 2.96;
N, 11.74. Found: C, 50.51; H, 2.65; N, 11.88.
(E)-5-(Chloromethylidene)-2-(4-methoxyphenyl)-4,5-dihydrooxa-
zole (6b). Colorless oil (142 mg, 64%). Eluent: petroleum ether/
AcOEt 3/2. νmax/cm−1: 1664 (CN). 1H NMR (400 MHz, CDCl3):
δ 3.87 (s, 3H), 4.74 (br s, 2H), 6.07 (br s, 1H), 6.94 (d, J = 8.1 Hz,
2H), 7.94 (d, J = 8.1 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 29.7
(t), 55.4 (q), 94.5 (d), 114.0 (d), 114.2 (d), 117.7 (s), 118.4 (s), 129.9
(d), 162.7 (s), 163.0 (s). MS (%) ESI: 224 [M + H]+. Anal. Calcd for
C11H10ClNO2: C, 59.07; H, 4.51; N, 6.26. Found: C, 58.79; H, 4.78;
N, 6.01.
1
ether/AcOEt 4/1. νmax/cm−1: 1641 (CN); H NMR (400 MHz,
CDCl3): δ 4.06 (d, J = 2.8 Hz, 2H), 4.68 (s, 2H), 5.89 (t, J = 2.7 Hz,
1H), 7.04 (d, J = 8.6 Hz, 2H), 7.20−7.29 (m, 2H), 7.32−7.46 (m,
5H). 13C NMR (100 MHz, CDCl3): δ 29.7 (t), 48.8 (t), 83.7 (d),
124.9 (d), 128.1 (d), 128.3 (d), 128.7 (d), 129.0 (d), 132.1 (s), 134.8
(s), 143.2 (s), 148.1 (s), 150.8 (s) MS: m/z 376 (M+). Anal. Calcd for
C17H14BrClN2O: C,54.06; H, 3.74; N, 7.42. Found: C, 54.10; H, 3.97;
N, 7.65.
(E)-5-(Iodomethylidene)-3-methyl-2-[(4-nitrophenyl)imino]-
oxazolidine (4a). White solid (244 mg, 68%). Eluent: petroleum
1
ether/AcOEt 3/2. Mp: 133 °C. νmax/cm−1: 1642 (CN); H NMR
(400 MHz, CDCl3): δ 3.11 (s, 3H), 4.22 (d, J = 2.7 Hz, 2H), 5.80 (t, J
= 2.7 Hz, 1H), 7.13 (d, J = 9.1 Hz, 2H), 8.14 (d, J = 9.1 Hz, 2H). 13C
NMR (100 MHz, CDCl3): δ 31.6 (q), 50.5 (d), 53.4 (t), 123.8 (d),
124.6 (d), 142.5 (s), 149.9 (s), 151.3 (s), 153.1 (s). MS: m/z 359
(M+). Anal. Calcd for C11H10IN3O3: C, 36.79; H, 2.81; N, 11.70.
Found: C, 37.02; H, 2.52; N,11.91.
(E)-5-(Iodomethylidene)-3-methyl-2-(phenylimino0oxazolidine
(4b). Pale yellow oil (197 mg, 63%). Eluent: petroleum ether/AcOEt
1
3/2. νmax/cm−1: 1644 (CN). H NMR (400 MHz, CDCl3): δ 3.11
(s, 3H), 4.17 (d, J = 2.6 Hz, 2H), 5.80 (t, J = 2.7 Hz, 1H), 7.02−7.08
(m, 2H), 7.25−7.30 (m, 3H). 13C NMR (100 MHz, CDCl3): δ 31.9
(q), 49.6 (d), 53.6 (t), 122.9 (d), 123.3 (d), 128.7 (d), 145.3 (s), 150.5
(s), 150.6 (s). MS: m/z 314 (M+). Anal. Calcd for C11H11IN2O: C,
42.06; H, 3.53; N, 8.92. Found: C, 42.01; H, 3.77, N, 8.59.
(E)-2-[(4-Chlorophenyl)imino]-5-(iodomethylidene)-3-methyloxa-
zolidine (4d). Colorless oil (330 mg, 95%). Eluent: petroleum ether/
AcOEt 3/2. νmax/cm−1: 1649 (CN). 1H NMR (400 MHz, CDCl3):
δ 2.97 (s, 3H), 4.08 (d, J = 2.6 Hz, 2H), 5.64 (t, J = 2.6 Hz, 1H), 6.95
(dd, J = 6.7, 1.9 Hz, 1H), 7.18 (dd, J = 6.7, 1.9 Hz, 1H). 13C NMR
(100 MHz, CDCl3): δ 31.6 (q), 49.5 (d), 53.4 (t), 124.8 (d), 128.5
(d), 137.6 (s), 144.9 (s), 150.5 (s), 178.2 (s) MS (%) ESI: 349 [M +
H]+. Anal. Calcd for C11H10ClIN2O: C, 37.90; H, 2.89; N, 8.04.
Found: C, 38.12; H, 2.61; N, 8.29.
(E)-4-(Chloromethylidene)-3-oxa-2-phenyl-1-azaspiro[4,5]dec-1-
ene (6g). Colorless oil (83 mg, 32%). 1H NMR (200 MHz, CDCl3): δ
1.23−2.05 (m, 8H), 2.35−2.50 (m, 2H), 6.07 (s, 1H), 7.38−7.54 (m,
3H), 7.99 (d, J = 6.0 Hz, 2H). These data are in good agreement with
those reported in the literature.4b
(E)-5-(Iodomethylidene)-2-[(1-naphthyl)imino]-3-methyloxazoli-
dine (4e). Colorless oil (266 mg, 73%). Eluent: petroleum ether/
AcOEt 3/2. νmax/cm−1: 1653 (CN); 1H NMR (400 MHz, CDCl3):
General Procedure for Catalytic Intramolecular Alkoxyiodi-
nation of Alkynyl Amides. A solution of alkynyl amide (1 mmol),
CuCl2 (0.05 mmol) and NIS (1 mmol) in MeCN (14 mL) was stirred
G
DOI: 10.1021/acs.joc.5b01227
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
at room temperature until all reagent disappeared (12−24 h). The
solvent was removed under reduced pressure, and the crude product
was purified by silica gel column chromatography.
ASSOCIATED CONTENT
■
S
* Supporting Information
Text, figures, and a CIF file giving 1H and 13C NMR spectra of
new compounds and crystallographic data for compound 4j.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b01227.
(E)-5-(Iodomethylidene)-2-(4-nitrophenyl)-4,5-dihydrooxazole
(7a). White solid (240 mg, 73%). Eluent: petroleum ether/AcOEt 7/3.
Mp: 125 °C. νmax/cm−1: 1661 (CN). 1H NMR (400 MHz, CDCl3):
δ 4.68 (d, J = 3.2 Hz, 2H), 5.88 (t, J = 3.2 Hz, 1H), 8.16 (d, J = 8.6 Hz,
2H), 8.32 (d, J = 8.6 Hz, 2H). 13C NMR (CDCl3): δ 48.3 (d), 61.4 (t),
123.8 (d), 129.0 (d), 132.2 (s), 149.9 (s), 157.3 (s), 162.2 (s). MS (%)
ESI: 331 [M + H]+. Anal. Calcd for C10H7IN2O3: C, 36.39; H, 2.14; N,
8.49. Found: C, 36.61; H, 1.88; N, 8.26.
AUTHOR INFORMATION
Corresponding Author
*E-mail for G.B.: gianluigi.broggini@uninsubria.it.
■
(E)-5-(Iodomethylidene)-2-(thiophen-2-yl)-4,5-dihydrooxazole
(7c). Pale yellow solid (218 mg, 75%. 1H NMR (300 MHz, CDCl3): δ
4.64 (d, J = 3.1 Hz, 2H), 5.84 (t, J = 3.2 Hz, 1H), 7.16 (dd, J = 5.0, 3.7
Hz, 1H), 7.58 (dd, J = 5.0, 1.2 Hz, 1H), 7.77 (d, J = 3.7 Hz, 1H).
These data are in good agreement with those reported in the
literature.10
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Thanks are due to Universita
dell’Universita
■
̀
dell’Insubria and Ministero
della Ricerca (project PRIN
(E)-2-(Furan-2-yl)-5-(iodomethylidene)-4,5-dihydrooxazole (7d).
̀
e
1
Gray solid (112 mg, 41%). H NMR (300 MHz, CDCl3): δ 4.64(d,
2012C5YJSK_001) for financial support.
J = 3.2 Hz, 2H), 5.83 (t, J = 3.2 Hz, 1H), 6.56 (dd, J = 3.5, 1.8 Hz,
1H), 7.12 (d, J = 3.5 Hz, 1H), 7.63 (d, J = 1.8 Hz, 1H). These data are
in good agreement with those reported in the literature.10
REFERENCES
■
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Chem., Int. Ed. 2005, 44, 257. (f) Tang, Y.; Zhang, Y.; Dai, M.; Luo, T.;
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4980.
(E)-5-(Iodomethylidene)-2-(methylpyrrol-2-yl)-4,5-dihydrooxa-
zole (7e). Pale yellow solid (149 mg, 52%). Eluent: petroleum ether/
1
Et2O 9/1. Mp: 108−109 °C. νmax/cm−1: 1645 (CN); H NMR
(200 MHz, CDCl3): δ 3.94 (s, 3H), 4.58 (d, J = 3.1 Hz, 2H), 5.69 (t, J
= 3.1 Hz, 1H), 6.15 (dd, J = 3.9, 2.6 Hz, 1H), 6.75−6.90 (m, 2H). 13C
NMR (100 MHz, CDCl3): δ 37.1 (q), 46.9 (d), 60.7 (t), 108.7 (d),
116.9 (d), 119.4 (s), 129.7 (d), 156.9 (s), 158.5 (s). MS (%) ESI: 289
[M + H]+. Anal. Calcd for C9H9lN2O: C, 37.52; H, 3.15; N, 9.72.
Found: C, 37.21; H, 3.41; N, 9.47.
(E)-5-(Iodomethylidene)-2-(3,4,5-trimethoxyphenyl)-4,5-dihy-
drooxazole (7f). White solid (266 mg, 71%). Eluent: petroleum ether/
1
AcOEt 4/1. Mp: 107−108 °C. νmax/cm−1: 1671 (CN). H NMR
(200 MHz, CDCl3): δ 3.89−3.96 (m, 9H), 4.69 (d, J = 2.8 Hz, 2H),
7.16 (d, J = 2.8 Hz, 1H), 7.27−7.32 (m, 2H). 13C NMR (100 MHz,
CDCl3): δ 35.0 (t), 56.6 (q), 61.2 (d), 104.1 (d), 122.3 (s), 135.8 (s),
140.9 (s), 147.6 (s), 153.8 (s). MS (%) ESI: 376 [M + H]+. Anal.
Calcd for C13H14INO4: C, 41.62; H, 3.76; N, 3.73. Found: C, 41,35;
H, 4.03; N, 3.51.
(E)-4-(Iodomethylidene)-2-phenyl-3-oxa-1-azaspiro[4.5]dec-1-
ene (7g). Colorless oil (215 mg, 61%). 1H NMR (300 MHz, CDCl3):
δ 1.23−2.07 (m, 8H), 2.49−2.59 (m, 2H), 5.74 (s, 1H), 7.41−7.55 (m,
3H), 8.00 (d, J = 6.0 Hz, 2H). These data are in good agreement with
those reported in the literature.10
General Procedure for Stoichiometric Intramolecular Alkox-
ylation of Urea (1a) (Path B, Scheme 2). A solution of urea 1a (1
mmol) and CuCl (1 mmol) in MeCN (14 mL) was stirred at reflux
under an oxygen atmosphere for 5 h. The solvent was removed under
reduced pressure, and the crude product 8 was purified by silica gel
column chromatography.
General Procedure for Catalytic Intramolecular Alkoxylation
of Urea (1a) (Path D, Scheme 2). A solution of urea 1a (1 mmol),
CuCl (10 mol %), and LiCl (3 mmol) in MeCN (14 mL) was stirred
at reflux under an oxygen atmosphere for 5 h. The solvent was
removed under reduced pressure, and the crude product 8 was purified
by silica gel column chromatography.
(3) Hintermann, L. Topics in Organometallic Chemistry 2010, 31, 123.
For Pd-catalyzed reactions, see: (a) Asao, N.; Nogami, T.; Takahashi,
K.; Yamamoto, Y. J. Am. Chem. Soc. 2002, 124, 764. (b) Cavicchioli,
́
M.; Decortiat, S.; Bouyssi, D.; Gore, J.; Balme, G. Tetrahedron 1996,
52, 11463. (c) Rossi, R.; Bellina, F.; Biagetti, M.; Mannina, L.
Tetrahedron Lett. 1998, 39, 7599. (d) Wang, Z.; Lu, X. J. Org. Chem.
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Saejueng, P.; Murphy, J. M.; Venkataraman, D. Org. Lett. 2002, 4,
4727. For Au-catalyzed reactions, see: (f) Belting, V.; Krause, N. Org.
Biomol. Chem. 2009, 7, 1221. (g) Antoniotti, S.; Genin, E.; Michelet,
3,5-Dimethyl-2-[(4-nitrophenyl)imino]-4,5-dihydrooxazole (8).
Yellow oil (path B, 37 mg, 16%; path D, 193 mg, 83%). Eluent:
petroleum ether/AcOEt 2/1. νmax/cm−1: 1641 (CN); 1H NMR
(400 MHz, CDCl3): δ 2.03 (d, J = 1.4 Hz, 3H), 3.29 (s, 3H), 6.11 (d, J
̂
V.; Genet, J.-P. J. Am. Chem. Soc. 2005, 127, 9976. For Ru-catalyzed
reactions, see: (h) Li, M.; Hua, R. J. Org. Chem. 2008, 73, 8658. For Ir-
catalyzed reactions, see: (i) Genin, E.; Antoniotti, S.; Michelet, V.;
̂
Genet, J.-P. Angew. Chem., Int. Ed. 2005, 44, 4949. For Pt-catalyzed
= 1.4 Hz, 1H), 7.54 (d, J = 8.7 Hz, 2H), 8.32 (d, J = 8.7 Hz, 2H). 13
C
reactions, see: (j) Hartman, J. W.; Sperry, L. Tetrahedron Lett. 2004,
45, 3787. For Rh-catalyzed reactions, see: (k) Isono, N.; Lautens, M.
Org. Lett. 2009, 11, 1329.
NMR (100 MHz, CDCl3): δ 11.4 (q), 30.2 (q), 110.4 (d), 117.6 (s),
124.5 (d), 127.0 (d), 141.1 (s), 146.1 (s), 152.6 (s). MS (%) ESI: 234
[M + H]+. Anal. Calcd for C11H11N3O3: C, 56.65; H, 4.75; N,18.02
Found: C, 56.74; H, 5.06; N, 18.29.
(4) (a) Fujino, D.; Hayashi, S.; Yorimitsu, H.; Oshima, K. Chem.
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H
DOI: 10.1021/acs.joc.5b01227
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The Journal of Organic Chemistry
Article
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(14) Attempts to directly obtain acetoxy-substituted oxazole
derivatives were performed on urea 1a. However, its treatment with
stoichiometric Cu(OAc)2 in different solvents and at different
temperatures returned only unreacted starting material.
(15) CCDC-1403146 contains supplementary crystallographic data
for this paper.
I
DOI: 10.1021/acs.joc.5b01227
J. Org. Chem. XXXX, XXX, XXX−XXX