Microwave-assisted cerium(III)-promoted cyclization of propargyl amides to polysubstituted oxazole derivatives

Article abstract of DOI:10.1002/ejoc.201101302

Functionalized polysubstituted oxazoles are an important class of five-membered N,O-heterocycles that occur widely in the structure of natural products and fine chemicals. They are also often used as building blocks in the synthesis ofheterocyclic molecules with more complex structures. Therefore, efficient synthetic protocols based on Lewis acid promoted reactions are desirable. In this context, we report that, under microwave irradiation, the CeCl₃·7H₂O/NaI/I₂ system is capable of promoting a 5-exo-dig cyclization of propargyl amides with good functional group tolerance. The microwave reactor also provides a more convenient and safer method for heating the reaction. This methodology represents a straightforward CeCl₃·7H₂O/NaI/I₂ promoted cyclization using microwave irradiation to accomplish the synthesis of polysubstituted oxazole derivatives. After a wide-ranging scientific investigation on the use of cerium(III) salts as promoters for useful organic transformations, we describe here a new, microwave-assisted reaction involving the combinationof CeCl ₃·7H₂O/NaI/I₂ for the construction of N,O-heterocycles. The study concerns the preparation of highly substituted oxazoles starting from N-propargyl carboxamides. Copyright

Full text of DOI:10.1002/ejoc.201101302

FULL PAPER
DOI: 10.1002/ejoc.201101302
Microwave-Assisted Cerium(III)-Promoted Cyclization of Propargyl Amides to
Polysubstituted Oxazole Derivatives
Giuseppe Bartoli,[a] Cristina Cimarelli,[b] Roberto Cipolletti,[b] Simone Diomedi,[b,c]
Riccardo Giovannini,*[c] Margherita Mari,[b] Laura Marsili,[b] and Enrico Marcantoni*[b]
Keywords: Synthetic methods / Cyclization / Microwave chemistry / Heterocycles / Amides / Cerium
Functionalized polysubstituted oxazoles are an important
class of five-membered N,O-heterocycles that occur widely
in the structure of natural products and fine chemicals. They
are also often used as building blocks in the synthesis ofhet-
erocyclic molecules with more complex structures. Therefore,
efficient synthetic protocols based on Lewis acid promoted
reactions are desirable. In this context, we report that, under
microwave irradiation, the CeCl3·7H2O/NaI/I2 system is cap-
able of promoting a 5-exo-dig cyclization of propargyl amides
with good functional group tolerance. The microwave reactor
also provides a more convenient and safer method for heat-
ing the reaction. This methodology represents a straightfor-
ward CeCl3·7H2O/NaI/I2 promoted cyclization using micro-
wave irradiation to accomplish the synthesis of polysubsti-
tuted oxazole derivatives.
Polysubstituted oxazoles represent an important struc-
tural motif found in numerous molecules that evidence bio-
logical and pharmacological activities.[7] They are also often
used as synthetic intermediates in the preparation of hetero-
cyclic compounds of higher complexity.[8] In the public do-
main, examples of complex molecules containing a single
oxazole moiety such as SC-ααδ9 (1)[9] have been reported;
in addition, many molecules showing biological activity,
containing two or more axazole rings, are also described.
These heterocyclic moieties can be either directly linked
(2,4Ј-bisoxazoles) such as in Hennoxazole A (2)[10] or sepa-
rated by at least two atoms, as in Siphonazole A (3)[11] (Fig-
ure 1).
Introduction
Molecules containing heterocyclic moieties continue to
be attractive targets in organic chemistry because they exhi-
bit diverse and important biological activities.[1] In this con-
text, a key point is the presence of nitrogen and oxygen
donor atoms, which act cooperatively in the underlying
chemical properties of pharmaceuticals.[2] The efficiency of
the preparation of N,O-heterocycles is important not only
because it affects the production costs, but also because it
has an environmental impact. One of the best options to
produce, in an environmentally benign fashion, the great
number of heterocycles required is that of using catalysts[3]
and applying microwave methodology.[4] In particular, the
microwave-assisted approach is, compared with classical
heating, potentially important in organic synthesis because
its use can lead to reduced reaction times and higher yields,
under milder reaction conditions. Today, available synthetic
methodologies are not only expected to be simple and eco-
nomical, but also environmentally benign.[5] For these
reasons, even if limited to 2-aryl-substituted products, the
microwave-assisted silver-catalyzed procedure to generate
polysubstituted oxazoles is of interest.[6]
[a] Department of Organic Chemistry “A. Mangini”, University of
Bologna,
v.le Risorgimento 4, 40136 Bologna, Italy
[b] School of Science and Technology, Chemistry Division,
University of Camerino,
Figure 1. Examples of biologically active compounds that incorpo-
rate oxazoles.
via S. Agostino 1, 62032 Camerino, Italy
Fax: +39-0737-402297
E-mail: enrico.marcantoni@unicam.it
[c] BI Research Italia S.a.s. of BI IT S.r.l.,
via Lorenzini 8, 20139 Milano, Italy
Clearly, the direct oxidation of oxazolines[12] and the in-
troduction of substituents into the preformed oxazoles[13]
630
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Eur. J. Org. Chem. 2012, 630–636

Cyclization of Propargyl Amides
are interesting synthetic strategies. However, the usefulness
and efficiency of these methods is sometimes compromised
by unwanted side reactions, which can lead to lower
yields.[14] Alternatively, a promising approach to the prepa-
ration of polysubstituted oxazoles based on the synthesis of
acyclic precursors and subsequent cyclization, is also fre-
quently reported in the literature.[15] Functionalized propar-
gylic amides, from which 5-exo-dig cyclization provides the
corresponding polysubstituted oxazoles, are easily access-
ible substrates. The most common methods for the prepara-
tion of 2,5-disubstituted oxazoles include Pd0[16] and AuIII
catalyzed[17] coupling/cyclization of N-propargyl carbox-
amides. Because the presence of a terminal alkyne is crucial
for the success of the approach, these methodologies are
limited to the synthesis of 5-methyl-substituted oxazoles.
Inspired by Nagao and co-workers, who reported the for-
mation of trisubstituted oxazoles under basic reaction con-
ditions,[18] Ciufolini described the condensation of an alu-
minum acetylide with an α-chloroglycinate for the prepara-
tion of various polysubstituted oxazole-4-carboxylic ester
building blocks.[11b,19] Unfortunately, the aluminum-cata-
lyzed strategy suffers from moderate yields, limited sub-
strate scope, and exhibits poor functional-group toler-
ance.[20] In fact, all the methods that have been developed
for the preparation of functionalized polysubstituted ox-
Results and Discussion
When propargyl amide 4a was employed under standard
reaction conditions typically used to obtain alkenyl iodides,
we observed two principal products by GC/MS analysis
(Scheme 1): the expected iodoalkene 6 (15%) together the
trisubstituted oxazole 5a (25%). Given that the preparation
of this type of heterocycle has triggered much interest
among organic chemists, we investigated the scope of this
reaction with the aim of increasing the yields of the oxazole
ring compounds, reducing the reaction time, and obtaining
a clean product.
Scheme 1. Hydroiodination reaction of propargyl amide 4a.
Prolonged reaction times (three days) failed, and analysis
azoles starting from acyclic precursors suffer from one or of the reaction mixtures revealed that the yields of the cycli-
more drawbacks such as harsh reaction conditions, long re- zation were compromised by competing decomposition of
action times, use of excess of reagents, tedious workup pro- 4a under the harsh conditions and lengthy reaction times.
cedures, and/or low yields of the heterocyclic targets. Given that the use of microwave irradiation often decreases
Furthermore, some of the catalysts used are expensive, reaction times and reduces the required temperature com-
toxic, and air/moisture sensitive. Therefore, the need to im- pared to reactions performed under thermal conditions,[25]
prove synthetic access to functionalized polysubstituted ox- the effect of using microwave control of temperature/time
azole derivatives is rather high. A straightforward method- (the microwave controls the irradiation power to maintain
ology will help researchers to obtain these heterocycles in the fixed temperature) with a single-mode microwave reac-
efficient and cost-effective ways.
tor equipped with a cooling system for automatic micro-
Over recent years, we and other groups have witnessed wave regulation was examined.[26] Gratifyingly, CeCl3·
the wide-ranging development of cerium trichloride pro- 7H2O/NaI promoted cyclization under these conditions
moted carbon–carbon and carbon–heteroatom bond-form- lead to the formation of the trisubstituted oxazole 5a in
ing methodologies, which have become central tools for the 50% yield in only 60 min (Table 1, entry 3). Acetonitrile
synthesis of biologically active molecules both in academia remained the solvent of choice; other solvents, such as eth-
and industry.[21] In particular, the combination of anol and water, led to low yields of oxazole and decomposi-
CeCl3·7H2O and NaI has been shown to be a highly versa- tion of the propargyl amide substrate (Table 1, entries 1 and
tile reagent system[22] that is capable of promoting three- 2).
component, diastereoselective syntheses of various poten-
By screening a range of conditions, we observed that the
tially pharmacologically relevant heterocycles.[23] This wide addition of iodine gave higher selectivity and better yields.
variety of applications, together with the ability of the It should be noted that molecular iodine as catalyst for ef-
Lewis acid system to promote the regio- and diastereoselec- fecting various organic transformations[27] has lately drawn
tive addition to alkynes,[24] led us to explore whether the considerable attention. In our case, the absence of iodo-
application of the CeCl3·7H2O/NaI system can promote cy- methyleneoxazoline[28] excludes an iodocyclization mecha-
clization of functionalized propargyl amides to oxazoles, nism.[29] Although the role of I2 in the mechanism is still
which are otherwise unapproachable by conventional largely unclear, it can be rationalized by assuming the for-
routes. Thus, as a result of our efforts, we can herein report mation of a triiodide ion by the known reaction of iodine
a mild and efficient microwave-assisted synthesis of ox- with iodide ions.[30] We have analyzed the interaction be-
azoles through a 5-exo-dig cyclization of functionalized N- tween CeCl3·7H2O and the NaI/I2 combination by X-ray
propargyl carboxamides. Our results in this field provide photoelectron spectroscopy, and observed that there is no
important evidence that even carbonyl oxygen atoms can direct interaction between the cerium(III) site and the tri-
act as nucleophiles in cerium(III)-promoted addition to iodide ion. However, we believe that a chloro-bridged oligo-
carbon–carbon triple bonds.
meric structure[31] of CeCl3·7H2O is more effectively broken
Eur. J. Org. Chem. 2012, 630–636
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Table 1. Optimizing microwave-assisted synthesis of oxazole 5a.[a]
Entry
CeCl3·7H2O NaI
I2
MW power
[W]
Solvent
Time
[min]
Temp.
[°C]
Yield[b]
[%]
(equiv.)
(equiv.)
(equiv.)
1
2
3
4
5
6
7
8
3.00
3.00
3.00
0.25
3.00
0.00
1.30
1.30
2.00
2.00
2.00
0.25
0.00
0.50
0.50
0.25
0.00
0.00
0.00
0.25
2.00
0.50
0.50
0.25
100
100
40
30
30
30
30
30
EtOH
H2O
30
30
60
60
60
60
60
45
130
130
100
130
130
110
110
110
10
18
50
39
13
28
57
95
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
[a] All reaction were carried out by irradiation in a PowerMax Cooling microwave oven with a mixture of 4a and reagent system at a
given power for the selected times. [b] All yields refer to pure isolated compounds.
by donor species such as triiodide ion than by iodide ions.
Encouraged by the experimental evidence, we examined
The resulting monomeric CeCl3·7H2O/NaI/I2 complex is a the effect of the nature of the substituents on the propargyl
more active Lewis acid promoter. Thus, the incorporation amide substrate (Table 2). Functional groups, such as nitro,
of NaI/I2 in CeCl3·7H2O results in remarkable improve- benzyloxycarbonyl (Cbz), and esters are stable under the
ments in the key Lewis acid activity of the system; further- reaction conditions, and, especially, the results indicate that
more, the equimolar ratio of NaI and I2 plays a pivotal role an α-carboalkoxy group in propargyl amide is not neces-
in determining the yield of the oxazole product. As shown sary. Only when the ester moiety was directly bound to the
in Table 1, entries 7 and 8, when 0.5 equiv. of NaI and triple bond was the corresponding oxazole 5k obtained in
0.5 equiv. of I2 were used, a yield of 57% 5a was found, poor yield; in this case, LC/MS analysis of the reaction mix-
whereas the use of 0.25 equiv. NaI and 0.25 equiv. I2 gave ture showed significant amounts of hydroiodination reac-
95% yield. It is rare but not unknown that lower catalyst tion and subsequent hydrolysis to the carbonyl moiety
loading can result in better yields.[32] In the present case, (Scheme 2).[24]
the reduced yield of 5a at higher promoter loading can be
We were also interested in examining the utility of our
explained by the fact that the monomeric CeCl3·7H2O/NaI/ method with different substituents on the carboxamide
I2 complex, which is derived from this process, turns out to moiety, and were pleased to find that the reaction tolerates
be much more active, but its efficiency also promotes the alkyl, heteroaryl, and aryl substituents. The presence of
decomposition of amide substrate.
electron-withdrawing or -donating substituents had little in-
As summarized in Table 1, the reaction proceeds with fluence on the reactivity. On the other hand, it should be
good yield when the molar ratio of propargyl amide, noted that carboalkoxy groups and basic residues deactivate
CeCl3·7H2O, NaI, and I2 was 1:1.3:0.25:0.25 with a micro- the CeCl3·7H2O/NaI/I2 system (Table 2, entries 13 and 14,
wave irradiation power of 30 W for 45 min. The choice of respectively). Furthermore, we have shown that N-protected
hydrated CeCl3 plays a crucial role in the ability of the substrates can undergo oxazole formation (Table 2, entry
CeCl3·7H2O/NaI/I2 system to promote this cyclization to 12), however, the choice of protecting group is crucial; when
oxazoles. When a similar reaction was performed in the tert-butoxycarbonyl (Boc) or trialkylsilyl groups were em-
presence of NaI and I2 without using CeCl3·7H2O, the yield ployed the reaction failed to give any of the desired 5-alk-
was insufficient, with significant amounts of unreacted ylamino-oxazoles.[34]
starting material remaining. The findings suggest that the
The importance of 5-aminoxazoles as valuable building
CeCl3·7H2O/NaI/I2 system under microwave irradiation blocks for the assembly of bioactive agents,[35] prompted us
leads to a more powerful Lewis acid methodology for the to examine the cyclization of propargyl urea 4o (Table 2,
preparation of functionalized polysubstituted oxazoles entry 15). Unfortunately, the reaction was unsatisfactory,
starting from propargyl amides. This efficient strategy could and the desired 5-amino-oxazole 5o was obtained only as
find application in the synthesis of substituted polyox- complex mixture together with starting material degrada-
azoles.[33] In fact, a generic oxazole-4-carboxylic ester 5 tion products (Scheme 3). As mentioned above, because bis-
could be converted into oxazole-4-carboxamide, which, af- oxazoles are a common motif in many natural products,[36]
ter transformation into the corresponding functionalized a different approach was envisaged. First, the N-(α-benzo-
propargyl amide, and subject to the cyclization described triazolylalkyl)-substituted amide 15 was prepared by follow-
herein could give the corresponding bisoxazole. The generic ing the well-known Mannich three-component condensa-
polyoxazole would emerge after n such procedures.
tion of benzotriazole (12), benzamide (13), and phenylprop-
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Cyclization of Propargyl Amides
Table 2. Synthesis of oxazoles 5a–o under microwave-assisted irra-
diation.[a]
Scheme 2. LC/MS analysis of the reaction mixture with propargyl
amide 4k.
Scheme 3. LC/MS analysis of the degradation products from sub-
strate 4o.
[a] All products were identified by their IR, NMR, and ESI-MS
spectra. [b] Yields of products after isolation by flash chromatog-
raphy. [c] Together with degradation products of the starting mate-
rial. [d] Starting material and only traces of oxazole product (de-
tected by GC/MS). [e] Complex reaction mixture from which the
1
oxazole could not be fully purified. Yield of 5o estimated from H
NMR spectroscopic analysis.
argyl aldehyde (14) in the presence of catalytic p-toluene-
sulfonic acid (Scheme 4).[37] The capability of the benzo-
triazolyl moiety to act as a leaving group[38] enabled the
dimerization of 15 to the corresponding dimer 4p in good
yield by SmI2-promoted elimination and subsequent self-
coupling reaction.[39] At this stage we observed that when
substrate 4p was subjected to our experimental conditions,
the bis-oxazole 5p was recovered in 59% isolated yield. This
preliminary result encouraged more detailed studies.
Scheme 4. Synthesis of simple bis-oxazole 5p.
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The precise reaction mechanism is unclear at present, tional heating.[43] Efforts along these lines are in progress in
and all our efforts to study the complexation of propargyl our group, and the results will be reported subsequently.
amides with the CeCl3·7H2O/NaI/I2 combination failed. No
1
identifiable species could be discerned from the H or 13C
NMR spectra, due, very probably, to the presence of para- Experimental Section
magnetic CeIII species.[40] Moreover, from the data available
to us, we cannot say whether the microwave irradiation acti-
General Remarks: Commercially available reagents were used
throughout, without purification, unless otherwise stated. Solvents
(EtOAc and hexanes) for flash chromatography were distilled. Ana-
lytical thin layer chromatography was carried out on precoated
vates the cyclization reaction or makes the CeCl3·7H2O/
NaI/I2 a more active Lewis acid promoter.[41] By employing
α-disubstituted propargyl amide 4q, we isolated only 5-
hydroxyoxazoline 16 (Scheme 5), without any trace of the UV light at 254 nm and/or by dipping the plates into iodine vapor
glass-backed plates (Merck Kieselgel 60 F254), and visualized under
and/or Von’s reagent (1.0 g ceric sulfate and 24.0 g of ammonium
molybdate in 31 mL of sulfuric acid and 470 mL of water) and/or
basic potassium permanganate solution. Solutions were evaporated
under reduced pressure with a rotary evaporator and the residue
was purified by chromatography on silica gel column (EtOAc/hex-
anes, 30%).
corresponding methylenedihydroxazole, which suggests that
perhaps the possible intramolecular addition of a carbonyl
oxygen atom to an alkyne moiety is not the only effective
mechanism. In fact, this intramolecular hydroalkoxylation
reaction provides access to the 5-exo-dig cyclic ether inter-
mediate, which, after protodemetalation[42] and isomeriza-
tion, would allow the final furan to be generated. However,
this reasoning does not explain why only 16 was formed
from 4q. Thus, further studies on the mechanistic aspects
of the 5-exo-dig cyclization of acyclic precursors mediated
by the CeCl3·7H2O/NaI/I2 system are underway in our
laboratories and will be reported in due course.
All microwave irradiation experiments described herein were per-
formed with a CEM Discover monomode reactor using standard
Pyrex vessels. Experiments were performed in temperature-control
mode where the temperature was controlled using the built-in, cal-
ibrated IR sensor. This reactor is equipped with PowerMax tech-
nology that allows simultaneous cooling of a reaction with com-
pressed gas, while it irradiates the sample with microwave energy
(enhanced microwave synthesis). Thus, energy can be continuously
applied while keeping bulk temperature at a set level: this feature
prevents unwanted side reactions and allows for cleaner and faster
reactions.
Fully characterized compounds were chromatographically homo-
geneous. IR spectra were recorded with a Perkin–Elmer FTIR
Paragon 500 spectrometer as thin films on NaCl plates. Only the
characteristic peaks are quoted. NMR spectra were recorded at 300
(1H NMR) or 75 MHz (13C NMR). Chemical shifts are quoted in
ppm and are referenced to residual protons in the deuterated sol-
vent as the internal standard; J values are given in Hz. In the 13C
NMR spectra, signals corresponding to CH, CH2, or CH3 groups
were assigned from DEPT spectra. ESI/APCI low-resolution mass
spectra were recorded with an Agilent 1100 MSD ion-trap mass
spectrometer equipped with a standard ESI/APCI source. Nitrogen
served both as the nebulizer gas and the dry gas. The samples were
prepared by dissolving the obtained oxazoles (10 mg) in the appro-
priate mobile phase (1 mL), and introduced by direct infusion with
a syringe pump.
Scheme 5. Cyclization of α-disubstituted propargyl amide 4q.
Conclusions
We have reported a Lewis acid promoted cyclization of
propargyl amides with good functional-group tolerance by
using the CeCl3·7H2O/NaI/I2 system under microwave irra-
diation. The simplicity of the approach, the low cost of the
reagents, and the fact that no special precautions are re-
quired to exclude moisture or oxygen from the reaction sys-
tem, suggest that the approach could find applicability in
further cyclization reactions leading to the formation of
new heterocycles. The applicability of the microwave-
assisted CeCl3·7H2O/NaI/I2 combination for the prepara-
tion of highly substituted heterocyclic compounds is under
study. In fact, the importance of a number of small hetero-
cycles as key structural units in the synthesis of bioactive
complex heterocycles has fostered a general interest in a
more facile and versatile preparation of such precursors.
Without doubt, the activation seen under this microwave-
assisted synthesis of functionalized polysubstituted ox-
azoles cannot be obtained by conventional heating. Al-
though the vast majority of microwave-assisted organic
transformations are still performed on a laboratory scale, it
is likely that this enabling technology may be used on a
The functionalized propargyl amides used as starting materials
were obtained by acylation of functionalized primary proparg-
ylamines. The latter were generated through the Knochel procedure
by a copper-catalyzed three-component reaction of an aldehyde, a
terminal alkyne, and bis(phenallyl)amine. The final deprotection
of the corresponding protected propargylamines by palladium(0)
allows to obtain primery propargylamine targets.[44] Unfortunately,
the homo-coupling product was found to be the major product
instead of the desired functionalized propargyl amides when zinc-
acetylides[45] or copper-acetylides[46] were reacted with N-trimethyl-
silyl imines and acid chlorides.
General Procedure for the Synthesis of Polysubstituted Oxazoles 5a–
n: The procedure was performed in a CEM Discover in PowerMax
mode with the temperature monitored by a built-in infrared sensor.
A
mixture of propargyl amide 4 (1.0 mmol), CeCl3·7H2O
(1.3 mmol), NaI (0.25 mmol), and I2 (0.25 mmol) in acetonitrile
(10 mL) was subjected to microwave irradiation at 30 W for 45 min
larger scale in conjugation with radio frequency or conven- at 110 °C, until complete consumption of starting material was ob-
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Cyclization of Propargyl Amides
served (reaction monitored by TLC and GC analyses). When the
reaction was complete, the mixture was diluted with EtOAc and
filtered through a short plug of neutral alumina. The filtrate was
washed with aqueous 10% NaHCO3 solution, saturated Na2S2O3
solution, and brine, and dried with Na2SO4. After removal of the
solvent in vacuum, the residue was purified by flash column
chromatography on silica gel (EtOAc/hexanes) to afford the desired
product 5.
1 H) ppm. 13C NMR ([D6]DMSO): δ = 11.7, 122.3, 123.5, 124.2,
147.9, 150.3, 155.0, 168.3 ppm. MS-ESI: m/z = 195 [M + H+], 217
[M + Na+]. C8H6N2O4 (194.14): calcd. C 49.49, H 3.12, N 14.43;
found C 49.40, H 3.10, N 14.39.
3-(5-Methyloxazol-2-yl)-2-phenoxypyridine (5i): 1H NMR (CDCl3):
δ = 2.40 (s, 3 H), 6.93 (s, 1 H), 7.06–7.41 (m, 6 H, ArH), 8.18–8.21
(m, 1 H, ArH) ppm. 13C NMR ([D6]DMSO): δ = 10.7, 112.0, 119.3,
121.4, 124.4, 124.9, 129.6, 139.2, 148.6, 149.8, 153.9, 156.3,
159.2 ppm. MS-ESI: m/z = 253 [M + H+], 275 [M + Na+].
C15H12N2O2 (252.27): calcd. C 71.42, H 4.79, N 11.10; found C
71.36, H 4.82, N 11.08.
Ethyl 5-Benzyl-2-methyloxazole-4-carboxylate (5a): IR (neat): ν =
˜
1
3094, 1743, 1620, 1319, 1109 cm–1. H NMR (CDCl3): δ = 1.40 (t,
J = 7.2 Hz, 3 H), 2.42 (s, 3 H), 4.34 (s, 2 H), 4.40 (q, J = 7.2 Hz,
2 H), 7.26–7.31 (m, 5 H, ArH) ppm. 13C NMR ([D6]DMSO): δ =
13.6, 14.9, 31.0, 62.0, 126.7, 128.2, 129.4, 132.1, 134.9, 150.8, 159.2,
162.0 ppm. MS-ESI: m/z = 246 [M + H+], 268 [M + Na+].
C14H15NO3 (245.11): calcd. C 68.56, H 6.16, N 5.71; found C
68.64, H 6.10, N 5.49.
Benzyl [(5-Methyloxazol-2-yl)methyl]carbamate (5l): IR (neat): ν =
˜
3214, 3063, 1745, 1616, 1315, 1089 cm–1. 1H NMR (CDCl3): δ =
2.40 (s, 3 H), 4.17 (s, 2 H), 4.75 (s, 3 H), 6.93 (s, 1 H), 7.15–7.42
(m, 5 H, ArH) ppm. 13C NMR ([D6]DMSO): δ = 10.9, 34.3, 68.2,
118.4, 127.9, 128.6, 129.0, 136.6, 147.0, 150.5, 161.3 ppm. MS-ESI:
m/z = 247 [M + H+], 269 [M + Na+]. C13H14N2O3 (246.26): calcd.
C 63.40, H 5.73, N 11.38; found C 63.34, H 5.70, N 11.35.
Ethyl
2-[(1,3-Dioxo-2H-benzo[e]isoindolin-2-yl)methyl]oxazole-4-
carboxylate (5b): IR (neat): ν = 3133, 3068, 1730, 1650, 1317,
˜
1
1107 cm–1. H NMR (CDCl3): δ = 1.22 (t, J = 7.2 Hz, 3 H), 3.83
1
5-Benzyl-N,4-diphenyloxazol-2-amine (5n): H NMR (CDCl3): δ =
(s, 2 H), 4.14 (q, J = 7.2 Hz, 2 H), 4.93 (s, 2 H), 6.92 (s, 1 H), 7.78–
7.84 (m, 3 H, ArH), 8.19 (d, J = 8.1 Hz, 1 H, ArH), 8.42–8.45 (m,
1 H, ArH), 8.79 (d, J = 8.1 Hz, 1 H, ArH) ppm. 13C NMR ([D6]-
DMSO): δ = 14.5, 31.4, 34.9, 61.2, 119.0, 125.4, 127.6, 129.7, 130.5,
131.4, 131.7, 136.0, 136.3, 126.7, 146.8, 158.6, 167.0, 167.9,
169.2 ppm. MS-ESI: m/z = 365 [M + H+]. C20H16N2O5 (364.11):
calcd. C 65.93, H 4.43, N 7.69; found C 65.90, H 4.38, N 7.65.
3.41 (s, 2 H), 6.60 (br. s, 1 H, NH), 7.05–7.17 (m, 3 H, ArH), 7.19–
7.34 (m, 8 H, ArH), 7.36–7.41 (m, 4 H, ArH) ppm. 13C NMR ([D6]-
DMSO): δ = 35.6, 116.3, 121.9, 126.3, 127.4, 127.7, 129.3, 129.9,
130.3, 130.8, 131.4, 134.6, 136.8, 138.5, 142.0, 160.8 ppm. MS-ESI:
m/z = 327 [M + H+]. C22H18N2O (326.39): calcd. C 80.96, H 5.56,
N 8.58; found C 80.98, H 5.54, N 8.61.
2-(2,4-Dimethylphenyl)-4,4,5-trimethyl-4,5-dihydrooxazol-5-ol (16):
4-(4-Isopropyl-5-methyloxazol-2-yl)benzonitrile (5c): IR (neat): ν =
IR (neat): ν = 3346, 3098, 1650, 1319, 1074 cm–1. 1H NMR
˜
˜
3068, 2231, 1730, 1319, 1105 cm–1. 1H NMR (DMSO): δ = 1.18 (d,
J = 6.9 Hz, 6 H), 2.35 (s, 3 H), 2.93 (sept, J = 6.9 Hz, 1 H), 7.75–
7.82 (m, 4 H, ArH) ppm. 13C NMR ([D6]DMSO): δ = 10.4, 25.4,
26.1, 112.4, 118.9, 126.4, 131.4, 133.5, 142.4, 144.1, 157.1 ppm.
MS-ESI: m/z = 215 [M + H+], 237 [M + Na+]. C13H14N2O
(214.26): calcd. C 72.87, H 6.59, N 13.07; found C 72.86, H 6.57,
N 13.05.
(CDCl3): δ = 1.60 (s, 6 H), 2.27 (s, 3 H), 2.42 (s, 3 H), 6.53 (br. s,
1 H, OH), 6.99–7.03 (m, 2 H, ArH), 7.25–7.28 (m, 1 H, ArH) ppm.
13C NMR ([D6]DMSO): δ = 19.2, 20.7, 23.3, 23.4, 60.3, 125.9,
127.3, 131.0, 133.4, 135.3, 139.0, 169.1, 208.2 ppm. MS-ESI: m/z =
234 [M + H+], 266 [M + Na+]. C14H19NO2 (233.31): calcd. C 72.07,
H 8.21, N 6.00; found C 72.04, H 8.16, N 5.94.
2-(2,4-Dimethylphenyl)-4,5-dimethyloxazole (5d): IR (neat): ν =
˜
Acknowledgments
1
3073, 1321, 1104 cm–1. H NMR (CDCl3): δ = 2.15 (s, 3 H), 2.30
(s, 3 H), 2.34 (s, 3 H), 2.61 (s, 3 H), 7.02 (d, J = 8.7 Hz, 1 H, ArH),
7.06 (s, 1 H, ArH), 7.80 (d, J = 8.7 Hz, 1 H, ArH) ppm. 13C NMR
([D6]DMSO): δ = 9.6, 11.0, 20.7, 21.4, 123.5, 126.7, 131.1, 132.1,
136.0, 139.0, 142.5, 158.5 ppm. MS-ESI: m/z = 202 [M + H+], 224
[M + Na+]. C13H15NO (201.26): calcd. C 77.58, H 7.51, N 6.96;
found C 77.54, H 7.48, N 6.90.
The authors are grateful to Prof. Marco A. Ciufolini of the Univer-
sity of British Columbia, Vancouver, for many useful suggestions,
and thanks are due to the University of Camerino. S. D. gratefully
acknowledges BI Research Italia for a doctoral fellowship.
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˜
1307, 1109 cm–1. 1H NMR (CDCl3): δ = 4.17 (s, 2 H), 7.20–7.31
(m, 6 H, ArH), 7.39–7.44 (m, 5 H, ArH), 7.82–7.85 (m, 2 H,
ArH) ppm. 13C NMR ([D6]DMSO): δ = 32.2, 120.5, 121.8, 123.0,
125.7, 126.0, 126.3, 126.7, 127.9, 128.0, 128.9, 129.7, 133.0, 134.9,
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1
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Eur. J. Org. Chem. 2012, 630–636
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Received: September 7, 2011
Published Online: December 2, 2011
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Eur. J. Org. Chem. 2012, 630–636