Single-step microwave-mediated synthesis of oxazoles and thiazoles from 3-oxetanone: A synthetic and computational study

Article abstract of DOI:10.1002/chem.201301011

The direct microwave-mediated condensation between 3-oxetanone and primary amides and thioamides has delivered moderate to good yields of (hydroxymethyl)oxazoles and (hydroxymethyl)thiazoles. The reactions use a sustainable solvent and only require short reaction times. These are highly competitive methods for the construction of two classes of valuable heteroarenes, which bear a useful locus for further elaboration. Electronic structure calculations have shown that the order of events involves chalcogen atom attack at sp³ carbon and alkyl-oxygen cleavage. The critical role of acid catalysis was shown clearly, and the importance of acid strength was demonstrated. The calculated barriers were also fully consistent with the observed order of thioamide and amide reactivity. Spontaneous ring opening involves a modest degree of C-O cleavage, moderating the extent of strain relief. On the acid-catalysed pathway, C-O cleavage is less extensive still, but proton transfer to the nucleofuge is well advanced with the carboxylic acid catalysts, and essentially complete with methanesulfonic acid. Open sesame: The direct microwave-mediated condensation between 3-oxetanone and primary amides and thioamides has delivered moderate to good yields of oxazoles and thiazoles. The reactions use a sustainable solvent, require only short reaction times and represent a highly competitive method for the construction of two classes of valuable heteroarenes. Electronic structure calculations have been used to probe a range of potential reaction mechanisms (see figure). Copyright

Full text of DOI:10.1002/chem.201301011

FULL PAPER
DOI: 10.1002/chem.201301011
Single-Step Microwave-Mediated Syntheses of Oxazoles and Thiazoles from
3-Oxetanone: A Synthetic and Computational Study
David Orr,[a] Alexandra Tolfrey,[a] Jonathan M. Percy,*[a] Joanna Frieman,[a]
Zoꢀ A. Harrison,*[b] Matthew Campbell-Crawford,[c] and Vipulkumar K. Patel[b]
Abstract: The direct microwave-medi-
ated condensation between 3-oxeta-
none and primary amides and thio-
structure calculations have shown that
the order of events involves chalcogen
atom attack at sp3 carbon and alkyl–
oxygen cleavage. The critical role of
acid catalysis was shown clearly, and
the importance of acid strength was
demonstrated. The calculated barriers
were also fully consistent with the ob-
served order of thioamide and amide
reactivity. Spontaneous ring opening
À
ACHTUNGTRENNUNGamides has delivered moderate to good
yields of (hydroxymethyl)oxazoles and
(hydroxymethyl)thiazoles. The reac-
tions use a sustainable solvent and only
require short reaction times. These are
highly competitive methods for the
construction of two classes of valuable
heteroarenes, which bear a useful locus
for further elaboration. Electronic
involves a modest degree of C O
cleavage, moderating the extent of
strain relief. On the acid-catalysed
À
pathway, C O cleavage is less exten-
Keywords: annulation
·
density
sive still, but proton transfer to the nu-
cleofuge is well advanced with the car-
boxylic acid catalysts, and essentially
complete with methanesulfonic acid.
functional calculations · microwave
chemistry · nitrogen heterocycles ·
sulfur heterocycles
Introduction
Oxetanes are rapidly becoming an important part of the
repertoire of the medicinal chemist, because of the ability of
these heterocycles to mimic ketonic carbonyl groups and
gem-dimethylated sp3 centres.[1] Methods for the introduc-
tion of the oxetanyl motif are becoming more developed[2]
and there is a growing array of procedures that allow the
complete oxetane unit to be introduced.[3] However, oxetane
derivatives may also be interesting synthetic building blocks
for the construction of other heterocycles. There are rela-
tively few examples of oxetane ring-opening reactions in the
literature, but recently, Carreira and co-workers[4] showed
how isoxazoles 2 could be formed in a sequence begun by
the reaction of the conjugate base of a nitroalkane with 3-
Scheme 1. Carreira and co-workersꢀ isoxazole synthesis from 3-oxetanone
begins with a Henry reaction and features a pivotal ring opening through
an oxete intermediate.
oxetanone (1; Scheme 1). The heterocyclic ketone 1 is now
commercially available and, while it is relatively expensive,
its latent reactivity in strain-relieving ring opening makes it
a very interesting species for further exploration.
During the course of the synthesis of a drug lead, we dis-
covered trace amounts of an oxazole product when a benz-
AHCTUNGTREGaNNNU mide was condensed with 1 under acidic conditions (acetic
acid/sulfamic acid). Oxazoles and the related thiazoles occur
widely in natural products, including species in which they
are linked, and in some drug leads. Figure 1 shows a number
of natural products that contain these heteroarenes. Virgin-
iamycin M1 (3) is used to treat resistant bacterial infec-
tions,[5] (À)-Mycothiazole (4) is a marine natural product
with cytotoxicity against lung cancer cells,[6] while Bistrat-
[a] D. Orr, A. Tolfrey, Prof. Dr. J. M. Percy, J. Frieman
WestCHEM Department of Pure and Applied Chemistry
University of Strathclyde, Thomas Graham Building
295 Cathedral Street, Glasgow G1 1XL (UK)
Fax : (+44)0141-548-4822
E-mail: jonathan.percy@strath.ac.uk
AHCTUNGTREGaNNNU mide C (5) is one of the Lissoclinum cyclopeptides, a class
[b] Z. A. Harrison, Dr. V. K. Patel
of cyctotoxic agents from marine Ascidians.[7] There has
been considerable recent interest in the synthesis of these
heteroarenes[8] reflecting their frequent occurrence, prompt-
ing us to explore our serendipitous finding to see if a useful
synthetic method could be discovered. It has also provided
an opportunity to explore some of the mechanisms available
for oxetanone ring opening, a process that has not been ex-
plored to our knowledge, apart from in a preliminary
manner by Carreira and co-workers.
Refractory Respiratory Inflammation DPU
GlaxoSmithKline Medicines Research Centre
Gunnels Wood Road, Stevenage SG1 2NY (UK)
Fax : (+44)01438768302
E-mail: zoe.x.harrison@gask.com
[c] M. Campbell-Crawford
Fibrosis DPU, GlaxoSmithKline Medicines Research Centre
Gunnels Wood Road, Stevenage SG1 2NY (UK)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201301011.
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Table 1. First-generation microwave-mediated azole syntheses in tri-
fluoroacetic acid/acetic acid mixtures.
Amide or thioamide
X
Product Method[a,b]
T
Time Yield
[oC] [h]
[%][c]
6a, R=Ph
O
O
O
O
S
8a
8b
8c
8d
9a
A
B
A
B
A
B
A
B
A
120
80
120
80
120
80
120
80
3.5 47[d]
28
48
6b, E-PhHC=CH
6c, 2-thiophenyl
6d, cyclohexyl
7a, Ph
2.5 60
51
52
2.5 50
52
68[e]
3.0 21
192
31[f]
3.5 52
85
[a] Method A: microwave heating. [b] Method B: conventional heating.
[c] All reactions were carried out on 1–2 mmol scale at 1208C.
[d] 10 mmol scale, 1208C. [e] Crude GC/MS yield. [f] Crude yield.
Figure 1. Oxazole- and thiazole-containing natural products.
Results and Discussion
into a series of short pulses as described by Ley and co-
workers,[10] but there was no improvement in isolated yield
(20 min periods of heating at 1208C, followed by 10 min rest
periods).
To optimise our use of costly 3-oxetanone, we fixed the ini-
tial stoichiometry for the reaction with benzamide at 1:1 and
retained acetic acid as the solvent, because it is inexpensive,
polar and sustainable.[9] A reaction screen was carried out
on a 0.5 mmol scale in the microwave; the parameters
varied were temperature (80–1408C), time (20–300 min),
stronger acid catalyst (none, sulfamic acid, trifluoroacetic
acid, and HCl, generated in situ from tetramethylsilyl chlo-
Conventional heating at 808C could also be used to pre-
pare 8a–d; yields were comparable though a very long reac-
tion time was required for 8d. These results were pleasing,
but the products would have more value if the free hydroxyl
group was available for oxidation to the aldehyde or other
manipulation without the need for an ester cleavage. Anoth-
er reaction solvent that could not act as an acetyl donor was
clearly required and we selected dimethyl carbonate, which
has a lower dielectric constant (eS =3.1)[11] than acetic acid
(eS =6.2). Solvents with such low dielectric constants do not
usually respond strongly to microwave heating,[12] but di-
methyl carbonate has good solvent characteristics for scale-
up and sustainable synthesis,[13] and some promise as a sus-
tainable methylating agent.[14] A range of acids were de-
ployed including trifluoroacetic, oxalic, sulfamic, methane-
sulfonic and p-toluenesulfonic acids; the effective combina-
tion emerging from the screen was methanesulfonic acid in
DMC. There was no correlation between acid strength and
performance; the relevant pKa values are TsOH (pKa
À2.8),[15a] MsOH (pKa À1.9),[15a] TFA (pKa 0.23),[15b]
H2NSO3H (pKa 1.0),[15c] oxalic acid (pKa 1.23),[15d] and acetic
acid (pKa 4.76)[15d] so the most effective acid was neither the
strongest nor the weakest.[15] Scheme 3 shows the best condi-
tions discovered from a screen; the yields of free (oxazolyl)-
methyl alcohols were lower than those of the acetates, but
are still acceptable given the directness and simplicity of the
synthetic procedures. Crystals of sufficiently high quality to
allow analysis by X-ray diffraction were grown for alcohol
10a, confirming its structure. However, the method is much
ACHTUNGTRENNUNGride), equivalents of stronger acid (0.1–0.5 equivalents) and
reaction concentration (0.4–2.1m). Reactions that achieved
the highest conversions of benzamide with the lowest levels
of side-product formation (assayed by GC-MS) were select-
ed for further investigation. The following generalities
emerged; a stronger acid catalyst was essential (or the reac-
tion was very slow) and trifluoroacetic acid was the most ef-
fective of the three used in the initial screen (Scheme 2).
Scheme 2. First-generation microwave-mediated azole syntheses in tri-
fluoroacetic acid/acetic acid mixtures.
A high loading of catalyst (0.5 equivalents) was required
and the combination of a reaction temperature of 1208C
and concentration of 0.4m gave high (>95%) conversion of
the amide and consistent results. Acetates 8a–c were pre-
pared in good (47–60%) yields under these conditions
(Table 1); cyclohexyl congener 8d reacted less successfully
(21% isolated yield at full conversion). Thiazolyl analogue
9a (52%) was also prepared from commercial thiobenz-
ACHTUNGTRENNUNGamide. The mass balance in these reactions is unfortunately
accounted for by tar formation; in some cases, traces of the
corresponding trifluoroacetate esters were detected in the
crude products by GC-MS, but we were unable to isolate
them. We tried dividing the total microwave irradiation time
Scheme 3. Second-generation microwave-mediated oxazole and thiazole
syntheses in methanesulfonic acid/dimethyl carbonate mixtures.
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Syntheses of Oxazoles and Thiazoles
FULL PAPER
more effective for thiazole synthesis. A higher (54%) yield
of thiazole 11a was obtained under these conditions, and a
change in reaction stoichiometry to use a 50% molar excess
of thioamide increased the yield further to 64% (with thio-
with ammonia (MP2ACHTUNGERTG(NUNN Full)/6-311+ +GAHCTUNRTGEGUN(NN d,p)//MP2ACHTUNGTRENNUNG(Full)/6-
31+G*). We have used electronic structure calculations to
examine a range of possible ring-opening modes and at-
tempt to gain insight into the reaction mechanism. Because
of the high kinetic cost of opening the ring, we assume that
locating the lowest energy transition structure which in-
ACHTUNGTRENNUNGamide recovery possible). Unfortunately, this tactic was not
effective for oxazole synthesis because the amides and oxa-
zole products often had very similar RF values, making chro-
matographic purification very difficult.
À
volves C O scission will reveal the most favoured mode of
ring opening and that mapping the entire energy surface will
provide no additional insights.
A range of primary thioamides[16] was prepared (see the
Supporting Information for details) using the extremely con-
venient microwave method of Perlmutter and co-workers,[17]
which exposes the primary amides (we held a stock of these
compounds) to diphosphorus pentasulfide supported on alu-
mina; Table 2 summarises the results obtained to date and
makes clear the efficacy of this approach for thiazole syn-
thesis.
Initial structures were obtained at the RI-MP2/6-31G*
level of theory, then reoptimised (MP2/6-31+G*) with full
frequency calculations, implemented in Spartanꢀ08.[24] Tran-
sition structure 12a (Figure 2) reported by Banks was repro-
Table 2. Second-generation microwave-mediated azole syntheses in
methanesulfonic acid/dimethyl carbonate mixtures.
R
Amide X=O Yield Thioamide X=S Yield
[%]
[%][a]
Ph
6a
10a
10b
10c
10d
n.d.
10 f
10g
10h
10i
–
36
24
22
17
n.d.
15
13
24
14
7a
7b
7c
7d
7e
7 f
7g
7h
7i
11a
11b
11c
11d
11e
11 f
11g
11h
11i
64
E-PhHC=CH 6b
2-thiophenyl
cyclohexyl
44
6c
6d
6e
6 f
6g
6h
6i
50[b]
63
T
47[b]
50
ACHTUNGTRENNUNG
Figure 2. Calculated DG° (kcalmolÀ1, 298 K) for nucleophilic ring open-
ing of oxetane, 3-oxetanone and 2-oxetanone with ammonia, (MP2/6-
31+G* and B3LYP/6-311+G**) and the products of ring opening used
to evaluate leaving group pKa.
N
37
N
36
40[b]
41
[c]
T
6j
6k
–
–
7j
7k
11j
11k
A
–
48
[a] All yields were obtained with 1.5 equivalents of thioamide unless
stated otherwise. [b] In this case, better yield was obtained with
1.0 equivalent of thioamide; the use of an excess resulted in yield loss in
mixed fractions in the chromatography. [c] Reaction attempted for 4 h
with incomplete conversion.
a
duced by an MP2/6-31+G* geometry optimisation; DG°
(gas phase) calculated by this method was 59.8 kcalmolÀ1,
which is in excellent agreement with the published value
and instils confidence that the use of the much smaller basis
will deliver useful results. Carriera and co-workers used a
A range of aromatic substituents were tolerated as were
secondary and tertiary alkyl groups; the E-cinnamyl group
also survived the reaction conditions. There were no trends
between substituent character and reaction yield; the main
factor determining the yield was the ease of separation of
heteroarene product from unreacted amide or thioamide.
Literature routes that build thiazoles with this 2,4-disubstitu-
tion pattern include Hantzsch syntheses[18] (thioamide con-
densations with pyruvate-type electrophiles), and thiazoline
oxidation[19] or bromination/dehydrobromination[20] proce-
dures. Our procedure is extremely competitive because of
its directness and high atom-efficiency.
different level of theory (B3LYP/6-311GACTHNGUTERN(UNG d,p), or 6-311G**)
to interrogate aspects of the isoxazole-forming reaction of
Scheme 1. Because the implementation of this method is
more economical with Spartanꢀ08, we also examined all the
key reactions using this additional level of theory. The use
of the B3LYP functional has been subject to criticism in
recent years, but Goodman[25] has provided evidence of its
effectiveness for dealing with transition states of reactions
of small organic molecules, and of its relatively low degree
of vulnerability to the integration grid errors attributed[26] to
the Q-CHEM grid used by the Spartan programmes.
We did not expect that the presence of the carbonyl
À
There is very little mechanistic work on oxetane or oxeta-
none ring-opening in the literature. Oxetane, the parent het-
erocycle for the synthetic building block used in this study,
is a strained cyclic ether; opening of this ring[21] releases a
significant strain energy of 25.5 kcalmolÀ1 according to ex-
periment[22] and theory.[23] However, ring-opening reactions
must overcome a high kinetic barrier; Banks evaluated DG°
(gas phase) at 58.4 kcalmolÀ1 for the ring-opening reaction
group in 3-oxetanone would lower the barrier to C O scis-
sion significantly; while nucleophilic substitution next to a
carbonyl group is usually accelerated,[27] the scissile s-bond
and the relevant carbonyl group orbital would be expected
to be orthogonal[28] if the oxetanone ring was planar. How-
ever, the barrier to oxetane ring opening is considerably
lower at 45.1 kcalmolÀ1, predicting that the ring-opening re-
action of 3-oxetanone with ammonia would be 1011 times
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J. M. Percy, Z. A. Harrison et al.
Table 3. Free-energy barriers (DG°, kcalmolÀ1, 298 K) calculated for
opening of 3-oxetanone 1 for nucleophilic O- and S-attack by amides and
thioamides transition structures 19a–h and 20.
faster than the reaction of oxetane itself. The products of
ring opening are 13 and 14 and their hydroxyl group pKa
values (in water at 298 K, calculated using ACD/Labs soft-
ware within CAS SciFinder) are 14.95 and 12.94, so it is
clear that lower nucleofuge basicity alone cannot be respon-
sible for the higher reactivity of 3-oxetanone. A decrease in
leaving group basicity of 2 pKa units and a Brønsted bL of
À1.0 predicts only a 100-fold increase in reactivity. In the
transition structures 12a and b, the ring is twisted, resem-
bling the puckered conformation of cyclobutane; in the 3-
oxetanone structure 12b, the C=O bond sits at approximate-
Structure R1
X
R2
MP2/gas[a] MP2/acetic acid[a] B3LYP/gas[b]
18a
18b
19a
19b
19c
19d
19e
19 f
19g
19h
20
–
–
O
S
O
S
O
S
O
S
–
–
49.3
41.4
47.1
40.4
38.7
34.2
29.0
27.5
–
–
–
–
–
51.7
43.2
38.0
35.5
31.2
27.1
37.7
34.3
30.7
29.0
–
H
H
H
H
Ph
Ph
Ph
Ph
–
CH3 35.8
CH3 31.4
CF3 26.7
CF3 24.0
CH3 33.7
CH3 30.2
CF3 23.2
CF3 22.5
21.2
O
S
À
ly 458 to the forming C N bond. This twisting distorts the
O-C-N angle to 1648 (from 175.58 in 12a) and 12b is slightly
À
À
earlier with respect to C N bond formation (C N is 1.83
compared to 1.76 ꢂ in 12a). The location of the carbonyl
group suggests strongly that some degree of transition state
[a] (MP2/6-31+G*) gas phase and [SM8]. [b] (B3LYP/6-311+G**).
À
stabilisation is being achieved by the C=O group. The C2
C3 bond length changes from 1.53 to 1.48 ꢂ between 1 and
transition structure 12b, consistent with the development of
some partial double bond character between the two car-
bons at the transition state. The DG° (gas phase) value cal-
culated for 12c is lower still at 41.2 kcalmolÀ1, and the
À
À
atoms of the opening ring are coplanar, with C O and C N
distances similar to those for 12a; in this case, the calculated
carboxylate pKa is 3.65. Scheme 4 shows the ring opening of
Figure 3. Spontaneous and acid-catalysed transition structure types for
opening of 3-oxetanone
amides and thioamides.
1 through nucleophilic O- and S-attack by
mode of ring-opening was therefore examined further. A
molecule of acetic acid or trifluoroacetic acid was placed so
À
Scheme 4. Competitive acyl and alkyl C O cleavage modes for 2-oxeta-
none derivative 16.
À
that the acid O H proton was within approximately hydro-
gen bonding distance of the oxetanyl oxygen, and optimisa-
tion was carried out without constraint. Allowing the opti-
misation to find the best position for the proton should ac-
commodate both general and specific acid catalysis. Various
changes occurred during the optimisation, including flatten-
ing of the oxetanyl ring, turning of the attacking amide to
hydrogen bond to the acetic acid molecule and partial
proton transfer to the oxetanyl oxygen (see the Supporting
Information for graphical representations of the transition
structures and an overlay).
With the acetic acid molecule present in 19a (Figure 4b),
DG° fell to 35.8 kcalmolÀ1 (gas phase). The lower DG°
value for this reaction is remarkable given the high entropic
cost of termolecular reactions compared to their bimolecular
counterparts.[30]
16 by benzylamine in dichloromethane; this reaction in-
À
volves competitive acyl and alkyl C O cleavage to afford
17a and b respectively under mild conditions,[29] and sug-
gests very strongly that a calculated barrier of 40 kcalmolÀ1
in the gas phase corresponds to a cleavage reaction, which
can occur readily in solution under relatively mild condi-
tions.
Amides are significantly less nucleophilic than ammonia
so we examined a wider set of reactions related to the ring
opening of 1; however, simple intermolecular reactions lead
to the lowest energy barriers (Table 3) via transition struc-
tures of types 18 or 19 (Figure 3; a wider set of ring-opening
reactions is described fully in the Supporting Information).
The barrier DG° calculated for the ring opening of 1 with
model amide formamide (O-attack) rose to 49.3 kcalmolÀ1
from the lower value (45.1 kcalmolÀ1) for the more nucleo-
philic ammonia. A higher barrier (59.1 kcalmolÀ1) was cal-
À
The C2 C3 distance is longer when the acetic acid is pres-
ent and the natural charge on the carbonyl oxygen is lower
(À0.479) compared to the structure in the absence of the
acetic acid (À0.689); these differences are consistent with an
interaction between the substitution centre and the carbonyl
group in 18a; once the acetic acid is present in 19a, strong
stabilisation of the developing charge on the leaving group
can occur and the need for ring twisting is relieved. With tri-
fluoroacetic acid posed near the oxetanyl oxygen, the
energy for opening by formamide fell still further to
culated for formamide N-attack while S-attack for thio
ACHTUNGTNERfNUNG orm-
ACHTUNGTRENNUNG
pathway. All the modes of intermolecular attack involved
À
N H···O=C hydrogen-bond formation; these interactions
formed during the optimisation even when the two function-
al groups were initially remote. The intermolecular O-attack
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Syntheses of Oxazoles and Thiazoles
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effect in acetic acid. Finally, selected calculations were car-
ried out with the full benzamide or thiobenzamide nucleo-
philes (19e–h) reproducing the trends observed for the
formACTHNUTRGNEUGaN mide and thioformamide models.
The optimised structures from the gas phase calculations
À
were used to quantify approximately the extent of C O
cleavage in the spontaneous and catalysed reactions. The
sum of the carbon and oxygen van der Waals radii was used
À
as an estimate of full C O cleavage and the extension of the
À
À
C O bond relative to the oxetanone C O bond length was
used to calculate the percentage extension. A similar ap-
À
proach was used to quantify the extent of O H formation.
In the spontaneous ring opening with ammonia and form-
Figure 4. Optimised (gas phase, MP2/6-31+G*) transition structures for
a) 3-oxetanone opening with formamide 18a; b) 3-oxetanone opening
with formamide in the presence of acetic acid 19a. Distances are shown
in ꢂ.
À
amide, C O cleavage approaches 30%, indicating that the
release of ring strain will be modest at the transition state.
À
On the acid catalysed pathway, C O cleavage is less well ad-
vanced at approximately 20%, whereas proton transfer to
the oxetanyl oxygen is well advanced (approximately 90%)
at the transition state with proton movement involved in the
imaginary frequency, whereas proton transfer was complete
with the stronger methanesulfonic acid. The two pathways
are represented in the More–OꢀFerrall–Jencks[32] diagram of
Figure 6. After ring opening, a sequence of conventional
steps is proposed for oxazole or thiazole formation, summa-
26.7 kcalmolÀ1 (gas phase), consistent with the significantly
higher acidity of trifluoroacetic acid (the pKa values of tri-
fluoroacetic acid and acetic acid are 0.23 and 4.76 respec-
tively, vide infra). With thioformamide as the nucleophile
and trifluoroacetic acid as the catalyst, the barrier fell to
24 kcalmolÀ1 (gas phase), while for formamide in the pres-
ence of methanesulfonic acid (pKa À1.9), DG° fell further
still to 21.2 kcalmolÀ1 (gas phase). Transition structures were
reoptimised (MP2/6-31+G*) using Cramer and Truhlarꢀs
SM8 method[31] specifying acetic acid as the reaction solvent;
unfortunately, a full range of parameters are not available
for dimethyl carbonate or related species, so while we can
treat the initial reaction conditions (acetic acid/trifluoroace-
tic acid), the second generation method cannot be dealt
with using this solvation treatment. As expected, lower
values of DG° were obtained using the SM8 method (by
14.6, 8.0 and 12.4 kcalmolÀ1 for 12a, b and c respectively),
but structural differences between gas phase and solution
structures were minimal. Intermolecular transition structures
18a and b were slightly lower in (free) energy in acetic acid,
but the barriers calculated for 19a–d were all slightly higher
in acetic acid. To gain some insight into this behaviour, we
compared the dipole moments of complex 21 (D=
4.14 debye), obtained by relaxing transition structure 19a,
with transition structure 19a itself (D=4.18 debye)
(Figure 5). There was no significant change in dipole
AHCTUNGTREGrNNUN ised in Scheme 5 for 10a with acetic acid catalysis.
Scheme 5. Intermediates on the pathway to oxazole product 10a and
their free energies (kcal mol-1, 298 K, MP2/6-31+G*).
moment on progression to the transition structure, con
ACHTUNGTRENNUNGent with the absence of a strong transition state stabilising
sist-
Overall, the sequence is strongly exergonic, consistent
with strain relief and the formation of an aromatic product.
Conclusion
The direct microwave-mediated condensation between 3-ox-
etanone and primary amides and thioamides has delivered
moderate to good yields of (hydroxymethyl)oxazoles and
(hydroxymethyl)thiazoles. The reactions use a sustainable
solvent and require only short reaction times. These are
highly competitive methods for the construction of two
classes of valuable heteroarenes, which bear a useful locus
for further elaboration.
Figure 5. Structures used to calculate dipole moment changes during ring
opening of 1 by formamide (gas phase). Free energies (Grel/kcalmolÀ1
are calculated relative to 1, formamide and acetic acid as separate mole-
)
cules.
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J. M. Percy, Z. A. Harrison et al.
Figure 6. More–OꢀFerrall–Jencks diagram showing spontaneous and acid-catalysed oxetanone ring-opening reactions. The bottom right-hand structure is
unstable with respect to proton transfer from cationic N to anionic O.
trometer with a Pike MIRacle horizontal single reflection ATR attach-
Electronic structure calculations have shown that the
ment. Thin layer chromatography was performed on pre-coated alumini-
um-backed silica gel plates (silica gel 60 F254, thickness 0.2 mm, Merck
order of events involves chalcogen atom attack at sp3
carbon and alkyl–oxygen cleavage; the favoured termolecu-
lar mode of ring opening revealed by the computational
study was unexpected. The critical role of acid catalysis was
shown clearly, and the importance of acid strength was dem-
onstrated. The calculated barriers were also fully consistent
with the observed order of thioamide and amide reactivities.
KGaA, Darmstadt). Visualisation was achieved using vanillin or anisalde-
hyde staining and UV detection at 254 and 356 nm. Semi-automated
column chromatography was performed on silica gel (Zeoprep 60 HYD,
40–63 mm, Zeochem) using a Bꢄchi Sepacore system. Hexane was distil-
led before chromatography. Tetrahydrofuran and diethyl ether (for thio-
AHCTUNGERTGaNNUN mide synthesis) were dried using a PureSolv system from Innovative
Technology, Inc. Dimethyl carbonate was used as obtained from a chemi-
cal supplier. Microwave reactions were carried out in sealed vials in a
À
Spontaneous ring opening involves a modest degree of C O
BioACHTNUTRGNEUNGtage Initiator 2.5.
cleavage, moderating the extent of strain relief. On the acid-
Typical procedure: Preparation of 8a: Oxetan-3-one (0.68 mL,
10.6 mmol) followed by trifluoroacetic acid (0.40 mL, 5 mmol) were
À
catalysed pathway, C O cleavage is less extensive still, but
proton transfer to the nucleofuge is well advanced with the
carboxylic acid catalysts, and essentially complete with
methanesulfonic acid.
added to
a solution of benzamide (1.21 g, 10 mmol) in acetic acid
(20 mL). The colourless solution was heated to 1208C for 3.5 h in a mi-
crowave reactor, then allowed to cool to room temperature. After vent-
ing and opening the vial, the black reaction mixture was concentrated
under reduced pressure to remove any residual acid. The residue was
treated with toluene (10 mL) then evaporated to afford crude product as
a black tar (2.29 g). The crude product was taken up in a minimum
volume of ethyl acetate (20 mL) and evaporated onto silica gel (1.5 g).
The silica gel was made into a pad in a sinter funnel and washed with di-
ethyl ether (250 mL). The washings were concentrated under reduced
pressure to afford crude product as an orange/brown oil (2.1 g). Purifica-
tion by column chromatography over silica gel (gradient 1:2 to 1:1 diethyl
ether/hexane) afforded 2-phenyl 4-(acetoxymethyl)-oxazole (8a) as a col-
ourless solid (932 mg, 47%); Rf =0.36 (2:5 diethyl ether/hexane); m.p.
39–408C (lit. m.p. 39.5–408C);[33] 1H NMR (400 MHz, CDCl3): d=8.08–
8.05 (m, 2H; ArH), 7.74 (s, 1H; H5), 7.49–7.46 (m, 3H; ArH), 5.12 (d,
4J=0.7 Hz, 2H; CH2OAc), 2.13 ppm (s, 3H; CH3); 13C NMR (100 MHz,
CDCl3): d=170.3, 161.7, 136.7, 136.6, 130.1, 128.3, 126.7, 126.0, 57.6,
20.4 ppm; IR (film): n˜ =1735, 1554, 1383, 1449, 1382, 1362, 1343,
1229 cmÀ1; MS (CI): m/z (%): 258 (6) [M+C2H5]+, 246 (10), [M+C2H5]+,
218 (22) [M+H]+, 174 (11) [MÀAc], 158 (100) [MÀOAc], 104 (12);
HRMS (ES-TOF): m/z calcd for C12H12NO3: 218.0812 [M+H]+; found:
218.0806; tR (GC)=12.20 min.
Experimental Section
General: NMR spectra were recorded on Bruker DPX-400 or Avance
DRX-500 spectrometers. 1H, 19F and 13C NMR spectra were recorded
using the deuterated solvent as the lock and the residual solvent as the
internal reference. The multiplicities of the spectroscopic data are pre-
sented in the following manner: s=singlet, bs=broad singlet, d=dou-
blet, dd=double doublet, ddd=doublet of double doublets, dt=doublet
of triplets, qd=quartet of doublets, t=triplet, tt=triplet of triplets and
À
À
À
m=multiplet. Homocouplings (H H, H F, C F) are given in Hertz and
specified by J; the nuclei involved in heteronuclear couplings are defined
with the observed nucleus given first. Unless stated otherwise, all refer to
3J couplings. HRMS measurements were obtained from Thermofisher
LTQ Orbitrap XL at the Engineering and Physical Sciences Research
Council National Mass Spectrometry Service Centre, Swansea. Elemental
analysis was performed on a PerkinElmer 2400 CHN analyser. GC-MS
spectra were obtained on an instrument fitted with a DB5-type column
(30 mꢃ0.25 mm) running a 40–3208C (70–3208C for acetates) tempera-
ture program, ramp rate 208CminÀ1 with helium carrier gas flow at
1 cm3 minÀ1. Electrospray mass spectra were obtained on a Thermo Fin-
negan LCQ Duo mass spectrometer (spray voltage 4.5 kV, mobile phase
methanol). Melting points were recorded on a Griffin apparatus using
open capillaries. IR spectra were recorded as films on a Shimadzu spec-
Typical procedure: Preparation of 10a: Oxetan-3-one (0.13 mL, 2 mmol)
followed by methanesulfonic acid (65 mL, 1 mmol) were added to a sus-
pension of benzamide (245 mg, 2.0 mmol) in dimethyl carbonate (4 mL).
The reaction mixture was heated in a microwave reactor at 1208C for
80 min; TLC confirmed full conversion. The reaction mixture was loaded
onto a dry pad of celite (7.6 g), which was washed with dichloromethane
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Syntheses of Oxazoles and Thiazoles
FULL PAPER
(125 mL). The filtrate was concentrated under reduced pressure and puri-
fied by column chromatography on silica gel (2:3 to 1:1 gradient of ethyl
acetate in hexane) to afford 2-phenyl-4-(hydroxymethyl)-oxazole (10a)
[1] G. Wuitschik, E. M. Carreira, B. Wagner, H. Fischer, I. Parrilla, F.
Schuler, M. Rogers-Evans, K. Muller, J. Med. Chem. 2010, 53, 3227–
3246.
as
a light brown solid (125 mg, 36%); Rf =0.25 (1:1 ethyl acetate/
hexane); m.p. 80–818C (lit. m.p. 82–838C);[32] 1H NMR (400 MHz,
CDCl3): d=8.08–8.05 (m, 2H; ArH), 7.68 (s, 1H; H5), 7.49–7.47 (m, 3H;
ArH), 4.71 (d, J=4.6 Hz, 2H; ArCH2OH); 2.26 ppm (brs, 1H; CH2OH);
13C NMR (100 MHz, CDCl3): d=161.7, 141.1, 134.5, 130.0, 128.3, 126.8,
126.0, 58.4 ppm; IR (film): n˜ =3221, 3116, 1740, 1552, 1351, 1231,
1023 cmÀ1; MS (CI): m/z (%): 216 (7) [M+C3H5]+, 204 (13) [M+C2H5]+,
176 (40) [M+H]+, 158 (100) [MÀOH]+), 130 (5); HRMS (ESI): m/z
calcd for C10H10NO2: 176.0706 [M+H]+; found: 176.0705; tR (GC)=
12.71 min. Crystal data for C10H9NO2: Formula weight: 175.18; Tempera-
ture: 123(2) K; l=0.71073 ꢂ; Monoclinic system; Crystal size: 0.24ꢃ
0.18ꢃ0.10 mm3; Unit cell dimensions: a=8.5610(5), b=14.5900(8), c=
7.0504(4) ꢂ, a=90, b=104.625(6), g=908; Z=4; Reflection collected:
3925; R indices (all data): R1=0.0647, wR2=0.1033.
[2] a) L. W. Ye, W. M. He, L. M. Zhang, J. Am. Chem. Soc. 2010, 132,
8550–8551; b) B. O. Beasley, G. J. Clarkson, M. Shipman, Tetrahe-
dron Lett. 2012, 53, 2951–2953.
[3] a) M. A. J. Duncton, M. A. Estiarte, D. Tan, C. Kaub, D. J. R.
OꢀMahony, R. J. Johnson, M. Cox, W. T. Edwards, M. Wan, J. Kin-
caid, M. G. Kelly, Org. Lett. 2008, 10, 3259–3262; b) M. A. J. Dunc-
ton, M. A. Estiarte, R. J. Johnson, M. Cox, D. J. R. OꢀMahony, W. T.
Edwards, M. G. Kelly, J. Org. Chem. 2009, 74, 6354–6357.
[4] J. A. Burkhard, B. H. Tchitchanov, E. M. Carreira, Angew. Chem.
2011, 123, 5491–5494; Angew. Chem. Int. Ed. 2011, 50, 5379–5382.
[5] T. A. Mukhtar, G. D. Wright, Chem. Rev. 2005, 105, 529–542.
[6] F. Batt, F. Fache, Eur. J. Org. Chem. 2011, 6039–6055.
[7] P. Wipf, Chem. Rev. 1995, 95, 2115–2134.
[8] a) R. Martꢅn, A. Cuenca, S. L. Buchwald, Org. Lett. 2007, 9, 5521–
5524; b) E. F. Flegeau, M. E. Popkin, M. F. Greaney, Org. Lett. 2008,
10, 2717–2720; c) S. A. Ohnmacht, P. Mamone, A. J. Culshaw, M. F.
Greaney, Chem. Commun. 2008, 1241–1243; d) C. K. Skepper, T.
Quach, T. F. Molinski, J. Am. Chem. Soc. 2010, 132, 10286–10292;
e) C. M. Counceller, C. C. Eichman, N. Proust, J. P. Stambuli, Adv.
Synth. Catal. 2011, 353, 79–83; f) I. Cano, E. Alvares, M. C. Nicasio,
P. J. Perez, J. Am. Chem. Soc. 2011, 133, 191–193; g) C. L. Paradise,
P. R. Sarkar, M. Razzak, J. K. De Brabander, Org. Biomol. Chem.
2011, 9, 4017–4020; h) G. Bartoli, C. Cimarelli, R. Cipolletti, S. Dio-
medi, R. Giovannini, M. Mari, L. Marsili, E. Marcantoni, Eur. J.
Org. Chem. 2012, 630–636; i) A. E. Wendlandt, S. S. Stahl, Org.
Biomol. Chem. 2012, 10, 3866–3870.
Typical procedure: Preparation of 7 f: 4-Methoxybenzamide (376 mg,
2.5 mmol) was added to a suspension of P2S5/alumina reagent (773 mg,
3.5 mmol) in anhydrous THF (5 mL) and the reaction mixture was
heated in a microwave reactor at 608C for 20 min until TLC showed
complete conversion. The reaction mixture was evaporated onto a pad of
silica gel (8.6 g), eluted with diethyl ether (50 mL), and the eluent was
concentrated under reduced pressure to afford crude thioamide 7 f as a
yellow solid (660 mg). The crude product was taken up in anhydrous
THF (4 mL) and evaporated onto silica gel (2.6 g). The solid was trans-
ferred onto a pad of silica (10.6 g) in a sinter funnel that had been condi-
tioned with 1:1 diethyl ether/hexane. Non-polar impurities were removed
using 1:1 diethyl ether/hexane and product was eluted with 4:1 diethyl
ether/hexane to afforded 4-(methoxy)thiobenzamide 7 f as a yellow solid
(280 mg, 67%); Rf =0.23 (4:1 diethyl ether/hexane); m.p. 141–1438C;
1H NMR (400 MHz, CDCl3): d=7.92–7.88 (m, 2H; one half of an
AA’BB’ system, ArH), 7.48 (brs, 1H; C(S)NHaHb), 7.09 (brs, 1H;
C(S)NHaHb), 6.92–6.88 (m, 2H; one half of an AA’BB’ system ArH),
3.86 ppm (s, 3H; ArOCH3); 13C NMR (100 MHz, CDCl3): d=201.4,
163.0, 131.3, 129.1, 113.6, 55.6 ppm; IR (film): n˜ =3367, 3278, 3157, 2363,
1626, 1597, 1510, 1427, 1389, 1330, 1285, 1258, 1184, 1138, 1020 cmÀ1; MS
(ESI): m/z (%): 168 (100) [M+H]+, 151 (30) [MÀNH2], 135 (15). The
spectroscopic data were in agreement with those reported in the litera-
[9] R. K. Henderson, C. Jimenez-Gonzalez, D. J. C. Constable, S. R.
Alston, G. G. A. Inglis, G. Fisher, J. Sherwood, S. P. Binks, A. D.
Curzons, Green Chem. 2011, 13, 854–862.
[10] T. Durand-Reville, L. B. Gobbi, B. L. Gray, S. V. Ley, J. S. Scott,
Org. Lett. 2002, 4, 3847–3850.
[11] M. L. P. Le, L. Cointeaux, P. Strobel, J. C. Lepretre, P. Judeinstein, F.
Alloin, J. Phys. Chem. C 2012, 116, 7712–7718.
[12] a) C. Gabriel, S. Gabriel, E. H. Grant, B. S. J. Halstead, D. M. P.
Mingos, Chem. Soc. Rev. 1998, 27, 213–223; b) P. Lidstrçm, J. Tier-
ney, B. Wathey, J. Westman, Tetrahedron 2001, 57, 9225–9283.
[13] a) H. Bilel, N. Hamdi, F. Zagrouba, C. Fischmeister, C. Bruneau,
Green Chem. 2011, 13, 1448–1452; b) X. W. Miao, C. Fischmeister,
C. Bruneau, P. H. Dixneuf, ChemSusChem 2008, 1, 813–816.
[14] a) C. M. Hou, Y. F. Chen, W. Li, Carbohydr. Res. 2012, 355, 87–91;
b) U. Tilstam, Org. Process Res. Dev. 2012, 16, 1150–1153.
[15] a) J. P. Guthrie, Can. J. Chem. 1978, 56, 2342–2354; b) J. F. J. Dippy,
S. R. C. Hughes, A. Rozanski, J. Chem. Soc. 1959, 2492–2498;
c) J. P. Candlin, R. G. Wilkins, J. Chem. Soc. 1960, 4236–4241;
d) W. P. Jencks, J. Regenstein in Handbook of Biochemistry and Mo-
lecular Biology (Ed.: G. D. Fasman), CRC, Boca Raton, 1976,
pp. 305–351.
[16] For syntheses of thioamides from nitriles, see: a) P. Y. Lin, W. S. Ku,
M. J. Shiao, Synthesis 1992, 1219–1220; b) M. C. Bagley, K. Chapa-
neri, C. Glover, E. A. Merritt, Synlett 2004, 2615–2617; c) M. Nagl,
C. Panuschka, A. Barta, W. Schmid, Synthesis 2008, 4012–4018.
[17] H. R. Lagiakos, A. Walker, M. I. Aguilar, P. Perlmutter, Tetrahedron
Lett. 2011, 52, 5131–5132.
ACHTUNGTRENNUNG
ture.[16a]
Computational methods: Electronic structure calculations were carried
out on a Dell Precision T1500 (Intel 4 Core i7 CPU 870@ 2.93 GHz Pro-
cessor, 8 GB RAM) running Spartanꢀ08 V1.2.0, 64 Bit. Transition struc-
tures were located via initial guesses that were optimised using the PM3
semi-empirical method, then re-optimised initially at the RI-MP2/6-31G*
or B3LYP/6-31G* levels of theory. These structures were then used as
the starting points for MP2/6-31+G*or B3LYP/6-311+G** optimisa-
tions with full frequency calculation at 298 K. Free energies were evaluat-
ed (in au) using Spartanꢀs internal algorithm and transferred to Excel for
further manipulation. Optimised structures had no imaginary frequen-
cies; unique imaginary frequencies were found for transition structures
and these are listed fully with the Cartesian coordinates in the Support-
ing Information.
Acknowledgements
[18] a) P. Ratcliffe, J. M. Adam, J. Baker, R. Bursi, R. Campbell, J. K.
Clark, J. E. Cottney, M. Deehan, A. M. Easson, D. Ecker, D. Ed-
wards, O. Epemolu, L. Evans, R. Fields, S. Francis, P. Harradine, F.
Jeremiah, T. Kiyoi, D. McArthur, A. Morrison, P. Passier, J. Pick,
P. G. Schnabel, J. Schulz, H. Steinbrede, G. Walker, P. Westwood, G.
Wishart, J. U. de Haes, Bioorg. Med. Chem. Lett. 2011, 21, 2541–
2546; b) M. Rega, P. Candal, C. Jimenez, J. Rodriguez, Eur. J. Org.
Chem. 2007, 934–942; c) R. Uy, L. Q. Yang, H. X. Zhou, S. C. Price,
W. You, Macromolecules 2011, 44, 9146–9154.
We thank EPSRC and GSK (Industrial CASE studentship to A.T.), GSK
and the University of Strathclyde (studentship to D. O.), GSK Refractory
Respiratory Inflammation DPU for consumables, the EPSRC National
Mass Spectrometry Service Centre, Swansea for accurate mass measure-
ments, Dr Alan Kennedy (Pure and Applied Chemistry, University of
Strathclyde) for the X-ray structural determination of 10a, Dr. Rob
Young (GSK Stevenage) for helpful discussions about work-up methods,
and David Black (University of Strathclyde) for preliminary syntheses of
oxazoles 10.
[19] a) Z. Y. Li, L. Ma, J. Y. Xu, L. Y. Kong, X. M. Wu, H. Q. Yao,
Chem. Commun. 2012, 48, 3763–3765; b) B. Di Credico, G. Regina-
to, L. Gonsalvi, M. Peruzzini, A. Rossin, Tetrahedron 2011, 67, 267–
Chem. Eur. J. 2013, 00, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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ÞÞ
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J. M. Percy, Z. A. Harrison et al.
274; c) H. Sugiyama, F. Yokokawa, T. Shioiri, Org. Lett. 2000, 2,
2149–2152.
[20] D. Sellanes, F. Campot, I. Nunez, G. Lin, P. Esposito, S. Dematteis,
J. Saldana, L. Dominguez, E. Manta, G. Serra, Tetrahedron 2010, 66,
5384–5395.
[30] A reviewer pointed out that the usual ideal gas equation penalises
bimolecular reactions entropically at the expense of unimolecular
reactions, and that termolecular reactions may suffer a still more
severe penalty; for QM calculations on termolecular reaction steps,
see a) S. K. Ignatov, P. G. Sennikov, A. G. Razuvaev, O. Schrems, J.
Phys. Chem. A 2004, 108, 3642–3649; b) M. Ismael, R. Sahnoun, A.
Suzuki, M. Koyama, H. Tsuboi, N. Hatakeyama, A. Endou, H.
Takaba, M. Kubo, S. Shimizu, C. A. Del Carpio, A. Miyamoto, Int. J.
Greenhouse Gas Control 2009, 3, 612–616; c) H. Yamada, Y. Matsu-
zaki, T. Higashii, S. Kazama, J. Phys. Chem. A 2011, 115, 3079–
3086; d) M. Torrent-Sucarrat, J. S. Francisco, J. M. Anglada, J. Am.
Chem. Soc. 2012, 134, 20632–20644; for an approach to the evalua-
tion of Gibbs energy barriers for reactions of higher molecularity,
see D. Ardura, R. Lopez, T. L. Sordo, J. Phys. Chem. B 2005, 109,
23618–23623.
[21] M. Yamaguchi, Y. Nobayashi, I. Hirao, Tetrahedron Lett. 1983, 24,
5121–5122.
[22] C. J. M. Stirling, Tetrahedron 1985, 41, 1613–1666.
[23] H. D. Banks, Org. Biomol. Chem. 2009, 7, 4496–4501.
[24] Spartan ꢆ08, Wavefunction, Irvine, CA, 2008.
[25] L. Simꢇn, J. M. Goodman, Org. Biomol. Chem. 2011, 9, 689–700.
[26] S. E. Wheeler, K. N. Houk, J. Chem. Theory Comput. 2010, 6, 395–
404.
[27] a) J. B. Conant, W. R. Kirner, R. E. Hussey, J. Am. Chem. Soc. 1925,
47, 488–501; for examples in which adjacent unsaturation has little
or no effect on the rate of nucleophilic substitution at sp3 carbon,
see b) D. N. Kevill, C. B. Kim, J. Org. Chem. 2005, 70, 1490–1493.
[28] For detailed MO treatments of the effect of adjacent unsaturation
on nucleophilic substitution at sp3 carbon, see a) D. Kost, K.
Aviram, J. Am. Chem. Soc. 1986, 108, 2006–2013; b) R. E. Rawlings,
A. K. McKerlie, D. J. Bates, Y. R. Mo, J. M. Karty, Eur. J. Org.
Chem. 2012, 5991–6004.
[31] a) A. C. Chamberlin, C. J. Cramer, D. G. Truhlar, J. Phys. Chem. B
2008, 112, 8651–8655; b) C. J. Cramer, D. G. Truhlar, Acc. Chem.
Res. 2008, 41, 760–768.
[32] a) W. P. Jencks, Chem. Rev. 1972, 72, 705–718; b) R. A. OꢀFerrall, J.
Chem. Soc. B 1970, 274–277.
[33] A. B. A. Jansen, M. Szelke, J. Chem. Soc. 1961, 405–411.
[29] A. Noel, B. Delpech, D. Crich, Org. Biomol. Chem. 2012, 10, 6480–
6483.
Received: March 16, 2013
Published online: && &&, 0000
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Syntheses of Oxazoles and Thiazoles
FULL PAPER
Open sesame: The direct microwave-
mediated condensation between 3-oxe-
tanone and primary amides and thio-
Heterocyclic Synthesis
D. Orr, A. Tolfrey, J. M. Percy,*
J. Frieman, Z. A. Harrison,*
M. Campbell-Crawford,
ACHTUNGTRENNUNGamides has delivered moderate to
good yields of oxazoles and thiazoles.
The reactions use a sustainable sol-
vent, require only short reaction times
and represent a highly competitive
method for the construction of two
classes of valuable heteroarenes. Elec-
tronic structure calculations have been
used to probe a range of potential
reaction mechanisms (see figure).
V. K. Patel ..................... &&&& — &&&&
Single-Step Microwave-Mediated
Syntheses of Oxazoles and Thiazoles
from 3-Oxetanone: A Synthetic and
Computational Study
Chem. Eur. J. 2013, 00, 0 – 0
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