Preparation of oxazolines and oxazoles via a PhI(OAc)2-promoted cyclization of N-propargylamides

Article abstract of DOI:10.1039/c8ob01474d

A metal-free cyclization of N-propargylamides for the synthesis of various oxazolines and oxazoles via a 5-exo-dig process is presented. Using (diacetoxyiodo)benzene (PIDA) as a reaction promoter and lithium iodide (LiI) as an iodine source, intramolecula

Full text of DOI:10.1039/c8ob01474d

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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Preparation of oxazolines and oxazoles via a PhI(OAc)2-promoted
cyclization of N-propargylamides
Received 00th January 20xx,
Accepted 00th January 20xx
Wei Yi , Qing-Yun Liu, Xing-Xiao Fang, Sheng-Chun Lou and Gong-Qing Liu,*
DOI: 10.1039/x0xx00000x
A metal-free cyclization of N-propargylamides for the synthesis of various oxazodines and oxazoles via a 5-exo-dig process
is presented. Using (diacetoxyiodo)benzene (PIDA) as the reaction promoter and lithium iodide (LiI) as the iodine source,
intramolecular iodooxygenation of N-propargylamides proceeded readily, leading to the corresponding (E)-5-
iodomethylene-2-oxazolines in good to excellent isolated yields. In addition, uisng PhI(OAc)2/LiI system, N-
propargylamides can be converted to the corresponding oxazole-5-carbaldehydes in the presence of oxygen under visible
light irradiation. The resulting products can be further converted into various oxazoline and oxazole derivatives after
simple derivatizations, and this method ultimately offers an efficient route to a variety of biologically active structures.
www.rsc.org/
propargylic amides is one of the most attractive strategies for
the synthesis of oxazolines and oxazoles due to the rapid
assembly of structural complexity and good functional group
Introduction
Oxazolines and oxazoles are important structural motifs in
many natural products1 and biologically active molecules2
(Figure 1). Moreover, these functional groups are also
frequently employed in synthesis as versatile precursors,3
protecting groups,4 directing groups5 and ligands/auxiliaries.6
To this end, continuous efforts have been devoted to the
development of novel methods for the synthesis of these
compounds.7
compatibility as well as step economy of this method (Scheme
1).8 Thus, substantial efforts have been devoted to these
transformations, and a variety of efficient catalysts such as
14
gold,9 palladium,10 copper,11 silver,12 iron,13 zinc,13b,
ruthenium,15 tungsten,16 mercury,17 and Brønsted acids18 as
well as strong bases19 have been developed.
In addition, a halogen-induced electrophilic cyclization of
propargyl amides has also been demonstrated as an efficient
means of accessing oxazoline or oxazole derivatives. For
example, Caristi et al. reported the first electrophilic
cyclization of propargylic amides into halomethyloxazolines,
which are potential synthetic intermediates in the synthesis of
functionalized oxazoles.20 A variety of electrophiles such as
iodine,21 bromine,22 and N-iodosuccinimide23 could trigger this
reaction. Finally, the cyclization of N-propargylamides could
also be realized with hypervalent iodine reagents. For instance,
Saito et al. demonstrated an iodine(III)-mediated oxidative
cycloisomerization of propargylic amides into various
functionalized oxazoles.24
Figure 1. Oxazoline- and oxazole-containing compounds.
Among the various methods developed, cyclization of
Scheme 1. Synthetic approach to oxazolines and oxazoles.
Recently, we reported
a (diacetoxyiodo)benzene (PIDA)-
promoted intramolecular cyclization of N-allylamides into 5-
halomethyloxazolines (Scheme 2a).25 As a continuation of our
studies on the cyclization of unsaturated (sulfon)amides,26 we
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Journal Name
a
PIDA-mediated iodocyclization of N- a All the reactions were run at 0.5 mmol scale in 2 mVieLwoArfticCleHO2nCliln2e
envisioned that
b
c
DOI: 10.1039/C8OB01474D
propargylamides would be of great synthetic value since the under N2. DMP=Dess-Martin periodinane. IBX=2-
resulting vinyl iodides can undergo other useful Iodoxybenzoic acid d NR=No reaction,
transformations, transition metal-catalyzed cross-couplings in
particular, which provides opportunities for constructing more To our delight, substrate 1a underwent 5-exo-dig cyclization in
complex frameworks. Herein, we report the PIDA-promoted the presence of PIDA and TMSI under a nitrogen atmosphere
regioselective iodocyclization of N-propargylamides to provide giving (E)-5-(iodomethylene)-2-phenyl-4,5-dihydrooxazole (2a
)
various
iodomethylenedihydrooxazoles
through
an in 73% yield (entry 1). The E configuration was determined by
intramolecular 5-exo-dig process (Scheme 2b, left). In addition, comparing the 1H NMR data of this compound with those with
we disclose that N-propargylamides can be converted to the known compounds.27 Encouraged by these preliminary result,
corresponding oxazole-5-carbaldehydes in the presence of different iodine sources were tested to further improve the
oxygen under visible light irradiation (Scheme 2b, right).
yield, and the investigation showed that LiI gave the best
results (entries 1−4). Iodosobenzene, IBX or Dess-Martin
periodinane in combination with LiI could also be used for
cyclization of 1a, but the yields were generally lower than
PIDA-induced reactions (entries 5−7). Other oxidants, such as
mCPBA, K2S2O8, Oxone and (NH4)2SO4, were also tested, but
they were found to be less efficient than PhI(OAc)2 (entries 8-
11). The effect of the solvents on the course of the reaction
was also noteworthy (entries 12−16), and CH2Cl2 was the most
suitable solvent for the reaction. No product was obtained in
the absence of an iodine source, indicating that the iodine
atom in the product came from LiI rather than from the PIDA
(entry 17). No reaction occurred in the absence of PIDA,
indicating that PIDA played an important role in the reaction
(entry 18). The three notable features of the present approach
are (i) a 5-exo-dig ring closure to give an oxazoline without any
indication of competing 6-endo-dig ring closure, (ii) no further
isomerization to the oxazole due to the mild reaction
conditions and (iii) no additional iodination of the phenyl ring.
Scheme 2. PIDA-mediated functionalization of N-allyl or N-
propynyl amide
Results and Discussion
We commenced our investigation with the optimization of the
reaction conditions using N-(prop-2-yn-1-yl)benzamide (1a) as
the model substrate, and the preliminary results are
summarized in Table 1.
Table 1. Optimization of the reaction conditions.a
Under the optimized reaction conditions, the scope of the
formation of
2 from various N-propargyl amides 1 is
summarized in Scheme 3. As these results showed, (E)-5-
iodomethylene-2-oxazolines could be obtained in good to
excellent isolated yields. Compared with known cyclization of
iodine
source
TMSI
NaI
KI
LiI
LiI
LiI
LiI
LiI
LiI
LiI
LiI
LiI
LiI
LiI
LiI
isolated
yield (%)
73
N-propargylamides in which a strong Thorpe-Ingold effect was
entry
reagent
solvent
19b
observed,10d,
the current reaction system was less
1
2
3
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhIO
DMP
IBX
mCPBA
K2S2O8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Cl(CH2)2Cl
CCl4
dependent on the substituents at the propargylic position, and
substrates without gem-disubstituents all gave good isolated
yields. Electronic effects of the substituents on the aryl groups
showed some effect on the reaction, and substrates with
either electron-donating groups or halides on the aromatic
88
83
91
60
80
72
78
4
5
6b
7c
8
rings could all be cyclized in good isolated yields (2a−2i).
Phenyl rings bearing a nitro or a cyano moiety gave slightly
lower yields probably due to the low reactivity of the substrate
caused by the strong electron-withdrawing effects of the
substituents (2j and 2k). The reaction could also be scaled up
to 10 mmol to give 2.60 g (87%) of product 2e. The
naphthalene-derived substrate worked well in the current
reaction system, and the corresponding oxazoline was
obtained in good yield (2l). Oxazoline-containing heterocycles
have been used as important functional groups in
antibacterial,28 antituberculosis,29 and antitumor agents.30
Thus, structurally diverse heterocyclic oxazoline compounds
were also prepared using the developed method. As shown in
Scheme 3, thiophene-, furan-, pyrrole- and pyridine-containing
9
NRd
NRd
NRd
85
79
88
6
10
11
12
13
14
15
16
17
18
Oxone
(NH4)2SO4
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
-
CHCl3
DMF
CH3CN
CH2Cl2
CH2Cl2
LiI
-
LiI
20
NRd
NRd
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oxazoline compounds 2m
−
2p could be obtained in satisfactory need to be revised since the NMR data are not iVniewagArrteicelemOnelinnet
could
isolated yields. Ferrocene rings and styryl groups could also be with literature values.12b, 31 (E)-Alkene 3 DaOndI: 1(0Z.)1-0a3l9k/eCn8eOB01474D
4
tolerated in the current system (2q and 2r). Substrates bearing be separated by flash column chromatography, and the
a quaternary carbon center also reacted very well and provide structures of the compounds were established by NOE
the corresponding products in excellent yields (2s). Again, the experiments. The geometric configuration of
4 was established
reaction could be carried out on a 10 mmol without significant by the strong NOESY correlation between the methyl protons
decreases in yield. Moreover, no additional iodination of the and the vinylic proton, which were in agreement with the
aromatic ring was observed in any case (2a-
2s). Further, results reported by Strand and co-workers.31
cyclization of N-propynyl amides of aliphatic carboxylic acids
and natural α-amino acids were also tested and afforded the
corresponding oxazoline products 2t−2w in good isolated
yields. To further evaluate the synthetic utility and generality
of current procedure, more complex small molecules were
then investigated. Gratifyingly, substrates bearing
a
phenanthrene group were compatible with the standard
reaction conditions and provided desired oxazoline 2x in 83%
yield. Finally, dehydrocholic acid and artesunate derivatives
were good candidates for this transformation (2y and 2z),
further highlighting the generality and great potential of the
developed method.
Scheme 4. Suzuki coupling of 2s and p-tolylboronic acid
In the course of optimizing the reaction conditions, we found
that when the reaction was carried out in the open air,
oxazoline 2a was obtained along with a small amount of
oxazole-5-carbaldehyde 5a (Scheme 5a); however, no 5a was
observed when the reaction was carried out under nitrogen
(Table 1). These results indicated that the carbonyl oxygen
atom in 5a was from air.
Scheme 3. Synthesis of (E)-5-iodomethylene-2-oxazolines a
Wang et al. recently discovered that the oxidative deiodination
of 2a to give 5a can be achieved at 80 °C in the presence of
dioxygen.23a Flynn and co-workers also showed that the
deiodination of an analogous vinyl iodide can take place at
elevated temperature and give the corresponding aldehydes in
good yields.32 Consistent with their reports, iodoalkene 2a
could be converted to 5a under an oxygen atmosphere at
ambient temperature, albeit at a lower yield (Scheme 5b). No
transformation was observed when the reaction was carried
out under nitrogen (Scheme 5b). Additionally, vinyl iodide 2a
could be stored for an extended period when it was kept in the
dark under a nitrogen atmosphere. However, in the presence
of air and light, 2a gradually decomposed into aldehyde 5a
with a concomitant color change to red, owing to the
generation of iodine. These results indicated that light and
oxygen had
a significant impact in deiodination step.
Encouraged by the above results, we envisage that this process
would proceed readily if the reaction was irradiated by visible
light under an oxygen atmosphere. Therefore, 2a was
dissolved in CH2Cl2 under 1 atm of O2 at ambient temperature,
and the reaction mixture was irradiated by a standard 24 W
household fluorescent bulb. As expected, 2a could be nearly
quantitatively converted to 5a (Scheme 5c).
a
Reaction conditions: 0.5 mmol of substrate, 0.5 mmol of
b
PhI(OAc)2, 0.5 mmol of LiI, 2 mL of CH2Cl2, 1 atm of N2, 12 h.
10 mmol scale.
The resulting iodomethylene-substituted cyclic compounds
could be easily converted into trisubstituted alkenes via
transition metal-catalyzed coupling reactions. For instance,
almost an equimolar ratio of E/Z-isomers were obtained from
the Suzuki coupling of (E)-alkene 2s with p-tolylboronic acid in
1,4-dioxane (Scheme 4), which was not consistent with the
observations made by Xu that the Suzuki coupling of 2s and
boronic acids produced a single geometric isomer.11c In
addition, the structure of the product reported in Xu’s work
Given the importance of oxazole-5-carbaldehyde,17b, 17c, 33 we
then tried to combine the iodocyclization and oxidative
deiodination into a one-pot procedure to prepare these
compounds directly from propargylamides. During the
preparation of this work, Wang et al. showed that
propargylamides could be converted to the corresponding
oxazole aldehydes using an I2/visible light system.34 Similarly,
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we found this transformation could also be accomplished using
10 mol % PIDA and LiI under visible light irradiation (Scheme PhI(OAc)2, 0.05 mmol of LiI, 2 mL of CH2Cl2, 1 atm of O2, visible
5d). Lowering the amount of PIDA and LiI to 5 mol % led to a light, 24 h. b 10 mmol scale.
slight drop of conversion, but this could be overcome by
Journal Name
a
Reaction conditions: 0.5 mmol of substrate, 0V.0iew5 AmrticmleoOlnlionef
DOI: 10.1039/C8OB01474D
elongating the reaction time to 36 h.
To demonstrate the synthetic value of the developed
methodology, the aldehyde group in 5a was converted to a
variety of functional groups (Scheme 7). For example, using the
procedure reported by Nantz,35 aldehyde 5a was smoothly
transformed to corresponding nitrile
(diphenylphosphinyl)hydroxylamine (DPPH) in toluene. Sodium
borohydride reduction of 5a could generate alcohol , a key
intermediate in the synthesis of herbicides.36 5a can be easily
converted carboxylic acid
, a potential antibacterial agent,37
under oxidative conditions. Insect growth regulator can be
6 by heating with O-
7
8
9
easily prepared by the reductive amination of 5a and 4-
chloroaniline.17b
Scheme 5. Synthesis of oxazole-5-carbaldehyde 5a
Scheme 7. Derivatizations of aldehyde 5a.
Given theirs low price, 10 mol % PIDA and 10 mol% LiI were A plausible mechanism, as outlined in Scheme 8, was proposed
finally chosen to test the scope of the reaction, and the results for the formation of oxazolines and oxazoles. First, PIDA
are summarized in Scheme 6. As shown in Scheme 6, promoted the oxidation of the iodide anion, producing
propargylamides of aromatic, heteroaromatic, and aliphatic iodoacetic acid (IOAc) as an intermediate,38 which induced the
carboxyacids as well as those of natural α-amino acids all electrophile-mediated cyclization of N-propargylamide to
delivered the corresponding oxazole aldehydes in good yield. provide iodomethylenedihydrooxazole 2a. The E-configuration
The cyclization could be run on more than a gram scale and of 2a is generated by the anti-attack of the carbonyl group on
provided the aldehyde in 80% isolated yield (5a).
the triple bond.39 Radical intermediate
are created by homolytic cleavage of the C-I bond under visible
A and an iodine radical
Scheme 6. Synthesis of oxazole aldehydes a
light irradiation.40 Species
A
then quickly reacts with O2 to give
and the subsequently formed six-
a peroxy-radical species B 41
,
membered-ring transition state affords radical species
C, which
is a resonance structure of D 23a
.
Species releases a hydroxyl
D
radical to yield aldehyde 5a. The combination of iodine radicals
and hydroxyl radicals results in the formation of HIO, which
can decompose into iodine for the next catalytic cycle.
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Scheme 8. Proposed mechanism
recorded with KBr pellet, and wavenumbers were given in
cm−1. High resolution mass spectrometry (HRMS) analyses
were carried out on an FTICR HR-ESI-MS.
Conclusions
General procedure for the preparation of (E)-5-
iodomethylene-2-oxazolines: A flame-dried Schlenk flask was
charged with 0.5 mmol N-propargylamide, 0.5 mmol PhI(OAc)2,
0.5 mmol LiI and 2 mL of CH2Cl2. The reaction mixture was
stirred at room temperature until complete disappearance of
the starting material as shown by TLC (usually 12 h). CH2Cl2 (10
mL) was then added, and the mixture was washed with
aqueous Na2S2O3. The organic layer was dried over Na2SO4 and
concentrated to give crude residue, which was purified by
flash column chromatography to give the corresponding
products.
In summary, we have reported a simple, mild, and efficient
method for the preparation of oxazolines and oxazoles. Using
1.0 equiv. of (diacetoxyiodo)benzene as the reaction promoter
and 1.0 equiv. of LiI as the iodide source, (E)-5-
(iodomethylene)-4,5-dihydrooxazole products could be
obtained in good to excellent isolated yields. Moreover, N-
propargylamides can be converted to the corresponding
oxazole-5-carbaldehydes in the presence of oxygen under
visible
light
irradiation.
The
resulting
iodomethylenedihydrooxazole and oxazole-5-carbaldehyde
compounds can be further converted into various oxazoline
and oxazole derivatives after simple derivatizations, and this
method ultimately offers an efficient route to a variety of
biologically active structures. The good isolated yields, mild
conditions, and operational simplicity make the current
reaction an attractive method for the syntheses of a variety of
medicinally and agrochemically relevant compounds.
(E)-5-(Iodomethylene)-2-phenyl-4,5-dihydrooxazole
(2a).
Compound 2a was prepared according to the general
procedure and isolated as a yellow solid (130 mg, 91% yield)
after flash chromatography (petroleum ether/ethyl acetate =
1
30/1); mp = 107–108 °C ( ref,21b mp = 104 °C ). H NMR (400
MHz, CDCl3): δ/ppm= 7.98 – 7.94 (m, 2H), 7.56 – 7.51 (m, 1H),
7.47 – 7.43 (m, 2H), 5.78 (t, J = 3.2 Hz, 1H), 4.62 (d, J = 3.2 Hz,
2H). 13C NMR (100 MHz, CDCl3): δ/ppm= 162.9, 156.9, 131.1,
127.6, 127.0, 125.4, 60.2, 46.2. Spectral data are in agreement
with literature values.11c
Experimental section
General information
General procedure for the preparation of oxazole aldehydes
:
All reagents were used as received without further purification
unless otherwise indicated. Solvents were dried and distilled
prior to use. Reactions were monitored with thin layer
chromatography using silica gel GF254 plates. Organic solutions
were concentrated in vacuo with a rotavapor. Flash column
chromatography was performed using silica gel (200−300
meshes). Petroleum ether used had a boiling point range of
60−90 °C. Melting points were measured on a digital melting
point apparatus without correction of the thermometer.
Nuclear magnetic resonance spectra were recorded at ambient
temperature (unless otherwise stated) at 400 MHz (100 MHz
for 13C) in CDCl3. Chemical shifts were reported in ppm (δ)
using TMS as internal standard, and spin−spin coupling
constants (J) were given in Hz. Infrared (IR) spectra were
A
solution of N-propargylamide (0.5 mmol, 1.0 equiv.),
PhI(OAc)2 (0.005 mmol, 0.1 equiv.), and LiI (0.005 mmol, 0.1
equiv.) in 2 mL of CH2Cl2 was irradiated under oxygen
atmosphere with a 24 W fluorescent household bulb at room
temperature. Upon completion (monitored by TLC
，usually 24
h), CH2Cl2 (10 mL) was added, and the mixture was washed
with aqueous Na2S2O3. The organic layer was dried over
Na2SO4 and concentrated to give crude residue, which was
purified by flash column chromatography to give the
corresponding products.
2-Phenyloxazole-5-carbaldehyde (5a)
prepared according to the general procedure and isolated as a
white solid (71 mg, 82% yield) after flash chromatography
. Compound 5a was
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(petroleum ether/ethyl acetate = 6/1); mp = 71–73 °C, (ref,42
mp = 74–76 °C). 1H NMR (400 MHz, CDCl3): δ/ppm= 9.82 (s, 1H),
8.19 – 8.16 (m, 2H), 7.95 (s, 1H), 7.59 – 7.49 (m, 3H). 13C NMR
(100 MHz, CDCl3): δ/ppm= 176.3, 165.5, 149.6, 139.1, 132.3,
129.1, 127.7, 125.9. Spectral data are in agreement with
literature values.34
Chem. Rev., 1971, 71, 483; (f)M. Reuman and A. I.
Meyers, Tetrahedron, 1985, 41, 837.
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DOI: 10.1039/C8OB01474D
4
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Haidukewych and A. I. Meyers, Tetrahedron Lett., 1972,
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Soc., 1970, 92, 6644; (d)R. J. B. H. N. van den Berg, H.
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Conflicts of interest
There are no conflicts to declare.
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Acknowledgements
This study was supported by the Natural Science Foundation of
Jiangsu Province in China (BK20170439), Advanced Research
Foundation for Natural Science of Nantong University (16ZY15),
Start-Up Funding for Research of Nantong University (17R40),
Lager Instruments Open Foundation of Nantong University
(KFJN1853), and Science and Technology Plan Projects of
Nantong
.
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One review proposed an alternative pathway involving
activation alkyne by PIDA followed by subsequent
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DOI: 10.1039/C8OB01474D
Table of Contents Entry
1.0 equiv. PhI(OAc)2
1.0 equiv. LiI
N
R
I
O
CH2Cl2, r.t., N2
O
N
R
10 mol% PhI(OAc)2
10 mol% LiI
H
O
R
CHO
N
hv, O2, CH2Cl2, r.t.,
A metal-free cyclization of N-propargylamides for the synthesis of various oxazodines
and oxazoles via a 5-exo-dig process is reported herein.