A bench-stableN-trifluoroacetyl nitrene equivalent for a simple synthesis of 2-trifluoromethyl oxazoles

Article abstract of DOI:10.1039/d1ob00947h

ortho-Nitro-substitutedN-trifluoroacetyl imino-λ³-iodane is a bench-stable trifluoroacetyl nitrene precursor, in which intra- and intermolecular halogen bonding (XB) plays an important role. Potential synthetic applications of this novel precursor were explored.

Full text of DOI:10.1039/d1ob00947h

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A bench-stable N-trifluoroacetyl nitrene
equivalent for a simple synthesis of
2-trifluoromethyl oxazoles†
Cite this: Org. Biomol. Chem., 2021,
19, 6628
Received 14th May 2021,
Accepted 7th July 2021
Yusuke Kobayashi, *a Sota Masakado,b Takuya Murai,a Shohei Hamada,
a
b
Takumi Furuta a and Yoshiji Takemoto
*
DOI: 10.1039/d1ob00947h
rsc.li/obc
ortho-Nitro-substituted N-trifluoroacetyl imino-λ3-iodane is
a
acetamide (CF3CONH2) requires relatively strong basic con-
bench-stable trifluoroacetyl nitrene precursor, in which intra- and ditions (NaH in ether/DCM).11 We therefore intended to over-
intermolecular halogen bonding (XB) plays an important role. come these issues by tuning the substituents on the aromatic
Potential synthetic applications of this novel precursor were ring of N-acyliminoiodinane.9
explored.
Based on the previously reported ortho-coordinating groups
to the hypervalent iodine atoms,9 we synthesized several
N-trifluoroacetyliminoiodinanes that bear ortho-substituents.
Of all the substituents screened, ortho-nitro-substituted10e
Nitrene insertion1 is one of the most reliable and versatile
methods to introduce nitrogen atoms into molecules.2 It has
been used to synthesize a wide range of natural products as
well as biologically active compounds. N-Sulfonylimino-λ3-
iodane3 and N-carbamoyl- or N-alkyl-O-sulfonyl hydroxyl-
amines4 are often used as nitrene precursors. Conversely,
N-acyl nitrene precursors have not yet been studied as well,
most likely due to their propensity to undergo the Hofmann
rearrangement.5,6 While several N-acyl nitrene precursors,
including N-trifluoroacetylazide 1,6 1,4,2-dioxazole-5-one 2,7
and sulfonyl ylide 3,8 have been reported (Fig. 1), few synthetic
applications of these precursors have been demonstrated.7,8
Therefore, we envisaged that readily accessible and stable
N-acyl nitrene precursors would probably result in new syn-
thetic applications. We have recently reported the synthesis of
N-trifluoroacetyliminoiodinane 5, in which the coordinating
methoxylmethyl group ortho to the hypervalent iodine atom9,10
is crucial for its improved stability and solubility over the non-
substituted iodane 4.5 These enhanced properties enabled the
application of 5 in the amination of silyl enol ethers11 and the
amino-etherification of glycals.12 However, iodinane 5 still
suffers from problems associated with its storage and prepa-
ration. For example, iodinane 5 cannot be stored at room
temperature, and the final step in its preparation using the
corresponding iodoarene diacetate (ArI(OAc)2) and trifluoro-
N-trifluoroacetyliminoiodinane
6 was found to have an
increased stability even at room temperature, i.e., it could be
stored for more than one month at this temperature. In
addition, 6 was readily synthesized by simply mixing iodoarene
diacetate 7 13 with trifluoroacetamide in pyridine/ether2a,11 to
form a yellow precipitate that was collected via filtration. This
synthetic advance allowed a simple scaled-up synthesis of 6 in
a high yield (Scheme 1).
To our delight, recrystallization of 6 afforded a crystalline
solid that was subjected to X-ray crystallographic analysis
(Fig. 2A). Similar to our previous report,11 the oxygen atom of
the N-trifluoroacetyl group and the iodine atom were within
the sum of their van der Waals radii (2.720 Å vs. 1.98 Å +
1.52 Å = 3.50 Å), indicating the presence of intramolecular
halogen bonding (XB)14 (donor: lone pair of O; acceptor: C–I
σ*). Furthermore, the distance between the oxygen atom of the
nitro group and the iodine atom (2.667 Å) suggests a coordi-
nation from the nitro group to the iodine atom (donor: lone
pair of O; acceptor: N–I σ*). The natural bond orbital (NBO)
aDepartment of Pharmaceutical Chemistry, Kyoto Pharmaceutical University,
Yamashina-ku, Kyoto 607-8414, Japan. E-mail: ykobayashi@mb.kyoto-phu.ac.jp
bGraduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku,
Kyoto 606-8501, Japan. E-mail: takemoto@pharm.kyoto-u.ac.jp
†Electronic supplementary information (ESI) available. CCDC 2080533. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
d1ob00947h
Fig. 1 Examples of N-trifluoroacetyl nitrene precursors.
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increasing number of methods for the synthesis and
functionalization of oxazole scaffolds have been reported
recently. In particular, oxazoles that contain trifluoromethyl
(CF3) groups have attracted much attention because the intro-
duction of fluorine atoms into pharmaceuticals and agrochem-
icals can favorably modify their properties and biological
activities.19,20 In fact, several synthetic methods have been
reported that yield 2-CF3-substituted oxazoles;21–25 examples
include the acid-mediated cyclization of trifluoroacetate,21 the
base-mediated condensation of trifluoroacetamide,22 the
trifluoromethylation of 2-bromooxazoles,23 and the photo-
induced isomerization of isoxazole.24 However, there is still
room for improvement in terms of the accessibility of the sub-
strates. We envisaged that our iminoiodinane trifluoroacetyl
nitrene equivalent could, in conjunction with various alkynes,
afford CF3-substituted oxazoles via a [3 + 2] cycloaddition
(Fig. 3). The alkynes are accessible from readily available alde-
hydes via the Seyferth–Gilbert reaction or from haloarenes via
Sonogashira coupling reactions.
Scheme 1 Synthesis of ortho-nitro-substituted iminoiodinane 6.
According to a previous report,11 iminoiodinane 5 is best
activated via photo-irradiation at 365 nm. Thus, we first exam-
ined the reaction of ethynylbenzene 8a with iodane 5 with the
use of photo-irradiation (Fig. 3), and the desired oxazole 9a
was obtained in 41% yield. The regioselectivity was confirmed
by hydrolysis of the oxazole to exclusively form the corres-
ponding 2-aminoacetophenone.11 Regioisomers were not
detected in the 19F NMR analysis of the crude mixture. The
use of ortho-nitro-substituted iminoiodinane 6 instead of 5
improved the yield to 56% under otherwise identical con-
Fig. 2 X-ray and computational studies of iminoiodinane 6. (A) ORTEP
drawing of 6 (B) Intramolecular XB 1 (C) Intramolecular XB 2 (D)
Intermolecular XB.
analyses of each interaction were estimated to be 8.30 kcal
mol−1 and 8.63 kcal mol−1 for the N-trifluoroacetyl and nitro
groups, respectively (Fig. 2B and C).15,16 Notably, a detailed
analysis of the packing structure of 6 suggested that two mole-
cules of 6 were located mostly in the same plane (∠C–O–I–N:
164°). Moreover, two intermolecular XB-type interactions
between the carbonyl oxygen atoms and the iodine atoms were
found (2.944 Å in each case; Fig. 2D) and the interaction
energy of these XB interactions was estimated to be 2.58 kcal
mol−1. No such intermolecular XB interaction was found in
iminoiodinane 5.17 This difference may be due to the steric
hindrance of the methoxy group in 5, and this hindrance may
also be responsible for the relative stability of iminoiodinane 6
at room temperature.
Having found the optimum N-trifluoroacetyl nitrene precur-
sor, we next investigated a synthetic application of iodane 6 in
the synthesis of trifluoromethyl (CF3)-substituted oxazoles.
Oxazoles are important compounds that are found in various
natural products and pharmaceuticals and exhibit unique bio-
logical activities, including anti-inflammatory, anti-tumor,
anti-diabetic, and anti-fungal properties.18 Therefore, an Fig. 3 Substrate scope for the synthesis of 2-CF3-substituted oxazoles.
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ditions.26 We next investigated the substrate scope of the reac-
tion using iodinane 6 in dichloromethane under UV irradiation
at 365 nm. Ethynylbenzenes with a variety of substituents, such
as methoxy, methyl, chloro, bromo, methoxycarbonyl, and tri-
fluoromethyl groups, on the aromatic ring were found to be well
tolerated under these reaction conditions, and the corres-
ponding oxazoles (9b–9g) were obtained in 35–71% yields. It is
worth mentioning here that an aliphatic terminal alkyne could
also be used in this oxazole synthesis, although the product
yield of 9h was relatively low. When internal alkynes were used
as substrates, 2,4,5-trisubstituted oxazoles were obtained in mod-
erate yields. In the case of an unsymmetric internal alkyne with
an aryl group and an alkyl group, the regioselectivity was con-
trolled well to afford the corresponding oxazole as a single
isomer, whereas unsymmetric internal alkynes with different
aryl groups furnished mixtures of regioisomers that were
difficult to separate. Notably, the cycloaddition proceeded even
in the presence of amide and adamantyl groups, which can be
seen in various pharmaceuticals, to give oxazole 9k. This
example implies that various carboxylic acids could in principle
be the substrates for the [3 + 2]-cycloaddition after condensation
with p-ethynylaniline.
Scheme 3 A plausible reaction mechanism.
singlet and triplet nitrenes has already been reported.6 The
singlet nitrene species B would form an azirine D via a [2 + 1]
cycloaddition and the subsequent rearrangement of D would
then furnish the corresponding oxazole 9. The regioselectivity
of the product can be explained by the rearrangement of the
carbonyl oxygen to the relatively electron-deficient benzylic
position.
Conclusions
In conclusion, we have developed an improved
N-trifluoroacetyliminoiodinane as a bench-stable trifluoroace-
tyl nitrene equivalent. The introduction of an ortho-nitro group
allows using milder reaction conditions and permits an easy
scale-up of the synthesis. The resulting iodinane is quite
stable in the solid state, even at ambient temperature, presum-
ably due to the observed intra- and intermolecular halogen
bonding. Compound 6 can be activated photolytically to gene-
rate an N-trifluoroacetyl nitrene that reacts with various
alkynes to afford the corresponding 2-trifluoromethyl substi-
tuted oxazoles. We are convinced that this N-acyl nitrene equi-
valent will find applications in the synthesis of trifluoro-
methyl-substituted heterocycles and contribute to the discov-
ery of new drugs.
To gain mechanistic insight into this reaction and to better
understand its active species, several control experiments were
carried out (Scheme 2). To detect the N-trifluoroacetyl nitrene
species, iminoiodinane 6 was photo-irradiated in MeCN-d3. An 19
F
NMR analysis showed a new peak at −66.4 ppm,8a indicative of
the formation of an oxadiazole via a formal [3 + 2] cycloaddition
between N-trifluoroacetyl nitrene and MeCN-d3 (Scheme 2A). The
addition of radical scavengers such as 2,6-di-tert-butyl-p-cresol
(BHT) or 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) only
slightly decreased the yield of 9a (Scheme 2B). These results
suggest that the reaction mainly proceeds via a nitrene species,
although a radical pathway cannot be ruled out.11
Based on these results, we would like to propose a plausible
reaction mechanism (Scheme 3). Iminoiodinane 6 is activated
photolytically27 to generate a diradical species A, and the sub-
sequent elimination of 2-nitroiodobenzene would form
N-trifluoroacetyl nitrene B and/or C. The isomerization of
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This work was partly supported by the JSPS KAKENHI grant
19K06974 as well as a research grant from the Hoansha
Foundation. We thank Dr Yasunao Hattori and Dr Tomoshige
Ando (Kyoto Pharmaceutical University) for the assistance with
the HRMS measurements.
Notes and references
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Scheme 2 Mechanistic studies. (A) Detection of the oxadiazoles (B)
Effect of radical scavengers.
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