Development of a continuous flow photoisomerization reaction converting isoxazoles into diverse oxazole products

Article abstract of DOI:10.1021/acs.joc.9b03399

A continuous flow process is presented, which directly converts isoxazoles into their oxazole counterparts via a photochemical transposition reaction. This results in the first reported exploitation of this transformation to establish its scope and synthe

Full text of DOI:10.1021/acs.joc.9b03399

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Article
Development of a Continuous Flow Photoisomerization
Reaction Converting Isoxazoles into Diverse Oxazole Products
Cormac Bracken, and Marcus Baumann
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03399 • Publication Date (Web): 13 Jan 2020
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Page 1 of 27
The Journal of Organic Chemistry
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Development of a Continuous Flow Photoisomerization Reaction
Converting Isoxazoles into Diverse Oxazole Products
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Cormac Bracken, Marcus Baumann*
School of Chemistry, University College Dublin, Science Centre South, Belfield, Dublin 4, Ireland.
marcus.baumann@ucd.ie
Supporting Information Placeholder
ABSTRACT: A continuous flow process is presented that directly converts isoxazoles into their oxazole counterparts via a
photochemical transposition reaction. This results in the first reported exploitation of this transformation to establish its scope and
synthetic utility. A series of various di- and trisubstituted oxazole products bearing different appendages including different
heterocyclic moieties was realized through this rapid and mild flow process. Furthermore, the robustness of this approach was
demonstrated by generating gram quantities of selected products whilst also providing insights into likely intermediates.
INTRODUCTION
Oxazoles and isoxazoles represent members of valuable and oftentimes biologically active five-membered heteroaromatic
structures.1 These can be found in both natural products as well as synthetic entities such as pharmaceutical and agrochemical
agents.2 Oxazoles are particularly prevalent in alkaloid natural products as they arise from cyclodehydration of suitable amino
acid precursors, rendering a variety of small bioactive molecules including texaline (1), pimprinin (2) and annuloline (3, Figure
1).
OMe
N
OMe
O
O
N
N
O
O
O
N
N
H
1
2
3
, annuloline
, texaline
, pimprinin
MeO
Figure 1: Selected oxazole containing natural products.
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Whilst conventional synthesis strategies are in place that allow for the preparation of either isoxazole or oxazole heterocycles
from suitable acyclic precursors, the direct transposition of isoxazoles into oxazoles is an overlooked alternative. Singh and
coworkers reported on a photochemical transformation several decades ago providing evidence that this could be achieved.3
More recently, Jones and co-workers reported on a thermal process based on isoxazole systems bearing crucial phenolic
appendages.4 Whilst in the latter case a mechanistic rationale based on Boulton-Katrizky as well as Neber rearrangements was
put forward, extensive studies on the photochemical process are in support of a homolytic cleavage of the O–N bond, followed
by generation of an acyl azirine species (7), which ring-opens followed by ring-closure of the resulting nitrilium enolate species
(Scheme 1).5 The latter part of this mechanism is reminiscent of the Cornforth rearrangement, which may provide further
support for this pathway.6
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photochemical heterocycle
transposition reaction
N
R3
R2
O
O
R1
R1
R3
N
R2
4
5
R1
N
N
O
O
R1
O
R1
N
R3
R2
7
R3
R3
R2
8
R2
6
Scheme 1: Photoisomerization of isoxazoles and its proposed mechanism.
Despite a considerable amount of interest in this heterocycle transposition reaction and related processes,7 to date no robust
and generally viable means to effectively generate oxazoles from isoxazoles has been reported. This may be because in the
thermal process a phenolic moiety is required, whereas the photochemical process suffers from intrinsic limitations such as
long reaction time in specialized reaction glassware, formation of undesirable photodegradation products as well as limited
scalability.
We therefore set out to realize such a general and scalable method that would facilitate the generation of sets of different
oxazole products in a simple and effective manner. To achieve this, we opted to exploit continuous flow technology8 in
combination with a UV-photo-reactor that would impart high process control, uniform radiation profiles as well as high
reproducibility as evident from many recent reports.9 Several non-photochemical oxazole syntheses have been reported in
continuous flow mode highlighting the advantageous nature of this technology.10 Specifically, we opted to use a Vapourtec
UV150 flow reactor system that provides a temperature-controlled flow coil (10 mL, PFA) unit in combination with a medium-
pressure mercury lamp. The use of specific filters additionally allows to block wavelengths above 400 nm (see SI for details).
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The Journal of Organic Chemistry
RESULTS AND DISCUSSION
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We commenced our studies by devising an effective two-step preparation into a series of isoxazole substrates that was realized
by a Claisen condensation between different commercially available acetophenones 9 and diethyl oxalate. The resulting 1,3-
dicarbonyls (10) were subsequently treated with hydroxylamine hydrochloride in a thermal cyclocondensation process
furnishing the desired isoxazoles in high yields. Pleasingly, this approach allowed for the rapid generation of a diverse set of
isoxazole starting materials in which the nature and substitution pattern of the aryl appendage (R3) could be varied to
subsequently study the scope of this unusual heterocycle transposition process in detail (Scheme 2, see SI for full details).
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HONH2.HCl,
H
N
(CO2Et)2,
KOtBu,
R1
R2
O
O
O
O
MeCN,
R2
70 oC, 3 h
R3
R1
R3
THF, rt, 4 h
R3
R2
9
10
4
73-92%
25 examples
R1 = CO2Et; R2 = H, Me; R3 = aryl
Scheme 2: General batch synthesis of isoxazole substrates (4).
Having secured a reliable access into the required isoxazoles we next turned to their photochemical transposition into the
desired oxazole products. Using the aforementioned photo-flow reactor set-up, we were able to quickly screen a variety of
different reaction conditions focusing on solvent choice, concentration and temperature. Therefore, solutions of test substrate
4a were pumped via a peristaltic pump of the Vapourtec E-Series module at a flow rate of 0.5 mL/min. As a light source a
medium-pressure Hg lamp was used that can be adjusted to operate between 75-150 W.
As outlined in Table 1, this study highlighted that acetonitrile was the best solvent with ideal concentrations at 10-15 mM.
Other solvents such as DCM, acetone, THF and EtOH were tolerated however, slower reactions were observed in these cases.
Temperatures ranging between 25-45 °C were well tolerated, whilst above ~50 °C impurity formation was increased. To control
the temperature within the photo-reactor a stream of chilled nitrogen gas was passed into this unit that is controlled by the
system’s software via a pincher valve. Most notably, we established that residence times within the reactor of 20 minutes were
sufficient to observe conversions greater than 90%, while most batch reports state reaction times of 4-8 h. We ascribe this
improvement to the uniform radiation profile in this flow set-up that does not suffer from limitations such as the penetration
depth of light into conventional reaction vessels due to the Beer-Lambert law. Additionally, we found that using a filter that
blocks wavelengths greater 400 nm to be beneficial as it avoids temperature increase and thus minimizes formation of colored
by-products and other side reactions.
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Table 1: Optimization of reaction conditions in flow (4a → 5a).
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5
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8
O
O
N
O
O
O
N
OEt
5a
4a
OEt
9
solvent, UV-B,
rt-60 oC, 20 min
O
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entry
solvent
concentration
Temperaturea)
(°C)
yieldb)
(mM)
(%)
1
2
DCM
THF
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10
10
10
10
10
15
20
15
35
23
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76
70
81
73
53
35
4
acetone
EtOH
35
5
35
6
MeCN
MeCN
MeCN
MeCN
MeCN
35
7
60
35
8
9
35
10
35, no filter
Reaction conditions: residence time 20 minutes (flow rate 0.5 mL/min), lamp power 150 W; a) ±5 °C; b) 1H NMR yield with 1,3,5-trimethoxybenzene as internal standard.
The optimal set of conditions (Table 1, entry 9, filter used) were subsequently applied to the continuous preparation of oxazole
5a from its isoxazole precursor 4a over a period of 12 hours. This experiment proved robustness of the system as well as
scalability to generate 1.5 g of the desired product 5a. In addition, we were able to crystalize both substrate and product and
secure their molecular structures by single crystal X-ray diffraction experiments thus proving the anticipated
photorearrangement process (Figure 2).
O
O
N
O
O
OEt
O
N
5a
4a
OEt
O
Figure 2: X-ray crystal structure substrate-product pair.
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The Journal of Organic Chemistry
Having succeeded in generating gram quantities of desired oxazole products in a continuous manner, we next wished to explore
the substrate scope of this photochemical heterocycle transposition reaction. We exploited our short entry into the isoxazole
substrates (Scheme 2) that enabled rapid supply of diverse building blocks that were subjected to the optimized reaction
conditions (Table 1, entry 9).
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9
Pleasingly, it was found that a wide variety of substrates bearing different aryl moieties furnished the desired oxazole products
in an effective and high yielding flow process. Different substitution patterns on the aryl moiety in the 5-position of the
isoxazole ring were all well-tolerated, including methoxy and methylenedioxy groups and free phenols (Scheme 3). In addition,
photo-labile bromide substituents as well as chlorides and fluorides all successfully underwent the desired transformation. It
was also established that styryl moieties were competent motifs to undergo this photoisomerization process delivering the
corresponding oxazole product (5m) in good yield.
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1
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4
O
N
O
R
O
O
N
OEt
R
5
4
OEt
MeCN, UV-B,
rt-50 oC, 20 min
5
6
7
O
O
8
9
O
O
O
N
O
O
OEt
N
OEt
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5a
, 81%
5b
, 75%
O
O
O
O
O
N
O
O
N
O
OEt
OEt
5d
, 77%
5c
, 73%
O
O
HO
O
O
N
O
O
N
OEt
O
OEt
5f
, 75%
5e
, 68%
O
O
O
O
N
N
OEt
OEt
5g
5h
, 70%
, 75%
Br
O
O
O
O
O
F
N
OEt
N
OEt
5i
, 71%
5j
, 74%
Cl
F
F
Cl
O
N
F
O
O
O
N
OEt
OEt
5l
, 55%
5k
, 68%
O
O
O
O
O
O
N
N
OEt
N
OEt
OEt
a
b
5m
5n
, 77%
, 72%
5o
, 24 -39 %
Scheme 3: Photoisomerization product scope; a) 20 min residence time, b) 40 min residence time.
At this stage a correlation between the isolated yield and the electronic properties of the aryl moieties was noted. Namely,
electron-rich systems gave consistently higher yields than electron-poor ones. While initially surprising, we surmise that this
phenomenon is correlated to the specific UV-Vis absorption maximum of each substrate. This appears to best match the
emission spectrum of the medium-pressure Hg lamp in case of electron-rich substrates (λmax > 300 nm), whilst electron-poor
ones (λmax < 300 nm) are more mismatched (see SI for details). This observation was compounded when substituting the aryl
moiety with a tert-butyl group leading to a significant decrease in conversion and isolated yield even when doubling the
residence time (5o). It was furthermore established that substituents such as a methyl group at the 4-position of the isoxazole
scaffold (R2 = Me) are tolerated giving rise to trisubstituted oxazole products in high yield.
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The Journal of Organic Chemistry
We furthermore subjected a selection of isoxazole substrates bearing modified substituents to this flow process. These included
isoxazoles 4p and 4q bearing either an additional amide substituent or the amide as a replacement of the ester. Interestingly, it
was observed that amide 4p did not show any conversion (Scheme 4A), whereas amide 4q gave the desired oxazole product
(5q), albeit with a reduced yield (Scheme 4B). In the latter case, we also isolated a small amount of a ring opened species
bearing a nitrile (11). Additionally, we noticed that substrate 4r bearing a tertiary amine was converted into an alternative
nitrile-bearing photoproduct (12) in good yield without rendering isolable amounts of the expected oxazole product (Scheme
4C). While the former nitrile product may arise from a competitive fragmentation pathway,11 the latter nitrile appears to result
from a formal 1,2-migration of the adjacent ester moiety.12 Importantly, both cases support the intermediacy of radical species
in this transformation and provide further insight into their fate.
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N
OEt
O
A
F
O
O
N
H
4p
, no conversion, 98% recovery of substrate
B
H
O
O
N
N
O
HN
O
N
N
O
O
O
H
O
N
O
7q
4q
5q
, 39%
O
O
fragmentation
N
11
, 20%
OEt
C
OEt
N
N
N
O
O
HO
O
O
O
EtO
12
N
4r
7r
, 68%
N
N
Scheme 4: Amide and amine-based isoxazole substrates and plausible mechanistic rationales for the formation of 11 and 12.
We next turned our attention to studying heteroaryl substituted isoxazoles in this photo-rearrangement reaction. We thus
employed our general substrate synthesis (Scheme 2) to convert a small series of commercially available acylated heteroarenes
to access the desired isoxazole substrates within two steps.
Subjecting these materials to our previously established flow conditions did indeed confirm that various heteroaromatic
appendages are well-tolerated in this flow process. These include furans, thiophenes, indoles as well as pyrroles (Figure 3).
Due to the nature of this process, no protecting groups on the nitrogen atoms of either the indole or the pyrrole substrate were
required. We furthermore were able to secure a single crystal structure for pyrrole-oxazole product 5u which confirms the
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connectivity and integrity of this system. This showcases the mild and general nature of this flow process that serves as a rapid
entry into interesting heterocyclic building blocks. Additionally, variations on the ester moiety were found to not impact the
efficiency of the overall transformation allowing different ester products (e.g. dodecyl ester 5x and heteroaryl ester 5y) to be
suitable replacements for the previous ethyl esters.
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O
O
O
O
O
N
S
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N
OEt
OEt
5t
, 76%
5s
, 78%
NH
O
O
N
OEt
5u
, 72%
H
N
O
O
O
O
O
O
N
N
OEt
OEt
5w
, 73%
O
5v
, 80%
O
O
N
O
O
O
N
O
N
OC12H25
5y
N
, 73%
5x
, 78%
Figure 3: Product scope for heteroaromatic substrates.
The simplicity with which such scaffolds comprising of different linked heteroaryl moieties can be assembled is remarkable.
Therefore, this simple and effective entry into these drug-like fragments does demonstrate their potential to inspire screening
libraries in current and future medicinal chemistry campaigns.
In conclusion, we have demonstrated the feasibility of effectively performing this intriguing photoisomerization reaction to
yield versatile oxazole products via a continuous photochemical process. An effective two-step preparation of various isoxazole
precursors furnished a selection of substrates that allowed us to study the substrate scope of this transformation. The resulting
flow process delivered the desired products in generally high yields and in a scalable manner allowing further exploitation of
this unique heterocycle transposition reaction in the future.
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The Journal of Organic Chemistry
EXPERIMENTAL SECTION
1
2
3
General Information
4
5
6
7
Unless otherwise stated, all solvents were purchased from Fisher Scientific and used without further purification. Substrates and reagents
were purchased from Fluorochem or Sigma Aldrich and used as received.
8
9
1H-NMR spectra were recorded on 400 MHz and 500 MHz instruments and are reported relative to residual solvent: CHCl3 (δ 7.26 ppm),
d6-DMSO (δ 2.50 ppm). 13C-NMR spectra were recorded on the same instruments (100 and 125 MHz) and are reported relative to CHCl3 (δ
77.16 ppm), d6-DMSO (δ 39.52 ppm). 19F-NMR were recorded at 376 MHz. Data for 1H-NMR are reported as follows: chemical shift (δ/
ppm) (integration, multiplicity, coupling constant (Hz)). Multiplicities are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet,
p = pentet, m = multiplet, br. s = broad singlet, app = apparent. Data for 13C{1H} NMR are reported in terms of chemical shift (δ/ ppm) and
multiplicity (C, CH, CH2 or CH3). DEPT-135, COSY, HSQC, HMBC and NOESY experiments were used in the structural assignment.
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IR spectra were obtained by use of a Bruker Platinum spectrometer (neat, ATR sampling) with the intensities of the characteristic signals
being reported as weak (w, <20% of tallest signal), medium (m, 21-70% of tallest signal) or strong (s, >71% of tallest signal).
High-resolution mass spectrometry was performed using the indicated techniques on a micromass LCT orthogonal time-of-flight mass
spectrometer with leucine-enkephalin (Tyr-Gly-Phe-Leu) as an internal lock mass. GC-MS was performed on a Waters GCT Premier Agilent
7898 system (column Macherey-Nagel; Optima 5 MS, length 15 m, diameter: 0.25 mm).
For UV-Vis measurements a Shimadzu UV-1800 UV spectrophotometer was used. Melting points were recorded on a Stuart SMP10 melting
point apparatus and are uncorrected.
Continuous flow experiments were performed on a Vapourtec E-series system equipped with the UV150 photoreactor that is based on a
medium pressure Hg lamp (150 W).
Synthetic Procedures and Spectroscopic Data
Synthesis of Claisen Condensation Products 10a – 10y: General Procedure:
To a solution of the appropriate acetophenone (1.0 equiv.) in THF (1.5 M) was added diethyl oxalate (1.2 equiv.). The resulting mixture was
stirred at room temperature for 10 minutes, before KOtBU (1.1 equiv.) was added in small portions resulting in the formation and precipitation
of the potassium salt of the Claisen adduct. After 10 hours stirring at room temperature, the resulting suspension was filtered, and the solid
product was washed with further THF to remove unreacted starting materials. After treating the solid product with HCl (1 M, aqueous), the
Claisen adduct typically formed a solid that was filtered and dried. In cases where no precipitation was observed an aqueous extraction with
DCM was performed rendering the desired product after evaporation of the combined, dried organic layers.
Claisen condensation products derived from propiophenone and 2-acetyl pyrrole were used as crude materials directly in the subsequent step.
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Ethyl (Z)-2-hydroxy-4-(4-methoxyphenyl)-4-oxobut-2-enoate, 10a:
1
2
3
4
5
6
7
8
9
Isolated yield: 2.30 g (9.3 mmol, 93%). Appearance: off-white solid. Melting range: 58-60 °C. 1H-NMR (400 MHz, CDCl3) δ/ppm 7.98 (d,
J = 9.0 Hz, 2H) 7.03 (s, 1H) 6.98 (d, J = 9.0 Hz, 2H) 4.39 (q, J = 7.1 Hz, 2H) 1.40 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3)
δ/ppm 190.3 (C), 168.1 (C), 164.3 (C), 162.5 (C), 130.3 (2CH), 127.7 (C), 114.2 (2CH), 97.7 (CH), 62.5 (CH2), 55.6 (CH3), 14.1 (CH3). IR
(neat) ν/cm-1 2981 (w), 1719 (m), 1581 (s), 1510 (m), 1255 (s), 1165 (s), 1107 (s), 1021 (s), 825 (s), 769 (s), 583 (s). HRMS (TOF-ESI+)
calculated for C13H15O5 251.0919, found 251.0928 (M+H+).
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Ethyl (Z)-4-(3,4-dimethoxyphenyl)-2-hydroxy-4-oxobut-2-enoate, 10b:
Isolated yield: 2.57 g (9.2 mmol, 92%). Appearance: yellow solid. Melting range: 99-101 °C. 1H-NMR (400 MHz, CDCl3) δ/ppm 7.65 (dd,
J = 8.4, 2.0 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.05 (s, 1H), 6.94 (d, J = 8.4 Hz, 1H), 4.40 (q, J = 7.2 Hz, 2H), 3.97 (s, 3H), 3.97 (s, 3H), 1.42
(t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ/ppm 190.8 (C), 167.2 (C), 162.5 (C), 154.1 (C), 149.3 (C), 128.1 (C), 122.9 (CH),
110.4 (CH), 109.9 (CH), 98.0 (CH), 62.5 (CH2), 56.2 (CH3), 56.1 (CH3), 14.1 (CH3). IR (neat) ν/cm-1 2940 (w), 1730 (w), 1595 (m), 1518
(m), 1466 (m), 1266 (s), 1214 (m), 1021 (m), 772 (m). HRMS (TOF-ESI+) calculated for C14H17O6 281.1025, found 281.1021.
Ethyl (Z)-4-(benzo[d][1,3]dioxol-5-yl)-2-hydroxy-4-oxobut-2-enoate, 10c:
Isolated yield: 2.22 g (8.4 mmol, 84%). Appearance: yellow solid. Melting range: 69-71 °C. 1H-NMR (400 MHz, CDCl3) δ/ppm 7.61 (dd, J
= 8.2, 1.7 Hz, 1H), 7.46 (d, J = 1.7 Hz, 1H), 6.98 (s, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.08 (s, 2H), 4.39 (q, J = 7.2 Hz, 2H), 1.40 (t, J = 7.2 Hz,
3H). 13C{1H} NMR (100 MHz, CDCl3) δ/ppm 190.2 (C), 167.6 (C), 162.3 (C), 152.6 (C), 148.5 (C), 129.7 (C), 124.5 (CH), 108.3 (CH),
107.6 (CH), 102.1 (CH2), 97.9 (CH), 62.5 (CH2), 14.1 (CH3). IR (neat) ν/cm-1 2985 (w), 2907 (w), 1727 (m), 1601 (m), 1504 (m), 1451 (m),
1251 (s), 1110 (m), 1036 (m), 931 (m), 814 (m). HRMS (TOF-ESI+) calculated for C13H13O6 265.0713, found 265.0712 (M+H+).
Ethyl (Z)-4-(2,4-dimethoxyphenyl)-2-hydroxy-4-oxobut-2-enoate, 10d:
Isolated yield: 2.26 g (8.1 mmol, 80%). Appearance: yellow solid. Melting range: 39-41 °C. 1H-NMR (400 MHz, CDCl3) δ/ppm 7.96 (d, J
= 8.8 Hz, 1H), 7.32 (s, 1H), 6.58 (dd, J = 8.8, 2.3 Hz, 1H), 6.47 (d, J = 2.3 Hz, 1H), 4.37 (q, J = 7.2 Hz, 2H), 3.93 (s, 3H), 3.88 (s, 3H), 1.40
(t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ/ppm 189.2 (C), 168.6 (C), 165.3 (C), 162.9 (C), 161.3 (C), 132.9 (CH), 117.5 (C),
105.7 (CH), 102.6 (CH), 98.5 (CH), 62.2 (CH2), 55.7 (CH3), 55.6 (CH3), 14.1 (CH3). IR (neat) ν/cm-1 2977 (w), 1742 (m), 1725 (m), 1607
(m), 1573 (s), 1237 (s), 1115 (m), 1018 (s), 783 (m), 730 (m). HRMS (TOF-ESI+) calculated for C14H17O6 281.1025, found 281.1027
(M+H+).
Ethyl (Z)-2-hydroxy-4-oxo-4-(2,4,6-trimethoxyphenyl)but-2-enoate, 10e:
Isolated yield: 1.2 g (3.9 mmol, 83%). Appearance: yellow solid. Melting range: 81-83 °C. 1H-NMR (400 MHz, CDCl3) δ/ppm 6.63 (s, 1H),
6.09 (s, 2H), 4.32 (q, J = 7.2 Hz, 2H), 3.82 (s, 3H), 3.78 (s, 6H), 1.34 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ/ppm 194.6
(C), 163.7 (C), 163.1 (C), 162.7 (C), 159.8 (C), 110.2 (C), 106.7 (CH), 90.7 (2CH), 62.2 (CH2), 56.0 (2CH3), 55.4 (CH3), 14.1 (CH3). IR
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(neat) ν/cm-1 2990 (w), 2944 (w), 2838 (w), 1741 (m), 1579 (s), 1447 (m), 1264 (s), 1185 (s). HRMS (TOF-ESI+) calculated for C15H18O7Na
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Ethyl (Z)-2-hydroxy-4-(3-hydroxyphenyl)-4-oxobut-2-enoate, 10f:
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Isolated yield: 1.01 g (4.4 mmol, 88%). Appearance: beige amorphous powder. 1H-NMR (400 MHz, DMSO-d6) δ/ppm δ 9.89 (s, 1H), 7.45
(d, J = 7.7 Hz, 1H), 7.39 – 7.29 (m, 2H), 7.05 (d, J = 8.0 Hz, 1H), 6.96 (s, 1H), 4.26 (q, J = 7.1 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H). 13C{1H}
NMR (100 MHz, DMSO-d6) δ/ppm 190.7 (C), 169.2 (C), 162.0 (C), 158.4 (C), 136.1 (C), 130.7 (CH), 121.8 (CH), 119.2 (CH), 114.2 (CH),
98.4 (CH), 62.6 (CH2), 14.2 (CH3). IR (neat) ν/cm-1 3437 (s), 2980 (w), 1713 (s), 1583 (s), 1440 (m), 1284 (s), 1212 (s), 767 (s), 584 (s).
HRMS (TOF-ESI+) calculated for C12H13O5 237.0763, found 237.0763.
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Ethyl (Z)-2-hydroxy-4-oxo-4-phenylbut-2-enoate, 10g:
Isolated yield: 2.07 g (8.6 mmol, 86%). Appearance: yellow oil. 1H-NMR (400 MHz, CDCl3) δ/ppm 8.00 – 7.94 (m, 2H), 7.62 – 7.56 (m,
1H), 7.48 (dd, J = 8.4, 7.0 Hz, 2H), 7.06 (s, 1H), 4.38 (q, J = 7.2 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ/ppm
190.7 (C), 169.8 (C), 162.2 (C), 134.9 (C), 133.8 (CH), 128.9 (2CH), 127.9 (2CH), 97.9 (CH), 62.6 (CH2), 14.1 (CH3). IR (neat) ν/cm-1 3065
(w), 2983 (w), 1729 (s), 1597 (s), 1450 (m), 1236 (s), 700 (s). HRMS (TOF-ESI+) calculated for C12H13O4 221.0814, found 221.0810.
Ethyl (Z)-4-(4-(tert-butyl)phenyl)-2-hydroxy-4-oxobut-2-enoate, 10h:
Isolated yield: 2.2 g (8.0 mmol, 80%). Appearance: yellow liquid. 1H-NMR (400 MHz, CDCl3) δ/ppm 7.92 (d, J = 8.4 Hz, 2H), 7.50 (d, J =
8.4 Hz, 2H), 7.05 (s, 1H), 4.38 (q, J = 7.2 Hz, 2H), 1.39 (t, J = 7.2 Hz, 3H), 1.33 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3) δ/ppm 190.6
(C), 169.4 (C), 162.3 (C), 157.9 (C), 132.2 (C), 127.9 (2CH), 125.9 (2CH), 97.9 (CH), 62.5 (CH2), 35.2 (C), 31.0 (3CH3), 14.1 (CH3). IR
(neat) ν/cm-1 2963 (w), 2906 (w), 2870 (w), 1730 (m), 1602 (s), 1473 (w), 1365 (m), 1264 (s), 1242 (s). HRMS (TOF-ESI+) calculated for
C16H21O4 277.1440, found 277.1444.
Ethyl (Z)-4-(2-fluoro-4-methoxyphenyl)-2-hydroxy-4-oxobut-2-enoate, 10i:
Isolated yield: 2.44 g (9.1 mmol, 91%). Appearance: off-white solid. Melting range: 85-88 °C. 1H-NMR (400 MHz, CDCl3) δ/ppm 7.95 (app
t, J = 8.8 Hz, 1H), 7.08 (d, J = 1.2 Hz, 1H), 6.80 (dd, J = 8.8, 2.4 Hz, 1H), 6.65 (dd, J = 13.6, 2.4 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 3.87 (s,
3H), 1.39 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ/ppm 187.3 (C, d, J = 4 Hz), 168.7 (C, d, J = 1 Hz), 165.4 (C, d, J = 12
Hz), 163.4 (CF, d, J = 256 Hz), 162.3 (C), 131.9 (CH, d, J = 3 Hz), 116.2 (C, d, J = 11 Hz), 111.1 (CH, d, J = 3 Hz), 102.3 (CH), 101.9 (CH,
d, J = 15 Hz), 62.5 (CH2), 55.9 (CH3), 14.0 (CH3). 19F-NMR (376 MHz, CDCl3) δ/ppm -105.4. IR (neat) ν/cm-1 2997 (w), 2959 (w), 1720
(m), 1617 (m), 1585 (m), 1276 (s), 1253 (s), 1231 (s), 1108 (s), 1020 (m), 956 (m), 836 (m), 780 (s), 554 (m). HRMS (GC-TOF EI+)
calculated for C13H13FO5 268.0747, found 268.0738 (M+).
Ethyl (Z)-4-(4-bromophenyl)-2-hydroxy-4-oxobut-2-enoate, 10j:
Isolated yield: 1.17 g (3.9 mmol, 78%). Appearance: yellow powder. Melting range: 62-64 °C 1H-NMR (400 MHz, CDCl3) δ/ppm 7.83 (d,
J = 8.8 Hz, 2H) 7.62 (d, J = 8.8 Hz, 2H) 7.0 (s, 1H) 4.38 (q, J = 7.1 Hz, 2H) 1.39 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3)
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δ/ppm 189.4 (C), 170.1 (C), 162.0 (C), 133.6 (C), 132.2 (2CH), 129.3 (2CH), 129.0 (C), 97.7 (CH), 62.7 (CH2), 14.1 (CH3). IR (neat) ν/cm-1
3415 (w), 2980 (w), 2934 (w), 1719 (s), 1679 (m), 1584 (s), 1478 (m), 1242 (s), 1004 (s). HRMS (TOF-ESI+) calculated for C12H12O4Br
298.9919, found 298.9908.
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Ethyl (Z)-4-(2,4-dichloro-5-fluorophenyl)-2-hydroxy-4-oxobut-2-enoate, 10k:
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Isolated yield: 2.69 g (8.8 mmol, 88%). Appearance: off-white solid. Melting range: 133-136 °C. 1H-NMR (400 MHz, CDCl3) δ/ppm 7.55
(d, J = 6.3 Hz, 1H), 7.48 (d, J = 8.7 Hz, 1H), 6.96 (s, 1H), 4.39 (q, J = 7.2 Hz, 2H), 1.40 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ/ppm 189.7 (C), 168.9 (C), 161.5 (C), 156.8 (CF, d, J = 252 Hz), 135.2 (C, d, J = 6 Hz), 132.7 (CH), 127.6 (C, d, J = 4 Hz), 125.7
(C, d, J = 19 Hz), 117.9 (CH, d, J = 24 Hz), 102.5 (CH), 62.8 (CH2), 14.0 (CH3). 19F-NMR (376 MHz, CDCl3) δ/ppm -115.6. IR (neat) ν/cm-1
3095 (w), 3040 (w), 1733 (s), 1629 (s), 1469 (m), 1378 (s), 1303 (s), 1264 (s), 1191 (s), 1088 (s), 1022 (s), 780 (s), 725 (s), 557 (m), 531
(m). HRMS (TOF-ESI+) calculated for C12H9Cl2FO4Na 328.9760, found 328.9775.
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Ethyl (Z)-4-(2,4-difluorophenyl)-2-hydroxy-4-oxobut-2-enoate, 10l:
Isolated yield: 2.02 g (7.9 mmol, 79%). Appearance: yellow solid. Melting range: 194-197 °C. 1H-NMR (400 MHz, CDCl3) δ/ppm 7.99 (td,
J = 8.7, 6.5 Hz, 1H), 7.06 (d, J = 1.5 Hz, 1H), 7.03 – 6.97 (m, 1H), 6.90 (ddd, J = 11.1, 8.6, 2.4 Hz, 1H), 6.33 (br s, 1H), 4.37 (q, J = 7.1 Hz,
2H), 1.38 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ/ppm 186.5 (d, J = 4 Hz, C), 169.7 (C), 166.1 (dd, J = 259, 13 Hz, CF),
162.4 (dd, J = 260, 13 Hz, CF), 161.9 (C), 132.4 (dd, J = 11, 3 Hz, CH), 120.2 – 120.0 (m, C), 112.5 (dd, J = 21, 4 Hz, CH), 105.7 – 104.6
(m, CH), 102.0 (d, J = 13 Hz, CH), 62.7 (CH2), 14.0 (CH3). 19F-NMR (376 MHz, CDCl3) δ/ppm -100.3 (m), -104.2 (m). IR (neat) ν/cm-1
3156 (w), 3082 (w), 2994 (w), 2906 (w), 1723 (s), 1599 (s) 1260 (s), 1234 (s), 776 (s). HRMS (TOF-ESI+) calculated for C12H11F2O4
257.0625, found 257.0635.
Ethyl (2Z,5E)-2-hydroxy-4-oxo-6-phenylhexa-2,5-dienoate, 10m:
Isolated yield: 1.83 g (7.5 mmol, 75%). Pale yellow oil. 1H-NMR (400 MHz, CDCl3) δ/ppm 7.72 (d, J = 15.8 Hz, 1H), 7.55 (dd, J = 6.7, 3.1
Hz, 2H), 7.45 – 7.35 (m, 3H), 6.64 (d, J = 15.8 Hz, 1H), 6.52 (s, 1H), 4.35 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100
MHz, CDCl3) δ/ppm 185.0 (C), 174.4 (C), 162.0 (C), 143.3 (CH), 134.3 (C), 130.9 (CH), 129.0 (2CH), 128.4 (2CH), 123.0 (CH), 100.6
(CH), 62.5 (CH2), 14.0 (CH3). IR (neat) ν/cm-1 2988 (w), 1729 (s), 1630 (m), 1579 (m), 1259 (s), 1119 (m), 977 (m), 788 (m). HRMS (TOF-
ESI+) calculated for C14H14O4Na 269.0790, found 269.0800.
Ethyl (Z)-2-hydroxy-5,5-dimethyl-4-oxohex-2-enoate, 10o:
Isolated yield: 1.6 g (7.9 mmol, 79%). Appearance: colorless oil. 1H-NMR (400 MHz, CDCl3) δ/ppm 6.53 – 6.51 (m, 1H), 4.38 – 4.31 (m,
2H), 1.39 – 1.33 (m, 3H), 1.21 – 1.19 (m, 9H). 13C{1H} NMR (100 MHz, CDCl3) δ/ppm 209.2 (C), 167.4 (C), 162.3 (C), 97.9 (CH), 62.4
(CH2), 41.6 (C), 26.6 (3CH3), 14.0 (CH3). IR (neat) ν/cm-1 2972 (w), 1732 (m), 1633 (m), 1594 (m), 1281 (m), 1243 (s), 1109 (s), 1013 (m),
891 (m), 780 (m). HRMS (TOF-ESI+) calculated for C10H17O4 201.1127, found 201.1131 (M+H+).
Ethyl (Z)-4-(4-(2-fluorobenzamido)phenyl)-2-hydroxy-4-oxobut-2-enoate, 10p:
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Isolated yield: 1.04 g (2.9 mmol, 81%). Appearance: pale yellow powder. 1H-NMR (400 MHz, DMSO-d6) δ/ppm 10.85 (s, 1H), 8.08 (d, J =
8.6 Hz, 2H), 7.90 (d, J = 8.6 Hz, 2H), 7.67 (td, J = 7.5, 1.9 Hz, 1H), 7.58 (tdd, J = 7.3, 5.2, 1.8 Hz, 1H), 7.35 (d, J = 10.5 Hz, 1H), 7.31 (d, J
= 7.4 Hz, 1H), 7.08 (s, 1H), 4.28 (q, J = 7.1 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, DMSO-d6) δ/ppm 190.0 (C), 168.7
(C), 163.8 (C), 162.1 (C), 159.4 (d, J = 249 Hz, CF), 144.7 (C), 133.4 (d, J = 9 Hz, CH), 130.4 (d, J = 3 Hz, CH), 129.9 (2CH), 129.8 (C),
125.1 (d, J = 4 Hz, CH), 124.9 (d, J = 15 Hz, C), 119.8 (2CH), 116.7 (d, J = 22 Hz, CH), 98.2 (CH), 62.6 (CH2), 14.3 (CH3). 19F-NMR (376
MHz, DMSO-d6) δ/ppm -114.5. IR (neat) ν/cm-1 3335 (m), 1727 (m), 1656 (m), 1597 (m), 1519 (s), 1239 (s), 1204 (s), 853 (m), 778 (s),
751 (s), 652 (s), 499 (m). HRMS (TOF-ESI+) calculated for C19H17NO5F 358.1091, found 358.1094.
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Ethyl (Z)-4-(4-(dimethylamino)phenyl)-2-hydroxy-4-oxobut-2-enoate, 10r:
Isolated yield: 1.41 g (5.4 mmol, 88%). Appearance: orange solid. Melting range: 100-103 °C. 1H-NMR (400 MHz, CDCl3) δ/ppm 7.89 (d,
J = 9.2 Hz, 2H), 6.97 (s, 1H), 6.66 (d, J = 9.2 Hz, 2H), 4.36 (q, J = 7.2 Hz, 2H), 3.07 (s, 6H), 1.38 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100
MHz, CDCl3) δ/ppm 189.8 (C), 166.7 (C), 163.0 (C), 154.1 (C), 130.4 (2CH), 122.1 (C), 111.0 (2CH), 97.6 (CH), 62.2 (CH2), 40.0 (2CH3),
14.1 (CH3). IR (neat) ν/cm-1 2905 (w), 1723 (m), 1562 (m), 1523 (w), 1317 (s), 1251 (s), 1110 (s), 707 (s). HRMS (TOF-ESI+) calculated
for C14H18NO4 264.1246, found 264.1242.
Ethyl (Z)-2-hydroxy-4-oxo-4-(thiophen-2-yl)but-2-enoate, 10s:
Isolated yield: 927 mg (4.1 mmol, 81%). Appearance: yellow oil. 1H-NMR (400 MHz, CDCl3) δ/ppm 7.84 (dd, J = 3.9, 1.1 Hz, 1H), 7.73
(dd, J = 5.1, 1.2 Hz, 1H), 7.18 (dd, J = 4.9, 3.8 Hz, 1H), 6.90 (s, 1H), 4.38 (q, J = 7.2 Hz, 2H), 1.39 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100
MHz, CDCl3) δ/ppm 186.0 (C), 164.8 (C), 162.2 (C), 142.1 (C), 135.2 (CH), 132.6 (CH), 128.7 (CH), 99.4 (CH), 62.6 (CH2), 14.1 (CH3).
IR (neat) ν/cm-1 3109 (w), 2984 (w), 1735 (m), 1617 (s), 1406 (m), 1274 (s), 775 (m). HRMS (ESI-TOF+) calculated for C10H11O4S 227.0378,
found 227.0367.
Ethyl (Z)-4-(furan-2-yl)-2-hydroxy-4-oxobut-2-enoate, 10t:
Isolated yield: 1.66 g (7.9 mmol, 79%). Appearance: pale yellow oil. 1H-NMR (400 MHz, CDCl3) δ/ppm 7.64 (d, J = 1.9 Hz, 1H), 7.30 (d,
J = 3.8 Hz, 1H), 6.90 (s, 1H), 6.58 (dd, J = 3.5, 1.6 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ/ppm 181.0 (C), 166.0 (C), 161.9 (C), 150.8 (C), 147.7 (CH), 118.4 (CH), 113.1 (CH), 98.9 (CH), 62.5 (CH2), 14.0 (CH3). IR
(neat) ν/cm-1 3125 (m), 2987 (w), 1739 (m), 1612 (s), 1552 (s), 1467 (m), 1282 (s), 1246 (s), 1129 (s), 1015 (s), 771 (s). HRMS (TOF-ESI+)
calculated for C10H11O5 211.0606, found 211.0605.
Ethyl (Z)-2-hydroxy-4-(5-methylfuran-2-yl)-4-oxobut-2-enoate, 10v:
Isolated yield: 1.91 g (8.5 mmol, 85%). Appearance: yellow solid. Melting range: 88-90 °C. 1H-NMR (400 MHz, CDCl3) δ/ppm 7.26 – 7.23
(m, 1H), 6.85 (s, 1H), 6.23 (dd, J = 3.5, 1.2 Hz, 1H), 4.37 (q, J = 7.2 Hz, 2H), 2.42 (s, 3H), 1.38 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100
MHz, CDCl3) δ/ppm 180.6 (C), 164.9 (C), 162.2 (C), 159.5 (C), 149.7 (C), 120.6 (CH), 110.1 (CH), 99.0 (CH), 62.5 (CH2), 14.2 (CH3). IR
(neat) ν/cm-1 3122 (w), 2991 (w), 1737 (s), 1606 (s), 1519 (s), 1287 (s), 1245 (s), 1209 (s), 1124 (s), 1017 (s), 822 (s), 776 (s). HRMS (TOF-
ESI+) calculated for C11H12O5Na 247.0582, found 247.0583.
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Ethyl (Z)-2-hydroxy-4-(1H-indol-3-yl)-4-oxobut-2-enoate, 10w:
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Isolated yield: 2.02 g (7.9 mmol, 79%). Appearance: yellow solid. Melting range: 178-180 °C. 1H-NMR (400 MHz, d6-DMSO) δ/ppm 12.42
(s, 1H), 8.70 (s, 1H), 8.19 (d, J = 7.2 Hz, 1H), 7.48 (d, J = 7.5 Hz, 1H), 7.24 (m, 2H), 6.99 (s, 1H), 4.27 (q, J = 7.2 Hz, 2H), 1.28 (t, J = 7.2
Hz, 3H). 13C{1H} NMR (100 MHz, d6-DMSO) δ/ppm 189.7 (C), 162.8 (C), 162.4 (C), 137.6 (C), 136.5 (CH), 125.6 (C), 124.0 (CH), 123.0
(CH), 122.0 (CH), 115.2 (C), 113.1 (CH), 101.0 (CH), 62.2 (CH2), 14.4 (CH3). IR (neat) ν/cm-1 3248 (broad), 1723 (m), 1523 (s), 1409 (s),
1242 (s), 1166 (s), 1124 (s), 994 (s), 772 (m), 740 (s), 712 (m), 626 (m). HRMS (TOF-ES+) calculated for C14H14NO4 260.0923, found
260.0918.
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Synthesis of Isoxazole Products 4a – 4y: General Procedure:
To a solution of the appropriate Claisen adduct (10a-10y, 1.0 equiv.) in MeCN (1 M) was added hydroxylamine hydrochloride (1.1 equiv.).
The resulting mixture was heated at 70 °C until complete consumption of starting material was observed by TLC (~3-6 h). After cooling to
room temperature, the mixture was concentrated to ~20% of its volume and loaded onto a pad of silica (~10 g per 10 mmol product). Elution
with EtOAc/hexanes (10%) yielded the desired isoxazole product after evaporation of all volatiles under reduced pressure.
Ethyl 5-(4-methoxyphenyl)isoxazole-3-carboxylate, 4a:
Isolated yield: 2.1 g (8.5 mmol, 85%). Appearance: light yellow solid. Melting range: 86-88 °C. 1H-NMR (400 MHz, CDCl3) δ/ppm 7.75
(d, J = 8.9 Hz, 2H), 7.00 (d, J = 8.9 Hz, 2H), 6.80 (s, 1H), 4.47 (q, J = 7.2 Hz, 2H), 3.87 (s, 3H), 1.44 (t, J = 7.2 Hz, 3H). 13C{1H} NMR
(100 MHz, CDCl3) δ/ppm 171.7 (C), 161.5 (C), 160.2 (C), 156.9 (C), 127.6 (2CH), 119.4 (C), 114.5 (2CH), 98.5 (CH), 62.1 (CH2), 55.4
(CH3), 14.1 (CH3). IR (neat) ν/cm-1 3135 (w), 2997 (w), 1733 (s), 1618 (m), 1510 (m), 1452 (m), 1267 (s), 1188 (m), 1148 (m), 1021 (m),
827 (m), 780 (m). HRMS (TOF-EI+) calculated for C13H13NO4 247.0845, found 247.0849 (M+). UV-vis (λmax, DCM) 289 nm. X-ray data:
for C13H13NO4; P21/c, α = 90, β = 109.660(7), γ = 90, a = 13.350(1), b = 8.1964(5), c = 11.5379(7) – CCDC1967212.
Ethyl 5-(3,4-dimethoxyphenyl)isoxazole-3-carboxylate, 4b:
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Isolated yield: 2.1 g (7.7 mmol, 77%). Appearance: off-white solid. Melting range: 142-144 °C. H-NMR (400 MHz, CDCl3) δ/ppm 7.39
(dd, J = 8.4, 2.0 Hz, 1H), 7.30 (d, J = 2.0 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.81 (s, 1H), 4.47 (q, J = 7.1 Hz, 2H), 3.96 (s, 3H), 3.94 (s, 3H),
1.44 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ/ppm 171.7 (C), 160.1 (C), 156.9 (C), 151.2 (C), 149.4 (C), 119.5 (C), 119.4
(CH), 111.3 (CH), 108.6 (CH), 98.8 (CH), 62.2 (CH2), 56.1 (CH3), 56.0 (CH3), 14.2 (CH3). IR (neat) ν/cm-1 2972 (w), 2901 (w), 1717 (m),
1579 (m), 1455 (m), 1276 (s), 1244 (s), 1017 (s), 856 (s), 764 (s). HRMS (TOF-EI+) calculated for C14H15NO5 277.0950, found 277.0950
(M+). UV-vis (λmax, DCM) 308 nm.
Ethyl 5-(benzo[d][1,3]dioxol-5-yl)isoxazole-3-carboxylate; 4c:
Isolated yield: 418 mg (1.60 mmol, 70%). Appearance: pale yellow solid. Melting range: 158-160 °C. 1H-NMR (400 MHz, CDCl3) δ/ppm
7.34 (dd, J = 8.1, 1.7 Hz, 1H), 7.24 (d, J = 1.7 Hz, 1H), 6.90 (d, J = 8.1, 1H), 6.76 (s, 1H), 6.05 (s, 2H), 4.46 (q, J = 7.1 Hz, 2H), 1.43 (t, J =
7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ/ppm 171.4 (C), 160 (C), 156.9 (C), 149.8 (C), 148.4 (C), 120.8 (CH), 120.7 (C), 108.9
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(CH), 106.1 (CH), 101.7 (CH2), 98.9 (CH), 62.2 (CH2), 14.1 (CH3). IR (neat) ν/cm-1 3136 (w), 1725 (s), 1504 (m), 1463 (s), 1269 (s), 1236
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(m), 1023 (m), 927 (m), 779 (m). HRMS (TOF-EI+) calculated for C13H11NO5 261.0637, found 261.0642 (M+). UV-vis (λmax, DCM) 325
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Ethyl 5-(2,4-dimethoxyphenyl)isoxazole-3-carboxylate, 4d:
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Isolated yield: 1.15 g (4.2 mmol, 83%). Appearance: pale yellow solid. Melting range: 123-125 °C. 1H-NMR (400 MHz, CDCl3) δ/ppm 7.90
(d, J = 8.6 Hz, 1H), 7.03 (s, 1H), 6.60 (dd, J = 8.6, 2.4 Hz, 1H), 6.53 (d, J = 2.4 Hz, 1H), 4.46 (q, J = 7.2 Hz, 2H), 3.94 (s, 3H), 3.86 (s, 3H),
1.43 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ/ppm 167.9 (C), 162.8 (C), 160.5 (C), 157.8 (C), 156.9 (C), 128.8 (CH), 109.0
(C), 105.3 (CH), 102.1 (CH), 98.6 (CH), 62.0 (CH2), 55.6 (CH3), 55.5 (CH3), 14.2 (CH3). IR (neat) ν/cm-1 3002 (w), 2942 (w), 1725 (m),
1613 (s), 1449 (s), 1292 (s), 1226 (s), 1209 (s), 1157 (m), 1111 (m), 1022 (m), 830 (m), 773 (m). HRMS (TOF-ESI+) calculated for
C14H15NO5 277.0950, found 277.0952 (M+). UV-vis (λmax, DCM) 314 nm.
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Ethyl 5-(2,4,6-trimethoxyphenyl)isoxazole-3-carboxylate, 4e:
Isolated yield: 700 mg (2.3 mmol, 88%). Appearance: yellow solid. Melting range: 105-107 °C. 1H-NMR (400 MHz, CDCl3) δ/ppm 6.79 (s,
1H), 6.15 (s, 2H), 4.43 (q, J = 7.2 Hz, 2H), 3.84 (s, 3H), 3.79 (s, 6H), 1.40 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ/ppm
167.1 (C), 163.3 (C), 160.6 (C), 159.6 (C), 155.9 (C), 105.3 (CH), 98.6 (C), 90.7 (2CH), 61.8 (CH2), 55.9 (2CH3), 55.4 (CH3), 14.2 (CH3).
IR (neat) ν/cm-1 3032 (w), 3001 (w), 2977 (w), 2838 (w), 1741 (m), 1613 (m), 1591 (s), 1224 (s), 1123 (s). HRMS (TOF-ES+) calculated
for C15H17NO6 307.1056, found 307.1045. UV-vis (λmax, DCM) 300 nm.
Ethyl (2Z,5E)-2-hydroxy-4-oxo-6-phenylhexa-2,5-dienoate, 4f:
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Isolated yield: 870 mg (3.75 mmol, 75%). Appearance: off-white powder. Melting range: 191-193 °C. H-NMR (400 MHz, DMSO-d6)
δ/ppm 9.85 (s, 1H), 7.36 (s, 1H), 7.36 – 7.29 (m, 2H), 7.26 (t, J = 2.0 Hz, 1H), 6.90 (dt, J = 7.7, 2.1 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 1.30
(t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, DMSO-d6) δ/ppm 171.6 (C), 159.8 (C), 158.4 (C), 157.2 (C), 131.0 (CH), 127.6 (C), 118.5
(CH), 117.2 (CH), 112.6 (CH), 101.1 (CH), 62.3 (CH2), 14.4 (CH3). IR (neat) ν/cm-1 3317 (broad), 2939 (w), 1769 (m), 1732 (s), 1577 (m),
1243 (s), 1183 (s), 1027 (m). HRMS (TOF-ESI+) calculated for C12H11NO4Na 256.0586, found 256.0584. UV-vis (λmax, DCM) 271 nm.
Ethyl 5-phenylisoxazole-3-carboxylate, 4g:
Isolated yield: 333 mg (1.53 mmol, 90%). Appearance: colorless solid. Melting range: 54-57 °C. 1H-NMR (400 MHz, CDCl3) δ/ppm 7.81 –
7.76 (m, 2H), 7.46 (m, 3H), 6.90 (s, 1H), 4.45 (q, J = 7.2 Hz, 2H), 1.42 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ/ppm 171.7
(C), 160.0 (C), 156.9 (C), 130.8 (CH), 129.1 (2CH), 126.6 (C), 125.9 (2CH), 99.9 (CH), 62.2 (CH2), 14.1 (CH3). IR (neat) ν/cm-1 3147 (w),
3131 (w), 2986 (w), 2940 (w), 1729 (s), 1389 (s), 1247 (s), 1148 (s). HRMS (TOF-ESI+) calculated for C12H12NO3 218.0817, found
218.0827. UV-vis (λmax, DCM) 272 nm.
Ethyl 5-(4-(tert-butyl)phenyl)isoxazole-3-carboxylate, 4h:
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Isolated yield: 294 mg (1.1 mmol, 82%). Appearance: yellow solid. Melting range: 57-59 °C. 1H-NMR (400 MHz, CDCl3) δ/ppm 7.72 (d, J
= 8.6 Hz, 2H), 7.49 (d, J = 8.6 Hz, 2H), 6.86 (s, 1H), 4.45 (q, J = 7.2 Hz, 2H), 1.42 (t, J = 7.2 Hz, 3H), 1.33 (s, 9H). 13C{1H} NMR (100
MHz, CDCl3) δ/ppm 171.9 (C), 160.1 (C), 156.9 (C), 154.3 (C), 126.1 (2CH), 125.7 (2CH), 123.9 (C), 99.4 (CH), 62.2 (CH2), 35.0 (C), 31.1
(3CH3), 14.1 (CH3). IR (neat) ν/cm-1 2962 (m), 2904 (w), 2868 (w), 1712 (s), 1613 (m), 1444 (m), 1244 (m), 1143 (m). HRMS (TOF-ESI+)
calculated for C16H20NO3 274.1443, found 274.1440. UV-vis (λmax, DCM) 279 nm.
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Ethyl 5-(2-fluoro-4-methoxyphenyl)isoxazole-3-carboxylate, 4i:
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Isolated yield: 1.2 g (4.5 mmol, 90%). Appearance: off-white solid. Melting range: 102-104 °C. H-NMR (400 MHz, CDCl3) δ/ppm 7.87
(app t, J = 8.6 Hz, 1H), 6.95 (d, J = 3.8 Hz, 1H), 6.81 (dd, J = 8.6, 2.5 Hz, 1H), 6.73 (dd, J = 12.7, 2.5 Hz, 1H), 4.46 (q, J = 7.2 Hz, 2H),
3.85 (s, 3H), 1.43 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ/ppm 165.8 (C, d, J = 3 Hz), 162.9 (C), 160.2 (CF, d, J = 252 Hz),
160.0 (C), 157.1 (C), 128.3 (CH, d, J = 4 Hz), 110.9 (CH, d, J = 2 Hz), 107.8 (C, d, J = 13 Hz), 102.2 (CH, d, J = 24 Hz), 102.1 (CH, d, J =
10 Hz), 62.1 (CH2), 55.8 (CH3), 14.1 (CH3). 19F-NMR (376 MHz, CDCl3) δ/ppm -109.1. IR (neat) ν/cm-1 2987 (w), 1731 (m), 1624 (m),
1335 (m), 1269 (m), 1224 (s), 1103 (m), 1014 (s), 842 (s), 809 (s), 772 (s), 632 (m). HRMS (TOF-EI+) calculated for C13H12NO4F 265.0750,
found 265.0744 (M+). UV-vis (λmax, DCM) 297 nm.
Ethyl 5-(4-bromophenyl)isoxazole-3-carboxylate, 4j:
Isolated yield: 866 mg (2.92 mmol, 77%). Appearance: colorless solid. Melting range: 130-132 °C. 1H-NMR (500 MHz, CDCl3) δ/ppm 7.68
(d, J = 8.7 Hz, 2H), 7.63 (d, J = 8.7 Hz, 2H), 6.93 (s, 1H), 4.48 (q, J = 7.2 Hz, 2H), 1.45 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (125 MHz,
CDCl3) δ/ppm 170.6 (C), 159.8 (C), 157.1 (C), 132.5 (2CH), 127.3 (2CH), 125.5 (C), 125.3 (C), 100.3 (CH), 62.3 (CH2), 14.2 (CH3). IR
(neat) ν/cm-1 2984 (w), 1724 (s), 1606 (m), 1445 (m), 1248 (s), 1150 (m), 996 (m), 944 (s), 829 (s), 780 (s), 499 (s). HRMS (TOF-ESI+)
calculated for C12H11NO3Br 295.9922, found 295.9930. UV-vis (λmax, DCM) 278 nm.
Ethyl 5-(2,4-dichloro-5-fluorophenyl)isoxazole-3-carboxylate, 4k:
Isolated yield: 1.2 g (4.0 mmol, 80%). Appearance: off-white solid. Melting range: 76-79 °C. 1H-NMR (400 MHz, CDCl3) δ/ppm 7.78 (d, J
= 9.4 Hz, 1H), 7.59 (d, J = 6.7 Hz, 1H), 7.38 (s, 1H), 4.48 (q, J = 7.2 Hz, 2H), 1.44 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3)
δ/ppm 165.9 (C), 159.5 (C), 157.1 (C), 156.9 (CF, d, J = 250 Hz), 133 (CH), 127.1 (C, d, J = 4 Hz), 125.1 (C, d, J = 7 Hz), 124.2 (C, d, J =
19 Hz), 116.7 (CH, d, J = 25 Hz), 105.3 (CH), 62.4 (CH2), 14.1 (CH3). 19F-NMR (376 MHz, CDCl3) δ/ppm -115.3. IR (neat) ν/cm-1 2985
(w), 1720 (s), 1474 (m), 1447 (m), 1287 (s), 1134 (w), 1023 (w), 780 (m), 734 (m). HRMS (TOF-EI+) calculated for C12H8NO3FCl2
302.9865, found 302.9874 (M+). UV-vis (λmax, DCM) 269 nm.
Ethyl 5-(2,4-difluorophenyl)isoxazole-3-carboxylate, 4l:
Isolated yield: 393 mg (1.55 mmol, 97%). Appearance: colorless solid. Melting range: 113-115 °C. 1H-NMR (400 MHz, CDCl3) δ/ppm 7.97
(td, J = 8.5, 6.2 Hz, 1H), 7.06 – 7.00 (m, 2H), 6.96 (ddd, J = 10.9, 8.6, 2.5 Hz, 1H), 4.46 (q, J = 7.2 Hz, 2H), 1.42 (t, J = 7.2 Hz, 3H). 13C{1H}
NMR (100 MHz, CDCl3) δ/ppm 164.7 (d, J = 3 Hz, C), 163.8 (dd, J = 254, 14 Hz, CF), 159.8 (C), 159.5 (dd, J = 255, 14 Hz, CF), 157.2
(C), 128.9 (dd, J = 10, 3 Hz, CH), 112.5 (dd, J = 22, 4 Hz, CH), 112.0 – 111.6 (m, C), 105.3 – 104.7 (m, CH), 103.4 (d, J = 11 Hz, CH),
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62.30 (CH2), 14.12 (CH3). 19F-NMR (376 MHz, CDCl3) δ/ppm -104.6 (m), -107.0 (m). IR (neat) ν/cm-1 3186 (w), 3079 (w), 2996 (w), 1727
(s), 1618 (m), 1602 (m), 1504 (s), 823 (s). HRMS (TOF-ESI+) calculated for C12H10NO3F2 254.0629, found 254.0640. UV-vis (λmax, DCM)
260 nm.
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Isolated yield: 632 mg (2.6 mmol, 85%). Appearance: beige solid. Melting range: 116-118 °C. 1H-NMR (400 MHz, CDCl3) δ/ppm 7.54 –
7.48 (m, 2H), 7.42 – 7.30 (m, 4H), 6.95 (d, J = 16.5 Hz, 1H), 6.65 (s, 1H), 4.44 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H). 13C{1H} NMR
(100 MHz, CDCl3) δ/ppm 170.3 (C), 160.0 (C), 156.7 (C), 136.1 (CH), 135.1 (C), 129.5 (CH), 128.9 (2CH), 127.3 (2CH), 112.3 (CH), 101.5
(CH), 62.2 (CH2), 14.1 (CH3). IR (neat) ν/cm-1 2978 (m), 1733 (s), 1639 (m), 1499 (m), 1391 (m), 1292 (m), 1232 (s), 1029 (m), 970 (m),
834 (m), 694 (m). HRMS (TOF-ESI+) calculated for C14H14NO3 244.0974, found 244.0962. UV-vis (λmax, DCM) 312 nm.
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Ethyl 4-methyl-5-phenylisoxazole-3-carboxylate, 4n:
Isolated yield: 721 mg (3.1 mmol, 78%). Appearance: pale yellow oil. 1H-NMR (400 MHz, CDCl3) δ/ppm 7.72 (dd, J = 8.2, 1.6 Hz, 2H),
7.54 – 7.43 (m, 3H), 4.47 (q, J = 7.2 Hz, 2H), 2.43 (s, 3H), 1.45 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ/ppm 167.4 (C),
160.8 (C), 155.6 (C), 130.0 (CH), 128.9 (2CH), 127.6 (C), 127.0 (2CH), 111.4 (C), 61.8 (CH2), 14.2 (CH3), 8.5 (CH3). IR (neat) ν/cm-1 2983
(w), 1728 (s), 1499 (s), 1303 (m), 1223 (s), 1097 (s), 1017 (m), 769 (m), 693 (s). HRMS (TOF- EI+) calculated for C13H13NO3 (M+)
231.0895, found 231.0901. UV-vis (λmax, DCM) 274 nm.
Ethyl 5-(tert-butyl)isoxazole-3-carboxylate, 4o:
Isolated yield: 1.8 g (9.1 mmol, 91%). Appearance: colorless oil. 1H-NMR (400 MHz, CDCl3) δ/ppm 6.35 (s, 1H), 4.41 (q, J = 7.2 Hz, 3H),
1.39 (t, J = 7.2 Hz, 3H), 1.35 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3) δ/ppm 183.1 (C), 160.3 (C), 156.1 (C), 99.1 (CH), 61.9 (CH2), 32.9
(C), 28.7 (3CH3), 14.1 (CH3). IR (neat) ν/cm-1 2970 (w), 1731 (s), 1585 (w), 1454 (m), 1240 (s), 1211 (s), 1154 (s), 1020 (m), 777 (s). HRMS
(TOF-EI+) calculated for C10H15NO3 197.1052, found 197.1059 (M+). UV-vis (λmax, DCM) 238 nm.
Ethyl 5-(4-(2-fluorobenzamido)phenyl)isoxazole-3-carboxylate, 4p:
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Isolated yield: 517 mg (1.46 mmol, 73%). Appearance: off-white powder. Melting range: 184-186 °C. H-NMR (400 MHz, DMSO-d6)
δ/ppm 10.68 (s, 1H), 7.92 (d, J = 8.9 Hz, 2H), 7.88 (d, J = 8.9 Hz, 2H), 7.67 (td, J = 7.6, 1.7 Hz, 1H), 7.61 – 7.51 (m, 1H), 7.37 – 7.32 (m,
2H), 7.32 – 7.28 (m, 1H), 4.36 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, DMSO-d6) δ/ppm 171.3 (C), 163.6
(C), 159.9 (C), 159.4 (d, J = 250 Hz, CF), 157.2 (C), 141.6 (C), 133.2 (d, J = 8 Hz, CH), 130.4 (d, J = 3 Hz, CH), 127.1 (2CH), 125.2 (C),
125.0 (d, J = 4 Hz, CH), 121.8 (C), 120.3 (2CH), 116.7 (d, J = 22 Hz, CH), 100.3 (CH), 62.3 (CH2), 14.4 (CH3). 19F-NMR (376 MHz,
DMSO-d6) δ/ppm -114.5. IR (neat) ν/cm-1 3327 (w), 2986 (w), 1727 (s), 1651 (s), 1527 (s), 1443 (m), 1237 (s), 1132 (s), 781 (m), 751 (s),
512 (m). HRMS (TOF-ESI+) calculated for C19H16N2O4F 355.1094, found 355.1102. UV-vis (λmax, DCM) 308 nm.
N-Allyl-5-(5-methylfuran-2-yl)isoxazole-3-carboxamide, 4q:
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Isolated yield: 415 mg (1.8 mmol, 90%). Appearance: waxy yellow solid. 1H-NMR (400 MHz, CDCl3) δ/ppm 6.93 (br s, 1H), 6.83 (d, J =
3.3 Hz, 1H), 6.78 (s, 1H), 6.16 – 6.12 (m, 1H), 5.91 (ddt, J = 17.2, 10.2, 5.7 Hz, 1H), 5.28 (dq, J = 17.2, 1.6 Hz, 1H), 5.20 (dt, J = 10.2, 1.3
Hz, 1H), 4.08 (tt, J = 5.9, 1.6 Hz, 2H), 2.38 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ/ppm 163.3 (C), 158.6 (C), 158.5 (C), 155.2 (C),
140.9 (C), 133.3 (CH), 117.1 (CH2), 112.4 (CH), 108.3 (CH), 97.7 (CH), 41.8 (CH2), 13.7 (CH3). IR (neat) ν/cm-1 3324 (m), 3126 (w), 1676
(s), 1626 (m), 1551 (s), 1436 (s), 1275 (s), 939 (m), 838 (m), 784 (s), 656 (m), 598 (m). HRMS (TOF-EI+) calculated for C12H12N2O3
232.0848, found 232.0855 (M+).
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Ethyl 5-(4-(dimethylamino)phenyl)isoxazole-3-carboxylate, 4r:
Isolated yield: 396 mg (1.52 mmol, 95%). Appearance: light orange solid. Melting range: 120-122 °C. 1H-NMR (400 MHz, CDCl3) δ/ppm
7.64 (d, J = 9.0 Hz, 2H), 6.71 (d, J = 9.0 Hz, 2H), 6.67 (s, 1H), 4.43 (q, J = 7.2 Hz, 2H), 3.01 (s, 6H), 1.41 (t, J = 7.2 Hz, 3H). 13C{1H} NMR
(100 MHz, CDCl3) δ/ppm 172.5 (C), 160.4 (C), 156.7 (C), 151.6 (C), 127.2 (2CH), 114.5 (C), 111.8 (2CH), 97.0 (CH), 62.0 (CH2), 40.1
(2CH3), 14.2 (CH3). IR (neat) ν/cm-1 3298 (w), 2996 (w), 2982 (w), 2901 (w), 1717 (s), 1605 (s), 1518 (s), 1436 (s), 1253 (s). HRMS (TOF-
ESI+) calculated for C14H17N2O3 261.1239, found 261.1229. UV-vis (λmax, DCM) 340 nm.
Ethyl 5-(thiophen-2-yl)isoxazole-3-carboxylate, 4s:
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Isolated yield: 2.0 g (9.0 mmol, 90%). Appearance: pale yellow solid. Melting range: 48-50 °C. H-NMR (400 MHz, CDCl3) δ/ppm 7.56
(dd, J = 3.8, 1.2 Hz, 1H), 7.50 (dd, J = 5.0, 1.2 Hz, 1H), 7.15 (dd, J = 5.0, 3.8 Hz, 1H), 6.78 (s, 1H), 4.46 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1
Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ/ppm 166.7 (C), 159.8 (C), 156.9 (C), 128.8 (CH), 128.2 (CH), 128.2 (C), 127.8 (CH), 99.5
(CH), 62.3 (CH2), 14.1 (CH3). IR (neat) ν/cm-1 2986 (w), 1727 (s), 1592 (m), 1453 (s), 1237 (s), 1189 (s), 1113 (s), 1014 (s), 829 (m), 778
(s), 727 (s). HRMS (TOF-EI+) calculated for C10H9NO3S 223.0303, found 223.0310 (M+). UV-vis (λmax, DCM) 298 nm. X-ray data: for
C10H9NO3S; P21/n, α = 90, β = 93.837(2), γ = 90, a = 5.29000(9), b = 16.4483(2), c = 12.6312(2) – CCDC1967213.
Ethyl 5-(furan-2-yl)isoxazole-3-carboxylate, 4t:
Isolated yield: 373 mg (1.8 mmol, 90%). Appearance: beige powder. 1H-NMR (400 MHz, CDCl3) δ/ppm 7.54 (d, J = 1.8 Hz, 1H), 6.95 (d,
J = 3.6 Hz, 1H), 6.79 (s, 1H), 6.53 (dd, J = 3.6, 1.8 Hz, 1H), 4.43 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ/ppm 163.2 (C), 159.7 (C), 156.6 (C), 144.7 (CH), 142.4 (C), 112.0 (CH), 111.4 (CH), 99.4 (CH), 62.3 (CH2), 14.1 (CH3). IR (neat)
ν/cm-1 3127 (w), 2992 (w), 1722 (s), 1642 (s), 1432 (m), 1247 (s), 1225 (s), 1012 (s), 768 (s). HRMS (TOF-ESI+) calculated for C10H10NO4
208.0610, found 208.0614. UV-vis (λmax, DCM) 291 nm.
Ethyl 5-(1H-pyrrol-2-yl)isoxazole-3-carboxylate, 4u:
Isolated yield: 330 mg (1.6 mmol, 81%). Appearance: yellow solid. Melting range: 117-119 °C. 1H-NMR (400 MHz, CDCl3) δ/ppm 9.23 (s,
1H), 7.00 (td, J = 2.6, 1.4 Hz, 1H), 6.74 (ddd, J = 3.8, 2.6, 1.4 Hz, 1H), 6.69 (s, 1H), 6.34 (dt, J = 3.8, 2.6 Hz, 1H), 4.46 (q, J = 7.1 Hz, 2H),
1.43 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ/ppm 165.3 (C), 160.1 (C), 156.8 (C), 121.8 (CH), 119.4 (C), 110.9 (CH), 110.7
(CH), 96.9 (CH), 62.2 (CH2), 14.1 (CH3). IR (neat) ν/cm-1 3226 (m), 3154 (w), 1731 (m), 1627 (m), 1473 (m), 1450 (m), 1242 (s), 1155 (m),
1022 (m), 772 (s), 739 (s). HRMS (TOF-EI+) calculated for C10H10N2O3 206.0691, found 206.0693 (M+). UV-vis (λmax, DCM) 307 nm.
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Ethyl 5-(5-methylfuran-2-yl)isoxazole-3-carboxylate, 4v:
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Isolated yield: 886 mg (4.0 mmol, 80%). Appearance: yellow oil. 1H-NMR (400 MHz, CDCl3) δ/ppm 6.85 (d, J = 3.4 Hz, 1H), 6.73 (s, 1H),
6.18 – 6.10 (m, 1H), 4.44 (q, J = 7.2 Hz, 2H), 2.37 (d, J = 0.8 Hz, 3H), 1.41 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ/ppm
163.4 (C), 159.8 (C), 156.6 (C), 155.3 (C), 140.8 (C), 112.6 (CH), 108.3 (CH), 98.4 (CH), 62.2 (CH2), 14.1 (CH3), 13.7 (CH3). IR (neat)
ν/cm-1 2985 (w), 1731 (s), 1644 (m), 1579 (m), 1439 (m), 1235 (s), 1143 (s), 1021 (s), 771 (s). HRMS (TOF-ESI+) calculated for C11H12NO4
222.0766, found 222.0759. UV-vis (λmax, DCM) 303 nm.
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Ethyl 5-(1H-indol-3-yl)isoxazole-3-carboxylate, 4w:
Isolated yield: 1.0 g (4.1 mmol, 82%). Appearance: grey solid. Melting range: 176-178 °C. 1H-NMR (400 MHz, CDCl3) δ/ppm 8.66 (s, 1H),
8.00 – 7.93 (m, 1H), 7.81 (d, J = 2.8 Hz, 1H), 7.53 – 7.44 (m, 1H), 7.36 – 7.29 (m, 2H), 6.86 (s, 1H), 4.49 (q, J = 7.2 Hz, 2H), 1.46 (t, J =
7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ/ppm 168.4 (C), 160.4 (C), 156.7 (C), 136.1 (C), 124.7 (CH), 123.9 (C), 123.5 (CH), 121.8
(CH), 119.9 (CH), 111.8 (CH), 105.0 (C), 98.0 (CH), 62.1 (CH2), 14.2 (CH3). IR (neat) ν/cm-1 3172 (broad), 2984 (w), 1731 (m), 1603 (s),
1462 (s), 1239 (s), 1106 (s), 754 (s), 689 (s). HRMS (TOF-EI+) calculated for C14H12N2O3 256.0848, found 256.0845 (M+). UV-vis (λmax
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DCM) 309 nm.
Dodecyl 5-(furan-2-yl)isoxazole-3-carboxylate, 4x:
Isolated yield: 519 mg (1.5 mmol, 75%). Appearance: off-white powder. 1H-NMR (400 MHz, CDCl3) δ/ppm 7.57 (d, J = 1.9 Hz, 1H), 6.98
(d, J = 3.5 Hz, 1H), 6.81 (s, 1H), 6.56 (dd, J = 3.5, 1.9 Hz, 1H), 4.39 (t, J = 6.8 Hz, 2H), 1.79 (dt, J = 15.0, 6.8 Hz, 2H), 1.49 – 1.38 (m, 2H),
1.37 – 1.21 (m, 16H), 0.93 – 0.84 (m, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ/ppm 163.2 (C), 159.8 (C), 156.7 (C), 144.7 (CH), 142.4 (C),
112.1 (CH), 111.4 (CH), 99.4 (CH), 66.4 (CH2), 31.9 (CH2), 29.6 (CH2), 29.6 (CH2), 29.5 (CH2), 29.5 (CH2), 29.3 (CH2), 29.2 (CH2), 28.5
(CH2), 25.8 (CH2), 22.7 (CH2), 14.1 (CH3). IR (neat) ν/cm-1 2922 (m), 2853 (m), 1736 (s), 1516 (m), 1286 (s), 1157 (s), 1010 (m), 888 (m),
739 (m), 652 (m). HRMS (TOF-EI+) calculated for C20H29NO4 347.2097, found 347.2101 (M+).
(1-(Furan-2-ylmethyl)-1H-imidazol-5-yl)methyl 5-(furan-2-yl)isoxazole-3-carboxylate, 4y:
Isolated yield: 455 mg (1.34 mmol, 82%). Appearance: beige waxy solid. 1H-NMR (400 MHz, CDCl3) δ/ppm 7.56 (s, 1H), 7.55 (d, J = 2.0
Hz, 1H), 7.33 (dd, J = 2.0, 1.1 Hz, 1H), 7.19 (s, 1H), 6.95 (d, J = 3.5 Hz, 1H), 6.75 (s, 1H), 6.53 (dd, J = 3.5, 2.0 Hz, 1H), 6.30 (d, J = 3.5
Hz, 1H), 6.29 (dd, J = 3.5, 2.0 Hz, 1H), 5.40 (s, 2H), 5.18 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ/ppm 163.4 (C), 159.2 (C), 156.1 (C),
148.5 (C), 144.8 (CH), 143.3 (CH), 142.2 (C), 139.5 (CH), 132.2 (CH), 125.0 (C), 112.1 (CH), 111.6 (CH), 110.6 (CH), 109.1 (CH), 99.4
(CH), 56.6 (CH2), 42.0 (CH2). IR (neat) ν/cm-1 3126 (w), 1738 (s), 1644 (m), 1490 (m), 1438 (m), 1239 (s), 1218 (s), 1113 (m), 1012 (m),
767 (s), 745 (s). HRMS (TOF-ESI+) calculated for C17H14N3O5 340.0933, found 340.0921. X-ray data: for C34H28N6O11; C2/c, α = 90, β =
105.039(3), γ = 90, a = 19.0650(5), b = 8.0448(2), c = 21.6927(5) – CCDC1967210.
Synthesis of Oxazole Products 5a – 5y and Derivatives 11 and 12: General Procedure:
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A solution of the corresponding isoxazole precursor (4a-y) in MeCN (10-20 mM) was pumped at a flow rate of 0.5 mL/min (for 20-minute
residence time, reactor volume: 10 mL) through the UV150 photoreactor of a Vapourtec E-series flow reactor. The medium-pressure Hg
lamp was used at 90-100% power setting (equivalent to 135-150 W) in combination with a suitable broadband filter. The temperature within
the reactor was controlled via a stream of chilled air resulting in a temperature of 25-40 °C. The crude reaction products were evaporated
under reduced pressure and purified by silica column chromatography (EtOAc/ hexane 5-25%) yielding the desired photoisomerization
products.
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Ethyl 5-(4-methoxyphenyl)oxazole-2-carboxylate, 5a:
Isolated yield: 200 mg (0.81 mmol, 81%). Appearance: pale yellow solid. Melting range: 75-78 °C. 1H-NMR (400 MHz, CDCl3) δ/ppm 7.68
(d, J = 8.9 Hz, 2H), 7.38 (s, 1H), 6.96 (d, J = 8.9 Hz, 2H), 4.47 (q, J = 7.2 Hz, 2H), 3.84 (s, 3H), 1.44 (t, J = 7.2 Hz, 3H). 13C{1H} NMR
(100 MHz, CDCl3) δ/ppm 160.8 (C), 155.8 (C), 154.5 (C), 151.1 (C), 126.7 (2CH), 122.5 (CH), 119.4 (C), 114.5 (2CH), 62.5 (CH2), 55.4
(CH3), 14.2 (CH3). IR (neat) ν/cm-1 2981 (w), 1733 (s), 1614 (m), 1490 (s), 1302 (m), 1261 (s), 1173 (s), 1024 (m), 832 (m). HRMS (TOF-
ESI+) calculated for C13H14NO4 248.0923, found 248.0933. UV-vis (λmax, DCM) 315 nm. X-ray data: for C13H13NO4; P21/n, α = 90, β =
92.793(2), γ = 90, a = 6.7593(2), b = 13.8328(3), c = 12.7123(3) – CCDC1967211.
Ethyl 5-(3,4-dimethoxyphenyl)oxazole-2-carboxylate, 5b:
Isolated yield: 207 mg (0.75 mmol, 75%). Appearance: yellow oil. 1H-NMR (400 MHz, CDCl3) δ/ppm 7.41 (s, 1H), 7.34 (dd, J = 8.4, 2.0
Hz, 1H), 7.22 (d, J = 2.0 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 4.49 (q, J = 7.2 Hz, 2H), 3.96 (s, 3H), 3.93 (s, 3H), 1.46 (t, J = 7.2 Hz, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ/ppm 155.8 (C), 154.5 (C), 151.1 (C), 150.5 (C), 149.4 (C), 122.7 (CH), 119.6 (C), 118.5 (CH), 111.4
(CH), 108.0 (CH), 62.5 (CH2), 56.1 (CH3), 56.0 (CH3), 14.2 (CH3). IR (neat) ν/cm-1 2940 (w), 1733 (s), 1495 (s), 1252 (s), 1176 (s), 1145
(s), 1023 (m), 857 (m). HRMS (TOF-EI+) calculated for C14H15NO5 277.0950, found 277.0940 (M+).
Ethyl 5-(benzo[d][1,3]dioxol-5-yl)oxazole-2-carboxylate; 5c:
Isolated yield: 190 mg (0.73 mmol, 73%). Appearance: yellow solid. Melting range: 135-138 °C. 1H-NMR (400 MHz, CDCl3) δ/ppm 7.38
(s, 1H), 7.20 (dd, J = 8.1, 1.8 Hz, 1H), 7.20 (d, J = 1.8 Hz, 1H), 6.89 (d, J = 8.1 Hz, 1H), 6.03 (s, 2H), 4.48 (q, J = 7.1 Hz, 2H), 1.45 (t, J =
7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ/ppm 155.6 (C), 154.2 (C), 150.9 (C), 149.2 (C), 148.3 (C), 123.1 (CH), 120.7 (C), 119.6
(CH), 108.8 (CH), 105.3 (CH), 101.3 (CH2), 62.3 (CH2), 14.4 (CH3). IR (neat) ν/cm-1 2992 (w), 1729 (s), 1612 (s), 1488 (s), 1452 (m), 1374
(m), 1308 (m), 1266 (m), 1209 (s), 1158 (s), 1056 (s), 1032 (s). HRMS (TOF-EI+) calculated for C13H11NO5 261.0637, found 261.0630
(M+). UV-vis (λmax, DCM) 314 nm.
Ethyl 5-(2,4-dimethoxyphenyl)oxazole-2-carboxylate, 5d:
Isolated yield: 213 mg (0.77 mmol, 77%). Appearance: yellow solid. Melting range: 115-118 °C. 1H-NMR (400 MHz, CDCl3) δ/ppm 7.84
(d, J = 8.7 Hz, 1H), 7.58 (s, 1H), 6.60 (dd, J = 8.7, 2.3 Hz, 1H), 6.53 (d, J = 2.3 Hz, 1H), 4.48 (q, J = 7.1 Hz, 2H), 3.95 (s, 3H), 3.86 (s, 3H),
1.45 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ/ppm 161.9 (C), 157.7 (C), 156.0 (C), 151.3 (C), 150.0 (C), 128.0 (CH), 126.1
(CH), 109.3 (C), 105.2 (CH), 98.5 (CH), 62.3 (CH2), 55.5 (2xCH3), 14.2 (CH3). IR (neat) ν/cm-1 2992 (w), 1945 (w), 1731 (s), 1614 (s),
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1489 (s), 1461 (m), 1350 (m), 1210 (s), 1159 (s), 1057 (m), 831 (m). HRMS (TOF-EI+) calculated for C14H16NO5 278.1028, found 278.1030
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Ethyl 5-(2,4,6-trimethoxyphenyl)oxazole-2-carboxylate, 5e:
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Isolated yield: 208 mg (0.7 mmol, 68%). Appearance: yellow solid. Melting range: 89-91 °C. 1H-NMR (400 MHz, CDCl3) δ/ppm 7.35 (s,
1H), 6.14 (s, 2H), 4.44 (q, J = 7.2 Hz, 2H), 3.83 (s, 3H), 3.80 (s, 6H), 1.41 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ/ppm
162.8 (C), 159.6 (C), 156.1 (C), 151.0 (C), 148.8 (C), 128.9 (CH), 98.4 (C), 90.7 (2CH), 62.2 (CH2), 55.9 (2CH3), 55.4 (CH3), 14.2 (CH3).
IR (neat) ν/cm-1 3013 (w), 2965 (w), 2840 (w), 1722 (m), 1603 (m), 1586 (s), 1453 (s), 1429 (s). HRMS (TOF-ESI+) calculated for
C15H18NO6 308.1141, found 308.1134.
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Ethyl 5-(3-hydroxyphenyl)oxazole-2-carboxylate, 5f:
Isolated yield: 175 mg (0.75 mmol, 75%). Appearance: colourless waxy solid. 1H-NMR (400 MHz, d4-MeOD) δ/ppm 7.64 (s, 1H), 7.31 –
7.22 (m, 2H), 7.18 (t, J = 1.9 Hz, 1H), 6.86 – 6.82 (m, 1H), 4.44 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, d4-
MeOD) δ/ppm 157.9 (C), 155.3 (C), 154.4 (C), 151.6 (C), 130.0 (CH), 127.6 (C), 123.3 (CH), 116.7 (CH), 115.9 (CH), 111.2 (CH), 62.2
(CH2), 13.0 (CH3). IR (neat) ν/cm-1 3207 (broad), 2907 (w), 1727 (s), 1524 (m), 1479 (m), 1448 (m), 1298 (m), 1241 (s), 1195 (m). HRMS
(TOF-ESI+) calculated for C12H11NO4Na 256.0586, found 256.0576.
Ethyl 5-phenyloxazole-2-carboxylate, 5g:
Isolated yield: 109 mg (0.5 mmol, 75%). Appearance: yellow solid. Melting range: 56-58 °C. 1H-NMR (400 MHz, CDCl3) δ/ppm δ 7.75 –
7.71 (m, 2H), 7.49 (s, 1H), 7.46 – 7.41 (m, 2H), 7.40 – 7.36 (m, 1H), 4.47 (q, J = 7.2 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100
MHz, CDCl3) δ/ppm 155.7 (C), 154.3 (C), 151.6 (C), 129.8 (CH), 129.1 (2CH), 126.7 (C), 125.1 (2CH), 123.9 (CH), 62.6 (CH2), 14.2 (CH3).
IR (neat) ν/cm-1 3115 (w), 3065 (w), 2979 (w), 2906 (w), 1717 (s), 1597 (s), 1515 (s), 1474 (s), 1446 (s), 1172 (s). HRMS (TOF-ESI+)
calculated for C12H12NO3 218.0817, found 218.0807.
Ethyl 5-(4-(tert-butyl)phenyl)oxazole-2-carboxylate, 5h:
Isolated yield: 184 mg (0.7 mmol, 70%). Appearance: yellow solid. Melting range: 79-82 °C. 1H-NMR (400 MHz, CDCl3) δ/ppm 7.67 (d, J
= 8.5 Hz, 2H), 7.49 – 7.43 (m, 3H), 4.48 (q, J = 7.1 Hz, 2H), 1.44 (t, J = 7.1 Hz, 3H), 1.33 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3) δ/ppm
155.8 (C), 154.6 (C), 153.3 (C), 151.4 (C), 126.0 (2CH), 124.9 (2CH), 123.9 (C), 123.4 (CH), 62.5 (CH2), 34.9 (C), 31.1 (3CH3), 14.2 (CH3).
IR (neat) ν/cm-1 2962 (m), 2905 (w), 2869 (w), 1733 (s), 1614 (w), 1488 (s), 1174 (s), 1154 (s). HRMS (TOF-ESI+) calculated for C16H20NO3
274.1443, found 274.1447.
Ethyl 5-(2-fluoro-4-methoxyphenyl)oxazole-2-carboxylate, 5i:
Isolated yield: 187 mg (0.71 mmol, 71%). Appearance: off-white solid. Melting range: 107-109 °C. 1H-NMR (400 MHz, CDCl3) δ/ppm 7.82
(t, J = 8.7 Hz, 1H), 7.53 (d, J = 3.9 Hz, 1H), 6.81 (dd, J = 8.7, 2.5 Hz, 1H), 6.73 (dd, J = 12.7, 2.5 Hz, 1H), 4.49 (q, J = 7.2 Hz, 2H), 3.86 (s,
3H), 1.46 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ/ppm 161.9 (C, d, J = 11 Hz), 160.3 (CF, d, J = 251 Hz), 155.7 (C), 150.8
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(C), 149.1 (C), 127.7 (CH, d, J = 5 Hz), 126.2 (CH, d, J = 12 Hz), 110.8 (CH, d, J = 2 Hz), 108.0 (C, d, J = 14 Hz), 102.1 (CH, d, J = 24
Hz), 62.6 (CH3), 55.8 (CH3), 14.2 (CH3). 19F-NMR (376 MHz, CDCl3) δ/ppm -109.2. IR (neat) ν/cm-1 2980 (w), 1737 (s), 1626 (s), 1489
(s), 1264 (m), 1181 (s), 1117 (m), 1060 (m), 1024 (m), 871 (m), 815 (m). HRMS (TOF-EI+) calculated for C13H12NO4F 265.0750, found
265.0742 (M+).
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Isolated yield: 354 mg (1.2 mmol, 74%). Appearance: colorless solid. Melting range: 104-106 °C. 1H-NMR (400 MHz, CDCl3) δ/ppm 7.61
(d, J = 8.8 Hz, 2H), 7.57 (d, J = 8.8 Hz, 1H), 7.50 (s, 1H), 4.48 (q, J = 7.2 Hz, 2H), 1.44 (t, J = 7.2 Hz 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ/ppm 155.6 (C), 153.3 (C), 151.8 (C), 132.3 (2CH), 126.5 (2CH), 125.6 (C), 124.2 (CH), 124.0 (C), 62.7 (CH2), 14.2 (CH3). IR
(neat) ν/cm-1 2981 (w), 1721 (s), 1475 (m), 1409 (m), 1183 (m), 941 (m), 830 (m). HRMS (TOF-ESI+) calculated for C12H10NO3BrNa
317.9742, found 317.9748.
Ethyl 5-(2,4-dichloro-5-fluorophenyl)oxazole-2-carboxylate, 5k:
Isolated yield: 205 mg (0.68 mmol, 68%). Appearance: off-white solid. Melting range: 108-111 °C. 1H-NMR (400 MHz, CDCl3) δ/ppm 7.99
(s, 1H), 7.76 (d, J = 9.4 Hz, 1H), 7.58 (d, J = 6.6 Hz, 1H), 4.52 (q, J = 7.2 Hz, 2H), 1.47 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ/ppm 156.8 (CF, d, J = 290 Hz), 155.8 (C), 151.7 (C), 148.9 (C), 132.4 (CH), 129.2 (CH), 126.4 (C, d, J = 4 Hz), 125.6 (C, d, J =
8 Hz), 122.8 (C, d, J = 19 Hz), 115.9 (CH, d, J = 25 Hz), 63.0 (CH2), 14.1 (CH3). 19F-NMR (376 MHz, CDCl3) δ/ppm -115.7. IR (neat)
ν/cm-1 2985 (w), 1738 (s), 1522 (m), 1471 (s), 1378 (m), 1257 (s), 1208 (s), 885 (m), 732 (m). HRMS (TOF-EI+) calculated for
C12H8NO3FCl2 302.9865, found 302.9873 (M+). UV-vis (λmax, DCM) 294 nm.
Ethyl 5-(2,4-difluorophenyl)oxazole-2-carboxylate, 5l:
Isolated yield: 177 mg (0.7 mmol, 55%). Appearance: yellow solid. Melting range: 70-72 °C. 1H-NMR (400 MHz, CDCl3) δ/ppm 7.90 (td,
J = 8.5, 6.2 Hz, 1H), 7.59 (d, J = 4.0 Hz, 1H), 7.04 – 6.98 (m, 1H), 6.95 (ddd, J = 10.9, 8.5, 2.5 Hz, 1H), 4.48 (q, J = 7.2 Hz, 2H), 1.44 (t, J
= 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ/ppm 163.4 (dd, J = 253, 12 Hz, CF), 158.4 (dd, J = 254, 12 Hz, CF), 155.6 (C), 151.3
(C), 148.0 (m, C), 128.1 (dd, J = 10, 4. Hz, CH), 127.3 (d, J = 13 Hz, CH), 112.4 (dd, J = 22, 4 Hz, CH), 111.8 (m, C), 105.3 – 104.4 (m,
CH), 62.8 (CH2), 14.2 (CH3). 19F-NMR (376 MHz, CDCl3) δ/ppm -106.5 (m), -107.2 (m). IR (neat) ν/cm-1 3063 (w), 3038 (w), 2920 (s),
2851 (s), 1731 (m), 1620 (m), 1488 (m), 1272 (s), 1178 (m). HRMS (TOF-ESI+) calculated for C12H10NO3F2 254.0629, found 254.0637.
Ethyl (E)-5-styryloxazole-2-carboxylate, 5m:
Isolated yield: 267 mg (1.1 mmol, 72%). Appearance: yellow oil. 1H-NMR (400 MHz, CDCl3) δ/ppm 7.35 (m, 5H), 6.94 (d, J = 12.5 Hz,
1H), 6.51 (d, J = 12.5 Hz, 1H), 6.40 (s, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ/ppm
169.3 (C), 159.9 (C), 156.3 (C), 137.2 (CH), 135.5 (C), 128.8 (CH), 128.6 (2CH), 128.3 (2CH), 114.6 (CH), 103.0 (CH), 62.1 (CH2), 14.1
(CH3). IR (neat) ν/cm-1 2984 (w), 1730 (s), 1443 (m), 1258 (s), 1230 (s), 1156 (m), 1096 (m), 1021 (m), 778 (s), 698 (s). HRMS (TOF-ESI+)
calculated for C14H13O3NNa 266.0793, found 266.0802.
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Ethyl 4-methyl-5-phenyloxazole-2-carboxylate, 5n:
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Isolated yield: 176 mg (0.77 mmol, 77%). Appearance: pale yellow oil. 1H-NMR (400 MHz, CDCl3) δ/ppm 7.73 – 7.68 (m, 2H), 7.50 – 7.44
(m, 2H), 7.42 – 7.37 (m, 1H), 4.49 (q, J = 7.1 Hz, 2H), 2.51 (s, 3H), 1.45 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ/ppm 155.8
(C), 149.8 (C), 148.9 (C), 134.2 (C), 128.9 (2CH), 128.9 (CH), 127.8 (C), 126.1 (2CH), 62.5 (CH2), 14.2 (CH3), 13.5 (CH3). IR (neat) ν/cm-1
2982 (w), 1733 (s), 1529 (m), 1447 (m), 1327 (m), 1314 (m), 1187 (s), 1016 (m), 766 (m), 692 (m). HRMS (TOF-EI+) calculated for
C13H13NO3 231.0895, found 231.0905. UV-vis (λmax, DCM) 304 nm.
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Ethyl 5-(tert-butyl)oxazole-2-carboxylate, 5o:
Isolated yield: 95 mg (0.48 mmol, 24%). Appearance: light brown oil. 1H-NMR (400 MHz, CDCl3) δ/ppm 6.89 (s, 1H), 4.42 (q, J = 7.2 Hz,
2H), 1.40 (t, J = 7.2 Hz, 3H), 1.32 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3) δ/ppm 164.6 (C), 155.9 (C), 151.5 (C), 122.3 (CH), 62.3 (CH2),
31.8 (C), 28.5 (3CH3), 14.2 (CH3). IR (neat) ν/cm-1 2970 (m), 1738 (s), 1523 (s), 1368 (m), 1336 (m), 1269 (s), 1178 (s), 1136 (m), 1018
(m), 977 (m), 705 (m). HRMS (TOF-ESI+) calculated for C10H16NO3 198.1125, found 198.1120.
N-Allyl-5-(5-methylfuran-2-yl)oxazole-2-carboxamide, 5q:
Isolated yield: 91 mg (0.39 mmol, 39%). Appearance: pale yellow oil. 1H-NMR (400 MHz, CDCl3) δ/ppm 7.22 (s, 1H), 7.08 (br s, 1H), 6.74
(d, J = 3.4 Hz, 1H), 6.11 (d, J = 3.4 Hz, 1H), 5.91 (ddt, J = 17.4, 11.0, 5.7 Hz, 1H), 5.33 – 5.25 (m, 1H), 5.21 (dd, J = 10.3, 1.4 Hz, 1H), 4.11
– 4.04 (m, 2H), 2.36 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ/ppm 154.9 (C), 154.1 (C), 153.1 (C), 146.6 (C), 140.9 (C), 133.2 (CH),
121.3 (CH), 117.2 (CH2), 110.6 (CH), 108.1 (CH), 41.9 (CH2), 13.6 (CH3). IR (neat) ν/cm-1 3305 (broad), 1759 (w), 1679 (s), 1582 (m),
1546 (s), 1516 (m), 1200 (m), 1022 (s), 788 (m). HRMS (TOF-EI+) calculated for C12H12N2O3 232.0848, found 232.0840 (M+).
3-(5-Methylfuran-2-yl)-3-oxopropanenitrile, 11:
Isolated yield: 30 mg (0.20 mmol, 20%). Appearance: yellow oil. 1H-NMR (400 MHz, CDCl3) δ/ppm 7.28 (d, J = 3.6 Hz, 1H), 6.27 – 6.22
(m, 1H), 3.87 (s, 2H), 2.41 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ/ppm 174.7 (C), 159.5 (C), 149.2 (C), 121.3 (CH), 113.6 (C), 110.2
(CH), 28.4 (CH2), 14.1 (CH3). IR (neat) ν/cm-1 2948 (w), 2917 (w), 2361 (m), 1678 (m), 1668 (s), 1517 (s), 1382 (m), 1370 (m), 1262 (m),
1056 (m), 1036 (m), 799 (m). HRMS (TOF-ESI+) calculated for C8H7NO2Na 172.0374, found 172.0379.
Ethyl 2-cyano-3-(4-(dimethylamino)phenyl)-3-hydroxyacrylate, 12:
Isolated yield: 128 mg (0.5 mmol, 68%). Appearance: yellow solid. Melting range: 113-116 °C. 1H-NMR (400 MHz, CDCl3) δ/ppm 8.07 (d,
J = 9.3 Hz, 2H), 6.67 (d, J = 9.3 Hz, 2H), 4.35 (q, J = 7.2 Hz, 2H), 3.06 (s, 6H), 1.38 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3)
δ/ppm 181.6 (C), 172.3 (C), 153.6 (C), 130.9 (2CH), 117.71 (C), 117.67 (C), 110.8 (2CH), 74.2 (C), 62.2 (CH2), 39.9 (2CH3), 14.2 (CH3).
IR (neat) ν/cm-1 2980 (w), 2924 (w), 2212 (m), 1709 (s), 1577 (s), 1518 (s), 1166 (s), 1128 (s), 820 (s). HRMS (TOF-ESI+) calculated for
C14H16N2O3Na 283.1059, found 283.1059.
Ethyl 5-(thiophen-2-yl)oxazole-2-carboxylate, 5s:
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Isolated yield: 176 mg (0.80 mmol, 78%). Appearance: dark yellow oil. 1H-NMR (500 MHz, CDCl3) δ/ppm 7.49 (dd, J = 3.9, 1.4 Hz, 1H),
7.44 – 7.41 (m, 1H), 7.37 (s, 1H), 7.12 (dd, J = 5.3, 3.5 Hz, 1H), 4.49 (q, J = 7.1 Hz, 3H), 1.45 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (126 MHz,
CDCl3) δ/ppm 155.5 (C), 151.0 (C), 149.8 (C), 128.4 (C), 128.1 (CH), 127.6 (CH), 126.5 (CH), 123.4 (CH), 62.7 (CH2), 14.2 (CH3). IR
(neat) ν/cm-1 3111 (w), 2984 (w), 1735 (s), 1530 (m), 1487 (m), 1376 (m), 1276 (m), 1176 (s), 1155 (m), 1019 (m), 850 (m), 707 (m). HRMS
(TOF-EI+) calculated for C10H9NO3S 223.0303, found 223.0297 (M+).
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Ethyl 5-(furan-2-yl)oxazole-2-carboxylate, 5t:
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Isolated yield: 355 mg (1.71 mmol, 76%). Appearance: pale waxy solid. 1H-NMR (400 MHz, CDCl3) δ/ppm 7.52 (d, J = 1.7 Hz, 1H), 7.41
(s, 1H), 6.86 (d, J = 3.4 Hz, 1H), 6.53 (dd, J = 3.4, 1.7 Hz, 1H), 4.48 (q, J = 7.2 Hz, 2H), 1.44 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ/ppm 155.5 (C), 151.0 (C), 146.4 (C), 144.0 (CH), 142.4 (C), 123.5 (CH), 111.9 (CH), 109.9 (CH), 62.7 (CH2), 14.1 (CH3). IR
(neat) ν/cm-1 3131 (w), 2984 (w), 1732 (s), 1515 (s), 1447 (m), 1286 (s), 1174 (s), 1152 (s), 1115 (m), 1010 (s), 966 (m), 888 (m), 742 (s),
651 (m), 591 (m). HRMS (TOF-EI+) calculated for C10H9NO4 207.0532, found 207.0540 (M+). UV-vis (λmax, DCM) 312 nm.
Ethyl 5-(1H-pyrrol-2-yl)oxazole-2-carboxylate, 5u:
Isolated yield: 170 mg (0.83 mmol, 72%). Appearance: yellow solid. Melting range: 148-150 °C. 1H-NMR (400 MHz, CDCl3) δ/ppm 9.02
(br s, 1H), 7.30 (s, 1H), 6.95 (td, J = 2.7, 1.5 Hz, 1H), 6.67 (ddd, J = 3.9, 2.7, 1.5 Hz, 1H), 6.32 (dt, J = 3.9, 2.7 Hz, 1H), 4.47 (q, J = 7.1 Hz,
2H), 1.44 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ/ppm 155.8 (C), 149.7 (C), 148.7 (C), 121.1 (CH), 121.0 (CH), 119.1 (C),
110.7 (CH), 109.5 (CH), 62.5 (CH2), 14.2 (CH3). IR (neat) ν/cm-1 3220 (broad), 3132 (w), 1716 (s), 1617 (s), 1500 (s), 1376 (m), 1344 (m),
1279 (m), 1251 (s), 1168 (s), 738 (m). HRMS (TOF-EI+) calculated for C10H10N2O3 206.0691, found 206.0706 (M+). UV-vis (λmax, DCM)
338 nm. X-ray data: for C10H10N2O3; P21/c, α = 90, β = 115.800(3), γ = 90, a = 9.6285(2), b = 11.3962(2), c = 9.9019(3) – CCDC1967214.
Ethyl 5-(5-methylfuran-2-yl)oxazole-2-carboxylate, 5v:
Isolated yield: 884 mg (4.0 mmol, 80%). Appearance: waxy yellow solid. 1H-NMR (400 MHz, CDCl3) δ/ppm 7.32 (s, 1H), 6.73 (d, J = 3.4
Hz, 1H), 6.10 (dd, J = 3.4, 1.0 Hz, 1H), 4.46 (q, J = 7.2 Hz, 2H), 2.35 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3)
δ/ppm 155.6 (C), 154.5 (C), 150.6 (C), 146.8 (C), 140.8 (C), 122.6 (CH), 111.1 (CH), 108.2 (CH), 62.6 (CH2), 14.2 (CH3), 13.6 (CH3). IR
(neat) ν/cm-1 2985 (w), 1736 (s), 1641 (m), 1581 (m), 1535 (m), 1467 (m), 1292 (s), 1176 (s), 1021 (s), 788 (m). HRMS (TOF-ESI+)
calculated for C11H12NO4 222.0766, found 222.0757.
Ethyl 5-(1H-indol-3-yl)oxazole-2-carboxylate, 5w:
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Isolated yield: 193 mg (0.76 mmol, 73%). Appearance: yellow solid. Melting range: 180-182 °C. H-NMR (400 MHz, DMSO-d6) δ/ppm
11.79 (s, 1H), 7.97 (d, J = 2.8 Hz, 1H), 7.91 (dd, J = 7.5, 1.4 Hz, 1H), 7.71 (s, 1H), 7.47 (dd, J = 7.5, 1.4 Hz, 1H), 7.21 (ddd, J = 8.1, 7.1, 1.4
Hz, 1H), 7.16 (td, J = 7.5, 1.4 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, DMSO-d6) δ/ppm 155.7
(C), 151.8 (C), 149.6 (C), 136.9 (C), 125.9 (CH), 123.9 (C), 123.0 (CH), 122.0 (CH), 121.2 (CH), 119.8 (CH), 112.8 (CH), 103.0 (C), 62.2
(CH2), 14.5 (CH3). IR (neat) ν/cm-1 3294 (br), 1720 (s), 1623 (s), 1609 (s), 1540 (s), 1480 (m), 1355 (s), 1258 (s), 1232 (m), 1120 (m), 787
(m), 746 (s), 734 (s), 643 (m). HRMS (TOF-EI+) calculated for C14H12N2O3 256.0848, found 256.0840 (M+). UV-vis (λmax, DCM) 333 nm.
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Dodecyl 5-(furan-2-yl)oxazole-2-carboxylate, 5x:
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Isolated yield: 271 mg (0.78 mmol, 78%). Appearance: waxy solid. 1H-NMR (400 MHz, CDCl3) δ/ppm 7.52 (d, J = 1.7 Hz, 1H), 7.41 (s,
1H), 6.86 (d, J = 3.5 Hz, 1H), 6.53 (dd, J = 3.5, 1.7 Hz, 1H), 4.41 (t, J = 6.8 Hz, 2H), 1.81 (app p, J = 6.9 Hz, 2H), 1.42 (td, J = 6.8, 6.4, 2.4
Hz, 2H), 1.38 – 1.21 (m, 16H), 0.91 – 0.83 (m, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ/ppm 155.6 (C), 151.0 (C), 146.4 (C), 144.0 (CH),
142.5 (C), 123.5 (CH), 111.9 (CH), 109.9 (CH), 66.8 (CH2), 31.9 (CH2), 29.6 (CH2), 29.6 (CH2), 29.5 (CH2), 29.4 (CH2), 29.3 (CH2), 29.2
(CH2), 28.5 (CH2), 25.8 (CH2), 22.6 (CH2), 14.1 (CH3). IR (neat) ν/cm-1 2923 (s), 2853 (m), 1736 (s), 1544 (m), 1466 (m), 1349 (m), 1287
(s), 1158 (s), 1011 (m), 888 (m), 732 (s), 651 (m), 591 (m). HRMS (TOF-EI+) calculated for C20H29NO4 347.2097, found 347.2088 (M+).
UV-vis (λmax, DCM) 314 nm.
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(1-(Furan-2-ylmethyl)-1H-imidazol-5-yl)methyl 5-(furan-2-yl)oxazole-2-carboxylate; 5y:
Isolated yield: 366 mg (1.08 mmol, 73%). Appearance: waxy solid. 1H-NMR (400 MHz, CDCl3) δ/ppm 7.58 (d, J = 1.1 Hz, 1H), 7.53 (d, J
= 1.8 Hz, 1H), 7.42 (s, 1H), 7.35 (d, J = 2.2 Hz, 1H), 7.24 (s, 1H), 6.86 (d, J = 3.4 Hz, 1H), 6.55 (dd, J = 3.4, 1.8 Hz, 1H), 6.34 (d, J = 3.4
Hz, 1H), 6.30 (dd, J = 3.4, 1.8 Hz, 1H), 5.45 (s, 2H), 5.22 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ/ppm 155.0 (C), 150.3 (C), 148.4 (C),
146.7 (C), 144.2 (CH), 143.3 (CH), 142.3 (C), 139.4 (CH), 132.4 (CH), 124.9 (C), 123.7 (CH), 112.0 (CH), 110.6 (CH), 110.2 (CH), 109.1
(CH), 56.9 (CH2), 42.1 (CH2). IR (neat) ν/cm-1 3126 (w), 1735 (s), 1515 (s), 1288 (s), 1166 (s), 1112 (m), 1013 (m), 889 (m), 707 (m). HRMS
(TOF-ESI+) calculated for C17H14N3O5 340.0933, found 340.0940. UV-vis (λmax, DCM) 320 nm.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
Copies of 1H and 13C NMR spectra, representative UV-vis spectra of substrates and Hg-lamp emission spectra (pdf).
AUTHOR INFORMATION
Corresponding Author
* marcus.baumann@ucd.ie
ACKNOWLEDGMENT
We gratefully acknowledge support from the School of Chemistry at University College Dublin for a Research Demonstratorship (to CB)
and general support (to MB). We are thankful to Dr Helge Müller-Bunz for solving the X-ray crystal structures reported herein. We are
furthermore grateful to UCD for providing seed funding (SF1606 and SF1609) and SSPC for supporting our work through PharM5.
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(10) (a) Baumann, M.; Baxendale, I.R.; Ley, S.V.; Smith, C.D.; Tranmer, G.K. Fully Automated Continuous Flow Synthesis of 4,5-Disubstituted
Oxazoles. Org. Lett. 2006, 8, 5231-5234. (b) Baumann, M.; Baxendale, I.R.; Brasholz, M.; Hayward, J.J.; Ley, S.V.; Nikbin, N. An automated flow
and batch-based approach for the synthesis of O-methyl siphonazole. Synlett 2011, 10, 1375-1380. (c) Fernandez, A.; Levine, Z.G.; Baumann, M.;
Sulzer-Mosse, S.; Sparr, C.; Schläger, S.; Metzger, A.; Baxendale, I.R.; Ley, S.V. Synthesis of (–)-hennoxazole A: integrating batch and flow
chemistry methods. Synlett 2013, 24, 514-518. (d) Glöckner, S.; Tran, D.N.; Ingham, R.J.; Fenner, S.; Wilson, Z.E.; Battilocchio, C.; Ley, S.V. The
rapid synthesis of oxazolines and their heterogeneous oxidation to oxazoles under flow conditions. Org. Biomol. Chem. 2015, 13, 207-214. (e) Bay,
S.; Baumeister, T.; Hashmi, A.S.K.; Röder, T. Safe and Fast Flow Synthesis of Functionalized Oxazoles with Molecular Oxygen in a Microstructured
Reactor. Org. Process Res. Dev. 2016, 20, 7, 1297-1304. (f) Rossa, T.A.; Suveges, N.S.; Sa, M.M.; Cantillo, D.; Kappe, C.O. Continuous multistep
synthesis of 2-(azidomethyl)oxazoles. Beilstein J. Org. Chem. 2018, 14, 506-514.
(11) According to this, allyl isocyanate is produced as a by-product, however we have not been able to isolate this material or a derivative.
(12) For cases based on related 2-aryl azirines, please see: (a) Knittel, D.; Hemetsberger, H.; Leipert, R.; Weidmann, H. Thermolysereaktionen von
Enazidocarbonylverbindungen. Tetrahedron Lett. 1970, 11, 1459-1462. (b) Gilchrist, T.L.; Rees, C.W.; Rodrigues, J.A.R. Synthesis of Fused
Pyridines under Neutral Conditions. J. Chem. Soc. Chem. Commun. 1979, 14, 627-628.
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