Hypervalent Iodine(III) Reagent Mediated Regioselective Cycloaddition of Aldoximes with Enaminones

Article abstract of DOI:10.1002/ejoc.201901258

An efficient oxidative cycloaddition of enaminones with nitrile oxides generated in situ from respective aldoximes using hypervalent iodine reagents has been developed. Reactions of various aldoximes with enaminones in the presence of [hydroxy(tosyloxy)iodo]benzene involved the regioselective cycloaddition reaction resulting in the formation of the 3,4-disubstituted isoxazoles in moderate to good yields. Structures of several isoxazole products were confirmed by a single X-ray crystallography.

Full text of DOI:10.1002/ejoc.201901258

DOI: 10.1002/ejoc.201901258
Full Paper
Regioselective Cycloaddition
Hypervalent Iodine(III) Reagent Mediated Regioselective
Cycloaddition of Aldoximes with Enaminones
Akira Yoshimura,*[a,b] Melissa E. Jarvi,[b] Michael T. Shea,[b] Cody L. Makitalo,[b]
Gregory T. Rohde,[c] Mekhman S. Yusubov,[a] Akio Saito,[d] and Viktor V. Zhdankin[b]
Abstract: An efficient oxidative cycloaddition of enaminones cycloaddition reaction resulting in the formation of the 3,4-dis-
with nitrile oxides generated in situ from respective aldoximes ubstituted isoxazoles in moderate to good yields. Structures of
using hypervalent iodine reagents has been developed. Reac- several isoxazole products were confirmed by a single X-ray
tions of various aldoximes with enaminones in the presence crystallography.
of [hydroxy(tosyloxy)iodo]benzene involved the regioselective
Introduction
cently, the catalytic hypervalent iodine(III) species mediated
oxidative cycloaddition of aldoximes using alkenes or alkynes
to form the isoxazoles or isoxazolines have been reported.[11] In
previously reported cycloadditions of aldoximes with alkenes
or alkynes using hypervalent iodine(III) species, most obtained
compounds were 3,5-disubstituted products as major isomers
(Scheme 1, Equation 1).[6a,6d,12] Previously, our research group
reported that the oxidative cycloaddition of aldoximes using
heterocyclic alkenes gave the corresponding 3,4,5-trisubstituted
products in moderate to good yields (Scheme 1, Equation
2).[9b,11b] However, to the best of our knowledge, hypervalent
iodine(III) reagent mediated regioselective synthesis of 3,4-dis-
ubstituted isoxazoles from aldoximes with unsaturated com-
pounds has not been developed. On the other hand, enamin-
ones are versatile unsaturated substrates used in the generation
of heterocyclic compounds.[13] In particular, the useful cyclo-
addition strategies of various substrates using enaminones
via the elimination of the amino groups have been re-
ported.[13d,13f,13g,14] Herein, we report the hypervalent iodine(III)
reagent mediated regioselective cycloaddition of aldoximes
1,3-Dipolar cycloaddition reaction is an important chemical
transformation used for the construction of various heterocyclic
compounds.[1] In particular, the oxidative cycloaddition of nitrile
oxide species generated from aldoximes or related derivatives
with unsaturated substrates represents an efficient procedures
for preparation of isoxazoles or isoxazolines, which have nitro-
gen and oxygen atoms in a five-membered ring and are com-
monly found in natural products, medicinal drugs, and bio-
active compounds.[2] The generation of nitrile oxide species from
aldoximes or related derivatives under various synthetic condi-
tions has been explored by many research groups.[2a,2c,2f,2h]
Organohypervalent iodine compounds have been known as
broadly efficient and sustainable reagents, which have been
widely used in the various oxidative reactions.[3] Numerous
oxidative reactions or oxidative cycloaddition of aldoximes us-
ing hypervalent iodine(III) reagents have been explored.[4] Previ-
ously, some research groups including our group reported that
reactions of aldoximes with unsaturated substrates using hyper-
valent iodine(III) reagents such as (diacetoxyiodo)benzene,[5]
[bis(trifluoroacetoxy)iodo]benzene,[6] iodosylbenzene,[7] (di-
chloroiodo)benzene,[8] [hydroxy(tosyloxy)iodo]benzene,[9] or
2-[hydroxy(trifluoromethanesulfonyloxy)iodobenzoic
acid[10]
could allow the oxidative cycloaddition reactions to produce
the corresponding isoxazolines, isoxazoles, or oxadiazoles. Re-
[a] Research School of Chemistry and Applied Biomedical Sciences,
The Tomsk Polytechnic University,
634050 Tomsk, Russia
E-mail: ayoshimu@d.umn.edu
[b] Department of Chemistry and Biochemistry,
University of Minnesota Duluth,
Minnesota 55812, USA
[c] Marshall school, Duluth, Minnesota 55811, USA
[d] Division of Applied Chemistry, Institute of Engineering,
Tokyo University of Agriculture and Technology,
2-23-16 Naka-cho, Koganei, Tokyo 184-8588, Japan
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201901258.
Scheme 1. Hypervalent iodine(III) compounds mediated regioselective cyclo-
addition of aldoximes.
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with enaminones to produce 3,4-disubstituted isoxazoles which
structures are potentially important for bioactive compounds
(Scheme 1, Equation 3).
Results and Discussion
In the initial study of our experiment, we investigated the regio-
selective cycloaddition of benzaldoxime 1a (1 equiv.) with en-
aminone 2a (3 equiv.) using [hydroxy(tosyloxy)iodo]benzene,
Koser's reagent, 3a (2 equiv.) in various solvents at room tem-
perature for 3 hours (Table 1, entries 1–7). We have found that
dichloromethane is the best solvent for the formation of the
desired isoxazole product 4a (entry 1). The regioselectivity of
the obtained structure 4a was confirmed by X-ray crystallogra-
phy (Figure 1, see in the Supporting Information for details).
Screening of other iodine reagents 3 and Lewis acid, AlCl3, in-
stead of iodine reagent has indicated that Koser's reagent 3a
is an appropriate oxidant for this regioselective cycloaddition
(entries 1, 8–14). Finally, decreasing the amount of enaminone
2a or Koser's reagent 3a led to a slightly suppressed product
yield (entries 15 and 16).
Figure 1. X-ray crystal structure of compound 4a.
gave the respective desired products 4a–p in moderate to good
yields (entries 1–16). In the reaction of ortho-substituted
benzaldoximes 1d or 1i, the desired corresponding isoxazoles
4d, 4i were obtained in moderate to good yields (entries 4, 9).
However, performing the reaction of 4-(methylthio)benzaldox-
ime 1q afforded the desired product 4q in 34 % yield. During
this reaction, competitive sulfide oxidation was probably in-
volved in the reaction mixture.[15] The structures of isoxazoles
4p and 4q were established by X-ray crystallography (Figure 2,
see in the Supporting Information for details). The reaction of
enaminone 2a with naphthyl aldoximes 1r, s or heterocyclic
aldoximes 1t, u also proceeded efficiently producing the de-
Table 1. Optimization of regioselective cycloaddition of benzaldoxime 1a
with enaminone 2a using iodine reagents 3.[a]
Table 2. Preparation of 3,4-isoxazoles from various aldoximes 1 with 2a.[a]
Entry[a]
Solvent
Iodine reagent 3
4a Yield [%][b]
Entry
1, R
Time [h]
4 Yields [%][b]
1
2
3
4
5
6
7
8
CH2Cl2
CHCl3
ClCH2CH2Cl
Heptane
MeCN
PhI(OH)OTs 3a
PhI(OH)OTs 3a
PhI(OH)OTs 3a
PhI(OH)OTs 3a
PhI(OH)OTs 3a
PhI(OH)OTs 3a
PhI(OH)OTs 3a
PhI(OAc)2 3b
PhI(OCOCF3)2 3c
PhIO 3d
94 (92)
90
1
2
3
4
5
6
7
8
1a, Ph
3
4a, 92 (85)[c]
4b, 74
4c, 95
4d, 59
4e, 72
4f, 85
4g, 97
4h, 81
4i, 91
76[c]
11[c]
80[c]
32[c]
91
1b, 4-MeC6H4
1c, 2,4-Me2C6H3
1d, 2,6-Me2C6H3
1e, 4-MeOC6H4
1f, 4-ClC6H4
1g, 3-ClC6H4
1h, 2-ClC6H4
1i, 2,6-Cl2C6H3
1g, 4-BrC6H4
1k, 4-NO2C6H4
1l, 3-NO2C6H4
1m, 4-NCC6H4
1n, 4-MeO2CC6H4
1o, 4-AcOC6H4
1p, 4-PhC6H4
1q, 4-MeSC6H4
1r, 2-Naphthyl
1s, 1-Naphthyl
1t, 5-Benzodioxole
1u, 5-NO2furyl
1v, Propyl
1.5
24
24
3
3
3
AcOEt
MeOH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
49[c]
8[c]
9
6
3
10
11
12
13
14
15[e]
16[f]
16[c]
0[c]
9
KI 3e
I2 3f
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
24
24
3
24
6.5
24
3
24
24
24
24
24
24
24
3
4j, 90
4k, 76
4l, 98
0[c]
PhI 3g
0[c]
[d]
–
0[c]
4m, 94
4n, 82
4o, 81
4p, 74
4q, 34
4r, 88
4s, 88
4t, 83
4u, 93
4v, 46
4w, 56
4x, 62
PhI(OH)OTs 3a
PhI(OH)OTs 3a
76[c]
82 (67)[c]
[a] Reaction conditions: benzaldoxime 1a (1 equiv.), enaminone 2a (2–
3 equiv.), and iodine(III) reagent 3 (1.2–2 equiv.) in a solvent was stirred for
3 hours at room temperature. [b] Yields of product 4a determined from 1H
NMR spectra of reaction mixtures are shown (number in parenthesis is iso-
lated yield of 4a). [c] Benzaldoxime 1a was recovered from reaction mixture.
[d] AlCl3 was used instead of iodine reagent 3. [e] 2 equiv. of 2a was used.
[f] 1.2 equiv. of 3a was used.
1w, PhCH2CH2
1x, (E)-PhCH=CH
In the next step, we investigated the reaction of various sub-
stituted aldoximes 1 with enaminone 2a using optimized con-
ditions leading to the formation of the corresponding 3,4-dis-
ubstituted isoxazole products 4 (Table 2). In general, the reac-
tion of substituted benzaldoximes 1 with either electron-donat-
ing or electron-withdrawing groups under optimized conditions
[a] Reaction conditions: aldoxime 1 (1 equiv.), enaminone 2a (3 equiv.), and
Koser's reagent 3a (2 equiv.) in a dichloromethane was stirred for 24 hours
at room temperature. [b] Yields of isolated yield of 4. [c] Large scale reaction:
aldoxime 1a (1 mmol; 1 equiv.), enaminone 2a (3 mmol; 3 equiv.), and Koser's
reagent 3a (2 mmol, 2 equiv.) in a dichloromethane was stirred for 3 hours
at room temperature.
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Figure 2. X-ray crystal structures of 4p and 4q.
sired products 4r–u in good yields (entries 18–21). When using between Koser's reagent and the hydroxy group of the aldox-
the aliphatic aldoximes 1v, w or cinnamaldoxime 1x under opti- ime is important in this reaction. Next, the reaction using aceto-
mized conditions, the corresponding isoxazoles 4v–x were ob- phenone oxime 6b under optimized conditions did not pro-
tained in moderate yields (entries 22–24). In particular, the scale ceed, and 6b was recovered from the reaction mixture (Equa-
up reaction of 1a could be also applicable under optimized tion 2).[17] This result implies that the oxidation step of aldoxime
conditions to give the desired product 4a in 85 % yield.
Using the optimized conditions, we attempted to perform
the regioselective cycloaddition of benzaldoxime 1a with vari-
ous enaminones 2b–g (Scheme 2). In general, the reaction of
enaminones 2b–e with isopropyl, cyclopropyl, ethoxy, or
phenyl group instead of methyl group gave the corresponding
isoxazoles 5a-d in good yields. When performing the reaction
using enaminal 2f under the same conditions, the desired prod-
uct 5e was received in 46 % yield. In the reaction of ꢀ-methyl-
substituted enaminone 2g, the respective isoxazole 5f was ob-
tained in 48 %. The reaction using (E)- or (Z)-ꢀ-methyl-substi-
tuted enaminones with cyclic amino group 2h, 2i also pro-
ceeded smoothly to give the 3,4,5-trisubstituted isoxazole 5g in
moderate yields.
is required in this cycloaddition.
Scheme 3. Control experiment.
Based on these observations and related literature reports
of reactions of aldoxime species using hypervalent iodine(III)
reagents, we suggested a regioselective cycloaddition reaction
mechanism (Scheme 4).[9,16b] Firstly, the aldoxime 1 reacts with
Koser's reagent 3a to generate the nitrile oxide species 7 in the
reaction mixture. Subsequently, the 1,3-dipolar reaction be-
tween nitrile oxide 7 and enaminone 2a are involved in the
reaction to produce the cyclized compound 8 followed by
ꢀ-elimination of dimethylamine group to give the final 3,4-di-
substituted isoxazoles 4.[13g,14,18]
Scheme 4. Proposed reaction mechanism.
Scheme 2. Oxidative cycloaddition of 1a using various enaminones 2b–i.
For understanding the reaction mechanism, we performed
several blank experiments. Based on previously reported reac-
tions, nitrile oxide species were probably generated from the
Conclusions
aldoxime and hypervalent iodine(III) reagent in the reaction In summary, we have developed the cycloaddition of aldoximes
mixture.[9b,11a,16] The reaction using protected benzaldoxime, o- with enaminones using Koser's reagent. Our procedure pro-
methyl oxime 6a, under optimized conditions did not proceed, duced the desired regioselective isoxazole compounds in mod-
and 6a was recovered from reaction mixture (Scheme 3, Equa- erate to good yields. This regioselective cycloaddition probably
tion 1). This result indicated that the ligand exchange reaction initially involved the 1,3-dipolar reaction between the gener-
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and trans-4-dimethylamino-3-buten-2-one 2a (85 mg, 0.750 mmol)
according to the general procedure afforded 51 mg (95 %) of prod-
ated nitrile oxide and enaminone followed by ꢀ-elimination of
dialkylamine to afford the desired 3,4-disubstituted isoxazoles.
uct 4c, isolated as a white solid: m.p. 86.0–86.9 °C; IR (neat) cm–1
:
1
ν = 3363, 3094, 3008, 2924, 2859, 1696, 1563, 1385, 1361; H NMR
˜
(500 MHz, CDCl3): δ = 9.01 (s, 1H), 7.17 (d, J = 7.8 Hz, 1H), 7.13 (s,
1H), 7.09 (d, J = 7.8 Hz, 1H), 2.37 (s, 3H), 2.23 (s, 3H), 2.16 (s, 3H);
13C NMR (125 MHz, CDCl3): δ = 190.6, 162.7, 160.6, 139.9, 136.9,
133.2, 129.6, 126.5, 124.3, 122.2, 29.2, 21.3, 19.7; HRMS (APCI-posi-
tive ionization): calcd. for C13H14NO2 ([M + H]+): 216.1025, found
216.1036.
Experimental Section
General Experimental Remarks: All reactions were performed un-
der dry argon atmosphere with flame-dried glassware. Dichloro-
methane was distilled immediately prior to use. All commercial rea-
gents were ACS reagent grade and used without further purifica-
tion. All employed aldoximes and enaminones were commercially
available from reagent companies. Melting points were determined
in an open capillary tube with a Mel-temp II melting point appara-
tus. Infrared spectra were recorded on a PerkinElmer 1600 series
FT-IR spectrophotometer. 1H NMR spectra were recorded on
a Varian Inova 500 and 300 MHz NMR spectrometer; 13C NMR spec-
tra were recorded on Varian Inova 500 and Varian 300 MHz NMR
spectrometers at 125 and 75 MHz, respectively. Chemical shifts are
1-(3-(2,6-Dimethylphenyl)isoxazol-4-yl)ethan-1-one (4d): Reac-
tion of 2,6-dimethylbenzaldehyde oxime 1d (37 mg, 0.250 mmol)
and trans-4-dimethylamino-3-buten-2-one 2a (85 mg, 0.750 mmol)
according to the general procedure afforded 32 mg (59 %) of prod-
uct 4d, isolated as a white solid: m.p. 96.7–97.9 °C; IR (neat) cm–1
:
1
ν = 3359, 3093, 2955, 2925, 2858, 1685, 1565, 1466, 1386; H NMR
˜
(500 MHz, CDCl3): δ = 9.09 (s, 1H), 7.28 (d, J = 7.8 Hz, 1H), 7.14 (d,
J = 7.8 Hz, 2H), 2.13 (s, 3H), 2.09 (s, 6H); 13C NMR (125 MHz, CDCl3):
δ = 190.6, 163.1, 159.7, 137.1, 129.6, 127.6, 127.2, 122.1, 28.7, 20.2;
HRMS (APCI-positive ionization): calcd. for C13H14NO2 ([M + H]+):
216.1025, found 216.1032.
1
reported in parts per million (ppm). H and 13C chemical shifts are
referenced relative to the tetramethylsilane. X-ray crystal analysis
was performed by Rigaku RAPID II XRD Image Plate using graphite-
monochromated Mo-Kα radiation (λ = 0.71073 Å) at 173 K. Please
see the supporting information or the cif file for more detaied crys-
tallography information.
1-(3-(4-Methoxyphenyl)isoxazol-4-yl)ethan-1-one (4e): Reaction
of (E)-4-methoxybenzaldehyde oxime 1e (38 mg, 0.250 mmol) and
trans-4-dimethylamino-3-buten-2-one 2a (85 mg, 0.750 mmol) ac-
cording to the general procedure afforded 39 mg (72 %) of product
General Procedure for Preparation of isoxazoles: Aldoxime 1
(0.250 mmol) and enaminone 2 (0.750 mmol) were added to a solu-
tion of Koser's reagent 3a (196 mg, 0.500 mmol) in dichloro-
methane (2 mL). The reaction was stirred at room temperature for
1.5–24 h. After completion of the reaction, 5 % aqueous Na2S2O3
(5 mL) was added, and the mixture was extracted with dichloro-
methane. The organic phase was dried with anhydrous Na2SO4 and
concentrated under reduced pressure. Purification by column chro-
matography (hexane/ethyl acetate = 9:1 to 1:1) afforded analytically
pure products 4 and 5.
1-(3-Phenylisoxazol-4-yl)ethan-1-one (4a):[19] Reaction of (E)-
benzaldehyde oxime 1a (30 mg, 0.250 mmol) and trans-4-dimethyl-
amino-3-buten-2-one 2a (85 mg, 0.750 mmol) according to the gen-
eral procedure afforded 43 mg (92 %) of product 4a, isolated as a
4e, isolated as a white solid: m.p. 95.4–96.7 °C; IR (neat) cm–1: ν =
˜
3371, 3056, 2965, 2917, 2849, 1693, 1613, 1425, 1383, 1255, 1036;
1H NMR (300 MHz, CDCl3): δ = 8.97 (s, 1H), 7.68 (d, J = 9.0 Hz, 2H),
6.98 (d, J = 9.0 Hz, 2H), 3.86 (s, 3H), 2.46 (s, 3H); 13C NMR (75 MHz,
CDCl3): δ = 190.4, 163.4, 161.1, 160.3, 130.8, 120.6, 119.4, 113.7, 55.3,
29.7; HRMS (APCI-positive ionization): calcd. for C12H12NO3 ([M +
H]+): 218.0817, found 218.0825.
1-(3-(4-Chlorophenyl)isoxazol-4-yl)ethan-1-one (4f):[20] Reaction
of (E)-4-chlorobenzaldehyde oxime 1f (39 mg, 0.250 mmol) and
trans-4-dimethylamino-3-buten-2-one 2a (85 mg, 0.750 mmol) ac-
cording to the general procedure afforded 47 mg (85 %) of product
4f, isolated as a white solid: m.p. 111.7–112.1 °C; IR (neat) cm–1: ν =
˜
white solid: m.p. 78.0–78.8 °C (lit.[19] m.p. 83.0 °C); IR (neat) cm–1
:
3345, 3113, 3077, 2923, 2856, 1691, 1577, 1413, 1383, 1095; 1H NMR
(300 MHz, CDCl3): δ = 9.01 (s, 1H), 7.68 (d. J = 8.4 Hz, 2H), 7.44 (d,
J = 8.4 Hz, 2H), 2.49 (s, 3H); 13C NMR (75 MHz, CDCl3): δ = 190.0,
163.6, 159.9, 136.5, 130.8, 128.6, 125.8, 120.5, 29.7; HRMS (APCI-
positive ionization): calcd. for C11H935ClNO2 ([M + H]+): 222.0322,
found 222.0332.
1
ν = 3366, 3127, 3091, 3006, 2923, 2852, 1685, 1560, 1445, 1387; H
˜
NMR (300 MHz, CDCl3): δ = 9.00 (s, 1H), 7.72–7.65 (m, 2H), 7.54–7.42
(m, 3H), 2.44 (s, 3H); 13C NMR (300 MHz, CDCl3): δ = 190.4, 163.4,
160.8, 130.3, 129.4, 128.4, 127.4, 120.9, 29.7; HRMS (APCI-positive
ionization): calcd. for C11H10NO2 ([M + H]+): 188.0712, found
188.0727.
1-(3-(3-Chlorophenyl)isoxazol-4-yl)ethan-1-one (4g): Reaction of
(E)-3-chlorobenzaldehyde oxime 1g (39 mg, 0.250 mmol) and trans-
4-dimethylamino-3-buten-2-one 2a (85 mg, 0.750 mmol) according
to the general procedure afforded 54 mg (97 %) of product 4g,
Single crystals of product 4a suitable for X-ray crystallographic anal-
ysis were obtained by slow evaporation of dichloromethane solu-
tion. For details on crystal structure of compound 4a see the CIF
file in Supporting Information. CCDC 1942937.
isolated as a white solid: m.p. 118.3–119.6 °C; IR (neat) cm–1: ν =
˜
3351, 3123, 3092, 2924, 2853, 1689, 1557, 1409, 1390, 1121; 1H NMR
(300 MHz, CDCl3): δ = 9.02 (s, 1H), 7.72 (d. J = 1.5 Hz, 1H), 7.60 (dd,
J = 7.5 Hz, 1.5 Hz, 1H), 7.49–7.45 (m, 1H), 7.42–7.37 (m, 1H), 2.48 (s,
3H); 13CNMR (75 MHz, CDCl3): δ = 190.0, 163.7, 159.7, 134.2, 130.3,
129.6, 129.5, 129.1, 127.7, 120.6, 29.7; HRMS (APCI-positive ioniza-
tion): calcd. for C11H935ClNO2 ([M + H]+): 222.0322, found 222.0333.
1-(3-(p-Tolyl)isoxazol-4-yl)ethan-1-one (4b): Reaction of (E)-4-
methylbenzaldehyde oxime 1b (34 mg, 0.250 mmol) and trans-4-
dimethylamino-3-buten-2-one 2a (85 mg, 0.750 mmol) according
to the general procedure afforded 37 mg (74 %) of product 4b,
isolated as a white solid: m.p. 86.3–88.0 °C; IR (neat) cm–1: ν = 3372,
˜
3057, 2918, 2849, 1690, 1556, 1417, 1381; 1H NMR (300 MHz, CDCl3):
δ = 8.97 (s, 1H), 7.58 (d, J = 7.5 Hz, 2H), 7.27 (d, J = 7.5 Hz, 2H), 2.43
(s, 3H), 2.41 (s, 3H); 13C NMR (75 MHz, CDCl3): δ = 190.4, 163.3,
160.7, 140.4, 129.2, 129.0, 124.3, 120.8, 29.7, 21.4; HRMS (APCI-posi-
tive ionization): calcd. for C12H12NO2 ([M + H]+): 202.0868, found
202.0876.
1-(3-(2-Chlorophenyl)isoxazol-4-yl)ethan-1-one (4h): Reaction of
(E)-2-chlorobenzaldehyde oxime 1h (39 mg, 0.250 mmol) and trans-
4-dimethylamino-3-buten-2-one 2a (85 mg, 0.750 mmol) according
to the general procedure afforded 45 mg (81 %) of product 4h,
isolated as a white solid: m.p. 62.1–62.6 °C; IR (neat) cm–1: ν = 3365,
˜
1-(3-(2,4-Dimethylphenyl)isoxazol-4-yl)ethan-1-one (4c): Reac-
tion of (E)-2,4-dimethylbenzaldehyde oxime 1c (37 mg, 0.250 mmol)
3139, 3095, 2924, 2854, 1685, 1563, 1437, 1387, 1118; 1H NMR
(300 MHz, CDCl3): δ = 9.01 (s, 1H), 7.55–7.34 (m, 4H), 2.34 (s, 3H);
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13C NMR (75 MHz, CDCl3): δ = 189.9, 162.1, 158.9, 133.8, 131.2, 131.0, 0.750 mmol) according to the general procedure afforded 50 mg
129.7, 127.4, 126.8, 122.1, 28.9; HRMS (APCI-positive ionization):
(82 %) of product 4n, isolated as a white solid: m.p. 116.2–117.4 °C;
calcd. for C11H935ClNO2 ([M + H]+): 222.0322, found 222.0331.
IR (neat) cm–1: ν = 3371, 3093, 3005, 2916, 2849, 1705, 1689, 1559,
˜
1
1413, 1119; H NMR (500 MHz, CDCl3): δ = 9.06 (s, 1H), 8.13 (d, J =
1-(3-(2,6-Dichlorophenyl)isoxazol-4-yl)ethan-1-one (4i):[21] Reac-
tion of (E)-2,6-dichlorobenzaldoxime 1i (48 mg, 0.250 mmol) and
trans-4-dimethylamino-3-buten-2-one 2a (85 mg, 0.750 mmol) ac-
cording to the general procedure afforded 58 mg (91 %) of product
4i, isolated as a white solid: m.p. 107.4–108.8 °C (lit.[21] m.p. 118–
8.3 Hz, 2H), 7.79 (d, J = 8.3 Hz, 2H), 3.94 (s, 3H), 2.49 (s, 3H); 13C
NMR (125 MHz, CDCl3): δ = 190.0, 166.5, 163.8, 160.1, 131.8, 131.6,
129.5, 129.5, 120.7, 52.3, 29.7; HRMS (APCI-positive ionization):
calcd. for C13H12NO4 ([M + H]+): 246.0766, found 246.0779.
120 °C); IR (neat) cm–1: ν = 3350, 3134, 3091, 3066, 2925, 2857,
˜
4-(4-Acetylisoxazol-3-yl)phenyl acetate (4o): Reaction of (E)-4-
((hydroxyimino)methyl)phenyl acetate 1o (45 mg, 0.250 mmol) and
trans-4-dimethylamino-3-buten-2-one 2a (85 mg, 0.750 mmol) ac-
cording to the general procedure afforded 50 mg (81 %) of product
1688, 1567, 1424, 1391, 1095; 1H NMR (500 MHz, CDCl3): δ = 9.09
(s, 1H), 7.44 (d. J = 7.5 Hz, 1H), 7.41–7.36 (m, 2H), 2.35 (s, 3H); 13C
NMR (125 MHz, CDCl3): δ = 189.4, 162.7, 156.8, 135.3, 131.5, 128.0,
127.1, 121.8, 28.8; HRMS (APCI-positive ionization): calcd. for
C11H835Cl2NO2 ([M + H]+): 255.9932, found 255.9945.
4o, isolated as a white solid: m.p. 83.5–84.3 °C; IR (neat) cm–1: ν =
˜
3366, 3131, 3091, 2926, 2854, 1748, 1685, 1560, 1419, 1365, 1165,
1111; 1H NMR (500 MHz, CDCl3): δ = 9.00 (s, 1H), 7.77 (d, J = 8.8 Hz,
2H), 7.20 (d, J = 8.8 Hz, 2H), 2.47 (s, 3H), 2.32 (s, 3H); 13C NMR
(300 MHz, CDCl3): δ = 190.2, 169.1, 163.7, 160.0, 152.2, 130.8, 124.9,
121.6, 120.6, 29.7, 21.2; HRMS (APCI-positive ionization): calcd. for
C13H12NO4 ([M + H]+): 246.0766, found 246.0774.
1-(3-(4-Bromophenyl)isoxazol-4-yl)ethan-1-one (4j): Reaction of
(E)-4-bromobenzaldehyde oxime 1j (50 mg, 0.250 mmol) and trans-
4-dimethylamino-3-buten-2-one 2a (85 mg, 0.750 mmol) according
to the general procedure afforded 60 mg (90 %) of product 4j, iso-
lated as a white solid: m.p. 111.5–112.1 °C; IR (neat) cm–1: ν = 3348,
˜
3111, 3082, 3068, 2925, 2854, 1692, 1575, 1408, 1380; 1H NMR
(300 MHz, CDCl3): δ = 9.02 (s, 1H), 7.64–7.58 (m, 4H), 2.49 (s, 3H);
13C NMR (75 MHz, CDCl3): δ = 190.3, 163.9, 160.2, 131.8, 131.2, 126.5,
125.1, 120.7, 29.9; HRMS (APCI-positive ionization): calcd. for
C11H979BrNO2 ([M + H]+): 265.9817, found 265.9828.
1-(3-([1,1′-Biphenyl]-4-yl)isoxazol-4-yl)ethan-1-one (4p): Reac-
tion of (E)-([1,1′-biphenyl]-4-carbaldehyde oxime 1p (49 mg,
0.250 mmol) and trans-4-dimethylamino-3-buten-2-one 2a (85 mg,
0.750 mmol) according to the general procedure afforded 49 mg
(74 %) of product 4p, isolated as a white solid: m.p. 146.8–147.7 °C;
IR (neat) cm–1: ν = 3353, 3126, 3083, 2926, 2856, 1692, 1572, 1446,
1-(3-(4-Nitrophenyl)isoxazol-4-yl)ethan-1-one (4k):[21] Reaction
of (E)-4-nitrobenzaldehyde 1k (42 mg, 0.250 mmol) and trans-4-
dimethylamino-3-buten-2-one 2a (85 mg, 0.750 mmol) according
to the general procedure afforded 44 mg (76 %) of product 4k,
˜
1411; 1H NMR (300 MHz, CDCl3): δ = 9.00 (s, 1H), 7.79 (d, J = 7.8 Hz,
2H), 7.68 (d, J = 7.8 Hz, 2H), 7.63 (d, J = 8.1 Hz, 2H), 7.50–7.42 (m,
1H), 7.37 (t, J = 6.9 Hz, 1H), 2.47 (s, 3H); 13C NMR (75 MHz, CDCl3):
δ = 190.5, 163.7, 160.6, 143.2, 140.4, 130.0, 129.0, 127.9 127.3, 127.2,
126.3, 120.9, 29.9; HRMS (APCI-positive ionization): calcd. for
isolated as a white solid: m.p. 182.5–183.3 °C; IR (neat) cm–1: ν =
˜
3365, 3137, 3083, 3066, 2845, 1691, 1562, 1510, 1420, 1350, 856; 1H
NMR (300 MHz, CDCl3): δ = 9.08 (s, 1H), 8.33 (d, J = 9.5 Hz, 2H), 7.94
(d, J = 9.5 Hz, 2H), 2.56 (s, 3H); 13C NMR (125 MHz, CDCl3): δ = 189.8,
163.9, 159.2, 148.9, 133.7, 130.7, 123.4, 120.5, 29.7; HRMS (APCI-
positive ionization): calcd. for C11H9N2O4 ([M + H]+): 233.0562, found
233.0567.
C
17H14NO2 ([M + H]+): 264.1025, found 264.1032.
Single crystals of product 4p suitable for X-ray crystallographic
analysis were obtained by slow evaporation of dichloromethane so-
lution. For details on crystal structure of compound 4p see the CIF
file in Supporting Information. CCDC 1942938.
1-(3-(3-Nitrophenyl)isoxazol-4-yl)ethan-1-one (4l): Reaction of
(E)-3-nitrobenzaldehyde oxime 1l (42 mg, 0.250 mmol) and trans-4-
dimethylamino-3-buten-2-one 2a (85 mg, 0.750 mmol) according
to the general procedure afforded 57 mg (98 %) of product 4l, iso-
1-(3-(4-(Methylthio)phenyl)isoxazol-4-yl)ethan-1-one (4q): Reac-
tion of (E)-4-(methylthio)benzaldehyde 1q (42 mg, 0.250 mmol) and
trans-4-dimethylamino-3-buten-2-one 2a (85 mg, 0.750 mmol) ac-
cording to the general procedure afforded 20 mg (34 %) of product
lated as a light yellow solid: m.p. 118.7–119.3 °C; IR (neat) cm–1: ν =
˜
4q, isolated as a white solid: m.p. 93.1–94.8 °C; IR (neat) cm–1
:
3359, 3094, 2927, 2854, 1685, 1560, 1539, 1428, 1390, 1349, 861; 1H
NMR (300 MHz, CDCl3): δ = 9.11 (s, 1H), 8.65 (t, J = 1.5 Hz, 1H), 8.35
(dd, J = 8.4 Hz, 1.5 Hz, 1H), 8.09 (d, J = 7.5 Hz, 1H), 7.70–7.61 (m,
1H), 2.56 (s, 3H); 13C NMR (75 MHz, CDCl3): δ = 189.7, 163.9, 159.0,
147.9, 135.3, 129.2, 129.0, 124.8, 124.6, 120.2, 29.5; HRMS (APCI-
positive ionization): calcd. for C11H9N2O4 ([M + H]+): 233.0562, found
233.0576.
ν = 3363, 3099, 2924, 2854, 1685, 1573, 1411, 1379, 736; 1H NMR
˜
(500 MHz, CDCl3): δ = 8.99 (s, 1H), 7.65 (d, J = 8.5 Hz, 2H), 7.31 (d,
J = 8.5 Hz, 2H), 2.52 (s, 3H), 2.47 (s, 3H); 13C NMR (125 MHz, CDCl3):
δ = 190.3, 163.5, 160.3, 141.8, 129.7, 125.6, 123.6, 120.7, 29.8, 15.2;
HRMS (APCI-positive ionization): calcd. for C12H12NO2S ([M + H]+):
234.0589, found 234.0592.
Single crystals of product 4q suitable for X-ray crystallographic anal-
ysis were obtained by slow evaporation of dichloromethane solu-
tion. For details on crystal structure of compound 4q see the CIF
file in Supporting Information. CCDC 1942939.
4-(4-Acetylisoxazol-3-yl)benzonitrile (4m): Reaction of (E)-4-
(hydroxyamino)methyl) benzonitrile 1m (37 mg, 0.250 mmol) and
trans-4-dimethylamino-3-buten-2-one 2a (85 mg, 0.750 mmol) ac-
cording to the general procedure afforded 50 mg (94 %) of product
4m, isolated as a white solid: m.p. 181.3–181.7 °C; IR (neat) cm–1
:
1-(3-(Naphthalen-2-yl)isoxazol-4-yl)ethan-1-one (4r): Reaction of
(E)-2-naphthaldehyde oxime 1r (43 mg, 0.250 mmol) and trans-4-
dimethylamino-3-buten-2-one 2a (85 mg, 0.750 mmol) according
to the general procedure afforded 52 mg (88 %) of product, isolated
1
ν = 3370, 3134, 3090, 3057, 2922, 2232, 1689, 1577, 1421, 1386; H
˜
NMR (300 MHz, CDCl3): δ = 9.08 (s, 1H), 7.87 (d, J = 7.1 Hz, 2H), 7.75
(d, J = 7.1 Hz, 2H), 2.54 (s, 3H); 13C NMR (75 MHz, CDCl3): δ = 189.8,
163.9, 159.4, 131.9, 130.2, 120.4, 118.3, 113.9, 29.6; HRMS (APCI-
positive ionization): calcd. for C12H9N2O2 ([M + H]+): 213.0664, found
213.0667.
as a white solid: m.p. 93.5–95.1 °C; IR (neat) cm–1: ν = 3373, 3091,
˜
3056, 2925, 2854, 1691, 1561, 1434, 1394, 862, 831, 822; 1H NMR
(500 MHz, CDCl3): δ = 9.00 (s, 1H), 8.26 (s, 1H), 7.94–7.89 (m, 2H),
7.87 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.57–7.48 (m, 2H),
2.43 (s, 3H); 13C NMR (125 MHz, CDCl3): δ = 190.3, 163.6, 160.7,
133.9, 132.8, 129.5, 128.6, 127.9, 127.7, 127.2, 126.5, 126.2, 124.7,
Methyl 4-(4-acetylisoxazol-3-yl)benzoate (4n): Reaction of
methyl (E)-4-((hydroxyimino)methyl) benzoate 1n (45 mg,
0.250 mmol) and trans-4-dimethylamino-3-buten-2-one 2a (85 mg,
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120.9, 29.7; HRMS (APCI-positive ionization): calcd. for C15H12NO2 the general procedure afforded 33 mg (62 %) of product 4x, iso-
([M + H]+): 238.0868, found 238.0879.
lated as a white solid: m.p. 94.9–96.3 °C; IR (neat) cm–1: ν = 3345,
˜
3068, 3026, 2925, 2854, 1682, 1565, 1408, 1362, 854; 1H NMR
(500 MHz, CDCl3): δ = 8.91 (s, 1H), 7.68 (d, J = 16.8 Hz, 1H), 7.58 (d,
J = 7.5 Hz, 1H), 7.47 (d, J = 16.8 Hz, 1H), 7.41–7.36 (m, 2H), 7.33 (t,
J = 7.3 Hz, 1H), 2.52 (s, 3H); 13C NMR (125 MHz, CDCl3): δ = 190.9,
162.9, 158.2, 137.3, 135.9, 129.1, 128.8, 127.4, 120.0, 113.6, 29.4;
HRMS (APCI-positive ionization): calcd. for C13H12NO2 ([M + H]+):
214.0808, found 214.0879.
1-(3-(Naphthalen-1-yl)isoxazol-4-yl)ethan-1-one (4s): Reaction of
(E)-1-naphthaldehyde oxime 1s (43 mg, 0.250 mmol) and trans-4-
dimethylamino-3-buten-2-one 2a (85 mg, 0.750 mmol) according
to the general procedure afforded 52 mg (88 %) of product 4s,
isolated as a white solid: m.p. 139.8–141.1 °C; IR (neat) cm–1: ν =
˜
1
3364, 3090, 3060, 2923, 2854, 1685, 1564, 1423, 1383, 803; H NMR
(500 MHz, CDCl3): δ = 9.11 (s, 1H), 8.13–7.97 (m, 1H), 7.92 (d, J =
8.0 Hz, 1H), 7.62–7.54 (m, 3H), 7.52 (t, J = 7.3 Hz, 1H), 7.49–7.44 (m,
1H), 2.06 (s, 3H); 13C NMR (125 MHz, CDCl3): δ = 190.5, 162.0, 159.7,
133.4, 131.8, 130.5, 128.5, 128.1, 127.1, 126.4, 125.2. 125.0, 124.7,
123.0, 29.1; HRMS (APCI-positive ionization): calcd. for C15H12NO2
([M + H]+): 238.0868, found 238.0869.
2-Methyl-1-(3-phenylisoxazol-4-yl)propan-1-one (5a): Reaction
of (E)-benzaldehyde oxime 1a (30 mg, 0.250 mmol) and (E)-1-(di-
methylamino)-4-methylpent-1-en-3-one 2b (106 mg, 0.750 mmol)
according to the general procedure afforded 45 mg (84 %) of prod-
uct 5a, isolated as a light yellow oil; IR (neat) cm–1: ν = 3361, 3090,
˜
2974, 2934, 2875, 1688, 1558, 1444, 1387; 1H NMR (500 MHz, CDCl3):
δ = 8.98 (s, 1H), 7.67 (dd, J = 8.3 Hz, 1.8 Hz, 2H), 7.51–7.43 (m, 3H),
3.06 (sept, J = 7.0 Hz, 1H), 1.18 (d, J = 7.0 Hz, 6H); 13C NMR (125 MHz,
CDCl3): δ = 197.7, 162.4, 161.3, 130.2, 129.3, 128.3, 127.5, 119.3, 39.9,
18.8; HRMS (APCI-positive ionization): calcd. for C13H14NO2 ([M +
H]+): 216.1025, found 216.1032.
1-(3-(Benzo[d][1,3]dioxol-5-yl)isoxazol-4-yl)ethan-1-one
(4t):
Reaction of piperonaldoxime 1t (41 mg, 0.250 mmol) and trans-4-
dimethylamino-3-buten-2-one 2a (85 mg, 0.750 mmol) according
to the general procedure afforded 48 mg (83 %) of product 4t, iso-
lated as a white solid: m.p. 133.2–133.6 °C; IR (neat) cm–1: ν = 3339,
˜
3091, 3025, 2908, 1673, 1562, 1466, 1397, 1260, 1242, 1150; 1H NMR
(500 MHz, CDCl3): δ = 8.97 (s, 1H), 7.25 (dd, J = 7.8 Hz, 1.8 Hz, 1H),
7.19 (d, J = 1.8 Hz, 1H), 6.89 (d, J = 7.8 Hz, 1H), 6.03 (s, 2H), 2.47 (s,
3H); 13C NMR (125 MHz, CDCl3): δ = 190.4, 163.6, 160.3, 149.4, 147.6,
123.9, 120.8, 120.6, 109.8, 108.3, 101.5, 29.8; HRMS (APCI-positive
ionization): calcd. for C12H10NO4 ([M + H]+): 232.0610, found
232.0626.
Cyclopropyl(3-phenylisoxazol-4-yl)methanone (5b): Reaction of
(E)-benzaldehyde oxime 1a (30 mg, 0.250 mmol) and 1-cyclopropyl-
3-(dimethylamino)-2-propen-1-one 2c (104 mg, 0.750 mmol) ac-
cording to the general procedure afforded 53 mg (99 %) of product
5b, isolated as a yellow oil; IR (neat) cm–1: ν = 3337, 3090, 3011,
˜
2926, 2854, 1685, 1557, 1448; 1H NMR (500 MHz, CDCl3): δ = 9.06
(s, 1H), 7.72–7.67 (m, 2H), 7.51–7.43 (m, 3H), 2.18–2.11 (m, 1H), 1.23
(dt, J = 7.5 Hz, 3.5 Hz, 2H), 0.96 (dq, J = 8.0 Hz, 3.5 Hz, 2H); 13C NMR
(125 MHz, CDCl3): δ = 193.5, 162.6, 160.7, 130.2, 129.4, 128.3, 127.6,
121.5, 20.8, 12.1; HRMS (APCI-positive ionization): calcd. for
C14H14NO2 ([M + H]+): 214.0868, found 214.0881.
1-(3-(5-Nitrofuran-2-yl)isoxazol-4-yl)ethan-1-one (4u): Reaction
of (E)-5-nitrofuran-2-carbaldehyde oxime 1u (39 mg, 0.250 mmol)
and trans-4-dimethylamino-3-buten-2-one 2a (85 mg, 0.750 mmol)
according to the general procedure afforded 52 mg (93 %) of
product 4u, isolated as a yellow solid: m.p. 133.7–135.9 °C; IR (neat)
Ethyl-3-phenylisoxazole-4-carboxylate (5c):[22] Reaction of (E)-
benzaldehyde oxime 1a (30 mg, 0.250 mmol) and ethyl-N,N-dimeth-
ylamino-acrylate 2d (107 mg, 0.750 mmol) according to the general
procedure afforded 42 mg (72 %) of product 5c, isolated as a yellow
cm–1: ν = 3363, 3165, 3120, 2926, 2854, 1687, 1557, 1542, 1406,
˜
1
1359, 1346; H NMR (500 MHz, CDCl3): δ = 9.11 (s, 1H), 7.81 (d, J =
3.9 Hz, 1H), 7.42 (d, J = 3.9 Hz, 1H), 2.61 (s, 3H); 13C NMR (125 MHz,
CDCl3): δ = 189.3, 164.2, 150.1, 143.9, 120.5, 118.2, 112.1, 29.6; HRMS
(APCI-positive ionization): calcd. for C9H7N2O5 ([M + H]+): 223.0355,
found 223.0366.
oil; IR (neat) cm–1: ν = 3450, 3066, 3101, 2984, 2940, 1719, 1565,
˜
1448, 1387; 1H NMR (500 MHz, CDCl3): δ = 9.01 (s, 1H), 7.77 (dd, J =
8.0 Hz, 2.0 Hz, 2H), 7.52–7.43 (m, 3H), 4.29 (q, J = 7.0 Hz, 2H), 1.30
(t, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ = 164.1, 161.3,
160.9, 130.2, 129.5, 128.2, 127.3, 113.0, 61.1, 14,1; HRMS (APCI-posi-
tive ionization): calcd. for C12H12NO3 ([M + H]+): 218.0817, found
218.0827.
1-(3-Propylisoxazol-4-yl)ethan-1-one (4v): Reaction of butyr-
aldoxime 1v (24 mg, 0.250 mmol) and trans-4-dimethylamino-3-
buten-2-one 2a (85 mg, 0.750 mmol) according to the general pro-
cedure afforded 18 mg (46 %) of product 4v, isolated as a clear oil;
IR (neat) cm–1: ν = 3356, 3101, 2966, 2936, 2876, 1680, 1577, 1413,
˜
3-Phenylisoxazole-4-carbaldehyde (5d):[19] Reaction of (E)-benz-
aldehyde oxime 1a (30 mg, 0.250 mmol) and (E)-3-(dimethylamino)-
1-phenylprop-2-en-1-one 2e (131 mg, 0.750 mmol) according to the
general procedure afforded 45 mg (73 %) of product 5d, isolated
as a light yellow solid: m.p. 77.9–81.4 °C (lit.[22] m.p. 82–83 °C); IR
1
1363; H NMR (500 MHz, CDCl3): δ = 8.87 (s, 1H), 2.91 (t, J = 7.5 Hz,
2H), 2.48 (s, 3H), 1.72 (sext, J = 7.5 Hz, 2H), 0.99 (t, J = 7.5 Hz, 3H);
13C NMR (125 MHz, CDCl3): δ = 190.3, 162.0, 161.5, 119.9, 29.9, 28.8,
20.3, 13.3; HRMS (APCI-positive ionization): calcd. for C8H12NO2 ([M
+ H]+): 154.0868, found 154.0880.
(neat) cm–1: ν = 3313, 3128, 3064, 2931, 1652, 1557, 1448, 1387; 1H
˜
1-(3-Phenethylisoxazol-4-yl)ethan-1-one (4w): Reaction of (E)-3-
phenylpropanal oxime 1w (37 mg, 0.250 mmol) and trans-4-dimeth-
ylamino-3-buten-2-one 2a (85 mg, 0.750 mmol) according to the
general procedure afforded 30 mg (56 %) of product 4w, isolated
NMR (500 MHz, CDCl3): δ = 8.78 (s, 1H), 7.84 (dd, J = 8.3 Hz, 1.3 Hz,
2H), 7.68 (dd, J = 8.5 Hz, 1.5 Hz, 2H), 7.60 (t, J = 7.8 Hz, 1H) 7.49–
7.38 (m, 5H); 13C NMR (125 MHz, CDCl3): δ = 187.5, 162.7, 161.5,
137.9, 133.6, 130.2, 129.4, 129.0, 128.8, 128.5, 127.4, 119.2.
as a white solid: m.p. 52.8–53.9 °C; IR (neat) cm–1: ν = 3353, 3104,
˜
3-Phenylisoxazole-4-carbaldehyde (5e):[23] Reaction of (E)-benz-
aldehyde oxime 1a (30 mg, 0.250 mmol) and 3-(dimethylamino)-
acrolein 2f (74 mg, 0.750 mmol) according to the general procedure
afforded 20 mg (46 %) of product 5e, isolated as a white solid: m.p.
1
3064, 3028, 2934, 2865, 1685, 1578, 1412, 1363; H NMR (500 MHz,
CDCl3): δ = 8.85 (s, 1H), 7.33–7.25 (m, 4H), 7.23–7.18 (m, 1H), 3.24
(dd, J = 10.5 Hz, 8.3 Hz, 2H), 3.01 (dd, J = 10.5 Hz, 8.3 Hz, 2H), 2.48
(s, 3H); 13C NMR (125 MHz, CDCl3): δ = 190.8, 162.6, 161.4, 140.8,
128.5, 128.4, 126.2, 120.4, 33.6, 29.1, 27.6; HRMS (APCI-positive ioni-
zation): calcd. for C13H14NO2 ([M + H]+): 216.1025, found 216.1032.
45.5–46.9 °C (lit.[23] m.p. 41–42 °C); IR (neat) cm–1: ν = 3375, 3125,
˜
1
3093, 2926, 2854, 2751, 1696, 1559, 1448, 1384; H NMR (500 MHz,
CDCl3): δ = 10.0 (s, 1H), 9.09 (s, 1H), 7.80 (dd, J = 7.5 Hz, 2.0 Hz, 2H),
(E)-1-(3-Styrylisoxazol-4-yl)ethan-1-one (4x): Reaction of trans-
7.57–7.50 (m, 3H); 13C NMR (125 MHz, CDCl3): δ = 182.7, 165.2,
cinnamaldehyde oxime 1x (37 mg, 0.250 mmol) and trans-4-di- 160.5, 130.8, 129.1, 129.0, 126.7, 121.0; HRMS (APCI-positive ioniza-
methylamino-3-buten-2-one 2a (85 mg, 0.750 mmol) according to
tion): calcd. for C10H8NO2 ([M + H]+): 174.0555, found 174.0573.
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1-(5-Methyl-3-phenylisoxazol-4-yl)ethan-1-one (5f):[24] Reaction
of (E)-benzaldehyde oxime 1a (30 mg, 0.250 mmol) and (E)-4-(di-
methylamino)pent-3-en-2-one 2g (95 mg, 0.750 mmol) according
to the general procedure afforded 24 mg (48 %) of product 5f, iso-
lated as a white solid: m.p. 57.9–58.7 °C (lit.[24] m.p. 61.3–61.7 °C);
[2]
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Russ. Chem. Rev. 2015, 84, 335–377; c) D. Rane, M. Sibi, Curr. Org. Synth.
2011, 8, 616–627; d) F. M. Cordero, D. Giomi, L. Lascialfari, Prog. Hetero-
cycl. Chem. 2016, 28, 361–390; e) P. G. Baraldi, A. Barco, S. Benetti, G. P.
Pollini, D. Simoni, Synthesis 1987, 857–869; f) S. Tilvi, K. S. Singh, Curr.
Org. Chem. 2016, 20, 898–929; g) K. Kaur, V. Kumar, A. K. Sharma, G. K.
Gupta, Eur. J. Med. Chem. 2014, 77, 121–133; h) S. Roscales, J. Plumet,
Org. Biomol. Chem. 2018, 16, 8446–8461.
a) V. V. Zhdankin, Hypervalent Iodine Chemistry: Preparation, Structure and
Synthetic Application of Polyvalent Iodine Compounds, John Wiley & Sons
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IR (neat) cm–1: ν = 3345, 3004, 3065, 2927, 2854, 1683, 1570, 1409,
˜
1360; 1H NMR (500 MHz, CDCl3): δ = 7.53–7.47 (m, 5H), 2.71 (s, 3H),
2.09 (s, 3H); 13C NMR (125 MHz, CDCl3): δ = 193.3, 174.7, 161.9,
130.0, 129.1, 129.0, 128.7, 117.3, 30.6, 13.6; HRMS (APCI-positive ion-
ization): calcd. for C12H12NO2 ([M + H]+): 202.0868, found 202.0879.
[3]
Ethyl 5-methyl-3-phenylisoxazole-4-carboxylate (5g):[25] Reac-
tion of (E)-benzaldehyde oxime 1a (30 mg, 0.250 mmol) and ethyl-
(E)-3-(1-pyrrolindinyl)crotonate 2h (137 mg, 0.750 mmol) according
to the general procedure afforded 34 mg (59 %) of product 5g,
isolated as a white solid: m.p. 46.6–47.6 °C (lit.[25] m.p. 49–50 °C); IR
(neat) cm–1: ν = 3413, 3064, 2984, 2934, 2873, 1715, 1604, 1448,
˜
1
1425, 1150; H NMR (500 MHz, CDCl3): δ = 7.64–7.59 (m, 2H), 7.48–
7.39 (m, 3H), 4.23 (q, J = 7.0 Hz, 2H), 2.73 (s, 3H), 1.22 (t, J = 7.0 Hz,
3H); 13C NMR (125 MHz, CDCl3): δ = 175.8, 162.6, 162.0, 129.7, 129.4,
128.5, 127.9, 108.5, 60.7, 14.0, 13.6; HRMS (APCI-positive ionization):
calcd. for C13H14NO3 ([M + H]+): 232.0974, found 232.0990.
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Large scale reaction for preparation of 1-(3-phenylisoxazol-
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1.0 mmol) and trans-4-dimethylamino-3-buten-2-one 2a (339 mg,
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2 mmol) in dichloromethane (9 mL) and the reaction was stirred at
room temperature for 3 h. After completion of the reaction, 5 %
aqueous Na2S2O3 (20 mL) was added, and the mixture was ex-
tracted with dichloromethane. The organic phase was dried with
anhydrous Na2SO4 and concentrated under reduced pressure. Purifi-
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4q) contain the supplementary crystallographic data for this paper.
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Acknowledgments
This work was supported by a research grant from the Russian
Science Foundation (RSF-16-13-10081-P), the Tomsk Polytechnic
University Competitiveness Enhancement Program (VIU-69/
2019) and National Science Foundation ((CHE-1759798). A. S. is
thankful to JSPS Fund for the Promotion of Joint International
Research (Grant No 16KK0199).
[12]
[13]
Keywords: Hypervalent iodine(III) reagents · Cycloaddition ·
Isoxazoles · Regioselectivity · Aldoximes
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Received: August 23, 2019
Eur. J. Org. Chem. 2019, 6682–6689
www.eurjoc.org
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© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim