Synthesis of Substituted Indole-3-carboxylates by Iron(II)-Catalyzed Domino Isomerization of 3-Alkyl/aryl-4-aryl-5-methoxyisoxazoles

Article abstract of DOI:10.1055/s-0036-1591576

The iron(II)-catalyzed domino isomerization of 3-alkyl/aryl-4-arylisoxazoles provides a selective access to a wide range of structurally diverse highly substituted indole-3-carboxylates. The operational simplicity, high atom efficiency, and the use of stable starting materials and an inexpensive and low-toxicity catalyst are some of the attractive features of this tandem double ring-opening-ring-closure strategy.

Full text of DOI:10.1055/s-0036-1591576

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–O
paper
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V. A. Bodunov et al.
Paper
Synthesis
Synthesis of Substituted Indole-3-carboxylates by Iron(II)-Catalyzed
Domino Isomerization of 3-Alkyl/aryl-4-aryl-5-methoxyisoxazoles
Vladimir A. Bodunov
Ekaterina E. Galenko
Alexey V. Galenko
O
X
R
R'
R
OMe
FeCl2 (cat.)
DMSO, heat
X
N
R'
O
N
Mikhail S. Novikov
MeO
H
X = CH=CH, benzene-1,2-diyl, S
R = H, F, Cl, Br, Me, OMe, NO2
R' = alkyl, aryl, heteroaryl
Alexander F. Khlebnikov*
0
0
0
0
0-
0
0
2
6-
1
0
0
0-
3
0
9
22 examples
up to 95% yield
Saint Petersburg State University, Institute of Chemistry,
7/9 Universitetskaya nab., St. Petersburg, 199034,
Russian Federation
a.khlebnikov@spbu.ru
Received: 21.02.2018
Accepted after revision: 28.03.2018
Published online: 29.05.2018
transformation could also be performed at lower tempera-
7h
tures under Pd(PhCN)2Cl2,7b Rh2[OC(O)CF3]4,7f and FeCl2
catalysis. Some derivatives of indole-3-carboxylic acid were
obtained by both thermal and catalytic isomerization of the
corresponding 2H-azirines via the 1,5-cyclization of an in-
termediate styryl nitrene [Scheme 1, eq. 2, R2 = CN, CO2Et]7g
or a styryl nitrene complex [Scheme 1, eq. 3, R2 = mor-
pholinocarbonyl].7f,h
DOI: 10.1055/s-0036-1591576; Art ID: ss-2018-t0101-op
Abstract The iron(II)-catalyzed domino isomerization of 3-alkyl/aryl-
4-arylisoxazoles provides a selective access to a wide range of structur-
ally diverse highly substituted indole-3-carboxylates. The operational
simplicity, high atom efficiency, and the use of stable starting materials
and an inexpensive and low-toxicity catalyst are some of the attractive
features of this tandem double ring-opening–ring-closure strategy.
R3
R1
R3
Key words indoles, isoxazoles, isomerization, domino reactions,
iron(II) chloride catalysis
Au (cat.)
(1)
N
N
CH2Cl2
ref. 5
R1
R2
The indole moiety is widely present in natural com-
pounds, important marketed medicines, agrochemicals,
and progressive materials.1,2 Accordingly, the development
of atom-economical, practical, and safe synthesis of com-
pounds containing an indole ring is of immense interest to
synthetic chemists. While numerous methods for the
preparation of indoles have been developed,1,3 there still re-
mains a great need to find new methodologies for the selec-
tive preparation of functionalized indoles, substituted in
specific positions, from inexpensive and easily available
starting materials. The use of ring-to-ring intramolecular
isomerization for the preparation of indole derivatives is
quite rare,1 although these processes are 100% atom-eco-
nomical reactions.4
Two types of isomerizations involving ring opening fol-
lowed by recyclization are known: the gold-catalyzed rear-
rangement of 2-alkynyl-N-arylazetidines to pyrrolo[1,2-
a]indoles5 and the rearrangement of 2-aryl-2H-azirines to
indoles (Scheme 1).6,7 Since the first report on the thermal
rearrangement of 2-phenyl-2H-azirine and 3-methyl-2-
phenyl-2H-azirine to the corresponding indoles,7a this reac-
tion has been extended to a series of substituted 2-aryl-2H-
azirines, making this approach useful for the preparation of
some indoles having substituted benzene rings.7c,d,g The
R2
styryl nitrene
R3
R1
R2
heat
R1
(2)
refs. 7a,c–e,g
N
Ar
R2
N
R2
R3
R1
N
H
R3
R1
N
R2
Ar
R1
MLn
(3)
R2
N
MLn
MLn = Pd(PhCN)2Cl2 (ref. 7b)
MLn = Rh2[OC(O)CF3]4 (ref. 7f)
MLn = FeCl2 (ref. 7h)
styryl nitrene complex
Scheme 1 Different routes for the synthesis of indole derivatives by
isomerization
Nitriles of indole-3-carboxylic acids were prepared in
high yields by heating 2-aryl-2H-azirine-2-carbonitriles at
140 °C in xylene, albeit ethyl 3-benzyl-2-phenyl-2H-azir-
ine-2-carboxylate afforded ethyl 2-benzylindole-3-carbox-
ylate in only 42% yield under the same conditions.7g The
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–O

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V. A. Bodunov et al.
Paper
Synthesis
morpholide of 2-methylindole-3-carboxylic acid was ob-
tained by a FeCl2-catalyzed isomerization of the corre-
sponding azirine in 46% yield7h and by Rh2[OC(O)CF3]4-cata-
lyzed isomerization in 91% yield.7f The above-mentioned
isomerization of azirines to indoles depends strongly on the
nature of the substituents in the substrates and is applica-
ble mostly to reactive 3-alkyl-substituted 2H-azirines. This,
along with the limited availability and low stability of some
functionalized azirines, necessitates the search for new pre-
cursors and catalysts for the generation of styryl nitrenes
and their metal complexes.
nitriles gave the corresponding 1H-indole-3-carbonitriles
already at 140 °C. Heating isoxazole 1a in 1,4-dioxane with-
out catalyst at 170 °C for 20 hours afforded only azirine 4a.
Further experiments, therefore, were performed in the
presence iron(II) catalysts.
Table 1 Optimization of Reaction Conditionsa
CO2Me
Ph
Ph
Ph
Fe(II)
T1
Fe(II)
T2
N
N
MeO
N
O
H
MeO
O
In a search for more effective approaches to indole-3-
carboxylates based on nitrenoid-mediated reactions, we
turned our attention to 5-alkoxy-4-arylisoxazoles, which
can be considered, when using an isoxazole–azirine isom-
erization,8a as synthetic equivalents of difficult-to-access 2-
aryl-2H-azirine-2-carboxylates. It was previously found
that this isomerization is catalyzed by iron(II) com-
pounds,6,8 which, in turn, can promote isomerization of
azirine to indole. Taking into account these prerequisites
and especially the relatively low toxicity of many iron spe-
cies, which is of importance for applications in industry re-
lated to healthcare and medicine,9 we decided to search for
conditions for the implementation of a direct domino
transformation of isoxazoles into indole-3-carboxylates
within the green chemistry framework. We expected that
the generation of a nitrene complex 2 from isoxazole, rather
than azirine, can prevent some of the secondary processes
characteristic for non-complexed azirine-2-carboxylates.
This should improve the efficacy of the cyclization of styryl
nitrene complexes, leading to indoles and allow the use of
higher temperatures, which are necessary for the prepara-
tion of 2-arylindole-3-carboxylates, inaccessible until now
from the corresponding azirines6,7 (Scheme 2).
1a
4a
3a
Entry Catalyst
Solvent
Conditions
Yield of
3a (%)
1
2
FeCl2
THF
THF
25 °C, 15 h; 70 °C, 30 h
25 °C, 15 h; 70 °C, 30 h
110 °C, 7 h; 140 °C, 11 h
200 °C, 0.5 h
traces
traces
28
Fe(NTf2)2
Fe(NTf2)2
Fe(NTf2)2
FeCl2
3
o-Cl2C6H4
4
o-Cl2C6H4
1,4-dioxane
1,4-dioxane
neat
40b
50
5
170 °C, 7 h
6
Fe(NTf2)2
Fe(NTf2)2
Fe(NTf2)2
Fe(NTf2)2
FeCl2
170 °C, 7 h
54
7
200 °C, 3 min
13
8
neat
200 °C, 10 min
19
9
neat
200 °C, 1 h
12
10
11
DMSO
25 °C, 15 h; 165 °C, 5 h
170 °C, 5 h
65
FeCl2
DMSO
77b
a Reaction conditions: 1a (0.2 mmol), cat. (20 mol%), solvent (2 mL), heat
(indicated temperature), time (as shown), screw-capped thick-walled test
tube; then reaction mixture cooled down, passed through a short silica
pad; reaction progress followed by 1H NMR spectroscopy (1,1,2,2-tetrabro-
moethane as internal standard).
b Isolated yields.
When isoxazole 1a was stirred at room temperature in
the presence of FeCl2 or Fe(NTf2)2 for the transformation
into methyl 2,3-diphenyl-2H-azirine-2-carboxylate 4a and
was further heated at 70 °C in THF (the conditions used for
the transformation of 3-alkyl-2H-azirines into indoles7h),
only traces of indole 3a were detected by NMR analysis (Ta-
ble 1, entries 1 and 2). Increasing the temperature and us-
ing o-Cl2C6H4 or 1,4-dioxane as solvent improved the yield
to 54% (entries 3–6). Using solvent-free conditions was un-
successful, presumably due to decomposition of the prod-
uct under prolonged heating (entries 7–9). The reaction
carried out in DMSO under a dual temperature regime (en-
try 10) gave 3a in 65% yield. Finally, the domino reaction of
1a in the presence of FeCl2 in DMSO at 170 °C for 5 hours
gave 3a in 77% isolated yield (entry 11). Moreover, FeCl2·4H2O
proved to be as effective as anhydrous FeCl2.
RO
RO
O
O
RO
R1
Fe(II)Ln
O
N
R1
– Fe(II)Ln
N
N
H
R1
FeLn
3
1
2
Scheme 2 Route for the synthesis of indole derivatives by isomeriza-
tion of isoxazoles
In order to find the optimal reaction conditions, we
studied the model transformation of 5-methoxy-3,4-di-
phenylisoxazole (1a) and azirine 4a into methyl 2-
phenylindole-3-carboxylate (3a) without any catalyst and
with typical iron(II) catalysts, FeCl2 and Fe(NTf2)2,8 in differ-
ent solvents and at various temperatures (Table 1). To start,
azirine 4a, prepared by FeCl2·4H2O-catalyzed isomerization
of isoxazole 1a, was heated in xylene. However, even heat-
ing at 180 °C for 15 hours without catalyst led to the forma-
tion of only traces of 3a according to NMR analysis, al-
though in other work7g heating 2-aryl-2H-azirine-2-carbo-
The latter conditions were used for the preparation of a
series of indoles 3a–u from isoxazoles 1a–u (Scheme 3).
The structures of the isolated products were confirmed by
standard spectroscopic methods. The reactions of 5-me-
thoxy-4-phenylisoxazoles bearing 3-phenyl groups with
donor or acceptor substituents afforded the corresponding
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–O

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V. A. Bodunov et al.
Paper
Synthesis
methyl 2-arylindole carboxylates in 62–93% yield. The 3-(2-
naphthyl)-substituted isoxazole 1f gave only 40% yield of
indole 3f, whereas the less bulky 3-(2-benzothienyl)-sub-
stituted isoxazole 1g gave 89% yield of indole 3g. 3-Alkyl-
substituted isoxazoles 1h,i afforded indoles 3h,i in excellent
yields. The reaction of 5-methoxy-3-phenylisoxazoles with
4-(p-RC6H4) groups with R as halogen or MeO substituents
afforded the corresponding 6-substituted methyl 2-
phenylindole carboxylates 3j,l,m,n in 80–94% yield, where-
as the NO2 substituent lowered the yield of indole 3o to
39%.
The reaction of 5-methoxy-3-phenylisoxazoles with 4-
(m-NO2C6H4) and 4-(m-BrC6H4) substituents led selectively
to the corresponding 5-substituted methyl 2-phenylindole
carboxylates 3q and 3p in 62% and 71% yield, respectively
(Scheme 3). 5-Methoxy-4-(2-methoxyphenyl)-3-phenyli-
soxazole gave 4-substituted methyl 2-phenylindole 3r in
only 31% yield, most likely due to steric congestion in the
transition state of the cyclization of the corresponding com-
plex 2. 5-Methoxy-4-(1/2-naphthyl)-3-(4-tolyl)isoxazoles
1t,s react selectively, affording methyl 2-phenyl-3H-ben-
zo[e]indole-1-carboxylate 3t and methyl 2-phenyl-1H-ben-
zo[g]indole-3-carboxylate 3s in excellent yields. 5-Aminoi-
soxazoles are also suitable for the transformation into the
corresponding indoles, e.g. isoxazole 1u gave pyrrolidide of
2-phenylindole-3-carboxylic acid 3u in 74% yield. All these
results demonstrate that the method can be used for the se-
lective synthesis of various 2/4/5/6-substituted indole-3-
carboxylates and the benzo[e]- and -[g]- derivatives.
To verify the applicability of the method for the prepa-
ration of hetero analogues of indolecarboxylates, 4-(2-thie-
nyl)-substituted isoxazole 1v was treated with FeCl2 under
the standard reaction conditions to give methyl 5-phenyl-
4H-thieno[3,2-b]pyrrole-6-carboxylate (3v) in good yield
(Scheme 4).
O
R'
R
OMe
.
FeCl2 or FeCl2 4H2O (~20 mol%)
R
N
DMSO, 170 °C, 5 h
O
R'
N
H
MeO
1a–u
3a–u
CO2Me
CO2Me
CO2Me
CO2Me
OMe
Me
Cl
N
N
N
H
N
H
H
H
3a 77%
3b 62%
3c 85%
3d 84%
CO2Me
Me
CO2Me
CO2Me
CO2Me
CO2Me
Et
NO2
N
H
N
H
N
S
N
H
N
H
H
3e 93%
3f 40%
3g 89%
3h 89%
3i 86%
CO2Me
CO2Me
CO2Me
CO2Me
N
N
N
N
H
MeO
Me
F
Cl
H
H
H
3l 82%
O
3j 94%
3k 77%
CO2Me
3m 80%
O
CO2Me
OMe
OMe
Br
O2N
Me
N
H
N
H
Br
O2N
N
H
N
H
3n 80%
3o 39%
3p 71%
3q 62%
O
O
O
OMe
OMe
OMe
OMe
N
O
Me
N
N
N
H
H
H
N
H
3r 31%
3s 95%
3t 82%
3u 74%
Scheme 3 Reaction scope
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–O

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V. A. Bodunov et al.
Paper
Synthesis
portant features, including operational simplicity, high
atom-efficiency, and the use of stable starting materials, a
green solvent, and an inexpensive and low-toxicity catalyst.
The methodology is applicable to the preparation of benzo-
fused and hetero analogues of indole-3-carboxylates.
O
S
OMe
.
FeCl2 4H2O (20 mol%)
S
MeO
N
DMSO, 170 °C, 5 h
O
N
H
3v 73%
1v
Scheme 4 Synthesis of hetero analogue 3v
Melting points were determined on a Stuart SMP30 capillary melting
point apparatus. 1H (400 MHz) and 13C (100 MHz) NMR spectra of CD-
Cl3 or DMSO-d6 solutions were recorded with a Bruker AVANCE III 400
spectrometer. Chemical shifts (δ) are reported in ppm downfield from
On the basis of the obtained results and previous calcu-
lations,8c,d,10 we propose the plausible reaction pathway for
the iron(II)-catalyzed domino isomerization of isoxazoles to
indoles as shown in Scheme 5. The mechanism includes the
following steps: (a) the formation of the isoxazole–Fe com-
plex B, (b) opening of the isoxazole ring of the Fe–isoxazole
complex B via an N–O bond cleavage to form the Fe–nitrene
complex C having an inappropriate configuration for 1,5-
cyclization on the benzene ring, (c) the recyclization of Fe–
nitrene complex C into the Fe–azirine complex D, which,
according to calculated data,8c,d should occur via a low acti-
vation barrier, (d) low-energy conformational transforma-
tions in D followed by opening of the three-membered ring
leading to the Fe–nitrene complex E with a configuration
providing the possibility of 1,5-cyclization, (e) 1,5-cycliza-
tion giving the Fe complex of 7aH-indole F, and (f) and (g)
solvent-assisted10 H-shift and cleavage of the catalyst to
give the final product, indole H.
1
TMS (δ = 0.00). H NMR spectra were calibrated according to the re-
sidual peak of CHCl3 (δ = 7.26) or DMSO-d6 (δ = 2.50). 13C{1H} and 13
C
DEPT135 were calibrated according to the peak of CDCl3 (δ = 77.00) or
DMSO-d6 (δ = 39.51). Mass spectra were recorded on a Bruker maXis
HRMS-ESI-QTOF, electrospray ionization, positive mode. Thin-layer
chromatography (TLC) was conducted on aluminum sheets with 0.2
mm silica gel (fluorescent indicator, Macherey-Nagel) and Macherey-
Nagel Silica 60 M was used for column chromatography. THF was dis-
tilled from sodium benzophenone-ketyl under argon atmosphere be-
fore use. Dimethyl sulfoxide was distilled from calcium hydride under
reduced pressure.
Synthesis of Starting Materials
3-Substituted 4-Aryl-5-hydroxyisoxazoles/4-Arylisoxazol-5(4H)-
ones 6; General Procedure A (Scheme 6)
N
R'
O
O
R'
CO2R
H2NOH.HCl
MeOH
R'COCl
Ar
O
d
FeLn
R
O
R
Ar
HMDS, n-BuLi,
–78 °C, THF
e
N
N
Ar
CO2R
R'
N
OMe
MeO
O
LnFe
5
MeO2C
Ar
O
D
c
Ar
E
HO
6
LnFe
R
N
O
Scheme 6 Synthesis of 3-substituted 4-aryl-5-hydroxyisoxazoles/4-
arylisoxazol-5(4H)-ones 6
R
N
OMe
F
H
LnFe
Ar
f
C
b
O
A solution of 2.5 M n-BuLi in hexane (1.2 equiv) was added dropwise
to a solution of HMDS (1.2 equiv) in anhyd THF at –78 °C under argon,
and then, after stirring of the mixture for 10 min, a solution of alkyl 2-
arylacetate (1 equiv) in THF was added in one portion. The mixture
was stirred for 10 min, after which a solution of acyl chloride (1.15
equiv) in THF was added in one portion and the mixture was stirred
for 15 min at –78 °C and then overnight at r.t. The reaction mixture
was quenched with sat. aq NH4Cl, extracted with EtOAc or Et2O, and
the organic layer was washed with brine and dried over Na2SO4. The
solvents were evaporated to give 3-substituted alkyl 2-aryl-3-oxopro-
panoate 5, which was used without further purification.
FeLn
OMe
R
FeLn
g
N
O
LnFe
a
N
R
H
MeO2C
R
N
O
Ar
OMe
G
B
R
OMe
A
H
N
Ar
H
Scheme 5 Plausible reaction mechanism
NH2OH·HCl (2–5 equiv) was added to a solution of 5 in MeOH and the
mixture was refluxed for 24 h. The solvent was evaporated, the resi-
due was treated with H2O, and the precipitate that formed was fil-
tered, washed with H2O and a mixture of PE/EtOAc (10:1), and then
dried in air to give pure 3-substituted 4-aryl-5-hydroxyisoxazole/4-
arylisoxazol-5(4H)-one 6. The yields of 6 were calculated for the two
steps, and is based on the starting alkyl 2-arylacetate.
In summary, a selective, simple, and effective synthesis
of highly substituted 2-alkyl/aryl-indole-3-carboxylates
based on the isoxazole–azirine-indole domino isomeriza-
tion under FeCl2 catalysis has been described. This double
ring-opening–ring-closure strategy nicely complements ex-
isting methods based on the rearrangement of azirines to
indoles. The reported method is endowed with several im-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–O

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V. A. Bodunov et al.
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Synthesis
3,4-Diphenylisoxazol-5-ol/3,4-Diphenylisoxazol-5(4H)-one (6a)
Yield: 1.43 g (86%); colorless solid; mp 162–163 °C (MeOH).
1H NMR (400 MHz, DMSO-d6): δ = 2.35 (s, 3 H), 7.20–7.39 (m, 9 H),
12.67 (br s, 1 H).
Methyl Propanoate 5a
13C NMR (100 MHz, DMSO-d6): δ = 21.0 (CH3), 124.7 (C), 126.5 (CH),
127.8 (CH), 128.1 (CH), 128.3 (CH), 129.6 (CH), 130.2 (C), 140.9 (C),
160.4 (C), 170.6 (C).
Pale yellow oil, yield 1.88 g, was prepared from HMDS (1.29 g, 8.0
mmol) in THF (5 mL), n-BuLi (3.2 mL, 8.0 mmol), methyl 2-phenylace-
tate (1.00 g, 6.7 mmol) in THF (5 mL), and benzoyl chloride (1.08 g, 7.7
mmol) in THF (5 mL).
HRMS-ESI: m/z [M + Na]+ calcd for C16H13NNaO2+: 274.0838; found:
274.0842.
Isoxazol-5-ol 6a
Isoxazol-5-ol 6a was prepared from compound 5a (1.88 g) and
NH2OH·HCl (2.32 g, 33.5 mmol) in MeOH (40 mL).
Yield: 1.21 g (76%); colorless solid; mp 147–148 °C (MeOH) [Lit.11 157
°C (CHCl3)].
1H NMR (400 MHz, DMSO-d6): δ = 7.21–7.25 (m, 1 H), 7.28–7.33 (m, 4
3-(4-Chlorophenyl)-4-phenylisoxazol-5-ol/3-(4-Chlorophenyl)-4-
phenylisoxazol-5(4H)-one (6d)
Methyl Propanoate 5d
Pale green oil, yield 2.05 g, was prepared from HMDS (1.30 g, 8 mmol)
in THF (5 mL), n-BuLi (3.2 mL, 8 mmol), methyl 2-phenylacetate (1.00
g, 6.7 mmol) in THF (5 mL), and 4-chlorobenzoyl chloride (1.35 mg,
7.7 mmol) in THF (5 mL).
H), 7.44–7.50 (m, 4 H), 7.52–7.56 (m, 1 H), 12.83 (br s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 126.7 (CH), 127.5 (C), 127.9 (CH),
128.2 (CH), 128.3 (CH), 129.0 (CH), 129.8 (C), 131.0 (CH), 160.4 (C),
170.3 (C).
Isoxazol-5-ol 6d
HRMS-ESI: m/z [M + Na]+ calcd for C15Н11NNaO2+: 292.0744; found:
Compound 6d was prepared from compound 5d (2.05 g) and
292.0744.
NH2OH·HCl (2.09 g, 30 mmol) in MeOH (13 mL).
3-(4-Methoxyphenyl)-4-phenylisoxazol-5-ol/3-(4-Methoxyphe-
nyl)-4-phenylisoxazol-5(4H)-one (6b)
Yield: 1.41 g (78%); colorless solid; mp 141–142 °C (MeOH) [Lit.11 154
°C (CHCl3)].
1H NMR (400 MHz, DMSO-d6): δ = 7.20–7.39 (m, 5 H), 7.46 (d, J = 8.4
Hz, 2 H), 7.56 (d, J = 8.4 Hz, 2 H), 12.66 (br s, 1 H).
Methyl Propanoate 5b
13C NMR (100 MHz, DMSO-d6): δ = 126.6 (C), 126.8 (CH), 128.3 (CH),
128.4 (CH), 129.2 (CH), 129.6 (C), 129.8 (CH), 135.7 (C), 159.4 (C),
170.3 (C).
Red semi-solid, yield 1.98 g, was prepared from HMDS (1.29 g, 8.0
mmol) in THF (5 mL), n-BuLi (3.2 mL, 8 mmol), methyl 2-phenylace-
tate (1.00 g, 6.7 mmol) in THF (5 mL), and 4-methoxybenzoyl chloride
(1.31 g, 7.7 mmol) in THF (5 mL).
HRMS-ESI: m/z [M + Na]+ calcd for C15H1035ClNNaO2+: 294.0292;
found: 294.0295.
Isoxazol-5-ol 6b
Isoxazol-5-ol 6b was prepared from compound 5b (1.98 g) and
NH2OH·HCl (2.32 g, 33.5 mmol) in MeOH (13 mL).
3-(4-Nitrophenyl)-4-phenylisoxazol-5-ol/3-(4-Nitrophenyl)-4-
phenyl-5(4H)-one (6e)
Yield: 1.44 g (81%); yellowish solid; mp 147–148 °C (MeOH).
1H NMR (400 MHz, DMSO-d6): δ = 3.80 (s, 3 H), 7.03 (d, J = 8.8 Hz, 2
H), 7.22 – 7.28 (m, 1 H), 7.29 – 7.36 (m, 4 H), 7.39 (d, J = 8.8 Hz, 2 H),
12.68 (br s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 55.4 (CH3), 114.5 (CH), 119.3 (C),
126.7 (CH), 128.3 (CH), 128.3 (CH), 129.4 (CH), 130.1 (C), 160.2 (C),
161.3 (C), 170.5 (C).
Methyl Propanoate 5e
Yellowish solid, yield 2.00 g, was prepared from HMDS (1.16 g, 7.2
mmol) in THF (9 mL), n-BuLi (2.9 mL, 7.2 mmol), methyl 2-phenylace-
tate (901 mg, 6.0 mmol) in THF (11 mL), and 4-nitrobenzoyl chloride
(1.28 g, 6.9 mmol) in THF (10 mL).
Isoxazol-5-ol 6e
HRMS-ESI: m/z [M + Na]+ calcd for C16H13NNaO3+: 290.0788; found:
Compound 6e was prepared from compound 5e (2.00 g) and
290.0792.
NH2OH·HCl (1.05 g, 15.2 mmol) in MeOH (12 mL).
4-Phenyl-3-p-tolylisoxazol-5-ol/4-Phenyl-3-p-tolylisoxazol-5(4H)-
one (6c)
Yield: 1.35 g (82%); colorless solid; mp 154–155 °C (MeOH) [Lit.11 159
°C (CHCl3)].
1H NMR (400 MHz, DMSO-d6): δ = 7.24–7.28 (m, 3 H), 7.31–7.35 (m, 2
H), 7.69–7.72 (m, 2 H), 8.31 (d, J = 8.8 Hz, 2 H).
Methyl Propanoate 5c
13C NMR (100 MHz, DMSO-d6): δ = 95.8 (C), 124.1 (CH), 126.9 (CH),
128.4 (CH), 128.5 (CH), 129.3 (C), 129.5 (CH), 134.5 (C), 148.5 (C),
159.0 (C), 170.3 (C).
Colorless solid, yield 1.96 g, was prepared from HMDS (1.29 g, 8.0
mmol) in THF (8 mL), n-BuLi (3.2 mL, 8.0 mmol), methyl 2-phenylace-
tate (1.00 g, 6.7 mmol) in THF (10 mL) and 4-methylbenzoyl chloride
(1.18 g, 7.7 mmol) in THF (8 mL).
HRMS-ESI: m/z [M + Na]+ calcd for C15H10N2NaO4+: 305.0533; found:
305.0529.
Isoxazol-5-ol 6c
Compound 6c was prepared from compound 5c (1.96 g) and
NH2OH·HCl (1.35 g, 19.4 mmol) in MeOH (13 mL).
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Synthesis
3-(2-Naphthyl)-4-phenylisoxazol-5-ol/3-(2-Naphthyl)-4-phenyli-
soxazol-5(4H)-one (6f)
13C NMR (100 MHz, DMSO-d6): δ = 122.6 (СH), 124.7 (CH), 125.1 (CH),
125.9 (CH), 126.2 (CH), 127.6 (CH), 128.5 (CH), 129.1 (C), 129.4 (CH),
138.5 (C), 139.7 (C), 155.5 (C), 170.5 (C).
HRMS-ESI: m/z [M + H]+ calcd for C17H12NO2S+: 294.0583; found:
Methyl Propanoate 5f
294.0594.
Colorless solid, yield 1.80 g, was prepared from HMDS (1.07 g, 6.6
mmol) in THF (8 mL), n-BuLi (2.6 mL, 6.6 mmol), methyl phenylace-
tate (826 mg, 5.5 mmol) in THF (9 mL), and 2-naphthoyl chloride
(1.21 g, 6.3 mmol) in THF (13 mL).
3-Methyl-4-phenylisoxazol-5-ol/3-Methyl-4-phenylisoxazol-
5(4H)-one (6h)
Isoxazol-5-ol 6f
Methyl Propanoate 5h
Compound 6f was prepared from compound 5f (1.80 g) and
NH2OH·HCl (1.81 g, 26.0 mmol) in EtOH (20 mL) for 2 d. After evapo-
ration of MeOH and addition of H2O, the product was extracted with
Et2O, and the organic layer was washed with H2O and extracted with
5% aq KOH. The aqueous solution was washed with Et2O and acidified
with HCl. The precipitate was collected by filtration, washed with
H2O, and dried in air to give pure product.
Colorless oil, yield 1.50 g, was prepared from HMDS (1.29 g, 8.0
mmol) in THF (5 mL), n-BuLi (3.2 mL, 8 mmol), methyl 2-phenylace-
tate (1.00 g, 6.7 mmol) in THF (5 mL), and acetyl chloride (604 mg, 7.7
mmol) in THF (5 mL).
Isoxazol-5-ol 6h
Compound 6h was prepared from compound 5h (1.50 g) and
NH2OH·HCl (2.32 g, 33.5 mmol) in MeOH (15 mL). After evaporation
of MeOH and addition of H2O, the product was extracted with Et2O,
and the organic layer was washed with H2O and extracted with 5% aq
KOH. The aqueous solution was washed with Et2O and acidified with
HCl. The precipitate was filtered, washed with H2O, and dried in air to
give pure product.
Yield: 1.27g (80%); gray solid; mp 159–160 °C (H2O).
1H NMR (400 MHz, DMSO-d6): δ = 7.22–7.34 (m, 5 H), 7.41–7.43 (m, 1
H), 7.58–7.65 (m, 2 H), 7.97–7.99 (m, 3 H), 8.16 (s, 1 H), 13.00 (br s, 1
H).
13C NMR (100 MHz, DMSO-d6): δ = 96.8 (br s, C), 124.7 (CH), 125.0 (br
s, C), 126.7 (CH), 127.1 (CH), 127.76 (CH), 127.82 (CH), 127.9 (CH),
128.1 (CH), 128.3 (CH), 128.5 (CH), 128.6 (CH), 129.9 (C), 132.4 (C),
133.7 (C), 160.5 (C), 170.4 (C).
Yield: 552 mg (47%); yellowish solid; mp 106–107 °C (H2O).
1H NMR (400 MHz, DMSO-d6): δ = 2.31 (s, 3 H), 7.21–7.25 (m, 1 H),
7.36–7.40 (m, 2 H), 7.53–7.56 (m, 2 H), 11.78 (br s, 1 H).
HRMS-ESI: m/z [M + H]+ calcd for C19H14NO2+: 288.1019; found:
13C NMR (100 MHz, DMSO-d6): δ = 12.0 (CH3), 95.4 (C), 125.9 (CH),
288.1006.
126.8 (CH), 128.3 (CH), 130.8 (C), 159.4 (C), 170.1 (C).
3-(Benzo[b]thiophen-2-yl)-4-phenylisoxazol-5-ol/3-(Ben-
zo[b]thiophen-2-yl)-4-phenylisoxazol-5(4H)-one (6g)
HRMS-ESI: m/z [M + H]+ calcd for C10H9NO2+: 176.0706; found:
176.0714.
Methyl Propanoate 5g
3-Ethyl-4-phenylisoxazol-5-ol/3-Ethyl-4-phenylisoxazol-5(4H)-
Compound 5g was prepared from HMDS (1.16 g, 7.2 mmol) in THF
(10 mL), n-BuLi (2.9 mL, 7.2 mmol), methyl 2-phenylacetate (901 mg,
6.0 mmol) in THF (8 mL), and benzo[b]thiophene-2-carbonyl chloride
(1.36 g, 6.9 mmol) in THF (10 mL). Compound 5g was recrystallized
from MeOH.
one (6i)
Methyl Propanoate 5i
Red oil, yield 1.57 g, was prepared from HMDS (1.29 g, 8.0 mmol) in
THF (5 mL), n-BuLi (3.2 mL, 8 mmol), methyl 2-phenylacetate (1.00 g,
6.7 mmol) in THF (5 mL), and propionic anhydride (1.00 g, 7.7 mmol)
in THF (5 mL).
Yield 1.57 g (84%); colorless solid; mp 150–151 °C (MeOH).
1H NMR (400 MHz, DMSO-d6): δ = 3.70 (s, 3 H), 6.23 (s, 1 H), 7.32–
7.55 (m, 7 H), 8.02–8.06 (m, 2 H), 8.57 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 52.6 (CH3), 58.9 (CH), 123.2 (CH),
125.5 (CH), 126.6 (CH), 128.0 (CH), 128.3 (CH), 128.6 (CH), 129.5 (CH),
132.6 (CH), 133.2 (C), 138.8 (C), 141.6 (C), 142.0 (C), 168.8 (C), 188.4
(C).
HRMS-ESI: m/z [M + Na]+ calcd for C18H14NaO3S+: 333.0556; found:
333.0561.
Isoxazol-5-ol 6i
Compound 6i was prepared from compound 5i (1.57 g) and
NH2OH·HCl (2.32 g, 33.5 mmol) in MeOH (15 mL). After evaporation
of MeOH and addition of H2O, the product was extracted with Et2O,
and the organic layer was washed with H2O and extracted with 5% aq
KOH. The aqueous solution was washed with Et2O and acidified with
HCl. The precipitate was collected by filtration, washed with H2O, and
dried in air to give pure product.
Isoxazol-5-ol 6g
Yield: 728 mg (58%); light rose solid; mp 96–97 °C (H2O).
Compound 6g was prepared from compound 5g (1.35 g, 4.4 mmol)
and NH2OH·HCl (1.41 g, 20.3 mmol) in EtOH (26 mL) under reflux for
3 d.
1H NMR (400 MHz, DMSO-d6): δ = 1.15 (q, J = 7.6 Hz, 3 H), 2.73 (t, J =
7.6 Hz, 2 H), 7.26–7.27 (m, 1 H), 7.37–7.41 (m, 2 H), 7.48–7.50 (m, 2
H), 12.77 (br s, 1 H).
Yield: 986 mg (77%, 65% over two steps); yellowish solid; mp 138–
139 °C (EtOH).
13C NMR (100 MHz, DMSO-d6): δ = 11.1 (CH3), 19.2 (CH2), 126.2 (CH),
127.3 (CH), 128.4 (CH), 130.5 (C), 163.9 (C), 170.0 (C).
HRMS-ESI: m/z [M + Na]+ calcd for C11H11NNaO2+: 212.0682; found:
1H NMR (400 MHz, DMSO-d6): δ = 7.34–7.46 (m, 7 H), 7.66 (s, 1 H),
7.89–7.91 (m, 1 H), 8.00–8.02 (m, 1 H).
212.0691.
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Synthesis
4-(4-Methoxyphenyl)-3-phenylisoxazol-5-ol/4-(4-Methoxyphe-
nyl)-3-phenylisoxazol-5(4H)-one (6j)
13C NMR (100 MHz, DMSO-d6): δ = 115.3 (d, J = 21.5 Hz, CH), 126.2 (d,
J = 3.2 Hz, C), 127.4 (C), 127.9 (CH), 129.1 (CH), 130.1 (d, J = 8.1 Hz,
CH), 131.0 (CH), 160.3 (C), 160.9 (d, J = 244 Hz, C), 170.3 (C).
HRMS-ESI: m/z [M + Na]+ calcd for C15H10FNNaO2+: 278.0588; found:
Methyl Propanoate 5j
278.0600.
Pale yellow oil, yield 880 mg, was prepared from HMDS (549 mg, 3.4
mmol) in THF (5 mL), n-BuLi (1.4 mL, 3.4 mmol), methyl 2-(4-me-
thoxyphenyl)acetate (500 mg, 2.8 mmol) in THF (5 mL), and benzoyl
chloride (450 mg, 3.2 mmol) in THF (5 mL).
4-(4-Chlorophenyl)-3-phenylisoxazol-5-ol/4-(4-Chlorophenyl)-3-
phenylisoxazol-5(4H)-one (6m)
Isoxazol-5-ol 6j
Methyl Propanoate 5m
Compound 6j was prepared from compound 5j (880 mg) and
NH2OH·HCl (970 mg, 14.0 mmol) in MeOH (20 mL).
Colorless oily solid, yield 1.19 g, was prepared from HMDS (775 mg,
4.8 mmol) in THF (5 mL), n-BuLi (2.4 mL, 4.8 mmol), methyl 2-(4-
chlorophenyl)acetate (750 mg, 4.0 mmol) in THF (4 mL), and benzoyl
chloride (650 mg, 4.6 mmol) in THF (3 mL).
Yield: 530 mg (71%); light yellow solid; 151–152 °C (MeOH).
1H NMR (400 MHz, DMSO-d6): δ = 3.74 (s, 3 H), 6.89 (d, J = 8.7 Hz, 2
H), 7.21 (d, J = 8.7 Hz, 2 H), 12.7 (br s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 55.0 (CH3), 113.9 (CH), 121.8 (C),
127.7 (C), 127.8 (CH), 129.0 (CH), 129.5 (CH), 130.9 (CH), 158.1 (C),
160.0 (C), 170.6 (C).
Isoxazol-5-ol 6m
Compound 6m was prepared from compound 5m (1190 mg) and
NH2OH·HCl (1390 mg, 20.0 mmol) in MeOH (30 mL).
Yield: 760 mg (70%); colorless solid; mp 157–158 °C (MeOH) [Lit.11
159 °C (CHCl3)].
1H NMR (400 MHz, DMSO-d6): δ = 7.29–7.31 (m, 2 H), 7.36–7.38 (m, 2
HRMS-ESI: m/z [M + Na]+ calcd for C16H13NNaO3+: 290.0788; found:
290.0786.
H), 7.45–7.58 (m, 5 H), 12.80 (br s, 1 H).
3-Phenyl-4-p-tolylisoxazol-5-ol/3-Phenyl-4-p-tolylisoxazol-5(4H)-
one (6k)
13C NMR (100 MHz, DMSO-d6): δ = 94.9 (C), 127.3 (C), 128.0 (CH),
128.4 (CH), 128.9 (C), 129.2 (CH), 129.6 (CH), 131.1 (CH), 160.4 (C),
170.1 (C).
HRMS-ESI: m/z [M + Na]+ calcd for C15H1035ClNNaO2+: 294.0292;
found: 294.0298.
Methyl Propanoate 5k
Colorless oily solid, yield 2.72 g, was prepared from HMDS (1.89 g,
11.7 mmol) in THF (10 mL), n-BuLi (4.7 mL, 11.7 mmol), methyl 2-(4-
methylphenyl)acetate (1.46 g, 9.8 mmol) in THF (12 mL), and benzoyl
chloride (1.58 g, 11.2 mmol) in THF (9 mL).
4-(4-Bromophenyl)-3-phenylisoxazol-5-ol/4-(4-Bromophenyl)-3-
phenylisoxazol-5(4H)-one (6n)
Isoxazol-5-ol 6k
Methyl Propanoate 5n
Compound 6k was prepared from compound 5k (2.72 g) and
NH2OH·HCl (1.51 g, 21.7 mmol) in MeOH (13 mL).
Light yellow oil, yield 2.45 g, was prepared from HMDS (1.34 g, 8.3
mmol) in THF (10 mL), n-BuLi (3.3 mL, 8.3 mmol), methyl 2-(4-bro-
mophenyl)acetate (1.59 g, 6.9 mmol) in THF (14 mL), and benzoyl
chloride (1.12 g, 8.0 mmol) in THF (11 mL).
Yield: 1.69 mg (69%); colorless solid; mp 173–174 °C (MeOH).
1H NMR (400 MHz, DMSO-d6): δ = 2.28 (s, 3 H), 7.12 (d, J = 8.1 Hz, 2
H), 7.18 (d, J = 8.1 Hz, 2 H), 7.43–7.55 (m, 5 H), 12.78 (br s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 20.7 (CH3), 126.8 (C), 127.6 (C),
127.9 (CH), 128.1 (CH), 128.9 (CH), 129.0 (CH), 130.9 (CH), 136.0 (C),
160.3 (C), 170.5 (C).
HRMS-ESI: m/z [M + Na]+ calcd for C16H13NNaO2+: 274.0838; found:
274.0842.
Isoxazol-5-ol 6n
Compound 6n was prepared from compound 5n (2.45 g) and
NH2OH·HCl (1.66 g, 23.9 mmol) in MeOH (15 mL).
Yield: 1.75 g (80%); colorless solid; mp 157–158 °C (MeOH).
1H NMR (400 MHz, DMSO-d6): δ = 7.22–7.26 (m, 2 H), 7.45–7.58 (m, 7
H), 12.85 (br s, 1 H).
4-(4-Fluorophenyl)-3-phenylisoxazol-5-ol/4-(4-Fluorophenyl)-3-
phenylisoxazol-5(4H)-one (6l)
13C NMR (100 MHz, DMSO-d6): δ = 94.9 (C), 119.6 (C), 127.3 (C), 128.0
(CH), 129.2 (CH), 129.3 (C), 129.9 (CH), 131.1 (CH), 131.3 (CH), 160.4
(C), 170.0 (C).
HRMS-ESI: m/z [M + Na]+ calcd for C15H1079BrNNaO2+: 337.9787;
found: 337.9802.
Methyl Propanoate 5l
Colorless oily solid, yield 1.32 g, was prepared from HMDS (872 mg,
5.4 mmol) in THF (5 mL), n-BuLi (2.7 mL, 5.4 mmol), methyl 2-(4-flu-
orophenyl)acetate (750 mg, 4.5 mmol) in THF (5 mL), and benzoyl
chloride (730 mg, 5.2 mmol) in THF (3 mL).
4-(4-Nitrophenyl)-3-phenylisoxazol-5-ol/4-(4-Nitrophenyl)-3-
phenylisoxazol-5(4H)-one (6o)
Isoxazol-5-ol 6l
Methyl Propanoate 5o
Compound 6l was prepared from compound 5l (1.32 g) and
NH2OH·HCl (1.56 g, 22.5 mmol) in MeOH (35 mL).
Red oil, yield 790 mg, was prepared from HMDS (500 mg, 3.1 mmol)
in THF (2 mL), n-BuLi (1.2 mL, 3.1 mmol), methyl 2-(4-nitrophe-
nyl)acetate (500 mg, 2.6 mmol) in THF (3 mL), and benzoyl chloride
(420 mg, 3.0 mmol) in THF (2 mL).
Yield: 820 mg (72%); colorless solid; 162–163 °C (MeOH).
1H NMR (400 MHz, DMSO-d6): δ = 7.13–7.18 (m, 2 H), 7.29–7.33 (m, 2
H), 7.44–7.55 (m, 5 H), 12.89 (br s, 1 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–O

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V. A. Bodunov et al.
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Synthesis
Isoxazol-5-ol 6o
4-(2-Methoxyphenyl)-3-phenylisoxazol-5-ol/4-(2-Methoxyphe-
nyl)-3-phenyl-5(4H)-one (6r)
Compound 6o was prepared from compound 5o (790 mg) and
NH2OH·HCl (900 mg, 13.0 mmol) in MeOH (20 mL).
Methyl Propanoate 5r
Yield: 520 mg (70%); yellow solid; 184–185 °C (MeOH).
Brown oil, yield 550 mg, was prepared from HMDS (322 mg, 2 mmol)
in THF (2 mL), n-BuLi (0.8 mL, 2 mmol), methyl 2-(2-methoxyphe-
nyl)acetate (300 mg, 1.7 mmol) in THF (3 mL), and benzoyl chloride
(270 mg, 1.9 mmol) in THF (2 mL).
1H NMR (400 MHz, DMSO-d6): δ = 7.49–7.62 (m, 7 H), 8.12 (d, J = 8.9
Hz, 2 H), 12.17 (br s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 92.5 (C), 123.6 (CH), 127.3 (CH),
127.4, 128.2 (CH), 129.3 (CH), 131.2 (CH), 138.3, 144.7, 160.7, 169.9.
HRMS-ESI: m/z [M + Na]+ calcd for C15H10N2NaO4+: 305.0533; found:
305.0544.
Isoxazol-5-ol 6r
Compound 6r was prepared from compound 5r (550 mg) and
NH2OH·HCl (590 mg, 8.5 mmol) in MeOH (10 mL).
4-(3-Bromophenyl)-3-phenylisoxazol-5-ol/4-(3-Bromophenyl)-3-
phenylisoxazol-5(4H)-one (6p)
Yield: 280 mg (63%); creamy solid; mp 141–142 °C (MeOH).
1H NMR (400 MHz, DMSO-d6): δ = 3.44 (s, 3 H), 6.96–7.01 (m, 2 H),
7.23–7.25 (m, 1 H), 7.31–7.35 (m, 3 H), 7.38–7.42 (m, 2 H), 7.45–7.48
(m, 1 H), 12.69 (br s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 54.9 (CH3), 111.5 (CH), 118.6 (C),
120.4 (CH), 126.6 (CH), 128.7 (CH), 129.3 (CH), 130.7 (CH), 131.6 (CH),
157.0 (C), 161.2 (C), 170.6 (C).
Methyl Propanoate 5p
Light yellow solid, yield 2.46 g, was prepared from HMDS (1.37 g, 8.5
mmol) in THF (10 mL), n-BuLi (3.4 mL, 8.5 mmol), methyl 2-(3-bro-
mophenyl)acetate (1.51 g, 6.6 mmol) in THF (8 mL), and benzoyl chlo-
ride (1.14 g, 8.1 mmol) in THF (8 mL).
HRMS-ESI: m/z [M + Na]+ calcd for C16H13NNaO3+: 290.0788; found:
290.0798.
Isoxazol-5-ol 6p
Compound 6p was prepared from compound 5p (2.46 g) and
NH2OH·HCl (1.51 g, 21.7 mmol) in MeOH (13 mL).
4-(2-Naphthyl)-3-p-tolylisoxazol-5-ol/4-(2-Naphthyl)-3-p-tolyli-
soxazol-5(4H)-one (6s)
Yield: 1.59 g (71%); yellowish solid; mp 142–143 °C (MeOH).
1H NMR (400 MHz, DMSO-d6): δ = 7.22–7.24 (m, 2 H), 7.40–7.41 (m, 1
H), 7.48–7.58 (m, 6 H), 12.07 (br s, 1 H).
Methyl Propanoate 5s
Colorless solid, yield 1.72 g, was prepared from HMDS (947 mg, 5.9
mmol) in THF (8 mL), n-BuLi (2.4 mL, 5.9 mmol), methyl 2-(2-naphth-
yl)acetate (950 mg, 4.8 mmol) in THF (6 mL), and 4-methylbenzoyl
chloride (869 mg, 5.6 mmol) in THF (7 mL).
13C NMR (100 MHz, DMSO-d6): δ = 94.1 (C), 121.6 (C), 126.6 (CH),
127.2 (C), 128.0 (CH), 129.1 (CH), 129.1 (CH), 130.1 (CH), 130.3 (CH),
131.2 (CH), 132.6 (C), 160.5 (C), 170.0 (C).
HRMS-ESI: m/z [M + H]+ calcd for C15H1179BrNO2+: 315.9968; found:
315.9983.
Isoxazol-5-ol 6s
Compound 6s was prepared from compound 5s (1.72 g) and
NH2OH·HCl (1.53 g, 22.0 mmol) in MeOH (20 mL).
4-(3-Nitrophenyl)-3-p-tolylisoxazol-5-ol/4-(3-Nitrophenyl)-3-p-
tolylisoxazol-5(4H)-one (6q)
Yield: 1.10 g (75%); yellowish solid; mp 160–161 °C (MeOH).
1H NMR (400 MHz, DMSO-d6): δ = 2.34 (s, 3 H), 7.27–7.31 (m, 3 H),
7.37–7.39 (m, 2 H), 7.47–7.50 (m, 2 H), 7.79–7.87 (m, 3 H), 7.96 (s, 1
H), 12.90 (br s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 21.0 (CH3), 95.7 (C), 124.9 (C),
125.7 (CH), 126.2 (CH), 126.44 (CH), 126.50 (CH), 127.46 (CH), 127.52
(CH), 127.58 (CH), 127.8 (CH), 128.0 (C), 129.6 (CH), 131.6 (C), 133.0
(C), 141.0 (C), 160.5 (C), 170.8 (C).
Methyl Propanoate 5q
Brown oil, yield 1.43 g, was prepared from HMDS (780 mg, 4.8 mmol)
in THF (6 mL), n-BuLi (1.9 mL, 4.8 mmol), methyl 2-(3-nitrophe-
nyl)acetate (786 mg, 4.0 mmol) in THF (11 mL) and 4-methylbenzoyl
chloride (716 mg, 4.6 mmol) in THF (8 mL).
Isoxazol-5-ol 6q
HRMS-ESI: m/z [M + Na]+ calcd for C20H15NNaO2+: 324.0995; found:
324.1005.
Compound 6q was prepared from compound 5q (1.43 g) and
NH2OH·HCl (996 mg, 14.3 mmol) in MeOH (11 mL).
Yield: 992 mg (83%); yellowish solid; mp 162–163 °C (MeOH).
4-(1-Naphthyl)-3-phenylisoxazol-5-ol/4-(1-Naphthyl)-3-phenyli-
soxazol-5(4H)-one (6t)
1H NMR (400 MHz, DMSO-d6): δ = 2.38 (s, 3 H), 7.34 (d, J = 8.1 Hz, 2
H), 7.40 (d, J = 8.1 Hz, 2 H), 7.54–7.67 (m, 2 H), 8.04–8.06 (m, 1 H),
8.25 (m, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 21.0 (CH3), 92.0 (C), 120.9 (CH),
121.6 (CH), 124.0 (C), 127.9 (CH), 129.7 (CH), 129.9 (CH), 132.3 (C),
133.6 (CH), 141.4 (C), 147.8 (C), 160.5 (C), 170.0 (C).
Methyl Propanoate 5t
Colorless solid, yield 1.52 g, was prepared from HMDS (1.13 g, 7.0
mmol) in THF (6 mL), n-BuLi (2.8 mL, 7.0 mmol), methyl 2-(1-naphth-
yl)acetate (901 mg, 4.6 mmol) in THF (5 mL) and benzoyl chloride
(717 mg, 5.1 mmol) in THF (5 mL).
HRMS-ESI: m/z [M + H]+ calcd for C16H13N2O4+: 297.0870; found:
297.0877.
Isoxazol-5-ol 6t
Compound 6t was prepared from compound 5t (1.52 g) and
NH2OH·HCl (1.38 g, 19.9 mmol) in MeOH (50 mL).
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V. A. Bodunov et al.
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Synthesis
Yield: 926 mg (69%); yellowish solid; mp 158–159 °C (MeOH).
Yield: 370 mg (84%); colorless solid; mp 68–69 °C (PE/EtOAc).
1H NMR (400 MHz, DMSO-d6): δ = 7.28–7.32 (m, 4 H), 7.35–7.46 (m, 3
H), 7.50–7.54 (m, 2 H), 7.71–7.73 (m, 1 H), 7.95–7.98 (m, 2 H), 13.07
(br s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 125.1 (CH), 125.7 (CH), 126.0 (CH),
126.3 (CH), 127.2 (CH), 127.4 (C), 128.3 (CH), 128.4 (CH), 128.8 (CH),
129.3 (CH), 130.9 (CH), 131.8 (C), 133.4 (C), 161.4 (C), 170.7 (C).
1H NMR (400 MHz, CDCl3): δ = 3.82 (s, 3 H), 4.16 (s, 3 H), 6.86–6.89
(m, 2 H), 7.23–7.26 (m, 3 H), 7.29–7.33 (m, 2 H), 7.39–7.43 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 55.2 (CH3), 57.9 (CH3), 93.3 (C), 113.9
(CH), 121.9 (C), 126.8 (CH), 128.4 (CH), 129.1 (CH), 129.3 (C), 129.8
(CH), 160.6 (C), 163.2 (C), 168.9 (C).
HRMS-ESI: m/z [M + Na]+ calcd for C17H15NNaO3+: 304.0944; found:
304.0952.
HRMS-ESI: m/z [M + H]+ calcd for C19H14NO2+: 288.1019; found:
288.1026.
5-Methoxy-4-phenyl-3-p-tolylisoxazole (1c)
3-Phenyl-4-(2-thienyl)isoxazol-5-ol/3-Phenyl-4-(2-thienyl)isoxaz-
ol-5(4H)-one (6v)
Isoxazole 1c was prepared from compound 6c (616 mg, 2.5 mmol) in
THF (17 mL) and MNU (655 mg, 6.4 mmol) in Et2O (21 mL).
Yield: 438 mg (67%); colorless solid; mp 59–60 °C (PE/EtOAc).
Methyl Propanoate 5v
1H NMR (400 MHz, CDCl3): δ = 2.37 (s, 3 H), 4.17 (s, 3 H), 7.16 (d, J =
8.1 Hz, 2 H), 7.23–7.26 (m, 3 H), 7.29–7.33 (m, 2 H), 7.37 (d, J = 8.1 Hz,
2 H).
13C NMR (100 MHz, CDCl3): δ = 21.4 (CH3), 58.0 (CH3), 93.4 (C), 126.7
(C), 126.8 (CH), 128.30 (CH), 128.34 (CH), 129.0 (CH), 129.2 (CH),
129.3 (C), 139.6 (C), 163.6 (C), 168.9 (C).
Yellow oil, yield 1.86 g, was prepared from HMDS (1.28 g, 7.9 mmol)
in THF (5 mL), n-BuLi (3.2 mL, 7.9 mmol), methyl 2-(2-thienyl)acetate
(1.03 g, 6.59 mmol) in THF (10 mL), and benzoyl chloride (1.06 g, 7.6
mmol) in THF (5 mL).
Isoxazol-5-ol 6v
HRMS-ESI: m/z [M + Na]+ calcd for C17H15NNaO2+: 288.0995; found:
288.1001.
Compound 6v was prepared from compound 5v (1.86 g) and
NH2OH·HCl (1.28 g, 20.0 mmol) in MeOH (15 mL). After evaporation
of MeOH and addition of H2O, the product was extracted with Et2O,
and the organic layer was washed with H2O and extracted with 5% aq
KOH. The aqueous solution was washed with Et2O and acidified with
HCl. The precipitate was collected by filtration, washed with H2O and
dried in air to give 6v, which was used freshly prepared and without
further purification because of instability.
3-(4-Chlorophenyl)-5-methoxy-4-phenylisoxazole (1d)
Isoxazole 1d was prepared from compound 6d (350 mg, 1.3 mmol) in
THF (2 mL) and MNU (340 mg, 3.3 mmol) in Et2O (14 mL).
Yield: 272 mg (74%); colorless solid; mp 100–101 °C (PE/EtOAc).
1H NMR (400 MHz, CDCl3): δ = 4.17 (s, 3 H), 7.19–7.23 (m, 2 H), 7.26–
7.36 (m, 5 H), 7.40–7.44 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 58.1 (CH3), 93.5 (C), 127.1 (CH), 128.1
(C), 128.5 (CH), 128.79 (C), 128.82 (CH), 129.0 (CH), 129.7 (CH), 135.8
(C), 162.5 (C), 169.1 (C).
Yield: 1.16 g (72 %); violet solid; mp 95–96 °C (H2O).
HRMS-ESI: m/z [M + H]+ calcd for C13H10NO2S+: 244.0427; found:
244.0430.
3-Substituted 4-Aryl-5-methoxyisoxazoles 1a–v; General Proce-
dure B
HRMS-ESI: m/z [M + Na]+ calcd for C16H12ClNNaO2+: 308.0449; found:
308.0451.
A THF suspension/solution of the appropriate 6 (1 equiv) was cooled
to 0 °C and treated portionwise with a solution of diazomethane in
Et2O [prepared from N-methyl-N-nitrosourea (MNU) (2.5–3.0 equiv)
and a 40% solution of KOH (10–20 equiv)]. The reaction mixture was
stirred at r.t. for 1 h and quenched by AcOH. The solvents were evapo-
rated in vacuo, and the residue was dissolved in CH2Cl2 and purified
by column chromatography (silica gel, PE/EtOAc, 10:1 to 5:1).
5-Methoxy-3-(4-nitrophenyl)-4-phenylisoxazole (1e)
Isoxazole 1e was prepared from compound 6e (506 mg, 1.8 mmol) in
THF (16 mL) and MNU (481 mg, 4.7 mmol) in Et2O (25 mL).
Yield: 445 mg (83%); colorless solid; mp 124–125 °C (PE/EtOAc).
1H NMR (400 MHz, CDCl3): δ = 4.20 (s, 3 H), 7.18–7.21 (m, 2 H), 7.28–
7.36 (m, 3 H), 7.66 (d, J = 8.8 Hz, 2 H), 8.21 (d, J = 8.8 Hz, 2 H).
5-Methoxy-3,4-diphenylisoxazole (1a)
13C NMR (100 MHz, CDCl3): δ = 58.3 (CH3), 93.9 (C), 123.7 (CH), 127.5
(CH), 128.29 (C), 128.7 (CH), 129.1 (CH), 129.3 (CH), 136.09 (C),
148.59 (C), 161.69 (C), 169.59 (C).
Isoxazole 1a was prepared from compound 6a (1.00 g, 4.2 mmol) in
THF (5 mL) and MNU (1.08 g, 10.5 mmol) in Et2O (35 mL).
Yield: 750 mg (71%); colorless solid; mp 81–82 °C (PE/EtOAc) (Lit.12
81–83 °C).
HRMS-ESI: m/z [M + Na]+ calcd for C16H12N2NaO4+: 319.0689; found:
319.0704.
1H NMR (400 MHz, CDCl3): δ = 4.18 (s, 3 H), 7.22–7.41 (m, 8 H), 7.46–
7.49 (m, 2 H).
5-Methoxy-3-(2-naphthyl)-4-phenylisoxazole (1f)
13C NMR (100 MHz, CDCl3): δ = 58.0 (CH3), 93.5 (C), 126.9 (CH), 128.36
(CH), 128.43 (CH), 128.5 (CH), 129.0 (CH), 129.1 (C), 129.6 (CH), 129.6
(C), 163.6 (C), 168.9 (C).
HRMS-ESI: m/z [M + Na]+ calcd for C16H13NNaO2+: 274.0838; found:
274.0835.
Isoxazole 1f was prepared from compound 6f (650 mg, 2.3 mmol) in
THF (4 mL) and MNU (588 mg, 5.7 mmol) in Et2O (25 mL).
Yield: 408 mg (60%); colorless solid; mp 75–76 °C (PE/EtOAc).
1H NMR (400 MHz, CDCl3): δ = 4.21 (s, 3 H), 7.24–7.33 (m, 5 H), 7.47–
7.56 (m, 3 H), 7.78–7.87 (m, 3 H), 8.04 (pseudo-s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 58.1 (CH3), 93.7 (C), 125.6 (CH), 126.3
(CH), 126.88 (CH), 126,92 (CH), 127.0 (C), 127.7 (CH), 128.16 (CH),
128.20 (CH), 128.40 (CH), 128.49 (CH), 129.0 (CH), 129.1 (C), 133.0
(C), 133.7 (C), 163.6 (C), 169.0 (C).
5-Methoxy-3-(4-methoxyphenyl)-4-phenylisoxazole (1b)
Isoxazole 1b was prepared from compound 6b (418 mg, 1.6 mmol) in
THF (11 mL) and MNU (532 mg, 4.1 mmol) in Et2O (24 mL).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–O

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Synthesis
HRMS-ESI: m/z [M + Na]+ calcd for C20H15NNaO2+: 324.0995; found:
324.1009.
13C NMR (100 MHz, CDCl3): δ = 21.2 (CH3), 58.0 (CH3), 93.5 (C), 126.1
(C), 128.41 (CH), 128.45 (CH), 128.9 (CH), 129.1 (CH), 129.5 (CH),
129.7 (C), 136.7 (C), 163.6 (C), 168.9 (C).
HRMS-ESI: m/z [M + Na]+ calcd for C17H15NNaO2+: 288.0995; found:
3-(Benzo[b]thiophen-2-yl)-5-methoxy-4-phenylisoxazole (1g)
288.0994.
Isoxazole 1g was prepared from compound 6g (565 mg, 1.9 mmol) in
THF (10 mL) and MNU (515 mg, 5.0 mmol) in Et2O (25 mL).
4-(4-Fluorophenyl)-5-methoxy-3-phenylisoxazole (1l)
Yield: 440 mg (74%); colorless solid; mp 99–100 °C (PE/EtOAc).
Isoxazole 1l was prepared from compound 6l (600 mg, 2.4 mmol) in
THF (8 mL) and MNU (618 mg, 6 mmol) in Et2O (24 mL).
1H NMR (400 MHz, CDCl3): δ = 4.15 (s, 3 H), 7.31–7.42 (m, 8 H), 7.66–
7.68 (m, 1 H), 7.82–7.84 (m, 1 H).
Yield: 490 mg (76%); colorless solid; mp 79–80 °C (PE/EtOAc),
1H NMR (400 MHz, CDCl3): δ = 4.18 (s, 3Н), 6.96–7.03 (m, 2Н), 7.16–
7.22 (m, 2Н), 7.34–7.48 (m, 5Н).
13C NMR (100 MHz, CDCl3): δ = 58.2 (CH3), 93.8 (C), 122.3 (CH), 124.2
(CH), 124.5 (CH), 125.2 (CH), 125.4 (CH), 127.8 (CH), 128.5 (C), 128.6
(CH), 130.0 (CH), 130.8 (C), 135.3 (C), 140.0 (C), 158.4 (C), 169.3 (C).
HRMS-ESI: m/z [M + Na]+ calcd for C18H13NNaO2S+: 330.0559; found:
330.0568.
13C NMR (100 MHz, CDCl3): δ = 58.0 (CH3), 92.6 (C), 115.4 (d, J = 21.7
Hz, CH), 125.1 (d, J = 3.2 Hz, C), 128.4 (CH), 128.6 (CH), 129.4 (C),
129.7 (CH), 130.7 (d, J = 8.0 Hz, CH), 161.7 (d, J = 246.8 Hz, C), 163.5
(C), 168.9 (C).
5-Methoxy-3-methyl-4-phenylisoxazole (1h)
HRMS-ESI: m/z [M + Na]+ calcd for C16H12FNNaO2+: 292.0744; found:
Isoxazole 1h was prepared from compound 6h (300 mg, 1.7 mmol) in
292.0748.
THF (4 mL) and MNU (440 mg, 4.3 mmol) in Et2O (15 mL).
Yield: 195 mg (60%); orange solid; mp 31–32 °C (PE/EtOAc).
1H NMR (400 MHz, CDCl3): δ = 2.34 (s, 3 H), 4.13 (s, 3 H), 7.24–7.31
(m, 1 H), 7.37–7.42 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 12.4 (CH3), 57.8 (CH3), 93.9 (C), 126.6
(CH), 127.8 (CH), 128.6 (CH), 129.6 (C), 161.3 (C), 168.4 (C).
HRMS-ESI: m/z [M + H]+ calcd for C11H12NO2+: 190.0863; found:
190.0862.
4-(4-Chlorophenyl)-5-methoxy-3-phenylisoxazole (1m)
Isoxazole 1m was prepared from compound 6m (500 mg, 1.8 mmol)
in THF (4 mL) and MNU (464 mg, 4.5 mmol) in Et2O (19 mL).
Yield: 380 mg (74%); colorless solid; mp 111–112 °C (PE/EtOAc).
1H NMR (400 MHz, CDCl3): δ = 4.19 (s, 3 H), 7.14–7.17 (m, 2 H), 7.25–
7.28 (m, 2 H), 7.36–7.47 (m, 5 H).
13C NMR (100 MHz, CDCl3): δ = 58.0 (CH3), 92.4 (C), 127.6 (C), 128.4
(CH), 128.59 (CH), 128.60 (CH), 129.3 (C), 129.7 (CH), 130.1 (CH),
132.6 (C), 163.5 (C), 168.9 (C).
3-Ethyl-5-methoxy-4-phenylisoxazole (1i)
Isoxazole 1i was prepared from compound 6i (518 mg, 2.7 mmol) in
THF (7 mL) and MNU (742 mg, 7.2 mmol) in Et2O (28 mL).
HRMS-ESI: m/z [M + Na]+ calcd for C16H1235ClNNaO2+: 308.0449;
found: 308.0453.
Yield: 378 mg (68%); rose oil.
1H NMR (400 MHz, CDCl3): δ = 1.22 (t, J = 7.5 Hz, 3 H), 2.75 (q, J = 7.5
Hz, 2 H), 4.11 (s, 3 H), 7.25–7.30 (m, 1 H), 7.36–7.41 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 11.6 (CH3), 20.2 (CH2), 57.8 (CH3), 93.4
(C), 126.7 (CH), 128.1 (CH), 128.6 (CH), 129.6 (C), 166.0 (C), 168.4 (C).
HRMS-ESI: m/z [M + H]+ calcd for C12H14NO2+: 204.1019; found:
204.1025.
4-(4-Bromophenyl)-5-methoxy-3-phenylisoxazole (1n)
Isoxazole 1n was prepared from compound 6n (545 mg, 1.7 mmol) in
THF (9 mL) and MNU (464 mg, 4.5 mmol) in Et2O (20 mL).
Yield: 413 mg (73%); colorless solid; mp 103–104 °C (PE/EtOAc).
1H NMR (400 MHz, CDCl3): δ = 4.19 (s, 3 H), 7.08–7.11 (m, 2 H), 7.36–
7.47 (m, 7 H).
13C NMR (100 MHz, CDCl3): δ = 58.1 (CH3), 92.5 (C), 120.8(C), 128.1
(C), 128.4 (CH), 128.6 (CH), 129.3 (C), 129.8 (CH), 130.4 (CH), 131.6
(CH), 163.4 (C), 168.9 (C).
HRMS-ESI: m/z [M + Na]+ calcd for C16H1279BrNNaO2+: 351.9944;
found: 351.9951.
5-Methoxy-4-(4-methoxyphenyl)-3-phenylisoxazole (1j)
Isoxazole 1j was prepared from compound 6j (200 mg, 0.8 mmol) in
THF (2 mL) and MNU (206 mg, 2 mmol) in Et2O (10 mL).
Yield: 150 mg (71%); colorless solid; mp 78–79°C (PE/EtOAc).
1H NMR (400 MHz, CDCl3): δ = 3.80 (s, 3 H), 4.16 (s, 3 H), 6.83–6.87
(m, 2 H), 7.13–7.17 (m, 2 H), 7.33–7.42 (m, 3 H), 7.46–7.49 (m, 2 H).
5-Methoxy-4-(4-nitrophenyl)-3-phenylisoxazole (1o)
13C NMR (100 MHz, CDCl3): δ = 55.2 (CH3), 58.0 (CH3), 93.2 (C), 113.9
(CH), 121.3 (C), 128.4 (CH), 128.5 (CH), 129.5 (CH), 129.7 (C), 130.3
(CH), 158.6 (C), 163.5 (C), 168.8 (C).
HRMS-ESI: m/z [M + Na]+ calcd for C17H15NNaO3+: 304.0944; found:
304.0953.
Isoxazole 1o was prepared from compound 6o (120 mg, 0.4 mmol) in
THF (6 mL) and MNU (103 mg, 1 mmol) in Et2O (6 mL).
Yield: 90 mg (70%); yellowish solid; mp 133–134 °C (PE/EtOAc).
1H NMR (400 MHz, DMSO-d6): δ = 4.24 (s, 3 H), 7.42 (d, J = 8.9 Hz, 2
H), 7.40–7.43 (m, 2 H), 7.46–7.56 (m, 3 H), 8.19 (d, J = 8.9 Hz, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 58.9 (CH3), 91.4 (C), 123.7 (CH),
128.2 (CH), 128.6 (C), 128.9 (CH), 129.0 (CH), 130.2 (CH), 136.0 (C),
145.7 (C), 162.9 (C), 169.4 (C).
HRMS-ESI: m/z [M + Na]+ calcd for C16H12N2NaO4+: 319.0700; found:
319.0697.
5-Methoxy-3-phenyl-4-p-tolylisoxazole (1k)
Isoxazole 1k was prepared from compound 6k (624 mg, 2.5 mmol) in
THF (20 mL) and MNU (670 mg, 6.5 mmol) in Et2O (23 mL).
Yield: 561 mg (85%); colorless solid; mp 80–81 °C (PE/EtOAc).
1H NMR (400 MHz, CDCl3): δ = 2.35 (s, 3 H), 4.16 (s, 3 H), 7.12 (pseudo-
s, 4 H), 7.33–7.43 (m, 3 H), 7.48–7.50 (m, 2 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–O

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Synthesis
4-(3-Bromophenyl)-5-methoxy-3-phenylisoxazole (1p)
Yield: 321 mg (77%); colorless solid; mp 128–129 °C (PE/EtOAc).
1H NMR (400 MHz, CDCl3): δ = 4.05 (s, 3 H), 7.15–7.19 (m, 2 H), 7.24–
7.28 (m, 1 H), 7.36–7.38 (m, 3 H), 7.40–7.51 (m, 3 H), 7.75–7.77 (m, 1
H), 7.87–7.90 (m, 2 H).
Isoxazole 1p was prepared from compound 6p (500 mg, 1.6 mmol) in
THF (3 mL) and MNU (412 mg, 4 mmol) in Et2O (17 mL).
Yield: 443 mg (84%); light yellow-green oil.
13C NMR (100 MHz, CDCl3): δ = 58.1 (CH3), 91.5 (C), 125.4 (CH), 125.5
(CH), 126.0 (CH), 126.4 (CH), 126.6 (C), 127.6 (CH), 128.36 (CH),
128.40 (CH), 128.7 (CH), 129.46 (C), 129.48 (CH), 129.51 (CH), 132.6
(C), 133.8 (C), 164.1 (C), 169.6 (C).
HRMS-ESI: m/z [M + Na]+ calcd for C20H15NNaO2+: 324.0995; found:
324.1007.
1H NMR (400 MHz, CDCl3): δ = 4.21 (s, 3 H), 7.06–7.16 (M, 2 H), 7.35–
7.48 (m, 7 H).
13C NMR (100 MHz, CDCl3): δ = 58.1 (CH3), 92.2 (C), 122.4 (C), 127.4
(CH), 128.4 (CH), 128.6 (CH), 129.2 (C), 129.78 (CH), 129.80 (CH),
131.3 (C), 131.5 (CH), 163.5 (C), 169.0 (C).
HRMS-ESI: m/z [M + H]+ calcd for C16H1379BrNO2+: 330.0124; found:
330.0125.
3,4-Diphenyl-5-(pyrrolidin-1-yl)isoxazole (1u)
5-Chloro-3,4-diphenylisoxazole
5-Methoxy-4-(3-nitrophenyl)-3-p-tolylisoxazole (1q)
Isoxazole 1q was prepared from compound 6q (505 mg, 1.7 mmol) in
5-Chloro-3,4-diphenylisoxazole was prepared according to a modi-
fied procedure.11 A mixture of 3,4-diphenylisoxazol-5(4H)-one 6a
(880 mg, 3.7 mmol) and phosphorus oxychloride (3.4 mL, 37 mmol)
was stirred at 0 °C and Et3N (0.3 mL, 2.1 mmol) was added dropwise.
The solution was stirred at 0 °C for 20 min, slowly heated to r.t., and
then was heated under stirring at 80 °C for 4 d. After the mixture had
cooled to r.t., it was quenched with ice, and the precipitate that
formed was filtered and washed with H2O. The residue was dissolved
in EtOAc, and the solution was dried with Na2SO4, filtered, and con-
centrated to an oil that was crystallized after the addition of pentane.
THF (22 mL) and MNU (464 mg, 4.5 mmol) in Et2O (25 mL).
Yield: 387 mg (68%); colorless solid; mp 100–101 °C (PE/EtOAc).
1H NMR (400 MHz, CDCl3): δ = 2.39 (s, 3 H), 4.25 (s, 3 H), 7.20 (d, J =
8.0 Hz, 2 H), 7.32 (d, J = 8.0 Hz, 2 H), 7.41 (t, J = 8.0 Hz, 1 H), 7.47 (dt,
J = 7.7, 1.2 Hz, 1 H), 8.06 (ddd, J = 8.0, 2.0, 1.2 Hz, 1 H), 8.17 (t, J = 2.0
Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 21.4 (CH3), 58.2 (CH3), 91.4 (C), 121.4
(CH), 123.2 (CH), 125.9 (C), 128.3 (CH), 129.1 (CH), 129.5 (CH), 131.3
(C), 134.3 (CH), 140.2 (C), 148.4 (C), 163.5 (C), 169.2 (C).
Yield: 710 mg (74%); colorless solid; mp 85–86 °C (pentane) [Lit.11 72
°C (PE)].
1H NMR (400 MHz, CDCl3): δ = 7.24–7.29 (m, 2 H), 7.32–7.45 (m, 8 H).
HRMS-ESI: m/z [M + Na]+ calcd for C17H14N2NaO4+: 333.0846; found:
333.0846.
13C NMR (100 MHz, CDCl3): δ = 114.6 (C), 127.8 (C), 128.2 (C), 128.3
(CH), 128.5 (CH), 128.6 (CH), 128.7 (CH), 129.5 (CH), 130.0 (CH), 152.2
(C), 162.9 (C).
5-Methoxy-4-(2-methoxyphenyl)-3-phenylisoxazole (1r)
Isoxazole 1r was prepared from compound 6r (200 mg, 0.8 mmol) in
THF (2 mL) and MNU (206 mg, 2 mmol) in Et2O (10 mL).
Yield: 150 mg (71%); creamy solid; mp 97–98 °C (PE/EtOAc).
HRMS-ESI: m/z [M + Ag]+ calcd for C15H1035ClNOAg+: 361.9496; found:
361.9513.
1H NMR (400 MHz, CDCl3): δ = 3.45 (s, 3 H), 4.10 (s, 3 H), 6.85–6.87
(m, 1 H), 6.95–6.99 (m, 1 H), 7.21–7.24 (m, 1 H), 7.26–7.36 (m, 4 H),
7.41–7.43 (m, 2 H).
Isoxazole 1u
13C NMR (100 MHz, CDCl3): δ = 55.0 (CH3), 58.0 (CH3), 90.1 (C), 111.2
(CH), 118.2 (C), 120.6 (CH), 127.2 (CH), 128.2 (CH), 129.1 (CH), 129.3
(CH), 130.7 (C), 131.9 (CH), 157.3 (C), 164.2 (C), 169.1 (C).
HRMS-ESI: m/z [M + Na]+ calcd for C17H15NNaO3+: 304.0944; found:
304.0945.
A mixture of 5-chloro-3,4-diphenylisoxazole (180 mg, 0.70 mmol),
pyrrolidine (600 mg, 8.4 mmol), and K2CO3 (146 mg, 1.1 mmol) in
THF (4 mL) was refluxed under stirring for 4 h (monitoring by TLC).
The solvent was evaporated, H2O was added to the reaction mixture,
and the residue was filtered, washed with H2O, and dried in air to give
pure 1u.
Yield: 192 mg (94%); colorless solid; mp 157–158 °C (H2O).
1H NMR (400 MHz, CDCl3): δ = 1.84–1.88 (m, 4 H), 3.28–3.31 (m, 4 H),
7.20–7.31 (m, 8 H), 7.34–7.36 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 25.3 (CH2), 48.3 (CH2), 92.1 (C), 126.9
(CH), 127.8 (CH), 128.1 (CH), 128.4 (CH), 128.8 (CH), 130.2 (C), 131.6
(C), 132.0 (C), 162.9 (C), 165.2 (C).
HRMS-ESI: m/z [M + H]+ calcd for C19H19N2O+: 291.1492; found:
291.1504.
5-Methoxy-4-(2-naphthyl)-3-p-tolylisoxazole (1s)
Isoxazole 1s was prepared from compound 6s (400 mg, 1.3 mmol) in
THF (3 mL) and MNU (342 mg, 3.3 mmol) in Et2O (15 mL).
Yield: 300 mg (72%); light yellow oil; mp 89–90 °C (PE/EtOAc).
1H NMR (400 MHz, CDCl3): δ = 2.38 (s, 3 H), 4.20 (s, 3 H), 7.15 (d, J =
8.0 Hz, 2 H), 7.29–7.33 (m, 1 H), 7.41 (d, J = 8.0 Hz, 2 H), 7.45–7.49 (m,
2 H), 7.74–7.79 (m, 3 H), 7.80–7.84 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 21.4 (CH3), 58.0 (CH3), 93.4 (C), 125.9
(CH), 126.1 (CH), 126.6 (C), 126.7 (C), 127.1 (CH), 127.6 (CH), 127,82
(CH), 127.84 (CH), 128.3 (CH), 129.2 (CH), 132.2 (C), 133.3 (C), 139.7
(C), 163.6 (C), 169.1 (C).
5-Methoxy-3-phenyl-4-(2-thienyl)isoxazole (1v)
Isoxazole 1v was prepared from compound 6v (500 mg, 2 mmol) in
THF (5 mL) and MNU (620 mg, 6 mmol) in Et2O (20 mL).
HRMS-ESI: m/z [M + Na]+ calcd for C21H17NNaO2+: 338.1151; found:
338.1152.
Yield: 133 mg (25%); light yellow oil.
1H NMR (400 MHz, CDCl3): δ = 4.21 (s, 3 H), 6.90 (dd, J = 3.6, 1.1 Hz, 1
H), 6.98 (dd, J = 5.2, 3.6 Hz, 1 H), 7.23 (dd, J = 5.2, 1.1 Hz, 1 H), 7.38–
7.46 (m, 3 H), 7.52–7.57 (m, 2 H).
5-Methoxy-4-(1-naphthyl)-3-phenylisoxazole (1t)
Isoxazole 1t was prepared from compound 6t (400 mg, 1.4 mmol) in
THF (10 mL) and MNU (402 mg, 3.9 mmol) in Et2O (18 mL).
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13C NMR (100 MHz, CDCl3): δ = 58.2 (CH3), 88.4 (C), 124.9 (CH), 126.2
(CH), 126.9 (CH), 128.5 (CH), 128.6 (CH), 129.2 (C), 129.8 (CH), 129.9
(C), 163.5 (C), 168.7 (C).
1H NMR (400 MHz, CDCl3): δ = 3.81 (s, 3 H), 3.84 (s, 3 H), 6.92 (d, J =
8.1 Hz, 2 H), 7.26–7.35 (m, 3 H), 7.57 (d, J = 8.1 Hz, 2 H), 8.18–8.20 (m,
1 H), 8.63 (br s, 1 H).
HRMS-ESI: m/z [M + H]+ calcd for C14H12NO2S+: 258.0583; found:
258.0579.
13C NMR (100 MHz, CDCl3): δ = 50.8 (CH3), 55.3 (CH3), 103.8 (C), 110.9
(CH), 113.6 (CH), 121.96 (CH), 122.00 (CH), 123.0 (CH), 124.1 (C),
127.6 (C), 130.8 (CH), 135.0 (C), 144.8 (C), 160.3 (C), 166.0 (C).
HRMS-ESI: m/z [M + Na]+ calcd for C17H15NNaO3+: 304.0944; found:
Methyl 2,3-Diphenyl-2H-azirine-2-carboxylate (4a)
304.0949.
FeCl2 (11 mg, 25 mol%) was added to a solution of 1a (85 mg, 0.34
mmol) in 0.5 mL anhyd DMSO under an argon atmosphere. After stir-
ring for 4 h at r.t., the reaction mixture was poured into H2O, and ex-
tracted with EtOAc; the combined organic layer was washed with
brine and dried over Na2SO4. The solvent was evaporated and the res-
idue was filtered (silica gel, PE/EtOAc, 5:1).
Yield: 84 mg (99%); colorless solid; mp 67–68 °C (PE/EtOAc) (Lit.13 70–
71 °C for R-isomer).
1H NMR (400 MHz, CDCl3): δ = 3.75 (s, 3 H), 7.27–7.36 (m, 3 H), 7.47–
7.52 (m, 2 H), 7.55–7.61 (m, 2 H), 7.62–7.67 (m, 1 H), 7.91–7.96 (m, 2
H).
Methyl 2-p-Tolyl-1H-indole-3-carboxylate (3c)
Indole-3-carboxylate 3c was prepared from isoxazole 1c (106 mg,
0.29 mmol) and FeCl2·4H2O (12 mg, 0.06 mmol, 21 mol%) in DMSO (2
mL) for 4 h.
Yield: 90 mg (85%); colorless solid; mp 148–149 °C (PE/EtOAc) (Lit.14
148–149 °C).
1H NMR (400 MHz, CDCl3): δ = 2.38 (s, 3 H), 3.84 (s, 3 H), 7.21–7.23
(m, 2 H), 7.25–7.30 (m, 2 H), 7.34–7.36 (m, 1 H), 8.19–8.24 (m, 1 H),
8.60 (br s, 1 H). 13C NMR (100 MHz, CDCl3): δ = 21.3 (CH3), 50.8 (CH3),
104.2 (C), 111.0 (CH), 122.0 (CH), 122.1 (CH), 123.1 (CH), 127.6 (C),
128.85 (CH), 128.93 (C), 129.3 (CH), 135.1 (C), 139.3 (C), 145.9 (C),
166.9 (C).
13C NMR (100 MHz, CDCl3): δ = 41.1 (C), 52.6 (CH3), 122.0 (C), 127.7
(CH), 128.1 (CH), 128.2 (CH), 129.4 (CH), 130.4 (CH), 133.9 (CH), 136.2
(C), 160.7 (C), 171.6 (C).
HRMS-ESI: m/z [M + H]+ calcd for C16H13NNaO2+: 274.0838; found:
HRMS-ESI: m/z [M + Na]+ calcd for C17H15NNaO2+: 288.0995; found:
274.0849.
288.1002.
Substituted Indole-3-carboxylates 3a–v; General Procedure C
Methyl 2-(4-Chlorophenyl)-1H-indole-3-carboxylate (3d)
A mixture of the appropriate isoxazole 1 (1 mmol) and FeCl2·4H2O or
FeCl2 (20–30 mol%) in DMSO (2–3 mL) was stirred at 170 °C in a
screw-cap thick-wall test tube until the reaction reached completion
(TLC monitoring). The reaction mixture was cooled and H2O was add-
ed. The precipitate that formed was filtered, washed with H2O, and
dried to give pure indole 3. If a precipitate was not formed, the mix-
ture was extracted with EtOAc or Et2O, the organic layer was washed
with brine and dried over Na2SO4, the solvent was evaporated, and
the residue was purified by column chromatography (silica gel, EtOAc,
CH2Cl2 or PE/EtOAc).
Indole-3-carboxylate 3d was prepared from isoxazole 1d (110 mg,
0.39 mmol) and FeCl2·4H2O (15 mg 0.075 mmol, 20 mol%) in DMSO
(1.5 mL) for 3.5 h.
Yield: 82 mg (84%); colorless solid; mp 172–173 °C (CH2Cl2) (Lit.14
166–167 °C).
1H NMR (400 MHz, CDCl3): δ = 3.84 (s, 3 H), 7.27–7.31 (m, 2 H), 7.34–
7.39 (m, 3 H), 7.54–7.57 (m, 2 H), 8.18–8.21 (m, 1 H), 8.66 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 50.9 (CH3), 104.8 (C), 111.1 (CH), 122.2
(CH), 122.3 (CH), 123.5 (CH), 127.4 (C), 128.4 (CH), 130.3 (C), 130.8
(CH), 135.2 (C), 135.3 (C), 143.2 (C), 165.8 (C).
Methyl 2-Phenyl-1H-indole-3-carboxylate (3a)
HRMS-ESI: m/z [M + Na]+ calcd for C16H1235ClNNaO2+: 308.0449;
found: 308.0459.
Indole-3-carboxylate 3a was prepared from isoxazole 1a (90 mg, 0.36
mmol) and FeCl2 (11 mg 0.085 mmol, 24 mol%) in DMSO (0.5 mL) for
5 h.
Methyl 2-(4-Nitrophenyl)-1H-indole-3-carboxylate (3e)
Yield: 69 mg (77%); light orange solid; mp 146–147 °C (EtOAc) (Lit.14
137–139 °C).
1H NMR (400 MHz, CDCl3): δ = 3.82 (s, 3 H), 7.24–7.31 (m, 2 H), 7.33–
7.38 (m, 1 H), 7.41–7.46 (m, 3 H), 7.61–7.66 (m, 2 H), 8.20–8.23 (m, 1
H), 8.66 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 50.8 (CH3), 104.4 (C), 111.0 (CH),
122.07 (CH), 122.11 (CH), 123.2 (CH), 127.5 (C), 128.1 (CH), 129.2
(CH), 129.5 (CH), 131.9 (C), 135.1 (C), 144.6 (C), 165.8 (C).
Indole-3-carboxylate 3e was prepared from isoxazole 1e (137 mg,
0.46 mmol) and FeCl2·4H2O (19 mg, 0.095 mmol, 20 mol%) in DMSO
(2 mL) for 3.5 h.
Yield: 128 mg (93%); bright yellow solid; mp 192–193 °C (CH2Cl2).
1H NMR (400 MHz, DMSO-d6): δ = 3.76 (s, 3 H), 7.22–7.30 (m, 2 H),
7.51 (d, J = 7.6 Hz, 1 H), 7.97–7.99 (m, 2 H), 8.08 (d, J = 8.0 Hz, 1 H),
8.35 (d, J = 8.9 Hz, 2 H), 12.41 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 50.7 (CH3), 104.2 (C), 112.1 (CH),
121.5 (CH), 121.8 (CH), 122.9 (CH), 123.3 (CH), 127.0 (C), 131.2 (CH),
135.9 (C), 138.2 (C), 141.6 (C), 147.4 (C), 164.7 (C).
HRMS-ESI: m/z [M + Na]+ calcd for C16H13NNaO2+: 274.0838; found:
274.0844.
HRMS-ESI: m/z [M + Na]+ calcd for C16H12N2NaO4+: 319.0689; found:
Methyl 2-(4-Methoxyphenyl)-1H-indole-3-carboxylate (3b)
319.0705.
Indole-3-carboxylate 3b was prepared from isoxazole 1b (98 mg, 0.35
mmol) and FeCl2·4H2O (15 mg 0.07 mmol, 20 mol%) in DMSO (1.0 mL)
for 5 h.
Methyl 2-(2-Naphthyl)-1H-indole-3-carboxylate (3f)
Indole-3-carboxylate 3f was prepared from isoxazole 1f (100 mg, 0.33
mmol) and FeCl2·4H2O (7 mg, 0.035 mmol, 11 mol%) in DMSO (1 mL)
for 7 h.
Yield: 68 mg (62%); colorless solid; mp 144–145 °C (CH2Cl2).
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Yield: 40 mg (40%); orange solid; mp 133–134 °C (EtOAc) (Lit.14 140–
141 °C).
Methyl 6-Methoxy-2-phenyl-1H-indole-3-carboxylate (3j)
Indole-3-carboxylate 3j was prepared from isoxazole 1j (85 mg, 0.3
1H NMR (400 MHz, CDCl3): δ = 3.84 (s, 3 H), 7.28–7.33 (m, 2 H), 7.39–
7.44 (m, 1 H), 7.50–7.57 (m, 2 H), 7.75–7.79 (m, 1 H), 7.85–7.93 (m, 3
H), 8.09 (pseudo-s, 1 H), 8.21–8.27 (m, 1 H), 8.62 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 50.9 (CH3), 104.9 (C), 110.9 (CH),
122.18 (CH), 122.20 (CH), 123.3 (CH), 126.5 (CH), 126.9 (CH), 127.3
(CH), 127.65 (CH), 127.66 (C), 127.8 (CH), 128.3 (CH), 128.5 (CH),
129.5 (C), 132.9 (C), 133.5 (C), 135.2 (C), 144.4 (C), 165.7 (C).
mmol) and FeCl2 (16 mg, 0.08 mmol, 26 mol%) in DMSO (1.5 mL) for 4
h.
Yield: 80 mg (94%); colorless solid; mp 143–144 °C (EtOAc) [Lit.17
147–149 °C (EtOAc)].
1H NMR (400 MHz, CDCl3): δ = 3.83 (s, 3 H), 3.86 (s, 3 H), 6.86–6.87
(m, 1 H), 6.93–6.95 (m, 1 H), 7.41–7.48 (m, 3 H), 7.63–7.66 (m, 2 H),
8.07–8.09 (m, 1 H), 8.36 (br s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 50.4 (CH3), 55.2 (CH3), 94.5 (CH),
102.6 (C), 111.4 (CH), 121.2 (C), 122.0 (CH), 127.8 (CH), 128.6 (CH),
129.7 (CH), 131.9 (C), 136.3 (C), 143.4 (C), 156.2 (C), 164.9 (C).
HRMS-ESI: m/z [M + Na]+ calcd for C20H15NNaO2+: 324.0995; found:
324.1007.
Methyl 2-(Benzo[b]thiophen-2-yl)-1H-indole-3-carboxylate (3g)
HRMS-ESI: m/z [M + Na]+ calcd for C17H15NNaO3+: 304.0944; found:
Indole-3-carboxylate 3g was prepared from isoxazole 1g (121 mg,
0.39 mmol) and FeCl2·4H2O (16 mg, 0.08 mmol, 20 mol%) in DMSO
(1.5 mL) for 3.5 h.
304.0945.
Methyl 6-Methyl-2-phenyl-1H-indole-3-carboxylate (3k)
Yield: 86 mg (71%); light yellow solid; mp 174–175 °C (CH2Cl2).
Indole-3-carboxylate 3k was prepared from isoxazole 1k (110 mg,
0.42 mmol) and FeCl2·4H2O (17 mg, 0.085 mmol, 20 mol%) in DMSO
(1.5 mL) for 6.5 h.
1H NMR (400 MHz, DMSO-d6): δ = 3.87 (s, 3 H), 7.21–7.30 (m, 2 H),
7.41–7.47 (m, 2 H), 7.51–7.53 (m, 1 H), 7.95–7.99 (m, 1 H), 8.03–8.07
(m, 2 H), 8.12 (s, 1 H), 12.36 (s, 1 H).
Yield: 85 mg (77%); colorless solid; mp 146–147 °C (PE/EtOAc).
13C NMR (DMSO-d, 100 MHz): δ = 50.8 (CH3), 104.0 (C), 111.9 (CH),
112.5 (C),121.5 (CH), 121.7 (CH), 122.2 (CH), 123.4 (CH), 124.1 (CH),
124.8 (CH), 125.3 (CH), 126.1 (CH), 127.0 (C), 132.5 (C), 135.8 (C),
136.6 (C), 138.8 (C), 140.1 (C), 164.7 (C).
HRMS-ESI: m/z [M + Na]+ calcd for C18H13NNaO2S+: 330.0559; found:
330.0564.
1H NMR (400 MHz, DMSO-d6): δ = 2.42 (s, 3 H), 3.72 (s, 3 H), 7.01–
7.04 (m, 1 H), 7.24 (s, 1 H), 7.44–7.52 (m, 3 H), 7.66–7.69 (m, 2 H),
7.90–7.92 (m, 1 H), 11.96 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 21.2 (CH3), 50.4 (CH3), 102.5 (C),
111.5 (CH), 121.0 (CH), 123.1 (CH), 125.1 (C), 127.8 (CH), 128.7 (CH),
129.8 (CH), 131.8 (C), 131.9 (C), 135.9 (C), 144.0 (C), 164.9 (C).
HRMS-ESI: m/z [M + Na]+ calcd for C17H15NNaO2+: 288.0995; found:
288.0999.
Methyl 2-Methyl-1H-indole-3-carboxylate (3h)
Indole-3-carboxylate 3h was prepared from isoxazole 1h (95 mg, 0.50
mmol) and FeCl2·4H2O (20 mg, 0.10 mmol, 20 mol%) in DMSO (1.0
mL) for 4 h.
Yield: 85 mg (89%); colorless solid; mp 164–165 °C (CH2Cl2) (Lit.15 154
°C, decomp.).
1H NMR (400 MHz, CDCl3): δ = 2.74 (s, 3 H), 3.94 (s, 3 H), 7.18–7.25
(m, 2 H), 7.29–7.31 (m, 1 H), 8.09–8.11 (m, 1 H), 8.51 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 14.2 (CH3), 50.8 (CH3), 104.5 (C), 110.5
(CH), 121.2 (CH), 121.7 (CH), 122.4 (CH), 127.1 (C), 134.5 (C), 144.0
(C), 166.6 (C).
HRMS-ESI: m/z [M + Na]+ calcd for C11H11NNaO2+: 212.0682; found:
212.0684.
Methyl 6-Fluoro-2-phenyl-1H-indole-3-carboxylate (3l)
Indole-3-carboxylate 3l was prepared from isoxazole 1l (85 mg, 0.32
mmol) and FeCl2 (22 mg, 0.11 mmol, 33 mol%) in DMSO (1 mL) for 5 h.
Yield: 65 mg (82%); colorless solid; mp 201–202 °C (EtOAc) [Lit.17
202–205 °C (EtOAc)].
1H NMR (400 MHz, CDCl3): δ = 3.84 (s, 3 H), 7.02–7.09 (m, 2 H), 7.46–
7.50 (m, 3 H), 7.64–7.66 (m, 2 H), 8.13–8.17 (m, 1 H), 8.42 (br s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 50.6 (CH3), 97.8 (d, J = 25.7 Hz, CH),
102.7 (C), 109.8 (d, J = 24.0 Hz, CH), 122.5 (d, J = 9.9 Hz, CH), 123.8 (C),
127.9 (CH), 129.0 (CH), 129.7 (CH), 131.5 (C), 135.5 (d, J = 12.7 Hz, C),
145.2 (d, J = 2.5 Hz, C), 159.1 (d, J = 237.0 Hz, C), 164.6 (C).
HRMS-ESI: m/z [M + Na]+ calcd for C16H12FNNaO2+: 292.0744; found:
292.0744.
Methyl 2-Ethyl-1H-indole-3-carboxylate (3i)
Indole-3-carboxylate 3i was prepared from isoxazole 1i (146 mg, 0.70
mmol) and FeCl2·4H2O (28 mg, 0.140 mmol, 20 mol%) in DMSO (0.8
mL) for 4 h.
Yield: 126 mg (86%); rose solid; mp 72–73 °C (CH2Cl2) (Lit.16 72–73
°C).
Methyl 6-Chloro-2-phenyl-1H-indole-3-carboxylate (3m)
Indole-3-carboxylate 3m was prepared from 4-(4-chlorophenyl)-5-
methoxy-3-phenylisoxazole 1m (85 mg, 0.29 mmol) and FeCl2 (20
mg, 0.10 mmol, 33 mol%) in DMSO (1.5 mL) for 3.5 h.
1H NMR (400 MHz, CDCl3): δ = 1.35 (t, J = 7.6 Hz, 3 H), 3.20 (q, J = 7.6
Hz, 2 H), 3.95 (s, 3 H), 7.18–7.26 (m, 2 H), 7.31–7.34 (m, 1 H), 8.12–
8.14 (m, 1 H), 8.63 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 13.2 (CH3), 21.3 (CH2), 50.8 (CH3),
103.4 (C), 110.7 (CH), 121.4 (CH), 121.7 (CH), 122.3 (CH), 127.2 (C),
134.5 (C), 149.7 (C), 166.4 (C).
Yield: 60 mg (70%); colorless solid; mp 229–230 °C (EtOAc).
1H NMR (400 MHz, CDCl3): δ = 3.84 (s, 3 H), 7.24–7.25 (m, 1 H), 7.39–
7.40 (m, 1 H), 7.47–7.50 (m, 3 H), 7.65–7.67 (m, 2 H), 8.12–8.14 (m, 1
H), 8.40 (br s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 50.6 (CH3), 102.8 (C), 111.4 (CH),
121.7 (C), 122.6 (CH), 125.9 (C), 127.1 (C), 127.9 (CH), 129.1 (CH),
129.8 (CH), 131.3 (C), 135.9 (C), 145.4 (C), 164.5 (C).
HRMS-ESI: m/z [M + H]+ calcd for C12H14NO2+: 204.1019; found:
204.1024.
HRMS-ESI: m/z [M + Na]+ calcd for C16H1235ClNNaO2+: 308.0449;
found: 308.0453.
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Methyl 6-Bromo-2-phenyl-1H-indole-3-carboxylate (3n)
Methyl 4-Methoxy-2-phenyl-1H-indole-3-carboxylate (3r)
Indole-3-carboxylate 3n was prepared from isoxazole 1n (176 mg,
0.53 mmol) and FeCl2·4H2O (21 mg, 0.11 mmol, 20 mol%) in DMSO
(2.0 mL) for 4 h.
Indole-3-carboxylate 3r was prepared from isoxazole 1r (80 mg, 0.28
mmol) and FeCl2 (15 mg 0.075 mmol, 28 mol%) in DMSO (1 mL) for 7
h.
Yield: 141 mg (80%); colorless solid; mp 235–236 °C (CH2Cl2).
Yield: 25 mg (31%); yellowish solid; mp 142–143 °C (EtOAc).
1H NMR (400 MHz, DMSO-d6): δ = 3.73 (s, 3 H), 7.34 (dd, J = 8.6, 1.6
Hz, 1 H), 7.47–7.54 (m, 3 H), 7.60 (d, J = 1.6 Hz, 1 H), 7.68–7.70 (m, 2
H), 7.98 (d, J = 8.6 Hz, 1 H), 12.27 (s, 1 H).
1H NMR (400 MHz, DMSO-d6): δ = 3.74 (s, 3 H), 3.84 (s, 3 H), 6.59–
6.61 (m, 1 H), 7.04–7.06 (m, 1 H), 7.10–7.14 (m, 1 H), 7.39–7.42 (m, 1
H), 7.47–7.51 (m, 2 H), 7.61–7.62 (m, 2 H), 11.83 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 50.6 (CH3), 102.9, 114.3 (CH),
115.1 (C), 123.0 (CH), 124.3 (CH), 126.2 (C), 127.9 (CH), 129.2 (CH),
129.8 (CH), 131.3 (C), 136.4 (C), 145.3 (C), 164.5 (C).
13C NMR (100 MHz, DMSO-d6): δ = 51.5 (CH3), 55.5 (CH3), 101.1 (CH),
104.8 (CH), 104.9 (C), 116.6 (C), 123.5 (CH), 127.7 (CH), 128.3 (CH),
128.6 (CH), 131.4 (C), 136.8 (C), 138.9 (C), 152.9 (C), 167.2 (C).
HRMS-ESI: m/z [M + Na]+ calcd for C16H1279BrNNaO2+: 351.9944;
HRMS-ESI: m/z [M + Na]+ calcd for C17H15NNaO3+: 304.0944; found:
found: 351.9950.
304.0945.
Methyl 6-Nitro-2-phenyl-1H-indole-3-carboxylate (3o)
Methyl 2-p-Tolyl-1H-benzo[g]indole-3-carboxylate (3s)
Indole-3-carboxylate 3o was prepared from isoxazole 1o (85 mg, 0.29
mmol) and FeCl2 (16 mg, 0.080 mmol, 28 mol%) in DMSO (1.0 mL) for
5 h.
Indole-3-carboxylate 3s was prepared from isoxazole 1s (130 mg,
0.60 mmol) and FeCl2·4H2O (24 mg, 0.12 mmol, 20 mol%) in DMSO (2
mL) for 4 h.
Yield: 33 mg (39%); yellow solid; mp 268–269 °C (EtOAc).
Yield: 124 mg (95%); colorless solid; mp 217–218 °C (CH2Cl2).
1H NMR (400 MHz, DMSO-d6): δ = 3.77 (s, 3 H), 7.54–7.56 (m, 3 H),
7.73–7.75 (m, 2 H), 8.08–8.11 (m, 1 H), 8.20–8.22 (m, 1 H), 8.30–8.31
(m, 1 H), 12.84 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 50.9 (CH3), 103.8 (C), 108.2 (CH),
116.4 (CH), 121.5 (CH), 128.1 (CH), 129.76 (CH), 129.82 (CH), 130.7
(C), 132.1 (C), 134.1 (C), 142.8 (C), 149.6 (C), 164.1 (C).
1H NMR (400 MHz, DMSO-d6): δ = 2.41 (s, 3 H), 3.76 (s, 3 H), 7.31–
7.37 (m, 2 H), 7.44–7.51 (m, 1 H), 7.56–7.61 (m, 1 H), 7.61–7.68 (m, 3
H), 7.94–8.00 (m, 1 H), 8.16–8.21 (m, 1 H), 8.56–8.62 (m, 1 H), 12.67
(s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 20.9 (CH3), 50.5 (CH3), 104.4 (C),
120.7 (CH), 121.14 (CH), 121.5 (C), 121,9 (CH), 123.5 (C), 124.4 (CH),
125.8 (CH), 128.3 (CH), 128.4 (CH), 129.0 (C), 130.0 (CH), 130.3 (C),
138.2 (C), 142.8 (C), 165.0 (C).
HRMS-ESI: m/z [M + Na]+ calcd for C16H12N2NaO4+: 319.0700; found:
319.0689.
HRMS-ESI: m/z [M + Na]+ calcd for C21H17NNaO2+: 338.1151; found:
338.1162.
Methyl 5-Bromo-2-phenyl-1H-indole-3-carboxylate (3p)
Indole-3-carboxylate 3p was prepared from isoxazole 1p (138 mg,
0.42 mmol) and FeCl2·4H2O (17 mg, 0.085 mmol, 20 mol%) in DMSO
(2.0 mL) for 8 h.
Methyl 2-Phenyl-3H-benzo[e]indole-1-carboxylate (3t)
Indole-3-carboxylate 3t was prepared from isoxazole 1t (203 mg, 0.67
mmol) and FeCl2·4H2O (28 mg, 0.14 mmol, 20 mol%) in DMSO (2.5
mL) for 3.5 h.
Yield: 96 mg (71%); colorless solid; mp 175–176 °C (CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 3.84 (s, 3 H), 7.24 (d, J = 8.6 Hz, 1 H),
7.36 (dd, J = 8.6, 1.8 Hz, 1 H), 7.43–7.46 (m, 3 H), 7.62–7.65 (m, 2 H),
8.34 (d, J = 1.8 Hz, 1 H), 8.59 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 51.0 (CH3), 112.4 (CH), 115.6 (C), 124.8
(CH), 126.2 (CH), 128.3 (CH), 129.2 (C), 129.46 (CH), 129.54 (CH),
131.4 (C), 133.7 (C), 145.5 (C), 165.3 (C).
Yield: 166 mg (82%); yellowish solid; mp 183–184 °C (EtOAc).
1H NMR (400 MHz, CDCl3): δ = 3.81 (s, 3 H), 7.37 (m, 7 H), 7.56–7.59
(m, 1 H), 7.63–7.66 (m, 1 H), 7.90–7.92 (m, 1 H), 8.79 (br s, 1 H), 8.90–
8.92 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 51.6 (CH3), 108.3 (C), 112.1 (CH), 121.0
(C), 124.0 (CH), 124.8 (CH), 125.2 (CH), 126.1 (CH), 128.0 (C), 128.4
(CH), 128.54 (CH), 128.56 (CH), 128.8 (CH), 130.5 (C), 132.48 (C),
132.5 (C), 139.8 (C), 168.0 (C).
HRMS-ESI: m/z [M + Na]+ calcd for C16H1279BrNNaO2+: 351.9944;
found: 351.9951.
HRMS-ESI: m/z [M + Na]+ calcd for C20H15NNaO2+: 324.0995; found:
324.1010
Methyl 5-Nitro-2-p-tolyl-1H-indole-3-carboxylate (3q)
Indole-3-carboxylate 3q was prepared from isoxazole 1q (134 mg,
0.43 mmol) and FeCl2·4H2O (18 mg, 0.09 mmol, 20 mol%) in DMSO
(1.5 mL) for 6 h.
(2-Phenyl-1H-indol-3-yl)(pyrrolidin-1-yl)methanone (3u)
Indole-3-carboxylate 3u was prepared from isoxazole 1u (113 mg,
0.39 mmol) and FeCl2·4H2O (8 mg, 0.04 mmol, 20 mol%) in DMSO (2
mL) for 6 h.
Yield: 83 mg (62%); yellowish solid; mp 258–259 °C (CH2Cl2).
1H NMR (400 MHz, DMSO-d6): δ = 2.41 (s, 3 H), 3.77 (s, 3 H), 7.34 (d,
J = 7.9 Hz, 2 H), 7.59 (dd, J = 8.9, 1.6 Hz, 1 H), 7.63 (d, J = 7.9 Hz, 2 H),
8.09 (dd, J = 8.9, 1.7 Hz, 1 H), 8.87 (d, J = 1.7 Hz, 1 H), 12.68 (s, 1 H).
Yield: 84 mg (74%); colorless solid; mp 254–255 °C (EtOAc/CH2Cl2).
1H NMR (400 MHz, DMSO-d6): δ = 1.61–1.64 (m, 2 H), 1.77–1.81 (m, 1
H), 2.94–2.97 (m, 2 H), 3.52–3.55 (m, 2 H), 7.05–7.09 (m, 1 H), 7.14–
7.19 (m, 1 H), 7.36–7.41 (m, 1 H), 7.43–7.50 (m, 4 H), 7.67–7.69 (m, 1
H), 11.69 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 21.0 (CH3), 50.9 (CH3), 104.1 (C),
112.4 (CH), 117.6 (CH), 117.9 (CH), 126.6 (C), 127.7 (C), 128.6 (CH),
129.8 (CH), 138.7 (C), 139.4 (C), 142.3 (C), 148.0 (C), 164.1 (C).
HRMS-ESI: m/z [M + Na]+ calcd for C17H14N2NaO4+: 333.0846; found:
333.0862.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–O

O
V. A. Bodunov et al.
Paper
Synthesis
13C NMR (100 MHz, DMSO-d6): δ = 24.1 (CH2), 25.4 (CH2), 45.3 (CH2),
47.3 (CH2), 110.0 (C), 111.6 (CH), 119.2 (CH), 120.0 (CH), 122.2 (CH),
126.6 (C), 126.8 (CH), 128.1 (CH), 128.9 (CH), 131.8 (C), 134.9 (C),
135.7 (C), 165.5(C).
HRMS-ESI: m/z [M + H]+ calcd for C19H19N2O+: 291.1492; found:
291.1505.
(3) For reviews, see: (a) Humphrey, G. R.; Kuethe, J. T. Chem. Rev.
2006, 106, 2875. (b) Vicente, R. Org. Biomol. Chem. 2011, 9,
6469. (c) Taber, D. F.; Tirunahari, P. K. Tetrahedron 2011, 67,
7195. (d) Bartoli, G.; Dalpozzo, R.; Nardi, M. Chem. Soc. Rev.
2014, 43, 4728. (e) Pozharskii, A. F.; Kachalkina, S. G.;
Gulevskaya, A. V.; Filatova, E. A. Russ. Chem. Rev. 2017, 86, 589.
(f) Heravi, M. M.; Rohani, S.; Zadsirjan, V.; Zahedi, N. RSC Adv.
2017, 7, 52852.
(4) Ahluwalia, V. K.; Kidwai, M. New Trends in Green Chemistry
2004.
(5) Kern, N.; Hoffmann, M.; Blanc, A.; Weibel, J.-M.; Pale, P. Org.
Lett. 2013, 15, 836.
Methyl 5-Phenyl-4H-thieno[3,2-b]pyrrole-6-carboxylate (3v)
Indole-3-carboxylate 3v was prepared from isoxazole 1v (130 mg,
0.50 mmol) and FeCl2·4H2O (20 mg, 0.10 mmol, 20 mol%) in DMSO
(1.5 mL) for 4 h.
Yield: 95 mg (73%); light brown solid; mp 37–38 °C (EtOAc).
(6) (a) Khlebnikov, A. F.; Novikov, M. S. Top. Heterocycl. Chem. 2016,
41, 143. (b) Huang, C.-Y.; Doyle, A. G. Chem. Rev. 2014, 114,
8153. (c) Khlebnikov, A. F.; Novikov, M. S. Tetrahedron 2013, 69,
3363. (d) Padwa, A. Adv. Heterocycl. Chem. 2010, 99, 1.
(7) (a) Isomura, K.; Kobayashi, S.; Taniguchi, H. Tetrahedron Lett.
1968, 9, 3499. (b) Isomura, K.; Uto, K.; Taniguchi, H. J. Chem. Soc.,
Chem. Commun. 1977, 664. (c) Padwa, A.; Carlsen, P. H. J. J. Org.
Chem. 1978, 43, 2029. (d) Isomura, K.; Ayabe, G.-I.; Hatano, S.;
Taniguchi, H. J. Chem. Soc., Chem. Commun. 1980, 1252.
(e) Taber, D. F.; Tian, W. J. Am. Chem. Soc. 2006, 128, 1058.
(f) Chiba, S.; Hattoti, G.; Narasaka, K. Chem. Lett. 2007, 36, 52.
(g) Li, X.; Du, Y.; Liang, Z.; Li, X.; Pan, Y.; Zhao, K. Org. Lett. 2009,
11, 2643. (h) Jana, S.; Clements, M. D.; Sharp, B. K.; Zheng, N.
Org. Lett. 2010, 12, 3736.
1H NMR (400 MHz, CDCl3): δ = 3.84 (s, 3 H), 6.95 (d, J = 5.3 Hz, 1 H),
7.19 (d, J = 5.3 Hz, 1 H), 7.38–7.44 (m, 3 H), 7.65–7.67 (m, 2 H), 8.72
(br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 51.3 (CH3), 105.6 (C), 111.0 (CH), 125.7
(CH), 126.6 (C), 128.3 (CH), 128.8 (CH), 129.1 (CH), 131.8 (C), 136.9
(C), 142.0 (C), 164.5 (C).
HRMS-ESI: m/z [M + Na]+ calcd for C14H11NNaO2S+: 280.0403; found:
280.0415.
Funding Information
We gratefully acknowledge the financial support of the Russian Sci-
(8) (a) Galenko, E. E.; Khlebnikov, A. F.; Novikov, M. S. Chem. Hetero-
cycl. Compd. 2016, 52, 637. (b) Auricchio, S.; Bini, A.;
Pastormerlo, E.; Truscello, A. M. Tetrahedron 1997, 53, 10911.
(c) Mikhailov, K. I.; Galenko, E. E.; Galenko, A. V.; Novikov, M. S.;
Ivanov, A. Yu.; Starova, G. L.; Khlebnikov, A. F. J. Org. Chem. 2018,
83, 3177. (d) Galenko, E. E.; Bodunov, V. A.; Galenko, A. V.;
Novikov, M. S.; Khlebnikov, A. F. J. Org. Chem. 2017, 82, 8568.
(e) Galenko, A. V.; Galenko, E. E.; Shakirova, F. M.; Novikov, M.
S.; Khlebnikov, A. F. J. Org. Chem. 2017, 82, 5367. (f) Galenko, E.
E.; Galenko, A. V.; Khlebnikov, A. F.; Novikov, M. S.; Shakirova, J.
R. J. Org. Chem. 2016, 81, 8495. (g) Galenko, E. E.; Tomashenko,
O. A.; Khlebnikov, A. F.; Novikov, M. S.; Panikorovskii, T. L. Beil-
stein J. Org. Chem. 2015, 11, 1732. (h) Galenko, E. E.;
Tomashenko, O. A.; Khlebnikov, A. F.; Novikov, M. S. Org. Biomol.
Chem. 2015, 13, 9825. (i) Galenko, E. E.; Galenko, A. V.;
Khlebnikov, A. F.; Novikov, M. S. RSC Adv. 2015, 5, 18172.
(9) Bauer, I.; Knölker, H.-J. Chem. Rev. 2015, 115, 3170.
(10) Wu, C.; Li, J.; Yan, B. Dalton Trans. 2014, 43, 5364.
(11) Dannhardt, G.; Laufer, S.; Obergrusberger, I. Synthesis 1989, 275.
(12) Scarpati, R. Gazz. Chim. Ital. 1959, 89, 1511.
ence Foundation (Grant no. 16-13-10036).
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Acknowledgment
This research was carried out using the resources of the Centre for
Magnetic Resonance, and the Centre for Chemical Analysis and Mate-
rials of St. Petersburg State University.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591576.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–O