4-Bromo-2,3-dihydroisoxazoles: synthesis and application in halogen-lithium exchange reactions

Article abstract of DOI:10.1016/j.tet.2015.06.102

Abstract The synthesis of novel types of 4-bromo-2,3-dihydroisoxazoles using pyridinium tribromide in the presence of base is described. Reactivity of the initial substrates and the yields depend on the substituent at C3. To demonstrate a practical scope

Full text of DOI:10.1016/j.tet.2015.06.102

Tetrahedron 71 (2015) 6112e6115
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
4
-Bromo-2,3-dihydroisoxazoles: synthesis and application in
halogen-lithium exchange reactions
a
b
a,
*
Lucia Kle ꢀs ꢀc íkov aꢁ , Jana Doh aꢁ nꢀ o ꢀs ov aꢁ , R oꢁ bert Fischer
a
Institute of Organic Chemistry, Catalysis and Petrochemistry, Slovak University of Technology, Radlinsk ꢁe ho 9, 812 37 Bratislava, Slovak Republic
Institute of Analytical Chemistry, Department of NMR Spectroscopy and Mass Spectrometry, Slovak University of Technology, Radlinsk ꢁe ho 9,
12 37 Bratislava, Slovak Republic
b
8
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 May 2015
Received in revised form 18 June 2015
Accepted 29 June 2015
Available online 3 July 2015
The synthesis of novel types of 4-bromo-2,3-dihydroisoxazoles using pyridinium tribromide in the
presence of base is described. Reactivity of the initial substrates and the yields depend on the substituent
at C3. To demonstrate a practical scope of the 4-bromo-substituted 2,3-dihydroisoxazoles, representative
2-benzyl-4-bromo-3,5-diphenyl-2,3-dihydroisoxazole is subjected to halogen-lithium exchange reaction.
The corresponding (2,3-dihydroisoxazol-4-yl)lithium reacts with three selected electrophiles to afford 4-
substituted 2,3-dihydroisoxazoles in moderate yields.
Keywords:
Ó 2015 Elsevier Ltd. All rights reserved.
2,3-Dihydroisoxazole
Bromination
Pyridinium tribromide
Lithium
1. Introduction
substrates in the processes of screening for potent pharmacological
candidates. For instance, Valdecoxib (nonsteroidal antiin-
2
Small metalated heterocycles represent attractive substrates in
organic synthesis due to their wide applicability in forming new
carbonecarbon bonds. Specifically, five-membered aromatic (iso-
flammatory drug) and Oxacillin (b-lactamase-resistant antibiotic)
have been recently synthesized from 4-bromo-5-methylisoxazole 2
1
2a
using bromine-lithium exchange reaction at the 4-position also.
xazol-4-yl)lithium species 1 (Fig. 1) are powerful building blocks in
medicinal chemistry and play an important role as promising
On the other hand, a method for the successful preparation of
nonaromatic lithiated isoxazolines 3 has not been described to
date.
3
Based on our interest in the field of 2,3-dihydroisoxazoles, we
investigated the synthesis of such novel lithiated heterocycles. In
this paper, we report on the preparation of N-benzyl-4-bromo-2,3-
dihydroisoxazoles 4 by means of bromination reactions of 4-
unsubstituted 2,3-dihydroisoxazoles, and on their utilization in
bromine-lithium
exchange
reactions
to
afford
(2,3-
dihydroisoxazol-4-yl)lithium compounds 5 as suitable substrates
for carbonecarbon bond formation at C4 (Scheme 1). The presented
synthetic route provides the possibility for 4-substituted 2,3-
dihydroisoxazoles 6 that could be hard to prepare by other
methods.
Fig. 1. (Isoxazol-4-yl)lithium species as suitable substrates for biologically active
molecules.
Scheme 1. General synthetic route to 4-substituted 2,3-dihydroisoxazoles via
*
Corresponding author. E-mail address: robert.fischer@stuba.sk (R. Fischer).
bromine-lithium exchange.
http://dx.doi.org/10.1016/j.tet.2015.06.102
040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
0

L. Kle ꢀs ꢀc íkov aꢁ et al. / Tetrahedron 71 (2015) 6112e6115
6113
2
2
. Results and discussion
the desired product 15 gradually decomposed. Most likely, released
hydrobromic acid caused the quarternisation of N2, which resulted
in ring-opening reactions. The use of DBU or pyridine did not have
a positive effect on the reaction course. Finally, we prepared dihy-
droisoxazole 15 in satisfactory 60% yield. The reaction performed in
less concentrated solution led to higher yield of 15 (60% at 0.05 M,
26% at 0.1 M and 25% at 0.5 M). With optimized reaction conditions
in hand, we scaled up the reaction of 11 (1.6 mmol). Surprisingly,
the yield dropped dramatically to 13%. Based on our positive ex-
.1. Synthesis of 2,3-dihydroisoxazoles
In accordance with the literature, the starting N-benzyl-2,3-
dihydroizoxazoles 11 and 12 were readily available from the cor-
responding nitrones (Scheme 2). The reactions of nitrones 7 and
8
propargylic N-hydroxylamines, which upon zinc iodide catalyzed
cyclization gave 2,3-dihydroizoxazoles 11 and 12 in very good
4
4b
5
2
with phenylacetylene (10) in the presence of Zn(OTf) afforded
4
b
3
d
periences with 2-chloropyridine in elimination reactions, we
have replaced triethylamine for this base. Thus, the bromination of
11 with 1.1 equiv of pyridinium tribromide (14) and 3 equiv of 2-
4
c
yields (89% and 92%) nearly consistent with published results.
,3-Dihydroizoxazole 13 was prepared via direct 1,3-dipolar cy-
2
6
ꢀ
cloaddition of nitrone 9 with phenylacetylene (10) in satisfactory
6% yield (Scheme 2). Contrary to previously published procedures
chloropyridine in anhydrous THF at ꢁ40 C gave 4-bromo-2,3-
7
dihydroisoxazole 15 in 53% yield (Scheme 3). Contrary to bromi-
nation of 11, the reactions of 2,3-dihydroisoxazoles 12 and 13,
bearing isopropyl and ethoxycarbonyl groups at C3, proceeded
7
ꢀ
for 13, the presented reaction was performed in toluene at 60 C in
4 h without catalyst.
2
ꢀ
slower at ꢁ40 C, and therefore needed to be performed at higher
temperature, and moreover with a larger amount of pyridinium
tribromide (14). Interestingly, triethylamine was again a superior
base to 2-chloropyridine. Finally, desired 4-bromo-2,3-
dihydroisoxazoles 16 and 17 were prepared in 66% and 50%
yields, respectively (Scheme 3). The bromination at C4 was con-
1
13
firmed by H and C NMR experiments as follows. Signal of the H-4
proton disappeared and the multiplicity of the H-3 proton of 15 was
simplified (singlet,
of starting 2,3-dihydroisoxazole 11. Furthermore, the signals of C-4
and C-5 were shifted to low field (C-4, 11:
¼95.9 ppm; 15:
d¼4.98 ppm) compared to H-3 and H-4 protons
d
d
¼88.4 ppm and C-5, 11:
d
¼153.0 ppm; 15: ¼147.8 ppm). The
d
presence of the bromo atom was clearly confirmed by HRMS.
Scheme 2. Starting N-benzyl-2,3-dihydroisoxazoles prepared from the corresponding
nitrones.
2
.2. Bromination reactions
Only a few reports on the synthesis of 4-halogen-substituted
,3-dihydroizoxazoles have appeared to date. In general, such
Scheme 3. Bromination reactions of 2,3-dihydroisoxazoles into the 4-position.
2
compounds were considered to be unstable and therefore not ap-
plicable in subsequent reactions. They were obtained by reductions
8
a
of the corresponding isoxazolium salts with LiAlH
4
and NaBH
4
,
or
2.3. Bromine-lithium exchange reactions
8
b
by their reactions with organometallic reagents, and through the
iodocyclization of the propargylic N-hydroxylamines in the pres-
ence of ICl.8 As mentioned earlier, our experiences with the
chemistry of 2,3-dihydroisoxazoles inspired us to examine
a chemical behavior of such compounds in bromination reactions,
with the goal to prepare 4-bromo-2,3-dihydroisoxazoles as suitable
starting substrates for halogen-lithium exchange reactions.
To further demonstrate a practical scope of the 4-bromo-
substituted 2,3-dihydroisoxazoles, we focused our attention on
bromine-lithium exchange reactions. As shown in Scheme 4, rep-
resentative 2,3-dihydroisoxazole 15 was treated with n-BuLi in
c
ꢀ
anhydrous THF at ꢁ80 C. The rate of lithium insertion was moni-
2 2
tored by TLC (hexanes/CH Cl , 70:30) and HPLC-MS. The quenching
At the beginning, we focused our attention on searching for
a suitable bromination agent. First attempts were carried out with
model dihydroisoxazole 11 (0.16 mmol scale) in anhydrous THF in
4
of an analytical sample with satd aq NH Cl solution caused a rapid
hydrolysis of lithium species 18, affording 4-unsubstituted 2,3-
dihydroisoxazole 11. A starting substrate was completely con-
sumed after stirring for one hour. Subsequently, a neat electrophile
ꢀ
the presence of triethylamine at 0 C. NBS did not work, and the use
ꢀ
of bromine led to a rapid decomposition of 11 without any evidence
of the desired product. Fortunately, pyridinium tribromide (14)
reacted satisfactorily to afford 4-bromo-2,3-dihydroisoxazole 15
was added dropwise and the stirring continued for 24 h at ꢁ80 C.
Iodomethane, benzoyl chloride and isobutyraldehyde were se-
lected as appropriate electrophiles due to their good reactivity.
Three representative 2,3-dihydroisoxazoles 19, 20 and 21 were
successfully prepared in moderate 51%, 61% and 69% yields, re-
spectively (Scheme 4). Moreover, the reaction with iso-
butyraldehyde exclusively provided single isomer. Despite the
complete bromine-lithium exchange, 2,3-dihydroisoxazole 11 was
detected in all cases, even though 4 equiv of each electrophile were
(
Scheme 3). A dropwise addition of freshly prepared THF solution of
4 was preferred, compared to a solid. Solvents such as NMP,
CH CN, CHCl and CH Cl were also tested, however they were
1
3
3
2
2
found to be unsuitable. The best results in terms of chemical yield
and purity were obtained, when the reaction was performed at
ꢀ
ꢁ
40 C and with 3 equiv of triethylamine. It is worth noting that the
9
elimination also proceeded without any additional base, however
used and the reaction time was 24 h.

6114
L. Kle ꢀs ꢀc íkov aꢁ et al. / Tetrahedron 71 (2015) 6112e6115
column chromatography (hexanes/EtOAc, 90:10) to give 2,3-
dihydroisoxazole 13 (76%, 1.7 g, 5.5 mmol) as a pale yellow oil.
7
All spectroscopic data were in agreement with the literature.
4.3. Bromination reactions
4
.3.1. 2-Benzyl-4-bromo-3,5-diphenyl-2,3-dihydroisoxazole
(15). The reaction flask was charged with 2,3-dihydroisoxazole 11
(0.5 g, 1.60 mmol), sealed with a rubber septum and filled with
argon. Anhydrous THF (27 mL) was added and the solution was
ꢀ
cooled to ꢁ40 C. 2-Chloropyridine (0.45 mL, 4.8 mmol, 3 equiv)
was added followed by dropwise addition of pyridinium tribromide
(14) (0.63 g, 1.77 mmol, technical grade 90%, SigmaeAldrich,
ꢀ
Scheme 4. Reagents and conditions: a) n-BuLi (2.5 M in hexane), THF, e80 C;
b) electrophile (E), THF, e80 C.
ꢀ
1
.1 equiv) in anhydrous THF (5 mL) over 10 min. The reaction
ꢀ
mixture was stirred for 24 h at ꢁ40 C. Upon reaction completion,
3
. Conclusions
satd aq NH Cl solution was added and the reaction mixture was
4
allowed to warm to ambient temperature. Water was added
In conclusion, novel bromination of 2,3-dihydroisoxazoles into
(30 mL), and the mixture was extracted with Et O (4ꢂ50 mL),
2
the 4-position using pyridinium tribromide in the presence of base
is presented. Three representative 4-bromo-2,3-dihydroisoxazoles
are prepared and isolated in moderate yields for the first time.
Reactivity of the initial substrates and the yields depend on the
substituent at C3. To demonstrate a practical scope of the 4-bromo-
substituted 2,3-dihydroisoxazoles, representative 2-benzyl-4-
combined organic layers were dried over MgSO and the solvent
4
was evaporated in vacuo. The product was isolated by column
chromatography (hexanes/CH Cl , 70:30) to provide 4-bromo-2,3-
2
2
dihydroisoxazole 15 (53%, 0.33 g, 0.84 mmol) as a pale yellow
ꢀ
powder. Mp 83e85 C; IR (ATR): 3028, 2781, 1641, 1599, 1492, 1454,
ꢁ1 1
1901, 1067, 1028, 737, 688, 643 cm
3
; H NMR (600 MHz, CDCl ):
bromo-3,5-diphenyl-2,3-dihydroisoxazole
is
subjected
to
d
¼7.90e7.87 (m, 2H), 7.42e7.39 (m, 5H), 7.35e7.28 (m, 8H), 4.98 (s,
13
halogen-lithium exchange reaction. The corresponding (2,3-
dihydroisoxazol-4-yl)lithium reacts with three selected electro-
philes to afford 4-substituted 2,3-dihydroisoxazoles in moderate
yields. The presented synthetic route offers an alternative method
for the preparation of 2,3-dihydroisoxazoles that can be difficult to
obtain with 1,3-dipolar cycloadditions of nitrones with 1,2-
disubstituted alkynes.
1H), 4.46 (d, 1H, J¼12.9 Hz), 4.15 (d, 1H, J¼12.9 Hz); C NMR
(151 MHz, CDCl ):
¼147.8, 139.3, 135.7, 129.7, 129.6, 128.6, 128.5,
128.3, 128.2, 127.8, 127.7 (2xC), 127.3, 88.4, 78.3, 63.5; HRMS (ESI):
calcd for C22H19Br NO [MþH] : 392.0650, found: 392.0642.
3
d
7
9
þ
4.3.2. 2-Benzyl-4-bromo-3-isopropyl-5-phenyl-2,3-dihydroisoxazole
(16). The reaction flask was charged with 2,3-dihydroisoxazole 12
(0.6 g, 2.15 mmol), sealed with a rubber septum and filled with
4
4
. Experimental section
argon. The substrate was dissolved in anhydrous THF (17 mL).
Triethylamine (0.9 mL, 6.45 mmol, 3 equiv) was added, followed by
dropwise addition of pyridinium tribromide (14) (1.53 g, 4.3 mmol,
technical grade 90%, SigmaeAldrich, 2 equiv) in anhydrous THF
(5 mL) over 10 min. The reaction mixture was stirred for 5 h at
.1. General
All melting points were measured on a Melting Point B-540
apparatus (B u€ chi) and are uncorrected. HRMS analyses were per-
formed on Orbittrap Velos Pro spectrometer (Thermo Fisher Sci-
entific). Infrared (IR) spectra were recorded on a Nicolet 5700 FTIR
spectrometer with ATR Smart Orbit Diamond adapter (Thermo
ambient temperature. Upon reaction completion, satd aq NH Cl
solution was added followed by the addition of water (30 mL) and
4
the mixture was extracted with Et O (4x50 mL). Combined organic
2
layers were dried over MgSO4 and the solvent was evaporated in
ꢁ
1
Electron Corporation) and are reported as wave number (cm ).
vacuo. The product was isolated by column chromatography
(hexanes/CH Cl , 70:30) to provide 4-bromo-2,3-dihydroisoxazole
NMR spectra were recorded on a Varian VNMRS-600 spectrometer
2
2
1
H, 600 MHz and 13C, 151 MHz) in CDCl
(
3
using TMS as the internal
16 (66%, 0.51 g, 1.42 mmol) as a yellow oil. IR (ATR): 3033, 2964,
ꢁ
1
1
standard. TLC analysis was carried out using TLC Silica gel 60 F254
aluminum sheets, Merck) and visualized by UV light or with per-
1675, 1668, 1495, 1453, 1361, 1601, 1027, 739, 691, 674 cm
NMR (600 MHz, CDCl ):
; H
(
d
¼7.85e7.78 (m, 2H), 7.44e7.30 (m, 8H),
3
manganate solution followed by heating. Flash column chroma-
tography was performed on B u€ chi system (Pump Manager C-615
and Fraction Collector C-660), using Normasil 60 silica gel
4.30 (d, 1H, J¼12.5 Hz), 3.87 (d, 1H, J¼12.5 Hz), 3.82 (d, 1H,
J¼3.2 Hz), 2.04e1.94 (m, 1H), 0.91 (d, 3H, J¼6.9 Hz), 0.83 (d, 3H,
13
J¼6.9 Hz); C NMR (151 MHz, CDCl ): ¼147.3, 135.9, 132.7, 129.9,
3
d
(
0.040e0.063 mm) (VWR). All solvents were dried and distilled
129.4, 128.3, 128.2, 127.7, 127.3, 87.0, 79.2, 64.4, 30.6, 19.0, 15.9;
7
9
þ
according to conventional methods. THF, NMP, CH Cl , CHCl , tol-
2
2
3
HRMS (ESI): calcd for C19H21Br NO [MþH] : 358.0807, found:
uene and acetonitrile were stored over molecular sieves and han-
dled under inert atmosphere. All reagents were purchased from
SigmaeAldrich, Acros Organics, Alfa-Aesar, Merck or Mikrochem
Trade and were used without further purification.
358.0809.
4.3.3. Ethyl 2-benzyl-4-bromo-5-phenyl-2,3-dihydroisoxazole-3-
carboxylate (17). The reaction flask was charged with 2,3-
dihydroisoxazole 13 (0.5 g, 1.61 mmol), sealed with a rubber sep-
tum and filled with argon. The substrate was dissolved in anhy-
drous THF (11 mL). Triethylamine (0.67 mL, 4.83 mmol, 3 equiv)
was added, followed by dropwise addition of pyridinium tri-
bromide (14) (1.43 g, 4.03 mmol, technical grade 90%, Sigma-
eAldrich, 2.5 equiv) in anhydrous THF (5 mL) over 10 min. The
reaction mixture was stirred for 4 h at ambient temperature. Upon
4
.2. 1,3-Dipolar cycloaddition of nitrone 9 with phenyl-
acetylene (10)
4
.2.1. Ethyl 2-benzyl-5-phenyl-2,3-dihydroisoxazole-3-carboxylate
(13). Nitrone 9 (1.5 g, 7.2 mmol) was mixed with anhydrous tolu-
ene (100 mL), phenylacetylene (10) (4.8 mL, 43.7 mmol, 6 equiv)
ꢀ
was added and the mixture was stirred at 60 C for 24 h under
reaction completion, satd aq NH
the addition of water and the mixture was extracted with Et
(4ꢂ50 mL). Combined organic layers were dried over MgSO and
4
Cl solution was added followed by
argon. Upon reaction completion (TLC, hexanes/EtOAc, 80:20), the
solvent was evaporated in vacuo. The product was isolated by
2
O
4

L. Kle ꢀs ꢀc íkov aꢁ et al. / Tetrahedron 71 (2015) 6112e6115
6115
the solvent was evaporated in vacuo. The product was isolated by
column chromatography (hexanes/CH Cl , 60:40) to provide 4-
bromo-2,3-dihydroisoxazole 17 (50%, 0.31 g, 0.80 mmol) as a yel-
1599, 1493, 1454, 1027, 1004, 997, 762, 696 cmꢁ1; 1H NMR
(600 MHz, CDCl ):
2
2
3
d
¼7.68e7.65 (m, 2H), 7.43e7.25 (m, 13H), 4.94 (s,
1H), 4.44 (d, 1H, J¼12.5 Hz), 4.11 (d, 1H, J¼12.5 Hz), 4.07 (d, 1H,
low oil. IR (ATR): 3138, 2887, 1722, 1669, 1594, 1449, 1290, 1238,
J¼9.3 Hz), 1.85e1.77 (m, 1H), 0.99 (d, 3H, J¼6.5 Hz), 0.89 (d, 3H,
ꢁ
1
1
13
1
(
(
191, 1018, 730, 690 cm ; H NMR (600 MHz, CDCl
3
):
d
¼7.87e7.83
J¼6.5 Hz), 0.86 (bs, 1H); C NMR (151 MHz, CDCl
3
):
d
¼151.2, 142.7,
m, 2H), 7.42e7.31 (m, 8H), 4.58 (s, 1H), 4.43 (d, 1H, J¼12.7 Hz), 4.22
136.0, 129.6 (2xC), 129.4, 129.0, 128.5, 128.4 (2ꢂC), 128.1, 127.6,
1
3
q, 2H, J¼7.1 Hz), 4.07 (d, 1H, J¼12.7 Hz), 1.26 (t, 3H, J¼7.1 Hz);
):
C
127.3, 110.9, 73.6, 73.3, 63.3, 33.4, 19.5, 19.2; HRMS (ESI): calcd for
þ
NMR (151 MHz, CDCl
1
calcd for C19
3
d
¼168.8, 149.8, 134.6, 130.0, 129.6, 128.6,
C
26
H28NO
2
for [MþH] : 386.2120, found: 386.2106.
28.3, 128.1, 127.5, 127.1, 81.4, 76.0, 63.7, 61.8, 14.1; HRMS (ESI):
7
9
þ
H
19Br NO
3
[MþH] : 388.0548, found: 388.0546.
Acknowledgements
4
.4. Typical experimental procedure for bromine-lithium
This work was supported by Slovak Grant Agencies (APVV,
Bratislava, project No. APVV-14-0147, VEGA, Bratislava project No.
exchange
1
2
/0488/14 and ASFEU, Bratislava, ITMS projects No. 26240120001,
6240120025).
4
.4.1. 2-Benzyl-4-methyl-3,5-diphenyl-2,3-dihydroisoxazole (19). A
flame-dried reaction flask was flushed with argon and charged
with 4-bromo-2,3-dihydoisoxazole 15 (200 mg, 0.51 mmol) dis-
solved in anhydrous THF (5 mL, 0.1 M). The solution was cooled to
References and notes
ꢀ
ꢁ
80 C and n-BuLi (0.31 mL, 0.77 mmol, 2.5 M in hexane, 1.5 equiv)
1. (a) He, S.; Senter, T. J.; Pollock, J.; Han, C.; Kumar Upadhyay, S.; Purohit, T.; Go-
was added dropwise over 15 min. Stirring was continued for 1 h at
gliotti, R. D.; Lindsley, C. W.; Cierpicki, T.; Stauffer, S. R.; Grembecka, J. J. Med.
Chem. 2014, 57, 1543e1556; (b) Keenan, M.; Abbott, M. J.; Alexander, P. W.;
Armstrong, T.; Best, W. M.; Berven, B.; Botero, A.; Chaplin, J. H.; Charman, S. A.;
Chatelain, E.; von Geldern, T. W.; Kerfoot, M.; Khong, A.; Nguyen, T.; McManus, J.
D.; Morizzi, J.; Ryan, E.; Scandale, I.; Thompson, R. A.; Wang, S. Z.; White, K. L. J.
Med. Chem. 2012, 55, 4189e4204; (c) Oberli, M. A.; Buchwald, S. L. Org. Lett. 2012,
ꢀ
ꢁ
80 C. Thereafter, iodomethane (0.13 mL, 2.04 mmol, 4 equiv) was
added by portions and the mixture was stirred for additional 24 h at
ꢀ
ꢁ
80 C. The reaction was quenched by the addition of a satd aq
NH
ature. Water (20 mL) was added to dissolve a formed slurry and the
mixture was extracted with CH Cl
(3ꢂ20 mL). Combined organic
layers were dried over MgSO and the solvent was evaporated in
vacuo. The product was isolated by flash column chromatography
hexanes/CH Cl , 70:30) to give 2,3-dihydroisoxazole 19 (51%,
5 mg, 0.26 mmol) as a pale yellow oil. IR (ATR): 3060, 3028, 1695,
4
Cl solution and the mixture was warmed to ambient temper-
1
2
4, 4606e4609; (d) Liu, G.; Liu, M.; Pu, S.; Fan, C.; Cui, S. Tetrahedron 2012, 68,
267e2275; (e) Chinchilla, R.; N aꢁ jera, C.; Yus, M. ARKIVOC 2007, x, 152e231; (f)
2
2
Chinchilla, R.; N aꢁ jera, C.; Yus, M. Chem. Rev. 2004, 104, 2667e2722; (g) Dondoni,
A.; Marra, A. Chem. Rev. 2004, 104, 2557e2599.
4
2. (a) Dong, K.-Y.; Qin, H.-T.; Bao, X.-X.; Liu, F.; Zhu, C. Org. Lett. 2014, 16,
5266e5268; (b) Kamau, M. G.; Harikrishnan, L. S.; Finlay, H. J.; Qiao, J. X.; Jiang,
(
8
2
2
J.; Poss, M. A.; Salvati, M. E.; Wexler, R. R.; Michael Lawrence, R. Tetrahedron
2012, 68, 2696e2703; (c) Kumar Mittapalli, G.; Vellucci, D.; Yang, J.; Toussaint,
M.; Brothers, S. P.; Wahlestedt, C.; Roberts, E. Bioorg. Med. Chem. Lett. 2012, 22,
ꢁ1 1
1
(
4
668, 1599, 1495, 1449, 1232, 1068, 1026, 755, 694 cm ; H NMR
600 MHz, CDCl ):
¼7.57e7.53 (m, 2H), 7.43e7.23 (m, 13H),
.80e4.78 (m, 1H), 4.40 (d, 1H, J¼13.0 Hz), 4.09 (d, 1H, J¼13.0 Hz),
3916e3920; (d) Kawai, H.; Sugita, Y.; Tokunaga, E.; Shibata, N. Eur. J. Org. Chem.
3
d
2012, 1295e1298; (e) Ratcliffe, P.; Abernethy, L.; Ansari, N.; Cameron, K.;
Clarkson, T.; Dempster, M.; Dunn, D.; Easson, A.-M.; Edwards, D.; Everett, K.;
Feilden, H.; Ho, K.-K.; Kultgen, S.; Littlewood, P.; Maclean, J.; McArthur, D.;
McGregor, D.; McLuskey, H.; Neagu, I.; Nimz, O.; Nisbet, L.-A.; Ohlmeyer, M.;
Palin, R.; Pham, Q.; Rong, Y.; Roughton, A.; Sammons, M.; Swanson, R.; Tracey,
H.; Walker, G. Bioorg. Med. Chem. Lett. 2011, 21, 4652e4657.
13
1
.79 (d, 3H, J¼1.1 Hz); C NMR (151 MHz, CDCl
3
):
d
¼145.9, 141.3,
136.9, 130.2, 129.9, 129.1, 128.9, 128.8, 128.7, 128.6, 128.0, 127.9,
127.7, 105.6, 79.5, 63.7, 11.1; HRMS (ESI): calcd for C23
H22NO
þ
[MþH] : 328.1701, found: 328.1680.
3. (a) Fischer, R.; Lackovi ꢀc ov aꢁ , D.; Fi ꢀs era, L. Synthesis 2012, 44, 3783e3788; (b)
Fischer, R.; Stanko, B.; Pr oꢁ nayov aꢁ , N. Synlett 2013, 2132e2136; (c) Be nꢀ adikov ꢁa , D.;
ꢀ
ꢁ
ꢁ
ꢀ
ꢁꢀ ꢀ
ꢁ
Curillova, J.; Lacek, T.; Rakovsky, E.; Moncol, J.; Dohanosova, J.; Fischer, R. Tet-
4
.4.2. (2-Benzyl-3,5-diphenyl-2,3-dihydroisoxazol-4-yl)
(phenyl)
ꢀ
rahedron 2014, 70, 5585e5593; (d) Z aꢁ borsk yꢁ , O.; Soral, M.; Fischer, R. Tetrahe-
methanone (20). Yield 61% (140 mg, 0.34 mmol) after flash column
dron Lett. 2015, 56, 2155e2158.
4
. (a) Frantz, D. E.; F €a ssler, R.; Carreira, E. M. J. Am. Chem. Soc. 1999, 121,
chromatography (hexanes/CH
2
Cl
2
, 50:50), colorless powder, Mp
11245e11246; (b) Aschwanden, P.; Kvaernø, L.; Geisser, R. W.; Kleinbeck, F.;
ꢀ
9
8
4e96 C; IR (ATR): 3030, 2875, 1608, 1596, 1575, 1347, 1135, 1074,
89, 737, 690, 672 cm ; H NMR (600 MHz, CDCl
Carreira, E. M. Org. Lett. 2005, 7, 5741e5742; (c) Aschwanden, P.; Frantz, D. E.;
Carreira, E. M. Org. Lett. 2000, 2, 2331e2333.
. Dondoni, A.; Franco, S.; Junquera, F.; Merchan, F. L.; Merino, P.; Tejero, T. Synth.
Commun. 1994, 23, 2537e2550.
. Inouye, Y.; Watanabe, Y.; Takahashi, S.; Kakisawa, H. Bull. Chem. Soc. Jpn. 1979, 52,
3763e3764.
ꢁ
1 1
3
):
d¼7.46e7.01
5
6
(
m, 20H), 5.62 (s, 1H), 4.48 (d, 1H, J¼13.4 Hz), 4.30 (d, 1H,
13
J¼13.4 Hz); C NMR (151 MHz, CDCl
3
):
d¼192.2, 162.0, 140.5, 138.5,
1
1
35.4, 131.5, 130.6, 129.5 (3ꢂC), 128.9, 128.5 (3ꢂC), 127.9, 127.8,
27.7, 127.4, 113.3, 75.9, 63.1; HRMS (ESI): calcd for C29
H24NO
2
7. (a) Cantagrel, F.; Pinet, S.; Gimbert, Y.; Chavant, P. Y. Eur. J. Org. Chem. 2005,
2694e2701.
þ
[MþH] : 418.1807, found: 418.1809.
8
. (a) Albertola, A.; Gonz ꢁa lez, A. M.; Laguna, M. A.; Pulido, F. J. Synthesis 1984,
5
10e512; (b) Albertola, A.; Antolín, L. F.; Gonz aꢁ lez, A.; Laguna, M. A.; Pulido, F. J. J.
4
.4.3. 1-(2-Benzyl-3,5-diphenyl-2,3-dihydroisoxazol-4-yl)-2-
Chem. Soc., Perkin Trans. 11988, 791e794; (c) Debleds, O.; Gayon, E.; Ostaszuk, E.;
Vrancken, E.; Campagne, J.-M. Chem. Eur. J. 2010, 16, 12207e12213.
. The ratios of 4-unsubstituted 2,3-dihydroisoxazole 11 determined from 1H NMR
spectra of the crude reaction mixtures: the reaction with iodomethaned18%;
with benzoyl chlorided5%; with isobutyraldehyded22%.
methylpropan-1-ol (21). Yield 69% (140 mg, 0.36 mmol, single iso-
mer) after flash column chromatography (hexanes/CH
colorless powder, Mp 75e77 C; IR (ATR): 3566, 3432, 2954, 1678,
9
2
Cl
2
, 70:30),
ꢀ