A versatile iron-catalyzed protocol for the one-pot synthesis of isoxazoles or isoxazolines from the same propargylic alcohols

Article abstract of DOI:10.1002/chem.201001461

The use N-sulfonyl-protected hydroxylamines as bi-nucleophiles in iron-catalyzed propargylic substitutions allows the selective one-pot synthesis of four classes of substituted isoxazoles or isoxazolines from the same propargylic alcohols (21 examples) by

Full text of DOI:10.1002/chem.201001461

FULL PAPER
DOI: 10.1002/chem.201001461
A Versatile Iron-Catalyzed Protocol for the One-Pot Synthesis of
or Isoxazolines from the Same Propargylic Alcohols
ACHTUNGTRENUNING soxazoles
Olivier Debleds, Eric Gayon, Emilie Ostaszuk, Emmanuel Vrancken,* and
Jean-Marc Campagne*[a]
Abstract: The use N-sulfonyl-protected
hydroxylamines as bi-nucleophiles in
iron-catalyzed propargylic substitutions
allows the selective one-pot synthesis
of four classes of substituted isoxazoles
or isoxazolines from the same propar-
gylic alcohols (21 examples) by simply
tuning the nature of the base. By using
an iron(III) catalyst and a base such as
are obtained in good isolated yields
(56–95%), whereas N-sulfonyl-protect-
ed isoxazolines 6 are selectively ob-
tained (77–93% yield) by using iron
and gold catalysts in the presence of a
AHCTUNGTRENNUNG
triethylamine (3 equiv), isoxazoles
3
Keywords: alkynes · cyclization ·
gold · heterocycles · iron
catalytic
amount
of
pyridine
(10 mol%).
Introduction
The development of efficient, versatile, one-pot, multistep
methodologies is of general interest for economic, environ-
mental, and practical reasons. As part of a program aimed
at developing gold- and iron-catalyzed reactions,[1] we re-
cently described a concise, one-pot synthesis of 2,3-dihydro-
isoxazoles through a dual gold–iron-catalyzed condensation
Scheme 1. Selective access to isoxazolines (previous work)..
of an N-Cbz-protected hydroxylamine (Cbz=carboben
A
motes propargylic substitution[3,4] and subsequent addition
of a combination of NaAuCl4·2H2O and 4-dimethylamino-
pyridine (DMAP) ensures the second cyclization step
(Scheme 1).
zyl-
ing group on the nitrogen atom and in the presence of a
stoichiometric amount of base, isoxazoles (Scheme 2) could
oxy) with propargylic alcohols.[2] In the first step, FeCl3 pro-
N
ACHTUNGTRENNUNG
be obtained in a one-pot, multistep sequence from propar-
gylic alcohols. Because of their potential within medicinal
chemistry, isoxazoles constitute an important class of hetero-
cyclic compounds and, consequently, considerable effort has
been focused on their synthesis.[5–8] Very recently, She et al.
The main features of this reaction are the ability to utilize
an electron-withdrawing protecting group on the nitrogen
atom and that the goldACTHNUTRGNE(NUG III)-catalyzed cyclization process
takes place second, in the presence of a base. Thus, we an-
ticipated that, starting from substrates bearing a good leav-
[a] Dr. O. Debleds, E. Gayon, E. Ostaszuk, Dr. E. Vrancken,
Prof. J.-M. Campagne
Institut Charles Gerhardt
UMR 5253 CNRS-UM2-UM1ENSCM
8 rue de l’Ecole Normale
34296 Montpellier Cedex 5 (France)
Fax : (+33)467144322
E-mail: emmanuel.vrancken@enscm.fr
jean-marc.campagne@enscm.fr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001461.
Scheme 2. Selective access to isoxazoles (this work). LG=leaving group.
Chem. Eur. J. 2010, 16, 12207 – 12213
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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reported a regioselective one-pot route to 3,5-disubstituted
isoxazoles based upon the conjugate addition of N-hydroxy-
4-toluACHTUNGTRENNUNGeneACHTUNGTRENNUNGsulfonamide to a-b-unsaturated ketones, followed
by elimination of the tosyl (Ts) moiety, cyclization, and de-
hydration.[7] The concept of a one-pot procedure that uses
readily available starting materials, as proposed by these au-
thors, is of great interest, but up to seven equivalents of
TsNHOH must be used to ensure good conversion and iso-
lated yields are only moderate to good.
the presence of Et3N (3 equiv). Under these conditions, 3a
was obtained in an improved yield (90%, Table 1, entry 3).
In contrast, the reaction conducted in the absence of both
the base and the gold catalyst stops at the propargylic sub-
stitution step and gives 4a in an 84% yield [Eq. (1)]. Start-
ing from isolated (and purified) propargyl hydroxylamine
4a, isoxazole 3a can then be obtained in 86% yield, in re-
fluxing CH2Cl2, in the presence of Et3N (3 equiv) [Eq. (2)].
Results and Discussion
For our part, we decided to check the validity of our strat-
egy of engaging N-sulfonyl-protected hydroxylamine as a bi-
nucleophile in our dual gold–iron-catalyzed sequence. If a
1:1 mixture of model propargylic alcohol 1a and N-hydroxy-
benzene sulfonamide 2 are treated with a catalytic amount
of FeCl3 (5 mol%), followed by the addition of
NaAuCl4·2H2O (10 mol%) and DMAP (3 equiv), a clean
reaction takes place to give the expected isoxazole, 3a, in
82% isolated yield (Scheme 3).
These experiments suggest the following reaction se-
quence: an iron-catalyzed propargylic substitution, followed
by a base induced b-elimination of the sulfone moiety and
then cyclization of transient oxime derivative 5a
(Scheme 4).[9] Indeed, if 4a is treated with DMAP (3 equiva-
Scheme 3. The one-pot synthesis of isoxazole 3a.
A study into the influence of different reaction parame-
ters and, in particular, the nature of the base was then initi-
ated (Table 1). The use of tertiary amines such as Et3N en-
sures the formation of isoxazole 3a in a similar yield to that
with DMAP, despite the instantaneous formation of a gold
mirror following the addition of NaAuCl4·2H2O (Table 1,
entry 2). The role of gold was, therefore, questioned and a
control reaction was performed without the gold catalyst, in
Scheme 4. A probable reaction pathway for the iron-catalyzed isoxazole
synthesis.
lents) at room temperature, a clean elimination takes place
(by 1H NMR spectrum monitoring) to give oxime 5a,[10]
which subsequently leads to isoxazole 3a after heating to
reflux [Eq. (3)].[11]
Table 1. Optimization of the reaction conditions for the one-pot synthe-
sis of isoxazoles.
Entry
FeCl3
[mol%]
NaAuCl4·2H2O
[mol%]
Base
ACHTUNGTRENN(UNG [equiv])
Yield[a]
[%]
G
U
1
2
3
4
5
5
5
5
2.5
2.5
10
10
–
–
–
DMAP (3)
Et3N (3)
Et3N (3)
Et3N (3)
Et3N (1.5)
82
80
90
89
83
During the preparation of this manuscript, Perumal et al.
described a gold-catalyzed isoxazole synthesis from isolated
propargylic oximes.[8] It is worth noting that in our reaction
conditions, a cleaner crude mixture and better yields are ob-
served in the absence of gold (see Table 1, entries 1–3). Op-
[a] Isolated yield.
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Isoxazole and Isoxazoline Synthesis
FULL PAPER
Table 3. Optimization of the reaction conditions for the one-pot synthe-
sis of isoxazolines.
timization of the reaction conditions gave the following re-
sults: the amount of iron catalyst can be reduced to
2.5 mol% and still maintain a high yield (89%; Table 1,
entry 4), but moving to 1.5 equivalents of Et3N induced a
slightly lower yield (83%; Table 1, entry 5).
The scope of the isoxazole formation was then extended
to various propargylic alcohols by using the optimized reac-
tion conditions described in Table 1, entry 4. In most cases,
the reactions proceed cleanly and the expected isoxazoles
3b–g are obtained in good to excellent yields, whatever the
nature (alkyl or aryl) and steric hindrance (primary, secon-
dary, or tertiary alkyl) at the acetylenic position of 1b–i
(Table 2). Bromine in the para position of an propargylic
Entry
NaAuCl4
[mol%]
Co-catalyst
([mol%])
t
4a:3a:6a[a]
Yield[b]
[%]
G
G
[h]
1
2
3
4
5
6
–
5
5
5
5
5
–
–
6
4
2
2
2
2
100:0:0
63:0:37
0:27:73
0:8:92
0:9:91
0:0:100
–
32
51
81
80
87
DMAP (30)
DMAP (10)
Et3N (10)
pyridine (10)
Table 2. Scope of the one-pot synthesis of isoxazoles.
1
[a] Determined by H NMR spectroscopy of the crude product. [b] Isolat-
ed yield.
reaction takes place in the presence of pyridine, 6a being
obtained as the only product in a good yield (87%; Table 3,
entry 6)
This procedure can be efficiently extended to various ana-
logues of 1a, as illustrated in the Table 4. Bulky substituents
in the acetylenic position are well tolerated, as well as elec-
tron-donating or electron-withdrawing groups on the aro-
matic ring.
Entry
Ar
R
Product
Yield[a]
[%]
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
tBu
cPr[b]
iPr
3b
3c
3d
3e
3 f
3g
3h
3i
93
87
94
84
95
91
77
56
Ph
4-FC6H4
4-BrC6H4
4-MeOC6H4
thiophen-2-yl
nBu
nBu
nBu
nBu
Table 4. Scope of the one-pot synthesis of isoxazolines.
[a] Isolated yield. [b] cPr=cyclopropyl.
aryl group, which potentially allows further functionalization
of the aromatic ring, is well tolerated, as shown for 3g, iso-
lated in an excellent 91% yield (Table 2, entry 6). Lower
yields are obtained by using alcohols 1h and i, containing
electron-rich aromatic groups in the propargylic position
(Ar=thiophen-2-yl or 4-MeOC6H4, Table 2, entries 7 and 8).
We have previously shown that a catalytic amount of base
favors the gold-assisted cyclization of N-Cbz analogues of 4
to form isoxazolines [Eq. (1), Scheme 1, and reference [2]].
Here, the N-sulfonyl-substituted derivatives exhibit the
same behavior: a poor 32% yield of 6a is obtained if
Entry
Ar
R
Product
Yield[a]
[%]
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
tBu
cPr
iPr
6b
6c
6d
6e
6 f
6g
6h
6i
77
86
87
93
89
87
81
83
89
Ph
4-FC6H4
4-BrC6H4
4-MeOC6H4
thiophen-2-yl
4-MeC6H4
nBu
nBu
nBu
nBu
nBu
6j
NaAuCl4·2H2O is used without
a base as co-catalyst
(Table 3, entries 1 and 2). The presence of DMAP in the re-
action mixture helps the cyclization process, but induces the
formation of isoxazole 3a as a side product (Table 3,
entry 3). Notably, the isolated yield of 6a in this case is sig-
nificantly higher than that without the base co-catalyst,
which suggests that the gold-cyclization pathway is faster
than the oxime formation. A decrease in the amount of base
has a beneficial effect upon both the yield of 6a and the se-
lectivity for it, but the undesired isoxazole, 3a, is still pres-
ent in the crude mixture (Table 3, entries 4 and 5). The de-
velopment of a selective route to access 6a requires a subtle
choice of the base. Indeed, a highly selective and efficient
[a] Isolated yield.
Starting from readily available propargylic alcohols, iron-
catalyzed propargylic substitutions with N-hydroxy-4-tolu-
ACHUTNGRENeNUG neACHUTNGTRENsNGUN ulfonamide allow, by a judicious choice of reaction con-
ditions, efficient, versatile access to propargylic hydroxyla-
mines 4 or propargylic oximes 5 (by adding a base to the re-
action mixture). From these compounds, alternative modes
of cyclization can be envisioned. Larock et al. recently re-
ported the electrophilic cyclization of O-methyl oximes,[6b]
allowing elegant access to functionalized isoxazoles such as
Chem. Eur. J. 2010, 16, 12207 – 12213
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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12209

J.-M. Campagne, E. Vrancken et al.
valdecoxib.[6c] Inspired by this work, compounds 7 and 8
where obtained from 1j through the iodo cyclization of tran-
sient intermediates 4j and 5j, in a one-pot sequence, in 88
and 77% isolated yields, respectively (Scheme 5).
Experimental Section
General considerations: Unless otherwise stated all commercial materials
were used without further purification. Reactions were carried out in
round-bottomed flasks equipped with a magnetic stirring bar. Dichloro-
methane was distilled over CaH2. TLC analysis of all reactions was per-
formed on silica gel 60 F254 TLC plates. Chromatography was carried out
with silica gel 60 A (35–70 mm). FT-IR spectra were recorded with a
Perkin Elem Spectrum 1000. 1H and 13C NMR spectra were recorded
with a Bruker Ultra shield 400 plus and referenced to CDCl3, unless oth-
erwise noted. Mass spectra and high-resolution mass spectra were ob-
tained from the mass spectrometer operated by the Centre Commun de
Spectromꢁtrie de Masse of the University Claude Bernard Lyon 1 and
the Laboratoire de Mesure Physique of the University Montpellier 2.
General procedure A—the preparation of isoxazoles (3a–i): N-Benzene-
sulfonamide hydroxylamine (0.8 mmol) and ironACTHNURTGNEU(GN III) chloride
(0.02 mmol) were added to a solution of propargylic alcohol (1 mmol) in
CH2Cl2 (5 mL). The solution was stirred for 1.5 h at reflux and then tri-
AHCTUNGERTGeNNUN thylamine (TEA; 3.0 mmol) was added. The resulting reaction mixture
was stirred for an additional 3 h at reflux. Upon completion (1H NMR
spectrum monitoring), the reaction was filtered through Celite and con-
centrated in vacuo. Purification of the crude material by chromatography
through silica gel (cyclohexane/diethyl ether) afforded the expected prod-
uct.
Scheme 5. Versatile routes to iodoisoxazoline 7 or iodoisoxazole 8 in a
one-pot sequence from the same propargylic alcohol, 1j.
5-Butyl-3-phenylisoxazole (3a): By following general procedure A, com-
pound 3a was obtained in 90% yield as a pale-yellow oil. 1H NMR
(400 MHz, CDCl3): d=0.96 (t, J=7.4 Hz, 3H), 1.39–1.48 (m, 2H), 1.69–
1.77 (m, 2H), 2.80 (t, J=7.6 Hz, 2H), 6.28 (s, 1H), 7.41–7.47 (m, 3H),
7.78–7.8 ppm (m, 2H); 13C NMR (100 MHz, CDCl3): d=13.6, 22.1, 26.4,
29.5, 98.7, 126.7 (2C), 128.8 (2C), 129.4, 129.7, 162.2, 174.2 ppm; these
spectral data are consistent with those in the literature.[12]
Conclusion
In conclusion, the use of N-sulfonyl-protected hydroxyl-
ACHTUNGTRENNUNGamines as bi-nucleophiles in iron-catalyzed propargylic sub-
stitutions allows the selective, in situ formation of propargyl-
ic hydroxylamines or propargylic oximes from the same
starting propargylic alcohols. Simple tuning of the cycliza-
tion conditions gives a practical and efficient one-pot route
to various functionalized heterocycles (21 examples,
Scheme 6).
5-tert-Butyl-3-phenylisoxazole (3b): By following general procedure A,
compound 3b was obtained in 93% yield as a white solid. M.p. 418C;
1H NMR (400 MHz, CDCl3): d=1.4 (s, 9H), 6.24 (s, 1H), 7.42–7.46 (m,
3H), 7.78–7.8 ppm (m, 2H); 13C NMR (100 MHz, CDCl3): d=28.8, 32.8,
96.3, 126.7 (2C), 128.7 (2C), 129.5, 129.7, 162.0, 181.7 ppm; MS (EI): m/z
(%): 201 (37) [M]+, 186 (18), 144 (100), 116 (11), 77 (16); IR (FT-IR):
n˜ =3061, 2966, 2878, 1598, 1576, 1480, 1465, 1443, 1402, 1365, 1277, 1030,
982, 919, 801, 768, 698 cmꢀ1; HRMS (ESI+): m/z calcd for [C13H15NO+
H]+: 202.1232; found: 202.1227.
5-Cyclopropyl-3-phenylisoxazole (3c): By following general procedure A,
compound 3c was obtained in 87% yield as a white solid. M.p. 458C;
1H NMR (400 MHz, CDCl3): d=1.00–1.11 (m, 4H), 2.08 (tt, J=5.1,
8.4 Hz, 1H), 6.21 (s, 1H), 7.41–7.46 (m, 3H), 7.75–7.79 ppm (m, 2H);
13C NMR (100 MHz, CDCl3): d=8.1, 8.3 (2C), 96.8, 126.6 (2C), 128.7
(2C), 129.3, 129.7, 162.4, 175.2 ppm; MS (EI): m/z (%): 185 (100) [M]+,
170 (17), 156 (25), 144 (94), 117 (28), 89 (12), 77 (46); IR (FT-IR): n˜ =
3121, 3062, 3018, 1605, 1583, 1469, 1447, 1410, 1365, 1284, 1026, 993, 768,
691 cmꢀ1; HRMS (ESI+): m/z calcd for [C12H11NO+H]+: 186.0919;
found: 186.0913.
5-Isopropyl-3-phenylisoxazole (3d): By following general procedure A,
compound 3d was obtained in 94% yield as a pale-yellow oil. 1H NMR
(400 MHz, CDCl3): d=1.35 (s, 3H), 1.37 (s, 3H), 3.13 (dsept, J=0.7,
7.0 Hz, 1H), 6.27 (d, J=0.8 Hz, 1H), 7.41–7.45 (m, 3H), 7.78–7.80 ppm
(m, 2H); 13C NMR (100 MHz, CDCl3): d=20.8 (2C), 27.2, 97.0, 126.7
(2C), 128.7 (2C), 129.4, 129.7, 162.1, 179.2 ppm; MS (ESI+): m/z (%):
187 (32) [M]+, 144 (100), 116 (14), 77 (18); IR (FT-IR): n˜ =3062, 2966,
2929, 2878, 1601, 1572, 1476, 1439, 1410, 1340, 1181, 986, 912, 768,
694 cmꢀ1; HRMS (ESI+): m/z calcd for [C12H13NO+H]+: 188.1075;
found: 188.1070.
3,5-Biphenylisoxazole (3e): By following general procedure A, com-
pound 3e was obtained in 84% yield as a white solid. M.p. 1378C;
1H NMR (400 MHz, CDCl3): d=6.84 (s, 1H), 7.46 –7.51 (m, 6H), 7.84–
7.89 ppm (m, 4H); 13C NMR (100 MHz, CDCl3): d=97.4, 125.8 (2C),
126.8 (2C), 127.4, 128.9 (2C), 129.0 (2C), 129.1, 130.0, 130.2, 162.9,
170.4 ppm; MS (EI): m/z (%): 221 (84) [M]+, 193 (8), 144 (18), 105
(100), 77 (52), 51 (14); IR (FT-IR): n˜ =3114, 3062, 2981, 1612, 1594, 1568,
Scheme 6. Versatile routes to various substituted heterocycles from the
same propargylic alcohols 1a–j. p-Tol=para-tolyl.
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Isoxazole and Isoxazoline Synthesis
FULL PAPER
1485, 1450, 1402, 1266, 1078, 952, 916, 816, 739, 698, 529 cmꢀ1; HRMS
(EI): m/z calcd for [C15H11NO]: 221.0841; found: 221.0840.
2 h. After reaction completion (TLC monitoring), the mixture was con-
centrated in vacuo and the crude material loaded onto a silica gel
column and purified by chromatography.
5-Butyl-3-(4-fluorophenyl)isoxazole (3 f): By following general proACTHNUTRGENUGcN e-
A
5-Butyl-3-phenyl-2-(phenylsulfonyl)-2,3-dihydroisoxazole (6a): By follow-
ing general procedure B, compound 6a was obtained in 87% yield as a
pale-yellow solid. M.p. 788C; H NMR (400 MHz, CDCl3): d=0.86 (t, J=
M.p. 358C; 1H NMR (400 MHz, CDCl3): d=0.96 (t, J=7.4 Hz, 1H),
1.38–1.47 (m, 2H), 1.68–1.76 (m, 2H), 2.78 (t, J=7.6 Hz, 2H), 6.24 (s,
1H), 7.10–7.14 (m, 2H), 7.76–7.79 ppm (m, 2H); 13C NMR (100 MHz,
1
7.21 Hz, 3H), 1.22–1.40 (m, 4H), 1.96–2.12 (m, 2H), 4.53 (s, 1H), 5.79 (s,
1H), 7.30–7.37 (m, 5H), 7.56–7.60 (m, 2H), 7.69–7.72 (m, 1H), 8.02–
8.06 ppm (m, 2H); 13C NMR (100 MHz, CDCl3): d=13.6, 22.1, 25.2, 28.3,
69.1, 95.9, 127.05 (2C), 128.32, 128.71 (2C), 128.93 (2C), 129.43 (2C),
133.9, 134.1, 139.87, 156.44 ppm; MS (ESI+): m/z (%): 344 (88) [M+H]+,
308 (12), 288 (15), 254 (60), 218 (33), 202 (23) [MꢀPhSO2]+, 171 (24),
147 (43), 92 (41), 90 (100); IR (FT-IR): n˜ =3063, 2957, 2931, 2871, 1686,
1494, 1364, 1311, 1172, 1088, 1027, 925, 847, 755, 728, 697, 645, 580,
561 cmꢀ1; HRMS (ESI+): m/z calcd for [C19H21NO3S+H]+: 344.1320;
found: 344.1337.
CDCl3): d=13.6, 22.1, 26.4, 29.5, 98.6, 116.0 (d, J
125.7 (d, J(C,F)=3.4 Hz, 1C), 128.6 (d, J(C,F)=8.6 Hz, 2C), 161.4, 162.4,
164.9, 174.5 ppm; MS (EI): m/z (%): 219 (68) [M]+, 190 (11), 177 (64),
162 (100), 135 (78), 107 (16), 95 (20); IR (FT-IR): n˜ =3114, 3077, 2929,
2966, 2878, 1612, 1587, 1524, 1461, 1435, 1384, 1233, 1163, 949, 842, 599,
525 cmꢀ1; HRMS (ESI+): m/z calcd for [C13H14FNO+H]+: 220.1138;
found: 220.1125.
3-(4-Bromophenyl)-5-butylisoxazole (3g): By following general pro
ACHTUNGTRENNUNGdure A, compound 3g was obtained in 91% yield as a pale-yellow solid.
M.p. 678C; 1H NMR (400 MHz, CDCl3): d=0.95 (t, J=7.3 Hz, 3H),
1.37–1.46 (m, 2H), 1.67–1.75 (m, 2H), 2.78 (t, J=7.6 Hz), 6.25 (s, 1H),
7.54–7.57 (m, 2H), 7.63–7.67 ppm (m, 2H); 13C NMR (100 MHz, CDCl3):
d=13.7, 22.2, 26.5, 29.6, 98.6, 124.0, 128.2 (2C), 128.4, 132.0 (2C), 161.4,
174.6 ppm; MS (EI): m/z (%): 281 (96) [M+2]+, 279 (95) [M]+, 237 (79),
224 (100), 222 (98), 197 (79), 195 (78), 157 (23), 115 (13), 102 (11), 75
(19); IR (FT-IR): n˜ =3114, 3077, 2959, 2929, 2863, 1605, 1568, 1505, 1458,
1428, 1384, 1074, 1008, 952, 835, 790 cmꢀ1; HRMS (ESI+): m/z calcd for
[C13H14BrNO+H]+: 280.0337; found: 280.0330.
5-tert-Butyl-3-phenyl-2-(phenylsulfonyl)-2,3-dihydroisoxazole (6b): By
following general procedure B, compound 6b was obtained in 77% yield
as a white solid. M.p. 1298C; 1H NMR (400 MHz, CDCl3): d=1.06 (s,
9H), 4.60 (d, J=2.4 Hz, 1H), 5.90 (d, J=2.4 Hz, 1H), 7.30–7.39 (m, 5H),
7.54–7.58 (m, 2H), 7.66–7.70 (m, 1H), 8.0–8.02 ppm (m, 2H); 13C NMR
(100 MHz, CDCl3): d=28.0, 31.4, 68.7, 94.0, 127.08 (2C), 128.3, 128.7
(2C), 128.9 (2C), 129.6 (2C), 134.0, 134.5, 140.2, 163.9 ppm; MS (ESIꢀ):
m/z (%): 342 (24) [MꢀH]ꢀ, 324 (100), 260 (23), 227 (22), 141 (17); MS
(ESI+): m/z (%): 687 (66) [2M+H]+, 345 (47) [M+2H]2+, 344 (100)
[M+H]+, 260 (32), 220 (77); IR (FT-IR): n˜ =3062, 3021, 2966, 2907, 2863,
1701, 1675, 1598, 1480, 1450, 1362, 1170, 1089, 912, 757, 731, 687,
573 cmꢀ1; HRMS (ESI+): m/z calcd for [C19H21NO3S+H]+: 344.1320;
found: 344.1318.
5-Butyl-3-(4-methoxyphenyl)isoxazole (3h): By following general proce-
dure A, compound 3h was obtained in 77% yield as a pale-yellow solid.
M.p. 288C; 1H NMR (400 MHz, CDCl3): d=0.96 (t, J=7.4 Hz, 1H),
1.38–1.47 (m, 2H), 1.68–1.76 (m, 2H), 2.77 (t, J=7.6 Hz, 2H), 3.84 (s,
3H), 6.22 (s, 1H), 6.94–6.97 (m, 2H), 7.71–7.73 ppm (m, 2H); 13C NMR
(100 MHz, CDCl3): d=13.6, 22.1, 26.4, 29.5, 55.3, 98.5, 114.1 (2C), 121.9,
128.0 (2C), 160.7, 161.9, 173.9 ppm; MS (EI): m/z (%): 231 (100) [M]+,
189 (58), 174 (87), 146 (53), 132 (14), 92 (9), 77 (13); IR (FT-IR): n˜ =
3003, 2959, 2937, 2870, 1616, 1572, 1531, 1509, 1465, 1432, 1399, 1299,
1255, 1177, 1034, 912, 835, 801, 599, 532 cmꢀ1; HRMS (EI): m/z calcd for
[C14H17NO2]: 231.1259; found: 231.1256.
5-Cyclopropyl-3-phenyl-2-(phenylsulfonyl)-2,3-dihydroisoxazole (6c): By
following general procedure B, compound 6c was obtained in 86% yield
as a white solid. M.p. 788C; 1H NMR (400 MHz, CDCl3): d=0.46–0.52
(m, 1H), 0.59–0.64 (m, 1H), 0.66–0.79 (m, 2H), 1.31–1.38 (m, 1H), 4.51
(dd, J=0.6, 2.5 Hz, 1H), 5.80 (d, J=2.4 Hz, 1H), 7.29–7.38 (m, 5H),
7.55–7.59 (m, 2H), 7.68–7.71 (m, 1H), 8.00–8.02 ppm (m, 2H); 13 CNMR
(100 MHz, CDCl3): d=5.8, 6.2, 6.4, 69.2, 94.3, 127.0 (2C), 128.3, 128.7
(2C), 128.9 (2C), 129.4 (2C), 134.1, 137.0, 139.9, 157.6 ppm; MS (ESI+):
m/z (%): 655 (40) [2M+H]+, 328 (100) [M+H]+, 242 (9), 146 (13); IR
(FT-IR): n˜ =3084, 3062, 3011, 2974, 2937, 2892, 1686, 1594, 1487, 1443,
1358, 1314, 1170, 1089, 1056, 927, 753, 728, 694, 562 cmꢀ1; HRMS (ESI+):
m/z calcd for [C18H17NO3S+H]+: 328.1007; found: 328.1007.
5-Butyl-3-(thiophen-2-yl)isoxazole (3i): By following general pro
ACHTUNGERTNcNUNG e-
ACHTUNGTRENNUNG
1H NMR (400 MHz, CDCl3): d=1.02 (t, J=7.4 Hz, 3H), 1.72–1.81 (m,
2H), 2.75 (t, J=7.5 Hz, 2H), 6.22 (s, 1H), 7.10 (dd, J=3.6, 5.0 Hz, 1H),
7.39 (dd, J=1.1, 5.1 Hz, 1H), 7.43 ppm (dd, J=1.1, 3.6 Hz, 1H);
13C NMR (100 MHz, CDCl3): d=13.6, 20.8, 28.6, 98.9, 127.0, 127.2, 127.5,
131.2, 157.4, 174.0 ppm; MS (EI): m/z (%): 193 (100) [M]+, 165 (15), 150
(88), 123 (36), 110 (6), 95 (7), 71 (8); IR (FT-IR): n˜ =3114, 3091, 2966
5-Isopropyl-3-phenyl-2-(phenylsulfonyl)-2,3-dihydroisoxazole (6d): By
following general procedure B, compound 6d was obtained in 87% yield
as a white solid. M.p. 1098C; 1H NMR (400 MHz, CDCl3): d=0.96 (d,
J=6.9 Hz, 3H), 1.08 (d, J=6.9 Hz, 3H), 2.32–2.39 (m, 1H), 4.54 (dd, J=
1.1, 2.4 Hz, 1H), 5.83 (dd, J=1.6, 2.3 Hz, 1H), 7.30–7.39 (m, 5H), 7.54–
7.57 (m, 2H), 7.66–7.68 (m, 1H), 8.00–8.02 ppm (m, 2H); 13C NMR
(100 MHz, CDCl3): d=20.0, 20.2, 25.9, 68.9, 94.4, 127.0 (2C), 128.3 (C9),
128.7 (2C), 128.9 (2C), 129.5 (2C), 134.0, 134.2, 139.9, 161.6 ppm; MS
(ESI+): m/z (%): 659 (72) [2M+H]+, 330 (100) [M+H]+, 260 (4), 186
(13); IR (FT-IR): n˜ =3070, 3025, 2981, 2922, 2885, 1679, 1447, 1365, 1170,
1093, 1070, 1030, 916, 757, 728, 694, 643, 595, 573 cmꢀ1; HRMS (ESI+):
m/z calcd for [C18H19NO3S+H]+: 330.1164; found: 330.1158.
2929, 2870 1601, 1548, 1461, 1435, 1395, 1229, 912, 857, 787, 709 cmꢀ1
;
HRMS (ESI+): m/z calcd for [C11H13NOS+H]+: 194.0640; found:
194.0638.
N-Hydroxy-N-(1-phenylhept-2-ynyl)benzenesulfonamide (4a): N-Hy-
droxybenzenesulfonamide (1.2 mmol) and FeCl3 (0.1 mmol) were added
to a solution of propargylic alcohol (1 mmol) in dichloromethane (5 mL).
The mixture was refluxed for 1 h. Upon completion, the reaction was fil-
tered through Celite, concentrated in vacuo, and the crude material
loaded onto a silica gel column and purified by chromatography. Com-
pound 4a was obtained in 84% yield as a white solid. M.p. 998C;
1H NMR (400 MHz, CDCl3): d=0.87 (t, J=7.4 Hz, 3H), 1.25–1.29 (m,
4H), 1.83–1.86 (m, 2H), 5.84 (s, 1H), 6.54 (brs, 1H), 7.32–7.39 (m, 3H),
7.55–7.69 (m, 5H), 8.01–8.03 ppm (m, 2H); 13C NMR (100 MHz, CDCl3):
d=13.4, 18.1, 21.7, 30.1, 56.7, 71.7, 89.9, 128.0, 128.1 (2C), 128.2 (2C),
128.3 (2C), 129.8 (2C), 133.4, 134.7, 136.3 ppm; MS (ES+): m/z (%):
687 (21) [2M<M+>H]+, 344 (19) [M+H]+, 326 (6), 214 (8), 171 (11);
IR (FT-IR): n˜ =3380, 3064, 2957, 2931 2871, 1448, 1353, 1169, 1090, 755,
733, 686, 607, 571 cmꢀ1; HRMS (ESI+): m/z calcd for [C19H21NO3S+
H]+: 344.1320; found: 344.1314.
3,5-Diphenyl-2-(phenylsulfonyl)-2,3-dihydroisoxazole (6e): By following
general procedure B, compound 6e was obtained in 93% yield as a white
solid. M.p. 1388C; 1H NMR (400 MHz, CDCl3): d=5.19 (d, J=2.8 Hz,
1H), 5.96 (d, J=2.8 Hz, 1H), 7.33–7.44 (m, 12H), 7.56–7.60 (m, 1H),
7.99–8.02 ppm (m, 2H); 13C NMR (100 MHz, CDCl3): d=69.0, 69.8,
125.5 (2C), 126.6, 127.1 (2C), 128.4 (2C), 128.5, 128.8 (2C), 128.9 (2C),
129.2 (2C), 129.7, 133.6, 134.2, 139.2, 153.6 ppm; MS (ES+): m/z (%):
727 (33) [2M+H]+, 364 (100) [M+H]+; IR (FT-IR): n˜ =3121, 3062, 3018,
1668, 1583, 1494, 1450, 1365, 1170, 1089, 1015, 886, 757, 728, 691, 647,
610, 576 cmꢀ1
;
HRMS (ES+): m/z calcd for [C21H17NO3S+H]+:
364.1007; found: 364.1004.
General procedure B—the preparation of isoxazolines (6a–j): N-Hy-
A
E
5-Butyl-3-(4-fluorophenyl)-2-(phenylsulfonyl)-2,3-dihydroisoxazole (6 f):
By following general procedure B, compound 6 f was obtained in 89%
yield as a white solid. M.p. 768C; 1H NMR (400 MHz, CDCl3): d=0.86
(t, J=7.2 Hz, 3H), 1.22–1.42 (m, 4H), 1.96–2.12 (m, 2H), 4.52 (td, J=
to a solution of propargylic alcohol (1.2 mmol) in CH2Cl2 (5 mL). The
mixture was refluxed for 1 h, then NaAuCl4·2H2O (0.05 mmol) and pyri-
dine (0.1 mmol) were added and reflux was maintained for an additional
Chem. Eur. J. 2010, 16, 12207 – 12213
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
12211

J.-M. Campagne, E. Vrancken et al.
1.2, 2.2 Hz, 1H), 5.78 (d, J=1.2 Hz, 1H), 7.01–7.06 (m, 2H), 7.31–7.35
(m, 2H), 7.54–7.58 (m, 2H), 7.67–7.71 (m, 1H), 7.98–8.02 ppm (m, 2H);
13C NMR (100 MHz, CDCl3): d=13.6, 22.1, 25.1, 28.3, 68.4, 95.6, 115.5 (d,
(35 mL) and the mixture was heated at reflux for 2 h. The solution was
cooled to 08C and then pyridine (1 mL, 12.35 mmol, 3 equiv) and ICl
(1.0m in CH2Cl2, 12.4 mL, 12.35 mmol, 3 equiv) were added. The mixture
was stirred for 3 h at 08C. Then, the excess ICl was removed by washing
with a saturated aqueous solution of Na2S2O3. The aqueous solution was
then extracted with CH2Cl2 (2ꢂ20 mL). The combined organic layers
were dried over anhydrous MgSO4 and concentrated in vacuo to yield
the crude product, which was purified by flash column chromatography
on silica gel by using cyclohexane/Et2O as the eluent (100/0!92/8) to
J
N
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
MS (ESI+): m/z (%): 723 (78) [2M+H]+, 362 (100) [M+H]+, 188 (13);
IR (FT-IR): n˜ =3121, 3070, 2959, 2937, 2863, 1686, 1605, 1502, 1450, 1365,
1222, 1174, 1089, 1015, 901, 838, 753, 735, 691, 643, 580 cmꢀ1; HRMS
(ESI+): m/z calcd for [C19H20FNO3S+H]+: 362.1226; found: 362.1213.
give
7 as a
brown solid (1.76 g, 88% yield). M.p. 848C; 1H NMR
3-(4-Bromophenyl)-5-butyl-2-(phenylsulfonyl)-2,3-dihydroisoxazole (6g):
By following general procedure B, compound 6g was obtained in 87%
yield as a pale-yellow solid. M.p. 1178C; 1H NMR (400 MHz, CDCl3):
d=0.86 (t, J=7.2 Hz, 3H), 1.21–1.39 (m, 4H), 1.96–2.11 (m, 2H), 4.51
(td, J=1.1, 2.3 Hz, 1H), 5.75 (d, J=1.2 Hz, 1H), 7.22–7.26 (m, 2H),
7.47–7.49 (m, 2H), 7.54–7.58 (m, 2H), 7.67–7.71 (m, 1H), 7.98–8.02 ppm
(m, 2H); 13C NMR (100 MHz, CDCl3): d=13.6, 22.1, 25.1, 28.3, 68.4,
95.4, 122.3, 128.7 (2C), 128.9 (2C), 129.4 (2C), 131.8 (2C), 133.9, 134.2,
139.0, 156.9 ppm; MS (ESI+): m/z (%): 845 (47) [2M+H]+, 424 (62,
[M+H]+, 81Br), 422 (63, [M+H]+, 79Br), 188 (100); IR (FT-IR): n˜ =3114,
3070, 2959, 2929, 2870, 1682, 1483, 1443, 1362, 1166, 1085, 1011, 905, 827,
(400 MHz, CDCl3): d=0.91 (t, J=7.6 Hz, 3H; CH3 nBu), 1.28–1.37 (m,
2H; CH2 nBu), 1.38–1.49 (m, 2H; CH2 nBu), 2.07–2.21 (m, 2H; CH2
nBu), 2.27 (s, 3H; CH3Ar), 5.64 (s, 1H), 7.18–7.24 (m, 4H; Ar), 7.59 (m,
2H; Ar), 7.71 (tt, J=1.2, 7.6 Hz, 1H; Ar), 7.90 ppm (m, 2H; Ar);
13C NMR (100 MHz, CDCl3): d=13.7, 21.2, 22.1, 25.8, 28.3, 56.9, 74.2,
127.6, 129.1, 129.2, 129.5, 133.6, 134.2, 134.4, 138.8, 156.5 ppm; MS (ESI+):
m/z (%): 967 (30) [2M+H]+, 484 (100) [M+H]+, 405 (10), 357 (15), 311
(20), 203 (20); IR (KBr): n˜ =2957, 1675, 1511, 1446, 1358, 1170, 1087,
1014, 948, 907, 830, 774, 740, 687, 641, 596, 572 cmꢀ1; HRMS (ESI+):
m/z calcd for [C20H22NO3IS]: 484.0443; found: 484.0436.
731, 683, 632, 584, 554 cmꢀ1
;
HRMS (ESI+): m/z calcd for
5-Butyl-4-iodo-3-para-tolylisoxazole (8): N-hydroxybenzenesulfonamide
(720 mg, 4.12 mmol, 1 equiv) and FeCl3 (18 mg, 0.103 mmol, 2.5% mol)
were added to a solution of 1-para-tolylhept-2-yn-1-ol (1.01 g, 4.94 mmol,
1.2 equiv) in dichloromethane (35 mL) and the mixture was heated at
reflux for 2 h. The solution was cooled to room temperature, then
DMAP (551 mg, 4.54 mmol, 1.1 equiv) was added and the mixture was
stirred for 5 h. The solution was then cooled to 08C, ICl (1.0m in CH2Cl2,
12.4 mL, 12.35 mmol, 3 equiv) was added, and the mixture was stirred for
18 h at 08C. Then, the mixture was neutralized with aqueous NaOH
(3m). The organic layer was washed with a saturated aqueous solution of
Na2S2O3. The aqueous solution was then extracted with CH2Cl2 (2ꢂ
20 mL). The combined organic layers were dried over anhydrous MgSO4
and concentrated in vacuo to yield the crude product, which was purified
by flash column chromatography on silica gel by using cyclohexane/Et2O
as the eluent (100/0!98/2) to give 8 as a brown solid (1.08 g, 77% yield).
M.p. 408C; 1H NMR (400 MHz, CDCl3): d=0.98 (t, J=7.2 Hz, 3H; CH3
nBu), 1.38–1.48 (m, 2H; CH2 nBu), 1.71–1.79 (m, 2H; CH2 nBu), 2.42 (s,
3H; CH3Ar), 2.87 (t, J=7.6 Hz, 2H; CH2 nBu), 7.29 (d, J=8.4 Hz; 2H;
Ar), 7.69 ppm (d, J=8 Hz, 2H; Ar); 13C NMR (100 MHz, CDCl3): d=
13.7, 21.4, 22.2, 26.8, 29.2, 57.4, 125.8, 128.3, 129.2, 140.0, 162.6,
174.6 ppm; MS (ESI+): m/z (%): 983 (10) [2M+H]+, 342 (100) [M+H]+,
301 (18), 255 (7), 216 (20); IR (neat): n˜ =3025, 2957, 2929, 2871, 1582,
1567, 1457, 1415, 1380, 1184, 1133, 1106, 1032, 956, 933, 903, 820, 723,
610 cmꢀ1; HRMS (ESI+): m/z calcd for [C14H17NOI]: 342.0355; found:
342.0343.
[C19H20BrNO3S+H]+: 422.0426; found: 422.0426.
5-Butyl-3-(4-methoxyphenyl)-2-(phenylsulfonyl)-2,3-dihydroisoxazole
(6h): By following general procedure B, compound 6h was obtained in
81% yield as
a
pale-yellow solid. M.p. 968C; 1H NMR (400 MHz,
CDCl3): d=0.86 (t, J=7.2 Hz, 3H), 1.22–1.40 (m, 4H), 1.96–2.12 (m,
2H), 3.80 (s, 3H), 4.50 (td, J=1.1, 2.1 Hz, 1H), 5.76 (d, J=1.2 Hz, 1H),
6.87–6.91 (m, 2H), 7.26–7.30 (m, 2H), 7.53–7.58 (m, 2H), 7.66–7.71 (m,
1H), .799–8.03 ppm (m, 2H); 13C NMR (100 MHz, CDCl3): d=13.6, 22.1,
25.2, 28.4, 55.3, 68.8, 95.9, 114.0 (2C), 128.7 (2C), 128.9 (2C), 129.4 (2C),
131.9, 134.0, 134.1, 156.3, 159.6 ppm; MS (ESIꢀ): m/z (%): 372 (100)
[MꢀH]ꢀ, 324 (26), 227 (23), 157 (10), 141 (16); MS (ESI+): m/z (%):
747 (47) [2M+H]+, 375 (50) [M+2H]2+, 374 (100) [M+H]+, 220 (82); IR
(FT-IR): n˜ =3062, 2959, 2937, 2878, 2833, 1686, 1609, 1583, 1509, 1450,
1362, 1306, 1251, 1174, 1089, 1030, 838, 757, 731, 691, 643, 584, 558 cmꢀ1
;
HRMS (ESI+): m/z calcd for [C20H23NO4S+H]+: 374.1426; found:
374.1425.
2-(Phenylsulfonyl)-5-propyl-3-(thiophen-2-yl)-2,3-dihydroisoxazole (6i):
By following general procedure B, compound 6i was obtained in 83%
yield as a purple oil. 1H NMR (400 MHz, CDCl3): d=0.87 (t, J=7.4 Hz,
3H), 1.44 (sext, J=7.4 Hz, 2H), 1.95–2.01 (m, 2H), 4.61 (td, J=1.0,
2.1 Hz, 1H), 6.09 (d, J=1.8 Hz, 1H), 6.99 (dd, J=3.5, 5.1 Hz, 1H), 7.09
(d, J=3.5 Hz, 1H), 7.29 (dd, J=1.2, 5.1 Hz, 1H), 7.53–7.57 (m, 2H),
7.66–7.70 (m, 1H), 7.96–8.00 ppm (m, 2H); 13C NMR (100 MHz, CDCl3):
d=13.5, 19.6, 27.4, 64.5, 95.7, 125.6, 126.2, 127.1, 128.9 (2C), 129.4 (2C),
134.1, 134.2, 144.1, 157.2 ppm; MS (ESIꢀ): m/z (%): 334 (100) [MꢀH]ꢀ,
286 (9), 241 (18), 192 (22); MS (ESI+): m/z (%): 671 (21) [2M+H]+,
336 (100) [M+H]+, 230 (7), 194 (24); IR (FT-IR): n˜ =3114, 3070, 2966,
2929, 2870, 1686, 1579, 1450, 1365, 1314, 1174, 1089, 1019, 916, 764, 724,
691, 650, 599, 565 cmꢀ1; HRMS (ESIꢀ) m/z calcd for [C16H17NO3S2ꢀH]+:
334.0572; found: 334.0576.
Acknowledgements
5-Butyl-2-(phenylsulfonyl)-3-para-tolyl-2,3-dihydroisoxazole (6j): By fol-
lowing general procedure B, compound 6j was obtained in 89% yield as
a pale-yellow solid. M.p. 838C; 1H NMR (400 MHz, CDCl3): d=0.86 (t,
J=7.2 Hz, 3H; CH3 nBu), 1.21–1.41 (m, 4H; CH2 nBu), 1.95–2.12 (m,
2H; CH2 nBu), 2.34 (s, 3H; CH3Ar), 4.51–4.54 (m, 1H), 5.76–5.79 (m,
1H), 7.17 (d, J=8.0 Hz, 2H; Ar), 7.26 (d, J=8.0 Hz, 2H; Ar), 7.56–7.60
(m, 2H; Ar), 7.66–7.71 (m, 1H; Ar), 7.99–8.03 ppm (m, 2H; Ar);
13C NMR (100 MHz, CDCl3): d=13.7, 21.1, 22.1, 25.2, 28.4, 69.0, 96.0,
127.0 (2C), 128.9 (2C), 129.3 (2C), 129.4 (2C), 134.1, 137.0, 138.2,
156.3 ppm; MS (ESI+): m/z (%): 733 (10), 716 (35) [2M+H]+, 460 (20),
358 (100) [M+H]+, 185 (5); IR (KBr): n˜ =2977, 2933, 2863, 1446, 1382,
1350, 1123, 1077, 934, 845, 727, 610 cmꢀ1; HRMS (ESI+): m/z calcd for
[C20H23NO3S]: 358.1469; found: 358.1477.
We are grateful to the CNRS for financial support (ATIPE jeune
ꢁquipe), the Institut de Chimie des Substances Naturelles (Gif-sur-
Yvette) and the MESR for PhD grants (O.D., E.G., and J.M.C.).
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5-Butyl-4-iodo-2-(phenylsulfonyl)-3-para-tolyl-2,3-dihydroisoxazole (7):
N-hydroxybenzenesulfonamide (728 mg, 4.12 mmol, 1 equiv) and FeCl3
(17 mg, 0.103 mmol, 2.5% mol) were added to a solution of 1-para-tolyl-
hept-2-yn-1-ol (995 mg, 4.94 mmol, 1.2 equiv) in dichloromethane
12212
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 12207 – 12213

Isoxazole and Isoxazoline Synthesis
FULL PAPER
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mixture of oxime 5a and isoxazole 3a.
[5] For recent reviews, see: a) B. J. Wakefield in Science of Synthesis:
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Received: May 26, 2010
Published online: September 14, 2010
Chem. Eur. J. 2010, 16, 12207 – 12213
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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