New routes to 5-substituted oxazoles

Article abstract of DOI:10.1039/a908987j

Ultrasound-promoted desulfonylation of 5-substituted 4-tosyloxazoles, prepared from tosylmethyl isocyanide and carboxylic acid chlorides or by dianion chemistry, leads to 5-monosubstituted oxazoles. The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/a908987j

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New routes to 5-substituted oxazoles
Matthew S. Addie* and Richard J. K. Taylor*
Department of Chemistry, University of York, Heslington, York, UK YO10 5DD
E-mail: rjkt1@york.ac.uk
1
Received (in Cambridge, UK) 12th November 1999, Accepted 22nd December 1999
Ultrasound-promoted desulfonylation of 5-substituted 4-tosyloxazoles, prepared from tosylmethyl
isocyanide and carboxylic acid chlorides or by dianion chemistry, leads to 5-monosubstituted oxazoles.
Recent years have seen the isolation of many biologically active
oxazole-containing natural products from marine sources and
nearly all contain the 2,4-disubstituted oxazole ring system.1
However, a variety of Streptomyces strains have produced
examples of 5-monosubstituted oxazoles with biological activ-
ity profiles ranging from herbicidal to antitumour. These
include conglobatin2 1 and phthoxazolin A3 2, a member of
the oxazolomycin family.4
although this methodology has been employed in the total
syntheses of conglobatin6 1 and neooxazolomycin.7
The hazards associated with this alkyl isocyanide can be
largely avoided by employing tosylmethyl isocyanide (TosMIC).
The reaction of TosMIC with aldehydes under basic conditions
affords 5-substituted oxazoles directly, as described by van
Leusen et al.,8 although this method is limited by the avail-
ability and/or stability of the requisite aldehyde. The reaction
of the TosMIC anion with carboxylic acid chlorides8,
anhydrides8 and esters9 has also been carried out by van
Leusen et al. but the resulting 5-substituted oxazoles now also
possess a toluene-p-sulfonyl substituent in the 4-position
(Scheme 1b).
To the best of our knowledge, there has been no disclosure of
a method to remove this sulfonyl functionality from such
systems. We felt that such a methodology would extend the
usefulness of TosMIC in the preparation of 5-monosubstituted
oxazoles and we report herein our results in this area.
Results and discussion
a) Preparation of 5-substituted-4-tosyloxazoles 3a–d from acid
chlorides
Based on the work of van Leusen et al.8 5-substituted-4-
tosyloxazoles 3a–c could be prepared from lithiated TosMIC
and the appropriate carboxylic acid chloride in good yield. In
the case of 3d, the use of the more reactive TosMIC dianion9
was found to be necessary to achieve a reasonable yield
(Table 1).
From a synthetic viewpoint, the most common entry to
5-monosubstituted oxazoles is via the Schöllkopf condensation
of lithiated methyl isocyanide with carboxylic acid chlorides,
esters and amides (Scheme 1a).5 This involves the preparation
and use of the highly toxic and volatile methyl isocyanide,
b) Preparation of 5-substituted-4-tosyloxazoles 3a,e,f by dianion
chemistry
Shafer and Molinski have recently reported the preparation
of 5-substituted oxazoles by the selective C-5 lithiation of
2-(methylthio)oxazole followed by trapping with an electrophile
and reductive desulfurisation.10 Knight and co-workers have
previously reported the regioselective lithiation of N,N-diethyl-
2,5-dimethyloxazole-4-carboxamide at the 5-Me group.11
Quenching with a range of electrophiles elaborated the substi-
tution at the 5-position to give new trisubstituted oxazoles.
We prepared 5-methyl-4-tosyloxazole
4 from lithiated
TosMIC and acetic anhydride in 87% yield8 and decided to
examine its lithiation chemistry as a possible entry to
5-substituted oxazoles. We anticipated that the 2-position of the
oxazole ring would be the most acidic and it was hoped that a
second equivalent of butyllithium would afford dianion 5
(Scheme 2).
Indeed, treatment of 4 with one equivalent of butyllithium in
THF at Ϫ78 ЊC followed by the addition of D2O resulted in the
Scheme 1
DOI: 10.1039/a908987j
J. Chem. Soc., Perkin Trans. 1, 2000, 527–531
This journal is © The Royal Society of Chemistry 2000
527

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Table 1 Preparation of tosyloxazoles 3a–d
Scheme 2
RCOCl
3a–d (Yield)
Table 2 Preparation of tosyloxazoles 3a,e,f
PhCH2CH2COCl
PhCOCl
Electrophile
3a,e,f (Yield)
Piperonoyl chloride
CH3(CH2)5COCl
Benzyl bromide
Benzaldehyde
Allyl iodide
a Obtained using dilithiated TosMIC (see Experimental section).
Monolithiated TosMIC failed to give a clean, complete reaction.
1
loss of the singlet at δ 7.72 in the H NMR spectrum, corre-
sponding to the proton at the 2-position of the oxazole ring. It
was pleasing to see that the use of two equivalents of butyl-
lithium followed by the addition of D2O resulted in the loss of
the C-2 proton and a proton from the C-5 methyl group, giving
rise to the characteristic two-proton signal at δ 2.69 correspond-
ing to –CH2D. This confirmed that the dianion 5 could be
formed in solution, but would there be any regioselectivity in
reactions with electrophiles?
Table 3 Preliminary desulfonylation experiments
Conditions
Time/h
Yield of 6a (%)
The dianion 5 was formed in the usual manner and one
equivalent of benzyl bromide was added to the reaction. This
resulted in the formation of tosyloxazole 3a, previously pre-
pared by the alternative route, in 61% yield. It was found that
benzaldehyde and allyl iodide also reacted regioselectively to
give 5-substituted-4-tosyloxazoles 3e and 3f, respectively, and in
good yield (Table 2).
Unfortunately, dianion 5 did not give satisfactory results
with all electrophiles. Attempts at acylation with ethyl chloro-
formate and benzoyl chloride failed to give the desired
products, instead giving rise to intractable multicomponent
reaction mixtures.
8 eq. Na, 12 eq. EtOH,
THF, 0 ЊC
2
18
7
27
62
62
72
20 eq. 10% Na–Hga,b
MeOH–THF (1:1), )))))
5 eq. 10% Na–Hga,c
iPrOH–THF (1:1), )))))
10 eq. 10% Na–Hga,b
EtOH–THF (1:1), )))))
4
a Reaction run in the presence of 4 eq. disodium hydrogen orthophos-
phate. b Added in two equal portions over the course of the reaction.
c Added in one portion at the start of the reaction.
ature or use of 5% Na–Hg) resulted in no reaction taking
place.
c) Desulfonylation of 5-substituted-4-tosyloxazoles 3a–f
Initial attempts to effect reductive desulfonylation of 3a
were unsuccessful. Many well-established techniques failed to
give any observable reaction including use of samarium
diiodide12 in a range of solvents, magnesium in methanol13,14
and aluminium amalgam.15
Intrigued by the use of ultrasound18 to promote hetero-
geneous reactions we endeavoured to apply sonication to the
sodium amalgam reaction. Initial reactions were extremely
slow, but it was encouraging to see that the desired product 6a
was formed with sonication at room temperature. Most
encouraging was that the starting material 3a survived these
conditions with little or no decomposition.
We were delighted to find that running the reactions in a
1:1 mixture of alcohol and THF afforded the required 5-
monosubstituted oxazole 6a in good yield (Table 3). After a
basic aqueous work-up, it was found that the product of the
reaction required no further purification.
Using the optimum solvent mixture of EtOH–THF (1:1),
the desulfonylation of oxazoles 3b–f was investigated. It was
gratifying to find that desulfonylation was effective in all cases
(Table 4).
Where the 5-substituent was an aromatic ring, yields were
quantitative. Alkyl 5-substituents gave lower, but still good,
yields of desulfonylated products. Again, all reactions were very
clean and products could be analysed without further purifi-
cation. It was noted, however, that the 5-monosubstituted
Some success was realised with sodium metal in ethanol–
tetrahydrofuran (Table 3).16 After considerable experimen-
tation, however, the optimum conditions (8 eq. sodium, 12 eq.
ethanol, THF, 0 ЊC, 2 h) afforded only a 27% yield of the
1
desired 5-(2-phenylethyl)oxazole 6a. The H NMR spectrum
showed no evidence of the tosyl functionality and the new
oxazole proton at the 4-position was plainly visible at δ 6.75. No
other products or remaining starting material could be isolated
from the reaction as decomposition always accompanied the
desired transformation.
A similar result was encountered with 10% Na–Hg17 and
Na2HPO4 under the more forcing conditions of refluxing
methanol over a period of 5 hours. This reaction turned out to
be rather capricious, often with complete decomposition of the
starting material being the only result. Attempts to employ
milder conditions (i.e. running the reaction at room temper-
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Table 4 Desulfonylation of tosyloxazoles 3a–f
stirred solution of TosMIC (1.464 g, 7.5 mmol) in THF (35 mL)
at Ϫ78 ЊC was added n-butyllithium (1.6 M in hexanes, 5.2 mL,
8.25 mmol) dropwise. After 15 min, 3-phenylpropionyl chloride
(0.74 mL, 5 mmol) was added dropwise and stirring continued
at Ϫ78 ЊC for 1 h. The reaction mixture was then warmed to rt
for 1.5 h before being poured into water (25 mL). After extrac-
tion with EtOAc (2 × 25 mL), the combined organic layers were
washed with saturated NaHCO3 solution (2 × 25 mL) and brine
(25 mL), dried (Na2SO4), filtered and the solvent removed
under reduced pressure. The residue was purified by flash
column chromatography (PE–EtOAc, 3:1) to give the title
compound 3a as a yellow solid (1.394 g, 85%), mp 94–95 ЊC; Rf
0.56 (ether–PE, 3:1); νmax (Nujol)/cmϪ1 3141, 1718, 1587,
1510, 1377, 1329, 1240, 1147, 1101; δH (270 MHz; CDCl3) 7.72–
7.70 (3 H, m, 2 × tosyl-CH ϩ H-2), 7.29–7.16 (7 H, m,
2 × tosyl-CH ϩ Ph), 3.45 (2 H, t, J 7.5, CH2), 3.04 (2 H, t, J 7.5,
CH2), 2.41 (3 H, s, tosyl-CH3); δC (67.5 MHz; CDCl3) 156.1 (C),
149.6 (CH, C-2), 144.7 (C), 139.6 (C), 137.0 (C), 135.8 (C),
129.8 (2 × CH), 128.6 (2 × CH), 128.4 (2 × CH), 128.0
(2 × CH), 126.5 (CH), 33.9 (CH2), 27.3 (CH2), 21.6 (CH3); m/z
(CI) 345 (MNH4ϩ, 100%), 328 (MHϩ, 75), 91 (C7H7ϩ, 26)
[HRMS (CI): calcd. for C18H18NO3S, 328.1007. Found: MHϩ,
328.1006 (0.3 ppm error)].
4-Tosyloxazole, 3a–f
Product, 6a–f (Yield)
4-[(4-Methylphenyl)sulfonyl]-5-phenyl-1,3-oxazole 3b
This reaction was carried out as described for the preparation
of compound 3a with TosMIC (0.703 g, 3.6 mmol), n-butyl-
lithium (1.6 M in hexanes, 2.5 mL, 4 mmol) and benzoyl
chloride (0.35 mL, 3 mmol). Purification by flash column
chromatography (ether–PE, 1:1) afforded the title compound 3b
as a pale yellow solid (0.684 g, 64%), mp 143–144.5 ЊC (lit.8
142–143 ЊC); Rf 0.18 (ether–PE, 1:1); νmax (Nujol)/cmϪ1 3143,
1510, 1313, 1269, 1143; δH (270 MHz; CDCl3) 8.00–7.86 (5 H,
m, 2 × tosyl-CH ϩ 2 × phenyl-CH ϩ H-2), 7.52–7.50 (3 H, m,
3 × phenyl-CH), 7.34–7.31 (2 H, m, 2 × tosyl-CH), 2.42 (3 H, s,
tosyl-CH3); δC (67.5 MHz; CDCl3) 152.7 (C, C-5), 149.2 (CH,
C-2), 145.0 (C), 137.1 (C), 135.6 (C), 130.9 (CH), 129.8
(2 × CH), 129.0 (2 × CH), 128.6 (2 × CH), 128.3 (2 × CH),
125.5 (C), 21.6 (CH3); m/z (CI) 317 (MNH4ϩ, 97%), 300 (MHϩ,
100), 236 (20) [HRMS (CI): calcd. for C16H14NO3S, 300.0694.
Found: MHϩ, 300.0688 (2.1 ppm error)].
oxazoles were not as stable as their 4-tosyl precursors, which could
be stored for months under ambient conditions. The desulfonyl-
ated products 6a–f, isolated as colourless oils or solids, began to
decompose after a few days at ambient conditions.
In summary, the use of well-established routes, together with
novel dianion procedures, to 5-substituted-4-tosyloxazoles,
coupled with the ultrasound-promoted desulfonylation tech-
nology provides an efficient procedure for the synthesis of
5-monosubstituted oxazole systems.
Experimental
NMR spectra were recorded on a JEOL EX-270 instrument
using tetramethylsilane as the internal standard. Coupling
constants are given in Hz and 13C spectra were verified
using DEPT experiments. Melting points were recorded on an
Electrothermal IA9100 digital melting point apparatus and are
uncorrected. Infrared spectra were recorded on an ATI
Mattson Genesis FT-IR spectrometer using NaCl plates. Low
resolution electron impact (EI) mass spectra were recorded on
a Kratos MS 25 spectrometer. Chemical ionisation (CI) and
high resolution mass spectra were recorded on a Micromass
Autospec spectrometer. Elemental analyses were carried out at
the University of Newcastle. Flash column chromatography
was performed using Matrex silica gel 60 (70–200) and the
eluent specified. THF is tetrahydrofuran, PE is the fraction of
petroleum ether boiling in the range 40–60 ЊC, ether is diethyl
ether, EtOAc is ethyl acetate, DCM is dichloromethane and
EtOH is absolute ethanol. THF was distilled from sodium
benzophenone ketyl immediately before use and EtOH was
stored over 4 Å molecular sieves. Except where specified, all
reagents were purchased from commercial sources and were
used without further purification. TosMIC is [(4-methylphenyl)-
sulfonyl]methyl isocyanide. All reactions were carried out in
flame-dried apparatus under an atmosphere of oxygen-free
nitrogen. Sonication was carried out using a Hilsonic FM100
(50/60 Hz) ultrasonic bath.
5-(2H-1,3-Benzodioxol-5-yl)-4-[(4-methylphenyl)sulfonyl]-1,3-
oxazole 3c
This reaction was carried out as described for the preparation
of compound 3a with TosMIC (0.703 g, 3.6 mmol), n-butyl-
lithium (1.6 M in hexanes, 2.5 mL, 4 mmol) and piperonoyl
chloride (0.554 g, 3 mmol) added to the reaction as a solution in
THF (5 mL). The residue was taken up in DCM and passed
through a plug of silica to afford the title compound 3c as a pale
yellow solid (0.699 g, 68%), mp 167–168 ЊC; Rf 0.26 (ether–PE,
1:1); νmax (Nujol)/cmϪ1 3151, 1592, 1509, 1376, 1305, 1232,
1145, 1035; δH (270 MHz; CDCl3) 7.91–7.88 (2 H, m, 2 × tosyl-
CH), 7.80 (1 H, s, H-2), 7.55 (1 H, dd, J 8 and 2, H-6Ј), 7.46
(1 H, d, J 2, H-4Ј) 7.34–7.31 (2 H, m, 2 × tosyl-CH), 6.93 (1 H,
d, J 8, H-7Ј), 6.06 (2 H, s, –OCH2O–), 2.42 (3 H, s, tosyl-CH3);
δC (67.5 MHz; CDCl3) 152.4 (C), 149.9 (C), 148.7 (CH, C-2),
147.9 (C), 144.9 (C), 137.2 (C), 134.5 (C), 129.8 (2 × CH),
128.2 (2 × CH), 124.2 (CH), 119.2 (C), 109.0 (CH), 108.5
(CH), 107.7 (CH2), 21.6 (CH3); m/z (CI) 361 (MNH4ϩ, 100%),
344 (MHϩ, 96), 280 (17), 190 (16) [Found: C, 59.71; H, 3.84; N,
4.09. C17H13NO5S requires C, 59.47; H, 3.82; N, 4.08%].
5-Hexyl-4-[(4-methylphenyl)sulfonyl]-1,3-oxazole 3d
This reaction was carried out as described for the preparation
of compound 3a with TosMIC (0.703 g, 3.6 mmol), n-butyl-
lithium (1.6 M in hexanes, 5 mL, 8 mmol) and heptanoyl
chloride (0.46 mL, 3 mmol). Purification by flash column
4-[(4-Methylphenyl)sulfonyl]-5-(2-phenylethyl)-1,3-oxazole 3a
Prepared according to the method of van Leusen et al.8 To a
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chromatography (PE–ether, 1:1) afforded the title compound 3d
as a viscous yellow oil which solidifies on standing (0.490 g,
53%), mp 34–35 ЊC; Rf 0.36 (ether–PE, 3:1); νmax (Nujol)/cmϪ1
3134, 1718, 1593, 1517, 1331, 1240, 1149, 1085; δH (270 MHz;
CDCl3) 7.92–7.90 (2 H, m, 2 × tosyl-CH), 7.72 (1 H, s, H-2),
7.36–7.32 (2 H, m, 2 × tosyl-CH), 3.10 (2 H, t, J 7.5,
CH3(CH2)4CH2-), 2.43 (3 H, s, tosyl-CH3), 1.73–0.85 (11 H, m,
4 × CH2 ϩ CH3); δC (67.5 MHz; CDCl3) 157.3 (C), 149.4 (CH,
C-2), 144.8 (C), 137.4 (C), 135.2 (C), 129.8 (2 × CH), 128.0
(2 × CH), 31.3 (CH2), 28.7 (CH2), 27.8 (CH2), 25.3 (CH2), 22.4
(CH2), 21.6 (CH3), 14.0 (CH3); m/z (CI) 308 (MHϩ, 100%)
[Found: C, 62.37; H, 6.82; N, 4.39. C16H21NO3S requires C,
62.52; H, 6.89; N, 4.56%].
[Found: C, 63.04; H, 4.94; N, 3.98. C18H17NO4S requires C,
62.96; H, 4.99; N, 4.08%].
5-(But-3-enyl)-4-[(4-methylphenyl)sulfonyl]-1,3-oxazole
3f.
Using 4 (0.300 g, 1.27 mmol), n-butyllithium (1.6 M in hexanes,
1.75 mL, 2.8 mmol) and allyl iodide (0.12 mL, 1.33 mmol).
Purification by flash column chromatography (PE–ether, 1:1)
afforded the title compound 3f as a yellow oil which solidifies on
standing (0.219 g, 62%), mp 52–55 ЊC; Rf 0.26 (ether–PE, 1:1);
νmax (Nujol)/cmϪ1 3124, 3047, 1579, 1515, 1376, 1319, 1253,
1151, 1085; δH (270 MHz; CDCl3) 7.93–7.90 (2 H, m, 2 × tosyl-
CH), 7.73 (1 H, s, H-2), 7.35–7.33 (2 H, m, 2 × tosyl-CH), 5.89–
5.74 (1 H, m, vinyl-CH), 5.09–4.98 (2 H, m, vinyl-CH2), 3.23
(2 H, t, J 7, allyl-CH2), 2.52–2.43 (5 H, m, CH2 ϩ tosyl-CH3);
δC (67.5 MHz; CDCl3) 156.2 (C), 149.5 (CH), 144.7 (C), 137.2
(C), 135.7 (CH), 135.5 (C), 129.7 (2 × CH), 127.9 (2 × CH),
116.4 (CH2), 31.6 (CH2), 24.7 (CH2), 21.5 (CH3); m/z (CI) 295
(MNH4ϩ, 10%), 278 (MHϩ, 100), 238 (6), 139 (8), 122 (18)
[HRMS (CI): calcd. for C14H16NO3S, 278.0851. Found: MHϩ,
278.0856 (1.7 ppm error)] [Found: C, 60.18; H, 5.41; N, 4.94.
C14H15NO3S requires C, 60.63; H, 5.45; N, 5.05%].
5-Methyl-4-[(4-methylphenyl)sulfonyl]-1,3-oxazole 4
Prepared according to the method of van Leusen et al.8 To a
stirred solution of TosMIC (0.976 g, 5 mmol) in THF (20 mL)
at Ϫ78 ЊC was added n-butyllithium (1.6 M in hexanes, 3.4 mL,
5.5 mmol) dropwise. After 15 min, acetic anhydride (0.52 mL,
5.5 mmol) was added dropwise and stirring continued at
Ϫ78 ЊC for 1 h. The reaction mixture was then warmed to rt for
2 h before being poured onto water (20 mL). After extraction
with EtOAc (2 × 20 mL), the combined organic layers were
dried (Na2SO4), filtered and the solvent removed under reduced
pressure. The residue was taken up in a small amount of DCM
and passed through a very short column of silica (eluting with
EtOAc) to give the title compound 4 as a yellow solid (1.027g,
87%), mp 134–135.5 ЊC (lit.8 136–137 ЊC); Rf 0.27 (ether–PE,
3:1); νmax (Nujol)/cmϪ1 3141, 1592, 1376, 1326, 1294,
1241, 1149, 1100, 1066; δH (270 MHz; CDCl3) 7.93–7.89 (2 H,
m, 2 × tosyl-CH), 7.72 (1 H, s, H-2), 7.36–7.33 (2 H, m,
2 × tosyl-CH), 2.70 (3 H, s, oxazole-CH3), 2.43 (3 H, s, tosyl-
CH3); δC (67.5 MHz; CDCl3) 153.5 (C), 149.3 (CH, C-2),
144.8 (C), 137.3 (C), 135.6 (C), 129.8 (2 × CH), 127.9 (2 × CH),
21.6 (CH3, tosyl-CH3), 11.4 (CH3, oxazole-CH3); m/z (CI)
255 (MNH4ϩ, 30%), 238 (MHϩ, 100) [HRMS (CI): calcd.
for C11H12NO3S, 238.0538. Found: MHϩ, 238.0538 (0.2 ppm
error)].
General procedure for desulfonylation of tosyloxazoles 3a–f
To a solution of the tosyloxazole 3a–f (0.5 mmol) in THF–
EtOH (1:1, 10 mL) was added Na2HPO4 (0.283 g, 2 mmol).
Sonication was begun and 10% Na–Hg (0.575 g, 2.5 mmol Na)
was quickly added. After 2 h, another portion of 10% Na–Hg
(0.575 g, 2.5 mmol Na) was added and sonication continued for
a further 2 h. After the sonication had been stopped, EtOAc (20
mL) was added to the reaction and the whole mixture was
decanted into water (20 mL). The layers were separated and the
aqueous layer was further extracted with EtOAc (20 mL). The
combined organic layers were washed with saturated NaHCO3
solution (2 × 20 mL) and brine (20 mL), dried (Na2SO4), fil-
tered and the solvent removed under reduced pressure. The
compounds so afforded did not require further purification.
5-(2-Phenylethyl)-1,3-oxazole 6a. Pale yellow oil (0.062 g,
72%); Rf 0.33 (ether–PE, 1:1); νmax (neat)/cmϪ1 3127, 3085,
3028, 2929, 2862, 1670, 1602, 1510, 1454, 1101; δH (270 MHz;
CDCl3) 7.87 (1 H, s, H-2), 7.33–7.15 (5 H, m, 5 × phenyl-CH),
6.75 (1 H, s, H-4), 3.00–2.97 (4 H, br m, 2 × CH2); δC (67.5
MHz; CDCl3) 152.1 (C, C-5), 150.0 (CH, C-2), 140.3 (C,
phenyl), 128.4 (2 × CH, phenyl), 128.2 (2 × CH, phenyl), 126.3
(CH, phenyl), 122.2 (CH, C-4), 33.7 (CH2), 27.2 (CH2); m/z (CI)
174 (MHϩ, 100%), 91 (C7H7ϩ, 10) [HRMS (CI): calcd. for
C11H12NO, 174.0919. Found: MHϩ, 174.0916 (1.4 ppm error)].
General procedure for the reaction of 5 with electrophiles
To a stirred solution of 4 (0.237 g, 1 mmol) in THF (10 mL) at
Ϫ78 ЊC was added n-butyllithium (1.6 M in hexanes, 1.4 mL,
2.2 mmol). After 30 min, the electrophile (1.05 mmol) was
added and stirring continued at Ϫ78 ЊC for 1 h. The reaction
was then warmed to rt for 1 h before being poured into water
(20 mL) and extracted with EtOAc (2 × 20 mL). The combined
organic layers were washed with brine (20 mL), dried (Na2SO4),
filtered and the solvent removed under reduced pressure.
5-Phenyl-1,3-oxazole 6b. Pale brown solid (0.073 g, 100%),
mp 36–37 ЊC (lit.8 36–38 ЊC); Rf 0.35 (PE–ether, 1:1); δH (270
MHz; CDCl3) 7.92 (1 H, s, H-2), 7.68–7.26 (6 H, m, 5 ×
phenyl ϩ H-4). 13C NMR data consistent with published
values.19
4-[(4-Methylphenyl)sulfonyl]-5-(2-phenylethyl)-1,3-oxazole
3a. Using benzyl bromide (0.13 mL, 1.05 mmol). Purification
by flash column chromatography (PE–ether, 1:1) afforded the
title compound 3a as a pale yellow solid (0.2 g, 61%). Analytical
data was entirely consistent with that reported above.
5-(2H-1,3-Benzodioxol-5-yl)-1,3-oxazole 6c. Colourless solid
(0.093 g, 98%), mp 83–85 ЊC; Rf 0.27 (PE–ether, 1:1); νmax
(Nujol)/cmϪ1 3141, 1506, 1482, 1376, 1365, 1259, 1232, 1099,
1037; δH (270 MHz; CDCl3) 7.86 (1 H, s, H-2), 7.27–6.85 (4 H,
m, 3 × phenyl-CH ϩ H-4), 6.00 (2 H, s, –OCH2O–); δC (67.5
MHz; CDCl3) 151.4 (C), 149.9 (CH, C-2), 148.2 (C), 148.0 (C),
121.9 (C), 120.4 (CH), 118.5 (CH), 108.8 (CH), 105.0 (CH),
101.4 (CH2); m/z (CI) 190 (MHϩ, 100%) [HRMS (CI): calcd. for
C10H8NO3, 190.0504. Found: MHϩ, 190.0504 (0.3 ppm error)].
2-{4-[(4-Methylphenyl)sulfonyl]-1,3-oxazol-5-yl}-1-phenyl-
ethanol 3e. Using benzaldehyde (0.11 mL, 1.05 mmol). Purifica-
tion by flash column chromatography (ether–PE, 3:1) afforded
the title compound 3e as a colourless solid (0.267 g, 78%), mp
128.5–129.5 ЊC; Rf 0.13 (ether–PE, 3:1); νmax (Nujol)/cmϪ1
3529, 3137, 1579, 1513, 1313, 1244, 1142, 1060; δH (270 MHz;
CDCl3) 7.86–7.83 (2 H, m, 2 × tosyl-CH), 7.72 (1 H, s, H-2),
7.43–7.29 (7 H, m, 5 × phenyl-CH ϩ 2 × tosyl-CH), 5.16–5.12
(1 H, m, –CHOH), 3.62–3.46 (2 H, m, CH2), 2.58 (1 H, d, J 4,
–OH), 2.42 (3 H, s, tosyl-CH3); δC (67.5 MHz; CDCl3) 153.7
(C), 149.9 (CH, C-2), 145.0 (C), 142.7 (C), 136.9 (C), 136.8 (C),
129.8 (2 × CH), 128.7 (2 × CH), 128.1 (3 × CH), 125.6
(2 × CH), 72.7 (CH, –CHOH), 35.4 (CH2), 21.6 (CH3); m/z (CI)
361 (MNH4ϩ, 99%), 345 (25), 326 (100), 255 (35), 190 (35)
5-Hexyl-1,3-oxazole 6d. Yellow oil (0.049 g, 64%); Rf 0.39
(ether–PE, 1:1); νmax (neat)/cmϪ1 2929, 2856, 1724, 1662, 1464,
1379; δH (270 MHz; CDCl3) 7.76 (1 H, s, H-2), 6.75 (1 H, s,
H-4), 2.65 (2 H, t, J 7, –CH2(CH2)4CH3), 1.67–0.86 (11 H, m,
alkyl); δC (67.5 MHz; CDCl3) 153.3 (C), 149.9 (CH), 121.6
530
J. Chem. Soc., Perkin Trans. 1, 2000, 527–531

View Article Online
3 S. Omura, Y. Tanaka, I. Kanaya, M. Shinose and Y. Takahashi,
J. Antibiot., 1990, 43, 1034; for first total synthesis see N. Hénaff and
A. Whiting, Org. Lett., 1999, 1, 1137.
(CH), 31.4 (CH2), 28.6 (CH2), 27.4 (CH2), 25.3 (CH2), 22.4
(CH2), 14.0 (CH3); m/z (CI) 154 (MHϩ, 100%) [HRMS (CI):
calcd. for C9H16NO, 154.1232. Found: MHϩ, 154.1236 (2.6
ppm error)].
4 (a) Oxazolomycin: T. Mori, K. Takahashi, M. Kashiwabara and
D. Uemura, Tetrahedron Lett., 1985, 26, 1073; H. Kanzaki, K.-I.
Wada, T. Nitoda and K. Kawazu, Biosci. Biotechnol. Biochem.,
1998, 62, 438; (b) Neooxazolomycin: K. Takahashi, M. Kawabata
and D. Uemura, Tetrahedron Lett., 1985, 26, 1077.
5 U. Schöllkopf and R. Schröder, Angew. Chem., Int. Ed. Engl., 1971,
10, 333.
6 C. Schregenberger and D. Seebach, Liebigs Ann. Chem., 1986, 2081.
7 A. S. Kende, K. Kawamura and R. J. DeVita, J. Am. Chem Soc.,
1990, 112, 4070.
8 A. M. van Leusen, B. E. Hoogenboom and H. Siderius, Tetrahedron
Lett., 1972, 2369.
9 S. P. J. M. van Nispen, C. Mensink and A. M. van Leusen,
Tetrahedron Lett., 1980, 21, 3723.
10 C. M. Shafer and T. F. Molinski, J. Org. Chem., 1998, 63, 551.
11 P. Cornwall, C. P. Dell and D. W. Knight, J. Chem Soc., Perkin
Trans. 1, 1991, 2417.
12 H. Künzer, M. Stahnke, G. Sauer and R. Wiechert, Tetrahedron
Lett., 1991, 32, 1949.
13 A. C. Brown and L. A. Carpino, J. Org. Chem., 1985, 50, 1749.
14 G. H. Lee, E. B. Choi, E. Lee and C. S. Pak, Tetrahedron Lett., 1993,
34, 4541.
15 E. J. Corey and M. Chaykovsky, J. Am. Chem. Soc., 1965, 87, 1345.
16 Y. Fujita, M. Ishiguro, T. Onishi and T. Nishida, Bull. Chem. Soc.
Jpn., 1982, 55, 1325.
2-(1,3-Oxazol-5-yl)-1-phenylethanol 6e. Colourless oil
(0.097 g, 51%); Rf 0.13 (ether–PE, 3:1); νmax (neat)/cmϪ1 3332
(br), 2923, 1683, 1602, 1512, 1454, 1199, 1120, 1087, 1054;
δH (270 MHz; CDCl3) 7.64 (1 H, s, H-2), 7.33–7.26 (5 H, m,
phenyl), 6.69 (1 H, s, H-4), 4.94 (1 H, dd, J 7 and 5, –CHOH),
3.44 (1 H, br s, –OH), 3.14–2.94 (2 H, m, –CH2–); δC (67.5 MHz;
CDCl3) 150.3 (CH, C-2), 149.7 (C), 143.2 (C), 128.4 (2 × CH),
127.8 (CH) 125.6 (2 × CH), 123.5 (CH), 64.9 (CH, –CHOH),
35.3 (CH2); m/z (CI) 190 (MHϩ, 100%) [HRMS (CI): calcd. for
C11H12NO2, 190.0868. Found: MHϩ, 190.0867 (0.8 ppm error)].
5-(But-3-enyl)-1,3-oxazole 6f. Colourless oil (0.04 g, 65%); Rf
0.29 (ether–PE, 1:1); νmax (neat)/cmϪ1 3126, 3080, 2929, 1664,
1641, 1512, 1448, 1374, 1321, 1101; δH (270 MHz; CDCl3) 7.77
(1 H, s, H-2), 6.78 (1 H, s, H-4), 5.90–5.75 (1 H, m, vinyl-CH),
5.11–5.00 (2 H, m, vinyl-CH2), 2.77 (2 H, t, J 7, CH2), 2.45–2.04
(2 H, m, allyl-CH2); δC (67.5 MHz; CDCl3) 152.4 (C), 150.0
(CH), 136.6 (CH), 122.0 (CH), 115.8 (CH2), 31.5 (CH2), 24.9
(CH2); m/z (CI) 124 (MHϩ, 100%), 113 (6) [HRMS (CI): calcd.
for C7H10NO, 124.0760. Found: MHϩ, 124.0762 (1.8 ppm
error)].
17 See C. Najera and M. Yus, Tetrahedron, 1999, 55, 10547 and
references cited therein.
18 C. Einhorn, J. Einhorn and J. L. Luche, Synthesis, 1989, 787;
T. J. Mason, Chem. Soc. Rev., 1997, 26, 443.
19 A. R. Katritzky, Y.-X. Chen, K. Yannakopoulou and P. Lue,
Tetrahedron Lett., 1989, 30, 6657.
References
1 J. R. Lewis, Nat. Prod. Rep., 1999, 16, 389 and references cited
therein.
2 J. W. Westley, C.-M. Liu, R. H. Evans and J. F. Blount, J. Antibiot.,
1979, 32, 874.
Paper a908987j
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