Monosubstituted Oxazoles. 1. Synthesis of 5-Substituted Oxazoles by Directed Alkylation

Article abstract of DOI:10.1021/jo971410h

A general method is presented for synthesis of 2-(methylthio)-5-substituted oxazoles 2. Deprotonation of the readily available 2-(methylthio)oxazole (1) with n-BuLi occurs smoothly in the presence of TMEDA and regiospecifically at C5. The organometallic 1a added rapidly to aldehydes and other electrophiles to provide 5-substituted-2-(methylthio)oxazoles in very good to excellent yields. Reductive removal of the MeS group gave the desired 5-monosubstituted oxazoles 3 in good yield.

Full text of DOI:10.1021/jo971410h

J . Org. Chem. 1998, 63, 551-555
551
Mon osu bstitu ted Oxa zoles. 1. Syn th esis of 5-Su bstitu ted Oxa zoles
by Dir ected Alk yla tion
Cynthia M. Shafer and Tadeusz F. Molinski*
Department of Chemistry, University of California, Davis, California 95616
Received J uly 30, 1997
A general method is presented for synthesis of 2-(methylthio)-5-substituted oxazoles 2. Deproto-
nation of the readily available 2-(methylthio)oxazole (1) with n-BuLi occurs smoothly in the presence
of TMEDA and regiospecifically at C5. The organometallic 1a added rapidly to aldehydes and
other electrophiles to provide 5-substituted-2-(methylthio)oxazoles in very good to excellent yields.
Reductive removal of the MeS group gave the desired 5-monosubstituted oxazoles 3 in good yield.
Sch em e 1
A number of oxazole-containing natural products have
been isolated from marine invertebrates and microorgan-
isms,1-6 many of which exhibit potent biological activity.
Syntheses of oxazole-containing natural products7-12 has
mostly concentrated on targets bearing the common
biogenic 2,4-disubstituted oxazole. Surprisingly few
methods are available for oxazoles monosubstituted at
C5, a fact that is better understood with consideration
of the complex chemistry of substituted oxazoles. Metal-
ation on a preformed oxazole ring at C5 with strong base
followed by electrophilic addition is limited to 2-substi-
tuted oxazoles with 4-carboxylate substituents.13 Unfor-
tunately, the intermediate organometallics are poor
nucleophiles. Metalation of the parent oxazole at C5 is
generally not possible if H2 is unsubstituted due to
deprotonation of the more acidic H2 (pKA ∼ 20) leading
to ring-opened isonitrile-enolate ii (Scheme 1).14 Al-
though the ambident nucleophile ii has been exploited
for C-C bond formation, alkylation only occurs at C2 or
C4.15 Suppression of ring opening has been achieved by
placement of a TMS group at C215,16 or use of oxazole-
N-borane adducts to reduce electron density at nitrogen,
but again alkylation is directed to C2.17
We report here a solution to the problem of directed
additions to C5 of oxazole by introduction of a 2-meth-
ylthio group to the oxazole ring. The surrogate MeS
group allows low-temperature (-78 °C) metalation at C5,
and the resulting 5-lithiooxazole smoothly reacts with
aldehydes and other electrophiles to give 5-substituted
oxazoles. The MeS group is then easily removed by
reductive displacement. Since 2-(methylthio)oxazole (1)
is readily prepared,18 this two-step sequence allows
convenient access to a variety of 5-oxazoles. In addition,
we demonstrate that at room temperature the C2 MeS
group can undergo displacement with the carbanion of
isovaleronitrile to provide a 2-monosubstituted oxazole.
Thus, the common precursor 1 can be activated under
nucleophilic or electrophilic conditions for the tailored
preparation of 5- or 2-monosubstituted oxazoles.
* To whom correspondence should be addressed, 530 752 6358, 530
752 8995 FAX, tfmolinski@ucdavis.edu
(1) Adamczeski, M.; Quin˜oa`, E.; Crews, P. J . Am. Chem. Soc. 1988,
110, 1598-1602.
(2) Ichiba, T.; Yoshida, W. Y.; Scheuer, P. J . J . Am. Chem. Soc. 1991,
113, 3173-3174.
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1605-1607.
(4) Kobayashi, J .; Tsuda, M.; Fuse, H.; Sasaki, T.; Mikami, Y. J .
Nat. Prod. 1997, 60, 150-154.
Resu lts
(5) Takahashi, S.; Hashimoto, R.; Hamano, K.; Suzuki, T.; Naka-
gawa, A. J . Antibiot. 1996, 49, 513-518.
Oxazole-2-thione, readily prepared from dihydroxyma-
leic acid and hydrogen thiocyanate,18 was converted to
2-(methylthio)oxazole (1) by treatment with potassium
hydride and methyl iodide (76%). The choice of base was
important. Sodium hydride gave inferior yields and
ethanolic alkali19 produced mixtures of S- and N-methy-
lated products. Deprotonation of 1 with n-BuLi in
hexanes-THF followed by addition of benzaldehyde gave
the 5-oxazolyl carbinol 2a in modest yield (∼50%). After
(6) Lewis, J . R. Nat. Prod. Rep. 1996, 13, 435-467.
(7) Kende, A. S.; Kawamura, K.; DeVita, R. J . J . Am. Chem. Soc.
1990, 112, 4070-4072.
(8) Fukuyama, T.; Xu, L. J . Am. Chem. Soc. 1993, 115, 8449-8450.
(9) Evans, D. A.; Gage, J . R.; Leighton, J . L. J . Am. Chem. Soc. 1992,
114, 9434-9453.
(10) Nakada, M.; Kobayashi, S.; Shibasaki, M.; Iwasaki, S.; Ohno,
M. Tetrahedron Lett. 1993, 34, 1039-1042.
(11) Wipf, P.; Lim, S. J . Am. Chem. Soc. 1995, 117, 558-559.
(12) Kelly, T. R.; Lang, F. J . Org. Chem. 1996, 61, 4623-4633.
(13) Iddon, B. Heterocycles 1994, 37, 1321-1346 and references cited
within.
(14) Schro¨der, R.; Scho¨llkopf, U.; Blume, E.; Hoppe, I. Liebigs Ann.
Chem. 1975, 533.
(15) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A.; Pedrini, P.
J . Org. Chem. 1987, 52, 3413-3420.
(16) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Mastellari, A.; Medici,
A.; Negrini, E.; Pedrini, P. Gazz. Chim. Ital. 1988, 118, 211-231.
(17) Vedejs, E.; Monahan, S. D. J . Org. Chem. 1996, 61, 5192-5193.
(18) Lacasse, G.; Muchowski, J . M. Can. J . Chem. 1972, 50, 3082-
3083.
(19) Kjellin, G.; Sandstrom, J . Acta Chem. Scand. 1969, 23, 2879-
2887.
S0022-3263(97)01410-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/06/1998

552 J . Org. Chem., Vol. 63, No. 3, 1998
Shafer and Molinski
Ta ble 1. F or m a tion of 5-Su bstitu ted Oxa zoles by Meta la tion of 1 a n d Electr op h ilic Ad d ition
entry
electrophile (E+)
benzaldehyde
oxazole, equiv
E+, equiv
TMEDA, equiv
product
yield (%)a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1.0
1.0
1.0
1.0
2.0
1.0
1.0
1.0
1.0
1.0
2.0
1.0
1.0
1.0
2.3
2.2
2.2
2.0
1.0
2.2
2.2
2.1
1.4
2.2
1.0
19.9
15.9
2.2
10.4
10.0
10.4
10.3
16.2
10.5
12.2
10.4
14.0
10.4
16.0
9.9
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
4
84
85
84
77
p-anisaldehyde
p-bromobenzaldehyde
2-naphthaldehyde
2-furaldehyde
citral
decyl aldehyde
72
83b
73
pivaldehyde
69
2,3-O-isopropylidene-D-glyceraldehyde
3-methyl-2-butanone
cyclohexanone
benzoyl chloride
pivaloyl chloride
isovaleronitrile
60c
39d
53
38
9.9
9.9
71
33e
Yield of isolated product. Each new compound gave satisfactory HRMS and/or elemental analysis, IR, 1H NMR and 13C NMR. ∆2E/Z
a
b
ratio was 2:1 from E/Z-citral. c 2:1 diastereomeric ratio. Based on recovered starting material, 24% yield. e 3-Methyl-2-(2′-oxazolyl)bu-
d
tanenitrile (4).
considerable experimentation, the optimum conditions
were found to require TMEDA (10 equiv) during depro-
tonation at -78 °C followed by addition of carbanion 1a
to a solution of aldehyde at -78 °C, which improved the
yield of 2a to 84%.
Sch em e 2
The location of substitution of the oxazole ring in 2a
was confirmed by examination of the 1H NMR spectrum,
measurement of heteronuclear coupling constants, and
deuterium quench experiments (see below). The product
2a showed one aromatic singlet (δ 6.62) with a hetero-
1
nuclear coupling constant of J CH ) 195.8 Hz, most
conveniently measured from 13C satellites peaks in the
1H NMR spectrum. It has been shown that magnitudes
1
of coupling constants, J CH, in the oxazole ring vary
considerably with the electronic environment at different
positions around the ring (C2, C4, or C5), but are
essentially invariant with respect to alkyl substitution.1,20
The relatively low value of 1J CH of the remaining oxazole
ring proton signal in 2a is consistent with substitution
at C5 and not C4 (cf. oxazole, C4, 1J CH )194 Hz, C5, 1J CH
) 210 Hz).20
Deprotonation-addition of 1a was dependent upon the
nature of the electrophile. Aldehydes reacted rapidly
(complete in about 10 min) and gave high yields of
carbinols (Table 1, entries 1-9). Interestingly, the
reaction with p-bromobenzaldehyde showed no evidence
of halogen-metal exchange products. With ketones the
reaction was slower and did not always proceed to
completion (Table 1, entries 10 and 11), perhaps due to
competing enolization of ketone by proton exchange. Acid
chlorides also reacted rapidly with the anion (Table 1,
entries 12 and 13); however, a large excess of the acid
chloride was required to compete against addition of a
second equivalent of the anion of 1 to the ketone product.
The reaction with acyl chlorides is uncomplicated by
Cornforth-type rearrangement products.21,22
conditions (-78 °C) no reaction with isovaleronitrile was
observed (TLC), but upon allowing the mixture to warm
to 25 °C over 16 h a new product (33%) could be isolated
1
after workup and chromatography. The H NMR spec-
trum of the product showed loss of the MeS group and
addition of alkyl proton signals corresponding to isov-
aleronitrile, but some differences were apparent. In
particular, the methyl groups were now diastereotopic
as shown by two separate methyl signals (δ 1.11, d, J )
6.7 Hz; 1.12, d, J ) 6.7 Hz), and the R-methylene protons
were replaced by a one-proton doublet (δ 3.98, d, J ) 6.7
Hz). The IR spectrum showed that the nitrile group had
been retained (ν 2250 cm-1), thus the structure of the
product is 4.
The anion formed by deprotonation of 1 under opti-
mized conditions added smoothly to aldehydes, but when
an excess of n-BuLi (∼1.3 equiv) was used or the aldehyde
was added to the preformed oxazole anion (inverse
addition), signficant amounts of side-product due to
“double alkylation” were observed. The second alkylation
always occurred by deprotonation-addition to the MeS
group (for example, product 5d ). Although standard
conditions gave no products from addition to MeS group,
the low acidity of the methylthio hydrogens raised the
One example of addition to an alkanenitrile was
explored (Table 1, entry 14; Scheme 2). Under standard
(20) Turchi, I. J . In Oxazoles; Turchi, I. J ., Ed.; The Chemistry of
Heterocyclic Compounds, J ohn Wiley & Sons: New York, 1986; Vol.
45; pp 1-341.
(21) Dewar, M. J . S.; Turchi, I. J . J . Am. Chem. Soc. 1974, 96, 6148.
(22) Dewar, M. J . S.; Turchi, I. J . J . Org. Chem. 1975, 40, 1521.

Synthesis of 5-Substituted Oxazoles by Directed Alkylation
J . Org. Chem., Vol. 63, No. 3, 1998 553
Ta ble 2. Red u ctive Desu lfu r iza tion of 2 to 5-Su bstitu ted
Oxa zoles 3
entry
starting material (2)
product (3)
yield (%)a
1
2
3
4
5
2a
2d
2g
2h
2k
3a
3d
3g
3h
3k
68
60
60
59
60
possibility that in the presence of excess lithioanion 1a
proton exchange with 1 may rearrange the anion at C5
with the R-anion of the MeS group, perhaps via a doubly
charged intermediate. To examine the lability of the C5
anion, deuterium quench experiments were conducted.
The anion was prepared under standard conditions (1.0
equiv of BuLi, TMEDA, -78 °C) and after 20 min a
portion of this mixture was cannulated into a solution of
CH3OD at -78 °C. The carbanion solution was raised
to -40 °C, and two additional aliquots were quenched
with CH3OD after a further 15 min and 100 min. For
each sample, 1H NMR integration and GCMS showed
>90% deuterium incorporation at C5, but <5% incorpo-
ration at the MeS group (EIMS, m/z 100, M+ - Me). This
confirms that metalation occurred exclusively at C5 and,
within the limits of detection, no deuterium incorporation
was observed in the MeS group. Thus, the C5 carbanion
1a does not appear to be kinetically labile under the
conditions of the addition reaction.
a
Yield of isolated product. Each new compound gave satisfac-
tory HRMS and/or elemental analysis, IR, 1H NMR, and 13C NMR.
Ta ble 3. Ca lcu la ted Electr osta tic Ch a r ges a t C5 of
Heter ocyclic Ca r ba n ion s (P M3, Ma cSp a r ta n P lu s)
parent heterocycle
δ
- at C5
oxazole
-0.86
-0.88
-0.87
-0.81
-0.82
-0.81
2-(methylthio)oxazole
2-ethyoxazole
furan
2-(methythio)furan
2-ethyfuran
allowing construction of C-C bonds at preformed oxazole
rings. The secondary alcohol 2i prepared from addition
of 1 to a chiral aldehyde showed modest diastereoselec-
tivity (2:1, entry 9, Table 1); however, this was not
optimized.
The reaction of 1a with aldehydes is relatively rapid,
but somewhat slower with ketones, a tendency that
suggests the nucleophilicity of 1a is similar to that of
2-lithiofuran and may correlate with charge density at
C5. This was briefly examined by molecular orbital
calculations of the R-anions of 1, 2-ethyloxazole, 2-eth-
ylfuran, 2-methylthiofuran, and oxazole (PM3 level,
MacSpartan Plus, Table 3). Examination of fractional
electrostatic charge at each ring atom revealed that
>80% of the fractional charge resided at the anionic
carbon (C5 of 1). The formal carbanion corresponding
to 1a has charge localized in an sp2 orbital orthogonal to
the π system and is not expected to be stabilized by
classical resonance. All oxazoles anions examined gave
comparable charge densities (range, -0.86 to -0.88) and
were slightly higher than the corresponding furans
(∼-0.81), suggesting a negligible electron-withdrawing
effect of the SMe group on C5. While these calculations
do not allow for solvent effects, stabilization by counte-
rion, or coordination to the adjacent heteroatom, it
supports the hypothesis that C5 lithiated 2-(methylth-
io)oxazole is at least as nucleophilic as lithiofuran in
contrast with the poor nucleophilicity observed with
5-lithio 4-carboxylates.13
The differential reactivity of 1a toward electrophiles
indicates synthetic utility in selective addition reactions.
Slower reaction of 1a with ketones and poor reactivity
with isovaleronitrile suggests that 1a may add selectively
at low temperature to aldehydes in the presence of
ketones, nitriles, and perhaps esters. On the other hand,
the formation of 4 from 1a and isovaleronitrile indicates
the R-nitrile carbanion is preferentially formed by proton
transfer. The electrophilic nature of C2 is then revealed
by addition-elimination of the R-nitrile carbanion to 1
and displacement of the MeS group to provide a moderate
Reductive removal of the MeS group was carried out
with several examples of 2 using one of two reagents:
Raney nickel and nickel boride (created in situ from
NiCl2‚6H2O and NaBH4,23 Table 2). Raney nickel in
refluxing ethanol smoothly desulfurized the oxazole rings
giving 5-monosubstituted oxazoles in good yields (59-
68%). It was pleasing to note that the reductively
sensitive benzylic alcohols 3a and 3d were formed in good
yield without further deoxygenation to the corresponding
5-benzyl oxazoles. Although reactions involving Ni2B
were complete in a short time (<15 min), the yields were
lower than those obtained with Raney nickel due to poor
mass recovery from the insoluble Ni-containing residue.
Discu ssion
The preparation of 5-monosubstituted oxazoles by
deprotonation-addition of 2-(methylthio)oxazole to al-
dehydes efficiently generates 5-substituted oxazoles in
good yield. This method has an advantage over two
literature methods for 5-substituted oxazoles, Scho¨llkopf
condenstion of lithiated CH3NC with esters24 or conden-
sation of triethyl formate with phenacylamines,25,26 by
(23) Gamen, B.; Osby, J . O. Chem. Rev. (Washington, D.C.) 1986,
86, 763-780.
(24) Scho¨llkopf, U.; Schro¨der, R. Angew. Chem., Int. Ed. Engl. 1971,
10, 333.
(25) Demenchenko, N. P.; Grekov, A. P. Zh. Obshch. Khim. 1962,
32, 1219.
(26) LaMattina, J . L. J . Org. Chem. 1980, 45, 2261-2262.

554 J . Org. Chem., Vol. 63, No. 3, 1998
Shafer and Molinski
(OH); 1H NMR (300 MHz, CDCl3) δ 2.43 (s, 3 H), 5.58 (s, 1 H),
6.46 (s, 1H), 7.37 (d, 2 H, J ) 8.3 Hz), 7.37 (d, 2 H, J ) 8.3
Hz); 13C NMR (CDCl3) δ 14.4 (CH3), 67.0 (CH), 122.0 (C), 124.9
(CH), 128.1 (CH), 131.5 (CH), 138.6 (C), 154.1 (C), 161.8 (C);
HREIMS found m/z 298.9607 (M+), C11H10BrNO2S requires
298.9616. Anal. Calcd for C11H10BrNO2S: C, 44.02; H, 3.36;
N, 4.67; S, 10.68. Found: C, 44.30; H, 3.41; N, 4.49; S, 10.59.
1-[2′-(Met h ylt h io)oxa zol-5′-yl]-1-(2′-n a p h t h yl)m et h a -
n ol (2d ). Yellow oil (77%) which crystallized from ethyl
acetate/hexane, mp 106-107 °C; IR (NaCl, neat) ν 3284 (OH),
1603 (CdC), 1487 cm-1; 1H NMR (300 MHz, CDCl3) δ 2.47 (s,
3 H), 5.29 (bs, 1 H), 5.85 (s, 1 H), 6.62 (s, 1H), 7.48 (m, 3 H),
7.84 (m, 4 H); 13C NMR (CDCl3) δ 14.2 (CH3), 67.6 (CH), 124.1
(CH), 124.9 (CH), 125.2 (CH), 125.9 (CH), 126.0 (CH), 127.4
(CH), 127.8 (CH), 128.1 (CH), 132.8 (C), 132.9 (C), 137.0 (C),
(unoptimized) yield of 4. Thus, the MeS group, conve-
niently introduced in 1 as a robust surrogate group to
direct electrophilic C-C bond formation at C5 by reaction
with hard electrophiles (aldehydes), may also function
as a leaving group for C-C bond formation at C2 under
another set of conditions. This carbon-carbon bond-
forming reaction complements the successful Vedejs
modification for metalation-addition to 2-unsubstituted
oxazoles.17 We are now exploring both of these versatile
properties in C-C bond-forming reactions of oxazoles.
Exp er im en ta l Section
Gen er a l. THF and ether were purified by distillation from
sodium benzophenone ketyl. 1H NMR and 13C NMR were
recorded in CDCl3 (unless stated otherwise) at 300 and 75 MHz
and referenced to δ 7.26 and δ 77.00, respectively. Homo-
nuclear J couplings were confirmed by COSY or single-
frequency decoupling experiments. 13C NMR signal chemical
shift and multiplicity assignments (CH3, methyl; CH2, meth-
ylene; CH, methine; C, quaternary) were made from DEPT
spectra. High-resolution mass spectra were provided by the
University of California, Riverside, and the University of
Minnesota Mass Spectrometry Laboratories. Other procedures
are described elsewhere.27
2-(Meth ylth io)oxa zole (1). Oxazole-2-thione (4.98 g, 49.3
mmol) in THF (125 mL) was added to hexane-washed KH (35%
dispersion in oil, 6.38 g, 55.7 mmol) in THF (125 mL) at -60
°C, and, after 30 min, MeI was added. The reaction was
stirred for 3.25 h and was quenched with NH4Cl (aq, satd, 50
mL) and then diluted with H2O (40 mL). The aqueous layer
was extracted with Et2O (3 × 800 mL), and the combined
organic layers were dried (MgSO4) and reduced to a yellow oil
(6.6067 g). The crude material was purified by bulb-to-bulb
distillation (70-100 °C, 28 mmHg) to give 118 as a colorless
oil (4.315 g; 76%). 1H NMR (300 MHz, CDCl3) δ 2.65 (s, 3 H),
7.10 (s, 1 H), 7.66 (s, 1H); 13C NMR (CDCl3) δ 14.4 (CH3), 128.1
(CH), 139.8 (CH), 161.1 (C); HREIMS found m/z 115.0090 (M+),
C4H5NOS requires 115.0092.
154.6 (C), 161.5 (C); HREIMS found m/z 271.0656 (M+), C15H13
-
NO2S requires 271.0667. Anal. Calcd for C15H13NO2S: C,
66.40; H, 4.83; N, 5.16; S, 11.82. Found: C, 66.50; H, 4.91; N,
5.07; S, 11.64.
“Dou ble a lk yla tion ” of 1a : Bin a p h th yl Diol 5d . The
above reaction was repeated with 1.4 equiv of BuLi and
addition of metalated 1 to aldehyde (2.2 equiv) at -40 °C. Silica
gel chromatography gave 2d (33%) in addition to a new
compound 5d (44%) which crystallized from ethyl acetate/
hexane, mp 145-146 °C; IR (NaCl, neat) ν 3369 (OH), 1734,
1
1484 cm-1; H NMR (300 MHz, CDCl3) δ 3.37 (dd, 1 H, J )
13.7, 8.2 Hz), 3.57 (dd, 1 H, J ) 13.7, 3.3 Hz), 5.10 (dd, 1 H, J
) 8.2, 3.3 Hz), 5.55 (bs, 2 H), 5.90 (s, 1 H), 6.76 (s, 1H), 7.44
(m, 6 H), 7.82 (m, 8 H); 13C NMR (CDCl3) δ 40.7 (CH2), 67.2
(CH), 72.0 (CH), 123.6 (CH), 124.1 (CH), 124.4 (CH), 124.5
(CH), 124.9 (CH), 125.3 (CH), 125.6 (CH), 125.7 (CH), 127.0
(CH), 127.1 (CH), 127.4 (CH), 127.5 (CH), 127.6 (CH), 132.4
(C), 132.5 (C), 132.6 (C), 137.7 (C), 155.1 (C), 160.0 (C);
HRCIMS (NH3) found m/z 428.1332 (MH+), C26H21NO3S
requires 428.1320.
1-(2′-Fu r yl)-1-[2′-(m eth ylth io)oxazol-5′-yl]m eth an ol (2e).
1
Yellow oil (72%); IR (NaCl, neat) ν 3269 (OH), 1487 cm-1; H
NMR (300 MHz, CDCl3) δ 2.53 (s, 3 H), 5.75 (s, 1 H), 6.30 (m,
2 H), 6.80 (s, 1 H), 7.35 (s, 1 H); 13C NMR (CDCl3) δ 14.3 (CH3),
61.7 (CH), 107.8 (CH), 110.3 (CH), 125.3 (CH), 142.5 (CH),
152.2 (C), 161.6 (C); HREIMS found m/z 211.0299 (M+), C9H9-
NO3S requires 211.0303.
Gen er a l P r oced u r e for C-5 Alk yla tion . 1-P h en yl-1-[2′-
(m eth ylth io)oxa zol-5′-yl]m eth a n ol (2a ). 2-(Methylthio)ox-
azole (1) (0.2496 g, 2.17 mmol), TMEDA (3.4 mL, 22.5 mmol),
and THF (5 mL) were added to a solution of n-BuLi (0.88 mL,
2.31 mmol) in THF (5 mL) at -78 °C. In a separate flask,
benzaldehyde (0.50 mL, 4.92 mmol) was dissolved in THF (7
mL) and cooled to -78 °C. After 20 min, the oxazole anion of
1 was added to the aldehyde over 10 min via an insulated
cannula. The mixture was stirred for an additional 12 min,
quenched with NaHCO3 (aq, satd, 3 mL), diluted with 10 mL
H2O, and extracted with EtOAc (3 × 125 mL). The organic
layer was dried (MgSO4) and reduced to a yellow oil which
was purified by column chromatography (silica, 3:7 to 1:1
EtOAc:hexane) to give 2a as a colorless oil (0.4008 g, 84%). IR
1-[2′-(Meth ylth io)oxazol-5′-yl]-3,7-dim eth ylocta-2,6-dien -
1-ol (2f). Clear oil (83%, 2:1 E:Z); IR (NaCl, neat) ν 3336 (OH),
1
1726, 1668 (CdC), 1490 cm-1; H NMR (300 MHz, CDCl3) δ
1.51 (s, 3 H), 1.59 (s, 3 H), 1.61 (s, 3 H), 2.00 (m, 4 H), 2.52 (s,
3 H), 4.99 (m, 1 H), 5.34 (m, 2 H), 6.72 (s, 1 H; E), 6.75 (s, 1 H,
Z); 13C NMR (CDCl3) δ 14.4 (CH3), 16.5/17.5 (CH3), 22.4/23.2
(CH3), 25.4/25.5 (CH3), 26.0/26.2 (CH2), 32.2/ 39.2 (Z/E, CH2),
62.0/62.4 (CH), 122.6 (CH), 123.4 (CH), 123.8 (CH), 131.7/132.3
(C), 140.6/140.9 (C), 154.6/154.7 (C), 160.9 (C); HRCIMS (NH3)
found m/z 268.1368 (MH+), C14H22NO2S requires 268.1371.
1-[2′-(Meth ylth io)oxa zol-5′-yl]-n -d eca n ol (2g). Colorless
solid (73%); IR (NaCl, neat) ν 3338 (OH), 1491 cm-1; 1H NMR
(300 MHz, CDCl3) δ 0.80 (m, 3 H), 1.19 (s, 12 H), 1.36 (m, 2
H), 1.71 (m, 2 H), 2.52 (s, 3 H), 4.05 (bs, 1 H), 4.56 (t, 1 H, J
) 6.8 Hz), 6.75 (s, 1 H); 13C NMR (CDCl3) δ 13.9 (CH3), 14.3
(CH3), 22.5 (CH2), 25.3 (CH2), 29.1 (CH2), 29.3 (CH2), 29.2
(CH2), 31.7 (CH2), 34.9 (CH2), 65.3 (CH), 123.5 (CH), 155.6 (C),
(NaCl, neat) ν 3304 (OH), 1488 cm-1 1H NMR (300 MHz,
;
CDCl3) δ 2.56 (s, 3 H), 5.76 (s, 1 H), 6.62 (s, 1H, J C4-H4 ) 195.8
Hz), 7.37 (m, 5 H); 13C NMR (CDCl3) δ 14.5 (CH3), 68.04 (CH),
125.3 (CH), 126.5 (CH), 128.3 (CH), 128.5 (CH), 139.6 (C),
154.5 (C), 161.7 (C); HREIMS found m/z 221.0517 (M+), C11H11
-
160.6 (C); HRCIMS (NH3) found m/z 272.1679 (MH+), C14H26
-
NO2S requires 221.0511.
NO2S requires 272.1684.
1-(4′-Met h oxyp h en yl)-1-[2′-(m et h ylt h io)oxa zol-5′-yl]-
m eth a n ol (2b). Yellow oil (85%); IR (NaCl, neat) ν 3332 (OH),
1-[2′-(Met h ylt h io)oxa zol-5′-yl]-2,2-d im et h ylp r op a n ol
(2h ). Colorless solid (69%); mp 71-73 °C (recrystallized from
1
1614 cm-1 (CdC); H NMR (300 MHz, CDCl3) δ 2.56 (s, 3 H),
ethyl acetate/hexane); IR (NaCl, neat) ν 3285 (OH), 1490 cm-1
1H NMR (300 MHz, CDCl3) δ 0.89 (s, 9 H), 2.53 (s, 3 H), 4.28
(s, 1 H), 6.76 (s, 1 H); 13C NMR (CDCl3) δ 14.4 (CH3), 25.6
(CH3), 35.3 (C), 74.0 (CH), 125.0 (CH), 154.5 (C), 160.1 (C);
HRCIMS (NH3) found m/z 202.0901 (MH+), C9H16NO2S re-
quires 202.0902.
;
3.79 (s, 3 H), 5.70 (s, 1 H), 6.62 (s, 1H), 6.87 (d, 2 H, J ) 8.6
Hz), 7.31 (d, 2 H, J ) 8.6 Hz); 13C NMR (CDCl3) δ 14.5 (CH3),
55.2 (CH3), 67.7 (CH), 113.8 (CH), 125.1 (CH), 127.8 (CH),
131.8 (C), 154.8 (C), 159.5 (C), 161.4 (C); HREIMS found m/z
251.0604 (M+), C12H13NO3S requires 251.0616.
1-(4′-Br om oph en yl)-1-[2′-(m eth ylth io)oxazol-5′-yl]m eth -
a n ol (2c). Yellow oil (84%) which crystallized from ethyl
acetate and hexane, mp 96-97 °C; IR (NaCl, neat) ν 3270
1-[2′-(Met h ylt h io)oxa zol-5′-yl]-(2R)-2,3-O-Isop r op yli-
d en ep r op a n ol (2i). Yellow oil (60%, 2:1 ratio of diastereo-
mers); IR (NaCl, neat) ν 3412 (OH), 1490 cm-1; 1H NMR (300
MHz, CDCl3) δ 1.36/1.39 (s, 3 H), 1.42/1.46 (s, 3 H), 2.63 (s, 3
H), 3.43 (bs, 1 H), 3.80 (m, 2 H), 4.02 (m, 1 H), 4.08 (m, 1 H),
4.34 (m, 1 H)/ 4.38 (m, 1 H), 4.63 (d, 1 H, J ) 6.5 Hz)/4.75 (d,
(27) Searle, P. A.; Molinski, T. F. J . Org. Chem. 1993, 58, 7578-
7580.

Synthesis of 5-Substituted Oxazoles by Directed Alkylation
J . Org. Chem., Vol. 63, No. 3, 1998 555
1 H, J ) 5.9 Hz), 6.99/7.01 (s, 1 H); 13C NMR (CDCl3) δ 14.3
(CH3), 24.9 (CH3), 26.3 (CH3), 65.6/65.8 (CH2), 66.7 (CH), 76.4/
76.8 (CH), 109.5/109.9 (C), 125.1/125.4 (CH), 151.7/152.4 (C),
161.2/161.4 (C); HRCIMS (CH4) found m/z 246.0796 (MH+),
C10H16NO4S requires 246.0800.
hexane); IR (NaCl, neat) ν 3270 (OH), 1603 (CdC), 1508 cm-1
1H NMR (300 MHz, CDCl3) δ 3.56 (bs, 1 H), 5.99 (s, 1 H), 6.80
(s, 1 H), 7.47 (m, 3 H), 7.74 (s, 1 H), 7.80 (m, 4 H); 13C NMR
(CDCl3) δ 67.9 (CH), 123.1 (CH), 124.1 (CH), 125.3 (CH), 126.1
(CH), 126.2 (CH), 127.7 (CH), 127.9 (CH), 128.2 (CH), 132.9
(C), 133.0 (C), 137.2 (C), 151.0 (CH), 153.6 (C); HREIMS found
m/z 225.0800 (M+), C14H11NO2 requires 225.0790. Anal. Calcd
for C14H11NO2: C, 74.65; H, 4.92; N, 6.22. Found: C, 74.12;
H, 4.99; N, 6.06.
;
1-[2′-(Meth ylth io)oxazol-5′-yl]-2,2-dim eth ylpr opan ol (2j).
Colorless solid (27%, 39% based on consumed starting mate-
rial), recrystallized from ethyl acetate/hexane, mp 76-77 °C;
1
IR (NaCl, neat) ν 3385 (OH), 1492 cm-1; H NMR (300 MHz,
CDCl3) δ 0.77 (d, 3 H, J ) 6.8 Hz), 0.87 (d, 3 H, J ) 6.8 Hz),
1.36 (s, 3 H), 2.01 (2 overlapping q, 1 H, J ) 6.8 Hz), 2.52 (s,
3 H), 3.12 (bs, 1 H), 6.73 (s, 1 H); 13C NMR (CDCl3) δ 14.4
(CH3), 16.7 (CH3), 17.3 (CH3), 22.1 (CH3), 36.6 (CH), 72.9 (C),
123.4 (CH), 158.1 (C), 159.9 (C); HREIMS found m/z 201.0816
(M+), C9H15NO2S requires 201.0824. Anal. Calcd for
C9H15NO2S: C, 53.70; H, 7.51; N, 6.96; S, 15.93. Found: C,
53.88; H, 7.62; N, 6.82; S, 15.99.
1-(Oxa zol-5′-yl)d eca n ol (3 g). Yellow oil (60%); mp 62-
64 °C (recrystallized from ethyl acetate/hexane); IR (NaCl,
neat) ν 3364 (OH) cm-1 1H NMR (300 MHz, CDCl3) δ 0.88
;
(m, 3 H), 1.25 (m, 12 H), 1.46 (m, 2 H), 1.84 (m, 2 H), 2.65 (bs,
1 H), 4.76 (t, 1 H, J ) 6.8 Hz), 6.97 (s, 1 H), 7.84 (s, 1 H); 13C
NMR (CDCl3) δ 14.1, 22.6, 25.3, 29.3, 29.5, 31.8, 35.3, 65.9,
122.5, 150.6, 154.2; HRCIMS found m/z 226.1808 (MH+),
C
13H24NO2 requires 226.1807. Anal. Calcd for C13H23NO2: C,
1-[2′-(Meth ylth io)oxa zol-5′-yl]cycloh exa n ol (2k ). Color-
less oil (53%) which crystallized from ethyl acetate/hexane, mp
69.92; H, 9.48; N, 6.27. Found: C, 69.56; H, 10.03; N, 6.20.
1-(Oxa zol-5′-yl)-2,2-d im eth ylp r op a n ol (3h ). Yellow oil
(59%); mp 57-58 °C (recrystallized from ethyl acetate/hexane);
1
85-86 °C; IR (NaCl, neat) ν 3314 (OH), 1492 cm-1; H NMR
1
(300 MHz, CDCl3) δ 1.44 (m, 5 H), 1.79 (m, 5 H), 2.60 (s, 3 H),
3.31 (bs, 1 H), 6.79 (s, 1 H); 13C NMR (CDCl3) δ 14.4 (CH3),
21.8 (CH2), 25.2 (CH2), 36.1 (CH2), 68.7 (C), 122.7 (CH), 158.7
(C), 160.1 (C); HREIMS found m/z 213.0826 (M+), C10H15NO2S
requires 213.0824. Anal. Calcd for C10H15NO2S: C, 56.31; H,
7.09; N, 6.57; S, 15.03. Found: C, 56.59; H, 7.17; N, 6.49; S,
14.90.
IR (NaCl, neat) ν 3330 (OH), 1508, 1479 cm-1; H NMR (300
MHz, CDCl3) δ 0.91 (s, 9 H), 3.50 (bs, 1 H), 4.41 (s, 1 H), 6.87
(s, 1 H), 7.75 (s, 1 H); 13C NMR (CDCl3) δ 25.6 (CH3), 35.5 (C),
74.2 (CH), 123.4 (CH), 150.2 (C), 153.3 (C); HRCIMS (i-C4H9)
found m/z 156.1025 (MH+), C8H14NO2 requires 156.1025. Anal.
Calcd for C8H13NO2: C, 61.91; H, 8.44; N, 9.03. Found: C,
62.00; H, 8.43; N, 9.08.
2-(Meth ylth io)-5-ben zoyloxa zole (2l). Orange oil (38%)
which crystallized from tert-butyl methyl ether/hexane, mp
62-63 °C; UV (CHCl3) λmax 258 (ꢀ 7085), 311 (17810); IR (NaCl,
1-(Oxa zol-5′-yl)cycloh exa n ol (3k ). White solid (60%); mp
76-77 °C (recrystallized from ethyl acetate/hexane); IR (NaCl,
neat) ν 3355 (OH), 1648, 1505, 1449 cm-1; 1H NMR (300 MHz,
CDCl3) δ 1.47 (m, 4 H), 1.74 (m, 2 H), 1.91 (m, 4 H), 2.89 (bs,
1 H), 6.91 (s, 1 H), 7.79 (s, 1 H); 13C NMR (CDCl3) δ 21.8 (CH2),
25.2 (CH2), 36.3 (CH2), 68.9 (CH), 121.2 (CH), 150.2 (CH), 157.5
(C); HRCIMS (i-C4H9) found m/z 168.1025 (MH+), C9H14NO2
requires 168.1024. Anal. Calcd for C9H13NO2: C, 64.65; H,
7.84; N, 8.38. Found: C, 64.61; H, 7.82; N, 8.28.
neat) ν 1718 (CdO), 1653 (CdC), 1454 cm-1 1H NMR (300
;
MHz, CDCl3) δ 2.72 (s, 3 H), 7.53 (m, 3 H), 7.73 (s, 1 H), 7.91
(m, 2 H); 13C NMR (CDCl3) δ 14.3 (CH3), 128.4 (CH), 128.5
(CH), 132.9 (CH), 136.4 (C), 137.3 (CH), 150.6 (C), 167.2 (C),
180.2 (C); HREIMS found m/z 219.0363 (M+), C11H9NO2S
requires 219.0354. Anal. Calcd for C11H9NO2S: C, 60.26; H,
4.14; N, 6.39; S, 14.62. Found: C, 59.92; H, 4.14; N, 6.35; S,
14.77.
Deuterium Incorporation Experiment. 2-(Meth ylth io)ox-
a zole-5-d (2o). Compound 1 (0.2984 g, 2.59 mmol), TMEDA
(4.0 mL, 26.5 mmol), and THF (8 mL) were added to n-BuLi
(1.0 mL, 2.62 mmol) and THF (7 mL) at -78 °C. After 15 min,
approximately one-third of the reaction mixture was trans-
ferred via an insulated cannula to CH3OD (1 mL) in Et2O (5
mL) at -78 °C (sample 1). The temperature of the remaining
reaction mixture was raised to -40 °C, and after another 15
min, approximately one-third of the reaction mixture was
transferred to a mixture of CH3OD (1 mL) and Et2O (5 mL) at
-78 °C using an insulated cannula (sample 2). The remaining
reaction mixture was stirred for an additional 1.7 h at -40 °C
after which it was quenched by addition of CH3OD (1 mL,
sample 3). Each of the three samples was dried (MgSO4),
concentrated under vacuum, and purified by column chroma-
tography (silica, elution with Et2O). The 1H NMR signal of
H5 was integrated and compared to the H4 integral. Com-
parison of the integrations of H5 to H4 gave the following
results (atom % deuterium): sample 1 (96%); sample 2 (94%);
sample 3 (90%). Comparison of NMR integrations of H4 to
the MeS group indicated that in each case the ratio was 1:3
(∼(5% error). GC/MS (column DB-5, 30 m; Ti 50 °C, ti 1 min,
ramp 10 °C/min, Tf 280 °C, tf 5 min) gave % deuteration.
sample 1 (89%); sample 2 (95%); sample 3 (86%) error (2%.
[2′-(Met h ylt h io)oxa zol-5′-yl]-2,2-d im et h ylp r op a n on e
(2m ). Yellow oil (71%) which crystallized from n-hexane, mp
58-59 °C; UV (CHCl3) 292 (ꢀ 13026); IR (NaCl, neat) ν 1669,
1
1552, 1451 cm-1; H NMR (300 MHz, CDCl3) δ 1.24 (s, 9 H),
2.63 (s, 3 H), 7.66 (s, 1 H); 13C NMR (CDCl3) δ 14.3 (CH3),
26.4 (CH3), 43.0 (C), 135.2 (CH), 150.6 (C), 165.0 (C), 192.9
(C); HREIMS found m/z 199.0668 (M+), C9H13NO2S requires
199.0667. Anal. Calcd for C9H13NO2S: C, 54.25; H, 6.58; N,
7.03; S, 16.09. Found: C, 54.32; H, 6.46; N, 6.94; S, 16.02.
Ad d ition -Elim in a tion of Isova ler on itr ile to 2-(Meth -
ylth io)oxa zole. 3-Meth yl-2-(2-oxa zolyl)bu ta n en itr ile (4).
The reaction was carried out as for addition to aldehydes, but
the reaction mixture was allowed to warm to 25 °C over 16 h.
Workup and chromatography of the product gave 4 as a yellow
1
oil (33%); IR (NaCl, neat) ν 2250 (CN), 1571, 1467 cm-1; H
NMR (300 MHz, CDCl3) δ 1.11 (d, 3 H, J ) 6.7 Hz), 1.12 (d, 3
H, J ) 6.7 Hz), 2.47 (dq, 1 H, J ) 6.7 Hz), 3.98 (d, 1 H, J ) 6.1
Hz), 7.14 (d, 1 H, J ) 0.8 Hz), 7.71 (d, 1 H, J ) 0.8 Hz); 13C
NMR (CDCl3) δ 19.0 (CH3), 20.1 (CH3), 31.5 (CH), 38.8 (CH),
115.7 (C), 127.6 (CH), 139.8 (CH), 157.2 (C); HRCIMS (NH3)
found m/z 151.0866 (MH+), C8H11N2O requires 151.0871.
Gen er a l P r oced u r e for Red u ctive Disp la cem en t of th e
Met h ylt h io Gr ou p . 1-(Oxa zol-5′-yl)-1-p h en ylm et h a n ol
(3a ). Compound 2a (0.1071 g, 0.48 mmol) was dissolved in
absolute EtOH. Raney nickel in EtOH was added, and the
reaction mixture was refluxed for 1.5 h. The hot reaction
mixture was filtered through Celite which was washed with
hot absolute EtOH (500 mL). The solvent was removed to give
a cloudy oil which was purified by column chromatography
(1:1 ethyl acetate:hexane) to give 3a (0.0575 g, 68%). IR (NaCl,
neat) 3295 (OH), 1507, 1456 cm-1; 1H NMR (300 MHz, CDCl3)
δ 3.94 (bs, 1 H), 5.83 (s, 1 H), 6.75 (s, 1 H), 7.30 (m, 5 H), 7.71
(s, 1 H); 13C NMR (CDCl3) δ 68.2 (CH), 123.5 (CH), 126.5 (CH),
128.5 (CH), 128.6 (CH), 139.8 (C), 151.1 (C), 153.5 (C);
HREIMS found m/z 174.0565 (M+), C10H9NO2 requires 174.0555.
1-(Oxa zol-5′-yl)-1-(2-n a p h th yl)m eth a n ol (3d ). Off-white
solid (60%); mp 102-103 °C (recrystallized from chloroform/
Ack n ow led gm en t. C.M.S. gratefully acknowledges
a dissertation year fellowship from the UC Davis Office
of Graduate Studies. This research was supported in
part by the NIH (AI-31660 and AI-39987) and the UC
Davis Committee on Research.
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
and 13C NMR spectra of 1, 2a -m , 3a , 3d , 3g, 3h , 3k , 4, and
5d (42 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of this journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
J O971410H