A facile synthesis of oxazolines, thiazolines, and imidazolines using α,α-difluoroalkylamines

Article abstract of DOI:10.1055/s-2007-966038

β-Amino alcohols, β-amino thiols, and β-diamines can be converted to the corresponding oxazoline, thiazoline, and imidazoline derivatives, respectively, by reaction with α,α-difluoroalkylamines under mild conditions. The reaction is applicable for the synthesis of optically active heterocyclic compounds. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-966038

1528
PAPER
A Facile Synthesis of Oxazolines, Thiazolines, and Imidazolines Using
a,a-Difluoroalkylamines
Synthesis of
O
x
s
azolines,
u
y
andImidaz
o
o
lines shi Fukuhara, Chihiro Hasegawa, Shoji Hara*
Graduate School of Engineering, Hokkaido University, Sapporo 060-8628, Japan
Fax +81(11)7066556; E-mail: shara@eng.hokudai.ac.jp
Received 18 January 2007; revised 1 March 2007
hour at 40 °C to give the corresponding oxazolines 1a and
1b in 85 and 60% yield, respectively (Table 1). Under the
reaction conditions, deoxyfluorination of the hydroxy
group did not take place.12
Abstract: b-Amino alcohols, b-amino thiols, and b-diamines can
be converted to the corresponding oxazoline, thiazoline, and imida-
zoline derivatives, respectively, by reaction with a,a-difluoroalkyl-
amines under mild conditions. The reaction is applicable for the
synthesis of optically active heterocyclic compounds.
R2
H2N
R3
OH
O
N
R3
R2
Key words: a,a-difluoroalkylamine, heterocycle, amino alcohol,
oxazoline, thiazoline, imidazoline
R1CF2NR4
2
R1
1
Nitrogen-containing five-membered heterocyclic com-
pounds such as oxazolines, thiazolines, and imidazolines
are of great interest to organic chemists, because they are
present in various natural compounds having interesting
bioactivities.1 Furthermore, the optically active heterocy-
clic compounds have been successfully used in asymmet-
ric synthesis as chiral templates2 or ligands.3 Many
methods for their synthesis have been developed, includ-
ing cyclization of carboxyamide derivatives,4 and acid-
catalyzed condensation of amino compounds with car-
boxylic acid,5 ester,6 nitrile,7 or benzimidate.8 The cy-
clization reaction from N-acylamino alcohols or halides
using a dehydration reagent or a base has been most fre-
quently used for their synthesis. However, the method in-
cludes the problem of epimerization during the
cyclization.9 The acid-catalyzed cyclization of the N-acyl-
amino alcohols can avoid the problem but the reaction is
generally carried out at high temperature and the method
requires multi-step procedures from the starting
amines.2c,10 Though the acid-catalyzed condensation of
the amines with the carboxylic acid or its derivatives is
more direct and favored for their synthesis, high tempera-
ture and/or long reaction time is generally required.
Therefore, a new method for the direct conversion of the
amines to the heterocyclic compounds under mild condi-
tions has been desired. Recently, we reported a synthesis
of (fluoroalkyl)amides by the deoxyfluorination of N-pro-
tected amino alcohols using a,a-difluoroalkylamine.11
During the course of the study, we found that N-unpro-
tected b-amino alcohols were converted to the corre-
sponding oxazolines by reaction with the a,a-
difluoroalkylamines under mild conditions (Equation 1).
For instance, the reaction of 2-aminoethanol and 2-amino-
2-methylpropan-1-ol with N,N-diethyl-a,a-difluoro-3-
methylbenzylamine (DFMBA) was completed in one
Equation 1
Table 1 Synthesis of Heterocyclic Compounds Using DFMBAa
Substrate
Conditions
40 °C, 1 h
Product
Yield (%)b
O
OH
85
m-Tol
N
NH2
OH
1a
O
m-Tol
1b
40 °C, 1 h
60
N
NH2
OH
O
N
S
N
40 °C, 1 h
20 °C, 1 h
90
94
m-Tol
1c
NH2
SH
m-Tol
1d
NH2
NH2
H
N
83 °C, 1 hc
63
m-Tol
1e
N
NH2
a Unless otherwise stated, the reaction was carried out in CH2Cl2.
b Isolated yield based on DFMBA.
c 1,2-Dichloroethane was used as solvent.
The reaction of DFMBA was applied for the synthesis of
oxazole 1c, thiazole 1d, and imidazole 1e. The reaction
with 2-aminophenol and 2-aminothiophenol proceeded at
20–40 °C to give 1c and 1d in high yields, respectively.
On the other hand, the reaction with o-phenylenediamine
was sluggish and higher temperature (83 °C) was required
to complete the reaction and 1e was obtained in moderate
yield as shown in Table 1.
Various a,a-difluoroalkylamines, such as N-(a,a-difluo-
robenzyl)pyrrolidine (DFBP), N-(difluoromethyl)mor-
pholine (DFMM), N-(1,1-difluoro-2,2-dimethylpropyl)-
pyrrolidine (DFMPP), N,N-diethyl(a,a-difluoro-4-meth-
SYNTHESIS 2007, No. 10, pp 1528–1534
x
x.
x
x
.
2
0
0
7
Advanced online publication: 02.05.2007
DOI: 10.1055/s-2007-966038; Art ID: F01407SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Oxazolines, Thiazolines, and Imidazolines
1529
oxybenzyl)amine (DFMOBA), and N,N¢-(a,a,a¢,a¢-tetra-
fluoro-a,a¢-m-xylene)dipyrrolidine (TFXDP) can be
prepared from the corresponding amides in two steps,13
and were applied for the synthesis of heterocyclic com-
pounds (Figure 1).
Table 2 Synthesis of Optically Active Oxazolines Using a,a-Di-
fluoroalkylaminesa
Amino alcohol
Fluoroamine Product
Yield
(%)b
O
OH
DFMBA
DFMBA
DFBP
85 (>95)
82 (99)
74 (98)
78 (97)
m-Tol
1f
F
F
F
F
N
O
N
Me
NH2
Bn
Bn
Ph
N
NEt2
OH
m-Tol
1g
DFBP
DFMBA
NH2
Ph
Ph
F
F
F
F
O
OH
NEt2
Ph
H
N
N
OMe
NH2
i-Bu
i-Bu
O
1h
DFMOBA
DFMM
O
OH
DFBPc
Ph
N
NH2
t-Bu
t-Bu
1i
F
F
F
F
F
F
O
t-Bu
N
OH
N
N
DFBP
Ph 73 (98)
N
MeS(CH2)2
NH2
MeS(CH2)2
OH
1j
DFMPP
TFXDP
Figure 1 a,a-Difluoroalkylamines prepared
TFXDPd
79 (99)
O
O
N
NH2
Ph
N
1k
Recently, optically active oxazolines have been success-
fully used in asymmetric synthesis as the chiral ligands.2
Various kinds of optically active amino alcohols and their
precursors are commercially available and we used them
for the synthesis of the optically active oxazolines by re-
action with DFMBA, DFBP or TFXDP. The reaction pro-
ceeded without racemization and the optical purity of the
starting materials was completely kept in the products.14
By choosing the a,a-difluoroalkylamine and the amino
alcohol, various optically active oxazolines 1f–j can be
prepared in 73–85% yield (Table 2). (R,R)-1,3-Benzene-
bis(4-phenyl-4,5-dihydro-2-oxazole) (1k), which was
used as chiral ligand in asymmetric synthesis,15 can be di-
rectly prepared from (R)-2-amino-2-phenylethanol and
TFXDP in 79% yield.
Ph
Ph
a Unless otherwise stated, the reaction was carried out in CH2Cl2 at
40 °C for 1 h.
b Isolated yield based on a,a-difluoroalkylamine used. In parentheses,
ee (%) value determined by HPLC using a chiral column.
c The reaction was carried out in 1,2-dichloroethane at 60 °C for 1 h.
d The reaction was carried out at 40 °C for 2 h.
drochloride with DFMM, it was critical to add Et3N after
the addition of DFMM. By this method, 1o could be ob-
tained in 89% yield without racemization (99% ee). When
Et3N was added before DFMM to generate the free amino
thiol, the optically purity of the resulting 1o was low. Un-
der the same conditions, optically pure thiazoline deriva-
tives 1m and 1n were obtained in high yields from L-
cysteine ethyl ester hydrochloride using DFMPP and
DFBP, respectively. An oxazoline 1r was previously pre-
pared from L-threonine methyl ester in three steps2c and
used for asymmetric synthesis as a chiral template.2c,18 It
could be directly prepared from L-threonine methyl ester
using DFMOBA in 89% yield (>99% ee).
Heterocyclic compounds having an ester substituent on
their ring easily racemize and it is difficult to synthesize
them without losing the enantiomeric purity of the starting
amino precursors. Next, we applied our method for the
synthesis of optically active oxazoline and thiazoline de-
rivatives having an ester group on the ring. When L-serine
methyl ester hydrochloride was used, Et3N was initially
added at low temperature to generate free amino alcohol,
which was used in situ for the reaction with DFBP. By this
method, the corresponding optically active oxazoline de-
rivative 1l was obtained in 86% yield (98% ee). Similarly,
2-methoxyphenyloxazoline derivative 1p was obtained in
pure form using DFMOBA in high yield (Table 3). A thi-
azoline derivative 1o, which was used as a key intermedi-
ate for synthesis of b-lactam antibiotics,16 was previously
prepared from N-formyl-L-cysteine ethyl ester under acid-
ic conditions. However, racemization took place during
the reaction and the optically purity of the resulting 1o
was 70% ee.17 In the reaction of L-cysteine ethyl ester hy-
Though the reaction of N-protected amino alcohols with
DFMBA gave the fluorinated products,11 the reaction of
unprotected amino alcohols with DFMBA gave the ox-
azolines. This difference can be explained as follows: In
the reaction of the amino alcohol with DFMBA, an oxazo-
linium salt 2 was formed quickly at first. When the N-pro-
tected amino alcohol was used (R5 π H), the liberated
fluoride attacks at an oxygen attached carbon to give the
N-acylated fluoroalkylamine 3. This step is slow and rel-
atively high temperature is required. On the other hand,
when the N-unprotected amino alcohol was used
(R5 = H), deprotonation from the oxazolinium intermedi-
Synthesis 2007, No. 10, 1528–1534 © Thieme Stuttgart · New York

1530
T. Fukuhara et al.
PAPER
Table 3 Synthesis of Optically Active Heterocyclic Compounds Using a,a-Difluoroalkylaminesa
Amino acids
Fluoroamine
DFBP
Product
Yield (%)b
86 (98)
81 (>99)
92 (95)
OH
O
N
Ph
1l
NH2⋅HCl
SH
MeOOC
EtOOC
EtOOC
MeOOC
EtOOC
EtOOC
DFMPP
DFBP
S
t-Bu
1m
NH2⋅HCl
SH
N
S
Ph
1n
NH2⋅HCl
N
S
DFMM
89 (99)
SH
H
1o
NH2⋅HCl
N
EtOOC
EtOOC
DFMOBA
93 (>99)
OH
O
C6H4-p-MeO
NH2⋅HCl
N
MeOOC
MeOOC
1p
DFMBA
84 (>99)
89 (>99)
O
OH
m-Tol
N
NH2
OH
EtOOC
EtOOC
1q
DFMOBA
O
C6H4-p-MeO
NH2
N
1r
MeOOC
MeOOC
a The reaction conditions are given in the text.
b Isolated yield based on a,a-difluoroalkylamine used. In parentheses, ee % value determined by HPLC using chiral column.
ate takes place to give the oxazoline 1. This step is fast and proceeds under mild conditions, it can be applied to the
it takes place at lower temperature. Therefore, under the synthesis of optically active heterocyclic compounds
present conditions, the unprotected amino alcohol is se- which have been used as templates or ligands in asymmet-
lectively converted to the oxazoline 1 without the forma- ric synthesis.
tion of N-acylated fluoroalkylamine 3 (Scheme 1).
IR spectra were recorded using a JASCO FT/IR-410 spectropho-
tometer. The 1H NMR (270 MHz) and 13C NMR (68 MHz) spectra
F
R2
were recorded in CDCl3 on a JEOL JNM-A270II FT NMR spec-
trometer and the chemical shifts d are referred to tetramethylsilane.
The EI low- and high-resolution mass spectra were measured on a
JEOL JMS-700TZ, JMS-FABmate or JMS-HX110 spectrometer.
Enantiomeric excess was determined by HPLC (TOSOH SD-801)
using CHIRALCEL OD-H (0.46 cm ∆ × 25 cm) and hexane–pro-
pan-2-ol as eluents. Optical rotation was measured with a Horiba
High Sensitive Polarimeter. The Et3N·3HF was prepared by the ad-
dition of freshly distilled Et3N to anhyd HF in TeflonTM PFA vessel
at 0 °C.13 2-Aminoethanol, 2-methyl-2-aminopropan-1-ol, 2-ami-
nopropan-1-ol, 2-aminophenol, o-phenylenediamine were pur-
chased from Tokyo Chemical Industry Co., Ltd. 2-
Aminothiophenol was obtained from Kanto Chemical Co., Inc. (S)-
2-Amino-3,3-dimethylbutan-1-ol was obtained from Mitsubishi
Gas Chemical Co., Inc. (S)-2-Amino-3-phenylpropan-1-ol, (R)-2-
amino-2-phenylethanol, (S)-2-amino-4-methylpentan-1-ol, and (S)-
2-amino-4-methylthiobutan-1-ol were prepared by reduction of L-
phenylalanine, D-phenylglycine, L-leucine, L-methionine, respec-
tively,19 and the original amino acids were obtained from Tokyo
Chemical Industry Co., Ltd.
R2
F
R3
O
slow
R3
R5
O
N
R5
N
C
3
R5 ≠ H
Ar
R3
Ar
R2
N
R3
O
R2
R2
HO
R3
HN R5
Ar
CF
2 NEt2
R5
N R5
NEt2
O
– 2HF
fast
Ar
Ar
2
R2
N
R3
O
R2
R3
R
5 = H
fast
H
O
N
1
Ar
Ar
Scheme 1
In summary, we succeeded in the synthesis of various
five-membered heterocyclic compounds, such as oxazo-
line, thiazoline, and imidazoline derivatives, from amino
alcohols, amino thiols, and diamines respectively by the
reaction with a,a-difluoroalkylamines. As the reaction
N,N-Diethyl-a,a-difluoro-3-methylbenzylamine (DFMBA);
Typical Procedure
DFMBA was prepared by a modification of reported procedure.13
To a CH2Cl2 (50 mL) solution of N,N-diethyl-3-methylbenzamide
(13.8 g, 72 mmol), was added dropwise at 0 °C a CH2Cl2 (20 mL)
Synthesis 2007, No. 10, 1528–1534 © Thieme Stuttgart · New York

PAPER
Synthesis of Oxazolines, Thiazolines, and Imidazolines
1531
solution of oxalyl chloride (9.9 g, 78 mmol) and the mixture was
stirred at 40 °C for 2 h. The mixture was cooled again to 0 °C, and
Et3N·3HF (8.7 g, 53 mmol) and Et3N (10.1 g, 100 mmol) were add-
ed successively. The mixture was stirred at r.t. for 2 h and a gener-
ated precipitate was removed by filtration. The precipitate was
washed with CH2Cl2 (100 mL) and the combined filtrate was con-
centrated under reduced pressure. Hexane (100 mL) was added to
the residue and the generated solid was removed by filtration again.
The solid was washed with hexane (50 mL) and the filtrate was con-
centrated under reduced pressure. Distillation of the residue gave
DFMBA (12.6 g) in 82% yield; bp 81–83 °C/4 mmHg. Glassware
can be used, but all operations should be carried out under minimum
exposure to moisture.
13C NMR (CDCl3): d = 21.18, 54.82, 67.46, 125.17, 127.56, 128.16,
128.68, 131.97, 137.97, 164.71.
HRMS (EI): m/z calcd for C10H11NO (M+): 161.0841; found:
161.0848.
4,4-Dimethyl-2-(m-tolyl)-4,5-dihydrooxazole (1b)
The reaction was carried out as in the case of 1a using 2-methyl-2-
aminopropan-1-ol, and 1b was obtained in 60% yield.
IR (neat): 2967, 1650, 1312, 1193 cm–1.
1H NMR (CDCl3): d = 1.38 (s, 6 H), 2.37 (s, 3 H), 4.10 (s, 2 H),
7.26–7.29 (m, 2 H), 7.70–7.79 (m, 2 H).
13C NMR (CDCl3): d = 21.18, 28.42 (2 C), 67.49, 79.05, 125.24,
127.92, 128.17, 128.78, 131.93, 138.02, 162.20.
1H NMR (CDCl3): d = 1.07 (t, J = 7.1 Hz, 6 H), 2.39 (s, 3 H), 2.92
(q, J = 7.0 Hz, 4 H), 7.17–7.41 (m, 4 H).
HRMS (EI): m/z calcd for C12H15NO (M+): 189.1154; found:
189.1150.
N-(a,a-Difluorobenzyl)pyrrolidine (DFBP)
DFBP was prepared from N-benzoylpyrrolidine as in the case of
DFMBA in 76% yield; clear liquid; bp 95–99 °C/5 mmHg.
1H NMR (CDCl3): d = 1.80–1.84 (m, 4 H), 2.94–2.97 (m, 4 H),
7.41–7.43 (m, 3 H), 7.61–7.63 (m, 2 H).
2-(m-Tolyl)benzoxazole (1c)
The reaction was carried out as in the case of 1a using 2-aminophe-
nol, and 1c was obtained in 90% yield; white solid; mp 81 °C (Lit.20
mp 81–82 °C).
IR (KBr): 1551, 1453, 1245 cm–1.
1H NMR (CDCl3): d = 2.46 (s, 3 H), 7.32–7.45 (m, 4 H), 7.57–7.60
(m, 1 H), 7.76–7.79 (m, 1 H), 8.04–8.11 (m, 2 H).
N-(Difluoromethyl)morpholine (DFMM)
DFMM was prepared from N-formylmorpholine as in the case of
DFMBA in 80% yield; clear liquid; bp 49–52 °C/20 mmHg.
13C NMR (CDCl3): d = 21.33, 110.53, 119.96, 124.52, 124.75,
125.00, 127.03, 128.19, 128.81, 132.34, 138.73, 142.12, 150.75,
163.25.
1H NMR (CDCl3): d = 2.87 (t, J = 5.0 Hz, 4 H), 3.73 (t, J = 5.4 Hz,
4 H), 5.93 (t, J = 62.5 Hz, 1 H).
N-(1,1-Difluoro-2,2-dimethylpropyl)pyrrolidine (DFMPP)
DFMPP was prepared from N-pivaloylpyrrolidine as in the case of
DFMBA in 77% yield; clear liquid; bp 48–49 °C/7 mmHg.
HRMS (EI): m/z calcd for C14H11NO (M+): 209.0841; found:
209.0834.
1H NMR (CDCl3): d = 1.13 (s, 9 H), 1.76–1.80 (m, 4 H), 3.03–3.07
2-(m-Tolyl)benzothiazole (1d)
The reaction was carried out at 20 °C for 1 h as in the case of 1a
using 2-aminothiophenol, and 1d was obtained in 94% yield; white
solid; mp 69–70 °C (Lit.21 mp 67–68 °C).
IR (KBr): 1485, 1435, 1313 cm–1.
1H NMR (CDCl3): d = 2.46 (s, 3 H), 7.30–7.52 (m, 4 H), 7.86–7.95
(m, 3 H), 7.86 (d, J = 7.7 Hz, 1 H).
13C NMR (CDCl3): d = 21.34, 121.59, 123.17, 123.20, 124.86,
125.11, 126.27, 127.99, 128.91, 131.80, 133.54, 138.87, 154.14,
168.32.
(m, 4 H).
N,N-Diethyl(a,a-difluoro-4-methoxybenzyl)amine (DFMOBA)
DFMOBA was prepared from N,N-diethyl-4-methoxybenzamide as
in the case of DFMBA in 91% yield; clear liquid; bp 116–119 °C/5
mmHg.
1H NMR (CDCl3): d = 1.05 (t, J = 7.2 Hz, 6 H), 2.89 (q, J = 7.2 Hz,
4 H), 3.83 (s, 3 H), 6.91 (d, J = 8.8 Hz, 2 H), 7.52 (d, J = 8.8 Hz, 2
H).
HRMS (EI): m/z calcd for C14H11NS (M+): 225.0612; found:
225.0610.
N,N¢-(a,a,a¢,a¢-Tetrafluoro-a,a¢-m-xylene)dipyrrolidine
(TFXDP)
TFXDP was prepared from 1,1¢-isophthaloylbispyrrolidine using
2.2 equiv of oxalyl chloride, 1.5 equiv of Et3N·3HF, and 2.8 equiv
of Et3N to the amide as in the case of DFMBA in 67% yield; clear
liquid; bp 175–179 °C/5 mmHg.
1H NMR (CDCl3): d = 1.84–1.87 (m, 8 H), 3.02 (br s, 8 H), 7.51–
7.53 (m, 1 H), 7.74–7.76 (m, 2 H), 7.91 (s, 1 H).
2-(m-Tolyl)-1H-benzimidazole (1e)
The reaction was carried out in 1,2-dichloroethane at 83 °C for 1 h
using o-phenylenediamine, and 1e was obtained in 63% yield; white
solid; mp 211–212 °C (Lit.22 mp 217.0–219.0 °C).
IR (KBr): 3434, 2879, 1447, 1404 cm–1.
1H NMR (DMSO-d6): d = 2.42 (s, 3 H), 7.19–7.64 (m, 6 H), 7.95–
2-(m-Tolyl)-4,5-dihydrooxazole (1a); Typical Procedure
To a CH2Cl2 solution (4 mL) of 2-aminoethanol (146 mg, 2.4 mmol)
at –20 °C was added DFMBA (426 mg, 2 mmol) in CH2Cl2 (2 mL)
and the mixture was stirred at –20 °C for 5 min and at 40 °C for 1 h.
The mixture was poured into aq sat. K2CO3 (20 mL) and extracted
with Et2O (3 × 20 mL). The combined organic layers were dried
(MgSO4), and concentrated under reduced pressure. Purification by
column chromatography (silica gel, hexane–Et2O) gave 1a (274
mg) in 85% yield.
IR (neat): 1650, 1358, 1193 cm–1.
1H NMR (CDCl3): d = 2.38 (s, 3 H), 4.06 (t, J = 9.6 Hz, 2 H), 4.31
(t, J = 9.6 Hz, 2 H), 7.26–7.31 (m, 2 H), 7.71–7.81 (m, 2 H).
8.02 (m, 2 H), 12.85 (s, 1 H).
13C NMR (DMSO-d6): d = 21.02, 115.00 (2 C), 122.00 (2 C), 123.56
(2 C), 126.98 (2 C), 128.79, 130.06, 130.44, 138.11, 151.29.
HRMS (EI): m/z calcd for C14H12N2 (M+): 208.1000; found:
208.0994.
(S)-4-Benzyl-2-(m-tolyl)-4,5-dihydrooxazole (1f)
The reaction was carried out as in the case of 1a using (S)-2-amino-
3-phenylpropan-1-ol, and 1f was obtained in 85% yield (>95%ee);
[a]D23 +8.6 (c = 1.0, CHCl3).
IR (neat): 2921, 1649, 1357, 1194 cm–1.
Synthesis 2007, No. 10, 1528–1534 © Thieme Stuttgart · New York

1532
T. Fukuhara et al.
PAPER
1H NMR (CDCl3): d = 2.38 (s, 3 H), 2.73 (dd, J = 13.7, 8.9 Hz, 1 H),
3.27 (dd, J = 13.7, 5.0 Hz, 1 H), 4.13 (dd, J = 8.4, 8.5 Hz, 1 H), 4.32
(dd, J = 8.6, 9.2 Hz, 1 H), 4.55–4.60 (m, 1 H), 7.24–7.33 (m, 7 H),
7.72–7.79 (m, 2 H).
13C NMR (CDCl3): d = 21.21, 41.83, 67.84, 71.78, 125.31, 126.46,
127.61, 128.20, 128.52 (2 C), 128.81, 129.21 (2 C), 132.09, 138.00,
138.03, 164.11.
1H NMR (CDCl3): d = 1.88–2.02 (m, 2 H), 2.13 (s, 3 H), 2.64–2.71
(m, 2 H), 4.06 (dd, J = 7.5, 7.5 Hz, 1 H), 4.41–4.55 (m, 2 H), 7.37–
7.48 (m, 3 H), 7.92–7.96 (m, 2 H).
13C NMR (CDCl3): d = 15.52, 30.65, 35.41, 65.71, 72.32, 127.67,
128.19 (2 C), 128.25 (2 C), 131.27, 163.70.
HRMS (EI): m/z calcd for C12H15NOS (M+): 221.0874; found:
221.0875.
HRMS (EI): m/z calcd for C17H17NO (M+): 251.1310; found:
251.1308.
(R,R)-1,3-Benzenebis(4-phenyl-4,5-dihydro-2-oxazole) (1k)
To a CH2Cl2 solution (7 mL) of (R)-2-amino-2-phenylethanol (165
mg, 1.2 mmol) at –20 °C was added TFXDP (160 mg, 0.5 mmol) in
CH2Cl2 (1 mL) and the mixture was stirred at r.t. for 10 min. Then
the mixture was warmed to 40 °C and stirred for 2 h. The mixture
was then poured into aq sat. K2CO3 (20 mL) and extracted with Et2O
(3 × 20 mL). The combined organic layers were dried (MgSO4), and
concentrated under reduced pressure. Purification by column chro-
matography (silica gel, hexane–Et2O) gave 1k (145 mg) in 79%
yield (99% ee); [a]D23 +83.0 (c = 1.0, CHCl3) {Lit.15b for (S,S)-iso-
mer [a]D25 –74.4 (c = 1.04, CHCl3)}; white solid; mp 128–129 °C
(Lit.15a mp 129–130 °C).
(R)-4-Phenyl-2-(m-tolyl)-4,5-dihydrooxazole (1g)
The reaction was carried out as in the case of 1a using (R)-2-amino-
2-phenylethanol, and 1g was obtained in 82% yield (99% ee);
[a]D23 +28.0 (c = 1.0, CHCl3).
IR (neat): 2922, 1649, 1357, 1194 cm–1.
1H NMR (CDCl3): d = 2.40 (s, 3 H), 4.28 (t, J = 8.1 Hz, 1 H), 4.79
(dd, J = 7.1, 10.3 Hz, 1 H), 5.38 (dd, J = 7.1, 10.3 Hz, 1 H), 7.26–
7.36 (m, 7 H), 7.81–7.90 (m, 2 H).
13C NMR (CDCl3): d = 21.23, 70.10, 74.82, 125.53, 126.75 (2 C),
127.42, 127.58, 128.27, 128.73 (2 C), 129.06, 132.30, 138.13,
142.42, 164.88.
IR (KBr): 2901, 1654, 1454, 983 cm–1.
1H NMR (CDCl3): d = 4.30 (dd, J = 8.3, 8.4 Hz, 2 H), 4.82 (dd,
J = 8.4, 10.1 Hz, 2 H), 5.41 (dd, J = 8.3, 10.1 Hz, 2 H), 7.26–7.38
(m, 10 H), 7.52 (t, J = 7.8 Hz, 1 H), 8.20 (dd, J = 1.6, 7.8 Hz, 2 H),
8.69 (t, J = 1.6 Hz, 1 H).
HRMS (EI): m/z calcd for C16H15NO (M+): 237.1154; found:
237.1150.
(S)-4-Isobutyl-2-phenyl-4,5-dihydrooxazole (1h)
The reaction was carried out as in the case of 1a using (S)-2-amino-
4-methylpentan-1-ol and DFBP, and 1h was obtained in 74% yield
(98% ee); [a]D21 –76.9 (c = 1.0, CHCl3) {Lit.23 [a]D23 –79.9
(c = 0.95, CHCl3)}.
13C NMR (CDCl3): d = 70.21 (2 C), 74.97 (2 C), 126.73 (4 C),
127.66 (2 C), 127.97, 128.52 (2 C), 128.56, 128.76 (4 C), 131.37 (2
C), 142.18 (2 C), 164.07 (2 C).
Methyl (S)-2-Phenyl-4,5-dihydrooxazole-4-carboxylate (1l)
To a CH2Cl2 solution (4 mL) of L-serine methyl ester hydrochloride
(373 mg, 2.4 mmol) at –20 °C was added Et3N (606 mg, 6 mmol),
and the mixture was stirred at r.t. for 30 min. Then the mixture was
cooled to –20 °C again and DFBP (394 mg, 2 mmol) in CH2Cl2 (2
mL) was added. The mixture was warmed to 20 °C and stirred for 2
h. The mixture was poured into aq sat. K2CO3 (20 mL) and extracted
with Et2O (3 × 20 mL). The combined organic layers were dried
(MgSO4), and concentrated under reduced pressure. Purification by
column chromatography (silica gel, hexane–Et2O) gave 1l (352
mg) in 86% yield (98% ee); [a]D23 +122.7 (c = 1.0, CHCl3) {Lit.26
[a]D20 +117.2 (c = 0.053, CHCl3)}.
IR (neat): 2956, 1651, 1358, 1063 cm–1.
1H NMR (CDCl3): d = 0.96–1.00 (m, 6 H), 1.38–1.41 (m, 1 H),
1.70–1.83 (m, 2 H), 3.99 (dd, J = 7.8, 7.8 Hz, 1 H), 4.33–4.36 (m, 1
H), 4.51 (dd, J = 9.3, 7.8 Hz, 1 H), 7.37–7.46 (m, 3 H), 7.92–7.96
(m, 2 H).
13C NMR (CDCl3): d = 22.67, 22.91, 25.49, 45.59, 65.16, 73.08,
127.98, 128.17, 128.23 (2 C), 131.11 (2 C), 163.20.
HRMS (EI): m/z calcd for C13H17NO (M+): 203.1310; found:
203.1308.
(S)-4-tert-Butyl-2-phenyl-4,5-dihydrooxazole (1i)
The reaction was carried out in 1,2-dichloroethane at 60 °C for 1 h
using (S)-2-amino-3,3-dimethylbutan-1-ol and DFBP, and 1i was
obtained in 78% yield (97% ee); white solid; mp 31 °C (Lit.24 mp
32–33 °C; [a]D22 –80.39 (c = 1.02, CHCl3) {Lit.24 [a]D20 –99.4
(c = 1.3, CHCl3)}.
IR (neat): 2953, 1742, 1642, 1361 cm–1.
1H NMR (CDCl3): d = 3.83 (s, 3 H), 4.57–4.74 (m, 2 H), 4.96 (dd,
J = 10.6, 7.9 Hz, 1 H), 7.39–7.51 (m, 3 H), 7.97–8.01 (m, 2 H).
13C NMR (CDCl3): d = 52.61, 68.40, 69.50, 126.76, 128.27 (2 C),
128.51 (2 C), 131.82, 166.30, 171.51.
IR (KBr): 2956, 1653, 1356, 1086 cm–1.
HRMS (EI): m/z calcd for C11H11NO3 (M+): 205.0739; found:
1H NMR (CDCl3): d = 0.95 (s, 9 H), 4.05 (dd, J = 5.1, 6.7 Hz, 1 H),
4.24 (dd, J = 5.7, 5.7 Hz, 1 H), 4.35 (dd, J = 5.7, 6.7 Hz, 1 H), 7.38–
7.46 (m, 3 H), 7.94–7.97 (m, 2 H).
205.0738.
Ethyl (S)-2-tert-Butyl-4,5-dihydrothiazole-4-carboxylate (1m)
To a CH2Cl2 suspension (4 mL) of L-cysteine ethyl ester hydrochlo-
ride (445 mg, 2.4 mmol) at –20 °C, was added DFMPP (354 mg, 2
mmol) in CH2Cl2 (2 mL) and the mixture was stirred at r.t. for 30
min. Then the mixture was cooled to –20 °C again and Et3N (182
mg, 1.8 mmol) was added. The mixture was warmed to 40 °C and
stirred for 1 h. The mixture was poured into aq sat. K2CO3 (20 mL)
and extracted with Et2O (3 × 20 mL). The combined organic layers
were dried (MgSO4), and concentrated under reduced pressure. Pu-
rification by column chromatography (silica gel, hexane–Et2O)
gave 1m (348 mg) in 81% yield (>99% ee); [a]D23 +82.5 (c = 1.0,
CHCl3).
13C NMR (CDCl3): d = 25.86 (3 C), 34.03, 68.69, 76.19, 128.00,
128.21 (2 C), 128.23 (2 C), 131.07, 163.18.
HRMS (EI): m/z calcd for C13H17NO (M+): 203.1310; found:
203.1305.
(S)-4-(Methylthioethyl)-2-phenyl-4,5-dihydrooxazole (1j)
The reaction was carried out as in the case of 1a using (S)-2-amino-
4-methylthiobutan-1-ol and DFBP, and 1j was obtained in 73%
23
23
yield (98% ee); [a]D –91.6 (c = 1.10, acetone) {Lit.25 [a]D
–80.96 (c = 1.0, acetone)}.
IR (neat): 2915, 1650, 1359 cm–1.
IR (neat): 2967, 1741, 1613, 1184 cm–1.
Synthesis 2007, No. 10, 1528–1534 © Thieme Stuttgart · New York

PAPER
Synthesis of Oxazolines, Thiazolines, and Imidazolines
1533
1H NMR (CDCl3): d = 1.27 (s, 9 H), 1.30 (t, J = 7.2 Hz, 3 H), 3.46–
3.51 (m, 2 H), 4.24 (q, J = 7.2 Hz, 2 H), 5.07 (dd, J = 9.3, 8.1 Hz, 1
Methyl (4S,5R)-2-(4-Methoxyphenyl)-5-methyl-4,5-dihydro-
oxazole-4-carboxylate (1r)
H).
The reaction was carried out as in the case of 1q using DFMOBA,
and 1r was obtained in 89% yield (>99%ee); [a]D23 +75 (c = 1.0,
CHCl3) {Lit.2c [a]D23 +69.4 (c = 2.0, CHCl3)}; white solid; mp 86–
87 °C (Lit.2c mp 86–87 °C).
13C NMR (CDCl3): d = 13.92, 29.01 (3 C), 35.16, 37.99, 61.20,
77.81, 170.81, 183.13.
HRMS (EI): m/z calcd for C10H17NO2S (M+): 215.0980; found:
215.0985.
IR (KBr): 1735, 1637, 1253 cm–1.
1H NMR (CDCl3): d = 1.52 (d, J = 6.3 Hz, 3 H), 3.80 (s, 3 H), 3.85
(s, 3 H), 4.44 (d, J = 7.4 Hz, 1 H), 4.94–4.98 (m, 1 H), 6.90 (d,
J = 9.0 Hz, 2 H), 7.93 (d, J = 8.9 Hz, 2 H).
13C NMR (CDCl3): d = 21.00, 52.63, 55.37, 75.11, 78.68, 113.65 (2
C), 119.69, 130.32 (2 C), 162.41, 165.31, 171.83.
Ethyl (S)-2-Phenyl-4,5-dihydrothiazole-4-carboxylate (1n)
The reaction was carried out as in the case of 1m using DFBP, and
1n was obtained in 92% yield (95% ee); [a]D23 +47.6 (c = 1.0,
EtOH) {Lit.27 [a]D23.8 +14.6 (c = 1.098, EtOH)}.
IR (neat): 2981, 1739, 1602, 1188 cm–1.
1H NMR (CDCl3): d = 1.33 (t, J = 7.2 Hz, 3 H), 3.61–3.73 (m, 2 H),
4.29 (q, J = 7.2 Hz, 2 H), 5.27 (dd, J = 9.2, 9.2 Hz, 1 H), 7.27–7.49
(m, 3 H), 7.86–7.88 (m, 2 H).
Acknowledgment
We are grateful to Mitsubishi Gas Chemical Co., Inc. for their gift
of (S)-2-amino-3,3-dimethylbutan-1-ol.
13C NMR (CDCl3): d = 14.14, 35.36, 61.73, 78.58, 128.42 (2 C),
128.57 (2 C), 131.58, 132.66, 170.76, 170.79.
HRMS (EI): m/z calcd for C12H13NO2S (M+): 235.0667; found:
235.0670.
References
(1) For reviews, see: (a) Gant, T. G.; Meyers, A. I. Tetrahedron
1994, 50, 2297. (b) Wipf, P.; Venkatraman, S. Synlett 1997,
1. (c) Roy, R. S.; Gehring, A. M.; Milne, J. C.; Belshaw, P.
J.; Walsh, C. T. Nat. Prod. Rep. 1999, 16, 249. (d) Lewis, J.
R. Nat. Prod. Rep. 2002, 19, 223. (e) Jin, Z. Nat. Prod. Rep.
2003, 20, 584.
(2) (a) Saravanan, P.; Corey, E. J. J. Org. Chem. 2003, 68,
2760. (b) Cardillo, G.; Gentilucci, L.; Tolomelli, A.
Aldrichimica Acta 2003, 36, 39. (c) Reddy, L. R.;
Saravanan, P.; Corey, E. J. J. Am. Chem. Soc. 2004, 126,
6230. (d) Meyers, A. I. J. Org. Chem. 2005, 70, 6137.
(e) Gnas, Y.; Glorius, F. Synthesis 2006, 1899.
(3) For reviews, see: (a) Ghosh, A. K.; Mathivanan, P.;
Cappiello, J. Tetrahedron: Asymmetry 1998, 9, 1.
(b) Gómez, M.; Muller, G.; Rocamora, M. Coord. Chem.
Rev. 1999, 193, 769. (c) Johnson, J. S.; Evans, D. A. Acc.
Chem. Res. 2000, 33, 325. (d) Braunstein, P.; Naud, F.
Angew. Chem. Int. Ed. 2001, 40, 680. (e) Rechavi, D.;
Lemaire, M. Chem. Rev. 2002, 102, 3467. (f) McManus, H.
A.; Guiry, P. J. Chem. Rev. 2004, 104, 4151.
(4) Deoxycyclization by DAST: (a) Lafargue, P.; Guenot, P.;
Lellouche, J.-P. Heterocycles 1995, 41, 947. (b) Phillips, A.
J.; Uto, Y.; Wipf, P.; Reno, M. J.; Williams, D. R. Org. Lett.
2000, 2, 1165. By Burgess reagent: (c) Wipf, P.; Miller, C.
P. Tetrahedron Lett. 1992, 33, 907. (d) Wipf, P.; Miller, C.
P. Tetrahedron Lett. 1992, 33, 6267. By Mitsunobu
reagent: (e) Galéotti, N.; Montagne, C.; Poncet, J.; Jouin, P.
Tetrahedron Lett. 1992, 33, 2807. (f) Colman, B.; de Sousa,
S. E.; O’Brien, P.; Towers, T. D.; Watson, W. Tetrahedron:
Asymmetry 1999, 10, 4175. (g) Crosignani, S.; Young, A.
C.; Linclau, B. Tetrahedron Lett. 2004, 45, 9611; see also
ref. 1a.
Ethyl (S)-4,5-Dihydrothiazole-4-carboxylate (1o)
The reaction was carried out as in the case of 1m using DFMM, and
1o was obtained in 89% yield (99% ee); [a]D21 +191.2 (c = 1.2,
CHCl3).
IR (neat): 2982, 1738, 1570, 1191 cm–1.
1H NMR (CDCl3): d = 1.33 (t, J = 4.9 Hz, 3 H), 3.45–3.57 (m, 2 H),
4.25–4.31 (m, 2 H), 5.10 (ddd, J = 6.5, 6.5, 1.7 Hz, 1 H), 8.04 (d,
J = 1.7 Hz, 1 H).
13C NMR (CDCl3): d = 14.07, 33.19, 61.83, 77.78, 159.40, 170.38.
HRMS (EI): m/z calcd for C6H9NO2S (M+): 159.0354; found:
159.0358.
Methyl (S)-2-(4-Methoxyphenyl)-4,5-dihydrooxazole-4-carbox-
ylate (1p)
The reaction was carried out as in the case of 1l using DFMOBA,
and 1p was obtained in 93% yield (>99% ee); [a]D23 +100 (c = 1.0,
CHCl3); white solid; mp 115–119 °C.
IR (KBr): 1738, 1601, 1447, 1187 cm–1.
1H NMR (CDCl3): d = 3.81 (s, 3 H), 3.84 (s, 3 H), 4.57 (dd, J = 7.1,
5.9 Hz, 1 H), 4.93 (dd, J = 7.1, 5.3 Hz, 1 H), 4.66 (dd, J = 5.6, 5.6
Hz, 1 H), 6.90 (d, J = 6.0 Hz, 2 H), 7.92 (d, J = 6.0 Hz, 2 H).
13C NMR (CDCl3): d = 52.23, 54.96, 68.21, 69.08, 113.34 (2 C),
119.04, 129.99 (2 C), 162.14, 165.62, 171.44.
HRMS (EI): m/z calcd for C12H13NO4 (M+): 235.0844; found:
235.0849.
Ethyl (4S,5R)-5-Methyl-2-(m-tolyl)-4,5-dihydrooxazole-4-car-
boxylate (1q)
The reaction was carried out as in the case of 1a using D-threonine
ethyl ester, and 1q was obtained in 84% yield (>99% ee);
[a]D23 +98.5 (c = 1.0, CHCl3).
(5) (a) Vorbrüggen, H.; Krolikiewicz, K. Tetrahedron Lett.
1981, 22, 4471. (b) Vorbrüggen, H.; Krolikiewicz, K.
Tetrahedron 1993, 49, 9353. (c) Cwik, A.; Hell, Z.;
Hegedüs, A.; Finta, Z.; Horváth, Z. Tetrahedron Lett. 2002,
43, 3985. (d) Bandgar, B. P.; Pandit, S. S. Tetrahedron Lett.
2003, 44, 2331. (e) Chakraborti, A. K.; Selvam, C.; Kaur,
G.; Bhagat, S. Synlett 2004, 851.
(6) (a) Zhou, P.; Blubaum, J. E.; Burns, C. T.; Natale, N. R.
Tetrahedron Lett. 1997, 38, 7019. (b) Matsushita, H.; Lee,
S.-H.; Joung, M.; Clapham, B.; Janda, K. D. Tetrahedron
Lett. 2004, 45, 313.
IR (neat): 2979, 1739, 1641, 1196 cm–1.
1H NMR (CDCl3): d = 1.32 (t, J = 7.2 Hz, 3 H), 1.52 (d, J = 6.3 Hz,
3 H), 2.37 (s, 3 H), 4.26 (q, J = 7.2 Hz, 2 H), 4.45 (d, J = 7.4 Hz, 1
H), 4.94–4.99 (m, 1 H), 7.28–7.32 (m, 2 H), 7.76–7.84 (m, 2 H).
13C NMR (CDCl3): d = 14.03, 20.85, 21.05, 61.45, 75.02, 78.75,
125.52, 127.00, 128.08, 129.00, 132.42, 137.93, 165.56, 171.02.
HRMS (EI): m/z calcd for C14H17NO3 (M+): 247.1208; found:
247.1212.
Synthesis 2007, No. 10, 1528–1534 © Thieme Stuttgart · New York

1534
T. Fukuhara et al.
PAPER
(7) (a) Jnaneshwara, G. K.; Deshpande, V. H.; Lalithambika,
M.; Ravindranathan, T.; Bedekar, A. V. Tetrahedron Lett.
1998, 39, 459. (b) Baltork, I. M.; Khosropour, A. R.; Hojati,
S. F. Synlett 2005, 2747.
(8) Tkaczuk, P.; Thornton, E. R. J. Org. Chem. 1981, 46, 4393.
(9) (a) Wipf, P.; Miller, C. P.; Grant, C. M. Tetrahedron 2000,
56, 9143. (b) Lee, S.-H.; Qi, X.; Yoon, J.; Nakamura, K.;
Lee, Y.-S. Tetrahedron 2002, 58, 2777.
(17) Almqvist, F.; Guillaume, D.; Hultgren, S. J.; Marshall, G. R.
Tetrahedron Lett. 1998, 39, 2293.
(18) Reddy, L. R.; Fournier, J.-F.; Reddy, B. V. S.; Corey, E. J. J.
Am. Chem. Soc. 2005, 127, 8974.
(19) McKennon, M. J.; Meyers, A. I. J. Org. Chem. 1993, 58,
3568.
(20) El-Sheikh, M. I.; Marks, A.; Biehl, E. R. J. Org. Chem. 1981,
46, 3256.
(10) (a) Raman, P.; Razavi, H.; Kelly, J. W. Org. Lett. 2000, 2,
3289. (b) Sakakura, A.; Kondo, R.; Ishihara, K. Org. Lett.
2005, 7, 1971.
(11) Nomoto, T.; Fukuhara, T.; Hara, S. Synlett 2006, 1744.
(12) For the deoxyfluorination of the amino alcohols by
DFMBA, higher temperature (>70 °C) is required.11
(13) Furuya, T.; Fukuhara, T.; Hara, S. J. Fluorine Chem. 2005,
126, 721.
(21) Brembilla, A.; Roizard, D.; Lochon, P. Synth. Commun.
1990, 20, 3379.
(22) Hein, D. W.; Alheim, R. J.; Leavitt, J. J. J. Am. Chem. Soc.
1957, 79, 427.
(23) Koch, G.; Lloyd-Jones, G. C.; Loiseleur, O.; Pfalts, A.;
Pretot, R.; Schaffner, S.; Schnider, P.; von Matt, P. Recl.
Trav. Chim. Pays-Bas 1995, 114, 206.
(24) Bernardinelli, G.; Gillet, S.; Kündig, E. P.; Liu, R.; Ripa, A.;
(14) Optically purities of the products were determined by HPLC
using CHIRALCEL OD-H.
(15) (a) Stark, M. A.; Jones, G.; Richards, C. J. Organometallics
2000, 19, 1282. (b) Kanazawa, Y.; Tsuchiya, Y.; Kobayashi,
K.; Shiomi, T.; Itoh, J.; Kikuchi, M.; Yamamoto, Y.;
Nishiyama, H. Chem. Eur. J. 2006, 12, 63.
Saudan, L. Synthesis 2001, 2040.
(25) Dehmlow, E. V.; Westerheide, R. Synthesis 1992, 947.
(26) Huang, Y.; Dalton, D. R.; Carroll, P. J. J. Org. Chem. 1997,
62, 372.
(27) Crawhall, J. C.; Elliott, D. F.; Hooper, K. C. J. Chem. Soc.
1956, 4066.
(16) Xu, F.; Armstrong, J. D. III; Zhou, G. X.; Simmons, B.;
Hughes, D.; Ge, Z.; Grabowski, E. J. J. J. Am. Chem. Soc.
2004, 126, 13002.
Synthesis 2007, No. 10, 1528–1534 © Thieme Stuttgart · New York