Thionation of N-acylthreonine and its methyl ester with Lawesson's reagent: Synthesis of 5-oxazolones, 5-thiazolones and thiazolines

Article abstract of DOI:10.3987/com-00-s(i)17

The treatment of N-acylthreonine (1) with Lawesson's reagent [LR: 2,4-bis(p-methoxyphenyl)-1,3,2,4-dithiaphosphetane 2,4-disulfide] afforded 5-oxazolones (2) in moderate yields, along with 5-thiazolones (3). On the other hand, N- acylthreonine methyl este

Full text of DOI:10.3987/com-00-s(i)17

HETEROCYCLES, Vol. 54, No. 1, 2001, pp. 201 - 208, Received, 19th April, 2000
THIONATION OF N-ACYLTHREONINE AND ITS METHYL ESTER WITH
LAWESSON’S REAGENT: SYNTHESIS OF 5-OXAZOLONES, 5-
THIAZOLONES AND THIAZOLINES
Mayuko Ori# and Takehiko Nishio*
Graduate School of Environmental Sciences# and Department of Chemistry,
University of Tsukuba, Tsukuba-shi, Ibaraki, 305-8571 Japan
Abstract- The treatment of N-acylthreonine (1) with Lawesson’s reagent [LR:
2,4-bis(p-methoxyphenyl)-1,3,2,4-dithiaphosphetane 2,4-disulfide] afforded 5-
oxazolones (2) in moderate yields, along with 5-thiazolones (3). On the other hand,
N- acylthreonine methyl ester (5) reacted with LR to give 5-thiazolones (3) and 4-
methoxycarbonylthiazolines (6).
INTRODUCTION
2,4-Bis(p-methoxyphenyl)-1,3,2,4-dithiaphosphetane 2,4-disulfide, commonly known as Lawesson’s
reagent (LR), is utilized as a superior thionation reagent for a wide variety of carbonyl into thiocarbonyl
compounds.1 Several sulfur-2,3 and phosphorus-containing heterocycles4 have been synthesized by
reacting LR with compounds possessing one or several functional groups. Recently we reported the direct
conversion of alcohols into thiols by the treatment of alcohols with LR,5 and some sulfur-containing
heterocycles were synthesized by treating bifunctional compounds containing a hydroxyl group with LR.
For instance, tetrahydrothiophene-2-imines,6 tetrahydrothiophene-2-thiones,6 thiazolines,7 and
benzothiazines7 were obtained from the reaction of ω-hydroxy amides6 and ω-N-acylamino alcohols7
with LR. We extended the use of LR to multifunctional substrates and here report our results on the
reaction of N- acylthreonine (1) and its methyl ester (5) with LR.

Figure 1. Lawesson’s Reagent (LR)
S
S
MeO
P
P
S
OMe
S
RESULTS AND DISCUSSION
The reaction of N-acylthreonine (1) with an equimolar amount of LR in toluene at reflux temperature
afforded 5-oxazolones (2) in moderate yields, along with 5-thiazolones (3) (Scheme 1, Table 1). Olefins
(4), a dehydration product of 1, were isolated as byproducts when the amount of LR was dropped to 0.5
equiv. The structures of 5-oxazolones (2), 5-thiazolones (3) and olefins (4) were determined based on
their spectroscopic data and elemental analyses. The treatment of olefin (4a) with 0.5 equiv. of LR
yielded 5-oxazolone (2a) and 5-thiazolone (3a), where no cyclization occurred when olefin (4a) was
refluxed in toluene without LR. Moreover, the treatment of 5-oxazolone (2a) with LR resulted in the
recovery of 2a, indicating that 5-thiazolones (3) are not formed by the thionation of 5-oxazolones (2).
Therefore, these results suggest that both the cyclized products (2) and (3) are formed by the treatment of
olefins (4) with LR. The reaction of N-acylthreonine (1) with P2S5 gave similar results to that of 1 with
LR.
Scheme 1
Me
O
HO
Me
S
O
O
R
R
O
O
LR
OH
OH
N
N
H
H
R
N
H
R
N
H
Me
Me
O
O
1
2
3
4
1/2 LR
(From 4a; 2a: 12%, 3a: 2%)

Table 1. Yields of 5-oxazolones (2), 5-thiazolones (3) and olefins (4) in the reaction of
N-acylthreonine (1) with LRa
Molar ratio
Yield (%)
R
LR/1
2
3
4
1ab Ph
1
1
1
1.5
0.5
43
61
32
28e
30
41
41
50
50
40
39
63
4
trace
18
6e
11
-
-
-
15
-
-
13
-
-
6
-
1a
1ac
1a
1a
3
1ad
14
24
15
16
6
1b p-ClC6H4
1
0.5
1b
1bd
1c p-Tol
1
0.5
1c
12
12
1cd
aReaction conditions: Reflux in toluene for 2 h. bReflux in toluene for 30 min. cReflux in
toluene for 4 h. d1 was refluxed in toluene with 0.4 eq. of P2S5 for 2 h. eDetermined by 1H-NMR.
Consequently, we investigated the reaction of N-acylthreonine methyl ester with LR. It can be presumed
that the methyl ester group does not react with LR, due to the low reactivity of the ester carbonyl group
toward LR that has been previously reported.1,3 The treatment of N-acylthreonine methyl ester (5) with an
equimolar amount of LR afforded the 5-thiazolones (3) and 4-methoxycarbonyl thiazolines (6) as a
mixture of two stereoisomers (syn, anti) (Scheme 2, Table 2). By measuring the NOE of the thiazoline
(6a), the main product appeared to have an anti configuration; among the 4- and 5- substituents of the
thiazoline ring, the NOE between 4-H and the 5-H was not observed (Figure 2). The treatment of 5 with
0.5 eq. of LR led to inseparable mixtures, but the formation of the cyclized products 3 and 6 was detected
by TLC and HPLC. In contrast, the thiazoline (6b) was only obtained when N-acylthreonine methyl ester
(5b) was reacted with P2S5.

Scheme 2
S
S
HO
Me
O
R
Me
R
O
LR
N
OMe
N
H
MeO2C
R
N
H
Me
O
3
6
5
Table 2. Yields of 5-thiazolones (3) and 4-methoxycarbonyl thiazolines (6) in the reaction of
N-acylthreonine methyl ester (5) with LRa
Yield (%)
R
3
6 (anti:syn)d
Ph
37
20
11
-
21 (5.4:1)
30
37 (9.4:1)
26
37 (4.7:1)
5a
5ab
5b
5bc
5c
p-ClC6H4
p-Tol
23
aReaction conditions: Reflux in toluene with 1 eq. of LR for 2 h. bReflux in toluene
with 1 eq. of LR for 4 h. c5b was refluxed in toluene with 0.4 eq. of P2S5 for 2 h.
dDetermined by 1H-NMR.
Figure 2. The NOE measurement of 4-methoxycarbonyl thiazoline (6a)
NOE
H
S
Me
Ph
N
MeO2C
H
6a
On the basis of these results and our earlier findings,5,7 the mechanism for the formation of the cyclized
products (2), (3), (6) can be explained as shown in Scheme 3. The hydroxyl group of N-acylthreonine

derivatives (1), (5) is initially converted to the corresponding thiol group by LR. The olefins (4) are
formed by the subsequent loss of H2S, which then undergoes further thionation to form 5-oxazolones (2)
or 5-thiazolones (3) (Path A). On the formation of the 5-thiazolones (3), the amide group of the olefins (4)
are apparently thionated by LR, followed by the cyclization with the elimination of H2O or MeOH. The
role of LR in the formation of 5-oxazolones (2) requires more careful consideration. The pathway B,
which involves the formation of thioamide followed by the cyclization, leads to the formation of the
thiazolines (6). The similar reaction mechanism is proposed in the formation of thiazolines from the
reaction of 2-N-acylamino alcohols with LR.7
Scheme 3
HO
Me
HS
Me
O
O
LR
Path A,B
2
2
OR
OR
1
1
R
N
H
R
N
H
O
O
1 (R2=H)
5 (R2=Me)
Me
O
1
O
R
O
- H2S
LR (?)
2
Path A
OR
N
1
H
R
N
H
(R2=H or Me)
Me
O
4 (R2=H)
2
2
R O
O
LR
-H2O (R2=H)
or -MeOH (R2=Me)
S
S
1
O
R
1
N
R
N
H
H
Me
Me
3
HS
Me
S
S
1
Me
R
- H2S
LR
OMe
Path B
1
R
N
H
N
MeO C
2
(R2=Me)
O
6

ACKNOWLEDGEMENT
This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education,
Science, Sports, and Culture of Japan
EXPERIMENTAL
Flash column chromatography was carried out with silica gel Wakogel C-300. Melting points and boiling
points were determined on a Yanaco micro melting-point apparatus (MP-J3) and a Shibata glass tube
oven distillation apparatus (GTO-350RD), respectively, and are uncorrected. IR spectra were recorded on
1
13
a JASCO FT/IR-300 spectrophotometer, in cm-1. H- and C-NMR spectra were recorded on a JEOL
JNM-EX-270 (270 MHz) or VARIAN GEMINI 200 (200 MHz); measured in CDCl3 unless noted, using
TMS as an internal standard; δvalues in ppm, J values in Hz.
Reaction of N-acyl threonine (1) with LR: A solution of N-acylthreonine (1) (1 mmol) and LR (1-0.5
mmol) in toluene (30 mL) was refluxed under argon for 0.5-4 h. After removal of the solvent, the residue
was chromatographed with toluene-ethyl acetate (10:0-2:1-0:10) to give products (2), (3) and (4).
4-Ethylidene-2-phenyl-5-oxazolone (2a): mp 89-90℃ (CHCl3-hexane); IR (KBr) 1794, 1675; 1H-NMR
δ2.16 (3H, d, J=7.3), 6.66 (1H, q, J=7.3), 7.18-7.53 (3H, m), 7.93-8.01 (2H, m); 13C-NMRδ14.6, 125.6,
128.1, 128.8, 133.0, 134.8, 137.1, 139.3, 162.6, 165.8; HRMS: Calcd for C11H9NO2 187.1938. Found
187.0632. Anal. Calcd for C11H9NO2: C, 70.58; H, 4.85; N, 7.48. Found: C, 70.35; H, 4.98; N, 7.33.
2-(p-Chlorophenyl)-4-ethylidene-5-oxazolone (2b): mp 153-155℃ (CHCl3-hexane); IR (KBr) 1794,
1
13
1673; H-NMRδ2.25 (3H, d, J=7.6), 6.77 (1H, q, J=7.6), 7.47 (2H, d, J=8.6), 8.02 (2H, d, J=8.2); C-
NMRδ14.7, 124.1, 129.1, 129.3, 135.5, 136.9, 139.5, 161.8, 165.6. Anal. Calcd for C11H8NO2Cl: C,
59.61; H, 3.64; N, 6.32. Found: C, 59.28; H, 3.68; N, 6.25.
1
4-Ethylidene-2-(p-tolyl)-5-oxazolone (2c): mp 109-111℃ (CHCl3-hexane); IR (KBr) 1798, 1637; H-
NMRδ2.23 (3H, d, J=7.8), 2.43 (3H, s), 6.72 (1H, q, J=7.8), 7.30 (2H, d, J=7.8), 7.98 (2H, d, J=7.8);
13C-NMRδ14.5, 21.8, 122.8, 127.8, 128.1, 129.6, 130.0, 137.1, 138.5, 144.0, 162.8, 166.0. Anal. Calcd
for C12H11NO2: C, 71.62; H, 5.51; N, 6.96. Found: C, 71.31; H, 5.65; N, 6.90.
1
4-Ethylidene-2-phenyl-5-thiazolone (3a): mp 100-102℃ (CHCl3-hexane); IR (KBr) 1698, 1637; H-
NMRδ2.33 (3H, d, J=7.6), 6.76 (1H, q, J=7.6), 7.26-7.57 (3H, m), 7.93-7.96 (2H, m); 13C-NMRδ15.5,
127.9, 128.9, 132.4, 133.4, 134.8, 150.9, 165.2, 193.0. Anal. Calcd for C11H9NOS: C, 65.02; H, 4.46; N,

6.89. Found: C, 64.68; H, 4.57; N, 6.73.
2-(p-Chlorophenyl)-4-ethylidene-5-thiazolone (3b): mp 102-104℃ (CHCl3-hexane); IR (KBr) 1698,
1
13
1635; H-NMRδ2.33 (3H, d, J=7.6), 6.78 (1H, q, J=7.5), 7.46 (2H, d, J=8.4), 7.88 (2H, d, J=8.4); C-
NMRδ15.6, 129.1, 129.2, 129.3, 131.8, 135.5, 138.6, 150.7, 164.6, 193.0. Anal. Calcd for C11H8NOClS:
C, 55.58; H, 3.39; N, 5.89. Found: C, 55.58; H, 3.46; N, 5.82.
1
4-Ethylidene-2-(p-tolyl)-5-thiazolone (3c): mp 75-77℃ (CHCl3-hexane); IR (KBr) 1700, 1636; H-
NMRδ2.31 (3H, d, J=7.5), 2.43 (3H, s), 6.71 (1H, q, J=7.3), 7.28 (2H, d, J=7.9), 7.84 (2H, d, J=7.9);
13C-NMRδ15.5, 21.7, 125.9, 127.6, 127.9, 129.6, 130.7, 134.0, 143.2, 150.9, 165.1, 193.4. Anal. Calcd
for C12H11NOS: C, 66.33; H, 5.10; N, 6.45. Found: C, 66.01; H, 5.22; N, 6.34.
2-Ethylidene-4-oxo-4-phenylbutyric acid (4a): mp 189-191℃ (CHCl3-hexane); IR (KBr) 3220, 1698,
1641; 1H-NMR (CD3OD-CDCl3)δ1.85 (3H, d, J=6.9), 6.97 (1H, q, J=6.9), 7.44-7.58 (3H, m), 7.89-7.92
13
(2H, m); C-NMR (CD3OD-CDCl3)δ13.9, 126.7, 127.1, 128.2, 131.6, 133.4, 134.9, 166.2, 166.8; MS
m/z 205 (M+) and 105.
4-(p-Chlorophenyl)-2-ethylidene-4-oxobutyric acid (4b): mp 224-225℃ (CHCl3-hexane); IR (KBr)
3274, 1698, 1649; 1H-NMR (CD3OD)δ1.70 (3H, d, J=6.9), 6.86 (1H, q, J=6.9), 7.40 (2H, d, J=8.6), 7.80
13
(2H, J=8.6); C-NMR (CD3OD)δ14.8, 129.4, 130.5, 131.1, 134.4, 139.9 168.1 168.8; MS m/z 241 and
239 (M+), and 141 and 139.
2-Ethylidene-4-oxo-4-(p-tolyl)butyric acid (4c): mp 208-210℃ (CHCl3-hexane); IR (KBr) 3244, 1697,
1
1640; H-NMR (CD3OD)δ1.81 (3H, d, J=7.0), 2.40 (3H, s), 6.95 (1H, q, J=7.0), 7.30 (2H, d, J=8.0),
13
7.82 (2H, d, J=8.0); C-NMR (CD3OD)δ14.1, 21.5, 128.6, 129.2, 130.1, 132.1, 136.7, 143.8, 165.3,
166.8; MS m/z 219 (M+) and 119.
Reaction of N-acylthreonine methyl ester (5) with LR: A solution of N-acylthreonine methyl ester (5)
(1 mmol) and LR (1-0.5 mmol) in toluene (30 mL) was refluxed under argon for 2-4 h. After removal of
the solvent, the residue was chromatographed with toluene-hexane (2:1) or toluene-ethyl acetate (19:1) to
give products (3) and (6).
4-Methoxycarbonyl-5-methyl-2-phenylthiazoline (6a): bp 195℃ (3 mmHg); IR (film) 1738; 1H-NMR
δ1.54 (3H, d, J=6.8), 3.84 (3H, s), 4.26-4.40 (1H, m), 4.94 (1H, d, J=6.2), 7.35-7.52 (3H, m), 7.83-7.92
(2H, m); 13C-NMRδ21.7, 48.3, 52.6, 84.6, 128.4, 128.5, 131.5, 132.8, 170.7, 171.0. Anal. Calcd for
C12H13NO2S: C, 61.25; H, 5.57; N, 5.95. Found: C, 60.91; H, 5.79; N, 5.90.

2-(p-Chlorophenyl)-4-methoxycarbonyl-5-methylthiazoline (6b): bp: 200℃(3 mmHg); IR (film) 1740;
1H-NMRδ1.55 (3H, d, J=6.6), 3.81 (3H, s), 4.24-4.40 (1H, m), 4.91 (1H, d, J=6.3), 7.39 (2H, d, J=8.2),
7.79 (2H, d, J=8.2); 13C-NMRδ22.2, 49.3, 53.2, 85.2, 129.2, 130.3, 131.8, 138.2, 170.7, 171.4. Anal.
Calcd for C12H12NO2ClS: C, 53.43; H, 4.48; N, 5.19. Found: C, 53.27; H, 4.55; N, 5.19.
1
4-Methoxycarbonyl-5-methyl-2-(p-tolyl)thiazoline (6c): bp 197℃(3 mmHg); IR (film) 1738; H-NMR
δ1.54 (3H, d, J=6.8), 2.39 (3H, s), 3.80 (3H, s), 4.24-4.38 (1H, m), 4.91 (1H, d, J=6.4), 7.21 (2H, d,
13
J=8.2), 7.75 (2H, d, J=8.2); C-NMRδ21.5, 21.7, 48.3, 52.7, 84.7, 128.6, 129.2, 130.3, 142.2, 170.0,
171.3. Anal. Calcd for C13H15NO2S: C, 62.62; H, 6.06; N, 5.62. Found: C, 62.28; H, 6.30; N, 5.61.
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