Regioselectivity in formal [3 + 2] cycloaddition reaction of 5-alkoxyoxazoles with diethyl oxomalonate and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone

Article abstract of DOI:10.3987/COM-01-9277

Tin(IV) chloride-catalyzed formal [3 + 2] cycloaddition of 5-alkoxy-2-(p-methoxyphenyl)- or 2-phenyloxazoles with diethyl oxomalonate gave 4,5,5-tris(alkoxycarbonyl)-2-oxazolines in high regioselectivity. Under similar conditions, 4-substituted 5-alkoxy-2

Full text of DOI:10.3987/COM-01-9277

HETEROCYCLES, Vol. 55, No. 9, pp. 1711 - 1726, Received, 25th June, 2001
REGIOSELECTIVITY IN FORMAL [3 + 2] CYCLOADDITION
REACTION
OF
5-ALKOXYOXAZOLES
WITH
DIETHYL
OXOMALONATE
BENZOQUINONE
AND 2,3-DICHLORO-5,6-DICYANO-1,4-
Hiroyuki Suga,*,† Xiaolan Shi,‡ Toshikazu Ibata,‡ and Akikazu Kakehi†
†
Department of Chemistry and Material Engineering, Faculty of Engineering,
Shinshu University, Wakasato, Nagano 380-8553, Japan
‡
Department of Chemistry, Graduate School of Science, Osaka University,
Toyonaka, Osaka 560-0043, Japan
Abstract-
Tin(IV) chloride-catalyzed formal [3 + 2] cycloaddition of
5-alkoxy-2-(p-methoxyphenyl)- or 2-phenyloxazoles with diethyl oxomalonate
gave 4,5,5-tris(alkoxycarbonyl)-2-oxazolines in high regioselectivity. Under
similar conditions, 4-substituted 5-alkoxy-2-methyloxazoles showed a trend to
shift the regioselectivity in favor for 3-oxazolines rather than 2-oxazolines.
Reaction of 5-alkoxy-4-ethoxycarbonyloxazoles with 2,3-dichloro-5,6-dicyano-
1,4-benzoquinone proceeded only under high pressure to give 2-oxazolines
exclusively.
Although it is well known that oxazoles undergo Diels-Alder reaction with olefins or acetylenes,1 in this
decade, we and others have found that the use of highly electron deficient dienophiles, such as
tetracyanoethylene (TCNE),2 4-phenyl-3H-1,2,4-triazole-3,5(4H)-dione (PTAD),3 diethyl
azodicarboxylate (DEAD),3,4 nitrosobenzene,5 thioaldehydes,6 1,5-dihydro-2H-imidazole-2,5-dione,4
diethy oxomalonate (DEOM),4,7 and aldehydes8 gave no Diels-Alder adducts but formal [3 + 2]
cycloadducts of the ring-opened oxazoles. In the reaction of unsymmetrical dienophiles such as
nitrosobenzene, para-substituted nitrosobenzenes, thioaldehydes, and 1,5-dihydro-2H-imidazole-
2,5-dione4 under thermal conditions, the formal [3 + 2] cycloadducts were obtained regioselectively
probably depending on electronic character of dienophiles (Scheme 1). However, the reaction of
oxazoles with DEOM under thermal conditions showed only poor regioselectivity. For example,
5-ethoxy-2-phenyloxazole (1a) underwent the cycloaddition under reflux in xylene to give mixture of
4,5,5-tris(ethoxycarbonyl)-2-oxazoline (2a) and 2,5,5-tris(ethoxycalbonyl)-3-oxazoline (3a) in a 1.2 : 1
ratio (Scheme 1, Table 1, Entry 2).4 On the other hand, we have already found Lewis acid-catalyze
reaction of 5-methoxy-2-(p-methoxyphenyl)oxazole with aldehydes gave only 2-oxazolines
regioselectively.8 The primary factors to control the regioselectivity of the formal [3 + 2] cycloaddition
with carbonyl compounds have not been understood. In this paper, we give full account of our

investigations of regio-control in the formal [3 + 2] cycloaddtions of various 4-unsubstituted and
4-substituted 5-alkoxyoxazoles with DEOM.7 We also describe regioselectivity of the reactions with
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).
R2
R3
R2
R1
Ar
N
O
N
N
COR3
+
N O
R1
O
Ar
R
R2
OR3
R2
R1
N
S
S
N
CO2R3
+
R1
H
O
R
CO2Et
H
Ar
N
N
Ph
N
O
N
O
+
Ph
OEt
N
O
O
O
N
Ar
CO2Et
H
CO2Et
N
N
Ph
Ph
O
N
+
H
CO2Et
CO2Et
+
O
O
Ph
EtO2C
OEt
EtO2C
CO2Et
O
CO2Et
2a
3a
Scheme 1
RESULTS AND DISCUSSION
Reaction of 5-Alkoxy-2-aryloxazoles with DEOM. In contrast to the results of the thermal reaction
descried above, tin(IV) chloride-catalyzed reaction of oxazole (1a) with DEOM in MeCN gave only
2-oxazoline (2a) with complete regioselectivity (Table 1, Entry 1). Oxazole (1b) also underwent
regioselective formal [3 + 2] cycloaddition under similar conditions to give 2-oxazoline (2b) exclusively
(Entry 3). Regioselctivity of 4-pheny-, 4-(p-nitrophenyl)-, and 4-methyl-substituted 5-methoxy-2-
(p-methoxypheny)oxazoles (1c – 1e) could be also controlled by using tin(IV) chloride to give only
2-oxazolines (2c – 2e) (Entries 6, 8, and 9). It is interesting that the regioselectivity of the tin(IV)
chloride- catalyzed reaction of 1c was completely opposite from that under thermal conditions (Entries 6
vs 7). It is obvious that Lewis acid is extremely effective in controlling regioselectivity and
accelerating rate of the reaction of 5-alkoxy-2-aryloxazoles as shown in Table 1. In the case of oxazole
(1f), which substituted bulky isopropyl group at 4-position, a small amount of 3-oxazoline (3f) was
produced (Entry 10). This is probably due to inhibition of the initial attack from the 4-position of
oxazole to a carbonyl group by the steric interaction of 4-isopropyl group according to the proposed
stepwise pathway.2,3,5,8 The regiochemistry of 2-oxazoline (2f) and 3-oxazoline (3f) was easily

determined by comparison with the chemical shift of ring sp3-carbons. Thus, 2f showed these signals at
88.33 ppm (4-C) and 90.64 ppm (5-C), while 3f showed those at 93.78 ppm (5-C) and 114.80 ppm
(2-C). The observation of the lower field signal (114.80 ppm) obviously indicated the existence of the
3-oxazoline ring which include the carbon substituted by both oxygen and nitrogen. Consequently, the
tin(IV) chloride-catalyzed reaction of 4-unsubstituted and 4-substituted 5-alkoxy-2-aryloxazoles (1a –
1f) produced 2-oxazolines with high regioselectively regardless of the electronic factor of 4-substituents.
High pressure was not so effective in the reaction of 5-alkoxy-2-aryloxazoles. For example, oxazole
(1b) reacts under 0.85 GPa to give 2-oxazoline (2b) in a low yield along with hydrolysis product (5b)
and oxazole (6b) (Entry 4). However, under similar conditions, the addition of ZnCl2 accelerated the
reaction to give 2-oxazoline (2b) in 67% yield with hydrolysis product (5b) (11% yield) (Entry 5).
R2
OR3
R1
CO2R3
R2
R1
EtO2C
N
CO2R3
R2
N
N
O
+
+
O
R1
O
CO2Et
EtO2C
O
CO2Et
CO2Et
CO2Et
1
2
3
a: R1 = Ph, R2 = H, R3 = Et
b: R1 = p-MeOC6H4, R2 = H, R3 = Me
c: R1 = p-MeOC6H4, R2 = Ph, R3 = Me
d: R1 = p-MeOC6H4, R2 = p-NO2C6H4, R3 = Me
e: R1 = p-MeOC6H4, R2 = Me, R3 = Me
f: R1 = p-MeOC6H4, R2 = i-Pr, R3 = Me
g: R1 = Me, R2 = H, R3 = Et
h: R1 = Me, R2 = p-NO2C6H4, R3 = Me
i: R1 = Me, R2 = Me, R3 = Me
j: R1 = Me, R2 = i-Pr, R3 = Me
k: R1 = Me(CH2)8, R2 = H, R3 = Me
HO CO2Et
CO2Et
EtO2C
HO
CO2Et
N
N
H
R1
N
CO2R3
CO2Me
R2
OMe
O
O
CO2Et
CO2Et
O
HO
MeO
EtO2C
CO2Et
6b
5b: R1 = p-MeOC6H4, R3 = Me
5g: R1 = Me, R3 = Et
5k: R1 = Me(CH2)8, R3 = Me
4h: R2 = p-NO2C6H4
4i: R2 = Me
Scheme 2

Table 1. Reactions of 2-Aryloxazoles (1a – 1f) with Diethyl Oxomalonate
Entry Oxazole (1) Conditions (Time/h)a)
Products
Yield/%
2 : 3 or 4
Recovered 1/%
1
2b)
1a
1a
1b
1b
1b
1c
1c
1d
1e
1f
SnCl4 (19)
Reflux (44)
SnCl4 (19)
HP (44)
2a
2a, 3a
2b
79
100:0
55:45
100:0
100:0
100:0
100:0
1:99e)
100:0
100:0
78:22
4
–
96
3
79
5
4
2b
12c,d)
67c)
95
47
7
5
HP, ZnCl4 (111)
SnCl4 (20)
Reflux (69)
SnCl4 (72)
SnCl4 (2)
2b
6
2c
–
7
2c, 3c
2d
23
–
8
60
–
9
2e
97
–
10
SnCl4 (120)
2f, 3f
40
–
a) SnCl4: In the presence of SnCl4 (1 equiv) at rt in MeCN unless otherwise noted. HP: Under high
pressure (0.85 GPa) at 60 ºC in MeCN unless otherwise noted. HP, ZnCl4: Under high pressure (0.85
GPa) in the presence of ZnCl2 (1 equiv) at 40 ºC in MeCN. Reflux: Under reflux in xylene. b)
Results of Ref. 4. c) Hydrolysis product (5) was obtained (Entry 4: 13%, Entry 5: 11%). d) Product
(6b) was also obtained in 5% yield. e) A trace amount of 2-oxazoline (2c) was detected by 1H NMR.
The production of 4-substitued oxazole (6b) in the absence of ZnCl2 and the acceleration of reactions by
adding ZnCl2 suggest the proposed stepwise mechanism2,3,5,8 involving nuceophilic attack of oxazole to
carbonyl compounds (Scheme 3). Before cyclization of the initially formed zwitter ionic intermediate
(I), protonation followed by aromatization could produce oxazole (6b) (path (a)). The Lewis acid not
only activates carbonyl compounds but also accelerates the cyclization by coordination to the
imino-nirtogen.
-
H
(a)
O
CO2Et
CO2Et
OMe
O
CO2Et
CO2Et
OMe
(b)
CO2Me
N
Ar
N
(b)
N
H
O
+
CO2Et
Ar
O
Ar
O
CO2Et
I
(a)
CO2Et
CO2Et
HO
N
OMe
Ar
O
Scheme 3

Reaction of 5-Alkoxy-2-methyloxazoles with DEOM. 2-Methyl substituted oxazoles showed
different trend in terms of regioselectivity (Table 2, Entries 1 – 10). The tin(IV) chloride-catalyzed
reactions of 4-unsbstituted oxazole (1g) (R2 = H) and 4-(p-nitrophenyl)oxazole (1h) (R2 = p-NO2C6H4)
showed the same regioselectivity as that of 2-aryloxazoles (1a – 1f) to give 2-oxazolines (2g) and (2h)
along with a trace amount of 3-oxazolines (3g) and (3f), respectively. In the case of 4-methyloxazole
(1i), however, the regioselectivity turns out opposite to give 3-oxazoline (3i) as a major product (Entry
8). The tin chloride(IV)-catalyzed reaction of 4-isopropyloxazole (1j) completely changed the
regioselectivity to yield 3-oxazolie (3j) as a sole product (Entry 10). This may be attribute to the ease
of the initial attack from 2-position of 2-methyloxazoles comparable with 2-aryloxazoles probably due
to a steric factor of 2-substituents according to the proposed stepwise mechanism.2,3,5,8 Use of bulky
organoaluminum catalyst, methylaluminum bis(2,4,6-tribromophenoxide), was also effective in favor for
3-oxazoline preferentially in the reaction of 4-(p-nitrophenyl)oxazole (1h) (Entry 5).
Table 2. Reactions of 2-methyl- or 2-nonyloxazoles (1g – 1k) with Diethyl Oxomalonate
Entry Oxazole (1) Conditions (Time/h)a)
Products
Yield/%
2 : 3 or 4
Recovered 1/%
1
2
3b)
1g
1g
1g
1h
1h
1h
SnCl4 (72)
2g
16c)
73c)
10
100:0
96:4
0:100d)
–
–
HP, ZnCl4 (68.5)
Reflux (24)
SnCl4 (33)
2g, 3g
3g
–
4
5
6
2h, 3h
2h, 3h
3h, 4h
56
94:6
21
19
47
MATBr (62)
HP (120)
40
47e)
30:70
0:100
7
8
9
10
11
1h
1i
1i
1j
1k
HP (120)f)
SnCl4 (46)
HP (74)g)
SnCl4 (96)
HP, ZnCl4 (90)
4h
2i, 3i
4i
3j
2k
45
0:100
34:66
0:100
0:100
100:0
trace
89
68
78
55c)
–
–
–
4
a) SnCl4: In the presence of SnCl4 (1 equiv) at rt in MeCN unless otherwise noted. HP: Under high
pressure (0.85 GPa) at 40 ºC in MeCN unless otherwise noted. HP, ZnCl4: Under high pressure (0.85
GPa) in the presence of ZnCl2 (1 equiv) at 40 ºC in MeCN. Reflux: Under reflux in xylene. MATBr:
In the presence of methylaluminum bis(2,4,6-tribromophenoxide) (AlMe3 + 2,4,6-tribromophenol (2
equiv)) at rt in CH2Cl2. b) Results of Ref. 4. c) Hydrolysis product (5) was obtained (Entry 1: 31%,
Entry 2: 9%, Entry 11: 23%). d) See Ref. 4.9 e) 3h : 4h = 21 : 26. f) Two equiv of diethyl
oxomalonate was used. g) Three equiv of diethyl oxomalonate was used.
In the reaction of oxazole (1g) under high pressure, the addition of ZnCl2 was also effective in producing
2-oxazoline (2g) in good yield, while the reaction did not proceed without ZnCl2 (Entry 2). In the
presence of ZnCl2 under high pressure, 2-nonyloxazole (1k) also underwent cycloaddition with high
regioselectivity to give 2-oxazoline (2k) along with its hydrolysis product (5k) (Entry 11). It is also
interesting to note that 3-oxazolines were regioselectively formed under high pressure in the absence of

ZnCl2 in the reaction of oxazoles (1h) and (1i) (Entries 6, 7, and 9). In these cases, initially produced
3-oxazolines (3h) and (3i) reacted further with diethyl oxomalonate to give 1:2 products (4h) and (4i) as
major products. Production of the 1:2 products could be explained by nucleophilic attack of enamine
(7), which is generated from 2-methyl-3-oxazolines by imine-enamine tautomerism, to dimethyl
oxoxmalonate as shown in Scheme 4.
EtO2C
O
EtO2C
H2C
EtO2C
EtO2C
EtO2C
H
N
H
OH
N
R
R
N
R
H2C
CO2Me
CO2Me
CO2Me
O
O
O
EtO2C
EtO2C
CO2Et
CO2Et
CO2Et
7
Scheme 4
Reaction of 5-Alkoxyoxazoles with DDQ. Reactions of 5-alkoxyoxazoles (1a – 1h) with DDQ was
also investigated. Unfortunately, under thermal, Lewis acid-catalyzed, and high pressure conditions,
the reaction of 1a – 1h with DDQ did not give [3 + 2] cycloadducts but gave a complex mixture
probably due to instability of cycloadducts under the reaction conditions. On the other hand, only at high
pressure (8.6 GPa), the reaction of 2-alkyl-4-ethoxycarbonyl-5-methoxyoxazoles (1l) and (1m) gave
desired [3 + 2] cycloadducts (8l) and (8m) in 59% and 20% yields, respectively (Scheme 5).
R
O
O
N
CO2Et
CO2Et
Cl
CO2Et
OEt
8.5 GPa, 40 oC
in MeCN
O
Cl
Cl
NC
NC
N
NC
NC
+
R
O
Cl
O
1l: R=Me
1m: R=Me(CH2)8
8l: R=Me
8m: R=Me(CH2)8
Scheme 5
13
The regiochemistry of the cycloadducts was determined by C NMR and 2D-INADEQUAT spectra.
13
Thus, C NMR spectra of 8l and 8m showed 4-C at 93.91 and 93.96 ppm, and 5-C at 85.57 and 85.22
ppm, respectively. These values were consistent with those observed from the 2-oxazolines which were
obtained by the reactions of 5-alkoxy-2-aryloxazoles with diethyl oxomalonate. Furthermore,
2D-INADEQUAT spectrum of 8l showed correlation between C-4 (93.91 ppm) and C-5 (85.57 ppm) of
a 2-oxazoline ring. These spectra obviously indicate that the products are not 3-oxazolines but
2-oxazoline derivatives. It should be also noted that these products were difficult to purify by silica gel
chromatography, probably due to instability of the products. Only florisil could be used for flash

chromatographic purification and, even by this procedure, decomposition of the product seems to
proceed slowly.
CONCLUSION
The above-described methodology involving the tin(IV) chloride-catalyzed formal [3 + 2] cycloaddition
of 5-alkoxy-2-aryloxazoles with diethyl oxomalonate has the advantage of high yield and high
regioselectivity over thermal reactions from the viewpoint of 2-oxazoline syntheses. It was also found
that the bulkiness of 4-substituents greatly influences the regioselectivity in the reaction of
5-alkoxy-2-methyloxazoles which is catalyzed by tin(IV) chloride.
The reaction of
4-ethoxycarbonyloxazoles (8l) and (8m) with DDQ proceeds only at high pressure to give 2-oxazolines
exclusively.
EXPERIMENTAL
General. Melting points were determined on a Yanagimoto melting point apparatus and are
uncorrected. IR spectra were taken with a Perkin-Elmer model 983 spectrophotometer. 1H NMR
spectra were recoreded on a Varian EM-390 (90 MHz), a JEOL GX-500 (500 MHz), a JEOL GSX-400
(400 MHz) or JEOL EX-270 instrument (270 MHz), and 13C NMR on a JEOL GX-500, a JEOL
GSX-400 or JEOL EX-270 spectrometer. Chemical shifts are expressed in parts per million downfield
from tetramethylsilane as an internal standard. MS spectra were measured with a JEOL JMS-DX303
mass spectrometer. Elemental analyses were performed on a Yanaco CHN recorder MT-3. For
preparative column chromatography, Wakogel C-300 and Silica gel 60 (Merck) were employed.
Medium pressure liquid chromatography was carried out on Yamazen No. 540 pump using a column
packed with Silica gel 60 (Merck, size 0.040 ~ 0.063 mm). Solvents were evaporated with Tokyo
Rikakikai rotary evaporator at about 40 °C. All reactions except under high pressure were carried out
under an argon atmosphere in dried glassware. Oxazoles (1a – 1k) were prepared by the mothod
reported peviously.5,8
General procedure for the tin(IV) chloride-catalyzed reaction of oxazole (1a – 1j) with DEOM.
As a typical procedure, the reaction of 5-methoxy-2-(p-methoxyphenyl)oxazole (1b) is described below.
To a solution of oxazole (1b) (0.205 g, 1.0 mmol) and DEOM (0.174 g, 1.0 mmol) in acetonitrile (10
mL) was added tin(IV) chloride (0.261 g, 0.12 mL, 1.0 mmol) at rt. After stirring for 19 h, the mixture
was quenched with a saturated solution of NaHCO3. The mixture was extracted with CH2Cl2 (30 mL x
3), the separated organic layer was dried over anhydrous MgSO4, and the solvent was removed under a
reduced pressure. The residue was chromatographed over silica gel using hexane-ethyl acetate (17/3
v/v) as an eluent to give 2-oxazoline (2b) (0.300 g, 79%).
General procedure for the reaction of oxazole with DEOM at high pressure. As a typical
procedure, the reaction of 2,4-dimethyl-5-methoxyoxazoles (1i) is described below. A solution of
oxazole (1i) (0.127 g, 1.0 mmol) and DEOM (0.348 g, 2.0 mmol) in acetonitrile (4.5 mL) was kept in a

Teflon capsule and pressurized hydraulically using Hikari Kouatsu high pressure reaction apparatus at
0.85 GPa and 40 °C for 74 h. The mixture was concentrated under a reduced pressure, and the residue
was chromatographed over silica gel using hexane-ethyl acetate (17/3 v/v) as an eluent to give
3-oxazoline (4i) (0.322 g, 68%).
4,5,5-Tris(ethoxycarbonyl)-2-phenyl-2-oxazoline (2a): Colorless viscous oil; IR (Neat) 3646, 3473,
1
3063, 2982, 1749 (C=O), 1653 (C=N), 1603, 1579, 1493, 1450, 1369, 1217, 1098, 908, 861 cm-1; H
NMR (CDCl3, 500 MHz) δ =1.29 (3H, t, J = 7.1 Hz, Me of OEt), 1.30 (3H, t, J = 7.1 Hz, Me of OEt),
1.32 (3H, t, J = 7.1 Hz Me of OEt), 4.18-4.40 (6H, m, CH2 of OEt), 5.57 (1H, s, 4-H), 7.41-7.54 (3H, m,
13
Ph-H), 8.04-8.05 (2H, m, Ph-H); C NMR (CDCl3, 125.65 MHz) δ =13.88, 13.93, 14.03 (each q, each
3
Me of OEt), 62.02, 62.78, 63.28 (each t, each CH2 of OEt), 75.50 (d, 4-C), 88.01 (d, JC-H = 2.3 Hz,
5-C), 126.10 (s, 1-C of Ph), 128.46, 129.00 (each d, o-, m-C of Ph), 132.36 (d, p-C of Ph), 164.70 (s,
3
3
2-C), 165.40 (dt,3 J
= 4.1 Hz, JC-H = 3.2 Hz, CO2Et), 166.12 (dt,3JC-H = 6.4 Hz, JC-H = 3.2 Hz,
C-H
2
CO2Et), 168.41 (dt, JC-H = 6.9 Hz, JC-H = 3.2 Hz, CO2Et); Found: M+, 363.1317. Calcd for C18H21 N
3
O7: M, 363.1318.
5,5-Bis(ethoxycarbonyl)-4-methoxycarbonyl-2-(p-methoxyphenyl)-2-oxazoline (2b): Pale yellow
viscous oil; IR (Neat) 1750 (C=O), 1654 (C=N), 1608, 1512, 1306, 1260, 1220, 1174, 1098, 1071, 1028
cm-1; 1H NMR (CDCl3, 500 MHz) δ = 1.29 (3H, t, J = 7.1 Hz, Me of OEt), 1.32 (3H, t, J = 7.1 Hz, Me
of OEt), 3.77 (3H, s, OMe), 3.85 (3H, s, OMe), 4.21-4.40 (4H, m, CH2 of OEt), 5.56 (1H, s, 4-H), 6.92
13
(2H, dt, J = 8.9 Hz, J = 2.8 Hz, Ar-H), and 7.99 (2H, dt, J = 8.9 Hz, J = 3.0 Hz, Ar-H); C NMR
(CDCl3, 125.65 MHz) δ = 13.90, 13.93 (each q, each Me of OEt), 52.72, 55.45 (each q, each OMe),
2
62.83, 63.27 (each t, each CH2 of OEt), 75.36 (d, 4-C), 87.89 (d, JC-H = 2.3 Hz, 5-C), 113.91, 130.86
(each d, o-, m-C of Ar), 118.37 (t, 2J C-H = 8.3 Hz, 1-C of Ar), 163.05 (s, 4-C of Ar), 164.61 (dt, 3JC-H
=
5.1 Hz, JC-H = 5.1 Hz, 2-C), 165.52 (dt, 3JC-H = 4.1 Hz, JC-H = 3.7 Hz, CO2Et), 166.17 (dt, 3JC-H = 6.4
3
3
3
2
3
Hz, JC-H = 3.2 Hz, CO2Et), 169.04 (dq, JC-H = 6.9 Hz, JC-H = 4.1 Hz, CO2Me); Anal. Calcd for
C18H21NO8: C, 56.99; H, 5.58; N, 3.69. Found: C, 56.56; H, 5.60; N, 3.74. Found: M+, 379.1265.
Calcd for C18H21NO8: M, 379.1267.
Diethyl methyl 1-hydroxy-2-(p-methoxybenzoyl)amino-1,1,2-ethanetricarboxylate (5b): Pale yellow
viscous oil; IR (Neat) 3373 (OH, NH), 2981, 1750 (C=O), 1663 (C=O), 1607, 1528, 1499, 1465, 1443,
1258, 1178, 1147, 1029 cm-1; 1H NMR (CDCl3, 500 MHz) δ = 1.21 (3H, t, J = 7.1 Hz, Me of OEt), 1.34
(3H, t, J = 7.1 Hz, Me of OEt), 3.73 (3H, s, OMe), 3.84 (3H, s, OMe), 4.17-4.37 (3H, m, CH2 of OEt,
OH), 4.35 (2H, q, J = 7.1 Hz, CH2 of OEt), 5.93 (1H, d, J = 10.1 Hz, CHCO2Me), 6.74 (1H, d, J = 10.1
Hz, NH), 6.92 (2H, dt, J = 8.9 Hz, J = 3.0 Hz, Ar-H), 7.75 (2H, dt, J = 8.9 Hz, J = 3.0 Hz, Ar-H); 13C
NMR (CDCl3, 125.65 MHz) δ = 13.92, 13.96 (each q, each Me of OEt), 52.89 (q, OMe), 55.46 (q,
2
OMe), 56.11 (d, CHCO2Me), 63.31, 63.40 (each t, each CH2 of OEt), 80.53 (d, JC-H = 4.1 Hz, COH),
3
113.94, 129.21 (each d, o-, m-C of Ar), 125.88 (t, JC-H = 7.4 Hz, 1-C of Ar), 162.76 (s, 4-C of Ar),
166.74 (s, CONH), 167.78 (dt, 3JC-H = 1.4 Hz, 3JC-H = 3.2 Hz, CO2Et), 168.03 (dt, 3JC-H = 1.8 Hz, 3JC-H
=

2
3
3.7 Hz, CO2Et), 168.91 (dq, JC-H = 7.4 Hz, JC-H = 3.2 Hz, CO2Me). Satisfactory analytical data was
not obtained due to only a trace amount of 5b.
4-[Bis(ethoxycarbonyl)]hydroxymethyl-5-methoxy-2-(p-methoxyphenyl)oxazlole (6b): Pale yellow
1
viscous oil; IR (Neat) 1750 (C=O), 1654 (C=N), 1611, 1500, 1304, 1255, 1174, 1103, 1028 cm-1; H
NMR (CDCl3, 500 MHz) δ = 1.33 (6H, t, J = 7.1 Hz, Me of OEt), 1.86 (1H, br s, OH), 3.84 (3H, s,
OMe), 4.01 (3H, s, OMe), 4.35, 4.36 (each q, each J = 7.1 Hz, each CH2 of OEt), 6.92 (2H, dt, J = 8.9
Hz, J = 2.7 Hz, Ar-H), 7.83 (2H, dt, J = 8.9 Hz, J = 2.7 Hz, Ar-H); 13C NMR (CDCl3, 125.65 MHz) δ =
14.02 (q, Me of OEt), 55.38 (q, OMe), 60.95 (q, OMe), 63.00 (t, CH2 of OEt), 76.20 (s, COH), 114.01
(s, 4-C), 114.13, 127.45 (each d, o-, m-C of Ar), 120.19 (t, 3JC-H = 7.8 Hz, 1-C of Ar), 152.25 (t, 3JC-H
=
3
3
4.6 Hz, 2-C), 155.23 (q, JC-H = 4.1 Hz, 5-C), 161.14 (s, 4-C of Ar), 168.61 (t, JC-H = 3.2 Hz, CO2Et).
Satisfactory analytical data was not obtained due to hygroscopic property of 6a.
5,5-Bis(ethoxycarbonyl)-4-methoxycarbonyl-2-(p-methoxyphenyl)-4-phenyl-2-oxazoline
(2c):
Colorless prism (benzene-hexane); mp 149.7-152.1 ºC; IR (KBr) 3430, 1753 (C=O), 1647 (C=N),
1608, 1510, 1303, 1258, 1094, and 1018 cm-1; 1H NMR (CDCl3, 270 MHz) δ = 0.78 (2H, t, J = 7.3 Hz,
Me of OEt), 1.40 (3H, t, J = 7.3 Hz, Me of OEt), 3.47-3.68 (2H, m, CH2 of OEt), 3.71 (3H, s, OMe),
3.87 (3H, s, OMe), 4.41 (2H, q, J = 7.3 Hz, CH2 of OEt), 6.97 (2H, d, J = 8.9 Hz, Ar-H), 7.29-7.37 (3H,
m, Ph), 7.69-7.72 (2H, m, Ph), 8.10 (2H, d, J = 8.9 Hz, Ar-H); 13C NMR (CDCl3, 67.80 MHz) δ = 13.25
2
2
(t, JC-H = 3.1 Hz, Me of OEt), 13.99 (t, JC-H = 3.1 Hz, Me of OEt), 53.06 (q, OMe), 55.48 (q, OMe),
2
2
3
62.48 (q, JC-H = 4.3 Hz, CH2 of OEt), 62.69 (q, JC-H = 4.3 Hz, CH2 of Et), 86.88 (t, JC-H = 3.7 Hz,
2
4-C), 93.19 (s, 5-C), 113.86, 131.03 (each d, o-, m-C of Ar), 118.85 (t, JC-H = 7.9 Hz, 1-C of Ar),
2
127.60 (d, Ph), 128.42 (t, JC-H = 7.9 Hz, Ph), 128.69 (d, Ph), 135.68 (s, Ph), 163.07 (s, 4-C of Ar),
3
3
3
165.07 (t, JC-H = 3.1 Hz, CO2Et), 165.42 (t, JC-H = 3.7 Hz, 2-C), 166.00 (t, JC-H = 3.1 Hz, CO2Et),
170.22 (q, 3JC-H = 3.7 Hz, CO2Me); Anal. Calcd for C24H25NO8: C, 63.29; H, 5.53; N, 3.08. Found: C,
63.23; H, 5.52; N, 3.08.
5,5-Bis(ethoxycarbonyl)-2-methoxycarbonyl-4-(p-methoxyphenyl)-2-phenyl-3-oxazoline (3c) was
obtained as a mixture with 2c. 1H NMR (CDCl3, 270 MHz) δ = 1.05 (3H, t, J = 7.3 Hz, Me of OEt),
1.28 (3H, t, J = 7.3 Hz, Me of OEt), 3.76 (3H, s, OMe), 3.84 (3H, s, OMe), 4.03 – 4.18 (2H, m, CH2 of
OEt), 4.27 – 4.37 (2H, m, CH2 of OEt), 6.88 – 6.93 (2H, m, Ar-H), 7.31 – 7.41 (3H, m, Ar-H), 7.72 –
7.76 (2H, m, Ar-H), 8.02 – 8.09 (2H, m, Ar-H).
5,5-Bis(ethoxycarbonyl)-4-methoxycarbonyl-2-(p-methoxyphenyl)-4-(p-nitrophenyl)-2-oxazoline
(2d): Colorless prisms (benzene-hexane); mp 141.2-143.2 ºC; IR (KBr) 3443, 1752 (C=O), 1647 (C=N),
1
1607, 1513 (NO2), 1351 (NO2), 1306, 1259, 1219, 1173, 1092 cm-1; H NMR (CDCl3, 270 MHz) δ =
0.81 (3H, t, J = 7.3 Hz, Me of OEt), 1.24 (3H, t, J = 7.3 Hz, Me of OEt), 3.58 – 3.72 (2H, m, CH2 of
OEt), 3.70 (3H, s, OMe), 3.88 (3H, s, OMe), 4.44 (2H, q, J = 7.3 Hz, CH2 of OEt), 6.99 (2H, d, J = 9.2

Hz, Ar-H), 8.00 (2H, d, J = 9.2 Hz, Ar-H), 8.10 (2H, d, J = 9.2 Hz, Ar-H), 8.20 (2H, d, J = 9.2 Hz,
Ar-H); Anal. Calcd for C24H24N2O10: C, 57.60; H, 4.83; N, 5.60. Found: C, 57.76; H, 4.86; N, 5.57.
5,5-Bis(ethoxycarbonyl)-4-methoxycarbonyl-2-(p-methoxyphenyl)-4-methyl-2-oxazoline
(2e):
Colorless viscous oil; IR (Neat) 2981, 1750 (C=O), 1648 (C=N), 1608, 1577, 1509, 1450, 1422, 1368,
1
1258, 1172, 1139, 1090, 1027, 844, 792 cm-1; H NMR (CDCl3, 270 MHz) δ =1.29 (3H, t, J = 7.3 Hz,
Me of OEt), 1.31 (3H, t, J = 7.3 Hz, Me of OEt), 1.68 (3H, s, Me), 3.69 (3H, s, OMe), 3.85 (3H, s,
OMe), 4.287 (2H, q, J =7.3Hz, CH2 of OEt), 4.293 (2H, q, J = 7.3 Hz, CH2 of OEt), 6.93 (2H, d, J = 8.9
Hz, Ar-H), 7.98 (2H, d, J = 8.9 Hz, Ar-H); 13C NMR (CDCl3, 67.80 MHz) δ = 13.88 (t, 2JC-H = 3.1 Hz,
Me of OEt), 13.98 (t, 2JC-H = 3.1 Hz, Me of OEt), 20.58 (q, Me), 52.69, 55.43 (each q, each OMe), 62.59,
62.84 (each q, each 2JC-H = 4.3 Hz, each CH2 of CO2Et), 79.92 (q, 2JC-H = 4.9 Hz, 4-C), 91.63 (q, 3JC-H
=
=
4.3 Hz, 5-C), 113.81, 130.79 (each d, o-, m-C of Ar), (d, 2JC-H = 4.9 Hz, p-MeOC6H4), 118.72 (t, 2JC-H
3
7.9 Hz, 1-C of Ar), 162.94 (s, 4-C of Ar), 164.67 (t, JC-H = 4.3 Hz, 2-C), 165.51, 165.59 (each t, each
3JC-H = 3.1 Hz, each CO2Et), 170.72 (s, CO2Me); Found: M+, 393.1432. Calcd for C19H23NO8: M,
393.1424.
5,5-Bis(ethoxycarbonyl)-4-methoxycarbonyl-2-(p-methoxyphenyl)-4-isopropyl-2-oxazoline
(2f):
Colorless oil; IR (Neat) 2980, 2840, 1750 (C=O), 1663 (C=N), 1609, 1577, 1511, 1465, 1422, 1389,
1368, 1257, 1172, 1066, 1027, 843, 794, 738, 682 cm-1; 1H NMR (CDCl3, 270 MHz) δ = 0.79 (3H, d, J
= 6.6 Hz, Me of i-Pr), 1.04 (3H, d, J = 6.6 Hz, Me of i-Pr), 1.23 (3H, t, J = 7.3 Hz, Me of OEt), 1.38
(3H, t, J = 7.3 Hz, Me of OEt), 2.68 (1H, sept, J = 6.6 Hz, CH of i-Pr), 3.78 (3H, s, OMe), 3.85 (3H, s,
OMe), 4.19 (2H, qd, J = 7.3 Hz, J = 2.0 Hz, CH2 of CO2Et), 4.40 (2H, q, J = 7.3 Hz, CH2 of OEt), 6.93
(2H, d, J = 8.9 Hz, Ar-H), 8.02 (2H, d, J = 8.9 Hz, Ar-H); 13C NMR (CDCl3, 67.80 MHz) δ = 13.78 (t,
2JC-H = 2.4 Hz, Me of OEt), 13.94 (t, 2JC-H = 2.4 Hz, Me of OEt), 16.52 (q, Me of i-Pr), 18.73 (q, Me of
i-Pr), 34.11(d, CH of i-Pr), 52.33 (q, OMe), 55.43 (q, OMe), 62.48 (t, CH2 of OEt), 62.87 (t, CH2 of
OEt), 88.33 (dq, 2JC-H = 8.5 Hz, 3JC-H = 4.3 Hz, 4-C), 90.64 (s, 5-C), 113.76, 130.76 (each d, o-, m-C of
Ar) , 118.66 (t, 2JC-H = 7.9 Hz, 1-C of Ar), 161.95 (t, 3JC-H = 3.7 Hz, 2-C), 162.80 (s, 4-C of Ar), 165.34
(t, 3JC-H = 3.7 Hz, CO2Et), 166.54 (t, 3JC-H = 3.7 Hz, CO2Et), 171.66 (s, CO2Me); Found: M+, 421.1760.
Calcd for C21H27NO8: M 421.1737.
5,5-Bis(ethoxycarbonyl)-2-methoxycarbonyl-4-(p-methoxyphenyl)-2-isopropyl-3-oxazoline
(3f):
Colorless oil; IR (Neat) 2977, 2875, 2841, 1749 (C=O), 1605 (C=N), 1568, 1513, 1465, 1422, 1386,
1
1368, 1262, 1178, 1150, 1107, 1032, 943, 843 cm-1; H NMR (CDCl3, 270 MHz) δ = 1.01 (3H, d, J =
6.9 Hz, Me of i-Pr), 1.03 (3H, d, J = 6.9 Hz, Me of i-Pr), 1.23 (3H, t, J = 7.3 Hz, Me of OEt), 1.27 (3H,
t, J = 7.3 Hz, Me of OEt), 2.68 (1H, sept, J = 6.9 Hz, CH of i-Pr), 3.76 (3H, s, OMe), 3.84 (3H, s, OMe),
13
4.21-4.33 (4H, m, CH2 of OEt), 6.90 (2H, d, J = 8.9 Hz, Ar-H), 7.99 (2H, d, J = 8.9 Hz, Ar-H); C
NMR (CDCl3, 67.80 MHz) δ = 13.79, 13.85 (each q, each Me of OEt), 16.28, 16.36 (each q, each Me of
i-Pr), 34.61 (d, CH of i-Pr), 52.45, 55.34 (each q, OMe), 62.53 (t, CH2 of CO2Et), 62.61 (t, CH2 of
CO2Et), 93.78 (s, 5-C), 113.48, 131.85 (each d, o-, m-C of Ar), 114.80 (s, 2-C), 122.28 (t, 2JC-H = 7.9 Hz,

3
3
1-C of Ar), 162.38 (s, 4-C of Ar), 163.82 (s, 4-C), 165.93 (t, JC-H = 3.7 Hz, CO2Et), 166.29 (t, JC-H
=
3.7 Hz, CO2Et), 169.28 (s, CO2Me); Found: M+, 421.1708. Calcd for C21H27NO8: M, 421.1737.
5,5,4-Tris(ethoxycarbonyl)-2-methyl-2-oxazoline (2g): Colorless oil; IR (Neat) 3374, 1749 (C=O),
1670 (C=N), 1521, 1371, 1228, 1024 cm-1; 1H NMR (CDCl3, 500 MHz) δ = 1.28 (3H, t, J = 7.1 Hz, Me
of OEt), 1.29 (3H, t, J = 7.1 Hz, Me of OEt), 1.32 (3H, t, J = 7.3 Hz, Me of OEt), 2.15 (3H, d, J = 1.6
13
Hz, 2-Me), 4.15-4.40 (6H, m, CH2 of OEt), 5.32 (1H, q, J = 1.6 Hz, 4-H); C NMR (CDCl3, 125.65
MHz) δ=13.82, 13.86, 13.91, 14.01 (each q, each Me), 61.98, 62.78, 63.27 (each t, each CH2 of OEt),
75.11 (d, 4-C), 87.93 (d, 2JC-H = 2.3 Hz, 5-C), 165.39 (dt, 3JC-H = 4.6 Hz, 3JC-H = 3.2 Hz, CO2Et), 165.90
2
(dq, 3JC-H = 6.0 Hz, JC-H = 7.4 Hz, 2-C), 166.05 (dt, 3JC-H = 6.0 Hz, 3JC-H = 3.7 Hz, CO2Et), 168.45 (s,
CO2Et). Satisfactory analytical data was not obtained due to instability of 2g.
Triethyl 2-acetylamino-1-hydroxy-1,1,2-ethanetricarboxylate (5g): Colorless viscous oil; IR (Neat)
3367 (OH), 2983 (NH), 2939, 1750 (C=O), 1670 (C=O), 1526, 1465, 1447, 1136, 1216, 1159, 1097,
1024, 860 cm-1; 1H NMR (CDCl3, 500 MHz) δ = 1.24 (3H, J = 7.3 Hz, Me of OEt), 1.27 (3H, t, J = 7.1
Hz, Me of OEt, OH), 1.34 (3H, t, J = 7.1 Hz, Me of OEt), 2.03 (3H, s, COMe), 4.15 – 4.38 (7H, m, CH2
13
of OEt), 5.70 (1H, d, J = 10.1 Hz, CHNH), 6.26 (1H, d, J = 10.1 Hz, NH); C NMR (CDCl3, 125.65
MHz) δ = 13.90, 13.96 (each q, each Me of OEt), 23.02 (q, COMe), 55.75 (d, CHNH), 62.22, 63.17,
2
2
63.27 (each t, each CH2 of OEt), 80.39 (dd, JC-H = 2.8 Hz, JC-H = 3.7 Hz, COH), 167.86 (s, CO2Et),
167.88 (s, CO2Et), 168.16 (dt, 2JC-H = 6.9 Hz, 3JC-H = 2.8 Hz, CO2Et), 169.97 (s, COMe). Satisfactory
analytical data was not obtained due to hygroscopic property of 5g.
5,5-Bis(ethoxycarbonyl)-4-methoxycarbonyl-2-methyl-4-(p-nitrophenyl)-2-oxazoline (2h): Colorless
prism; A sharp melting point was not obtained probably due to lability of 2h; IR (KBr) 1752 (C=O),
1
1742 (C=O), 1675 (C=N), 1520 (NO2), 1353 (NO2), 1289, 1235, 1220, 1104, 1014, 855 cm-1; H NMR
(CDCl3, 270 MHz) δ = 0.86 (3H, t, J = 6.9 Hz, Me of CO2Et), 1.40 (3H, t, J = 6.9 Hz, Me of CO2Et),
2.30 (3H, s, 2-Me), 3.67 (2H, q, J = 6.9 Hz, CH2 of CO2Et), 3.71 (3H, s, OMe), 4.42 (2H, q, J = 6.9 Hz,
CH2 of CO2Et), 7.91 (2H, d, J = 8.9 Hz, Ar-H), 8.19 (2H, d, J = 8.9 Hz, Ar-H); 13C NMR (CDCl3, 67.80
MHz) δ = 13.33, 13.96, 14.30 (each q, each Me), 53.44 (q, OMe), 62.93, 63.23 (each t, each CH2 of
CO2Et), 86.16 (t, 3JC-H = 3.1 Hz, 4-C), 93.13 (s, 5-C), 122.64, 129.97 (each d, o-, m-C of Ar), 142.46 (t,
2JC-H = 7.9 Hz, 4-C of Ar), 147.90 (s, 1-C of Ar), 164.49 (t, 3JC-H = 3.1 Hz, CO2Et), 165.55 (t, 3JC-H = 3.1
2
3
Hz, CO2Et), 168.34 (q, JC-H = 7.3 Hz, 2-C), 169.31 (q, JC-H = 3.7 Hz, CO2Me). Hydrolysis product
was obtained by recrystallization. Pale yellow prisms (benzen-hexane), mp 118.0 – 120.0 ºC, Anal.
Calcd for C18H22N2O10: C, 50.71; H, 5.20; N, 6.57. Found: C, 50.99; H, 5.25; N, 6.49.
5,5-Bis(ethoxycarbonyl)-2-methoxycarbonyl-4-methyl-2-(p-nitrophenyl)-3-oxazoline (3h): Colorless
o
plate crystals (hexane); mp 77-78.5 C; IR (KBr) 1765 (C=O), 1743 (C=O), 1650 (C=N), 1526 (NO2),
1
1437, 1352 (NO2), 1297, 1222, 1127, 1114, 1064, 1013, 990, 976, 855 cm-1; H NMR (CDCl3, 500
MHz) δ = 1.21 (3H, t, J = 7.1 Hz, Me of OEt), 1.36 (3H, t, J = 7.1 Hz, Me of OEt), 2.37 (3H, s, 4-Me),

3.75 (3H, s, OMe), 4.18 – 4.27 (2H, m, CH2 of OEt), 4.36 (2H, q, J = 7.1 Hz, CH2 of OEt), 7.93 (2H, dt,
13
J = 8.9 Hz, J = 2.5 Hz, Ar-H), 8.23 (2H, dt, J = 8.9 Hz, J = 2.5 Hz, Ar-H); C NMR (CDCl3, 125.65
MHz) δ = 13.88 (q, Me of OEt), 14.00 (q, Me of OEt), 16.48 (q, 4-Me), 53.45 (q, OMe), 63.01, 63.02
(each t, each CH2 of OEt), 95.77 (q, 3JC-H = 2.3 Hz, 5-C), 111.15 (t, 3JC-H = 3.4 Hz, 2-C), 123.28, 127.76
(each d, o-, m-C of Ar), 143.97 (s, 4-C of Ar), 148.34 (s, 1-C of Ar), 164.49 (t, 3JC-H = 3.4 Hz, CO2Et),
3
2
164.54 (t, JC-H = 3.4 Hz, CO2Et), 167.58 (q, JC-H = 7.2 Hz, 4-C), 167.59 (s, CO2Me); Anal. Calcd for
C18H20N2O9: C, 52.94; H, 4.94; N, 6.86. Found: C, 52.83; H, 4.93; N, 6.96.
5,5-Bis(ethoxycarbonyl)-4-[2,2-di(ethoxycarbonyl)-2-hydroxyethyl]-2-methoxycarbonyl-2-(p-nitro-
phenyl)-3-oxazoline (4h): Colorless prisms (benzene-hexane); mp 96.5-97.5 ºC; IR (KBr) 3500 (OH),
1772 (C=O), 1759 (C=O), 1741 (C=O), 1657 (C=N), 1519 (NO2), 1444, 1352 (NO2), 1297, 1232, 1193,
1174, 1124, 1112, 1043, 1025, 1005 cm-1; 1H NMR (CDCl3, 500 MHz) δ = 1.18 (3H, t, J = 7.1 Hz, Me
of OEt), 1.19 (3H, t, J = 6.9 Hz, Me of OEt), 1.31 (3H, t, J = 7.1 Hz, Me of OEt), 1.36 (3H, t, J = 7.1 Hz,
Me of OEt), 3.47, 3.57 (2H, each d, each Jgem = 17.6 Hz, CH2), 3.71 (3H, s, OMe), 4.12-4.26 (5H, m,
CH2 of OEt and OH), 4.31 (2H, q, J = 7.1 Hz, CH2 of OEt), 4.36 (2H, q, J = 7.1 Hz, CH2 of OEt), 7.84
13
(2H, dt, J = 8.9 Hz, J = 2.3 Hz, Ar-H), 8.22 (2H, dt, J = 8.9 Hz, J = 2.3 Hz, Ar-H); C NMR (CDCl3,
125.65 MHz) δ = 13.81, 13.86, 13.91, 13.98 (each q, each Me of OEt), 34.63 (t, CH2), 53.42 (q, OMe),
62.68, 62.98, 63.12, 63.16 (each t, each CH2 of OEt), 77.71 (s, COH), 96.20 (s, 5-C), 111.43 (t, 3JC-H
=
2.7 Hz, 2-C), 123.26, 127.79 (each d, o-, m-C of Ar), 143.72 (s, 4-C of Ar), 148.36 (s, 1-C of Ar),
3
3
2
163.88 (t, JC-H = 3.1 Hz, CO2Et), 164.20 (t, JC-H = 3.1 Hz, CO2Et), 167.04 (t, JC-H = 6.7 Hz, 4-C),
167.17 (q, 3JC-H = 3.8 Hz, CO2Me), 168.86 (s, CO2Et), 169.25 (s, CO2Et); Anal. Calcd for C25H30N2O14:
C, 51.55; H, 5.19; N, 4.81. Found: C, 51.30; H, 5.13; N, 4.86.
1
5,5-Bis(ethoxycarbonyl)-2,4-dimethyl-4-methoxycarbonyl-2-oxazoline (2i): Colorless oil; H NMR
(CDCl3, 270 MHz) δ = 1.30 (3H, t, J = 6.9 Hz, Me of CO2Et), 1.32 (3H, t, J = 6.9 Hz, Me of CO2Et),
1.57 (3H, s, Me), 2.16 (3H, s, Me), 3.71 (3H, s, OMe), 4.28 (2H, q, J = 6.9 Hz, CH2 of CO2Et), 4.30
13
(2H, q, J = 6.9 Hz, CH2 of CO2Et); C NMR (CDCl3, 67.80 Mz) δ = 13.85, 13.98, 14.07, 20.42 (each
Me), 52.73 (OMe), 62.68, 62.91 (each CH2 of CO2Et), 165.25, 165.42 (each CO2Et), 166.18 (2-C),
170.68 (CO2Me). Satisfactory analytical data was not obtained due to instability of 2i.
1
5,5-Bis(ethoxycarbonyl)-2,4-dimethyl-2-methoxycarbonyl-3-oxazoline (3i): Colorless oil; H NMR
(CDCl3, 270 MHz) δ = 1.32 (3H, t, J = 7.3 Hz, Me of CO2Et), 1.33 (3H, t, J = 7.3 Hz, Me of CO2Et),
13
1.76 (3H, s, Me), 2.32 (3H, s, Me), 3.74 (3H, s, OMe), 4.31 (4H, q, J = 7.3 Hz, CH2 of CO2Et); C
NMR (CDCl3, 67.80 MHz) δ = 13.94, 13.98, 16.42, 23.40 (each q, each Me), 52.81 (q, OMe), 62.52,
3
2
62.93 (each t, each CH2 of CO2Et), 95.20 (q, JC-H = 1.8 Hz, 5-C), 110.10 (q, JC-H = 4.9 Hz, 2-C),
3
3
2
165.14 (t, JC-H = 3.1 Hz, CO2Et), 165.44 (t, JC-H = 3.1 Hz, CO2Et), 166.32 (q, JC-H = 7.3 Hz, 4-C),
168.95 (s, CO2Me). Satisfactory analytical data was not obtained due to instability of 3i.

5,5-Bis(ethoxycarbonyl)-4-[2,2-di(ethoxycarbonyl)-2-hydoroxyethyl]-2-methoxycarbonyl-2-meth-y
l-3-oxazoline (4i): Pale yellow viscous oil; IR (Neat) 3485 (OH), 2985, 1743 (C=O), 1662 (C=N), 1447,
1369, 1284, 1221, 1137, 1107, 1049 cm-1; 1H NMR (CDCl3, 500 MHz) δ = 1.277 (3H, t, J = 7.1 Hz, Me
of OEt), 1.278 (3H, t, J = 7.1 Hz, Me of OEt), 1.316 (3H, t, J = 7.1 Hz, Me of OEt), 1.317 (3H, t, J = 7.3
Hz, Me of OEt), 1.71 (3H, s, 2-Me), 3.39, 3.53 (2H, each d, each Jgem = 17.4 Hz, CH2), 3.70 (3H, s,
OMe), 4.22 – 4.36 (8H, m, CH2 of OEt), 4.44 (1H, br s, OH); 13C NMR (CDCl3, 125.65 MHz) δ =
13.88, 13.91, 13.96 (each q, Me of OEt), 23.09 (q, 2-Me), 34.61 (t, CH2), 52.75 (q, CO2Me), 62.58,
62.62, 62.77, 63.07 (each t, each CH2 of OEt), 78.05 (t, 2JC-H = 4.6 Hz, COH), 95.61 (s, 5-C), 110.38 (q,
2JC-H = 5.5 Hz, 2-C), 164.81 (t, 3JC-H = 2.3 Hz, CO2Et), 164.82 (t, 3JC-H = 3.2 Hz, CO2Et), 165.99 (t, 2JC-H
= 7.4 Hz, 4-C), 168.41, 168.92, 169.10 (each s, C=O); Anal. Calcd for C20H29NO12: C, 50.52; H, 6.15;
N, 2.95. Found: C, 50.36; H, 6.06; N, 2.99.
5,5-Bis(ethoxycarbonyl)-2-methoxycarbonyl-4-methyl-2-iso-propyl-3-oxazoline (3j): Colorless oil;
1H NMR (CDCl3, 270 MHz) δ = 0.94 (3H, d, J = 6.9 Hz, Me of i-Pr), 0.95 (3H, d, J = 6.9 Hz, Me of
i-Pr), 1.31 (3H, t, J = 7.3 Hz, Me of CO2Et), 1.33 (3H, t, J = 7.3 Hz, Me of CO2Et), 2.33 (3H, s, Me),
2.57 (1H, sept, J = 6.9 Hz, CH of i-Pr), 3.77 (3H, s, OMe), 4.28 (2H, q, J = 7.3 Hz, CH2 of CO2Et), 4.32
(2H, q, J = 7.3 Hz, CH2 of CO2Et); 13C NMR (CDCl3, 67.80 MHz) δ = 13.97, 13.99, 16.11, 16.41 (each
q, each Me), 34.01 (d, CH of i-Pr), 52.55 (q, OMe), 62.64, 62.67 (each t, each CH2 of OEt), 94.78 (s,
5-C), 115.08 (dq, 2JC-H = 9.2 Hz, 3JC-H = 4.3 Hz, 2-C), 164.99 (t, 2JC-H = 3.7 Hz, CO2Et), 165.32 (t, 2JC-H
= 3.7 Hz, CO2Et), 166.48 (q, 2JC-H = 7.3 Hz, 4-C), 169.06 (s, CO2Me). Satisfactory analytical data was
not obtained due to instability of 3j.
5,5-Bis(ethoxycarbonyl)-4-methoxycarbonyl-2-nonyl-2-oxazoline (2k): Colorless oil; IR (Neat) 2926,
2855, 1750 (C=O), 1677 (C=N), 1281, 1222, 1097, 939 cm-1; 1H NMR (500 MHz, CDCl3) δ = 0.88 (3H,
t, J = 7.1 Hz, Me of n-nonyl), 1.20 – 1.45 (18H, m, Me of OEt, CH2 of n-nonyl), 1.66 – 1.73 (2H, m,
CH2 of n-nonyl), 2.43 (2H, dt, J = 1.4 Hz, J = 7.8 Hz, CH2 of n-nonyl), 3.74 (3H, s, OMe), 4.19 – 4.38
13
(4H, m, CH2, OEt), 5.35 (1H, t, J = 1.4 Hz, Me); C NMR (CDCl3) δ = 13.88, 13.92, 14.08 (each q,
each Me), 22.67, 25.74, 27.83, 28.96, 29.19, 29.26, 29.42, 31.89 (each t, each CH2 of n-nonyl), 52.66 (q,
OMe), 62.81, 63.24 (each t, each CH2 of OEt), 74.97 (d, 4-C), 87.69 (d, 2JC-H = 2.3 Hz, 5-C), 165.46 (dt,
3
3
3
3JC-H = 4.6 Hz, JC-H = 3.2 Hz, CO2Et), 166.12 (dt, JC-H = 6.4 Hz, JC-H = 3.2 Hz, CO2Et), 168.94 (s,
CO2Me), 169.31 (s, 2-C). Satisfactory analytical data was obtained as the hydrolyzed product of 2k.
Anal. Calcd for C20H35NO5: C, 57.53; H, 8.45; N, 3.35. Found: C, 57.70; H, 8.29; N, 3.48.
Diethyl methyl 1-hydoroxy-2-decanoylamino-1,1,2-ethanetricarboxylate (5k): Colorless viscous oil;
1
IR (Neat) 3365 (OH, NH), 2927, 2852, 1750 (C=O), 1670 (C=O), 1525, 1222, 1171, 1156 cm-1; H
NMR (500 MHz, CDCl3) δ = 0.88 (3H, t, J = 7.3 Hz, Me of n-nonyl), 1.19 – 1.41 (18H, m, Me of OEt,
CH2 of n-nonyl), 1.57 – 1.66 (2H, m, CH2 of n-nonyl), 2.17 – 2.27 (2H, m, CH2 of n-nonyl), 3.71 (3H, s,
OMe), 4.19 – 4.36 (5H, m, CH2 of OEt, OH), 5.74 (1H, d, J = 10.1 Hz, CHCO2Me), 6.14 (1H, d, J =
10.1 Hz, NH); 13C NMR (125.65 MHz, CDCl3) δ = 13.92, 13.95, 14.07 (each q, each Me), 22.67, 25.63,

29.20, 29.27, 29.34, 29.46, 31.88, 36.56 (each t, each CH2 of n-nonyl), 52.80 (q, OMe), 55.58 (d,
2
2
CHCO2Me), 63.26, 63.30 (each t, each CH2 of OEt), 80.34 (dd, JC-H = 3.2 Hz, JC-H = 4.1 Hz, COH),
2
2
167.78, 167.86 (each s, each CO2Et), 168.81 (dq, JC-H = 6.9Hz, JC-H = 4.1 Hz, CO2Me), 173.01 (s,
NHCO). Anal. Calcd for C20H35NO5: C, 57.53; H, 8.45; N, 3.35. Found: C, 57.70; H, 8.29; N,
3.48.
General procedure for the reaction of oxazole with DDQ at high pressure. As a typical procedure,
the reaction of 4-ethoxycarbonyl-5-methoxy-2-methyloxazoles (1l) is described below. A solution of
oxazole (1l) (0.199 g, 1.0 mmol) and DDQ (0.227 g, 1.0 mmol) in acetonitrile (4.5 mL) was kept in a
Teflon capsule and pressurized hydraulically using Hikari Kouatsu High Pressure reaction apparatus at
0.85 GPa and 30 °C for 4 days. The mixture was concentrated under a reduced pressure, and the
residue was purified by flash chromatography over florisil using hexane-ethyl acetate (7/3 v/v) as an
eluent to give 2-oxazoline 8l (0.252 g, 68%).
6,7-Dichloro-9,10-dicyano-2-methyl-1,3-oxazaspiro[4,5]deca-2,6,9-trien-8-one
(8l):
Colorless
o
needles (benzene-hexane); mp 140-141 C, IR (KBr) 1765 (C=O), 1737 (C=O), 1698 (C=O, C=N),
1236, 1202 cm-1; 1H NMR (400 MHz, CDCl3) δ = 1.26 (3H, t, J = 7.1 Hz, Me of OEt), 1.33 (3H, t, J =
7.2 Hz, Me of OEt), 2.34 (3H, s, Me), 4.20 – 4.40 (4H. m, CH2 of OEt); 13C NMR (125.65 MHz,
CDCl3), δ = 13.74, 13.79, 13.85 (each q, each Me), 64.37, 64.93 (each t, each CH2 of OEt), 85.57 (s,
5-C), 93.91 (s, 4-C), 109.90 (s, CN), 110.96 (s, CN), 122.17 (s, 9-C), 133.37 (s, 7-C), 138.21 (s, 10-C),
3
3
2
147.34 (s, 6-C), 163.51 (t, JC-H = 3.2 Hz, CO2Et), 164.19 (t, JC-H = 3.7 Hz, CO2Et), 165.90 (q, JC-H
=
7.4 Hz, 2-C), 169.06 (s, C=O). Anal. Calcd for C17H13N3O6Cl: C, 47.91; H, 3.07; N, 9.86. Found: C,
48.06; H, 3.16; N, 9.92.
6,7-Dichloro-9,10-dicyano-2-nonyl-1,3-oxazaspiro[4,5]deca-2,6,9-trien-8-one (8m): Pale yellow
o
prisms (benzene-hexane); mp 80.5 – 81.5 C, IR (KBr) 2937, 2929, 1770 (C=O), 1744 (C=O), 1697
(C=O), 1677 (C=N), 1261, 1236, 1205, 1176 cm-1; 1H NMR (500 MHz, CDCl3) δ = 0.88 (3H, t, J = 7.1
Hz, Me of n-nonyl), 1.21 – 1.83 (17H, m, CH2 of n-nonyl and Me of OEt), 1.33 (3H, t, J = 7.1 Hz, Me of
13
OEt), 2.56 – 2.66 (2H, m, CH2 of n-nonyl), 4.19 – 4.38 (4H, m, CH2 of OEt); C NMR (125.65 Hz,
CDCl3) δ = 13.68, 13.72, 14.00 (each q, each Me), 22.59, 25.52, 27.87, 28.94, 29.04, 29.16, 29.30, 31.78
(each t, each CH2 of OEt), 64.24, 64.82 (each t, each CH2 of OEt), 85.22 (s, 5-C), 93.96 (s, 4-C), 109.86
(s, CN), 110.92 (s, CN), 122.07 (s, 9-C), 133.24 (s, 7-C), 138.26 (s, 10-C), 147.47 (s, 6-C), 163.55 (t, 3J
3
= 3.2 Hz, CO2Et), 164.28 (t, J
= 3.7 Hz, CO2Et), 168.96 (s, 2-C), 169.02 (s, C=O). Anal.
C-H
C-H
Calcd for C25H29N3O6Cl: C, 55.77; H, 5.43; N, 7.80. Found: C, 55.64; H, 5.25; N, 7.87.
REFERENCES AND NOTES
1. A. R. Katritzky, “Advances in Heterocyclic Chemistry,” Vol. 17, ed. by A. R. Katritzky, Academic
Press, New York, 1974; I. J. Turchi, “The Chemistry of Heterocyclic Compounds,” Vol. 45, ed. by I.
J. Turch, Wiley, New York, 1986, pp. 127 – 134; D. L. Boger and S. M. Weinreb, “Hetero

Diels-Alder Methodology in Organic Synthesis,” as Vol. 47 in “Organic Chemistry: A Series of
Monographs,” Chap. 10, ed. by H. H. Wasserman, Academic Press, San Diego, New York, Berkeley,
Boston, London, Sydney, Tokyo, and Tronto, 1987, pp. 300 – 310.
2. T. Ibata, Y. Isogami, S. Nakano, and H. Tamura, J. Chem. Soc., Chem. Commun., 1986, 1692; T.
Ibata, Y. Isogami, H. Nakawa, H. Tamura, H. Suga, X. Shi, and H. Fujieda, Bull. Chem. Soc. Jpn.,
1992, 65, 1171.
3. T. Ibata, Y. Isaogami, and H. Tamura, Chem. Lett., 1988, 1551; T. Ibata, H. Suga, Y. Isogami, H.
Tamura, and X. Shi, Bull. Chem. Soc. Jpn., 1992, 65, 2998.
4. A. Hassner and B. Fischer, Tetrahedron, 1989, 45, 3535; A. Hassner and B. Fischer, J. Org. Chem.,
1991, 56, 3419.
5. H. Suga and T. Ibata, Chem. Lett., 1991, 1221; H. Suga, X. Shi, and T. Ibata, Bull. Chem. Soc. Jpn.,
1998, 71, 1231.
6. E. Vedejs and S. Fields, J. Org. Chem., 1988, 53, 4663.
7. Part of this work was published as preliminary communication: H. Suga, X. Shi, and T. Ibata, Chem.
Lett., 1994, 1673.
8. H. Suga, X. Shi, H. Fujieda, and T. Ibata, Tetrahedron Lett., 1991, 32, 6911; H. Suga, X. Shi, and T.
Ibata, J. Org. Chem., 1993, 58, 7397; H. Suga, H. Fujieda, Y. Hirotsu, and T. Ibata, J. Org. Chem.,
1994, 59, 3359; The enantioselective version of this reaction: H. Suga, K. Ikai, and T. Ibata,
Tetrahedron Lett., 1998, 39, 869; H. Suga, K. Ikai, and T. Ibata, J. Org. Chem., 1999, 64, 7040; D.
A. Evans, J. M. Janey, N. Magomedov, and J. S. Tedrow, Angew. Chem., Int. Ed., 2001, 40,
1184.
9. The structure of the adduct assigned to 2-oxazoline by Hassner should be corrected to 3-oxazoline on
the basis of its 13C NMR spectrum.7