Heterocyclization of 4-trifluoroacetyl-1,3-oxazolium-5-olates with 1,4-bis-nucleophiles

Article abstract of DOI:10.3987/COM-01-9325

Reactions of aromatic 1,4-bis-nucleophiles such as o-phenylenediamine and o-aminothiophenol, with mesoionic 4-trifluoroacetyl-1,3-oxazolium-5-olates (1) gave regiospecifically seven member trifluoromethylated heterocycles such as 1,5-benzodiazepines (3) a

Full text of DOI:10.3987/COM-01-9325

HETEROCYCLES, Vol. 55, No. 10, 2001, pp. 1919 - 1926, Received, 22nd August, 2001
HETEROCYCLIZATION
OF
4-TRIFLUOROACETYL-1,3-
OXAZOLIUM-5-OLATES WITH 1,4-BIS-NUCLEOPHILES
a
a
a
Masami Kawase＊a, Hiromi Koiwai , Toru Tanaka , Satoru Tani , and
Hiroshi Miyamaeb
a Faculty of Pharmaceutical Sciences, Josai University, 1-1 Keyakidai,
Sakado, Saitama 350-0295, Japan
b
Faculty of Science, Josai University, 1-1 Keyakidai, Sakado, Saitama
350-0295, Japan
Abstract - Reactions of aromatic 1,4-bis-nucleophiles such as o-
phenylenediamine and o-aminothiophenol, with mesoionic 4-
trifluoroacetyl-1,3-oxazolium-5-olates (1) gave regiospecifically seven
member trifluoromethylated heterocycles such as 1,5-benzodiazepines
(3) and 1,5-benzothiazepines (4). The reaction with o-aminophenol
afforded non-cyclized products (5). The structures of 3, 4, and 5 were
established by X-Ray diffraction analysis.
During our studies on the chemistry of mesoionic 1,3-oxazolium-5-olates (munchnones),1 we
have focused on mesoionic 4-trifluoroacetyl-1,3-oxazolium-5-olates (1) as useful synthons for
trifluoromethyl-substituted heterocycles.2 These reactions proceed through the regioselective
attack of the nucleophiles such as amidines,2a, f ammonia,2b, g phenylhydrazine,2c and amino-
malonate 2e on 1, depending on the nature of the nucleophiles and the reaction conditions.
Recent studies have also demonstrated that munchnones are useful synthons for heterocycles
in combinatorial chemistry.
Thus, the 1,3-dipolar cycloaddition of polymer-bound
munchnones with a variety of alkynes has been developed to produce a library of up to 108
different pyrroles.3 The solid-phase synthesis of imidazoles is reported to utilize a munchnone
cycloaddition to aryltosylimines.4 The reaction of 1 with amidines 2a has also been applied to a
combinatorial solid-phase synthesis to prepare
a
library of two hundred 5-
trifluoroacetylimidazoles by Hamper et al.5 Thus, munchnone chemistries are suitable to
develop new synthesis in combinatorial chemistry.
In this study, we examined the question which position of 1 would be attacked by aromatic 1,4-
bis-nucleophiles such as o-phenylenediamine, o-aminothiophenol, and o-aminophenol.
Reactions of 1 with o-phenylenediamine
The 4-trifluoroacetyl-1,3-oxazolium-5-olates (1a-e) have been prepared by the reaction of N-

Table 1. Reaction of 1a with o-phenylenediamine.a
R1
CH2CO2H
NCOR2
COCF3
TFAA/pyridine
in CH2Cl2
N
Entry
Conditions
Solvent
Yield of
3a (%)
+
_
O
R2
O
R1
CH2Cl2
ClCH2CH2Cl
DMF
91
73
66
1
2
3
4
rt for 24 h
rt for 24 h
rt for 24 h
1
2
a: R1=Me, R2=4-MeOC6H4
b: R1=Me, R2=Me
c: R1=Bn, R2=Me
DMF
rt for 0.5 h, 80°C for 2 h 51
rt for 0.5 h, 80°C for 2 h 59
d: R1=Ph, R2=Me
benzene
5
e: R1=Me, R2=Ph
a The reactions were carried out on a 1 mmol
scale.
H
OH
CF3
OH
H
N
O
O
CF3
NCOR2
R1
S
NCOR2
N
H
CF3
R1
N
H
4
N
H
3
OH
NCOR2
R1
O
O
5
a: R1=Me, R2=4-MeOC6H4
b: R1=Me, R2=Me
c: R1=Bn, R2=Me
a: R1=Me, R2=4-MeOC6H4
a: R1=Me, R2=4-MeOC6H4
b: R1=Me, R2=Me
b: R1=Me, R2=Me
c: R1=Bn, R2=Me
d: R1=Ph, R2=Me
c: R1=Bn, R2=Me
d: R1=Ph, R2=Me
d: R1=Ph, R2=Me
e: R1=Me, R2=Ph
Table 2. Reactions of mesoionic 1 with nucleophiles.
Nucleophiles
(equiv)
Conditions
rt for 24 h
Entry Starting
material
Products,
Yield (%)
Solvent
o-phenylenediamine (1.05)
CH2Cl2
3a (91)
1
1a
o-phenylenediamine (1.05)
o-phenylenediamine (1.05)
o-phenylenediamine (1.02)
o-phenylenediamine (1.02)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
rt for 24 h
rt for 24 h
rt for 24 h
rt for 6 h
2
3
4
5
1b
1c
1d
1e
3b (80)
3c (89)
a
-
3e (98)
o-aminothiophenol (1.2)
o-aminothiophenol (1.2)
benzene
benzene
1a
1b
rt for 0.5 h, 80°C for 3 h
rt for 0.5 h, 80°C for 1 h
rt for 0.5 h, 80°C for 1 h
4a (93)
4b (81)
4c (86)
6
7
o-aminothiophenol (1.2)
o-aminothiophenol (1.2)
benzene
benzene
8
9
1c
1d
rt for 0.5 h, 80°C for 1 h 4d (82)
10
rt for 72 h
rt for 24 h
5a (78)
o-aminophenol (1.2)
o-aminophenol (1.05)
CH2Cl2
CH2Cl2
1a
1b
11
12
13
5b (70)
5c (75)
5d (77)
1c
1d
rt for 24 h
rt for 6 h
o-aminophenol (1.2)
o-aminophenol (1.2)
CH2Cl2
CH2Cl2
a complex mixture.

acyl-N-alkylglycines (2a-e) with trifluoroacetic anhydride (TFAA). Table 1 shows the results
when 1a was allowed to react with o-phenylenediamine under various conditions. The
reaction proceeded smoothly at room temperature. However, the higher temperature lowered
the yield. The best result was obtained when CH2Cl2 was used as a solvent. o-
Phenylenediamine reacted with 4-trifluoroacetyl-1,3-oxazolium-5-olates (1a-c, e) to produce
in good yields 1,5-benzodiazepine derivatives (3a-c, e), introduced both a trifluoromethyl and
amido groups in the diazepine segment (Table 2). This shows that the nucleophile exclusively
condenses on both of the C-5 and the trifluoroacetyl function with opening of the mesoionic ring.
However, reaction of 1d with o-phenylenediamine gave only complex mixture. The structures
were confirmed by elemental analyses, 1H and 13C NMR, MS, and IR spectroscopy (Tables 3, 4,
1
and 5). The H NMR spectrum of 3 exhibited the methine signal of H-3 at around 5.6 ppm
(singlet). Three peaks at 6.27, 7.68, and 10.18 ppm of 3 a were exchangeable with D2O. The
carbons of CF3 and C-4 appear at around 125 ppm (quartet, 1JC-F=289-294 ppm) and 92 ppm
(quartet, 2JC-F =27-28 Hz), respectively. The structure of 3e was unequivocally confirmed by
the X-Ray analysis (Figure 1).
Figure 1. X-Ray structure drawing of 3e.
Figure 2. X-Ray structure drawing of 4b.
N
X
CF
3
N
CH COCF
2
3
N
H
O
7: X=O
8: X=S
9: X=NH
6
CO H
2
O
C H
5
11
Cl
Cl
N
C H
N
H
(R)
5
11
O
(R)-Lorglumide
Figure 4. Structures of the related compounds
Figure 3. X-Ray structure drawing of 5c.

Reactions of 1 with o-aminothiophenol
The reaction of 1a-d with o-aminothiophenol also took place to produce 1,5-benzothiazepine
derivatives (4a-d) in good yields (Table 2). The reaction was complete at 80 °C. As the
same as o-phenylenediamine, the amino and thiol fuction of o-aminothiophenol condensed at
C-5 and trifluoroacetyl group, respectively. The structure of 4b was also determined by the
X-Ray analysis (Figure 2).
Reactions of 1 with o-aminophenol
We have also studied heterocyclizations with o-aminophenol. As we found, mesoionic 1a-d
reacted with o-aminophenol to give a product (5a-d) derived from a condensation reaction
between the amino group of o-aminophenol and the C-5 of 1 (Table 2). Methanolic solution of
5a turned violet in color on addition of a few drops of iron(III) chloride solution, thus confirming
the phenol group of the products. The phenolic hydroxyl group of the adduct (5) is not
nucleophilic enough to give the corresponding 1,5-benzoxazepine derivatives, which were not
isolated in these reactions. Structural assignments were made on the basis of analytical and
spectroscopic data (Tables 3 and 4) and the structure was secured by single-crystal X-Ray
diffraction analysis of 5c (Figure 3). The X-Ray analysis of 5c indicates that the enolic form is
stabilized by resonace and by the formation of an intramolecular hydrogen bond.
7
1,5-Benzodiazepine,6 1,5-benzothiazepine and the related derivatives constitute an important
class of heterocyclic compounds and many thousands of them have been synthesized as
potential drugs. The benzodiazepine derivatives have been well documented as nonpeptide
cholecystokinin (CCK) agonists and antagonists, which have potential as therapeutic agents for
treating both peptic ulcers and CNS disorders.8 The selected compounds (3a-c, 4a, 4c and
5 a) and related compounds (6-9) (Figure 4) were screened for CCK-A antagonistic activity, but
were inactive at 1 x 10-5 M concentration, compared with lorglumide (IC50 = 2.4 x 10-7 M), a
specific antagonist of CCK-8.
In conclusion, mesoionic 4-trifluoroacetyl-1,3-oxazolium-5-olates (1), readily available from N-
acyl-N-alkylglycines and TFAA, reacted with o-phenylenediamine or o-aminophenol giving
1,5-benzodiazepines (3) and 1,5-benzothiazepines (4) which were introduced by the
trifluoromethyl group at 4 position and amido group at 3-position. The method appears to be
useful and convenient in terms of the ready accessibility of the starting materials, cheap
reagents, and operational simplicity.
EXPERIMENTAL
Mps were determined on a Yanagimoto hot-stage apparatus and are uncorrected. 1H NMR
spectra were measured at 500 MHz with tetramethylsilane (Me4Si) as an internal reference and
DMSO-d6 as the solvent. J-Values are given in Hz. IR spectra were recorded on a JASCO
IR810 spectrophotometer. Only pertinent IR peaks are given. MS spectra (electron impact:

70 eV) were measured with a JEOL JMS-DS300 spectrometer. For column chromatography,
SiO2 (Merk, Art 9385) was used.
4-Trifluoroacetyl-2-(4’-methoxyphenyl)-3-methyl-1,3-oxazolium-5-olate (1a) was synthesized
in 86% yield by the reaction of N-(4’-methoxybenzoyl)-N-methylglycine9 with TFAA as
described previously.2g 1a: mp 142.5-144.5 ˚C (AcOEt-hexane), Anal. Calcd for C13H10NO4F3:
C, 51.84; H, 3.35; N, 4.65. Found: C, 51.86; H, 3.42; N, 4.62. MS m/z 301 (M+, 17), 135 (100);
IR υ
(cm-1) 1630, 1780; 1H NMR (CDCl3) δ 3.90 (s, 3H), 4.06 (s, 3H), 7.06 (d, 2H, J=9.0),
max/nujol
10
7.69 (d, 2H, J=9.0). 4-Trifluoroacetyl-2,3-dimethyl-1,3-oxazolium-5-olate (1b)
and 4-
trifluoromethyl-1H-1,5-benzodiazepin-2(3H)-one (6) 11 were prepared by the reported method.
Compounds (1c-e)2g and (7-9)12 were previously prepared.
General Procedure for the Reaction of 1 with o-Phenylenediamine, o-
Aminothiophenol or o-Aminophenol. A mixture of 1 (1 mmol) and the nucleophile
(1.02-1.2 mmol) in 5 mL of the indicated solvent (Table 2) was stirred under the conditions
described in Table 2. The reaction mixture was diluted with 5 mL of hexane and allowed to
stand for 3-5 h in an ice bath. The precipitate was then filtered, dried and crystallized to give
the corresponding product (Table 3).
Table 3. Physical and analytical data of new compounds.
Analysis (%)
F oun d (C alc ulated)
a
Com-
pound
IR, νmax/nujol
(c m -1)
Mp (solvent)
MS, m/z (%),
M+ and base peak
Formula
C
H
N
C19 H18N3 O4 F3
C13 H14N3 O3 F3
C19 H18N3 O3 F3
171-173
(A-H)
55.96 4.64 10.31
(55.75) (4.43) (10.26)
1610, 1680,
3300
409(3)
135
3a
156-157
(A-H)
161-163
(A)
49.14 4.44 13.29
(49.22) (4.45) (13.24)
57.94 4.61 10.61
(58.01) (4.61) (10.68)
1625, 1690,
3270
1625, 1675,
3400
317(18)
108
393(25)
91
3b
3c
3e
C18 H16N3 O3 F3
189-190
(A-H)
56.97 4.32 11.01
(56.99) (4.25) (11.08)
1615, 1680,
3400
379 (10)
105
C19 H17N2 O3 F3S
188-189
(A)
53.27 4.20 6.32
(53.52) (4.02) (6.57)
1610, 1675,
3050-3230
426 (52)
135
4a
4b
C
13 H13N2 O3 F3S
155-157
(E)
46.95 4.11 8.43
(46.71) (3.92) (8.38)
1625, 1690,
3120
334 (6)
152
C
C
19 H17N2 O3 F3S
18 H15N2 O3 F3S
154-156
(C-H)
171-173
(E)
55.20 4.26 6.66
(55.60) (4.17) (6.83)
54.29 3.99 7.07
(54.54) (3.81) (7.07)
1625, 1670,
3100
1630, 1690,
3180
410 (6)
91
396 (6)
203
4c
4d
C19 H17N2 O5 F3
C13 H13N2 O4 F3
183-185
(A)
410.1085
1620 ,
410 (2)
135
5a
5b
5c
(410.1089)
3370 (br)
162-163
(C -H )
48.89 4.09 9.00
(49.06) (4.12) (8.80)
1600, 1670,
3320, 3400
318 (4)
109
C19 H17N2 O4 F3
C18 H15N2 O4 F3
394 (9)
91
362 (0.2, M+-H2O)b
106
171-173
(E)
57.98 4.53 7.05
(57.87) (4.34) (7.10)
1595, 1640,
3220( br ), 3360
195-198
(A)
362.0865b
(362.0878)
1625 ,
2700 -3600 (br)
5d
aA=AcOEt, E=E tOH, C=CH2 Cl2, H=hexan e. bCalcd for C18H13N2O3F3 (M+ -H 2O.)

1
Table 4. H NMR dataof new compounds.
Compound
1H NMR (500 MHz) δ
3a 3.28 (s, 3H), 3.77 (s, 3H), 5.56 (s, 1H), 6.27 (s, 1H), 6.98 (d, 2H, J=8.9), 7.01-7.11 (m, 4H), 7.27 (d, 2H,
J=8.9), 7.68 (s, 1H), 10.18 (s, 1H)
3b 1.97 (s, 3H), 3.30 (s, 3H), 5.63 (s, 1H), 6.20 (s, 1H), 6.96-7.07 (m, 4H), 7.53 (s, 1H), 10.11 (s, 1H)
1.62 (s, 3H), 4.53 (d, 1H, J=17.4), 5.59 (d, 1H, J=17.4), 5.84 (s, 1H), 6.21 (s, 1H), 6.99-7.09 (m, 4H), 7.17-7.23
(m, 2H), 7.27-7.30 (m, 3H), 7.78 (s, 1H), 10.12 (s, 1H)
3c
3ea
4aa
3.23 + 3.32 (s, 3H), 4.50 + 5.65 (s, 1H), 6.11 + 6.30 (s,1H), 6.80-6.87 + 7.03-7.11 (m, 4H), 6.94-6.97 +
7.25-7.29 (m, 2H), 7.19-7.21 + 7.43-7.45 (m, 3H), 7.71 + 7.72 (s, 1H), 10.22 + 10.23 (s, 1H)
3.32 (s, 3H), 3.66 + 3.76 (s, 3H), 4.57 + 5.61 (s, 1H), 6.66 + 6.96 (d, 2H, J=8.6), 6.8 3 + 7.25 (d, 2 H, J=8.6),
7.02 + 7.25 (t, 1H, J=7.6), 7.20 (d, 1H, J=7.6), 7.39 + 7.53 (t, 1H, J=7.6), 7 .58 (d, 1H, J=7 .6 ), 8. 90 (s, 1H),
10.54 + 10.61 (s, 1H)
4b 1.93 (s, 3H), 3.33 (s, 3H), 5.73 (s, 1H), 7.18 (d, 1H, J=7.7), 7.22 (t, 1H, J=7.7), 7.50 (t, 1H, J=7.7), 7.55 (d,
1H, J=7.7), 8.73 (s, 1H), 10.47 (s, 1H)
4ca
1.57 + 1.61 (s, 3H), 4.55 (d, 1H, J=17.1), 5.54 + 5.80 (d, 1H, J=17.1), 5.74 + 6.08 (s, 1H), 7.16-7.21 (m,
3H), 7.23-7.31 (m, 4H), 7.50 (t, 1H, J=7.5), 7.59 (d, 1H, J=7.5), 8.84 + 9.05 (s, 1H), 10.56 + 10.65 (s, 1H)
4da
1.72 (s, 3H), 7.11-7.19 (m, 3H), 7.31-7.38 (m, 5H), 7.45 (t, 1H, J=7.6 ), 7.53 (d, 1H, J=7.6), 10.70 (s, 1H)
3.01 (s, 3H), 3.69 (s, 3H), 6.70 (t, 2H, J=7.5 ), 6.76 (d, 2H, J=8.9), 6.80 (d, 1H, J=7.5 ), 7.3 1 (d , 2H, J=8.9),
7.69 (d, 1H, J=7.5), 9.00-9.50 (br, 1H), 10.49 (br s, 1H), 12.16 (br s, 1H)
5a
5b 2.06 (s, 3H), 3.06 (s, 3H), 6.77 (d, 1H, J=7.3) , 6 .87 (d, 1H, J=7.9 ), 6.91 (d, 1H, J=7.6), 8.04 (d, 1H, J=7.9),
9.74 (s, 1H), 9.96 (br s, 1H), 10.84 (s, 1H)
5c 2.24 (s, 3H), 4.52 (d, 1H, J=13.9), 4.59 (d, 1H, J=13.9), 6.74 (t, 1H, J=7.5), 6.86 (d, 1H, J=8.2), 6.95 (t, 1H,
J=7.9), 7.20-7.40 (m, 5H), 7.95 (d, 1H, J=7.7), 9.70 (s, 1H), 9.90 (br s, 1H), 10.81 (br s, 1H)
2.00 (s, 3H), 6.70-6.73 (m, 2H), 6.82-6.83 (m, 2H), 6.99 (t, 1H, J=7.3 Hz), 7.19 (t, 2H, J=7.8), 7 .29 (d, 2H,
J=7.6), 7.84 (d, 1H, J=7.6), 10.26 (s, 1 H), 12.40 ( s, 1H)
5d
a Th e multiplicity of the signals suggests two confor mers due to hindered rotation around the amide bond.
13
Crystal data for 3e
(C18H16N3O3F3) FW=379.34, mp 189-190 ˚C.Monoclinic P21/a, a=7.2109(2), b=17.3810(7),
c=14.1745(5)Å,β= 99.818(1)°,V=1750.51(9)Å3,μ(Mo Kα)= 0.120 cm-1 using 0.20×0.12
×0.08mm colorless plateletcrystal by Rigaku Rapid (-9≦h≦9,-22≦k≦22, -18≦l≦18 with θ
max=27.48°). Final R and Rw were 0.068 and 0.025, respectively, for 2452 independent
reflections with F2≧σ(F2), S=1.506, final (Δ/σ)max = 0.033, Δρmax=0.57, Δρmin= -0.69 e
Å-3.
13
Crystal data for 4b
(C13H13N2O3F3S) FW=334.32, mp 155-157 ˚C.Tetragonal I41/a, a=20.547(1), c=13.7786(9)Å,
V=5817.2(5)Å3,μ(Mo Kα)= 0.271 cm-1 using 0.5×0.2×0.2 mm colorless prismatic crystal by
Rigaku Rapid (-27≦h≦27, -27≦k≦27, -17≦l≦18 with θmax=28.69°). Absorption
correction was applied (Tmin=0.428 and Tmax=0.947). Final R and Rw were 0.044 and 0.035,
respectively, for 1979 independent reflections with F2≧σ(F2), S=0.806, final (Δ/σ)max = 0.003,
Δρmax=0.68, Δρmin= -0.58 eÅ-3.

Table 5. 13C NMR data of new compounds.
Compound
13CNMR (127 MHz) δ
3a 37.5 (CH3), 52. 7 (C H), 55.3 (CH3 ), 92.3 (C, 2JCF =27), 113.7 (CH), 121.4 (CH), 123.4 (CH), 123.5 (CH),
1
125.1 (C), 126.25 (CF3, JCF=289), 127.6 (CH), 128.8 (C), 131.1 (C), 135.8 (C), 160.4 (C), 167.9 (C), 171.7
(C )
21 .5 (CH3), 35.0 (CH3), 51.6 (CH), 91.8 (C, 2JCF=27), 121.3 (CH), 123.1 (CH), 123.2 (CH), 123.6 (CF3,
3b
1JCF =294), 125.0 (CH), 130.7 (C), 135.8 (C), 168.1 (C), 171.4 (C)
3c 22.7 (CH3), 51.5 (CH2), 52.7 (CH), 92.3 (C, 2JCF=28) , 121. 4 (CH ), 1 23. 5 (C H), 123.6 ( CH), 12 3. 8 (CF 3,
1JCF=296), 125.2 (CH), 126.3 (CH), 126.8 (CH), 128.0 (CH), 131.1 (C), 136.1 (C), 140.3 (C), 167.3 (C),
173.0 (C)
2
3ea
32 .8 + 37.3 ( CH3), 52.4 + 58.7 (CH), 92.3 (C, JCF=28), 121.2 + 121.4 (CH), 123.1 + 123.4 (CH), 123.3 +
123.5 (CH), 125.1 + 125.2 (CH), 126.2 (CF3, 1JCF=294), 125.5 +126.4 (CH), 128.3 + 128.6 (CH), 129.3
+129.7 (CH), 130.5 + 131.0 (C), 135.4 + 135.8 (C), 135.6 +135.9 (C), 167.7 +167.8 (C), 171.2 + 171.9 (C)
4aa
37.4 (CH3), 52.3 (CH), 55.2 + 55.3 (CH3), 90.2 (C, 2JCF=32),113.7 + 113.8 (CH), 122.8 (CH), 124.3 (CH),
124.8 (CF3 , 1JCF=285), 126.0 (CH), 127.1 + 127.2 (C), 128.9 (CH), 131.0 + 131.5 (C), 134.4 + 134.7 (C),
141.1 + 141.9 (C), 159.7 + 160.5 (C), 167.7 + 168.3 (C), 171.1 + 171.6 (C)
4b 21.5 (CH3), 34.9 (CH3), 50.7 (CH), 91.9 (C, 2JCF =29), 122.7 (CH), 124.2 (CF3, 1JCF =287), 124.3 (C),
125.9 (CH), 131.4 (CH), 134.6 (CH), 141.9 (C), 168.2 (C), 171.3 (C)
22.4 (CH3), 50. 6 (C H), 50.8 (CH2 ), 9 2. 5 (C, 2JCF =32), 122.8 (CH), 124.2 (CF3, 1JCF =296), 124.6 (CH),
126.0 (CH), 126.2 (CH), 126.3 (CH), 128.1 (CH), 131.5 (CH), 134.8 (CH), 140.3 (CH), 141.7 + 141.9 (CH),
167.2 + 167.3 (C), 172.6 (C)
4ca
4da 23 .7 + 23.8 ( CH3), 54.9 + 57.9 (CH), 90.9 (C, 2JCF =32), 122.6 (CH), 123.9 (CH), 124.4 (CF3, 1JCF =288),
126.1 (CH), 128.5 (C), 128.6 (CH), 131.7 (CH), 134.8 (CH), 140.7 (C), 141.7 (C), 141.8 (CH), 166.2 + 166.3
(C), 166.3 + 166.4 (C)
a
The multiplicity of the signals suggests two conformers due to hindered rotation around the amide bond.
13
Crystal data for 5c
(C19H17N2O4F3) FW=394.35, mp 171-173 ˚C.Orthorhombic Pbca, a=25.5873(8), b=15.483(2),
c=9.3807(5)Å, V=3716.3(3)Å3,μ(Mo Kα)= 0.119 cm-1 using 0.40×0.35×0.10 mm colorless
platelet crystal by Rigaku Rapid (-32≦h≦33, -20≦k≦20, -12≦l≦12 with θmax=27.48°).
Final R and Rw were 0.048 and 0.113, respectively, for 2363 independent reflections with F2≧
σ(F2), S=3.146, final (Δ/σ)max = 0.015, Δρmax=0.39, Δρmin= -0.42 eÅ-3.
Pepsinogen release: Chief cells from the rat stomach were prepared by a Percoll
(Amercham Pharmacia Biotech, Uppsala, Sweden) gradient centrifugation after dispersing
from a everted sacs of the stomach with Dispase I (1 kU/ml) (Godo Shusei Co., Tokyo, Japan).
The cells were cultured in a mixture of Dulbecco’s modified Eagle’s minimum essential medium
and Ham’s F-12 (1:1) containing 10% fetal calf serum on collagen coated plastic dishes at 37 ˚C
in a CO2 incubator as described.14 After replacing the medium, the cells were incubated with
CCK-8 (1 x 10-8 M) and various concentrations of lorglumide or tested compounds (1 x 10-5 M)
for 30 min at 37 ˚C in a CO2 incubator. The concentration of pepsinogen was measured by the
avidin-biotin complex enzyme-linked immunosorbent assay (abcELISA).

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