Synthesis and root growth-inhibitory activity of 2- and 3-(haloacetylamino)-3-(2-furyl)propanoic acids.

Article abstract of DOI:10.1248/cpb.51.994

A convenient synthesis of 2- and 3-(chloroacetylamino)-3-(2-furyl)propanoic acids (6a, 7a) and their fluoro analogs were developed. Both 6a and 7a showed 51-55% root growth-inhibitory activity towards rape seedlings at the concentration of 1.0x10(-4) M.

Full text of DOI:10.1248/cpb.51.994

9
94
Notes
Chem. Pharm. Bull. 51(8) 994—998 (2003)
Vol. 51, No. 8
Synthesis and Root Growth-Inhibitory Activity of 2- and
-(Haloacetylamino)-3-(2-furyl)propanoic Acids
3
Tokujiro KITAGAWA,* Mizuki NAKAMURA, and Katunori MASAI
Faculty of Pharmaceutical Sciences and High Technology Research Center, Kobe Gakuin University; Ikawadani, Nishi-ku,
Kobe 651–2180, Japan. Received February 26, 2003; accepted April 30, 2003
A convenient synthesis of 2- and 3-(chloroacetylamino)-3-(2-furyl)propanoic acids (6a, 7a) and their fluoro
analogs were developed. Both 6a and 7a showed 51—55% root growth-inhibitory activity towards rape seedlings
؊4
at the concentration of 1.0؋10 M.
Key words furan derivative; chloroacetamide; herbicidal activity; propanoic acid; plant growth regulator
Compounds of the chloroacetamide family are major pre- (15a) at 70 °C for 2.5 h in the presence of sodium ethoxide as
emergence herbicides for control of seedling grass in corn a base gave a 61% yield of 16a. This diester (16a) was hy-
and soybean crops, and are among the most widely used her- drolyzed with 10% NaOH solution for 24 h at room tempera-
1
,2)
bicides in the world. For example, the thiophene derivative ture to give 2-(chloroacetylamino)-2-(2-furylmethyl)propane-
dimethenamid [2-chloro-N-(2,4-dimethyl-3-thienyl)-N-(2- dioic acid (17a) in 76% yield.
methoxy-1-methylethyl)acetamide] (1) is used for control of Concerning the experimental conditions for the decar-
annual grasses and certain broadleaf weeds, primarily in boxylation of propanedioic acid derivatives to give the corre-
3
—7)
corn and soybeans and also in peanuts.
In addition, sponding monoacid derivatives, the literature contains a vari-
thenylchlor [2-chloro-N-(3-methoxy-2-thienyl)methyl-2Ј,6Ј- ety of procedures, such as 1) refluxing for 2.5 h with 50%
1
5)
19,20)
dimethylacetanilide] (2) having a chloroacetamido moiety acetic acid, 2) boiling for 39 h in dioxane,
and 3) re-
2
1)
shows high herbicidal activity for barnyard grass in paddy fluxing for 2 h in toluene. Decarboxylation of our com-
8
—12)
fields.
pound (17a) for 2 h in refluxing toluene resulted in a 5%
In the course of work on furan derivatives as plant growth yield of 2-(chloroacetylamino)-3-(2-furyl)propanonic acid
regulators, Tamari reported that 3-(2-furyl)propanoic acid (3) (6a) together with a large amount of tarry material. We spec-
1
3)
has a weak plant growth-inhibitory activity. This stimu- ulated that toluene, which has a low solvating power, is un-
lated Kato et al. to examine the phytogrowth-inhibitory activ- able to stabilize the transition state in the pyrolysis of 17a.
ity of 3-(2-furyl)propanoates (4) and 3-(2-furyl)propan- Considering that the decarboxylation of propandioic acid de-
amides (5), though these compounds proved not to have rivatives to form the corresponding monoacid is a typical ex-
1
2)
high activity.
ample of intramolecular fragmentation, we thought that this
We hoped to find a new lead compound by introducing a reaction should be carried out in highly dilute solution and in
chloroacetylamino group into 3-(2-furyl)propanoic acid (3). a neutral hydrophilic solvent such as ethanol to minimize the
Thus, we set out to prepare 2- and 3-(chloroacetylamino)-3- intermolecular interaction. Finally, the reaction of 17a for 3 h
1
4)
(
2-furyl)propanoic acids (6a, 7a) and to examine their root in boiling ethanol in place of toluene resulted in a 93% yield
growth-inhibitory activities in rape seedlings.
Preparation of 2-(Haloacetylamino)-3-(2-furyl)propa-
of 6a.
As shown in Chart 2, 2-(fluoroacethylamino)-3-(2-furyl)-
noic Acids (6) We initially considered the synthesis of 2- propanoic acid (6b) was also prepared in order to study the
chloroacetylamino)-3-(2-furyl)propanoic acid (6a) by utiliz- effect of the halogen atom on the putative biological activi-
ing diethyl formamidomalonate (8) to prepare 2-amino-3-(2- ties.
(
1
5)
furyl)propanoic acid (12), followed by chloroacetylation of
2 using chloroacetyl chloride. However, 8 is expensive, so
1
we decided to employ the (chloroacetylamino)propanedioic
acid diethyl ester (15a) route shown in Chart 2.
First of all, 15a was synthesized in 90% yield by the reac-
tion of diethyl aminomalonate hydrochloride (14) with
chloroacetyl chloride in the presence of triethylamine, ac-
1
6)
cording the procedure of Sheehan and Bose. We found that
the reaction of 14 with chloroacetic acid using 1,1Ј-oxalyldi-
1
7)
imidazole (ODI) as a condensing reagent resulted in the
formation of 15a in 58% yield accompanied with a tarry ma-
terial. This result suggest that 15a is unstable in the presence
of basic reagents such as ODI or imidazole.
Next, synthesis of 2-(chloroacetylamino)-2-(2-furylmeth-
yl)propanedioic acid diethyl ester (16a) was successfully
achieved by means of the following reaction. Treatment of 2-
1
8)
bromomethylfuran (9) derived from 2-furylmethanol (13)
with 2-(chloroacetylamino)propanedioic acid diethyl ester
Chart 1
∗
To whom correspondence should be addressed. e-mail: kitagawa@pharm.kobegakuin.ac.jp
© 2003 Pharmaceutical Society of Japan

August 2003
995
Reagents and conditions: (a) EtONa, EtOH, reflux, 2 h; (b) 10% NaOH, reflux, 6 h; (c) 50% AcOH, reflux, 2.5 h; (d) PBr , THF; (e) for 15a, ClCH COCl, ClCH CH Cl, and for
3
2
2
2
1
5b, FCH COOH, ODI, CH CN, 60 °C, 2 h; (f) EtONa, EtOH, 70 °C, 2 h; (g) 10% NaOH, r.t., 24 h; (h) EtOH, reflux, 3 h.
2
3
Chart 2
dichlorophenoxyacetic acid (2,4-D) was used as a positive
control. The results are summarized in Table 1.
All four 2- or 3-haloacetylamino derivatives (6a, b, 7a, b)
inhibited the root growth in rape seedlings (Table 1). Thus,
the introduction of a chloroacetylamino group at the 2- or 3-
position of 3-(2-furyl)propanoic acid (3) clearly enhances the
inhibitory activity, whereas an acetylamino or amino group is
ineffective.
Among the 2-substituted 3-(2-furyl)propanoic acids (6a—
c, 12), 2-(chloroacetylamino)-3-(2-furyl)propanoic acid (6a)
showed 51% inhibitory activity at the concentration of
Ϫ4
1
ϫ10 M. The compound obtained by replacing the chlorine
Reagents and conditions: (a) malonic acid, ammonium acetate, EtOH, reflux, 8 h; (b)
SOCl , MeOH, r.t., 15 h; (c) for 21a, ClCH COCl, ClCH CH Cl, and for 21b,
atom of 6a with fluorine, namely the 2-fluoroacetylamino de-
rivative (6b) markedly enhanced the inhibitory activity, af-
fording 90% inhibition, which is similar to that of 2,4-D used
as a positive control.
2
2
2
2
FCH COOH, ODI, CH CN, 60 °C, 2 h; (d) 4% NaOH, r.t., 4 h.
2
3
Chart 3
Among the 3-substituted 3-(2-furyl)propanoic acids (7a—
Preparation of 3-(Haloacetylamino)-3-(2-furyl)propi- c, 19), 3-(chloroacetylamino)-3-(2-furyl)propanoic acid (7a)
onic Acids (7) The synthesis of 3-(chloroacetylamino)-3- showed 55% inhibitory activity. The inhibitory activity of the
(
2-furyl)propanoic acid (7a) started with furfural (18), which 3-substituted compounds (7a—c, 19) was in the following
was converted to methyl 3-amino-3-(2-furyl)propanoate hy- order; ClCH CONH– (7a)ϾFCH CONH– (7b)ϾCH CONH–
2
2
3
drochloride (20) in 30% overall yield via the formation of 3- (7c)ϾH N– (19). It seems noteworthy that the inhibitory ac-
2
amino-3-(2-furyl)propanoic acid (19). As mentioned above, tivity of the chloride derivative (7a) is somewhat stronger
chloroacetylation of 20 with chloroacetyl chloride gave rise than that of the fluoride derivative (7b), in contrast to the
to 3-(chloroacetylamino)-3-(2-furyl)propanoic acid methyl finding that the inhibitory activity of the 2-chloroacetylamino
ester (21a), which was subjected to hydrolytic cleavage of derivative (6a) is weaker than that of the 2-fluoroacetylamino
the methyl ester group in 4% sodium hydroxide solution to derivative (6b).
afford 3-(chloroacetylamino)-3-(2-furyl)propanoic acid (7a)
in 95% yield (calculated on the basis of 21a).
It is apparent that the halogen atom on the acetylamino
group is critical for potent root-growth inhibition activity in
The fluoroacetylamino derivative (7b) was similarly pre- rape seedling. However, the fluoroacetyl residue in 6b or 7b
pared by the reaction of 20 with fluoroacetic acid using ODI is likely to be undesirable from the viewpoint of environmen-
2
3,24)
to yield 3-(fluoroacetylamino)-3-(2-furyl)propanoic acid tal protection.
So, our interest was focused on 6a or 7a
methyl ester (21b), followed by hydrolysis of the methyl as candidate lead compounds for developing novel herbi-
ester group as shown in Chart 3.
These compounds (6a, 7a) and related compounds (6b,
cides.
In conclusion, the condensation of 2-(haloacetylamino)-
7
b, c, 12, 19) were tested for plant growth-regulating activi- propanedioic acid diethyl esters (15) with (2-bromomethyl)-
ties.
furan (9), followed by hydrolysis of the adduct with alkaline
Root Growth-Inhibitory Activity This activity was as- solution, is a convenient method for the preparation of 2-
2
2)
sayed according to the reported procedure using seeds of (haloacetylamino)-2-(2-furylmethyl)propanedioic acids (17).
rape, Brassica campestris L. (Brassicaceae), as a dicotyle- Thermal decomposition of 17 as a highly diluted solution in
don. The root length (in millimeters) of the seedlings was ethanol smoothly afforded 2-(haloacetylamino)-3-(2-furyl)-
measured and averaged for each group. The herbicide 2,4- propanoic acids (6a, b).

9
96
Vol. 51, No. 8
Table 1. Root Growth-Inhibitory Activities of 2- and 3-Substituted 3-(2-Furyl)propanoic Acids (6, 7) and Related Compounds (12, 19, 2,4-D)
2
-Substituted 3-(2-furyl)propanoic acids (6, 12)
Dicotyledoneae
3-Substituted 3-(2-furyl)propanoic acid (7, 19)
Dicotyledoneae
Rape; Brassica campestris L.
Rape; Brassica campestris L.
a)
a)
Growth (mm)
Growth (mm)
Ϫ4
c)
Ϫ4
c)
Compound 2-Substituent
Control
1.0ϫ10
M
Inhibition (%)
Compound 3-Substituent
Control
1.0ϫ10
M
Inhibition (%)
6
a
NHCOCH Cl
57Ϯ11.3
42Ϯ13.3
49Ϯ14.1
45Ϯ9.5
28Ϯ8.1∗ ∗
4Ϯ3.4∗ ∗
40Ϯ12.5∗ ∗
42Ϯ13.2
0∗ ∗
51
90
19
7
7a
7b
7c
19
2,4-D
NHCOCH Cl
62Ϯ11.4
53Ϯ7.5
58Ϯ12.1
62Ϯ17.6
64Ϯ25.7
28Ϯ8.1∗ ∗
30Ϯ7.9∗ ∗
45Ϯ13.1∗ ∗
52Ϯ13.3∗
0∗ ∗
55
43
22
16
100
2
2
6
b
NHCOCH2F
NHCOCH3
NH2
NHCOCH2F
NHCOCH3
NH2
6
1
,4-D
c
2
b)
b)
2
64Ϯ25.7
100
a) The values represent meanϮS.D. of 40 seeds after seven days. Significant differences from the corresponding control level are shown: ∗ and ∗ ∗ indicate pϽ0.05 and
Ϫ2 Ϫ1
pϽ0.01, respectively. Light intensity 127 mmol·m ·s . Temperature 25 °C. Relative humidity 60%. Experimental size; 20 seeds/group, 2 groups. b) 2,4-Dichlorophenoxy-
Ϫ4
acetic acid (2,4-D) was used as a positive control. c) % of inhibitionϭ[(mean value of controlϪmean value at the concentration (M) of 1.0ϫ10 )/mean value of control]ϫ100.
aminomalonate hydrochloride (14) (4.2 g, 20 mmol) was added in a single
portion at room temperature. The resultant mixture was stirred for 2 h at
Application of traditional esterification-acetylation-hydrol-
ysis methodology to the known 3-amino-3-(2-furyl)propa-
noic acid (19) smoothly gives the corresponding 3-(haloace-
tylamino)-3-(2-furyl)propanoic acids (7a, b).
6
0 °C. The solvent was removed in vacuo, and the residue was poured into
ice-water and extracted with ethyl acetate. Washing of the ethyl acetate ex-
tract with 5% sodium hydrogencarbonate, 5% hydrochloric acid and water,
followed by drying over Na SO and evaporation of the solvent, left the
Root growth-inhibitory activity assay revealed that 6a and
2
4
crude product (15b), which was recrystallized from toluene to give 4.3 g
7
a inhibited the root growth of rape seedlings by about 50%
(
(
91%) of 15b, mp 46—48 °C. IR (KBr): 3316 (N–H), 1749 (acid CO), 1656
Ϫ4
at the concentration of 1.0ϫ10 M. The halogen atom on the
acetylamino group appears to be critical for potent root
growth-inhibition activity.
Ϫ1 1
amide CO) cm . H-NMR (DMSO-d ): 1.20 (overlapping two 3H, each t,
6
Jϭ7.1 Hz, CH ϫ2), 4.15—4.22 (two 2H, each m, CH CH ϫ2), 4.93 (2H, d,
3
2
3
Jϭ46.7 Hz, CH F), 5.11 (1H, d, Jϭ7.1 Hz, CH), 8.95 (1H, br d, Jϭ7 Hz,
2
NH). Anal. Calcd for C H FNO : C, 45.95; H, 5.95; N, 5.95.
9
14
5
Experimental
2-(Chloroacetylamino)-2-(2-furylmethyl)propanedioic Acid Diethyl
Diethyl aminomalonate hydrochloride (14), diethyl formamidomalonate Ester (16a) 2-(Chloroacetylamino)propanedioic acid diethyl ester (15a)
8), chloroacetic acid, chloroacetyl chloride, 2-furylmethanol (13), furfural (25 g, 100 mmol) was dissolved in a sodium ethoxide solution [prepared
19), sodium fluoroacetate, malonic acid, oxalyl chloride and imidazole were from 2.3 g of sodium (0.1 g-atm) and 200 ml of absolute ethanol]. To this
(
(
18)
purchased from commercial sources and used as received. 2-(Bro- stirred solution, an ether solution containing crude 2-(bromomethyl)furan
1
8)
momethyl)furan (9) was prepared according to the reported procedure.
(9) [prepared from 2-furylmethanol (13) (13 g, 130 mmol)] was added in a
(12), 2-acetylamino-3-(2-furyl)pro- single portion. The mixture was distilled rapidly at atmospheric pressure
1
5)
2
-Amino-3-(2-furyl)propanoic acid
19,20)
25)
panoic acid (6c),
and 3-amino-3-(2-furyl)propanoic acid (19) were until about 300 ml of ether had been collected, and the remaining reaction
mixture was refluxed at 68—72 °C for 2 h. The ethanolic solution was con-
prepared as previously described.
Melting points were taken on a Yanagimoto melting point apparatus. All centrated in vacuo, then the residue was poured into ethyl acetate (50 ml),
melting points are uncorrected. IR spectra were measured on a Hitachi and the resultant mixture was filtered to remove insoluble materials. The fil-
model 270-30 IR spectrophotometer with attenuated total reflectance. NMR trate was washed with 3% HCl and water, then the ethyl acetate layer was
spectra were measured on a Bruker DPX-400 spectrometer (400 MHz) using dried over anhydrous Na SO . After removal of the solvent in vacuo, the re-
2
4
tetramethylsilane as an internal reference, and chemical shifts were recorded sulting oily residue was chromatographed on a silica gel column (250 g,
as delta-values.
70—230 mesh) with ethyl acetate/tolueneϭ3/7 to give the crude product
-(Chloroacetylamino)propanedioic Acid Diethyl Ester (15a) (16a, 24 g, 72%), which was purified by recrystallization from a mixture of
Method A: The preparation of 15a was carried out according to the method ether and pet. ether; colorless needles, mp 52—53 °C. IR (KBr): 3232
2
16)
Ϫ1
1
of Sheehan and Bose. To a mixture of diethyl aminomalonate hydrochlo- (N–H), 1743 (ester CO), 1659 (amide CO) cm
. H-NMR (DMSO-d6):
ride (14) (30 g, 140 mmol) and chloroacetyl chloride (11 g, 100 mmol) sus- 1.17 (overlapping 3H, each t, Jϭ7.0 Hz, CH ϫ2), 3.54 (2H, s, furan-CH ),
3
2
pended in 1,2-dichloroethane (300 ml) at 0—5 °C was added slowly a solu- 4.16—4.22 (two 2H, each m, CH CH ϫ2), 4.26 (2H, s, CH Cl), 6.14, 6.35
2
3
2
tion of triethylamine (30 g, 300 mmol) in 1,2-dichloroethane (100 ml). After and 7.51 (each 1H, each m, furan-3H, 4H and 5H), 8.60 (1H, s, NH). Anal.
the addition was complete, the mixture was brought rapidly to the boiling Calcd for C H ClNO : C, 50.67; H, 5.42; N, 4.22. Found: C, 50.49.06; H,
1
4
18
6
point and then allowed to stand overnight. Triethylamine hydrochloride was 5.23; N, 4.15.
removed by filtration, then the filtrate was washed with 2% hydrochloric
2-(Fluoroacetylamino)-2-(2-furylmethyl)propanedioic Acid Diethyl
acid and water. It was dried with sodium sulfate, the solvent was removed in Ester (16b) This compound (16b) was prepared as described above from
vacuo, and the resultant residue was recrystallized from cyclohexane to give the reaction of the crude 2-(bromomethyl)furan (9) [prepared from 2-furyl-
1
6)
Ϫ1
2
3
(
2 g (90%) of 15a, mp 94—96 °C (lit. 97.5—98.5 °C) IR (KBr) cm
:
methanol (13) (4.9 g, 50 mmol)] with 2-(fluoroacetylamino)propanedioic
316 (N–H), 1762 and 1740 (ester CO), 1656 (amido CO). H-NMR acid diethyl ester (15b) (9 g, 38 mmol) in 85% yield, bp 225—230/5 mmHg.
1
Ϫ1
1
DMSO-d ): 1.20 (overlapping two 3H, each t, Jϭ7.1 Hz, CH ϫ2), 4.13— IR (neat): 3430 (N–H), 1746 (ester CO), 1695 (amide CO) cm . H-NMR
6
3
4
.26 (overlapping two 2H, each m, CH CH ϫ2), 4.22 (2H, s, CH Cl), 5.09 (DMSO-d ): 1.18 (overlapping two 3H, each t, Jϭ7.0 Hz, CH ϫ2), 3.56
2 3 2
6 3
(
1H, d, Jϭ7.1 Hz, CH), 9.11 (1H, d, Jϭ7.1 Hz, NH). Anal. Calcd for (2H, s, furan-CH ), 4.17—4.23 (two 2H, each m, CH CH ϫ2), 4.93 (2H, d,
2
2
3
C H ClNO : C, 42.95; H, 5.59; N, 5.52. Found: C, 42.97; H, 5.57; N, 5.57.
Jϭ46.8 Hz, CH F), 6.14, 6.34 and 7.52 (each 1H, each m, furan-3H, 4H and
2
9
14
5
Method B: This compound (15a) was also synthesized in 58% yield from 5H), 8.11 (1H, s, NH). Anal. Calcd for C H FNO : C, 53.30; H, 5.71; N,
1
4
18
6
the reaction of 14 with chloroacetic acid using ODI by the following proce- 4.44. Found: C, 53.40; H, 5.82; N, 4.44.
dure for 15b. The mixture melting point with the compound prepared by the
method A was undepressed. The IR spectrum and the NMR spectrum were The preparation of 17a was carried out according to the method of Watanabe
2-(Chloroacetylamino)-2-(2-furylmethyl)propanedioic Acid (17a)
1
5)
identical with those of the compound prepared by the method A.
-(Fluoroacetylamino)propanedioic Acid Diethyl Ester (15b) A solu- tion (100 ml) was stirred at room temperature for 24 h. Unchanged 16a was
et al. A mixture of 16a (20 g, 60 mmol) with 10% sodium hydroxide solu-
2
tion of oxalyl chloride (2.5 g, 20 mmol) in acetonitrile (5 ml) was added removed by extraction with ethyl acetate, and the resulting solution was
dropwise to an ice-cold, stirred solution of imidazole (5.5 g, 80 mmol) in acidified with 10% HCl, and then extracted with ether. Drying and evapora-
acetonitrile (50 ml). The mixture was stirred at room temperature for 15 min, tion of the solvent left the crude product, 17a, which was recrystallized from
and then a mixture of sodium fluoroacetate (2 g, 20 mmol) and methanesul- a mixture of ether and pet. ether to afford 12.7 g (76%) of 17a, mp 135—
Ϫ1
1
fonic acid (3.4 g, 20 mmol) in acetonitrile (10 ml) was added rapidly in a sin- 138 °C. IR (KBr): 3376 (N–H), 1743 (acid CO), 1632 (amide CO) cm . H-
gle portion. The mixture was stirred at 45 °C for 40 min, and then diethyl NMR (DMSO-d ): 3.53 (2H, s, furan-CH ), 4.25 (2H, s, CH Cl), 6.08, 6.33
6
2
2

August 2003
997
and 7.49 (each 1H, each m, furan-3H, 4H and 5H), 8.21 (1H, s, NH). Anal. methyl ester hydrochloride (20) (4.1 g, 20 mmol) in 95% yield, mp 63—
Calcd for C H ClNO : C, 43.6; H, 3.62; N, 5.08. Found: C, 43.57; H, 3.89; 65 °C (ether/AcoEt). IR (KBr): 3262 (N–H), 1734 (acid CO), 1644 (amide
10
10
6
Ϫ1
1
N, 5.13.
CO) cm . H-NMR (DMSO-d ): 1.81 (3H, s, –COCH ), 2.74 (1H, dd,
6
3
2
-(Fluoroacetylamino)-2-(2-furylmethyl)propanedioic Acid (17b) Jϭ7.6, 15.5 Hz, one proton of CH ), 2.82 (1H, dd, Jϭ7.2, 15.5 Hz, one pro-
2
This compound 17b was prepared according to the method described for ton of CH ), 3.57 (3H, s, COOCH ), 5.30 (1H, m, CH), 6.23, 6.37 and 7.56
2
3
1
7a. The hydrolysis of 16b (18 g, 60 mmol) with 10% sodium hydroxide so-
(each 1H, each m, furan-3H, 4H and 5H), 8.33 (1H, d, Jϭ8.4 Hz, NH). Anal.
lution (100 ml) was carried out to give 13 g (98%) of crude product (17b), Calcd for C H NO : C, 56.87; H, 6.20; N, 6.63. Found: C, 56.61; H, 6.15;
1
0
13
4
which was recrystallized from a mixture of ether and pet. ether to afford N, 6.62.
1
7b, mp 147—150 °C. IR (KBr): 3418 (N–H), 1740 (acid CO), 1647 (amide
3-(Chloroacetylamino)-3-(2-furyl)propanoic Acid (7a) A 4% NaOH
Ϫ1
1
CO) cm
.
H-NMR (DMSO-d ): 3.56 (2H, s, furan-CH ), 4.91 (2H, d, solution (15 ml) was added to an ice-cold, stirred solution of 3-(chloroacetyl-
6
2
Jϭ46.8 Hz, CH F), 6.09, 6.34 and 7.50 (each 1H, each m, furan-3H, 4H and
amino)-3-(2-furyl)propanoic acid methyl ester (21a) (2.5 g, 10 mmol) in
MeOH (50 ml). The mixture was stirred at room temperature for 4 h, then
the solvent was removed in vacuo, and the resultant residue was poured into
2
5
H), 7.75 (1H, s, NH). Anal. Calcd for C H FNO : C, 46.3; H, 3.86; N,
10 10 6
5
.40. Found: C, 46.13; H, 3.86; N, 5.24.
2
-(Chloroacetylamino)-3-(2-furyl)propanoic Acid (6a) Compound ice-water. The cooled alkaline solution was washed with ether (20 ml), acidi-
1
7a (4.5 g, 16 mmol) was refluxed in ethanol (450 ml) for 3 h. The solvent fied with 5% HCl, and then extracted with ethyl acetate. The ethyl acetate
was removed in vacuo, and the resultant residue was recrystallized from a extract was washed with water, dried over Na SO and evaporated to afford a
2
4
mixture of ether and pet. ether to give 3.4 g (93%) of 6a, mp 88—90 °C. IR
crude product (7a), which was recrystallized from ethyl acetate to give 2.2 g
Ϫ1
1
(
KBr): 3364 (N–H), 1731 (acid CO), 1617 (amide CO) cm
.
H-NMR of 7a in 95% yield, mp 120—122 °C. IR (KBr): 3328 (N–H), 1716 (acid
Ϫ1
1
(
DMSO-d ): 3.01 (1H, dd, Jϭ8.3, 15.4 Hz, one proton of furan-CH ) 3.11 CO), 1650 (amide CO) cm . H-NMR (DMSO-d ): 2.72 (1H, dd, Jϭ7.3,
6
2
6
(
1H, dd, Jϭ5.0, 15.4 Hz, one proton of furan-CH ), 4.09 (2H, s, CH Cl), 16 Hz, one proton of CH ), 2.80 (1H, dd, Jϭ7.1, 16 Hz, one proton of CH ),
2 2 2 2
4
5
4
.49 (1H, m, CH), 6.15, 6.35 and 7.52 (each 1H, each m, furan-3H, 4H and
4.04 (1H, d, Jϭ13 Hz, one proton of CH Cl), 4.08 (1H, d, Jϭ13 Hz, one pro-
2
H), 8.51 (1H, d, Jϭ7.8 Hz, NH). Anal. Calcd for C H ClNO : C, 46.6; H, ton of CH Cl), 5.28 (1H, m, CH), 6.26, 6.39 and 7.58 (each 1H, each m,
9
10
4
2
.31; N, 6.04. Found: C, 46.32; H, 4.48; N, 5.83.
furan-3H, 4H and 5H), 8.68 (1H, d, Jϭ8.4 Hz, NH), 12.4 (1H, br s,
2
-(Fluoroacetylamino)-3-(2-furyl)propanoic Acid (6b) The decar- –COOH). Anal. Calcd for C H ClNO : C, 46.67; H, 4.35; N, 6.05.
9 10 4
boxylation of 17b (9.7 g, 40 mmol) in ethanol (1125 ml) was carried out ac-
3-(Fluoroacetylamino)-3-(2-furyl)propanoic Acid (7b) This com-
cording to the method described for 17b to give 7.3 g (91%) of 6b, which pound (7b) was prepared according to the method described above for 3-
was recrystallized from a mixture of ether and pet. ether to afford 6b, mp (chloroacetylamino)-3-(2-furyl)propanoic acid (7a) through the hydrolysis
Ϫ1
8
2—84 °C. IR (KBr): 3376 (N–H), 1734 (acid CO), 1632 (amide CO) cm
.
of 3-(fluoroacetylamino)-3-(2-furyl)propanoic acid methyl ester (21b)
1
H-NMR (DMSO-d ): 3.07 (1H, dd, Jϭ8.8, 15.4 Hz, one proton of furan- (2.3 g, 10 mmol) with 4% NaOH (15 ml) in 91% yield, mp 178—180 °C
6
CH ), 3.14 (1H, dd, Jϭ5.0, 15.4 Hz, one proton of furan-CH ) 4.55 (1H, m,
(AcOEt/EtOH). IR (KBr): 3304 (N–H), 1707 (acid CO), 1662 (amide CO)
2
2
Ϫ1
1
CH), 4.81 (2H, d, Jϭ46.9 Hz, CH F), 6.14, 6.34 and 7.52 (each 1H, each m,
cm
. H-NMR (DMSO-d ): 2.77 (1H, dd, Jϭ7.5, 16 Hz, one proton of
2
6
furan-3H, 4H and 5H), 8.36 (1H, d, Jϭ8.1 Hz, NH). Anal. Calcd for CH ), 2.84 (1H, dd, Jϭ6.9, 16 Hz, one proton of CH ), 4.81 (2H, d,
2
2
C H FNO : C, 50.23; H, 4.65; N, 6.51. Found: C, 50.46; H, 4.74; N, 6.47.
Jϭ47.0 Hz, CH F), 5.33 (1H, m, CH), 6.24, 6.38 and 7.56 (each 1H, each m,
2
9
10
4
3
-Amino-3-(2-furyl)propanoic Acid Methyl Ester Hydrochloride (20) furan-3H, 4H and 5H), 8.61 (1H, d, Jϭ8.6 Hz, NH), 12.4 (1H, br s,
Thionyl chloride (10.7 g, 90 mmol) was added dropwise to MeOH (30 ml) at –COOH). Anal. Calcd for C H FNO : C, 50.24; H, 4.68; N, 6.51. Found: C,
9
10
4
Ϫ10 °C. The reaction mixture was stirred at Ϫ10 °C for 10 min, then 3- 50.07; H, 4.65; N, 6.27.
amino-3-(2-furyl)propanoic acid (23, 4.6 g, 30 mmol) was added rapidly in a 3-Acetylamino-3-(2-furyl)propanoic Acid (7c) This compound (7c)
single portion. The mixture was stirred at room temperature for 15 h. The was prepared according to the method described above for 3-(chloroacetyl-
solvent was removed in vacuo, and the resultant mixture was recrystallized amino)-3-(2-furyl)propanoic acid (7a) through the hydrolysis of 3-(acetyl-
from MeOH to give 5.8 g of the corresponding methyl ester hydrochloride amino)-3-(2-furyl)propanoic acid methyl ester (21c) (2.1 g, 10 mmol) with
Ϫ1
1
(
20) in 92% yield, mp 145—148 °C. IR (KBr) cm : 1728 (ester CO). H- 4% NaOH (15 ml) in 96% yield, 178—179 °C (AcOEt/EtOH). IR (KBr):
Ϫ1
1
NMR (DMSO-d ): 3.07 (1H, dd, Jϭ8.9, 16 Hz, one proton of CH ), 3.19 3346 (N–H), 1734 (acid CO), 1614 (amide CO) cm . H-NMR (DMSO-
6
2
(
1H, dd, Jϭ5.5, 16 Hz, one proton of CH ) 3.60 (3H, s, CH ), 4.69 (1H, dd, d ): 1.81 (3H, t, Jϭ7.3 Hz, CH ), 2.64 (1H, dd, Jϭ7.3, 12 Hz, one proton of
2
3
6
3
Jϭ5.5, 8.9 Hz, CH), 6.48, 6.58 and 7.71 (each 1H, each m, furan-4H, 3H CH ), 2.73 (1H, dd, Jϭ7.3, 12 Hz, one proton of CH ), 5.27 (1H, m, CH),
2
2
ϩ
3
and 5H), 8.88 (3H, br s, NH ). Anal. Calcd for C H ClNO : C, 46.73; H,
6.22, 6.37 and 7.56 (each 1H, each m, furan-3H, 4H and 5H), 8.29 (1H, d,
8
12
3
5
.88; N, 6.81. Found: C, 46.69; H, 5.81; N, 6.64.
Jϭ8.5 Hz, NH), 12.3 (1H, br s, –COOH). Anal. Calcd for C H NO : C,
9
11
4
3
-(Chloroacetylamino)-3-(2-furyl)propanoic Acid Methyl Ester (21a) 54.82; H, 5.58; N, 7.10. Found: C, 54.84; H, 5.54; N, 7.05.
This compound (21a) was prepared according to the method described
above for 2-(chloroacetylamino)propanedioic acid diethyl ester (15a) References and Notes
through the reaction of chloroacetyl chloride (3 g, 27 mmol) with 3-amino-3-
2-furyl)propanoic acid methyl ester hydrochloride (20) (6.2 g, 30 mmol) in
3% yield, mp 82—83 °C (toluene/AcOEt). IR (KBr): 3460 (N–H), 1728
1) Honda H., Akatsuka T., Sato K., Konami M., “Shin Noyaku Gairon,”
Asakura Shoten, Tokyo, 1996, pp. 137—139.
2) Wilcut J.: ͗http://courses.cropsci.ncsu.edu/cs414/CH_7.htm͘, PSJ Web,
16 February 2003.
(
3
Ϫ1
1
(
ester CO), 1650 (amide CO) cm . H-NMR (DMSO-d ): 2.81 (1H, dd,
6
Jϭ7.6, 12 Hz, one proton of CH ), 2.89 (1H, dd, Jϭ7.0, 12 Hz, one proton
3) Schneider H., Ger.(East) DD236091 (28 May, 1986) [Chem. Abstr.,
106, 67095k (1987)].
2
of CH ), 3.58 (3H, s, OCH ), 4.05 (1H, d, Jϭ14 Hz, one proton of CH Cl),
2
3
2
4
.08 (1H, d, Jϭ14 Hz, one proton of CH Cl), 5.31 (1H, m, CH), 6.28, 6.39
4) Schneider H., Braz. Pedido PI BR 85 04,060 (31 May, 1987) [Chem.
Abstr., 108, 21708a (1988)].
5) Sandoz A.-G., Israeli IL 75967 (28 Sep, 1989) [Chem. Abstr., 113,
115073v (1990)].
2
and 7.59 (each 1H, each m, furan-3H, 4H and 5H), 8.70 (1H, d, Jϭ8.3 Hz,
NH). Anal. Calcd for C H ClNO : C, 48.89; H, 4.92; N, 5.70.
10
12
4
3
-(Fluoroacetylamino)-3-(2-furyl)propanoic Acid Methyl Ester (21b)
This compound (21b) was prepared according to the method described
above for 2-(fluoroacetylamino)propanedioic acid diethyl ester (15b)
through the reaction of sodium fluoroacetate (2 g, 20 mmol) with 3-amino-3-
6) Miller P., Westra P., Production, “Herbicide Selectivity and Perfor-
mance,” ͗http://www.ext.colostate.edu/pubs/crops/00563.pdf͘.
7) Martin J. R., “Cold Wet Soils and Injury from Chloroacetamide Herbi-
cides,” ͗http://www.uky.edu/Agriculture/kpn/kpn_99/pn990419.htm͘,
PSJ Web, 16 February 2003.
8) Ogasawara M., Konnai M., Takematsu T., Kato S., Ishizaki M., Zasso
Kenkyu, 34, 131—137 (1989) [Chem. Abstr., 112, 93795g (1990)].
9) Okamoto H., Kato S., Bull. Chem. Soc. Jpn., 64, 2128—2130 (1991).
(
8
(
2-furyl)propanoic acid methyl ester hydrochloride (20) (4 g, 20 mmol) in
1% yield, mp 70—72 °C IR (KBr): 3484 (N–H), 1743 (acid CO), 1659
Ϫ1
1
amide CO) cm . H-NMR (DMSO-d ): 2.87 (1H, dd, Jϭ8.0, 16 Hz, one
6
proton of CH ), 2.93 (1H, dd, Jϭ7.0, 16 Hz, one proton of CH ), 3.59 (3H, s,
2
2
OCH ), 4.81 (2H, d, Jϭ46.9 Hz, CH F), 5.40 (1H, m, CH), 6.25, 6.38 and
3
2
7
.56 (each 1H, each m, furan-3H, 4H and 5H), 8.62 (1H, d, Jϭ8.6 Hz, NH). 10) Kawahara S., Kato S., Jpn. Kokai Tokkyo Koho JP 61148183, [Chem.
Anal. Calcd for C H FNO : C, 52.40; H, 5.28; N, 6.11. Found: C, 52.70;
Abstr., 106, 18339j (1987)].
10
12
4
H, 5.23; N, 5.95.
-(Acetylamino)-3-(2-furyl)propanoic Acid Methyl Ester (21c) This
compound (21c) was prepared according to the method described above for
-(fluoroacetylamino)propanedioic diethyl ester (15b) through the reaction
of acetic acid (1.2 g, 20 mmol) with 3-amino-3-(2-furyl)propanoic acid
11) Ogasawara M., Konnai M., Takematsu T., Kato S., Ishizaki M., Zasso
Kenkyu, 34, 138—145 (1989) [Chem. Abstr., 112, 72184s (1990)].
12) Kato S., Suyama T., Takematsu T., J. Synth. Org. Chem. Jpn. (Yuki
Gosei Kagaku Kyokaishi), 56, 221—227 (1998) [Chem. Abstr., 128,
214349f (1998)].
3
2

9
1
1
1
98
Vol. 51, No. 8
3) Tamari K., J. Agr. Chem. Soc. Jpn. (Nippon Nogeikagaku Kaishi), 17, 21) Kretzchmar G., Hoppe H.-U., Ezanville F. R., Wicke H., Schlingmann
3
21—335 (1941) [Chem. Abstr., 41, 4545i (1947)].
M., Keller R., Sachse B., Ger. Offen., DE 38 20 302 (21 Dec., 1989)
[Chem. Abstr., 113, 23677s (1990)].
4) Each of the prepared 2- or 3-substituted 3-(2-furyl)propanoic acids (6
or 7) was used as a racemate in this study.
5) Watanabe H., Kuwata S., Nakajima S., Koshida K., Hayashi M., Bull.
Chem. Soc. Jpn., 38, 1461—1464 (1965).
22) Inamori Y., Muro C., Osaka K., Funakoshi Y., Usami Y., Tsujibo H.,
Numata A., Biosci. Biotech. Biochem., 58, 1150—1152 (1994).
23) Fluoroacetic acid, including its sodium salt, requires careful handling
according to the regulations for the control of toxic substances, and the
International Chemical Safety Card (ICSC) notes that it is harmful to
the environment, especially to mammalians; the International Pro-
gramme on Chemical Safety (IPCS), ͗http://www.ilo.org/public/eng-
lish/protection/safework/cis/products/icsc/index.htm͘.
1
1
6) Sheehan J. C., Bose A. K., J. Am. Chem. Soc., 73, 1761—1765 (1951).
7) Kitagawa T., Akiyama N., Masai K., Chem. Pharm. Bull., 49, 335—
3
39 (2001), see ref. 26.
8) Kitagawa T., Akiyama N., Chem. Pharm. Bull., 45, 1865—1866
1997).
9) Bladon C. M., J. Chem. Soc. Perkin Trans. 1, 1990, 1151—1158
1990).
1
1
2
(
24) In Japanese, ͗http://www.nihs.go.jp/ICSC/͘, PSJ Web, 16 February
2003.
(
0) Rao P. N., Burdett J. E., Cessac J. W., Dinunno C. M., Peterson D. M., 25) Baker B. R., Mcevoy F. J., Schaub R. E., Joseph J. P., Williams J. H., J.
Kim H. K., Int. J. Peptide Protein Res., 29, 118—125 (1987). Org. Chem., 18, 153—177 (1953).