Preparation of achiral and chiral (E)-enaminopyran-2,4-diones and their phytotoxic activity

Article abstract of DOI:10.1021/jf802805f

A short and efficient approach to a range of new chiral and achiral functionalized (E)-enaminopyran-2,4-diones starting with commercially available dehydroacetic acid is described. The phytotoxic properties of these (E)-enaminopyran-2,4-diones were evalua

Full text of DOI:10.1021/jf802805f

J. Agric. Food Chem. 2009, 57, 1399–1405 1399
Preparation of Achiral and Chiral
(E)-Enaminopyran-2,4-diones and Their Phytotoxic
Activity
†
,‡
‡
ˆ
ˆ
LUIZ C. DIAS, ANTONIO J. DEMUNER,* VANIA M. M. VALENTE,
‡
§
|
ˆ
LUIZ C. A. BARBOSA, FELIPE T. MARTINS, ANTONIO C. DORIGUETTO, AND
§
JAVIER ELLENA
Institute of Chemistry, University of Campinas, UNICAMP, P.O. Box 6154, 13084-971, Campinas,
SP, Brazil, Department of Chemistry, Federal University of Vic¸osa, Av. P.H. Rolfs, s/n, 36570-000,
Vic¸osa, MG, Brazil, Physics Institute of Sa˜o Carlos, University of Sa˜o Paulo, C.P. 369, 13560-970,
Sa˜o Carlos, SP, Brazil, and Department of Exact Science, Federal University of Alfenas, 37130-000,
Alfenas, MG, Brazil
A short and efficient approach to a range of new chiral and achiral functionalized (E)-enaminopyran-
2,4-diones starting with commercially available dehydroacetic acid is described. The phytotoxic
properties of these (E)-enaminopyran-2,4-diones were evaluated by their ability to interfere with the
growth of Sorghum bicolor and Cucumis sativus seedlings. A different sensitivity of the two crops
was evident with the (E)-enaminopyran-2,4-diones. The most active compounds were also tested
against two weeds, Ipomoea grandifolia and Brachiaria decumbens. To the best of our knowledge,
this is the first report describing enaminopyran-2,4-diones as potential plant growth regulators.
KEYWORDS: Pyran-2,4-diones; dehydroacetic acid; phytotoxic; herbicides; weeds
INTRODUCTION
Biologically active natural products are incredibly diverse in
terms of structural formulas. Among such compounds, many
presenting the pyran-2,4-dione ring as a structural unit have
pharmacological (5, 6) or phytotoxic activities (7). Several
approaches have been described for the synthesis of function-
alized pyran-2,4-diones (8-10), resulting in production of a
wide variety of nitrogen-containing heterocycles with important
pharmacological activities (11). In addition, several enaminones
have been prepared for pharmacological uses (12-15). Deriva-
tives of dehydroacetic acid 1 are very important due to the wide
spectrum of their chemical properties and biological activities
(16-20). Dehydroacetic acid is known to react with amines,
yielding the corresponding enamino derivatives at the acetyl
carbonyl group (20-25).
As part of our continuous efforts to develop new compounds
with potential use as herbicides (26-31), we decided to
investigate the potential phytotoxicity of new pyran-2,4-dione
derivatives. In this context, we describe in this paper the
synthesis of a series of chiral and achiral functionalized (E)-
enaminopyran-2,4-diones, some of them synthesized for the first
time, starting with commercially available dehydroacetic acid
(32), and their inhibitory potential against either crops (Sorghum
bicolor and Cucumis satiVus) or weeds (Brachiaria decumbens
and Ipomoea grandifolia).
In modern agriculture, organic synthetic pesticides are largely
used to reduce crop loss, as they are cost-effective and generally
increase productivity. Concerns related to environmental prob-
lems and human health associated with the use of hazardous
chemicals have stimulated agrochemical companies to search
for ecofriendly alternatives (1). One of the major problems
associated with crop production is the decrease in productivity
due to the presence of weeds. Since the 1940s, the use of organic
herbicides has become the most reliable and least expensive
tool for weed control throughout the world. During recent
decades, important advances have been achieved in the chemical
control of weeds, but the identification of novel herbicides is
still highly desirable, especially to overcome weed resistance,
rapidly raised as a result of severe selective pressure imposed
by continuous application of products with the same mechanism
of action (2). In this context, the development of herbicides with
new modes of action is a constant challenge. Among several
strategies used by chemical companies to search for compounds
with new modes of action is the use of phytotoxic natural
products as herbicides or to lead to the discovery of new
herbicides (3, 4).
* Author to whom correspondence should be addressed. Telephone:
(55) 031 3899 3070. Fax: (55) 31 3899 3065. E-mail: ademuner@ufv.br.
† State University of Campinas.
MATERIALS AND METHODS
‡ Federal University of Vic¸osa.
§ University of Sa˜o Paulo.
General Experimental Procedures. Ethyl acetate, hexane, 1,4-
dioxane, and amines were purified as described by Armarego and Chai
| Federal University of Alfenas.
10.1021/jf802805f CCC: $40.75  2009 American Chemical Society
Published on Web 01/26/2009

1400 J. Agric. Food Chem., Vol. 57, No. 4, 2009
Dias et al.
(33). The 1H and 13C NMR spectra were recorded on a Brucker
AVANCE DPX 250 spectrometer at 250 and 62.5 MHz using CDCl3
or DMSO-d6 as solvent and TMS as internal standard. Mass spectra
were recorded using high-resolution hybrid quadrupole (Q) and
orthogonal time-of-flight (TOF) instruments. Infrared spectra were
recorded on a Perkin-Elmer Paragon 1000 FTIR spectrophotometer,
with the samples prepared as a thin film on a NaCl plate, scanning
from 635 to 4000 cm-1. Optical rotation (R) was obtained using cubets
of 1 cm at 20 °C. Analytical thin layer chromatography analyses were
conducted on aluminum-packed precoated silica gel plates. Flash
chromatography was performed over silica gel (0.035-0.070 mm).
General Procedure for the Synthesis of (E)-Enaminopyran-2,4-
dione Derivatives (2a-k, 3a-b, and 4a-c). These compounds were
prepared by stirring a mixture of 1 (84 mg, 0.5 mmol), alkylamine or
arylamine or amino acid methyl ester hydrochloride (0.6 mmol),
triethylamine (2 mL), and 1,4-dioxane (8 mL) under reflux for 16 h.
The solvent was removed under reduced pressure, and the products
were purified by silica gel flash column chromatography, eluting with
a mixture of hexane and ethyl acetate.
Table 1. Crystal Data and Structure Refinement for Compound 2c
empirical formula
formula weight
temperature (K)
wavelength (Å)
crystal system
space group
C11H15NO3
209.24
150(2)
0.71073
monoclinic
P21/c
unit cell dimensions
a ) 4.6727(2) Å
b ) 20.8465(8) Å
c ) 10.8060(4) Å
ꢀ ) 94.325(2)°
1049.61(7)
4
volume (Å3)
Z
density (calc) (Mg/m3)
absorption coefficient (mm-1
F (000)
1.324
0.096
)
448
0.22 × 0.11 × 0.05
crystal size (mm3)
θ-range for data collection (deg)
index ranges
3.8-27.4
-5 e h e 5, -26 e k e 26,
-13 e l′ e 13
4497
(E)-3-(1-(benzylamino)ethylidene)-6-methyl-3H-pyran-2,4-dione (2a).
Yellow solid; yield, 87%; mp 79-81 °C; IR (NaCl, cm-1), νjmax 3686,
3621, 3454, 3018, 1695, 1643, 1577, 1481, 1394, 1328, 1215, 1062,
1000, 930, 771, 669; 1H NMR (250 MHz, DMSO-d6) δ 2.04 (d, 3H, J
) 0.5 Hz, CH3), 2.60 (s, 3H, CH3), 4.77 (d, 2H, J ) 5.2 Hz, CH2),
reflections collected
independent reflections
completeness to θ ) 27.4°
refinement method
data/restraints/parameters
goodness-of-fit on F2
final R for I > 2σ(I)
2308 [R(int) ) 0.0351]
97.7%
full-matrix least-squares on F2
2308/0/143
1.025
R1 ) 0.0504
wR2 ) 0.1393
0.235 and -0.212
5.67 (br s, 1H, H5), 7.30-7.44 (m, 5H, Ph), 14.10 (br s, 1H, NH); 13
C
NMR (62.5 MHz, DMSO-d6) δ 18.4 (C7), 19.6 (C9), 47.6 (C10), 96.2
(C3), 107.4 (C5), 128.0 (C2′ and C6′), 128.3 (C4′), 129.4 (C3′ and
C5′), 136.5 (C1′), 162.8 (C6), 163.3 (C2), 176.2 (C4), 183.8 (C8).
(S,E)-3-(1-(sec-butylamino)ethylidene)-6-methyl-3H-pyran-2,4-di-
R for all data
largest diff peak and hole (e·Å-3
)
20
one (2b). White solid; yield, 91%; mp 51-53 °C; [R]D ) +2 (c )
(E)-3-(1-(2-Hydroxy-5-nitrophenylamino)ethylidene)-6-methyl-2H-
pyran-2,4(3H)-dione (2g). White solid; yield, 76%; mp 196-197 °C;
IR (NaCl, cm-1), νjmax 3429, 2987, 2884, 1687, 1637, 1419, 1275, 897,
850; 1H NMR (250 MHz, DMSO-d6) δ 2.10 (s, 3H, CH3), 2.45 (s, 3H,
CH3), 5.79 (s, 1H, H5), 6.87 (d, 1H, J ) 8.2 Hz, H3′), 7.00 (dd, 1H,
J ) 8.2, 1.2 Hz, H4′), 7.22 (d, 1H, J ) 1.2 Hz, H6′), 10.27 (br s, 1H,
OH), 15.33 (br s, 1H, NH); 13C NMR (62.5 MHz, DMSO-d6) δ 20.4
(C7), 20.6 (C9), 97.4 (C3), 106.0 (C6), 107.4 (C5), 116.9 (C3′), 124.3
(C4′), 139.3 (C1′), 158.7 (C2), 145.4 (C2′), 148.6 (C5′) 163.4 (6), 172.1
(C8), 176.0 (C4). HRMS (ESI TOF-MS): calcd for C14H13N2O6,
305.0774; found, 305.0770.
0.36 g/100 mL); IR (NaCl, cm-1), νjmax 3446, 3018, 2987, 1695, 1640,
1
1577, 1477, 1394, 1217, 1062, 999, 772, 669; H NMR (250 MHz,
DMSO-d6) δ 0.87 (t, 3H, J ) 7.3 Hz, CH3), 1.19 (d, 3H, J ) 6.5 Hz,
CH3), 1.58 (quint, 2H, J ) 7.3 Hz, CH2), 2.05 (s, 3H, CH3), 2.55 (s,
3H, CH3), 3.95 (sextet, 1H, J ) 6.5 Hz, CH), 5.64 (s, 1H, H5), 11.92
(br s, 1H, NH); 13C NMR (62.5 MHz, DMSO-d6) δ 12.2 (C13), 18.3
(C7), 19.6 (C9), 20.5 (C10), 29.4 (C12), 51.2 (C11), 95.7 (C5), 107.4
(C3), 162.6 (C6), 163.3 (C2), 174.4 (C4), 183.9 (C8). HRMS (ESI
TOF-MS): calcd for C12H18NO3, 224.1287; found, 224.1338.
(E)-6-Methyl-3-(1-(propylamino)ethylidene)-3H-pyran-2,4-di-
one (2c). Yellow solid; yield, 90%; mp 74-75 °C; IR (NaCl, cm-1),
νjmax 3448, 3013, 2964, 2956, 2882, 1699, 1640, 1579, 1473, 1392,
(E)-3-(1-(5-Chloro-2-hydroxy-4-nitrophenylamino)ethylidene)-6-
methyl-2H-pyran-2,4(3H)-dione (2h). Red solid; yield, 83%; mp
230-232 °C; IR (NaCl, cm-1), νjmax 3483, 3371, 3020, 1637, 1531,
1
1338, 1216, 1058, 906, 831, 771; H NMR (250 MHz, DMSO-d6) δ
0.93 (t, 3H, J ) 7.3 Hz, CH3), 1.61 (sextet, 2H, J ) 7.3 Hz, CH2),
2.05 (s, 3H, CH3), 2.53 (s, 3H, CH3), 3.46 (q, 2H, J ) 7.3 Hz, CH2),
5.67 (d, 1H, J ) 0.5 Hz, H5), 13.80 (br s, 1H, NH); 13C NMR (62.5
MHz, DMSO-d6) δ 11.5 (C12), 18.1 (C7), 19.6 (C9), 22.2 (C11), 45.5
(C10), 95.9 (C5), 107.4 (C3), 162.6 (C6), 163.4 (C2), 175.9 (C4), 183.8
(C8);. HRMS (ESI TOF-MS): calcd for C11H16NO3, 210.1130; found,
210.1192.
1
1473, 1321, 1216, 873, 771, 669; H NMR (250 MHz, DMSO-d6) δ
2.24 (d, 3H, J ) 0.8 Hz, CH3), 2.53 (s, 3H, CH3), 6.24 (br s, 1H, H5),
6.68 (s, 1H, PhH), 7.46 (s, 1H, PhH), 8.57 (br s, 1H, OH), 10.28 (br
s, 1H, NH); 13C NMR (62.5 MHz, DMSO-d6) δ 14.9 (C7), 20.6 (C9),
99.9 (C3), 101.4 (C5), 113.7 (C3′), 120.8 (C6′), 121.6 (C5′), 133.2
(C4′), 142.1 (C2′), 145.4 (C1′), 148.6 (C2) 160.9 (6), 170.6 (C8), 180.9
(C4).
(E)-6-Methyl-3-(1-(phenylamino)ethylidene)-3H-pyran-2,4-di-
one (2d). White solid; yield, 79%; mp 127-128 °C; IR (NaCl, cm-1),
νjmax 3454, 3055, 2987, 1714, 1699, 1574, 1471, 1392, 1362, 1267,
Methyl 2(E)-(1-(6-Methyl-2,4-dioxopyridin-(2H)-pyran-3(4H)-ylide-
ne)ethylamino)acetate (2i). White solid; yield, 86%; mp 145-146 °C;
IR (NaCl, cm-1), νjmax 3454, 3018, 1720, 1699, 1642, 1581, 1475, 1394,
1
1190, 1161, 1064, 999, 952, 839, 742; H NMR (250 MHz, DMSO-
1
1363, 1218, 1064, 1000, 929, 771, 669; H NMR (250 MHz, DMSO-
d6) δ 2.11 (d, 3H, J ) 0.8 Hz, CH3), 2.49 (s, 3H, CH3), 5.82 (q, 1H,
J ) 0.8 Hz, H5), 7.30-7.56 (m, 5H, Ph), 15.66 (br s, 1H, NH); 13C
NMR (62.5 MHz, DMSO-d6) δ 19.9 (C7), 20.4 (C9), 97.3 (C5), 107.2
(C3), 125.6 (C3′ and C5′), 128.3 (C4′), 129.6 (C2′ and C6′), 136.4
(C1′), 163.5 (C6), 163.8 (C2), 175.4 (C4), 184.6 (C8).
(E)-3-(1-(2-Hydroxyphenylamino)ethylidene)-6-methyl-2H-pyran-2,4-
dione (2f). Yellow solid; yield, 74%; mp 171-172 °C; IR (NaCl, cm-1),
νjmax 3478, 3055, 2988, 1685, 1655, 1574, 1473, 1364, 1267, 1066,
1001, 897, 748; 1H NMR (250 MHz, DMSO-d6) δ 2.10 (br s, 3H,
CH3), 2.45 (s, 3H, CH3), 5.67 (s, 1H, H5), 6.88 (dt, 1H, J ) 7.7, 1.2
Hz, H3′), 7.01 (dd, 1H, J ) 8.2, 1.2 Hz, H6′), 7.22 (dt, 2H, J ) 8.2,
7.7, 1.2 Hz, H4′ and H5′), 10.27 (br s, 1H, OH), 15.36 (br s, 1H, NH);
13C NMR (62.5 MHz, DMSO-d6) δ 19.7 (C7), 20.3 (C9), 96.9 (C5),
108.1 (C3), 116.9 (C4′), 119.8 (C5′), 123.7 (C6′), 127.2 (C3′), 129.7
(C1′), 151.9 (C2′), 163.5 (C6) 168.5 (C2), 175.7 (C4), 183.0 (C8).
HRMS (ESI TOF-MS): calcd for C14H14NO4, 260.0923; found,
260.1182.
d6) δ 2.06 (d, 3H, J ) 0.5 Hz, CH3), 2.51 (s, 3H, CH3), 3.72 (s, 3H,
OCH3), 4.54 (d, 2H, J ) 5.0 Hz, CH2), 5.72 (d, 1H, J ) 0.5 Hz, H5),
14.02 (br s, 1H, NH); 13C NMR (62.5 MHz, DMSO-d6) δ 18.7 (C7),
19.6 (C9), 45.7 (C1′), 52.9 (OCH3), 96.4 (C5), 107.2 (C3), 162.4 (C6),
169.1 (C2 and C2′), 175.6 (C4), 183.2 (C8). HRMS (ESI TOF-MS):
calcd for C11H14NO5, 240.0872; found, 240.0870.
(E)-3-(1-(4-Methoxyphenylamino)ethylidene)-6-methyl-3H-pyran-2,4-
dione (2j). Yellow solid; yield, 66%; mp 180-182 °C; IR (NaCl, cm-1),
νjmax 3055, 2987, 2941, 2887, 1699, 1645, 1627, 1573, 1530, 1475,
1321, 1265, 1031, 999, 897, 840, 746; 1H NMR (250 MHz, CDCl3) δ
2.14 (s, 3H, CH3), 2.56 (s, 3H, CH3), 3.81 (s, 3H, OCH3), 5.74 (s, 1H,
H5), 6.93 (d, 2H, J ) 8.8 Hz, H2′ and H6′), 7.08 (d, 2H, J ) 8.8 Hz,
H3′ and H5′), 15.44 (br s, 1H, NH); 13C NMR (62.5 MHz, CDCl3) δ
20.0 (C7), 20.5 (C9), 55.6 (OCH3), 97.1 (C3), 107.0 (C5), 114.8 (C3′
and C5′), 126.7 (C2′ and C6′), 128.8 (C1′), 159.3 (C4′), 163.7 (C6),
163.9 (C2), 175.6 (C4), 184.3 (C8).

(E)-Enaminopyran-2,4-diones as Plant Growth Regulators
J. Agric. Food Chem., Vol. 57, No. 4, 2009 1401
1
1039, 897, 748; H NMR (250 MHz, DMSO-d6) δ 2.24 (d, 3H, J )
Scheme 1. Preparation of (E)-Enaminopyran-2,4-diones 2a-k and 3a,b
0.8 Hz, CH3), 2.45 (s, 1H, NH), 2.54 (s, 3H, CH3), 6.27 (br s, 1H,
H5), 8.18 (dd, 1H, J ) 9.0, 0.3 Hz, H6′), 8.72 (dd, 1H, J ) 9.0, 2.5
Hz, H5′), 8.88 (dd, 1H, J ) 2.5, 0.3 Hz, H3′); 13C NMR (62.5 MHz,
DMSO-d6) δ 14.7 (C9), 20.6 (C7), 99.9 (C3), 101.5 (C5), 105.8 (C6′),
122.0 (C3′), 132.9 (C5′), 146.8 (C2′), 147.8 (C4′), 151.5 (C1′), 154.7
(C6), 161.0 (C2), 170.7 (C8), 180.9 (C4). HRMS (ESI TOF-MS): calcd
for C14H13N4O7, 349.0784; found, 349.0781.
(S,E)-Methyl-3-methyl-2-(1-(6-methyl-2,4-dioxo-2H-pyran-3(4H)-
ylidene)ethylamino)propanoate (4a). White solid; yield, 78%; mp
121-122 °C; [R]D20 ) -7 (c ) 0.29 g/100 mL); IR (NaCl, cm-1) νjmax
3456, 3057, 2986, 2957, 1725, 1699, 1670, 1583, 1477, 1361, 1251,
1
1223, 1151, 1059, 1000, 895, 737; H NMR (250 MHz, DMSO-d6) δ
1.47 (d, 3H, J ) 7.3 Hz, CH3), 2.06 (d, 3H, J ) 0.8 Hz, CH3), 2.52 (s,
CH3), 3.72 (s, 3H, OCH3), 4.88 (quintet, 1H, J ) 7.3 Hz, CH), 5.71
(br s, 1H, H5), 14.23 (br s, 1H, NH); 13C NMR (62.5 MHz, DMSO-
d6) δ 18.6 (C7), 18.8 (C9), 19.6 (C12), 52.2 (C11), 53.3 (OCH3), 96.4
(C5), 107.4 (C3), 163.0 (C2 and C6), 171.5 (C10), 175.9 (C4), 184.0
(C8). HRMS (ESI TOF-MS): calcd for C12H16NO5, 254.1028; found,
254.1186.
(S,E)-Methyl-2-(1-(6-methyl-2,4-dioxo-2H-pyran-3(4H)-ylidene)ethyl-
amino)-3-phenylpropanoate (4b). White solid; yield, 97%; mp 91-92
°C; [R]D20 ) -202 (c ) 0.21 g/100 mL); IR (NaCl, cm-1), νjmax 3454,
3055, 2988, 2956, 1730, 1701, 1670, 1578, 1477, 1362, 1265, 1065,
999, 896, 746; 1H NMR (250 MHz, DMSO-d6) δ 2.05 (d, 3H, J ) 0.5
Hz, CH3), 2.34 (s, 3H, CH3), 3.11 (dd, 1H, J ) 14.0, 7.7 Hz, CH2),
3.26 (dd, 1H, J ) 14.0, 7.7 Hz, CH2), 3.71 (s, 3H, OCH3), 5.15 (t, 1H,
J ) 7.7 Hz, CH), 5.70 (br s, 1H, H5), 7.10-7.32 (m, 5H, Ph), 14.40
(br s, 1H, NH); 13C NMR (62.5 MHz, DMSO-d6) δ 18.4 (C7), 19.6
(C9), 35.7 (C12), 53.2 (OCH3), 57.9 (C11), 96.4 (C5), 107.8 (C3), 127.6
(C4′), 128.9 (C2′ and C6′), 129.9 (C3′ and C5′), 135.7 (C1′), 163.8
(C2), 170.2 (C10), 176.3 (C4), 185.2 (C8). HRMS (ESI TOF-MS):
calcd for C18H20NO5, 330.1341; found, 330.1362.
Scheme 2. Preparation of Chiral (E)-Enaminopyran-2,4-diones 4a-c
(S,E)-Methyl-3-methyl-2-(1-(6-methyl-2,4-dioxo-2H-pyran-3(4H)-
(E)-3-(1-(Butylamino)ethylidene)-6-methyl-3H-pyran-2,4-dione (2k).
Yellow oil; yield, 92%; IR (NaCl, cm-1), νjmax 3479, 3055, 2961, 2924,
2869, 1695, 1655, 1581, 1479, 1392, 1361, 1338, 1257, 1163, 1061,
20
ylidene)ethylamino)butanoate (4c). Yellow oil; yield, 82%; [R]D
)
+4 (c ) 1.18 g/100 mL); IR (NaCl, cm-1), νjmax 3448, 3020, 2971,
1
1705, 1697, 1650, 1577, 1479, 1394, 1363, 1216, 927, 777, 669; H
1
999, 926, 837, 735; H NMR (250 MHz, CDCl3) δ 0.95 (t, 3H, J )
NMR (250 MHz, DMSO-d6) δ 0.92 (d, 3H, J ) 6.5 Hz, CH3), 0.94 (d,
3H, J ) 6.5 Hz, CH3), 2.07 (d, 3H, J ) 0.5 Hz, CH3), 2.28 (m, 1H,
H3′), 2.50 (s, 3H, CH3), 3.72 (s, 3H, OCH3), 4.77 (dd, 1H, J ) 8.2,
6.5 Hz, H2′), 5.73 (br s, 1H, H5), 14.30 (br s, 1H, NH); 13C NMR
(62.5 MHz, DMSO-d6) δ 17.7 (C7), 18.6 (C4′), 18.8 (C5′), 19.6 (C3′),
31.4 (C9), 53.1 (OCH3), 61.7 (C2′), 96.6 (C5), 108.0 (C3), 163.2 (C2
and C6), 170.3 (C1′), 176.8 (C4), 198.0 (C8); HRMS (ESI TOF-MS):
calcd for C14H20NO5, 282.1342; found, 282.1308.
7.3 Hz, H4′), 1.44 (sextet, 2H, J ) 7.3 Hz, H3′), 1.68 (m, 2H, H2′),
2.10 (d, 3H, J ) 0.5 Hz, CH3), 2.52 (s, 3H, CH3), 3.46 (m, 2H, H1′),
5.68 (br d, 1H, J ) 0.5 Hz, H5), 13.98 (br s, 1H, NH); 13C NMR (62.5
MHz, DMSO-d6) δ 13.6 (C4′), 18.1 (C3′), 19.7 (C9), 20.0 (C2′), 30.9
(C1′), 43.9 (C7), 96.4 (C5), 107.0 (C4), 162.0 (C2), 175.0 (C4), 182.0
(C8).
(E)-6-Methyl-3-(1-(2-phenylhydrazinyl)ethylidene)-2H-pyran-2,4(3H)-
dione (3a). Red oil; yield, 62%; IR (NaCl, cm-1), νjmax 3460, 3055,
X-ray Analysis. A well-shaped single crystal of (E)-3-(1-(propy-
lamino)ethylidene)-6-methyl-3H-pyran-2,4-dione (2c) was selected for
the X-ray diffraction experiment. This crystal was mounted on a glass
fiber and afterward positioned on the goniometer head. Intensity data
were collected at low temperature (150(2) K) provided by a cryogenic
device (Oxford Cryosystem) and with graphite monochromated Mo
KR radiation (λ ) 0.71073 Å), using a Enraf-Nonius Kappa-CCD
diffractometer. The cell refinements were performed using the software
Collect (34) and Scalepack (35), and the final cell parameters were
obtained on all reflections. Data for compound 2c were measured up
to 27.4° in θ, totaling 4497 Bragg reflections. Data reduction was carried
out using the software Denzo-SMN and Scalepack (35) with XdisplayF
for visual representation of data. An absorption coefficient of 0.096
mm-1 was observed. Thus, absorption correction was not done.
The structure was solved using the software SHELXS-97 (36) and
refined using the software SHELXL-97 (37), where the C, N, and O
atoms were clearly solved and full-matrix least-squares refinement of
these atoms with anisotropic thermal parameters was carried out. The
amine hydrogen atom was located by difference Fourier analysis and
was set as isotropic. On the other hand, the C-H hydrogens were
positioned stereochemically and were refined with fixed individual
displacement parameters [Uiso(H) ) 1.2Ueq(Csp2) or 1.5Ueq(Csp3)] using
a riding model with CsH bond lengths ranging between 0.93 Å and
0.97 Å. Table 1 was prepared using WinGX (version 1.70.01) (38)
and presents a summary of the X-ray diffraction experiment. ORTEP-3
(39) and MERCURY (40) were also used in order to publish the crystal
1
2987, 1743, 1610, 1552, 1421, 1265, 1103, 897, 750; H NMR (250
MHz, DMSO-d6) δ 2.25 (d, 3H, J ) 0.8 Hz, CH3), 2.42 (s, 3H, CH3),
5.90 (br s, 1H, H5), 7.37 (t, 1H, J ) 7.8 Hz, H4′), 7.56 (m, 2H, H3′
and H5′), 7.73 (d, 2H, J ) 7.8 Hz, H2′ and H6′); 13C NMR (62.5 MHz,
DMSO-d6) δ 14.7 (C9), 19.6 (C7), 102.4 (C3), 104.9 (C5), 120.9 (C2′
and C6′, 127.6 (C4′), 129.9 (C3′ and C5′), 136.9 (C1′), 144.9 (C2),
150.3 (C8), 154.5 (C4), 159.3 (C6). HRMS (ESI TOF-MS): calcd for
C14H15N2O3, 259.1083; found, 259.1101.
(E)-3-(1-(2-(2,4-Dinitrophenyl)hydrazinyl)ethylidene)-6-methyl-2H-
pyran-2,4(3H)-dione (3b). Red oil; yield, 58%; IR (NaCl, cm-1), νjmax
3445, 3055, 2987, 1740, 1700, 1645, 1625, 1549, 1421, 1344, 1261,
Figure 1. ORTEP-3 representation of compound 2c.

1402 J. Agric. Food Chem., Vol. 57, No. 4, 2009
Dias et al.
Figure 2. Effect of the compounds, at 10-4 mol L-1 (0.1 mM) and 10-3 mol L-1 (1 mM), on the radicle development of C. sativus and S. bicolor.
Figure 3. Effect of the compounds, at 5 × 10-4 mol L-1, on the development of radicle and aerial parts of I. grandifolia and B. decumbens.
data, as well as MOGUL (41), a useful program to evaluate the
molecular conformation and geometry by matching the values of bond
distances and torsional and valence angles for a query compound with
the corresponding ones of similar structures that are deposited at the
Cambridge Structure Database (CSD) (42) (Table 1).
The crystallographic information file leading to the data sets (except
the structure factors) for compound 2c has been deposited with the
Cambridge Structural Data Base under deposit code CCDC 694825
(copies of these data may be obtained free of charge from The Director,
CCDC, 12 Union Road, Cambridge, CB2 1EZ, U.K.; fax, +44123-
336-033; e-mail, deposit@ccdc.cam.ac.uk; or http:www.ccdc.ac.uk).
Plant Growth Inhibition Assays. In order to evaluate the growth
regulatory potential of the synthesized (E)-enaminopyran-2,4-diones
(1, 2a-k, 3a-b, and 4a-c), three different bioassays were carried
out.
Radicle Elongation Assay on Filter Paper. The solutions of (E)-
enaminopyran-2,4-diones were prepared by dissolving a proper amount
in xylene (48 µL) and pentan-3-one (24 µL) (31). After addition of the
surfactant Tween 80 (72 µL), the resulting suspension was transferred
to a volumetric flask and diluted with water to 50 mL, so as to obtain
final concentrations of 1 × 10-3 mol L-1 and 1 × 10-4 mol L-1. These
suspensions were sonicated for 5 min, and then 4 mL aliquots were
used to imbibe two sheets of filter paper (Whatman no. 1) placed in
100 mm × 15 mm glass Petri dishes. To each dish were added 20
seeds of Sorghum bicolor L. Moench (Geneze Company, Paracatu,
Minas Gerais State, Brazil) or Cucumis satiVus L. (purchased from a
local market). The plates were incubated at 25 °C under fluorescent
light (8 × 40 W) for 72 h. Radicle length was then measured, and
total germination was recorded. Seeds were considered to have
germinated if a radicle protruded at least 1 mm. Treatments were carried
out in a completely randomized design with five replications. The data,
expressed as percentage of radical growth inhibition with respect to
untreated controls, were analyzed using Tukey’s test at the 0.05
probability level.
Radicle Elongation Assay in Sand. Solutions of the most active
compounds 1, 2a, 2b, 2g, 2h, 2i, 4a, and 4c were prepared by dissolving
a proper amount in xylene (84 µL) and pentan-3-one (42 µL). After
addition of the surfactant Tween 80 (127 µL), the resulting suspension
was transferred to a volumetric flask and diluted in water to 88 mL, so
as to obtain a final concentration of 5 × 10-4 mol L-1. These
suspensions were sonicated for 5 min and were used to imbibe acid-
washed sand (165 g) in 90-mm Petri dishes. Seven pregerminated seeds
of Ipomoea grandifolia or Brachiaria decumbens were transferred into
each plate, and dishes were sealed with Parafilm and incubated at 28
°C. After 24 and 48 h, the radicle length was measured to the nearest
millimeter. Treatments were carried out in a completely randomized
design with four replications. The data were expressed and analyzed
as above.
Greenhouse Trials. Plastic pots (0.13 L) were filled with acid-washed
sand, which was saturated with the solution of the test compound (60

(E)-Enaminopyran-2,4-diones as Plant Growth Regulators
J. Agric. Food Chem., Vol. 57, No. 4, 2009 1403
mL/450 g of sand, corresponding to 5.9 × 10-5 mmol a.i./g substrate).
Four seeds of I. grandifolia or B. decumbens were placed in each pot.
Seedlings were grown in a greenhouse and watered as required with
tap water or, twice a week, with half-strength Hoagland solution, to
maintain the humidity at 13.3% w/w. Twenty-one days after sowing,
plants were harvested, and the roots and aerial parts were separated
and weighed. Tissues were then dried at 60 °C until constant weight,
and the corresponding dry mass was determined. The percentage of
root and aerial part growth inhibition was calculated in relation to the
mass of the respective control. Data were expressed and analyzed as
previously indicated.
result could in principle suggest that chirality could have some
effect on the activity. This hypothesis was disproved, since it
was observed that chiral (E)-enaminopyran-2,4-diones (4a-c)
were as active as (63-81% of inhibition) the achiral compound
(2i) (69%) in inhibiting the radicle development of C. satiVus.
The aromatic enamine 2d bearing an unsubstituted phenyl
ring caused the best result of inhibition against C. satiVus,
compared with the aromatic enamines with substitutions in the
ring. Despite a stimulating effect on radicle growth at 10-4 mol
L-1, at the higher concentration 2d inhibits (81% inhibition) as
much as 2e (88%) and 2h (81%). These data and others
presented in Figure 2 suggest that the presence of substitution
on the aromatic ring of these enamines is not a requisite for
herbicide activity against C. satiVus.
RESULTS AND DISCUSSION
Synthesis of (E)-Enaminopyran-2,4-diones. Treatment of
dehydroacetic acid 1 with the corresponding primary alkyl or
aryl amines proceeded smoothly in the presence of triethylamine
in refluxing 1,4-dioxane to give the corresponding functionalized
(E)-enaminopyran-2,4-diones 2a-k in excellent yields (Scheme
1). The use of (S)-sec-butylamine gave chiral enamino-2,4-dione
2b in 91% isolated yield. Usually, the reaction with alkyl amines
led to better yields when compared with aryl amines.
For the hydrazines (3a and 3b) it was observed that the
presence of two nitro groups on the aromatic ring had a
significant impact on the activity. Compound 3b caused 78%
inhibition of radicle growth, while 3a was four times less active,
causing only 19% inhibition.
For S. bicolor, none of the compounds caused a significant
effect on the germination rate at 10-4 mol L-1. However, at
10-3 mol L-1 were observed inhibitions with 2a (16%), 2f and
2k (18%), 2d (22%), 2h (25%), 1 (73%), and 2e (76%).
Only 3a and 4b showed a stimulating effect at 10-4 mol L-1
(26% and 11%, respectively). A small inhibitory effect (less
than 10%) was noted for compounds 2d, 2g, 2h, 2i, and 3b,
while approximately 46% inhibition was observed for com-
pounds 2a, 2b, and 2k. At 10-3 mol L-1, compounds 3a and
4b showed lower inhibitory effects (27% and 24%, respectively),
while moderate inhibitory effects (2i, 59% and 2j, 48%) and
high inhibitions were found for compounds 2c and 3b (76%),
2b and 3k (80%), 1 (83%), and 2e (85%).
The next step involved the reactions of dehydroacetic acid 1
with phenylhydrazines to give the (E)-enaminopyran-2,4-diones
3a and 3b in good yields (Scheme 1). We next moved to the
reactions of dehydroacetic acid 1 with the corresponding chiral
R-amino esters (Scheme 2). We were able to get excellent yields
by reacting 1 with the R-amino esters derived from L-alanine,
L-phenylalanine, and L-valine, affording the desired (E)-
enaminopyran-2,4-diones 4a-c.
X-ray Analysis. The structures of the products were con-
firmed by X-ray analysis of compounds 2a-2c (Figure 1). Of
the two possible isomers, the (E)-enaminone is formed prefer-
entially as hydrogen bonding occurs with the more electron rich
oxygen. In Figure 1, an ORTEP-3 representation (38) of
compound 2c is shown. This compound crystallizes in the
centrosymmetric monoclinic space group P21/c with one entire
molecule in the asymmetric unit. In the solid state, the X-ray
diffraction analyses have revealed that the major tautomer is
the form presenting the nitrogen atom covalently hydrogen
bonded, whereas the two exocyclic oxygen atoms are either
carbonyl or carboxyl (Figure 1). An interesting intramolecular
feature in the 2c structure is the occurrence of a chelating six-
membered system closed by the classical noncovalent hydrogen
bond N1-H1· · ·O2 in which the nitrogen atom of the propy-
lamino moiety is the hydrogen donor and the carbonyl oxygen
of the δ-lactone ring is the acceptor.
Phytotoxic Assay. Compounds 1, 2a-k, 3a,b, and 4a-c
were then submitted to a plant growth bioassay to evaluate their
effect on the radicle growth of Cucumis satiVus and Sorghum
bicolor. The experiments were carried out at two concentrations
(10-4 and 10-3 mol L-1) of each compound, and the results are
shown in Figure 2.
None of the compounds caused a significant effect on the
germination rate for C. satiVus at the two concentrations tested.
However, at 10-4 mol L-1, several different effects were
observed: stimulating effects (2c and 2i, 15%), lesser inhibitory
effects (2a, 20%; 2h, 22%; 3b, 23%), and moderate inhibitory
effects (3a, 29%; 1, 37%; 2e, 54%). At 10-3 mol L-1, all
compounds showed inhibitory effects, ranging from 19% to
88%, on the radicle growth of C. satiVus. The six most active
compounds (1, 2b, 2d, 2e, 2h, and 4c) caused more than 80%
inhibition of radicle growth. It is interesting to note that
compound 2b, which presents a (S)-sec-butyl group attached
to the nitrogen, is much more active (88% inhibition) than
compound 2k (44% inhibition), bearing a butyl group. This
The chiral (4a-c) and achiral (2i) enamine methyl esters
showed large differences over the radicle development of S.
bicolor. The aromatic compound 4b showed a small inhibitory
effect (11% and 24%, at 10-4 and 10-3 mol L-1, respectively)
on radicle growth, while for the others high inhibitory activities
(2i, 7% and 59%; 4c, 17% and 70%; 4a, 22% and 72%) were
registered. Since the observed inhibitory activities for 2i, 4c,
and 4a are quite similar, it seems that for these compounds the
chirality is not a requirement for inhibitory activity. Moreover,
since the aromatic compound 4b displayed a small inhibitory
effect, it is apparent that the presence of an alkyl group attached
to the chiral carbon may contribute to the activity of compounds
(4a-c) against S. bicolor.
At 10-3 mol L-1 hydrazine 3b caused higher inhibition (76%)
on the radicle development of S. bicolor than 3a (27%
inhibition). These results are consistent with those reported for
C. satiVus, confirming the strong influence of the nitro groups
on the activity of these compounds.
Compound 2e, an aromatic enamine with a chorine in the
ring, presented the best result of inhibition (85% at 10-3 mol
L-1) against S. bicolor compared with other aromatic enamines.
The presence of a chlorine atom seems to have little effect on
herbicide activity, since 2d caused 62% of inhibition at the same
concentration. On the other hand, compound 2h, which differs
from 2g by the presence of chlorine in the ring and by the
position of the nitro group, was 8% more active at 10-3 mol
L-1, while 2f (with a hydroxyl in ring) was 11% less active
than 2e at 10-3 mol L-1
.
For the alkyl enamines 2b (79% inhibition), 2c (75%), and
2k (80%), no significant differences for the herbicide activity
at 10-3 mol L-1 were observed. At the same concentration,
compound 2c (20% inhibition) was much less active than the

1404 J. Agric. Food Chem., Vol. 57, No. 4, 2009
Dias et al.
others. These data suggest that the size of the alkyl chain could
be associated with activity. Futher investigation should be
carried out in order to evaluate this proposal.
Supporting Information Available: 1H NMR and 13C NMR
of compounds 2a, 2c, and 4c; experimental bond lengths and
angles for 2c; hydrogen-bonding geometry for 2c; and hydrogen
bond scheme for 2c. This material is available free of charge
via the Internet at http://pubs.acs.org.
After confirming the inhibitory activity of the pyran-2,4-
diones on the development of C. satiVus and S. bicolor, the
effect of the most active compounds (1, 2a, 2b, 2g-i, 4b, and
4d) on the growth of the important weeds Ipomoea grandifolia
and Brachiaria decumbens was investigated. At 5 × 10-4 mol
L-1, all the compounds caused inhibition of the biomass of the
roots (ranging from 32% to 83%) and on the aerial parts (from
8% to 84%) of I. grandifolia. Compounds 2a, 2b, and 2g were
the most active, causing around 81% (for the three compounds)
inhibition on root biomass development, and 84%, 84%, and
76% on the aerial parts of I. grandifolia, respectively. These
data suggest that the presence of sec-butyl, benzyl, or 2-hydroxy-
5-nitrophenyl groups has similar contributions to the herbicide
activity of these enamines. The same behavior was observed
for 4a and 4c, where a methyl or isopropyl on the chiral carbon
did not cause a significant change in herbicide activity (roots:
4a, 62% inhibition; 4c, 65%. aerial parts: 4a, 57% inhibition;
4c, 68%). When compared with 2i, the presence of methyl or
isopropyl groups (4a or 4c) significantly increases herbicide
activity (2i: roots, 34%; aerial parts, 42%) against I. grandifolia.
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Received for review September 10, 2008. Revised manuscript received
December 24, 2008. Accepted December 24, 2008. We are grateful to
FAPESP (Fundac¸a˜o de Amparo a` Pesquisa do Estado de Sa˜o Paulo)
and CNPq (Conselho Nacional de Desenvolvimento Cient´ıfico e Tec-
nolo´gico) for financial support and fellowships (A.J.D., L.C.A.B., L.C.D.,
F.T.M.) and to FAPEMIG (Fundac¸a˜o de Amparo a` Pesquisa do Estado
de Minas Gerais) for financial support and a fellowship (V.M.M.V.).
(30) Barbosa, L. C. A.; Demuner, A. J.; Maltha, C. R. A.; Da Silva,
P. S.; Silva, A. A. S´ıntese e avaliac¸a˜o da atividade fitoto´xica de
JF802805F