Synthesis of 3-Hexyl-4-cyan-6,7-dimethoxy Isocoumarin

Article abstract of DOI:10.14233/ajchem.2014.16703

4-(2-Amino-propanamideyl)-3,4,5,6,7,8,9,10-octahydro-5,6, 8-trihydroxy-3-methyl-isocoumarin, which was isolated from Flaveria bidentis (L) Kuntze, had herbicidal activity and its structure was modified in this research in order to get the isocoumarin comp

Full text of DOI:10.14233/ajchem.2014.16703

Asian Journal of Chemistry; Vol. 26, No. 12 (2014), 3623-3625
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2014.16703
Synthesis of 3-Hexyl-4-cyan-6,7-dimethoxy Isocoumarin
*
HAI JIAO DONG , XU DONG BAN, CHENG LI, JING QIAN HUO, ZHAN HU GONG, ZHAN HAI KANG, JIN GAO DONG and JIN LIN ZHANG
College of Plant Protection, Agricultural University of Hebei, Baoding 071000, P.R. China
*Corresponding author: Fax: +86 312 7528575; Tel: +86 151 28266168; E-mail: zhangjinlin@hebau.edu.cn; chenmeipen@126.com
Received: 16 November 2013;
Accepted: 28 February 2014;
Published online: 5 June 2014;
AJC-15306
4-(2-Amino-propanamideyl)-3,4,5,6,7,8,9,10-octahydro-5,6,8-trihydroxy-3-methyl-isocoumarin, which was isolated from Flaveria bidentis
(L) Kuntze, had herbicidal activity and its structure was modified in this research in order to get the isocoumarin compouds with higher
herbicidal activity. The reaction starts with 2-amino-4,5-dimethoxy benzoate and then diazo iodination, esterfication, heck coupling,
cyclization reaction and cyna substitution reaction were tested to obtain 3-hexyl-4-cyan-6,7-dimethoxy isocoumarin. The isocoumarin
derivative is an appropriate precursor for the synthesis of new herbicide.
Keywords: Isocoumarin, Herbicidal activity, Diazo iodination, Esterfication, Heck coupling, Cyclization reaction.
NH2
INTRODUCTION
O
Isocoumarin compounds were widely existed in the umbe-
lliferae, asteraceae, rutaceae, leguminosae, moraceae, rosaceae,
rubiaceae, solanaceae and other natural plants. Research and
NH OH
OH
application of coumarin and its derivatives in the field of
medicine was very active, especially for the development of
anti-cancer drugs1. In addition, coumarin was an important
pesticide intermediate. The bromine, tribromo-substituted
derivatives of hydroxymethyl coumarin could effectively kill
the newly hatched larvae of Aedes aegypti2. Coumarin was
also an important allelopathic compound. The furano-
coumarins had a high herbicidal activity and it could inhibit
the germination of wild mustard at the concentration of 10-9
mol/L3. The coumarin and 7-methoxycoumarin had been
isolated from lavender and they could inhibit the growth of
annual ryegrass4. The 4-(hydroxymethyl)-7-substituted
coumarin could inhibit the mung bean5. It has been found that
coumarin could inhibit bidens and barnyard grass as well as
the synthesis of plant cellulose6. In the previous study, we had
isolated a high herbicidal activity substance named 4-(2-amino-
propanamideyl)-3,4,5,6,7,8,9,10-octahydro-5,6, 8-hydroxy-3-
methyl-isocoumarin (1) (Fig. 1) from Flaveria bidentis (L)
Kuntze. However, the OH group in the molecule might be
unstable in plants. So under the condition of retaining the
precursor of isocoumarin, we try to modify its structure to get
a compound with a higher herbicidal activity by the following
two routes to synthetize the 3-hexyl group, 4-cyano-6,7-
dimethoxy isocoumarin (11).
O
1
Fig. 1.
EXPERIMENTAL
Route A: The synthesis of 5 was shown in Scheme-I. The
reaction was carried out under the joint action of K2CO3,
(CH3)2CO, CH3I at room temperature and began with 2 via
column chromatography separation and purification to give 3.
Compound 3 occurred sonogashira cross coupling reaction with
O
O
OH
esterfication
OMe
A:
I
I
2
3
coupling
O
O
annelation
OMe
O
C6H13
C6H13
5
Scheme-I: General route for the synthesis of 3-hexyl isocoumarin
4

3624 Dong et al.
Asian J. Chem.
CH3(CH2)4CH2CCH in the Pd(OAc)2, DABCO, KOH, PEG
400 catalytic system under the action and argon atmosphere
to obtain 4. Then FeCl3 promoted 4 in CH3CN to occurred
electrophilic cyclization reaction under the argon atmosphere
of 80 °C. However, it was difficult to obtained 11 when we used
6 as a starting material. Thus we developed route B (Scheme-II)
to yield 11.
ArH), 7.39 (s, 1H,ArH), 3.94-3.90 [m, 9H, (OCH3)3]. 13CNMR
(300 MHz, CDCl3): δ 165.9, 151.9, 148.7, 126.1, 123.8, 113.9,
84.6, 56.2, 56.0, 52.2. MS, m/z (% ): 322 (M+, 100).
O-octynyl 4,5-dimethoxybenzoate (9):A Et3N (250 mL,
1787.7 mmol) solution of 8 (50.04 g, 164.4 mmol ), C8H14 (20
g), C36H30Cl2P2Pd (1.0006 g, 1.43 mmol) and CuI (0.5063 g,
2.66 mmol) was stirred in a water bath of 55 °C for 6 h. The
reaction mixture was filtered twice and then the liquid was
dissolved in ethyl acetate (300 mL). The ethyl acetate phase
was washed with water (200 mL × 3) and dried over and concen-
trated under reduced pressure to give compound 9 (41.62 g,
4,5-Dimethoxy-2-iodo-benzoic acid (7): 36.5 % aqueous
HCl (105 mL) was added dropwise to a mixture of 6 (59.16 g,
300 mmol) in water (300 mL), which was stirred with cooling
in an ethanol bath of -10 °C. After that a solution of NaNO2
(22.2 g, 321.7 mmol ) in H2O (108 mL) was added dropwise
to the reaction mixture at -2 to 0 °C and srirred for 20 min and
then a solution of KI (99.6 g, 600 mmol) in water (120 mL)
was added to the mixture with a rapid dropwise and stirred for
0.5 h at -2 to 0 °C. The resulting mixture was slowly poured into
a 2000 mL beaker in a water bath of 90 °C, stirred for about
0.5 h. The solid deposited was isolated by filtration, washed
with water (100 mL × 3) at room temperature. The resulting
solid was dissolved with anhydrous CH3OH (630 mL) by
heating. The CH3OH solution was filtered again and then dried
over Na2SO4 and concentrated under reduced pressure to give
compound 7 (83.40 g, 90.24 % yield) as a slightly red solid.
m.p. 106-108 °C. 1H NMR (300 MHz, DMSO): δ 7.36 (s, 1H,
ArH), 7.33 (s, 1H,ArH), 3.82-3.77 [m, 6H, (OCH3)2]. 13C NMR
(300 MHz, DMSO): δ 167.6, 150.9, 148.4, 125.0, 123.2, 113.7,
84.3, 55.1, 55.7. MS, m/z (% ): 308 (M+, 75), 350 (100).
HPLC analysis showed that the purity of 7 was higher
than 98 %. This product was used in the next step without any
further purification and characterization.
1
88.01 % yield) as a yellow solid8. m.p. 47-49 °C. H NMR
(300 MHz CDCl3): δ 7.44 (s, 1H, ArH), 6.95 (s, 1H, ArH),
3.91 [s, 9H, (OCH3)3], 2.47 (t, J = 6.9 Hz, 2H, ≡C-CH2), 1.70-
1.60 (m, 2H, CH2), 1.53-1.43 [m, 2H, (CH2)], 1.38-1.25 [m,
4H, (CH2)2], 0.89 (t, J = 6.6 Hz, 3H, CH3). 13C NMR (300
MHz, CDCl3): δ 166.5, 151.5, 148.0, 124.3, 118.5, 116.1,
112.7, 94.6, 79.4, 56 (2C), 51.9, 31.4, 28.8, 28.7, 22.6, 19.9,
14.0. MS, m/z (% ): 304.2 (M+, 100).
3-Hexyl-4-iodo-6,7-dimethoxy isocoumarin (10): A
solution of ICl (2 g, 12.3 mmol) was slowly added to a CH2Cl2
(60 mL) solution of 9 (4 g, 13.14 mmol ) and the mixture was
stirred at room temperature for 45 min. The reaction mixture
was washed with water (50 mL × 3) and dried over Na2SO4 and
concentrated under reduced pressure. The solid was dissolved
in CH3OH (28 mL) under heating and cooled to 5-7 °C and
then filtered and repeated dissolution process twice to give 10
(3.668 g, 67.06 % yield) as a colorless solid9-10. m.p. 111-
1
113 °C. H NMR (300 MHz, CDCl3): δ 7.64 (s, 1H, ArH),
7.15 (s, 1H,ArH), 4.06 [s, 3H, (OCH3)], 3.99 [s, 3H, (OCH3)],
2.90 (t, J = 8.1 Hz, 2H, CH2), 1.76-1.68 (m, 2H, CH2), 1.43-
1.30 [m, 6H, (CH2)3], 0. 90 (t, J = 6.9 Hz, 3H, CH3). 13C NMR
(300 MHz, CDCl3): δ 155.8, 125, 111.9, 109.6, 106.1, 56.8,
56.5, 56.3, 37.3, 31.5, 31.4, 28.7, 28.7, 27.3, 22.5, 22.4, 14
MS, m/z (% ): 416.2 (M+, 100).
4,5-Dimethoxy-2-iodo-benzoate (8):A solution of 98 %
H2SO4 (30 mL) was slowly added to a solution of 7 (40.8 g,
132.4 mmol) in CH3OH (380 mL) and the mixture heated under
reflux for 6.5 h. The reaction mixture was evaporated CH3OH
(340 mL) under reduced pressure, filtered and then the solid
was dissolved in ethyl acetate (200 mL). The ethyl acetate
solution was added water (200 mL), K2CO3 (12 g, 86.8 mmol)
and stirred for about 10 min. After that the mixture solution
was extracted twice with ethyl acetate (50 mL). The organic
layers combined were washed with water (200 mL × 3) and
dried over Na2SO4 and concentrated under reduced pressure to
give compound 8 (40.09 g, 95.91 % yield) as a greenish solid7.
m.p. 107-109 °C. 1H NMR (300 MHz, CDCl3): δ 7.44 (s 1H,
3-Hexyl-4-cyano-6,7-dimethoxy isocoumarin (11): A
DMF (100 mL) solution of 10 (4.15 g, 1 mmol) and Cu2CN2
(1.088 g, 6.1 mmol ) was heated under reflux for 6 h. The
reaction mixture was filtered at the temperature of 90 °C,
concentrated DMF under reduced pressure and the solid
deposited in the bottle at a low temperature was added the
solution of 98 % H2SO4 (1 mL) in water (10 mL) and stirred in
a water bath of 60 °C for about 0.5 h. Then the mixture was
O
O
O
O
O
O
O
O
O
OMe
OH
NH2
diazo
OH
esterification
:
B
iodination
I
I
7
8
6
O
I
CN
O
O
O
C6H13
O
C6H13
OMe
annulation
coupling
cyanation
O
O
O
O
O
O
C6H13
10
9
11
Scheme-II: Route for the synthesis of 3-hexyl-4-formyl-6,7-dimethoxy-isocoumarin

Vol. 26, No. 12 (2014)
Synthesis of 3-Hexyl-4-cyan-6,7-dimethoxy Isocoumarin 3625
cooled to 25 °C and filtered to give 11 (3.01 g, 95.73 %) as a
gray solid11. m.p. 153-155 °C. 1H NMR (300 MHz, CDCl3): δ
7.62 (s, 1H, ArH), 7.03 (s, 1H, ArH), 4.06 [s, 3H, (OCH3)],
3.99 [s, 3H, (OCH3)], 2.85 (t, J = 7.5 Hz, 2H, CH2), 1.83-1.75
(m, 2H, CH2), 1.44-1.25 [m, 6H, (CH2)3], 0. 90 (t, J = 6.9 Hz,
3H, CH3). 13C NMR (300 MHz, CDCl3): δ 167.9, 159.8, 156.1,
150.5, 128.9, 114.6, 111.7, 109.8, 104.5, 91.8, 56.6, 56.5, 33.6,
31.3, 28.6, 27.3, 22.4, 14.0. MS, m/z (% ): 315.2 (M+, 100).
ACKNOWLEDGEMENTS
This research was supported by the National Natural
Science Foundation of China (31171877).
REFERENCES
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Conclusion
2-Amino-4,5-dimethoxy benzoate was used as the initiator
and then diazo iodination, esterfication, heck coupling, cycli-
zation reaction and cyna substitution reaction were experi-
mented to got 3-hexyl-4-cyan-6,7-dimethoxy isocoumarin. In
summary, we have explored a feasible and versatile approach
to compound 11. Each step of the reaction is easily performed
and has a considerable yield except the synthesis of compound
10. It should be noted that the route B is general and should be
applied to the synthesis of a large variety of isocoumarin
derivatives. A key step of this approach involves the reaction
of cyano-substituted iodine and it lays a foundation for the
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