A new and rapid N-alkylation of 3,6-epoxy-hexahydrophthalimides

Article abstract of DOI:10.1081/SCC-120002121

Rapid N-alkylation of 3,6-epoxyhexahydrophthalimides with a series of halides were performed under solvent-free conditions coupled with microwave irradiation. The isolated yield of N-substituted 3,6-epoxyhexa hydrophthalimides varied from 82 to 98%.

Full text of DOI:10.1081/SCC-120002121

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A NEW AND RAPID N-ALKYLATION OF 3,6-EPOXY-
HEXAHYDROPHTHALIMIDES
Guifa Su a , Xinsheng Li a & Hongjing Wan a
a Department of Chemistry & Chemical Engineering , Guangxi Normal University , Guilin,
541004, P. R. China
Published online: 16 Aug 2006.
To cite this article: Guifa Su , Xinsheng Li & Hongjing Wan (2002) A NEW AND RAPID N-ALKYLATION OF 3,6-EPOXY-
HEXAHYDROPHTHALIMIDES, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 32:3, 381-385
To link to this article: http://dx.doi.org/10.1081/SCC-120002121
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SYNTHETIC COMMUNICATIONS, 32(3), 381–385 (2002)
A NEW AND RAPID
N-ALKYLATION OF 3,6-EPOXY-
HEXAHYDROPHTHALIMIDES
Guifa Su,* XinshengLi, and HongjingWan
Department of Chemistry & Chemical Engineering,
Guangxi Normal University, Guilin 541004, P. R. China
ABSTRACT
Rapid N-alkylation of 3,6-epoxyhexahydrophthalimides with
a series of halides were performed under solvent-free
conditions coupled with microwave irradiation. The isolated
yield of N-substituted 3,6-epoxyhexahydrophthalimides
varied from 82 to 98%.
Cantharidin and norcantharidin (3,6-epoxyhexahydrophthalimide)
possess antitumor activity and were used as antitumor drug to cure liver
cancer.1–3 N-substituted 3,6-epoxyhexahydrophthalimides have been shown
to possess anticonvulsant, hypotensive, anthelmintic and antitumour activ-
ity, some of them can be used as insecticide and germicide.4–8
Microwave organic reaction enhancement chemistry (MOREC) is a
new subject developed in recent years,9 various organic reactions have been
investigated10,11 and several papers on its use in alkylations were reported
lately.12–14 Here we would like to describe a new and rapid synthesis of
*Corresponding author.
381
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

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382
SU, LI, AND WAN
N-alkyl-3,6-epoxyhexahydrophthalimides via alkylation of 3,6-epoxyhexa-
hydrophthalimide in ‘dry media’ under microwave irradiation.
The alkylation of 3,6-epoxyhexahydrophthalimide was simply achi-
eved by microwave irradiation of the mixture of 3,6-epoxyhexahydro-
phthalimides (1), alkyl halides (2), potassium carbonate and a catalytic
amount of tetrabutylammonium bromide (TBAB), followed by extraction
and purification to give the products in 82–98% yield (Tables 1 and 2).
Table 1. N-Alkylation of 3,6-Epoxyhexahydrophthalimide
2/1
(mol)
Irradiation Time
(min)
Irradiation Power
(W)
Yield
(%)
M.P.
(ꢀC)
Entry
3a
3b
3c
3d
3e
3f
1.25 : 1
1.1 : 1
1.1 : 1
1.1 : 1
1.1 : 1
1.1 : 1
1.1 : 1
1.0
1.5
1.5
1.5
1.5
1.5
1.5
240
95
94–95
101–102
24092
24098
400
400
400
40015
82
90
98
94
3g
116–119

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N-ALKYLATION OF 3,6-EPOXYHEXAHYDROPHTHALIMIDES
Table 2. Analytical Data of Products 3
383
Elementary Analyses (Calc., %)
Entry IR (cmꢁ1
)
1H NMR (d, CDCl3)
C
H
N
3a
3472, 1770, 4.9 (m, 2H, 3,6-H)
1743, 1714, 4.1–4.3 (q, 2H, -O-CH2-)
1222, 1187 4.2 (s, 2H, -N-CH2)
3.0(s, 2H, 1,2-H)
56.71
(56.91)
6.05
(5.97)
5.40
(5.53)
2.0–1.4 (m, 4H, 4,5-H)
1.3 (t, 3H, -CH3)
3b
3465, 1778, 4.9 (m, 2H, 3,6-H)
1735, 1707, 4.7 (q, 1H, -N-CHCH3)
1250, 1201 4.2 (m, 2H, -OCH2-)
2.9 (s, 2H, 1,2-H)
58.206.53
(58.42)
5.10
(6.41)
(5.24)
2.1–1.6 (m, 4H, 4,5-H)
1.5 (d, 3H, NCH-CH3)
1.2 (t, 3H, -CH2CH3)
3c
3465, 1778, 4.9 (m, 2H, 3,6-H)
1743, 1707, 4.6 (t, 1H, -N-CHCH2-)
1250, 1187 4.2 (m, 2H, -OCH2CH3)
2.9 (s, 2H, 1,2-H)
62.35
(62.12)
7.404.40
(7.49)
(4.53)
2.4–2.0, 1.0–1.6
(m, 6H, (CH2)3)
2.0–1.6 (m, 4H, 4,5-H)
1.2 (t, 3H, -OCH2CH3)
0.9 (t, 3H, -CH2CH3)
3d
3e
3460, 1771, 4.8 (m, 2H, 3,6-H)
1701, 1187 3.4 (t, 2H, -N-CH2)
2.9 (s, 2H, 1,2-H)
68.53
(68.79)
9.23
(9.02)
4.89
(5.01)
2.0–1.5 (m, 4H, 4,5-H)
1.4–0.6 (m, 15H,
N-C-(CH2)6CH3)
3458, 1770, 4.9 (m, 2H, 3,6-H)
1700, 1187 3.4 (t, 2H, -N-CH2-)
2.9 (s, 2H, 1,2-H)
70.58
(70.32)
9.26
(9.51)
4.79
(4.56)
2.0–1.6 (m, 4H, 4,5-H)
1.6–0.6 (m, 19H,
-N-C-(CH2)8CH3)
(continued )

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384
SU, LI, AND WAN
Table 2. Continued
Elementary Analyses (Calc., %)
Entry IR (cmꢁ1
)
1H NMR (d, CDCl3)
C
H
N
3f
3458, 1771, 4.9 (m, 2H, 3,6-H)
1700, 1187 3.4 (t, 2H, -N-CH2)
2.9 (s, 2H, 1,2-H)
71.85
(71.60)
9.92
(9.91)
4.02
(4.18)
2.0–1.6 (m, 4H, 4,5-H)
1.6–0.6 (m, 23H,
-N-C-(CH2)10CH3)
3g
3444, 3064, 7.3 (s, 5H, Ar-H)
3029, 1771, 4.9 (m, 2H, 3,6-H)
1693, 11804.6 (s, 2H, -N-CH 2-Ph)
2.9 (s, 2H, 1,2-H)
69.83
(70.02)
5.99
(5.88)
5.35
(5.44)
2.0–1.4 (m, 4H, 4,5-H)
EXPERIMENTAL
General Considerations
IR spectra were recorded on a Nicolet 5DXB-FT infrared spectro-
meter, 1H NMR spectra were recorded on a JEOL FX-90Q spectro-
meter using TMS as internal standard. Microanalyses were carried out
by Perkin-Elmer 2400 CHN elemental analysis instrument. Norcan-
tharidin and norcanthanridinimide were synthesized according to the
Refs 16 and 17.
General Procedure for the Alkylation of
3,6-Epoxyhexahydrophthalimides
A mixture of 3,6-epoxyhexahydrophthalimides (1, 0.48 g, 7.9 mmol),
ethyl chloroacetate (2a, 1.21 g, 9.88 mmol), TBAB (0.05 g, 0.16 mmol) and
potassium carbonate (1.5 g, 11 mmol) were irradiated in a Galanz
WP800BS domestic oven in an open container for 1 min at 240 W. The
cooled mixture was extracted with 50mL methylene chloride, then the solvent
was removed in vacuo and the residue purified by preparative thin layer
chromatography (silica gel: 100–200 mesh, eluent: ethyl acetate/cyclo-
hexane ¼ 1/1, v/v, Rf ¼ 0.47) to give 3a, the yield was 95%.

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N-ALKYLATION OF 3,6-EPOXYHEXAHYDROPHTHALIMIDES
385
ACKNOWLEDGMENT
The authors are grateful to Guangxi Government for financial grants.
REFERENCES
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1
This was confirmed by TLC, IR, H NMR and elemental analysis.
1H NMR (CHCl3) 8.0–7.6 (m, 5H, C6H5), 7.6–7.1 (m, 4H, C6H4),
4.84 (s, 2H, CH2-). Anal. calcd. for C15H11NO2: C, 75.95; H, 4.64;
N, 5.91. Found: C, 75.99; H, 4.81; N, 6.16. Because the bath allows
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Received in the USA March 19, 2001

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