Significantly enhanced reactivities of the nucleophilic substitution reactions induced by microwaves in ionic liquid

Article abstract of DOI:10.1080/00397910600588280

The reaction rate of nucleophilic substitution can be dramatically enhanced by microwave irradiation using the ionic liquid [Bmim]BF4 as a solvent. Nucleophilic reagents (anilines, thiophenol) react with ethoxymethylene isopropylidene malonate to give cor

Full text of DOI:10.1080/00397910600588280

Synthetic Communicationsw, 36: 1479–1484, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600588280
Significantly Enhanced Reactivities of the
Nucleophilic Substitution Reactions Induced
by Microwaves in Ionic Liquid
Sheng-Rong Guo and Yan-Qin Yuan
Department of Chemistry, Lishui University, Lishui, China
Abstract: The reaction rate of nucleophilic substitution can be dramatically enhanced
by microwave irradiation using the ionic liquid [Bmim]BF4 as a solvent. Nucleophilic
reagents (anilines, thiophenol) react with ethoxymethylene isopropylidene malonate to
give corresponding products in 5–10 min in good yields.
Keywords: Ethoxymethylene isopropylidene malonate, ionic liquid, microwave
irradiation, nucleophilic substitution
With the rapid advancement in the field of synthetic organic chemistry, more
and more environmentally benign and ecofriendly processes are coming up at
an overwhelming rate.[1] A system of room-temperature ionic liquids has been
developed that is of interest in both the academia and industry.[2] This is
because of not only their electrochemical properties,[2] but also their tremen-
dous potential as solvents and phase-transition catalysts.[3] They are being
used as green solvents with unique properties such as a wide liquid range,
good solvating ability, tunable polarity, high thermal stability, negligible
vapor pressure, and ease of recyclability.
The unsaturated carbon joined ethoxyl of the ethoxymethylene isopropy-
lidene malonate (compound 1) has a certain electrophilicity.[4] When it reacts
with nucleophilic reagents such as an aromatic amine, thiophenol, the ethoxyl
Received in Japan August 25, 2005
Address correspondence to Sheng-Rong Guo, Department of Chemistry, Lishui
University, Lishui, 323000, China. E-mail: guosr9608@sina.com
1479

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S.-R. Guo and Y.-Q. Yuan
Scheme 1.
is inclined to be substituted and give some significative compounds.[5–8]
Recently, we reported a highly efficient method for the nucleophilic
displacement reaction in ionic liquids such as [bmim]BF4 compared with
the previous method.[9,10] In this method, ionic liquids enhanced not only
the significant reactivity of nucleophile but also reduced the formation of
by-products. However, the reaction need high temperature and a long time.
Leadbeater and Torenius[11] and others[12,13] reported that the reaction in the
system of ionic liquid–mediated microwave heating of organic solvents is
successful and safe, so we considered using microwave irradiation
to shorten reaction time. In this article further investigation of the nucleo-
philic substitution reaction was made using the ionic liquid 1-butyl-3-
methylimidazonium tetrafluoroborate [bmim] BF4 as a solvent and ethyl
acetate; the microwave-irradiation technique was used instead of con-
ventional heat. Yields are good to excellent and the reaction time is
dramatically shortened. Some of the products are new compounds
(Scheme 1 and Table 1).
Although this nucleophilic displacement reaction can happen in tra-
ditional solvents such as ethyl acetate, a long time is needed to heat the
Table 1. Synthesis of compounds 3a–l
Product
O-
M-
P- Time (min) Yield (%)
3a
3b
3c
Cl
Cl
6
7
92
93
95
96
98
92
95
97
94
96
98
97
Cl
i-Pr
Me
8
3d
3e
7
OMe
6
3f
F
SH
8
3 g
3 ha
3i
6
NH2
COOH
5
10
9
3j
C2H5 OH
Cl CF3
3 k
3la
2 k552-naphthol
Cl
7
6
aFunctional group is amido.

Enhanced Reactivities of Nucleophilic Substitution Reactions
1481
Scheme 2.
reaction mixture and the reaction temperature must be strictly controlled. The
by-product increased if the reaction temperature exceeded 808C. The reaction
time reduced drastically when ionic liquids as organic solvents were used with
controlled microwave irradiation as compared to conventional methods, and
good yields were obtained. Generally, the ionic liquid [bmim]BF4 is too
thick to dissolve the reaction mixture homogeneously, so we added a
traditional solvent such as ethyl acetate to dilute the ionic liquid.
When the benzene ring connects more than one functional group, for
example, when the thiohydroxyl and the hydroxyl appeared together on one
benzene ring, the thiohydroxyl is more kinetic than the hydroxyl
(Scheme 2). The structure of product 3j proved to be the sulfanyl
1
methylene by comparing the H NMR spectra of 3j with the raw material
2-ethyl-4-mercaptophenol.
The compound 2k 2-amino-benzenethiol has two functional groups; when
it reacted with excessive compound 1, the hydrogen atom in the two functional
1
group disappeared, as evidenced by analyzing the H NMR spectra of its
product. When it reacted with equivalent compound 1, the –NH2 is more
active than the –SH (Scheme 3). The 1H NMR spectra of the product
3h has a distinct character: it has two more double peaks compared to
other products because the two hydrogen atoms coupled with each other in
the –NH- and 55CH.
In conclusion, these nucleophilic substitutions show that the order of the
nucleophilicity is ArNH2 . ArS21 ꢀ ArO21 when they reacted with the
compound 1. The reported effective microwave irradiation method for the
synthesis of compound 3a–l appears to be a more convenient and practical
method in terms of mild reaction conditions, shorter reaction time, simple
operation, the use of ionic liquid as “green solvents” and high yields.
Scheme 3.

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S.-R. Guo and Y.-Q. Yuan
EXPERIMENTAL
1H NMR spectra were recorded on Avance-300 spectrometer with TMS as
internal standard. IR spectra were determined on Vector-55 instrument. Silica
gel 60 GF254 was used for analytical and preparative TLC. All products
were characterized by comparison with authentic samples using IR, 1H NMR,
and mp. The ethoxymethylene isopropylidene malonate was prepared from
malonic acid cyclic isopropylidene ester and triethyl orthoformate.
General Procedure for the Synthesis of 3a–l
In a 25-mL beaker were placed 3 mL of [bmim]BF4 ionic liquid, 2 mmol of
ethoxymethylene isopropylidene malonate, 2 mmol of thiophenol, and 1 mL
ethyl acetate. The mixture in beaker was allowed to stir for a few minutes
until it was homogeneous and then irradiated in the microwave oven for
5 min. The cooled mixture was extracted with ethyl ether (5 mL Â 3), then
the extracts were concentrated under reduced pressure, and the residue was
purified by column chromatography on silica gel with cyclohexane and
ethyl acetate (19:1) as eluent. Upon completion of the ethyl ether extracts,
the resulting ionic liquid was evaporated half an hour under 4 mm Hg at
608C, using this ionic liquid solvent. A second run was performed under the
identical reaction conditions and no decreases in yields were found. The
results are presented in Table 1.
Data
3a: A white solid, mp 163–1648C. 1H NMR (CDC13): d ¼ 8.99 (s, 1H), 7.50
(q, J ¼ 8.7 Hz, 4H), 1.77 (s, 6H), IR (KBr) n ¼ 3038, 1705, 1537, 1479, 1285,
825 cm21. Anal. calcd. for C13H11ClO4S: C, 52.27; H, 3.71. Found: C, 52.79;
H, 3.84.
3b: A white solid, mp 110–1128C. 1H NMR (CDC13): d ¼ 9.04 (s, 1H), 7.47
(m, J ¼ 8.2 Hz, 3H), 1.77 (s, 6H); IR (KBr) n ¼ 3066, 2369, 1733, 1689,
1428, 1269, 767 cm21. Anal. calcd. for C13H10Cl2O4S: C, 46.86; H, 3.03.
Found: C, 47.39 H, 3.36.
1
3c: A white solid, mp 86–888C. H NMR (CDC13): d ¼ 8.96 (s, 1H), 7.45
(d, J ¼ 10.3 Hz, 2H), 7.30 (d, J ¼ 10.3 Hz, 2H), 4.08–4.15 (m, 1H), 1.77
(s, 6H); 1.2 (d, J ¼ 6.87 Hz, 6H); IR (KBr) n ¼ 3000, 2869, 1706, 1543,
1333, 1220, 924, 865, 795 cm21. Anal. calcd. for C16H18O4S: C, 62.72; H,
5.92. Found: C, 62.08, H, 6.26.
3d: A white solid, mp 142–1438C. 1H NMR (CDC13): d ¼ 9.06 (s, 1H), 7.49
(d, J ¼ 8.2 Hz, 2H), 7.27 (d, J ¼ 8.2 Hz, 2H), 2.41 (s, 3H), 1.77 (s, 6H); IR
(KBr): n ¼ 3017, 1717, 1542, 1340, 1219, 1208, 933, 814 cm21. Anal.
calcd. for C14H14O4S: C, 60.42; H, 5.07. Found: C, 60.03; H, 5.26.

Enhanced Reactivities of Nucleophilic Substitution Reactions
1483
3e: A white solid, mp 92–938C. 1H NMR (CDC13): d ¼ 9.09 (s, 1H), 6.98–
7.39 (m, J ¼ 8.2 Hz, 4H), 3.85 (s, 3H), 1.77 (s, 6H,); IR (KBr) n ¼ 3066, 2940,
2836, 1707, 1529, 1482, 1286, 869 cm21. Anal. calcd. for C14H14O5S: C,
57.13; H, 4.79. Found: C, 56.96, H, 5.06.
3f: A white solid, mp 136–1388C. 1H NMR (CDC13): d ¼ 9.05 (S, 1H), 7.57
(q, J ¼ 8.6 Hz, 2H); 7.2 (m, J ¼ 8.2 Hz, 2H), 1.77 (s, 6H); IR (KBr):
n ¼ 3426, 3099, 1738, 1712, 1492, 1034, 929, 869 cm21. Anal. calcd. for
C13H11FO4S: C, 55.31; H, 3.93. Found: C, 56.06, H, 3.86.
3g: A white solid, mp 186–1888C. 1H NMR (CDC13): d ¼ 9.01 (s, 2H), 7.67
(m, J ¼ 8.6 Hz, 4H), 1.77 (s, 12H); IR (KBr): n ¼ 3082, 2951, 1706,
1536,1394, 1198, 918 cm21. Anal. calcd. for C20H18O8S2: C, 53.32; H,
4.03. Found: C, 53.08, H, 4.26.
3h: A white solid, mp 150–1528C. 1H NMR (CDC13): d ¼ 11.80
(d, J ¼ 14.08 Hz, 1H), 8.50 (d, J ¼ 14.08 Hz, 1H), 7.13–7.47
(m, J ¼ 7.58 Hz, 4H), 1.77 (s, 6H,); IR (KBr): n ¼ 3254, 3084, 1720, 1518,
1302, 875 cm21. Anal. calcd. for C13H13NO4S: C, 55.90, H, 4.69; Found: C,
55.67, H, 4.78.
3i: A white solid, mp 184–185 8C. 1H NMR (CDC13): 9.08 (s, 1H), 8.1–7.78
(m, J ¼ 8.70 Hz, 4H), 1.77 (s, 6H); IR (KBr): n ¼ 3252, 3082, 1719, 1518,
1210, 874 cm21. Anal. calcd. for C14H12O6S: C, 54.54, H, 3.92. Found: C,
55.87; H, 4.08.
1
3j: A white solid, mp 174–1758C. H NMR (CDC13): 9.05 (s, 1H), 7.30
(m, J ¼ 8.3 Hz, 2H), 6.84 (d, J ¼ 8.3 Hz, 1H), 5.56 (b, s, 1H), 2.6
(q, J ¼ 7.68 Hz, 2H), 1.77 (s, 6H), 1.3,(t, J ¼ 7.68 Hz, 3H); IR (KBr): n ¼
3306, 2973, 2880, 2367, 1689, 1530, 1345, 1279, 924, 864 cm21. Anal.
calcd. for C15H16O5S: C, 58.43; H, 5. 23. Found: C, 58.87; H, 5.02.
1
3 k: A white solid, mp 187–189 8C. H NMR (CDC13): 9.01 (s, 1H), 7.76–
7.67 (m, 4H), 7.46–7.40 (m, 2H), 7.32 (q, J ¼ 8.7 Hz, 1H), 1.77 (s, 6H); IR
(KBr): n ¼ 3046, 2340, 1689, 1530, 1289, 924, 884 cm21
.
3l: A white solid, mp 164–165 8C. 1H NMR (CDC13): 11.26 (d, J ¼ 13.7 Hz,
1H), 8. 71 (d, J ¼ 13.6 Hz, 1H), 7. 7 (s, 2H), 1.77 (s, 6H); IR (KBr): n ¼ 3159,
3079, 2995, 1733, 1689, 1067, 1428, 1269, 1006, 935 cm21
.
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