Synthesis of 4-substituted 2-carenes in novel imidazolinium ionic liquids

Article abstract of DOI:10.1007/s10600-007-0063-8

4-Acetyl-, 4-acetoxymethyl-, and 4-hydroxymethyl-2-carenes were synthesized using novel ionic liquids.

Full text of DOI:10.1007/s10600-007-0063-8

Chemistry of Natural Compounds, Vol. 43, No. 2, 2007
SYNTHESIS OF 4-SUBSTITUTED 2-CARENES IN NOVEL
IMIDAZOLINIUM IONIC LIQUIDS
F. Macaev,1 K. Gavrilov,2 V. Muntyanu,1 E. Styngach,1
L. Vlad,1 L. Bets,1 S. Pogrebnoi,1 and A. Barba1
UDC 547.596/598+547.854.021
4-Acetyl-, 4-acetoxymethyl-, and 4-hydroxymethyl-2-carenes were synthesized using novel ionic liquids.
Key words:
(+)-3-carene, 4-substituted 2-carenes, 2-(1 -1-imidazolyl)ethylcarbonitrile, ionic liquids.
H
1
Derivatives of the monoterpene 3-carene ( ) such as (+)-4α-acetyl-2-carene (2), (+)-4α-hydroxymethyl-2-
carene (3), and (+)-4α-acetoxymethyl-2-carene (4) are widely used to synthesize optically active 1,3-disubstituted
2,2-dimethylcyclopropanes [1], including precursors of commercially important insecticides [2-6]. Known methods for
preparing 2-4 include heating 1 with ZnCl in Ac O solution or with paraformaldehyde in AcOH solution [7-9]. Syntheses of
2
2
5 and 6 from the corresponding epimers 2 and 3 have also been reported [3, 7].
Ionic liquids (IL) have in the last decade become of interest in organic synthesis. However, examples of the synthesis
of4-substituted 2-carenes using IL have not appeared [1, 10-14]. Furthermore, researchers have paid attention mainlytotesting
commercially available IL salts of N,N′-dialkyl substituted imidazoles whereas functionalized analogs, e.g., carbonitriles, have
been little studied [11].
Herein we report the ability to synthesize 4-substituted 2-carenes based on 1 using salts 8-10 as catalyst and solvent.
These were prepared using 2-(1H-1-imidazolyl)ethylcarbonitrile (7).
−
X
N
Et N (cat.)
3
NC
NC
HN
N
N
N
N
+
NC
+
7
8 - 10
8: X = Br; 9: X = BF4; 10: X = PF6
It was found that holding an equimolar mixture of 1, Ac O, and 6 mole % 8, 9, or 10 at +50°C enhances the Kondakov
2
reaction.
The catalytic activity of melts of the synthesized imidazole salts is probably due to initial formation of an acylium ion
from Ac O that involves the nitrile associated with the anion [14, 15]. Table 1 gives the reaction conditions and yields of 2
2
and 5.
Judging from GC data and the integrated intensities of the gem-dimethyl and acetyl groups in the PMR spectrum, the
reaction product is a mixture of two compounds in a 95:5 ratio. Signals assigned to the major product agreed with literature
data for 2 [7] whereas those for the minor product agreed well with those assigned to 4β-acetyl-2-carene (5). Moreover, the
difference in the chemical shifts of the geminal methyls of the minor and major isomers at 0.23 and 0.16 ppm, respectively, in
combination with the position of the H-3 signal provides additional confirmation of the proposed structures [7].
3
The carbonium ion formed by addition of the acyl cation to the ∆ -double bond of 1 is stabilized by elimination of a
2
proton to regenerate a ∆ -double bond (Scheme 1).
1) Institute of Chemistry, Academy of Sciences of Moldova, ul. Akademicheskaya, 3, Kishinev, MD-2028, Republic
of Moldova; 2) S. I. Esenin Ryazan′ State University, fax 373-22-73-99-54, e-mail: flmacaev@cc.acad.md. Translated from
Khimiya Prirodnykh Soedinenii, No. 2, pp. 114-116, March-April, 2007. Original article submitted November 13, 2006.
0009-3130/07/4302-0136 ©2007 Springer Science+Business Media, Inc.
136

TABLE 1. Reaction Conditions and Yield of 2 and 5
IL
Amount of IL
Total yield of 2 and 5, %
Reaction time, h
8
6 mole %
melt
32.58
36.7
49
25
46
48
9
6 mole %
6 mole %
38.26
29.21
10
4
9
5
6
O
O
3
O
O
+
1
7
8
5
1
2
Scheme 1.
The preferential formation of 2 is due to the directing effect of the 2,2-dimethylcyclopropane group [7]. Carrying out
the reaction in a melt of 8 halves the time and slightly increases the yield. If the reaction is carried out in a melt of 9 or 10, the
2,2-dimethylcyclopropane ring opens and produces a complicated product mixture in addition to the acetylation reaction.
Attempted hydroxymethylation of 1 using paraformaldehyde in a melt of the aforementioned salts or with a catalytic
amount of ZnCl added to the reaction mixture was unsuccessful. Only for a melt of 9 did addition of a stoichiometric amount
2
of AcOH lead to a Prins reaction. The α-hydroxy carbonium ion produced by binding of a proton to formaldehyde reacts with
2
1 to give the β-hydroxy carbonium ion that is stabilized by elimination of a proton to regenerate a ∆ -double bond.
H
4
H
H
9
H
4
3
OH
5
6
5
6
OH
OH
OH
OAc
3
+
+
1
1
7
7
8
3
1
4
6
The reaction products were isolated by column chromatography over silica gel. The less polar fraction contained 4
(38% yield), the physical chemical constants ofwhich were analogous tothose published [7-9]. The polar fraction was a mixture
of compounds in a 9:1 ratio according to GC and signal intensities of the gem-dimethyl group in the PMR spectrum. The
positions of the characteristic singlets for three methyls at 0.87, 1.05, 1.75 and 0.85, 0.96, and 1.69 ppm agreed with those
reported previously [7-9] for epimeric 4,7,7-trimethylbicyclo[4.1.0]hept-4-en-3-ylmethanols 3 and 6.
Thus, 4-substituted 2-carenes were synthesized from (+)-3-carene using novel 1-(2-ethylcarbonitrile)-3-propyl-1H-
imidazol-3-ium salts, which differ from the traditional solvents (Ac O, AcOH) in being nonvolatile and catalytic.
2
EXPERIMENTAL
13
IR spectra wererecorded on a Specord 75 spectrophotometer; PMR and C NMRspectra, on Bruker AC-E 200 (200.13
and 50.32 MHz) and Bruker AC-80 (80 and 20 MHz) spectrometer as 2-3% solutions in CDCl or DMSO-d with TMS internal
3
6
standard. Specific rotation was measured on a A1-EPO polarimeter. GC was performed on a Chrom-5 chromatograph with
a FI detector, glass column (1.2 × 3 mm), SE-30 (5%) stationary phase on Chromaton N-AW-DMCS (0.16-0.20 mm), and He
3
carrier gas (40 cm /min flow rate). Column chromatography used silica gel (SiO ) L 40/100, 100/160 µ (Czech Rep.) and
2
40/63 µ (Fluka); TLC, Silufol plates (Czechoslovakia). Compounds were detected byphosphomolybdic acid (5%) in EtOHwith
subsequent heating or dipping of plates in acidified aqueous KMnO (2%). Imidazole, acrylonitrile, KBF , and KPF were
4
4
6
reagent grade (Aldrich).
137

20
26
(+)-(1S,6R)-3,7,7-Trimethylbicyclo[4.1.0]hept-2-ene (1, Aldrich, 90%) gave n
1.4726 and [α]
+15.7° (l = 1,
D
D
without solvent).
Synthesisof a Mixture of [(1R,3R,6S)-4,7,7-Trimethylbicyclo[4.1.0]hept-4-en-3-yl]-1-ethanol (2)and[(1R,3S,6S)-
4,7,7-Trimethylbicyclo[4.1.0]hept-4-en-3-yl]-1-ethanol (5). Amixtureof2 and 5 was prepared bytwomethods. a) A mixture
of 1 (1 g, 7.3 mmol) and Ac O (0.83 g, 8 mmol) was treated with 8, 9, or 10 (0.44 mmol). The reaction mixture was stirred
2
with heating [50-55°C, TLC monitoring, benzene:CCl (1:1) eluent] and extracted with hexane (3 × 10 mL). The extract was
4
washed with saturated aqueous NaCl solution and dried over anhydrous Na SO . Solvent was distilled off. The solid (1.1 g)
2
4
was purified over a SiO (45 g) column with elution by hexane to afford a colorless mixture of 2 and 5 (for yield, see Table 1),
2
20
20
n
1.4869, [α]
+346.5° (c 1.33, CHCl ), C H O. PMR spectrum of the major isomer (80 MHz, CDCl , δ, ppm, J/Hz):
3 12 18 3
D
D
0.79, 1.02 (3H each, s, H-7, H-8), 0.93-1.05 (2H, m, H-1, H-6), 1.18-1.68 (2H, m, H-2), 1.73 (3H, s, H-4), 2.08 (3H, s, H-9),
3.18, 3.22 (1H, dd, H-3, J = 6.4, J3,2β = 10.6), 5.4-5.6 (1H, m, H-5).
3,2α
b) Stirring 1 (1 g, 7.3 mmol) and Ac O (0.83 g, 8 mmol) in 8, 9, or 10 (3 g) and work up analogously to that described
2
in a) gave a mixture of 2 and 5 identical to that described above.
Synthesis of (1R,3S,6S)-4,7,7-Trimethylbicyclo[4.1.0]hept-4-en-3-ylmethyl Acetate (4). Stirring a mixture of 1
(1.36 g, 10 mmol), AcOH (0.6 g, 10 mmol), and paraformaldehyde (0.3 g, 10 mmol) at 50-55°C in 9 (5 g) for 20 h [TLC
monitoring, CHCl :acetone (9.5:0.5) eluent] and extraction byether (3 × 50 mL) gave a solid (1.8 g) that was chromatographed
3
20
over a column of SiO (60 g) with elution by hexane to afford colorless 4 (0.79 g), yield 38%, [α]
+132° (c 3.1, CHCl ),
3
2
D
+133.6°. IR spectrum (ν, cm−1): 1380, 1385 (CMe ), 1670
20
20
20
n
1.4765, C H O ; lit. [8] [α]
+122° and [9] [α]
D
13 20
2
D
D
2
(C=CH), 1740 (CO ).
2
PMR spectrum (200.13 MHz, CDCl , δ, ppm, J/Hz): 0.87, 1.06 (3H each, s, Me C), 0.8-1.08 (2H, m, H-1, H-6), 1.69-
3
2
1.72 (3H, m, MeC=), 1.82-2.2 (2H, m, H-2), 2.06 (3H, s, MeCO), 2.35-2.55 (1H, m, H-3), 3.92, 4.03 (2H, dd, J
= 2.1,
3,2α
J
3,2β = 6.4, CH O), 5.42-5.58 (1H, m, H-5).
2
13
C NMR spectrum (20 MHz, CDCl ): 15.01 and 22.65 [C(CH ) ], 16.90 (C-6), 20.82 (CH CO), 21.80 (C-2), 23.11
3
3 2
3
(C-7), 37.60 (C-3), 23.24 (C-1), 27.61 (CH –C=), 65.86 (CH O), 122.12 (C-5), 136.04 (C-4), 170.76 (CO ).
3
2
2
Synthesis of a Mixture of (1R,3R,6S)-4,7,7-Trimethylbicyclo[4.1.0]hept-4-en-3-ylmethanol (3) and (1R,3S,6S)-
4,7,7-Trimethylbicyclo[4.1.0]hept-4-en-3-ylmethanol (6). Elution of the hydroxymethylation products (1.36 g) of 1 (see
20
synthesis of 4) by hexane:ethylacetate (7:3) gave a mixture of 3 and 6 (0.48 g), yield 29%, [α]
+101.9° (c 1.84, CHCl ),
3
D
C H O.
11 18
PMR spectrum of the major isomer (80 MHz, CDCl , δ, ppm, J/Hz): 0.87, 1.05 (3H each, s, H-7, H-8), 0.7-1.08 (2H,
3
m, H-1, H-6), 1.75 (3H, s, H-4), 1.81-2.13 (2H, m, H-2), 2.37-2.60 (1H, m, H-3), 3.92, 4.03 (2H, dd, J
H-9), 4.7 (1H, OH), 5.49-5.6 (1H, m, H-5).
= 2.0, J3,9β = 6.4,
3,9α
Synthesis of 2-(1H-1-Imidazolyl)ethylcarbonitrile (7). A solution of imidazole (40 g, 0.59 mol) in toluene (80 mL)
was treated with acrylonitrile (33.85 g, 0.59 mol) and Et N (0.1 mL). The mixture was stirred at 60-65°C for 30 h. The solvent
3
was distilled off to afford 7 (oil, 71 g, 99.75%), C H N . IR spectrum (ν, cm−1): 2250 (CN).
6
7 3
PMR spectrum (80 MHz, DMSO-d , δ, ppm, J/Hz): 2.69 (2H, t, J = 6.5, H-1, propionitrile), 4.13 (2H, t, J = 6.94, H-2,
6
propionitrile), 6.88-7.01 (2H, m, H-4, H-5, imidazole), 7.43 (1H, s, H-1, imidazole).
Synthesis of 1-(2-Ethylcarbonitrile)-3-propyl-1H-imidazol-3-iumBromide (8). A mixture of 7 (2.13 g, 0.018 mol)
and propylbromide (2.17 g, 0.022 mol) in acetone (5 mL) was stirred at room temperature for 15 h [TLC, CHCl :propan-2-ol
3
(3:7) eluent]. Solvent and the excess of starting bromide were distilled off to afford 8 (4.14 g of salt), yield 96.5%, yellow oil,
-1
C H BrN . IR spectrum (ν, cm ): 630 (Br), 1460, 1565 (C=C), 2250 (CN), 740, 2890, 2940, 2965 (aliphatic).
9
14
3
PMR spectrum (80 MHz, DMSO-d , δ, ppm, J/Hz): 0.82 (3H, t, J = 7.4, H-3, propyl), 1.6-1.91 (2H, m, H-2, propyl),
6
3.30 (2H, t, J = 6.5, H-1, propionitrile), 4.29 (2H, t, J = 6.4, H-2, propionitrile), 4.56 (2H, t, J = 6.5, H-1, propyl), 7.8-7.9 (2H,
m ,H-4, H-5, imidazole), 9.47 (1H, s, H-2, imidazole.
13
C NMR spectrum (20 MHz, DMSO-d ): 10.23 (C-3, propyl), 18.87 (C-1, propionitrile), 22.74 (C-2, propyl), 44.42
6
(C-1, propionitrile), 50.45 (C-1, propyl), 117.54 (C-4, imidazole), 118.23 (CN), 122.42 (C-5, imidazole), 122.70 (C-2,
imidazole).
Synthesis of 1-(2-Ethylcarbonitrile)-3-propyl-1H-imidazol-3-ium Tetrafluoroborate (9). A solution of 8 (25 g,
0.102 mol) in acetone (25 mL) was treated in portions (4 g) with KBF (12.85 g, 0.102 mol). The mixture was stirred at room
4
temperature for 30 h. The solvent was distilled off. The solid was extracted with CH Cl (3 × 70 mL). The combined extract
2
2
138

was dried over Na SO . The solvent was distilled off to afford 9 (22.69 g), yield 88.3%, yellow oil, C H BF N . IR spectrum
2
4
9
14
4 3
(ν, cm−1): 1020 (BF), 1455, 1570 (C=C), 2260 (CN), 740, 2895, 2985 (aliphatic).
PMR spectrum (80 MHz, DMSO-d , δ, ppm, J/Hz): 0.79 (3H, t, J = 7.49, H-3, propyl), 1.65-1.92 (2H, m, H-2, propyl),
6
3.34 (2H, t, J = 6.64, H-1, propionitrile), 4.20 (2H, t, J = 6.95, H-2, propionitrile), 4.57 (2H, t, J = 6.41, H-1, propyl), 7.9-8.03
(2H, m, H-4, H-5, imidazole), 9.58 (1H, s, H-2, imidazole).
13
C NMR spectrum (20 MHz, DMSO-d ): 10.32 (C-3, propyl), 18.86 (C-1, propionitrile), 22.82 (C-2, propyl), 44.50
6
(C-1, propionitrile), 50.55 (C-1, propyl), 117.62 (C-4, imidazole), 118.40 (CN), 122.49 (C-5, imidazole), 122.79 (C-2,
imidazole).
Synthesis of 1-(2-ethylcarbonitrile)-3-propyl-1H-imidazol-3-ium hexafluorophosphate (10) was prepared
analogously to 9 using equimolar amounts of 8 and KPF . Yield 96.6%, yellow oil, C H F N P. IR spectrum (ν, cm−1): 850
6
9 14 6 3
(PF), 1460, 1570 (C=C), 2260 (CN), 750, 2895, 2995 (aliphatic). PMRspectrum (80 MHz, DMSO-d , δ, ppm, J/Hz): 0.84 (3H,
6
t, J = 7.50, H-3, propyl), 1.58-1.94 (2H, m, H-2, propyl), 3.15 (2H, t, J = 6.64, H-1, ethyl), 4.14 (2H, t, J = 6.95, H-2,
propionitrile), 4.48 (2H, t, J = 6.42, H-1, propyl), 7.66-7.77 (2H, m, H-4, H-5, imidazole), 9.16 (1H, s, H-2, imidazole).
13
C NMR spectrum (20 MHz, DMSO-d ): 10.45 (C-3, propyl), 19.01 (C-1, propionitrile), 22.96 (C-2, propyl), 44.63
6
(C-1, propionitrile), 50.74 (C-1, propyl), 117.77 (C-4, imidazole), 120.30 (CN), 122.85 (C-5, imidazole), 122.91 (C-2,
imidazole).
ACKNOWLEDGMENT
The work was supported by Moldova—Russia projects No. 06.21 CRF and No. 06-03-90898-Mol-a.
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