Improved synthesis of methyl 3-oxo-2,6,6-trimethylcyclohex-1-ene-1- carboxylate, an A-ring intermediate for (±)strigol

Article abstract of DOI:10.3184/030823407X240881

Methyl 3-oxo-2,6,6-trimethylcyclohex-1-ene-1-carboxylate was synthesised over eight steps from the starting material of citral instead of α-ionone. KMnO₄, HC(OEt)₃ and O₂/TEMPO/CuCl were substituted for NaIO₄, CH₃I and pyridinium chlorochromate, respectively. Every step was simplified and gave a 48% overall yield. The procedure is suitable for large scale production.

Full text of DOI:10.3184/030823407X240881

494 RESEARCH PAPER
AUGUST, 494–496
JOURNAL OF CHEMICAL RESEARCH 2007
Improved synthesis of methyl 3-oxo-2,6,6-trimethylcyclohex-1-ene-
1-carboxylate, an A-ring intermediate for ( )strigol
Qianchaoa, Pi Shiqinga,b and Chen Xinzhia*
aCollege of Materials Science and Chemical Engineering, Zhejiang University, 310027, P. R. China
bXinchang Pharmaceutical Factory, Zhejiang Medicine Co. Ltd., Xinchang 312500, P. R. China
Methyl 3-oxo-2,6,6-trimethylcyclohex-1-ene-1-carboxylate was synthesised over eight steps from the starting
material of citral instead of a-ionone. KMnO4, HC(OEt)3 and O2/TEMPO/CuCl were substituted for NaIO4, CH3I and
pyridinium chlorochromate, respectively. Every step was simplified and gave a 48% overall yield. The procedure is
suitable for large scale production.
Keywords: strigol, citral, α-cyclocitral, TEMPO, methyl 3-oxo-2,6,6-trimethylcyclohex-1-ene-1-carboxylate
Strigol(1) is a highly potent seed germination stimulant for
witchweed, a harmful parasitic plant that attacks numerous
graminaceous crops. Several partial and total syntheses of
alcohol (6) in 96% yield. Oxidation of (6) with oxygen
catalysed by TEMPO and CuCl gave the desired enone (7) in
90% yield.
The synthesis of (7) was accomplished in eight steps from
the readily available and relatively inexpensive citral with a
48% overall yield. The synthesis utilises operationally simple
procedures and is suitable for industrial use.
(±) strigol had been reported1-5
.
o
o
O
H
O
Experimental
General
o
H
HO
Strigol(1)
1H NMR spectra were obtained in CDCl3 at BrukerAC-400. Chemical
shifts are given in ppm, with respect to internal TMS, J values are
quoted in Hz. IR spectra were obtained neat with a Nicolet NEXUS-
670 spectrophotometer, only the most significant absorptions in cm-1
are indicated. Mass spectra were obtained on a Trace DSQ GC-MS
spectrometer.
Methyl 3-oxo-2,6,6-trimethylcyclohex-1-ene-1-carboxylate
(7) is a key A-ring intermediate used in the synthesis
of (1). Dee W. Brooks reported a simple and efficient
synthesis of (7) from α-ionone in five steps (see Scheme 1).
The synthesis utilises operationally simple procedures,
involves no chromatography, and is suitable for large-scale
preparation. However, expensive and hazardous reagents were
used, such as NaIO4, CH3I and pyridinium chlorochromate.
The synthesis of (7) developed by Dee W. Brooks and co-
workers formed the basis for our efforts to devise an improved
practical synthesis (see Scheme 2).
α-Cyclocitral (2): Prepared according to the USP 4358614(1982).
Step 1: Methylamine 46.5 g (1.5 mol) was passed into citral 152 g
(1.0 mol) (in the form of the commercial cis–trans isomer mixture)
in the course of 45 min at 20–25°C, during which time an aqueous
phase separated. After a further 10 mins, the aqueous phase was
substantially separated (about 20 g of aqueous phase being obtained)
and the organic residue was partially freed from excess methylamine
at 20°C and 20 mbar.
According to ref. 6, α-cyclocitral (2) was obtained in
overall 70% yield by three steps of aminisation, cyclisation
and hydrolysis from the commercially available citral
as the starting material. Oxidation of (2) with potassium
permanganate afforded (3) in 90% yield. Epoxidation of (3)
with m-chloroperoxybenzoic acid (MCPBA) gave a mixture
of isomeric epoxides (4a) and (4b) in 98% yield. The mixture
(4a) and (4b) was esterified with trimethyl orthoformate afford
to (5) in 95% yield. Treatment of (5) with sodium methoxide
in methanol resulted in opening of the epoxide to the allylic
Step 2: The crude citral N-methylaldimine prepared according
to Step 1 was dripped into concentrated sulfuric acid 500 g in the
course of 35 min under a nitrogen atmosphere at –10 to –15°C, with
vigorous stirring. After the addition stirring was continued for 15 min
at –15°C.
Step 3: Ice 600 g was first added to the reaction mixture, containing
sulfuric acid, obtained from Step 2, and then sufficient 50% strength
by weight sodium hydroxide solution was added at 40°C to give a
pH of about 3.5. The pH rose to 6.8 in the course of 40 min, without
the addition of further sodium hydroxide solution. The mixture was
then brought to pH 7, after which, the aqueous phase and the sodium
O
O
O
1.MCPBA,CH2Cl2
NaIO ,KMnO (cat)
OR
4
4
CH3I , K2CO3
O
O
O
O
NaOCH3,CH3OH
OCH3
PCC,CH2Cl2
OCH3
OH
O
Scheme 1
* Correspondent. E-mail: xzchen@zju.edu.cn
PAPER: 07/4742

JOURNAL OF CHEMICAL RESEARCH 2007 495
O
H
N-R
H
N-R
H
O
O
O
OH
H
KMnO
MCPBA
4
OH
O
(3)
(4)
(2)
O
O
O
HC(OCH )
NaOCH ,CH OH
3 3
OCH3
3 3
OCH3
O2,TEMPO
CuCl
OCH3
O
OH
O
(5)
(6)
Scheme 1
(7)
sulfate which had crystallised out were separated off. The organic
phase was then steam-distilled and the cyclocitral was extracted from
the condensate (about 2.5l with diethyl ether (3 × 100 ml). The ether
solution was dried and the ether removed, leaving the cyclocitral
mixture 141.3 g. This corresponded to a yield of 90%, based on citral
employed. The isomer mixture was separated by fractional distillation
into pure 82 g α-cyclocitral (boiling point 39°C/0.4 mbar) and 51 g
pure β-cyclocitral (boiling point 52°C/0.2 mbar).
over night. The lower boiling substances were removed on a rotary
evaporator. The oil residue (5) 91 g was obtained. Crude oil 2 g was
purified by column chromatography (AcOEt:cyclohaxane = 4:6) for
analysis: IR(KBr) 2960(s), 1740(s), 1430(m), 1240(m), 1150(s) cm-1;
1H NMR(CDCl3) δ 0.90(3H, s), 0.95(3H, s), 1.39(3H, s), 1.7–2.0(4H,
m), 2.45(1H, s), 3.0(1H, t, J = 2 Hz), 3.72(3H,s). Anal. Calcd for
C11H18O3: C, 66.67; H, 9.09. Found: C, 66.70; H, 9.11%.
Methyl 3-hydroxy-2,6,6-trimethylcyclohex-ene-1-carboxylate (6):
To a stirred solution of sodium metal 10.0 g (0.43 mol) dissolved in
methanol (100 ml) was added dropwisely (5) 90.0 g in methanol
50 ml under a N2 atmosphere. The solution was refluxed for 6 h,
cooled to room temperature, and neutralised with 1NH2SO4, the
excess methanol was removed on a rotary evaporator, and the
aqueous residue was extracted with ethyl acetate (2 × 200 ml).
The combined organic layers were washed with aqueous saturated
NaCl solution (200 ml), dried over Na2SO4, filtered, and evaporated
to give (6) 87 g (96%), Crude oil 3 g was purified by column
chromatography AcOEt:cyclohaxane = 1:1) for analysis: IR(KBr)
3420(br), 2960(s), 1720(s), 1430(m), 1290(m) 1230(br), 1060(m),
1020(br), 900(m), 725(s) cm-1; 1H NMR(CDCl3) δ 1.05(3H, s),
1.10(3H, s), 1.2–2.1(4H, m), 1.78(3H, s), 2.2(1H, br s), 3.75(3H,
s), 4.2(1H, m). Anal. Calcd for C11H18O3: C, 66.67; H, 9.09. Found:
C, 66.72; H, 9.11%.
Methyl 3-oxo-2,6,6-trimethylcyclohex-1-ene-1-carboxylate (7):
To a stirred mixture of TEMPO 3.5 g (0.02 mol) and CuCl 2.0 g
(0.02 mol) in N,N-dimethyl formamide (150 ml) was added (6) 80 g. To
the above mixture, oxygen was bubbled for. 15 h at room temperature,
N,N-dimethyl formamide was then removed by distillation at reduced
pressure. To the residue was added dichloromethane (200 ml), and
the solid were removed by filtration, the filtrate was washed with
aqueous saturated NaCl solution (100 ml), the organic layers dried
with Na2SO4, filtered, and evaporated. The residue was then distilled
at reduced pressure to give 75 g(90%) of pure (7): b.p. 75°C (0.02
mm Hg). 1H NMR(CDCl3) δ 1.10(3H, s), 1.20(3H, s), 1.3–2.5(4H,m),
1.86(3H, s), 3.76(3H,s). GC-MS(EI, 70Ev): m/z(%) = 197 (M+ + H,
10), 196(M+, 100), 137(86). Anal. Calcd for C11H16O3: C, 67.32; H,
8.22. Found: C, 67.38; H, 8.02%.
α-Cyclocitral:1H NMR(CDCl3):δ1.1(3H, s), 1.32(3H, s), 1.7–2.1(4H,
m), 1.81(3H, s), 2.62(1H, s), 5.28(1H, s), 9.51(1H, s). GC-MS(EI,
70Ev): m/z(%) = 153 (M+ + H, 12), 152(M+, 100), 123(76). Anal. Calcd
for C10H16O: C, 78.95; H, 10.53. Found: C, 79.02; H, 10.55%.
2,6,6-Trimethylcyclohex-2-ene-1-carboxylic acid (3): To a solution
of α-cyclocitral (2) 152 g (1.0 mol) in 2-propanol 2.5l, potassium
carbonate 17 g (0.123 mol), and then potassium permanganate 17 g
(1.08 mol) in water (2.5l) were added in succession. The reaction
mixture was stirred for 5 h at room temperature. Then the solids were
removed by suction filtration and washed with water (2 × 50 ml). The
filtrate was concentrated on a rotary evaporator to approximately 2.5l
and extracted with ether (2 × 300 ml). The aqueous layer was acidified
to pH 2 with 1N HCl and extracted with ethyl acetate (4 × 500 ml).
The combined organic layers were dried over MgSO4, filtered, and
evaporated to give (3) as a yellow oil: 142.5 g (85%); crude oil 2 g
was purified by column chromatography (AcOEt: Cyclohexane:
AcOH = 10:10:1) for analysis; IR(KBr) 3450(br), 2960(s), 1725(s),
1608(s), 1510(s), 1360(m), 1250(br), 1040(m) cm-1; 1H NMR(CDCl3)
δ1.0(3H, s), 1.50(3H, s), 1.7–2.1(4H, m), 1.82(3H, s), 2.55(1H, s),
5.15(1H, s), 9.40(1H,br s). Anal. Calcd for C10H16O2: C, 71.43; H,
9.52. Found: C, 71.47; H, 9.53%.
2,3-Epoxy-2,6,6-trimethylcyclohexane-1-carboxylic acid (4a,b):
To a rapidly stirred solution of crude (3) 87 g (0.5 mol) from the
previous reaction in dichloromethane (1.5l) was added m-chloro-
peroxybenzoic acid (MCPBA) 105 g (0.60 mol) at 0°C. The solution
was kept between 0 and 5°C for 3 h. The solid was removed by
suction filtration and washed with dichloromethane (2 × 50 ml).
The filtrate was washed with aqueous saturated NaCl (1l), dried over
MgSO4, filtered, and evaporated to give 92 g (96%) of a mixture of
isomers 4a and 4b as a pale yellow oil .The crude oil 2 g was purified
by column chromatography (AcOEt:cyclohexane:AcOH = 10:10:1)
for analysis: IR(KBr) 3450(br), 2960(s), 1725(s), 1370(m), 1250(br),
Conclusions
We have designed an improved process for the synthesis
of the target compound (7) from the starting material of
citral without the need to remove three carbon atoms from
a-ionone as described in Dee Brook’s route. Every step was
modified to be more simple and gave high yields. The present
procedure is more effective and competitive, and is suitable
for large scale production.
1
1040(m) cm-1; H NMR(CDCl3) δ 0.95(3H, s),1.0(3H, s), 1.50(3H,
s), 1.7–2.1(4H, m), 2.55(1H, s), 3.15(1H, t, J = 2 Hz), 9.40(1H, br
s). Anal. Calcd for C10H16O3: C, 65.22; H, 8.70. Found: C, 65.27; H,
8.77%.
Methyl 2,3-epoxy-2,6,6-trimethylcyclohexane-1-carboxylate (5):
Crude (4a,b) 92 g, trimethyl orthoformate 64 g and p-toluenesulfonic
acid 0.5 g was mixed. The mixture was stirred at room temperature
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496 JOURNAL OF CHEMICAL RESEARCH 2007
2
3
(a) J.B. Heather, R.S.D. Mittal and C.J. Sih, J. Am. Chem. Soc., 1974, 96,
1976; (b) 1976, 98, 3661.
Received 12 July 2007; accepted 21 August 2007
Paper 07/4742 doi: 10.3184/030823407X240881
(a) G.A. MacAlpine, R.A. Raphael, A. Shaw, A.W. Taylor and H.J. Wild,
J. Chem. Soc., Chem. Commun., 1974, 20, 834; (b) J. Chem. Soc., Perkins
Trans1: Organic and Bio-Organic Chemistry, 1976, 4, 410.
D.W. Brooks, E. Kennedy, H.S. Bevinakatti, A.B. Pepperman and
J.M. Bradow, ACS Symp. Series, 1987, 355, 433.
D.W. Brooks, H.S. Bevinakatti and D.R. Powell, J. Org. Chem., 1985,
50, 3779.
L. Janitschke and W. Hoffmann, US 4,358,614, 1982.
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