Synthesis of (R)-(+)-4-methylcyclohex-2-ene-1-one

Article abstract of DOI:10.1021/jo3017956

A three-step synthesis of (R)-(+)-4-methylcyclohex-2-ene-1-one (1) from (R)-(+)-pulegone (3), proceeding in 44% overall yield, is described. The sequence comprises vinyl triflate formation, site-selective ozonolysis, and reduction. The route requires only one chromatographic purification and provides a convenient method to access multigram quantities of (R)-(+)-4-methylcyclohex- 2-ene-1-one (1).

Full text of DOI:10.1021/jo3017956

Note
pubs.acs.org/joc
Synthesis of (R)‑(+)-4-Methylcyclohex-2-ene-1-one
Maung Kyaw Moe Tun and Seth B. Herzon*
Department of Chemistry, Yale University, New Haven, Connecticut 06520, United States
S
* Supporting Information
ABSTRACT: A three-step synthesis of (R)-(+)-4-methylcyclohex-2-ene-1-one
(1) from (R)-(+)-pulegone (3), proceeding in 44% overall yield, is described.
The sequence comprises vinyl triflate formation, site-selective ozonolysis, and
reduction. The route requires only one chromatographic purification and
provides a convenient method to access multigram quantities of (R)-(+)-4-
methylcyclohex-2-ene-1-one (1).
e recently described a synthesis of the natural
Scheme 2. Published Routes to (R)-(+)-4-Methylcyclohex-2-
ene-1-one (1)
a
W
neuroprotective agent (−)-huperzine A (2) that
proceeds in eight steps and 35−45% overall yield from (R)-
(+)-4-methylcyclohex-2-ene-1-one (1, Scheme 1).1 (−)-Hu-
Scheme 1. Route to (−)-Huperzine A (2) by Tun et al.1
perzine A (2) is a candidate for the treatment of a variety of
neurological disorders,2−5 and substantial resources have been
devoted toward the development of an economical manufactur-
ing route to 2.6 The reagent (R)-(+)-4-methylcyclohex-2-ene-1-
one (1) has been employed in many synthetic sequences.7−11
We obtained 1 by a chiral pool approach, developed by Lee et
al.,12 which begins with (R)-(+)-pulegone (3). This sequence
was reproducibly executed in high overall yield on multigram
scales, but several lateral manipulations were required (Scheme
2a). A more direct route to 1 that we have investigated
comprises enantioselective deprotonation13 of 4-methylcyclo-
hexanone (4), trapping with chlorotrimethylsilane, and
oxidation14−16 (27%, Scheme 2c).17 In this approach useful
levels of stereoselectivity were obtained only if the deprotona-
tion was conducted at −100 °C, a temperature not easily
attained on large scales.
Several other methods to prepare (R)-(+)-4-methylcyclohex-
2-ene-1-one (1) have been disclosed, including two that begin
with (R)-(+)-pulgeone (3). Condensation of (R)-(+)-pulegone
(3) with trisylhydrazine, vinyllithium generation,18 protonation,
and selective ozonolysis of the resulting 1,3-diene provides 1 in
28% overall yield (Scheme 2b).19 Although this route is
efficient, trisylhydrazine is of high molecular weight and
relatively expensive on a molar basis. The application of
N,N,N′,N′-tetramethylethylenediamine (TMEDA) as a co-
solvent in the vinyllithium generation step18 was also
undesirable in large-scale experiments. Alternatively, degrada-
a
Abbreviated Conditions: (a) (i) NaBH4; (ii) O3 then DMS; (iii)
HOCH2CH2OH, CSA; (iv) Tf2O, pyridine; (v) DBU; (vi) H2SO4,
H2O. (b) (i) TrisNHNH2; (ii) n-BuLi; (iii) O3 then DMS. (c) (i) 7,
TMSCl; (ii) Pd(OAc)2. (d) (i) TiCl4, pyrrolidine; (ii) B2H6 then
H2O2, NaOH; (iii) H2O2, CH3OH; (iv) 120 °C, (v) PDC. (e) (i)
Cu(OTf)2, 8, (CH3)2Zn; (ii) PDC, CH2Cl2, 0 → 23 °C.
tion of (R)-(+)-pulegone (3) to (R)-(+)-3-methylcyclohex-
anone (5, 69%),20 followed by a five-step sequence provides the
target 1 (21% from 5, Scheme 2d).21 A recent strategy employs
ring-opening kinetic resolution of ( )-7-oxabicyclo[4.1.0]hept-
Received: August 28, 2012
© XXXX American Chemical Society
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The Journal of Organic Chemistry
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scale) downfield from tetramethylsilane and are referenced to residual
protium in the NMR solvent (CHCl3, δ 7.26). Data are represented as
follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet and/or multiple resonances, br = broad, app
= apparent), integration, coupling constant in Hertz, and assignment.
Proton-decoupled carbon nuclear magnetic resonance spectra (13C
NMR) were recorded at 100 or 125 MHz at 24 °C, unless otherwise
noted. Chemical shifts are expressed in parts per million (ppm, δ
scale) downfield from tetramethylsilane and are referenced to the
carbon resonances of the solvent (CDCl3, δ 77.0). Distortionless
enhancement by polarization transfer spectra [DEPT (135)] were
recorded at 100 or 125 MHz at 24 °C, unless otherwise noted. 13C
NMR and DEPT (135) data are combined and represented as follows:
chemical shift, carbon type [obtained from DEPT (135) experiments].
Fluorine nuclear magnetic resonance spectra (19F NMR) were
recorded at 282 MHz at 24 °C, unless otherwise noted. Chemical
shifts are expressed in parts per million (ppm, δ scale), and are
2-ene (6, prepared from 1,3-cyclohexadiene) with dimethylzinc,
followed by oxidation (30%, Scheme 2e).22
We have developed an alternative and highly practical route
to (R)-(+)-4-methylcyclohex-2-ene-1-one (1, Scheme 3).
Scheme 3. Improved Route to (R)-(+)-4-Methylcyclohex-2-
ene-1-one (1) from (R)-(+)-Pulegone (3)
1
referenced indirectly to the H frequency of CHCl3. Attenuated total
reflectance Fourier transform infrared spectra (ATR-FTIR) are
referenced to a polystyrene standard. Data are represented as follows:
frequency of absorption (cm−1), intensity of absorption (s = strong, m
= medium, w = weak, br = broad). High-resolution mass spectrometry
(HRMS) were obtained using an Fourier Transform Ion Cyclotron
Resonance (FT-ICR) mass spectrometer.
Synthesis of (R)-(+)-4-Methylcyclohex-2-ene-1-one (1). Step
1: Synthesis of Vinyl Triflate 9. (R)-(+)-Pulegone (3, 6.85 g, 45.0
mmol, 1 equiv) was added dropwise via syringe over 5 min to a stirred
solution of lithium hexamethylsilazide (7.91 g, 47.3 mmol, 1.05 equiv)
in tetrahydrofuran (45.0 mL) at −78 °C. Upon completion of the
addition, the reaction mixture was stirred for 30 min at −78 °C. A
solution of N-phenylbis(trifluoromethanesulfonimide) in tetrahydro-
furan (1.00 M, 47.0 mL, 47.0 mmol, 1.05 equiv) was added dropwise
via cannula over 10 min to the cold reaction mixture. Upon
completion of the addition, the reaction mixture was warmed over
30 min to 24 °C. The warmed solution was stirred for 2 h at 24 °C.
The warmed product mixture was diluted sequentially with ether (150
mL) and pentane (150 mL). The diluted solution was transferred to a
separatory funnel that had been charged with 1.0 N aqueous sulfuric
acid solution (150 mL). The layers that formed were separated. The
organic layer was washed sequentially with 1.0 N aqueous sodium
hydroxide solution (150 mL) and saturated aqueous sodium chloride
solution (150 mL). The washed organic layer was dried over sodium
sulfate. The dried solution was filtered, and the filtrate was
Deprotonation of (R)-(+)-pulegone (3, lithium hexamethylsi-
lazide) and trapping of the resulting enolate with N-phenyl-
bis(trifluoromethanesulfonimide) provided the vinyl triflate 9.23
The unpurified vinyl triflate 9 was selectively oxidized (ozone,
dichloromethane−methanol, −78 °C) to form the α-(trifluor-
omethanesulfonyloxy)-α,β-unsaturated ketone 10. Heating
solutions of the unpurified α-(trifluoromethanesulfonyloxy)-
α,β-unsaturated ketone 10 with palladium acetate (2 mol %),
triphenylphosphine, triethylamine, and formic acid provided
the target 1 (44%, >99% ee from 3). This final step required
significant optimization, as we have found that the α-
(trifluoromethanesulfonyloxy)-α,β-unsaturated ketone 10 is
susceptible to several decomposition pathways (including
epimerization, aromatization, and dimerization) under basic
reducing conditions. Overall, this sequence requires three
manipulations and one chromatographic purification, employs
inexpensive reagents and starting materials, and should be
preferable to published procedures.
1
concentrated to afford the vinyl triflate 9 as a pale yellow oil. H
and 13C NMR spectroscopic data for 9 prepared in this way were in
agreement with those reported.23
EXPERIMENTAL SECTION
■
Step 2: Synthesis of α-(Trifluoromethanesulfonyloxy)-α,β-unsa-
turated Ketone 10. The residue obtained in the preceding step was
dissolved in dichloromethane (220 mL) and methanol (54 mL), and
the resulting solution was cooled to −78 °C. The cooled solution was
treated with a continuous stream of ozone. Upon observation of a pale
blue color (approximately 20 min), the addition of ozone was arrested,
and the reaction mixture was purged with nitrogen (10 min) at −78
°C. Dimethyl sulfide (16.5 mL, 225 mmol, 5.00 equiv) was added, and
the resulting mixture was warmed over 30 min to 24 °C. The warmed
product mixture was concentrated to afford the α-(trifluoromethane-
sulfonyloxy)-α,β-unsaturated ketone 10 as a pale yellow oil. An
analytically pure sample of the α-(trifluoromethanesulfonyloxy)-α,β-
unsaturated ketone 10 was obtained by flash column chromatography
(eluting with 20% ether−pentane).
General Experimental Procedures. All reactions were per-
formed in single-neck, flame-dried, round-bottomed flasks fitted with
rubber septa under a positive pressure of argon, unless otherwise
noted. Air- and moisture-sensitive liquids were transferred via syringe
or stainless steel cannula. Organic solutions were concentrated by
rotary evaporation at 30−33 °C. Flash-column chromatography was
performed as described by Still et al.,24 employing silica gel (60 Å, 40−
63 μm particle size). Analytical thin layer chromatography (TLC) was
performed using glass plates precoated with silica gel (1.0 mm, 60 Å
pore size) impregnated with a fluorescent indicator (254 nm). TLC
plates were visualized by exposure to ultraviolet (UV) light or/and
submersion in aqueous potassium permanganate solution (KMnO4),
followed by brief heating on a hot plate (120 °C, 10−15 s).
Materials. Commercial solvents and reagents were used as received
with the following exceptions. Tetrahydrofuran was distilled from
sodium−benzophenone under an atmosphere of nitrogen immediately
before use. Triethylamine was distilled from calcium hydride under an
atmosphere of nitrogen immediately before use. Commercial samples
of 92% grade (R)-(+)-pulegone (3) and formic acid (>96% purity)
were employed.
1
Rf = 0.25 (20% ether−pentane, KMnO4). H NMR (400 MHz,
CDCl3) δ 6.74 (dd, 1H, J = 3.2, 1.2 Hz, H1), 2.90−2.79 (m, 1H, H2),
2.75−2.65 (m, 1H, H4), 2.57−2.49 (m, 1H, H4), 2.22−2.14 (m, 1H,
H3), 1.82−1.72 (m, 1H, H3), 1.26 (d, 3H, J = 7.2 Hz, H5). 13C NMR
(100 MHz, CDCl3) δ 189.6 (C), 144.2 (CH), 143.7 (C), 118.5 (C,
JC−F = 323 Hz), 36.4 (CH2), 31.3 (CH), 29.9 (CH2), 19.9 (CH3). 19
F
NMR (282 MHz, CDCl3) δ −73.9. IR (ATR-FTIR), cm−1 2968 (br),
1705 (s), 1421 (s), 1166 (s), 1137 (s), 1103 (s), 1085 (s). HRMS-
CI(m/z) [M + H]+ calcd for C8H10F3O4S, 259.0246; found, 259.0244.
Instrumentation. Proton nuclear magnetic resonance spectra (1H
NMR) were recorded at 400 or 500 MHz at 24 °C, unless otherwise
noted. Chemical shifts are expressed in parts per million (ppm, δ
B
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Note
1008 (m), 937 (w), 749 (s), 692 (s). HRMS-CI(m/z) [M + Na]+
calcd for C13H16NaOS, 243.0814; found, 243.0810.
Step 3: (R)-(+)-4-Methylcyclohex-2-ene-1-one (1). A 500-mL
round-bottomed flask was charged with the unpurified α-(trifluor-
omethanesulfonyloxy)-α,β-unsaturated ketone 10 obtained in the
preceding step. The residue was dried by azeotropic distillation with
benzene (10.0 mL), and the dried residue was dissolved in
tetrahydrofuran (60 mL). Palladium acetate (202 mg, 900 μmol,
0.02 equiv) and triphenylphosphine (472 mg, 1.80 mmol, 0.04 equiv)
were then added in sequence, and the resulting solution was stirred for
15 min at 24 °C. A solution of triethylamine (7.03 mL, 50.4 mmol,
1.12 equiv) and formic acid (1.87 mL, 49.5 mmol, 1.10 equiv) in
tetrahydrofuran (120 mL) was then added dropwise via cannula over 5
min to the reaction mixture. The reaction vessel was fitted with a reflux
condenser and then placed in an oil bath that had been preheated to
85 °C. The reaction mixture was stirred and heated for 12 h at 85 °C.
The product mixture was cooled over 30 min to 24 °C. The cooled
product mixture was diluted sequentially with ether (360 mL) and
pentane (360 mL). The diluted solution was transferred to a
separatory funnel that had been charged with saturated aqueous
sodium chloride solution (100 mL). The layers that formed were
separated, and the organic layer was washed with saturated aqueous
sodium chloride solution (2 × 100 mL). The washed organic layer was
dried over sodium sulfate, and the dried solution was filtered. The
filtrate was concentrated and the residue obtained was purified by flash
column chromatography (eluting with 30% ether−pentane) to provide
(R)-(+)-4-methylcyclohex-2-ene-1-one (1) as a pale yellow oil (2.20 g,
44% from 3). Spectroscopic data for 1 prepared in this way were in
agreement with those reported.12 The (R)-(+)-4-methylcyclohex-2-
ene-1-one (1) prepared in this way was determined to be of >99% ee
by chiral stationary phase HPLC analysis of the thiophenol 1,4-
addition products 11 and 12 (see below).
syn-Addition product 12: Rf = 0.22 (20% ether−pentane, KMnO4).
1H NMR (500 MHz, CDCl3) δ 7.43−7.41 (m, 2H, H7), 7.33−7.25
(m, 3H, H7), 3.62−3.59 (m, 1H, H2), 2.57−2.55 (m, 2H, H1), 2.50−
2.25 (m, 3H, H3/H5), 2.00−1.80 (m, 2H, H4),1.25 (d, 1H, J = 8.5 Hz,
H6). 13C NMR (125 MHz, CDCl3) δ 208.7 (C), 133.9 (C), 133.0
(CH), 129.1 (CH), 127.5 (CH), 52.6 (CH), 45.5 (CH2), 38.9 (CH2),
33.6 (CH), 30.2 (CH2), 16.4 (CH3). IR (ATR-FTIR), cm−1 2924 (s),
1715 (s), 1580 (m), 1453 (m), 1326 (w), 1186 (m), 1086 (w), 1020
(w), 905 (w), 740 (s), 700 (s). HRMS-CI(m/z) [M + Na]+ calcd for
C13H16NaOS, 243.0814; found, 243.0810.
The addition products 11 and 12 were determined to be of >99% ee
by chiral stationary phase HPLC analysis (see Supporting
Information).
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H, 13C, and 19F NMR for all new compounds and
HPLC chromatograms. This material is free of charge via the
Internet at http://pubs.acs.org/.
Determination of Enantiomeric Excess. Conjugate Addition of
Thiophenol to (R)-(+)-4-Methylcyclohex-2-ene-1-one (1). Triethyl-
amine (50.0 μL, 490 μmol, 0.49 equiv) was added to a stirred solution
of (R)-(+)-4-methylcyclohex-2-ene-1-one (1, 110 mg, 1.00 mmol, 1
equiv) and thiophenol (112 μL, 1.10 mmol, 1.10 equiv) in chloroform
(10 mL) at 0 °C. Upon completion of the addition, the reaction
mixture was warmed over 5 min to 24 °C. The warmed solution was
stirred for 30 min at 24 °C. Additional portions of triethylamine (50.0
μL, 490 μmol, 0.49 equiv) and thiophenol (112 μL, 1.10 mmol, 1.10
equiv) were added sequentially to the reaction mixture. The reaction
mixture was stirred for an additional 30 min at 24 °C. The product
mixture was diluted with ether (20 mL). The diluted solution was
transferred to a separatory funnel that had been charged with 1.0 N
aqueous sodium hydroxide solution (10 mL). The layers that formed
were separated, and the organic layer was washed sequentially with 1.0
N aqueous sodium hydroxide solution (10 mL) and saturated aqueous
sodium chloride solution (10 mL). The washed organic layer was dried
over sodium sulfate. The dried solution was filtered, and the filtrate
was concentrated to afford a mixture of the thiophenol addition
products 11 and 12 (1.5:1 mixture of diastereomers). The addition
products were purified by flash column chromatography (eluting with
20% ether−pentane) to afford separately the anti-1,4 addition product
11 as a colorless oil (65.0 mg, 30%) and the syn-1,4 addition product
12 as a white crystalline solid (31.1 mg, 14%, mp 84−86°).
AUTHOR INFORMATION
Corresponding Author
*E-mail: seth.herzon@yale.edu.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Miller group for use of their HPLC. Financial
support from the Searle Scholars Program and Yale University
is gratefully acknowledged.
REFERENCES
■
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1H NMR (500 MHz, CDCl3) δ 7.43−7.40 (m, 2H, H7), 7.35−7.38
(m, 3H, H7), 3.00 (ddd, 1H, J = 11.2, 9.8, 4.6, H2), 2.69−2.64 (ddd,
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