2-Chloro and 2-fluoro ketones derived from the chiral-pool

Article abstract of DOI:10.1016/S0957-4166(00)00013-6

Both (2R,5R)- and (2S,5R)-isomers of 2-chloro-2-isopropyl-5-methyl-, 2-chloro-2-methyl-5-isopropyl- and 2-fluoro-2-methyl-5-isopropylcyclohexanones have been synthesized and fully characterized. It is shown that a rapid overview of the ¹H NMR s

Full text of DOI:10.1016/S0957-4166(00)00013-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 935–941
2-Chloro and 2-fluoro ketones derived from the chiral-pool
Arlette Solladié-Cavallo ∗ and Laëtitia Bouérat
Laboratoire de Stéréochimie Organométallique/ESA 7008, ECPM, 25 rue Becquerel, 67087 Strasbourg, France
Received 29 November 1999; accepted 5 January 2000
Abstract
Both (2R,5R)- and (2S,5R)-isomers of 2-chloro-2-isopropyl-5-methyl-, 2-chloro-2-methyl-5-isopropyl- and 2-
fluoro-2-methyl-5-isopropylcyclohexanones have been synthesized and fully characterized. It is shown that a rapid
overview of the 1H NMR spectrum allows an unambiguous assignment of the axial or equatorial position of the
halogen atom and that the IR νCO absorption does not differ from one isomer to the other. © 2000 Published by
Elsevier Science Ltd. All rights reserved.
1. Introduction
Since the first use, by Curci1 in 1984, of chiral ketones as dioxirane precursors for the enantioselective
epoxidation of olefins, important breakthroughs (yields ≥70%, ee ≥85%) have been achieved by Yang et
al.2 with type 1 ketones and by Shi et al.3 with ketones 2. However, ketone 1 (and analogues) are available
only in low yield (∼20%) from enantiomerically pure but expensive binaphthylamine, the fructose-
derived ketone 2a is inefficient in reactions with electron-poor olefins and ten steps are necessary for
the preparation of ketone 2b from (−)-quinic acid.
Based on the activating effects of halogen substitution observed by Curci et al.,4 Yang et al.2 and
Denmark and Wu,5 the syntheses of chiral ketones 3–5 having a halogen atom in position-2 either axial
or equatorial and derived in a few steps (2 to 3) from natural compounds were envisaged.
Ketones 3 and 4 were first isolated in 1911,6 then 4 was obtained in 43% yield through iron(III)
chloride-catalyzed photo-oxidation of (R)-(+)-p-menthene in 19817a and the axial orientation of the
∗
Corresponding author. Tel: +33 3 88 13 69 79; fax: +33 3 88 13 69 49; e-mail: ascava@chimie.u-strasbg.fr
0957-4166/00/$ - see front matter © 2000 Published by Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00013-6
tetasy 3236

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A. Solladié-Cavallo, L. Bouérat / Tetrahedron: Asymmetry 11 (2000) 935–941
7b,c
chlorine atom [leading to the (2S,5R)-configuration, 4a] was deduced from the position of the IR νCO
Ketone 5 had been obtained from carvomenthene epoxide but the structure was not determined.8
.
We present here the syntheses of the 2-chloro ketones 3a, 3e and 4a, 4e and of the 2-fluoro ketones
5a and 5e from (2S,5R)-(−)-menthone (Scheme 1) and (+)-dihydrocarvone (77% for 2R,5R and 20% for
2S,5R) (Scheme 2), as well as their full characterization and the 1H NMR pattern which allows rapid and
unambiguous identification of the a- and e-isomers.
Scheme 1.
Scheme 2.
2. Results and discussion
The 2-chloro-2-isopropyl-5(R)-methylcyclohexanone was obtained as a 65:35 mixture of 3a (65%)
and 3e (35%) from (2S,5R)-(−)-menthone 6 (>98% ee) (Scheme 1). After chromatographic separation,
(2R,5R)-(+)-3a and (2S,5R)-(+)-3e were obtained and the overall yields were 61 and 33%, respectively.
Because carbon-5 was not involved in the chlorination reaction, the enantiomeric purity of isomers 3a
and 3e was thus assumed to be identical to that of the starting natural product, >98% ee.

A. Solladié-Cavallo, L. Bouérat / Tetrahedron: Asymmetry 11 (2000) 935–941
937
The 2-chloro-2-methyl-5(R)-isopropylcyclohexanone was obtained as a 77:23 mixture of 4a (77%)
and 4e (23%) in two steps from (+)-dihydrocarvone which contained 77% of (2R,5R)-(+)-dihydrocarvone
and 20% of (2S,5R)-(+)-isodihydrocarvone with at least 98% ee at C5 (Scheme 2). Dihydrocarvone (+)-7
was hydrogenated over Pd/C in EtOH under H2 (1 atm)9 prior to chlorination. After chromatographic
separation (2S,5R)-(+)-4a and (2R,5R)-(−)-4e were obtained, the overall yields were 61 and 10%,
respectively, and the enantiomeric purities identical to that of the starting compound 7 (98% ee).
The 2-fluoro-2-methyl-5(R)-isopropylcyclohexanone was obtained as a 54:46 mixture of 5a (54%) and
5e (46%) in three steps from (+)-dihydrocarvone 7 (99% for R at C5) (Scheme 2).
The thermodynamic silylenolate 9 was obtained in satisfactory yield after modification of the literature
work-up10 and the fluorination was preformed with Selectfluor according to literature procedures.11
After chromatographic separation (2S,5R)-(+)-5a and (2R,5R)-(+)-5e were obtained, the overall yields
(three steps) were 28 and 25%, respectively, and the enantiomeric purities identical to that of the starting
compound 7 at C5 (98% ee).
In all these ketones the signals of the H6-axial (H6a) proton and the H6-equatorial (H6e) proton are
expected to be double-doublets with two large coupling-constants in the case of H6a (2J ∼12 Hz, 3J180
∼11 Hz) but one large (2J ∼12 Hz) and one small (3J60 ∼5 Hz) in the case of H6e. However, because
of long range coupling(s) to H6e, H6a is, in fact, the only unambiguous signal. Therefore, in all cases,
assignment of the signals was completed using H/C-correlation experiments (combined with predicted
multiplicities).
An NOE-difference experiment demonstrated that, in ketone (+47)-3e, H6a and iPr as well as iPr and
H4a were in close vicinity. Therefore, the (2S,5R) configuration, having the chlorine atom equatorial,
was assigned to this ketone. The stability of the conformation having the large iPr-group in the axial
position is probably due to the fact that two substituents (Me and Cl) out of three adopt an equatorial
position. As a consequence the other diastereomer 3a was assigned the (2R,5R) configuration.
Similarly, positive NOEs were observed between Me, H6a and H4a for compounds 4e and 5e which
were thus assigned the configuration (2R,5R). As a consequence, 4a and 5a were assigned the (2S,5R)
configuration.
However, for standard and/or daily use a rapid identification of isomers-a (halogen axial) versus
1
isomers-e (halogen equatorial) is necessary. This can be done by a rapid overview of the H NMR
spectra, as shown in Fig. 1.
It indeed appears that the well recognizable H6a signal, a double-doublet or a triplet (with only two
large coupling-constants in the cases of ketones 3a, 3e, 4a, 4e and 5e) and a double-triplet (with two large
4
coupling-constants and one extra, but smaller, due to a JHF in the case of ketone 5a), is significantly
deshielded in isomers having the halogen in the axial position (3a, 4a and 5a) and is the most deshielded
signal in these isomers (Fig. 1A, C and E) while it is shielded in all e-isomers (3e, 4e and 5e) (Fig. 1B, D
and F).
Therefore, both (2R,5R)- and (2S,5R)-diastereomers of 2-chloro and 2-fluoro cyclohexanones 3, 4 and
5 with enantiomeric purities of 98% have been obtained pure and fully characterized. They can, now, be
easily identified through a rapid overview of their 1H NMR.

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A. Solladié-Cavallo, L. Bouérat / Tetrahedron: Asymmetry 11 (2000) 935–941
939
3. Experimental
1H and 13C NMR spectra were recorded on a Bruker AC 200 (200 MHz) or a Bruker Avance
(400 MHz) spectrometer with CDCl3 or C6D6 as the solvent. Chemical shifts (δ) are given in ppm
downfield from TMS as an internal standard. Optical rotation measurements were carried out with a
Perkin–Elmer 241 MC polarimeter. TLC was performed on Merck’s glass plates with silica gel 60
F254. Silica gel for column chromatography (Merck) was used for the chromatographic purifications.
(2S,5R)-(−)-Menthone, purchased from Fluka, was claimed to be >98% ee by GC. (+)-Dihydrocarvone,
purchased from Fluka, was a 77% (2R,5R) and 20% (2S,5R) mixture, having the enantiomeric purity of
the starting (−)-carvone, 99% R (98% ee).
3.1. Chlorination of menthone: 3a, 3e
A solution of (−)-menthone 6 (4 g, 26 mmol, 1 equiv.) in CCl4 (45 ml) was stirred at 0°C in a 250 ml
two-necked flask equipped with a gas trap (10% NaOH). Then a solution of freshly distilled SO2Cl2 (2.53
ml, 31.2 mmol, 1.2 equiv.) in CCl4 (15 ml) was added dropwise within 45 min. The reaction mixture was
further stirred for 7 h and then poured on ice (100 ml). The two phases were separated and the aqueous
phase was extracted with CH2Cl2. The organic phases were washed with saturated NaHCO3 and dried
over Na2SO4. After filtration and evaporation, the crude product was purified by column chromatography
using a gradient of pentane:CH2Cl2, from 80:20 to 40:60, to afford 3.015 g of 3a (61%) and 1.304 g of
3e (33%), respectively.
3.1.1. (2R,5R)-(+)-2-Chloro-2-isopropyl-5-methylcyclohexanone 3a
[α]D22=+190 (c 1.0, CHCl3). 1H NMR (CDCl3, 400 MHz): δ 0.95 (d, J=6.5 Hz, 3H, Me isopropyl),
1.04 (d, J=6 Hz, 3H, Me10), 1.06 (d, J=6.5 Hz, 3H, Me isopropyl), 1.80 (m, 4H, H4a, H4e, H5, H3a), 2.25
(dt, 3J=3J=3.5 Hz, 2J =14 Hz, 1H, H3e), 2.3 (dd, 3J=4 Hz, 2J=14 Hz, 1H, H6e), 2.47 (sept, J=6.5 Hz, 1H,
H7), 2.77 (dd, 3J=12 Hz, 2J=14 Hz, 1H, H6a); 13C NMR (CDCl3, 100 MHz): δ 18.3 (C8 and C9), 22.3
(C10), 29.6 (C4), 33.8 (C7), 34.5 (C5), 35.2 (C3), 46.2 (C6), 78.3 (C2), 204.9 (C1). IR (CHCl3): ν=3620,
2960, 2920, 2880, 1715, 1450, 1390, 1370, 1260–1180, 1050, 880 cm−1. Anal. calcd for C10H17ClO: C,
63.65; H, 9.08. Found: C, 63.30; H, 9.07.
3.1.2. (2S,5R)-(+)-2-Chloro-2-isopropyl-5-methylcyclohexanone 3e
1
[α]D22=+47 (c 1.0, CHCl3); H NMR (CDCl3, 400 MHz): δ 0.90 (d, J=6.5 Hz, 3H, Me isopropyl),
3
3
1.02 (d, J=6.5 Hz, 3H, Me10), 1.07 (d, J=6.5 Hz, 3H, Me isopropyl), 1.53 (qd, J=4 Hz, J=3J=2J=13
Hz, 1H, H4a), 1.87 (dqd, 4J=1.5 Hz, 3J=3J=3J=4 Hz, 2J=13 Hz, 1H, H4e), 2.05 (m, 2H, H3a, H5), 2.22
3
2
(dd, J=11 Hz, J=13.5 Hz, 1H, H6a), 2.48 (m, 1H, H3e), 2.5 (sept, J=6.5 Hz, 1H, H7), 2.71 (ddd,
4J=1.5 Hz, J=4.5 Hz, J=13.5 Hz, 1H, H6e); 13C NMR (CDCl3, 100 MHz): δ 16.9 (C8 or C9), 17.7
(C9 or C8), 21.5 (C10), 30.2 (C4), 32.7 (C7), 34.4 (C5), 38.0 (C3), 47.0 (C6), 83.0 (C2), 205.2 (C1). IR
(CHCl3): ν=3620, 2970 , 2930, 2890, 1720, 1450, 1390, 1375, 1260–1180, 1050, 875 cm−1. Anal. calcd
for C10H17ClO: C, 63.65; H, 9.08. Found: C, 63.84; H, 9.16.
3
2
3.2. Chlorination of tetrahydrocarvone: 4a, 4e
The chlorination was carried out following the same procedure. After column chromatography, using
CCl4 as eluant, 4a and 4e were isolated pure with 69 and 11% yield, respectively.

940
A. Solladié-Cavallo, L. Bouérat / Tetrahedron: Asymmetry 11 (2000) 935–941
3.2.1. (2S,5R)-(+)-2-Chloro-2-methyl-5-isopropylcyclohexanone 4a
[α]D22=+160 (c 1.05, CHCl3); 1H NMR (C6D6, 400 MHz): δ 0.65 (d, J=6.5 Hz, 3H, Me isopropyl),
0.66 (d, J=6.5 Hz, 3H, Me isopropyl), 1.08 (m, 1H, H5), 1.19 (oct, J=6.5 Hz, 1H, H7), 1.25 (m, 2H, H4e,
H3a), 1.55 (s, 3H, Me10), 1.6 (qd, 3J=3 Hz, 3J=3J=2J=12 Hz, 1H, H4a), 1.92 (m, 1H, H3e), 2.19 (ddd,
4J=2 Hz, 3J=4 Hz, 2J=13.5 Hz, 1H, H6e), 2.65 (t, 3J=2J=13.5 Hz, H6a); 13C NMR (C6D6, 100 MHz): δ
19.4 (C8 or C9), 19.5 (C9 or C8), 24.9 (C4), 26.7 (C10), 32.8 (C7), 40.4 (C6), 41.8 (C3), 45.7 (C5), 70.2
(C2), 204.0 (C1). IR (CHCl3): ν=3630, 2980, 2940, 2890, 1720, 1450, 1400, 1250–1200, 1100–1020,
865 cm−1. Anal. calcd for C10H17ClO: C, 63.65; H, 9.08. Found: C, 64.02; H, 9.00.
3.2.2. (2R,5R)-(−)-2-Chloro-2-methyl-5-isopropylcyclohexanone 4e
1
[α]D22=−36 (c 1.18, CHCl3); H NMR (C6D6, 400 MHz): δ 0.56 (d, J=6.5 Hz, 3H, Me isopropyl),
0.65 (d, J=6.5 Hz, 3H, Me isopropyl), 1.06 (oct, J=6.5 Hz, 1H, H7), 1.2 (m, 2H, H5, H4), 1.45 (s, 3H,
Me10), 1.65 (m, 2H, H4, H3), 1.80 (m, 1H, H3), 2.11 (ddd, 4J=3 Hz, 3J=9 Hz, 2J=14 Hz, 1H, H6a), 2.71
(dd, 3J=4.5 Hz, 2J=14 Hz, 1H, H6e); 13C NMR (C6D6, 100 MHz): δ 20.1 (C8 or C9), 20.3 (C9 or C8),
24.7 (C4), 27.0 (C10), 29.4 (C7), 40.2 (C3), 40.7 (C6), 44.2 (C5), 72.0 (C2), 203.3 (C1). IR (CHCl3):
ν=3620, 2960, 2880, 1720, 1450, 1390, 1270–1180, 1090, 1050, 875 cm−1. Anal. calcd for C10H17ClO:
C, 63.65; H, 9.08. Found: C, 63.19; H, 9.12.
3.3. Fluoration of tetrahydrocarvone: 5a, 5e
3.3.1. Preparation of silylenol ether 9
To a solution of (+)-tetrahydrocarvone 8 (4.55 g, 29 mmol, 1 equiv.) in acetonitrile (125 ml) under an
argon atmosphere was added rapidly anhydrous NaI (8.2 g, 53 mmol, 1.8 equiv.). Then triethylamine (7.3
ml, 53 mmol, 1.8 equiv.) and freshly distilled trimethylsilyl chloride (6.7 ml, 53 mmol, 1.8 equiv.) were
added, respectively, to the reaction mixture. After stirring at room temperature for 2 h, the mixture was
rapidly poured into a cold NaOH solution10 (2.2 g, 53 mmol, 1.8 equiv. NaOH in 200 ml H2O). Then
pentane (100 ml) was added. The two phases were separated and the aqueous phase was extracted with
pentane (3×120 ml). The organic phases were dried over MgSO4 and the solvent was evaporated to give
9 as a pure yellow oil (4.82 g, 73%).
1
2-Methyl-5-(R)-isopropyl-1-trimethylsiloxycyclohexene 9: [α]D22=+48 (c 1.0, CHCl3); H NMR
(CDCl3, 400 MHz): δ 0.18 (s, 9H, Me de TMS), 0.89 (d, J=6.5 Hz, 3H, Me isopropyl), 0.90 (d, J=6.5
Hz, 3H, Me isopropyl), 1.15 (qd, 3J=4 Hz, 2J=3J=3J=12 Hz, 1H, H4a), 1.3 (m, 2H), 1.49 (oct, J=6.5 Hz,
1H, H7), 1.56 (bs, 3H, Me10), 1.71 (d, 2J=12 Hz, 1H, H4e), 1.82 (ddm, 3J=12 Hz, 2J=13 Hz, 1H, H6a),
1.97 (bm, 2H); 13C NMR (CDCl3, 100 MHz): δ 1.1, 16.5, 20.1, 20.3, 26.9, 30.7, 32.5, 34.4, 34.5, 42.0,
111.8, 143.1. IR (CHCl3): ν=2880, 1680, 1450–1400, 1360, 1320, 1160, 910, 890, 830 cm−1
.
3.3.2. Fluoration: 5a, 5e
To a solution of 9 (1.5 g, 6.62 mmol, 1 equiv.) in dry DMF (25 ml) under an argon atmosphere was
added dropwise a solution of Selectfluor (3.29 g, 9.3 mmol, 1.4 equiv.) in DMF (40 ml). The mixture
was stirred at 0°C for 2 h. Then water (50 ml) was poured into the reaction mixture, the different phases
were separated and the aqueous phase was extracted with ether (3×100 ml). The organic phases were
dried over MgSO4. After filtration and evaporation, the residue (containing DMF) was directly purified
by column chromatography with a pentane:ether gradient [96:4 (for 5a), 10:90 (for starting material),
15:85 (for 5e)] to afford 0.478 g of 5a (42%) and 0.411 g of 5e (36%).
1
(2S,5R)-(+)-2-Fluoro-2-methyl-5-isopropylcyclohexanone 5a: [α]D22=+1 (c 1.0, CHCl3); H NMR
(C6D6, 400 MHz): δ 0.63 (d, J=6.5 Hz, 3H, Me isopropyl), 0.64 (d, J=6.5 Hz, 3H, Me isopropyl), 1.06

A. Solladié-Cavallo, L. Bouérat / Tetrahedron: Asymmetry 11 (2000) 935–941
941
3
3
2
3
(dddd, J=4 Hz, J=13 Hz, J=15 Hz, JHF=40 Hz, 1H, H3a), 1.15 (m, 3H, H4e, H5, H7), 1.34 (d,
3JHF=22 Hz, 3H, Me10), 1.49 (qd, 3J=4.5 Hz, 2J=3J=3J=13 Hz, 1H, H4a), 1.89 (dddd, 3J=2 Hz, 3J=4.5
Hz, 3JHF=10 Hz, 2J=15 Hz, 1H, H3e), 2.22 (dtd, 4JHF=4JHH= 2 Hz, 3J=4 Hz, 2J=12 Hz, 1H, H6e), 2.48
4
2
(td, JHF=6 Hz, J=3J=12 Hz, 1H, H6a); 13C NMR (C6D6, 100 MHz): δ 19.3 (C8 or C9), 19.5 (C9 or
C8), 20.3 (d, 2JCF=24 Hz, C10), 24.0 (d, 3JCF=9 Hz, C4), 32.7 (C7), 38.5 (d, 2JCF=23 Hz, C3), 41.9 (d,
3JCF=2 Hz, C6), 46.4 (C5), 95.5 (d, 1JCF=171 Hz, C2), 206.5 (d, 2JCF=25 Hz, C1). IR (CHCl3): ν=2920,
2850, 1720, 1420, 1360, 1310, 1150, 1130, 1090, 1070, 980, 890, 880 cm−1. Anal. calcd for C10H17FO:
C, 69.73; H, 9.95. Found: C, 69.22; H, 10.01.
1
(2R,5R)-(+)-2-Fluoro-2-methyl-5-isopropylcyclohexanone 5e: [α]D22=+75 (c 1.0, CHCl3); H NMR
(C6D6, 400 MHz): δ 0.58 (d, J=6.5 Hz, 3H, Me isopropyl), 0.60 (d, J=6.5 Hz, 3H, Me isopropyl), 0.9
(m, 1H, H4a), 1.06 (oct, J=6.5 Hz, 1H, H7), 1.10 (m, 1H, H5), 1.17 (d, 3JHF=21.5 Hz, 3H, Me10), 1.32
2
3
2
(bd, J=14 Hz, 1H, H4e), 1.65 (m, 2H, H3a and H3e), 1.78 (dd, J=11 Hz, J=14 Hz, 1H, H6a), 2.30
(dtd, 4J=2 Hz, 3J=4JHF=3 Hz, 2J=14 Hz, 1H, H6e); 13C NMR (C6D6, 100 MHz): δ 19.6 (C8 or C9), 19.7
(C9 or C8), 22.1 (d, 2JCF=25 Hz, C10), 25.8 (d, 3JCF=9 Hz, C4), 31.5 (C7), 37.9 (d, 2JCF=22 Hz, C3),
42.6 (C6), 45.0 (C5), 96.0 (d, 1JCF=184 Hz, C2), 205.6 (d, 2JCF=17 Hz, C1). IR (CHCl3): ν=2920, 2850,
1720, 1450, 1370, 1310, 1125, 1090, 980, 970, 950, 890 cm−1. Anal. calcd for C10H17FO: C, 69.73; H,
9.95. Found: C, 69.17; 10.02.
Acknowledgements
This work was supported by Dr. A. Wick and the Sylachim/Synthelabo Groupe as well as by the
MENRT, France with a grant to L.B. M. M. Schmitt (Laboratoire de Stéréochimie Organométallique) is
acknowledged for the 2D NMR studies and Mme A. Klein for technical participation.
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