Synthesis and characterisation of a suite of four chiral pyridyl alcohols derived from (-)-menthol

Article abstract of DOI:10.1039/b205872n

Reaction of menthylmagnesium chloride with pyridine-2-carbaldehyde gives a mixture of four isomeric chiral menthyl- and neomenthyl-substituted pyridylcarbinols which were fully characterised by a combination of spectroscopic and X-ray crystallographic methods. All of these alcohols catalyse the addition of diethylzinc to benzaldehyde, but with disappointing enantioselectivities.

Full text of DOI:10.1039/b205872n

View Article Online / Journal Homepage / Table of Contents for this issue
Synthesis and characterisation of a suite of four chiral pyridyl
alcohols derived from (؊)-menthol
Desmond Cunningham,b Eva T. Gallagher,a David H. Grayson,*a Patrick J. McArdle,†b
Christina B. Storeya and Deborah J. Wilcocka
1
a Centre for Synthesis and Chemical Biology, University Chemical Laboratory, Trinity College,
Dublin 2, Ireland
b Department of Chemistry, University College, Galway, Ireland
Received (in Cambridge, UK) 18th June 2002, Accepted 26th September 2002
First published as an Advance Article on the web 4th November 2002
Reaction of menthylmagnesium chloride with pyridine-2-carbaldehyde gives a mixture of four isomeric chiral
menthyl- and neomenthyl-substituted pyridylcarbinols which were fully characterised by a combination of
spectroscopic and X-ray crystallographic methods. All of these alcohols catalyse the addition of diethylzinc to
benzaldehyde, but with disappointing enantioselectivities.
Recently, much effort has been expended on the synthesis of
chiral pyridylcarbinol derivatives with a view to their appli-
cation as enantioselective catalysts or auxiliaries. A diversity of
reactions are amenable to catalysis which involves the interven-
tion of pyridylcarbinol ligands. These processes include, for
example, the epoxidation of allylic alcohols,1 the conjugate
addition of dialkylzinc reagents to α,β-unsaturated ketones2
and, especially, the nucleophilic addition of dialkylzinc reagents
to aldehydes.3 The latter process is of particular interest in that
a positive, non-linear relationship between the optical purity of
the catalyst and that of the addition product is often observed.4
In this paper, we describe the synthesis from (Ϫ)-menthol 1
of the suite of four chiral pyridyl alcohols 2a–2d. We chose the
monoterpenoid 1 to provide the major element of asymmetry in
the target molecules on the basis of its ready availability in both
enantiomeric forms, and also in the expectation that incorpor-
ation of its equatorially trisubstituted cyclohexane ring into the
alcohols 2a and 2b would restrict the conformational freedom
of these compounds in a beneficial way when they were applied
as chiral auxiliaries or as catalysts.5
of menthyl chloride 3 and neomenthyl chloride 4 was used to
form the Grignard reagent. We discuss this observation in more
detail below.
Unexpectedly, significant amounts of the equatorial ketone
5a and of the axial ketone 5b were also obtained as products of
the reaction between menthylmagnesium chloride and pyridine-
2-carbaldehyde. The formation of these ketones can reasonably
be accounted for by invoking the Cannizzaro-like mechanism
outlined in Scheme 1 where an initially formed chloro-
(Ϫ)-Menthyl chloride 3 was obtained according to Huckel
and Pietrzok’s6 method by reacting (Ϫ)-menthol 1 with phos-
phorus pentachloride in the presence of a small amount of
ferric chloride. The product contained variable but relatively
small (generally <10%) amounts of its axial neomenthyl isomer
4. The derived Grignard reagent, prepared in tetrahydrofuran
solution, reacted with pyridine-2-carbaldehyde to yield a mix-
ture containing all four of the possible product alcohols 2a–2d.
The ratio of the equatorial “menthyl” alcohols 2a and 2b to
the axial “neomenthyl” alcohols 2c and 2d that was obtained
from this reaction was typically 2 : 1 even when a 32 : 1 mixture
Scheme 1
magnesium alkoxide transfers a hydride ion to the strongly
electrophilic pyridine-2-carbaldehyde.
The more basic alcohols 2a–2d could be easily separated
from the ketones 5a and 5b via extraction into aqueous hydro-
chloric acid followed by later release from their salts. The
† To receive any correspondence regarding the X-ray crystallographic
structure of 6
2692
J. Chem. Soc., Perkin Trans. 1, 2002, 2692–2698
This journal is © The Royal Society of Chemistry 2002
DOI: 10.1039/b205872n

View Article Online
combined yield of the alcohols 2a–2d was 65%. Overlapping
resonances made it impossible to obtain reliable ratios for these
alcohols using 1H NMR spectroscopy, but “integration” of the
13C signals for their α-carbinyl carbon atoms suggested the
relative proportions of 2a : 2b : 2c : 2d to be 1.8 : 2.3 : 1 : 1. By
careful chromatography over silica gel it was possible to obtain
pure samples of each of these four alcohols.
The anti-Cram alcohol 2b could also be accessed via
Mitsunobu inversion of the alcohol 2a. Thus, employing condi-
tions recommended7 for the inversion of sterically hindered
alcohols, the (1R)-alcohol 2a was efficiently converted into
the (1S)-4-nitrobenzoate 7 which could then be hydrolysed to
provide 2b in 69% overall yield from 2a.
The menthyl alcohol (Ϫ)-(1R)-2a was obtained as an oil
which was laevorotatory in chloroform solution but dextrorota-
tory in ethanol, suggesting the possibility of intramolecular
hydrogen bonding in the former solvent. Its methyl ether 6 was
crystalline, enabling both the stereochemistry at C-1 of the
menthyl ring and the relative configuration of the secondary
carbinol centre to be obtained by X-ray crystallographic
analysis (Fig. 1). The absolute configurations of 6 and of
X-Ray crystallography was used to reveal the (1S)-
configuration of the crystalline neomenthyl alcohol (Ϫ)-2c, mp
68 ЊC, and clearly indicated that its hydroxy group did not
engage in intramolecular hydrogen-bonding with the adjacent
pyridyl nitrogen atom (Fig. 2).
Fig. 1
Fig. 2
compound 2c discussed below were not determined by X-ray
analysis but follow from the known absolute configuration of
the (Ϫ)-(1R,3R,4S)-menthol 1 used for their synthesis.
The epimeric anti-Cram alcohol (ϩ)-2d was obtained as
crystals, mp 33 ЊC, which were not suitable for X-ray analysis.
However, this compound could be oxidised with chromic acid
under two-phase conditions to give the neomenthyl ketone
(ϩ)-5b which showed a characteristic narrow multiplet for its
C-1 equatorial proton at δ 4.59 ppm with W1/2 = 11.4 Hz.
Appropriate 2D 1H NMR experiments revealed the
equatorial nature of H-1 on the cyclohexyl ring for both of
the neomenthyl systems 2c and 2d, confirming that the bulky
pyridylcarbinol substituent remains axial in each of these
compounds.
The alcohol 2a could be obtained more conveniently by
oxidation of the entire mixture of alcohols 2a–2d which was
obtained from the Grignard reaction to give a mixture (76%) of
(NMR) both the equatorial ketone 5a and the axial ketone 5b.
Base-catalysed equilibration of this mixture using potassium
tert-butoxide in DMSO led to almost complete (>20 : 1) form-
ation of the thermodynamically more stable equatorial
ketone 5a. Reduction of 5a in tetrahydrofuran solution using
sodium borohydride or lithium aluminium hydride proceeded
with relatively poor diastereoselectivity, but the more hindered
reagent lithium tri-tert-butoxyaluminium hydride gave a 14 : 1
mixture of 2a and its oily anti-Cram (Ϫ)-(1S)-epimer 2b in
93% yield. These alcohols were readily separable by column
chromatography.
The alcohols 2c and 2d have been claimed by Adolfsson
et al.,8 who obtained them by small-scale reaction of 2-
lithiopyridine with neomenthyl carbonitrile 8 (synthesised from
(Ϫ)-menthol 1), followed by reduction of the derived ketone 5b
with sodium borohydride. However, these authors do not report
either of the alcohols 2c or 2d as being crystalline. Further-
more, whilst the 1H and 13C NMR data which we have recorded
for 2c and 2d are generally in good agreement with that pro-
vided by Adolfsson et al., we have obtained a specific rotation
for 2c which conflicts in both sign and magnitude with that
reported by Adolfsson8 (see Experimental section). The con-
figurations for the carbinol centres of 2c and 2d that were sug-
gested by Adolfsson et al. relied on experiments with Mosher
esters, and our crystallographic results are in agreement with
these assignments.
The structure of 2b was confirmed by its oxidation to the
menthyl ketone (Ϫ)-5a, easily identified from its NMR spec-
trum which exhibited a typical double triplet at δ 4.14 ppm due
to the axial proton on C-1 of the menthyl ring.
The relative proportions of the equatorial alcohols 2a and 2b
and of the axial alcohols 2c and 2d which are formed by
reaction of menthylmagnesium chloride with pyridine-2-
J. Chem. Soc., Perkin Trans. 1, 2002, 2692–2698
2693

View Article Online
Table 1 Enantioselective addition of diethylizinc to benzaldehyde
catalysed by the alcohols 2a–2d
Catalyst
Yield of 14 (%)
Configuration
[α]D
Ee (%)
2a
2b
2c
2d
96
80
94
84
(R)
(R)
(R)
(R)
ϩ5.5
12.12
8.8
22.5
8.8
ϩ4.0
ϩ10.2
ϩ4.0
carbaldehyde are of interest in that a far greater proportion of
the product mixture than would be expected consists of the
neomenthyl derivatives 2c and 2d. Indeed, since neomenthyl
chloride
4 readily undergoes base-catalysed trans-diaxial
elimination of hydrogen chloride to yield menthenes, the total
absence of the neomenthyl compounds 2c and 2d from the
reaction mixture would not have been surprising.
It has been reported9 that menthylmagnesium chloride reacts
with carbon dioxide to give exclusively the equatorial carboxylic
acid 9. We have confirmed this result, obtaining unrecrystallised
acid 9 in 88% yield and in >100 : 1 ratio with the epimeric
neomenthyl acid 10. The possibility that dynamic interconver-
sion of menthyl- and neomenthylmagnesium chlorides takes
place in solution cannot be ruled out as an explanation for the
ratio of axial to equatorial products 2a–2d which we have
observed for the reaction with pyridine-2-carbaldehyde, but the
result of the carbonation experiment suggests that this does not
occur.10 It seems more likely that the menthyl ketone 5a, formed
(vide supra) as a secondary product when the Grignard reagent
derived from menthyl chloride 3 is reacted with pyridine-2-
carbaldehyde, subsequently equilibrates with its neomenthyl
isomer 5b, and that this latter ketone then enters into an
Oppenauer-like redox equilibrium with the menthyl-configured
chloromagnesium alkoxides which are the primary products of
the reaction. This can then lead to the mixture of equatorial
2a ϩ 2b and axial 2c ϩ 2d products which is obtained.
We briefly investigated a number of alternative routes to the
alcohols 2a–2d and to the ketones 5a–5b. Thus, one-pot Barbier
reaction11 between (Ϫ)-menthyl chloride 3 and pyridine-2-
carbaldehyde in the presence of lithium metal gave modest
amounts of the alcohols 2a–2d. Reaction of menthylmagne-
sium chloride with pyridine-2-carbonitrile was more successful,
yielding a mixture containing the imine 11 which was hydro-
lysed using concentrated aqueous hydrochloric acid to give
exclusively the menthyl ketone 5a. By contrast with the facile
base-catalysed isomerisation described above, prolonged treat-
ment with strong acid does not epimerise the axial neomenthyl
ketone 5b to its equatorial isomer 5a, and we therefore conclude
that the only imine formed as a product of the Grignard
reaction is the equatorial isomer 11.
It was clear, however, that only a part of the product mixture
that was obtained via reaction of menthylmagnesium chloride
with pyridine-2-carbonitrile had been successfully hydrolysed
by aqueous hydrochloric acid. Careful chromatography of the
remaining material, or of a sample of the crude product mix-
ture obtained from the Grignard reaction, led to the isolation
of a fraction that was identified as being the novel amidine 12.
This exhibited spectroscopic data that clearly established its
gross structure and confirmed that it was not the isomeric com-
pound 13. The amidine 12 was resistant to acid-catalysed
hydrolysis, being recovered unchanged after boiling with con-
centrated hydrochloric acid. We rationalise the formation of 12
as outlined in Scheme 2, but are unable to confidently assign a
Scheme 2
configuration to the double bond which is exocyclic to the
menthyl ring.
Each of the pyridyl alcohols 2a–2d proved to be an active
catalyst for the enantioselective addition of diethylzinc to benz-
aldehyde to give optically active 2-phenylpropanol (Table 1).
The results obtained were somewhat disappointing in terms of
the ee values of the phenylpropanol 14 produced, but it is note-
worthy that the (R)-alcohol was always favoured, regardless of
the configuration at C-1 of the catalyst that was employed.
2694
J. Chem. Soc., Perkin Trans. 1, 2002, 2692–2698

View Article Online
Further applications of the alcohols 2a–2d and of their
methyl ethers are under investigation.
were attached. The non-hydrogen atoms were refined aniso-
tropically. Final R indices [I > 2σ(I )] were R1 = 0.0350 and
wR2 = 0.1081. All calculations were performed on a Silicon
Graphics R4000 computer. The ORTEX program was used to
obtain the drawings.15
Experimental
1H NMR spectra were recorded for solutions in CDCl3 using
Bruker MSL-300 or Bruker AVANCE DPX-400 spectrometers.
J values are given in Hz. Assignments were verified by appro-
priate H–H COSY, C–H COSY and 13C-DEPT experiments. IR
spectra were recorded for Nujol mulls (N) or for liquid films (L)
between sodium chloride plates using Perkin Elmer 883 or
Paragon-FT spectrometers. High-resolution mass spectra were
obtained using a VG Alto Spec instrument. Melting points
(uncorrected) were measured in unsealed capillary tubes using a
Stuart Scientific SMP2 digital apparatus. Optical rotations were
measured for solutions in a 1 dm cell using a Perkin-Elmer 141
polarimeter; specific optical rotations are given in units of
10Ϫ1 deg cm2 gϪ1. Thin layer chromatography was carried out
using Merck Kieselgel 60 F254 0.2 mm silica gel plates. Column
chromatography was carried out using Merck Keiselgel 60
(70–230 mesh) silica gel. All solvents were distilled before use.
The (Ϫ)-menthol 2 used in this work had [α]D Ϫ 51.3 (c 2.38 in
EtOH).
Additional data available for structures 2c and 6 includes
tables of atomic coordinates and of bond lengths and angles
(CCDC reference numbers 186677 and 186678, respectively).
See http://www.rsc.org/suppdata/p1/b2/b205872n/ for these files
in electronic format.
(؊)-(1R,3R,4S )-3-Chloro-4-isopropyl-1-methylcyclohexane 36
A mixture of phosphorus pentachloride (40 g) and anhydrous
ferric chloride (1.0 g) suspended in hexane (55 cm3) was stirred
vigorously at 0 ЊC. A solution of (Ϫ)-menthol 2 (30 g) in hexane
(75 cm3) was added dropwise during 40 min. After a further
90 min, ice was added to quench the reaction. The hexane
extract was washed with water and with aqueous sodium
hydrogen carbonate solution, dried over anhydrous magnesium
sulfate, and evaporated to yield the derived chlorides 3 and 4
(30.3 g) which were distilled at reduced pressure, bp 94–96 ЊC/15
1
mmHg, [α]D Ϫ 44 (c 14.12 in MeOH). H NMR analysis by
integration of the signals for the axial and equatorial protons
on C-3 indicated a menthyl : neomenthyl ratio of 93 : 7. δH (400
MHz) 0.70 (3H, d, J 6.8), 0.86 (6H, d, J 6.3), 0.9 (2H, m), 1.4
(2H, m), 1.65 (2H, m), 1.80 (1H, m), 2.19 (1H, m), 2.35 (1H, m)
and 3.77 (0.93H, apparent dt, J 11.0, 11.0 and 4.2) and 4.44
(0.07 H, m) ppm; δC 15.1 (CH3), 20.95 (CH3), 21.88 (CH3),
24.23 (CH2), 27.09 (CH), 33.34 (CH), 34.21 (CH2), 46.71 (CH2),
50.40 (CH) and 63.81 (CH) ppm.
Crystal data for 2c
C16H25NO, M = 247.37. Monoclinic, a = 10.460(2), b =
5.5610(4), c = 13.412(2) Å, α = 90Њ, β = 110.951(7)Њ, γ = 90Њ, V =
728.5(2) Å3, space group P21, Z = 2, D (calculated) = 1.128 g
cm3, crystal dimensions 0.5 × 0.5 × 0.15 mm.
Occasionally, menthyl : neomenthyl ratios up to 87 : 13 were
observed, but this did not affect the stereochemical outcome of
any later reactions.
Data collection and processing. Enraf-Nonius CAD-4 dif-
fractometer, temperature 293(2) K, wavelength 0.71703 Å,
absorption coefficient 0.069 mmϪ1, theta range for data collec-
tion 1.64 to 25.21Њ, 1476 reflections collected, index ranges
Ϫ12 ≤ h ≤ 11; 0 ≤ k ≤ 6; 0 ≤ l ≤ 14, 1413 independent reflections
[R(int) = 0.0392].
Menthylmagnesium chloride
Magnesium turnings (5.56 g) were covered by dry THF and
stirred vigorously under an atmosphere of nitrogen. A small
crystal of iodine and/or one drop of 1,2-dibromoethane were
added, followed by freshly-distilled menthyl chloride 3 (12 g)
which had previously been dried over anhydrous sodium
carbonate to remove traces of hydrogen chloride. The mixture
was heated to induce reaction, and further menthyl chloride
(28 g) in THF (200 cm3) was added at such a rate that the
solution continued to reflux. Further THF was added when the
reaction was complete in order to adjust the Grignard reagent
concentration to ca. 0.5 M. Solutions of reagent were assayed
by titration in the usual way.
Structure analysis and refinement. The structure was solved
by direct methods, SHELXS-86,12 and refined to a final R value
of 0.0540 for I > 2σ(I ) by full matrix least squares analysis
on |F|2 (236 parameters) using SHELXL-93.13 All the non-
hydrogen atoms were refined anisotropically. The hydrogens,
with the exception of the hydroxy hydrogen which was located
from the difference map, were fixed geometrically and those in
similar environments were given common temperature factors
(CH 0.03651, CH2 0.3295, CH3 0.07375). The hydroxy hydro-
gen was isotropically refined with an independent temperature
factor. All calculations were carried out using a VAX-1 main-
frame computer. Figures were drawn using SCHAKAL.14
Reaction of menthylmagnesium chloride with pyridine-2-
carbaldehyde: formation of the ketones 5a and 5b, and of the
alcohols 2a–2d
Crystal data for 6
Freshly distilled pyridine-2-carbaldehyde (15.33 g) was added
slowly to an ice-cold solution of menthylmagnesium chloride in
tetrahydrofuran (0.53 M; 270 cm3). The mixture was allowed to
reach room temperature and then refluxed during 12 h, after
which time the reaction mixture was cooled and quenched with
water. Extraction with ether yielded a crude oily product (36 g).
This was dissolved in ether and shaken with 1 M HCl, and the
organic layer was washed with water, dried over magnesium
sulfate, and evaporated to give a mixture (9 g) containing
hydrocarbons (NMR suggested the presence of bimenthyls)
together with a 3 : 1 mixture of the ketones 5a and 5b. The
acidic aqueous layer was then basified using sodium carbonate
and extracted with ether. The ethereal extract was dried over
anhydrous potassium carbonate and evaporated to yield a
mixture (23 g) of the isomeric alcohols 2a–2d. The latter were
separated by chromatography on silica gel using an ethyl
acetate : hexane gradient as eluant. The alcohols were eluted in
the order 2d, 2b, 2a and 2c.
C17H27NO, M = 261.40. Orthorhombic, a = 10.8957(1), b =
11.2627(9), c = 13.3035(1) Å, V = 1632.5(2) Å3, space group
P212121, Z = 4, D (calculated) = 1.064 g cm3, crystal dimensions
0.5 × 0.5 × 0.5 mm.
Data collection and processing. Enraf-Nonius CAD-4 dif-
fractometer, temperature 293(2) K, wavelength 0.71069 Å,
absorption coefficient 0.065 mmϪ1, theta range for data collec-
tion 2.37 to 25.96Њ, 1904 reflections collected, index ranges
0 ≤ h ≤ 13; 0 ≤ k ≤ 13; 0 ≤ l ≤ 1838 independent reflections
[R(int) = 0.0168], 1523 reflections observed (>2σ).
Structure analysis and refinement. The structure was solved
by direct methods, SHELXS-86,12 and refined by full matrix
least squares analysis using SHELXL-93.13 Data were corrected
for Lorentz and polarisation effects but not for absorption.
Hydrogen atoms were included in calculated positions with
thermal parameters 30% larger than the atom to which they
J. Chem. Soc., Perkin Trans. 1, 2002, 2692–2698
2695

View Article Online
(؊)-(R)-[(1ЈR,2ЈS,5ЈR)-2Ј-Isopropyl-5Ј-methylcyclohexyl]-
(2Љ-pyridyl)methanol 2a. Obtained as an oil which had [α]D
Ϫ12.5 (c. 3.10 in CHCl3) or [α]D ϩ14.6 (c 1.30 in EtOH);
νmax (L) 3406, 3063, 3012, 2953, 2917, 2869, 1592, 1570, 1471,
1454, 1434, 1409, 1385, 1367, 1347, 1308, 1263, 1237, 1211,
1180, 1149, 1115, 1097, 1040, 1014, 993, 982, 967, 913, 876, 849,
812, 806, 777, 762, 750, 734, 678, 668, 646 and 621 cmϪ1; δH 0.13
(1H, apparent q, J 12.3), 0.55 (1H, m), 0.66 (3H, d, J 6.8), 0.69
(3H, d, J 6.7), 0.84 (3H, d, J 6.8), 0.8–1.1 (2H, overlapping
ms), 1.21 (1H, br m), 1.54 (2H, m), 1.79 (2H, m), 2.16 (1H, m,
-CHMe2), 4.85 (1H, br s, exch. D2O, -OH ), 4.90 (1H, s,
-CHOH), 7.04–7.10 (2H, overlapping ms, H-3Ј and H-5Ј), 7.54
(1H, dt, J 7.9 and 1.7, H-4Ј) and 8.41 (1H, dd, J 4.8 and 0.9,
H-6Ј) ppm; δC 15.22 (CH3), 21.39 (CH3), 22.59 (CH3), 24.21
(CH2), 26.73 (CH), 26.84 (CH), 32.59 (CH), 34.88 (CH2), 35.87
(CH2), 43.37 (CH), 46.25 (CH), 72.02 (-CHOH), 120.96 (CH),
121.98 (CH), 135.97 (CH), 147.67 (CH) and 160.08 (quat)
ppm. HRMS (EI) m/z 247.1944. Calculated for C16H25NO
247.1936.
(CH), 136.47 (CH), 147.55 (CH) and 162.68 (quat) ppm.
HRMS (EI) m/z 247.1919. Calculated for C16H25NO 247.1936.
(؊)-[(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl] 2Ј-pyridyl
ketone 5a and (؉)-[(1S,2S,5R)-2-isopropyl-5-methylcyclohexyl]
2Ј-pyridyl ketone 5b via oxidation of a mixture of the alcohols
2a–2d
A mixture of the crude alcohols 2a–2d (6 g), obtained as
described above, was dissolved in ether (60 cm3) at 0 ЊC. A
solution of sodium dichromate dihydrate (4.2 g) in water
(60 cm3) containing sulfuric acid (2.9 cm3) was added dropwise
with stirring and the resulting mixture was stirred during a fur-
ther 12 h. Ethanol (10 cm3) was added to break down the sticky
chromium complexes which had formed, and the reaction mix-
ture was extracted with ether. The ethereal extract was washed,
dried, and evaporated to give (NMR) an oily 3 : 1 mixture of
the ketones 5a and 5b (4.5 g; 76%), bp 165 ЊC at 0.5 mmHg.
(؊)-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl] 2Ј-pyridyl
ketone 5a via base-catalysed isomerisation of a mixture of 5a and
5b
(؊)-(S )-[(1ЈR,2ЈS,5ЈR)-2Ј-Isopropyl-5Ј-methylcyclohexyl]-
(2Љ-pyridyl)methanol 2b. Obtained as an oil which had [α]D Ϫ25
(c 1.16 in CHCl3); νmax (L) 3425, 2955, 2919, 2869, 1594, 1570,
1467, 1436, 1406, 1386, 1368, 1345, 1308, 1261, 1179, 1149,
1112, 1095, 1065, 1036, 900, 872, 841, 804, 779, 762, 748 and
679 cmϪ1; δH 0.7–1.2 (5H, overlapping ms), 0.73 (3H, d, J 6.4),
0.91 (3H, d, J 6.8), 1.00 (3H, d, J 6.8),1.5–1.8 (4H, overlapping
ms), 2.37 (1H, m, -CHMe2), 4.56 (1H, br s, exch. D2O, -OH ),
5.07 (1H, s, -CHOH), 7.16–7.21 (2H, overlapping ms, H-3Ј and
H-5Ј), 7.68 (1H, dt, J 7.9 and 1.7, H-4Ј) and 8.53 (1H, dd, J 4.6
and 1.5, H-6Ј) ppm; δC 15.58 (CH3), 21.59 (CH3), 22.72 (CH3),
24.32 (CH2), 26.37 (CH), 32.55 (CH), 32.79 (CH2), 35.08 (CH2),
43.01 (CH), 45.87 (CH), 70.47 (-CHOH), 120.0 (CH), 121.77
(CH), 136.52 (CH), 147.6 (CH) and 161.7 (quat) ppm. HRMS
(EI) m/z 247.1922. Calculated for C16H25NO 247.1936.
A 3 : 1 mixture of the ketones 5a and 5b (1.4 g) was dissolved
under nitrogen in DMSO (13 cm3) with a catalytic amount of
potassium tert-butoxide (50 mg). The mixture was stirred dur-
ing 12 h and then diluted with water and extracted with ether.
The extract was dried over magnesium sulfate and evaporated
to give an oil (1.3 g) which (NMR) was a 20 : 1 mixture of 5a
and 5b.
(؊)-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl] 2Ј-pyridyl
ketone 5a and N-[(2ЈS,5ЈR)-2Ј-isopropyl-5Ј-methylcyclohex-2Ј-
enylidene(2Љ-pyridyl)methyl]pyridine-2-carboxamidine 12 via
reaction of menthylmagnesium chloride with pyridine-2-carbo-
nitrile
(؊)-(S )-[1ЈS,2ЈS,5ЈR)-2Ј-Isopropyl-5Ј-methylcyclohexyl]-
(2Љ-pyridyl)methanol 2c. Obtained as plates, mp 68 ЊC (pentane)
which had [α]D Ϫ42 (c 1.08 in CHCl3) or [α]D Ϫ20 (c 0.24 in
EtOH) {lit.8 an oil, [α]D ϩ 5.3 (c 0.79 in EtOH)}; νmax (N) 3277,
3055, 3021, 2928, 2865, 1594, 1573, 1456, 1436, 1378, 1366,
1343, 1284, 1258, 1242, 1216, 1170, 1150, 1092, 1044, 1028,
1013, 1001, 990, 960, 935, 916, 892, 866, 806, 786, 751, 723, 678
and 625 cmϪ1; δH 0.64 (3H, d, J 7.9), 0.75–1.15 (4H, overlapping
ms), 0.90 (3H, d, J 6.4), 1.02 (3H, d, J 6.4), 1.48 (2H, m, includ-
ing -CHMe), 1.79 (2H, m), 2.07 (1H, m, -CHMe2), 2.35 (1H, m,
H-1), 3.40 (1H, br s, exch. D2O, -OH ), 4.94 (1H, d, J 8.8,
-CHOH), 7.15 (1H, m, H-5Ј), 7.24 (1H, d, J 8.1, H-3Ј), 7.61
(1H, dt, J 7.7 and 1.8, H-4Ј) and 8.50 (1H, dd, J 4.2 and 0.9,
H-6Ј) ppm; δC 22.22 (CH3), 22.48 (CH3), 22.68 (CH3), 24.97
(CH2), 27.05 (CH), 29.98 (CH), 36.01 (CH2), 39.09 (CH2), 42.34
(CH), 49.90 (CH), 74.63 (-CHOH), 121.68 (CH), 122.25 (CH),
136.13 (CH), 148.85 (CH) and 163.38 (quat) ppm [Calculated
for C16H25NO: C 77.73, H 10.12, N 5.67; found C 77.69, H
10.40, H 5.63%].
Pyridine-2-carbonitrile (2.73 g) was added to a solution of
menthylmagnesium chloride in THF (1.03 M; 25 cm3). After
the exothermic reaction had subsided, the mixture was refluxed
during 8 h, cooled and poured onto ice. Extraction using
ether gave a thick brown oil (2.8 g) from which hydrocarbons
(menthenes, bimenthyls) were removed by vacuum distillation
to leave a non-volatile residue (1.9 g). This (NMR) did not
contain any of the ketones 5a or 5b.
A part of this residue was stirred with dilute hydrochloric
acid and then extracted with ether to give an oil which now
(NMR, IR) consisted partly of the ketone 5a. This was isolated
by distillation; it had bp 135 ЊC/0.5 mmHg; [α]D Ϫ48.27 (c 0.959
in CHCl3); νmax (L) 3053, 2953, 2921, 2869, 1690, 1583, 1568,
1508, 1456, 1435, 1385, 1368, 1338, 1294, 1273, 1237, 1208,
1183, 1137, 1088, 1044, 1016, 995, 974, 928, 866, 818, 802, 744,
702, 685, 668 and 618 cmϪ1; δH 0.68 (3H, d, J 6.9), 0.7–1.2 (3H,
overlapping ms), 0.84 (3H, d, J 6.9), 0.86 (3H, d, J 6.6), 1.4–1.8
(6H, overlapping ms), 4.14 (1H, apparent dt, J 11.2, 11.2 and
3.4, -CHC᎐O), 7.41 (1H, ddd, J 6.5, 4.8 and 1.3, H-5Ј), 7.80
᎐
(1H, dt, J 7.9 and 1.8, H-4Ј), 8.03 (1H, d, J 7,9, H-3Ј) and 8.68
(1H, dd, J 4.8 and 1.0, H-6Ј) ppm; δC 16.51 (CH3), 21.45 (CH3),
22.36 (CH3), 24.22 (CH2), 29.12 (CH), 32.40 (CH), 34.72 (CH2),
39.33 (CH2), 44.17 (CH), 45.87 (CH), 122.2 (CH), 126.9 (CH),
(؉)-(R)-[1ЈS,2ЈS,5ЈR)-2Ј-Isopropyl-5Ј-methylcyclohexyl]-
(2Љ-pyridyl)methanol 2d. Obtained as needles, mp 33 ЊC (chloro-
form) which had [α]D ϩ30.5 (c 1.51 in CHCl3) or [α]D ϩ30 (c 0.8
in EtOH) {lit.8 an oil, [α]D ϩ10 (c 0.8 in EtOH)}; νmax (N) 3396,
2954, 2923, 2853, 1594, 1570, 1456, 1407, 1377, 1260, 1225,
1148, 1101, 1062, 1028, 865, 800, 748, 724 and 668 cmϪ1; δH 0.68
(3H, d, J 6.6), 0.7–1.2 (5H, overlapping ms), 0.99 (3H, d, J 6.4),
1.01 (3H, d, J 6.4), 1.7–1.9 (3H, overlapping ms), 1.95 (1H, m,
-CHMe2), 2.17 (1H, m, H-1), 4.5 (1H, br s, exch. D2O, -OH ),
5.09 (1H, d, J 2.2, -CHOH), 7.18 (1H, m, H-5Ј), 7.21 (1H, d,
J 7.9, H-3Ј), 7.64 (1H, dt, J 7.9 and 1.8, H-4Ј) and 8.53 (1H, d,
J 4.8, H-6Ј) ppm; δC 21.58 (CH3), 21.74 (CH3), 23.39 (CH3),
26.27 (CH2), 28.12 (CH), 29.36 (CH), 35.78 (CH2), 35.95 (CH2),
40.88 (CH), 47.83 (CH), 72.87 (-CHOH), 120.24 (CH), 121.74
136.8 (CH), 148.9 (quat) and 205.9 (C᎐O) ppm [Calculated
᎐
for C16H23NO: C 78.37, H 9.39, N 5.71; found C 78.65, H 9.63,
N 5.67%].
A further portion (1.3 g) of the non-volatile residue obtained
as described above was subjected to chromatography on silica
gel using 10% ethyl acetate : 85% hexane : 5% triethylamine as
eluant to give the following fractions: (a) the menthyl ketone 5a
(150 mg; 11.5%), (b) a fraction (143 mg; 11%) containing
several components which yielded the ketone 5a on treatment
with hydrochloric acid, and (c) the oily amidine 12 (260 mg;
20%) which was unaffected by treatment with hydrochloric acid
2696
J. Chem. Soc., Perkin Trans. 1, 2002, 2692–2698

View Article Online
and which had νmax(L) 3460, 3378, 3056, 2955, 2927, 2867, 1739,
1640, 1586, 1566, 1508, 1469, 1442, 1426, 1374, 1242, 1169,
1147, 1112, 1091, 1047, 997, 979, 958, 938, 921, 884, 847, 802,
792, 748, 695 and 668 cmϪ1; δH (400 MHz) 0.77 (6H, over-
lapping ds, 2 × Me groups), 0.86 (2H, m), 1.04 (3H, d, J 7.0, Me
group), 1.18 (2H, m), 1.57–2.10 (4H, overlapping ms), 2.48 (1H,
d, J 12.7), 6.29 (2H, br s, exch. D20, -NH2), 7.10 (1H, dd, J 7.6
and 4.6, 5Ј-H ), 7.27 (1H, dd, J 7.5 and 4.7, 5Љ-H ), 7.48 (1H, d,
J 7.3, 3Ј-H ), 7.59 (1H, dt, J 7.4, 7.4 and 1.3, 4Ј-H ), 7.71 (1, dt,
J 7.5, 7.5 and 1.8, 4Љ-H ), 8.34 (1H, dd, J 7.9 and 1.1, 3Љ-H ),
8.46 (1H, dd, J 4.6 and 0.9, 6Љ-H ) and 8.54 (1H, dd, J 4.7 and
0.9, 6Ј-H ) ppm; δC (100 MHz) 18.47 (CH3), 20.82 (CH3), 21.71
(CH3), 23.95 (CH2), 26.60 (CH), 26.84 (CH2), 29.70 (CH), 30.20
(CH2), 44.15 (CH), 121.40 and 121.60 (CH), 124.59 and 124.87
(CH), 126.87 (quat.), 136.03 (CH), 136.43 (CH), 136.75 (quat.),
139.82 (quat.), 147.65 (CH), 148.09 (CH), 152.04 (quat.) and
152.83 (quat.) ppm, m/z 348 (Mϩ), 331 (M Ϫ NH3), 316, 305,
263, 227, 212 (100%), 201, 184, 168, 157, 143, 132, 122, 105, 92
and 78 amu. HRMS: C22H28N4 (M); found: m/z 348.2318. Calc.
m/z 348.2314.
butoxyaluminium hydride (1.45 g) was added to the stirred
solution, the ice-bath was removed, and the mixture was stirred
for 16 h. It was then diluted with water and extracted with ether
to give a mixture of the alcohols 2a and 2b (1.08 g) in the ratio
(1H NMR) 14 : 1 as judged by integration of their -CHOH
resonances.
(؊)-(S )-[(1ЈR,2ЈS,5ЈR)-2Ј-Isopropyl-5Ј-methylcyclohexyl]-
(2Љ-pyridyl)methanol 2b via Mitsunobu inversion7 of (Ϫ)-(R)-
[(1ЈR,2ЈS,5ЈR)-2Ј-isopropyl-5Ј-methylcyclohexyl](2Љ-pyridyl)-
methanol 2a
The alcohol 2a (100 mg), triphenylphosphine (410 mg) and
4-nitrobenzoic acid (270 mg) in dry THF (7.5 cm3) were stirred
together at 0 ЊC under nitrogen. Diethyl azidodicarboxylate
(278 mg) was added dropwise, and the reaction mixture was
then stirred at room temperature during 12 h followed by 3 h at
40 ЊC. The mixture was cooled, diluted with ether and washed
with sodium hydrogen carbonate solution. Ether was removed
under reduced pressure and the ester 7 was purified by chrom-
atography over silica gel using ethyl acetate–hexane 10 : 90 as
eluant from which it was obtained as an oil (120 mg; 75%)
which had νmax (L) 2923, 1732, 1609, 1591, 1573, 1531, 1470,
1436, 1410, 1388, 1348, 1266, 1171, 1148, 1102, 1016, 999, 976,
873, 854, 833, 802, 784, 761, 720 and 665 cmϪ1; δH (400 MHz)
0.77 (3H, d, J 6.4), 0.82 (3H, d, J 6.8), 0.89 (3H, d, J 6.8), 1.04
(2H, m), 1.17 (2H, m), 1.27 (2H, m), 1.66 (2H, m), 2.07 (2H, m),
6.30 (1H, s, -CHOCOAr), 7.11 (2H, m, H-2-py and H-5-py),
7.55 (1H, t, J 7.8, H-4-py), 8.25 (4H, m, Ar-H) and 8.52 (1H, d,
J 3.3, H-6-py) ppm; δC 15.45 (CH3), 21.38 (CH3), 22.56
(CH3), 24.19 (CH2), 26.55 (CH), 32.55 (CH), 34.53 (CH2), 35.04
(CH2), 43.53 (CH), 43.70 (CH), 76.75 (CH), 119.78 (py-CH),
121.97 (py-CH), 123.62 (Ar-CH), 130.73 (Ar-CH), 135 (Ar-C),
136.06 (py-CH), 149.28 (py-CH), 150 (Ar-C), 158.9 (py-C)
(؉)-[(1S,2S,5R)-2-Isopropyl-5-methylcyclohexyl] 2Ј-pyridyl
ketone 5b. Obtained as an oil by careful column chromato-
graphy of a small portion of the crude reaction mixture
obtained from pyridine-2-carbaldehyde as described above. It
had bp 165 ЊC/0.6 mmHg; [α]D ϩ12.75 (c 1.96 in CHCl3);
νmax (L) 3053, 2949, 2867, 2843, 1689, 1583, 1569, 1472, 1456,
1434, 1386, 1368, 1339, 1298, 1274, 1260, 1226, 1195, 1169,
1148, 1123, 1088, 1045, 1025, 1017, 994, 982, 945, 928, 900, 884,
858, 826, 813, 778, 760, 743, 709, 668 and 618 cmϪ1; δH 0.76
(6H, d, J 6.5), 0.89 (3H, d, J 6.6), 0.82–0.97 (1H, m), 1.08–1.20
(1H, m), 1.25–1.50 (2H, ms), 1.60 (1H, m, -CHMe2), 1.72–2.04
(4H, overlapping ms), 4.59 (1H, m, W1/2 11.4 Hz, -CHC᎐O),
᎐
7.42 (1H, ddd, J 7.6, 4.8 and 1.3, H-5Ј), 7.81 (1H, dt, J 7.7 and
1.7, H-4Ј), 7.99 (1H, d, J 7.9, H-3Ј) and 8.65 (1H, d, J 4.0, H-6Ј)
ppm; δC 21.56 (2 × CH3), 22.28 (CH3), 26.34 (CH2), 27.12 (CH),
and 164 (C᎐O) ppm. HRMS (EI) m/z 396.2048. Calculated for
᎐
C23H28N2O4 396.2049.
This ester 7 (120 mg) was refluxed during 4 h with aqueous
sodium hydroxide solution (10%; 5 cm3). The mixture was then
cooled and extracted with ether. The ether extract was dried
and evaporated to give the alcohol 2b (65 mg; 92%), identical in
every respect with material obtained as described above.
30.07 (CH), 35.46 (CH ), 37.37 (CH ), 40.51 (CHC᎐O), 46.86
᎐
2
2
(CH), 122.04 (CH), 126.6 (CH), 136.9 (CH), 148.8 (CH), 153.7
(quat) and 204.4 (C᎐O) ppm. HRMS (EI) m/z 245.11774.
᎐
Calculated for C16H23NO 245.1779.
Oxidation of (؊)-(S )-[(1ЈR,2ЈS,5ЈR)-2Ј-isopropyl-5Ј-methyl-
cyclohexyl](2Љ-pyridyl)methanol 2b to (؊)-[(1R,2S,5R)-2-
isopropyl-5-methylcyclohexyl] 2Ј-pyridyl ketone 5a
(؉)-(R)-[(1ЈR,2ЈS,5ЈR)-2Ј-Isopropyl-5Ј-methylcyclohexyl]-
(2Љ-pyridyl)methyl methyl ether 6
The alcohol 2a (1.04 g) was dissolved in DMSO (10 cm3).
Sodium hydride (60% dispersion in oil; 0.25 g) was added. After
evolution of hydrogen had ceased, iodomethane (0.9 g) was
added and the mixture was stirred at rt during 13 h. Excess
sodium hydride was quenched using ethanol, and the mixture
was diluted with water and extracted with ether to give a brown
semi-crystalline mass (1.3 g). TLC indicated that a single
product had been formed, and chromatography over silica gel
using 1% ether : 99% hexane afforded the pure ether 6 as plates,
mp 77 ЊC (pentane) which had [α]D ϩ50.78 (c 0.128 in CHCl3)
or [α]D ϩ40.17 (c 1.17 in EtOH]; νmax (N) 3052, 2955, 2859,
2825, 1589, 1571, 1460, 1433, 1377, 1364, 1351, 1345, 1260,
1197, 1178, 1151, 1109, 1086, 1048, 1022, 994, 975, 930, 917,
873, 854, 811, 782, 756, 720 and 685 cmϪ1; δH 0.3–0.7 (2H, ms),
0.78 (3H, d, J 6.9), 0.79 (3H, d, J 6.6), 0.87 (3H, d, J 6.9), 0.9–
1.05 (1H, m), 1.22–1.38 (1H, m), 1.55–1.68 (2H, m), 1.77–1.84
(1H, m), 1.87–1.97 (1H, m), 2.50–2.59 (1H, d of septets, J 6.9
and 3.0, -CHMe2), 3.28 (3H, s, -OCH3), 4.54 (1H, d, J 4.0,
-CH(OCH3)), 7.15 (1H, ddd, J 8.6, 4.8 and 1.2, H-5Ј), 7.34 (1H,
d, J 7.9, H-3Ј), 7.66 (1H, dt, J 7.8, 7.8 and 1.7, H-4Ј) and 8.53
(1H, ddd, J 4.8, 1.9 and 1.0, H-6Ј) ppm; δC 15.09 (CH3), 21.43
(CH3), 22.68 (CH3), 24.11 (CH2), 26.56 (CH), 32.57 (CH), 34.90
(CH2), 35.76 (CH2), 43.61 (CH), 44.59 (CH), 57.32 (-OCH3),
85.07 (-CHOCH3), 121.8 (2 × CH), 135.6 (CH), 148.5 (CH) and
160.3 (quat) ppm. HRMS (EI) m/z 261.2087. Calculated for
C17H27NO 261.2093.
The alcohol 2b (40 mg) was dissolved in ether (1 cm3) and
stirred with a solution of sodium dichromate dihydrate (28 mg)
and sulfuric acid (0.2 cm3) in water 0.4 cm3) until oxidation was
complete. The reaction mixture was diluted with further ether,
washed sequentially with water and with sodium hydrogen
carbonate solution, dried and evaporated to give the ketone 5a
(32 mg; 81%), identical in every respect with material isolated as
described above.
Oxidation of (؉)-(S )-[(1ЈS,2ЈS,5ЈR)-2Ј-isopropyl-5Ј-methyl-
cyclohexyl](2Љ-pyridyl)methanol 2d to (؉)-[(1S,2S,5R)-2-
isopropyl-5-methylcyclohexyl] 2Ј-pyridyl ketone 5b
The alcohol 2 (30 mg) was dissolved in ether (1 cm3) and stirred
with a solution of sodium dichromate dihydrate (21 mg) and
sulfuric acid (0.15 cm3) in water 0.3 cm3) until oxidation was
complete. The reaction mixture was diluted with further ether,
washed sequentially with water and with sodium hydrogen
carbonate solution, dried and evaporated to give the ketone 5b
(23 mg; 77%), identical in every respect with material isolated as
described above.
Reduction of [(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl] 2Ј-
pyridyl ketone 5a by lithium tri-tert-butoxyaluminium hydride
The pure ketone 5a (1.17 g) was dissolved, under nitrogen, in
anhydrous tetrahydrofuran (12.5 cm3) at 0 ЊC. Lithium tri-tert-
J. Chem. Soc., Perkin Trans. 1, 2002, 2692–2698
2697

View Article Online
Barbier reaction of menthyllithium with pyridine-2-carbaldehyde
unreacted benzaldehyde and from recovered catalyst by column
chromatography. The purities of the samples of (ϩ)-(R)-1-
phenylpropanol 14 which were thus obtained were validated
A mixture of menthyl chloride 3 (8.7 g) and pyridine-2-
carbaldehyde (5.4 g) was slowly added to a stirred suspension of
small pieces of lithium (1.4 g) in dry THF (200 cm3) at 0 ЊC
under nitrogen. A dark red colour slowly developed. After a
further 4 h the mixture was decanted from the remaining
lithium into dilute sulfuric acid. The mixture was neutralised
using sodium carbonate and extracted with ethyl acetate. Evap-
oration yielded a dark red oil (10.2 g) which was further pro-
cessed as described above for the Grignard reaction between
menthylmagnesium chloride and pyridine-2-carbaldehyde to
give a mixture of the alcohols 2a–2d (ca. 3 g).
1
by H NMR spectroscopy, and ee values were determined by
polarimetry for chloroform solutions with reference to the
literature16 value of [α]D = ϩ45.45 (c 5.15 in CHCl3) for material
of 100% ee.
Acknowledgements
We gratefully acknowledge Dr John O’Brien’s skill in providing
NMR spectra, the V. K. Krieble Fund for financial support
to E. T. G. and to C. B. S., EOLAS for a research award to
E. T. G., the Trinity Trust for financial support to E. T. G. and
Foran Chemicals Ltd. for a gift of (Ϫ)-menthol.
Reaction of menthylmagnesium chloride with carbon dioxide:
(؊)-(1R,3R,4S )-4-isopropyl-1-methylcyclohexane-3-carboxylic
acid 9
References
A solution of menthylmagnesium chloride (0.65 M in THF;
5 cm3) was added with swirling to excess powdered carbon
dioxide (4 g). The resulting mixture was poured on to ice to
which concentrated hydrochloric acid (2 cm3) had been added,
and extracted with ether. The ethereal extract was washed with
water and then with sodium hydroxide solution. The alkaline
aqueous layer was acidified using hydrochloric acid and
extracted with ether. The ether extract was dried and evapor-
ated to give the crude acid 9 as colourless needles (0.52 g; 88%),
mp 56–57 ЊC (lit.9 mp 60–63 ЊC for the pure compound); [α]D
Ϫ50.7 ( c 2.13 in CHCl3) {lit.9 [α]D Ϫ56.1 (c 5.2 in EtOH)};
νmax (N) 3100, 2974, 2650, 1702, 1458, 1420, 1388, 1371, 1340,
1295, 1242, 1226, 1206, 1139, 1086, 1056, 1006, 963, 879 and
700 cmϪ1; δH 0.80 (3H, d, J 6.8), 0.90 (3H, d, J 6.4), 0.91 (3H, d,
J 6.8), 0.9–1.1 (2H, overlapping ms), 1.21 (1H, m), 1.35 (1H, m,
-CHMe2), 1.50 (1H, tt), 1.64–1.78 (3H, overlapping ms), 1.91
(1H, m), 2.29 (1H, dt, J 11.5, 11.5 and 3.3, H-3) and 10.52 (1H,
br s, exch. D2O, -OH ) ppm; δC 15.91 (CH3), 21.24 (CH3), 22.24
(CH3), 23.65 (CH2), 29.10 (CH), 31.97 (CH), 34.45 (CH2), 38.72
(CH2), 44.15 (CH), 47.62 (CH) and 183.21 (CO2H) ppm.
1 J. M. Hawkins and K. B. Sharpless, Tetrahedron Lett., 1987, 28,
2835.
2 (a) C. Bolm and M. Ewald, Tetrahedron Lett., 1990, 31, 5011;
(b) C. Bolm, Tetrahedron: Asymmetry, 1991, 2, 701; (c) C. Bolm,
M. Ewald and M. Felder, Chem. Ber., 1992, 125, 1205.
3 (a) M. Ishizaki, K. Fujita, M. Shimamoto and O. Hoshino,
Tetrahedron: Asymmetry, 1994, 5, 411; (b) M. Ishizaki and
O. Hoshino, Tetrahedron: Asymmetry, 1994, 5, 1901; (c) M. Ishizaki
and O. Hoshino, Chem. Lett., 1994, 1357; (d ) C. Bolm,
H. Schlingoff and K. Harms, Chem. Ber., 1992, 125, 1191;
(e) G. Chelucci and F. Soccolini, Tetrahedron: Asymmetry, 1992, 3,
1235.
4 (a) M. Kitamura, S. Suga, M. Niwa and R. Noyori, J. Am. Chem.
Soc., 1995, 117, 4832 and references therein; (b) T. Shibata,
H. Morioka, T. Hayase, K. Choji and K. Soai, J. Am. Chem. Soc.,
1996, 118, 471; (c) C. Girard and H. Kagan, Angew. Chem., Int. Ed.,
1998, 37, 2922.
5 (a) T. Shono, N. Kise, T. Fujimoto, A. Yamanami and R. Nomura,
J. Org. Chem., 1994, 59, 1730; (b) M. Genov, V. Dimitrov and
V. Ivanova, Tetrahedron: Asymmetry, 1997, 8, 3703; (c) for a review
of menthyl-based chiral auxiliaries see J. K. Whitesell, Chem. Rev.,
1992, 92, 953.
6 W. Huckel and H. Pietrzok, Justus Liebigs Ann. Chem., 1939, 540,
250.
7 J. A. Dodge, J. S. Nissen and M. Presnell, Org. Synth., 1996, 73,
110.
Enantioselective addition of diethylzinc to benzaldehyde
catalysed by alcohols 2a–2d
The general procedure described by Bolm3d was applied. The
following paragraph gives details of a representative experi-
ment. One of the alcohols 2a–2d (24.7 mg; 5 mol%) was dis-
solved in dry toluene (4 cm3) under a nitrogen atmosphere. This
solution was cooled in an ice-bath and benzaldehyde (212 mg)
was added. A solution of diethylzinc in hexane (1 M; 4 cm3,
2 eq.) was then added dropwise during 5 min. The resulting pale
yellow solution was stirred at 0 ЊC during 3 h and then at room
temperature during a further 20 h. The then colourless reaction
mixture was quenched by the slow addition of dilute hydro-
chloric acid, neutralised using solid sodium carbonate, and
extracted with ether. The ethereal extract was washed with
brine, dried over anhydrous sodium carbonate, and evapor-
ated to give a crude product that was separated from any
8 H. Adolfsson, K. Nordstrom, K. Warnmark and C. Moberg,
Tetrahedron: Asymmetry, 1996, 7, 1967.
9 D. G. Rowsell, BP 1 392 907/1975 (Chem. Abstr., 1975, 83, 114682t).
10 The ratio of menthyl and neomenthyl carboxylic acids which are
obtained via the carbonation of menthyllithium is both
temperature- and solvent-dependent: W. H. Glaze and C. M.
Selman, J. Org. Chem., 1968, 33, 1987.
11 (a) J. C. de Souza-Barboza, C. Petrier and J-L. Luche, J. Org. Chem.,
1988, 53, 1212; (b) P. J. Pearce, D. H. Richards and N. F. Scully,
J. Chem. Soc., Perkin Trans. 1, 1972, 1655.
12 G. M. Sheldrick, Acta Crystallogr., Sect. A, 1990, 46, 467.
13 G. M. Sheldrick, SHELXL-93, A computer program for crystal
structure determination, University of Gottingen, 1993.
14 E. Keller, University of Freiburg, Germany.
15 P. McArdle, J. Appl. Crystallogr., 1995, 28, 65.
16 R. H. Pickard and J. Kenyon, J. Chem. Soc., 1914, 1115.
2698
J. Chem. Soc., Perkin Trans. 1, 2002, 2692–2698