Enantioselective catalysis. Part 119: New chiral 2-(2- pyridinyl)oxazoline ligands containing an additional optically active substituent in the pyridine system

Article abstract of DOI:10.1016/S0957-4166(97)00619-8

The synthesis of novel chiral nitrogen ligands and their precursors is described. They consist of an optically active oxazoline bound to pyridine in the 2-position. In addition, another optically active substituent is attached to the pyridine ring. The effect of the two independent stereogenic units in one ligand was studied in the Rh(I)catalysed enantioselective hydrosilylation of acetophenone with diphenylsilane.

Full text of DOI:10.1016/S0957-4166(97)00619-8

Pergamon
Tetrahedron: Asymmetry 9 (1998) 407–422
Enantioselective catalysis. Part 119:1 New chiral 2-(2-
pyridinyl)oxazoline ligands containing an additional optically
active substituent in the pyridine system
Henri Brunner,a,∗ Reinhard Störiko a and Bernhard Nuber b
aInstitut für Anorganische Chemie der Universität Regensburg, D-93040 Regensburg, Germany
bAnorganisch-Chemisches Institut der Universität Heidelberg, INF 270, D-69120 Heidelberg, Germany
Received 14 October 1997; accepted 2 December 1997
Abstract
The synthesis of novel chiral nitrogen ligands and their precursors is described. They consist of an optically
active oxazoline bound to pyridine in the 2-position. In addition, another optically active substituent is attached
to the pyridine ring. The effect of the two independent stereogenic units in one ligand was studied in the Rh(I)-
catalysed enantioselective hydrosilylation of acetophenone with diphenylsilane. © 1998 Elsevier Science Ltd. All
rights reserved.
1. Introduction
Nitrogen-containing chiral ligands proved to be efficient in the Rh(I)-catalysed enantioselective
hydrosilylation.2,3 These ligands usually carry one optically active substituent (which of course can
have more than one stereogenic centre).2–4 In addition, there are C2-symmetrical ligands (e.g. 2,6-bis(2-
oxazolinyl)pyridines) which possess two identical chiral substituents.5–9 In the present approach we tried
to combine two different optically active substituents on both sides of the pyridine system (Scheme 1).
As chiral oxazolines tend to induce high enantiomeric excess2–9 and are in addition easily accessible
by condensation of enantiopure amino alcohols with suitable precursors,10 the oxazoline system was
maintained as one of the chiral substituents, whereas the other chiral substituent was varied (Scheme 1).
By this substitution pattern diastereomeric ligands are produced allowing a kind of internal double
stereoselection. The new ligands were tested in the Rh(I)-catalysed enantioselective hydrosilylation and
the results were compared with those obtained using ligands containing single chiral substituents.
∗
Corresponding author. E-mail: henri.brunner@chemie.uni-regensburg.de and hans@wasi0.aci.uni-heidelberg.de
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(97)00619-8

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H. Brunner et al. / Tetrahedron: Asymmetry 9 (1998) 407–422
Scheme 1.
2. Synthesis and characterisation of the ligands
Chiral pyridines can be prepared by attaching an optically active frame to the pyridine system via
Kröhnke condensation11 between optically active pinane derivatives and suitable Michael synthons.12
Our system should have a substituent in the 2-position which can be the transformed to an oxazo-
line ring. Thus, the previously unknown compounds 3–5 were prepared by Kröhnke reaction of (+)-
pinocarvone 2 with the pyruvate 1 (Scheme 2). Although different conditions were used following
literature procedures,13–15 only moderate yields of the condensation products 3–5 were obtained (max.
23%). The undesired carboxamide 5 was always present in yields of 7–10%. Hence, the separation of the
products was difficult. The reaction in refluxing methanol following the method of Hünig et al.13 gave
the methylate 3 (15%) besides the ethylate 4 (<1%) and the amide 5 (7%). Compound 5 was converted
into the nitrile 6, another possible oxazoline-precursor (Scheme 2).10 The esters 3 and 4 were saponified
yielding the acid 7 which subsequently was converted into the acid chloride 8. (S)-Valinol and 8 gave the
oxazoline 9 via a three-step reaction in 49% yield (Scheme 2).
Scheme 2.
1
Recrystallised 9 was diastereomerically pure by H NMR spectroscopy.16 Compound 9 and all
its precursors were extensively characterised by NMR spectroscopy. 2-D NMR experiments allowed
complete assignment of all hydrogen and carbon signals. The protons of the pinane system exhibited an
4
interesting coupling pattern due to the long range coupling between H-5 and H-7 (Fig. 1). Since J5,7
has exactly the same value as 3J5,6exo and 3J6exo,7, pseudo-triplets appear. H-6endo only couples with the
geminal H-6exo, because it is orthogonally orientated to H-5 as well as H-7 and hence does not give rise
to any coupling.
Hentges and Sharpless had used 2-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]pyridine [(−)-2-
L-menthylpyridine]17 as a chiral base for asymmetric oxidations, but its synthesis has never been
published.18 We chose (−)-2-L-menthylpyridine, because by α-cyanation of the pyridine ring a

H. Brunner et al. / Tetrahedron: Asymmetry 9 (1998) 407–422
409
Fig. 1. 1H–1H-Coupling constants in the pinane system, values taken from 3 (R=COOMe)
suitable oxazoline-precursor could be synthesised. Moberg and Macedo had prepared similar 6-(2-
oxazolinyl)pyridine-2-carbinols using this reaction sequence.19 We synthesised (−)-2-L-menthylpyridine
11a following Hentges’ Grignard cross coupling of menthyl Grignard 10a (derived from (−)-L-
menthylchloride) with 2-bromopyridine (Scheme 3), but could not reproduce the reported 18% yield.20
With Pd(dppf)Cl2 as a catalyst (recommended for the coupling of secondary alkyl Grignards)21 the
highest yield of 11a was 9.2%. All hydrogen and carbon signals of 11a were completely assigned by
1
analysis of 13C/1H and H/1H NMR correlation spectra, proving 11a to be diastereomerically pure,
because no signals of a possible diastereomer were evident.
Scheme 3.
Although menthyl Grignards are easily prepared22 and tend to couple smoothly with halides yield-
ing usually only one main product,22,23 there were problems in the cross coupling reaction with 2-
bromopyridine. Besides uncharacterised menthyl derivatives, we always isolated 2,20-bipyridine originat-
ing from a homo-coupling of 2-bromopyridine. Thus, for the synthesis of (+)-2-D-menthylpyridine 11b

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H. Brunner et al. / Tetrahedron: Asymmetry 9 (1998) 407–422
Fig. 2. Molecular structure of 13b (Ortep plot)
we turned to the method of Bell et al., who prepared alkylated heterocycles using 2:1 alkyl Grignard:Cu(I)
mixtures.24 However, to obtain good yields they had to use an eightfold excess of alkyl Grignard
relative to the halide.24 We succeeded in synthesising (+)-2-D-menthylpyridine 11b in 36% yield from
2-bromopyridine and menthyl Grignard 10b (derived from (+)-D-menthylchloride) using a ratio of 1:1
(Scheme 3).
The subsequent synthesis was straightforward. 2-D-Menthylpyridine 11 was oxidised with m-cpba
yielding the N-oxide 12, which was converted into the nitrile 13 using trimethylsilylcyanide and
dimethylcarbamoylchloride in CH2Cl2 (Scheme 3).25 An X-ray structure analysis of 13b proved the
expected equatorial orientation of the menthyl substituents (Fig. 2). Thus, the Cu(I)-mediated reaction of
menthyl Grignard 10b with 2-bromopyridine proceeded diastereoselectively with retention of configura-
tion at C-3 of the menthyl system. The nitrile 13b exhibited the same specific rotation as its counterpart
13a, but with opposite sign. The same situation was found for the two N-oxides 12a and 12b. Hence, also
the Pd(II)-catalysed Grignard cross coupling was highly diastereoselective. The methyl carboximidate
14 was prepared by stirring the nitrile 13 in methanol with catalytic amounts of methanolate.26 The
following reaction with the amino alcohol required acid catalysis. However, already three drops of conc.
HCl led to hydrolysis of the iminoether 14a yielding the carboxamide 17 (Scheme 4). With only tiny
amounts of conc. HCl 14a/b reacted smoothly with (S)-phenylalaninol in chlorobenzene at 80°C to
give the oxazolines 15a/b (Scheme 3). The resinous diastereomers 15a and 15b did not crystallise and
they showed almost identical spectroscopic behaviour. Ligand 16, having an achiral oxazoline ring, was
analogously prepared from ethanolamine and 14b (Scheme 3). With this ligand the asymmetric induction
of the menthyl part of the ligand should be tested in catalysis. By reaction of 15b with [Rh(cod)Cl]2 ( 1/2
mol equivalent) in methylene chloride and subsequent anion exchange with NH4PF6 the Rh(I)-complex
18 was prepared in 64% yield (Scheme 4).
3. Catalytic results
All the new ligands were tested in the enantioselective hydrosilylation of acetophenone with
diphenylsilane (Scheme 5).1 The amount of silylenol ether [III/(II+III)], the degree of hydrosilylation
(i.e. the conversion of acetophenone) [(II+III)/(I+II+III)] and the chemical yield of silylalkyl ether

H. Brunner et al. / Tetrahedron: Asymmetry 9 (1998) 407–422
411
Scheme 4.
1
[II/(I+II+III)] were calculated from H NMR spectra recorded after each catalytic run.1 The enan-
tiomeric excess was determined after hydrolysis by GC (see experimental).
Scheme 5.
The only comparable ligands with two different chiral substituents, having been tested in the Rh(I)-
catalysed asymmetric hydrosilylation, are the 6-(2-oxazolinyl)pyridine-2-carbinols and their methyl
ethers.19 Although these ligands gave good optical yields in other asymmetric catalyses,19,27 in the
hydrosilylation reactions only racemic products were obtained.19
Entries 1–3 of Table 1 show the catalytic results obtained with oxazoline 9 and the ligands containing
either optically active pinane or oxazoline substituents (19 and 20, Scheme 6). The values for 20 were
taken from the literature,28 those for 1929 were established in this study.30 Ligand 9 proved to be the
best ligand. Surprisingly, 9 and 19 induced the opposite configuration in the product compared to 20.
Inversion of the product configuration has been reported,31,32 if 2-(2-pyridinyl)oxazolines, unsubstituted
in the pyridine ring, are replaced by the corresponding picoline- or quinoline-oxazolines, containing
substituents in the 5- and/or 6-position of the pyridine ring as cocatalysts.
The results of the menthyl-substituted ligands and the corresponding 2-(2-pyridinyl)oxazoline 2128
Table 1
Hydrosilylation of acetophenone with diphenylsilane (CCl4 as solvent); reaction time: 18 h; catalyst:
0.24 mol% [Rh(cod)Cl]2 (0.48 mol% Rh); 2.35 mol% ligand, substrate/Rh: 210:1

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H. Brunner et al. / Tetrahedron: Asymmetry 9 (1998) 407–422
Scheme 6.
are displayed in entries 4–9. Only 16, the ligand with the achiral oxazoline, tends to induce asymmetry
(entry 8). The diastereomers 15a and 15b did not lead to significant enantioselectivities, contrary to
the good enantiomeric excesses of ligand 21 (entry 9) having the same oxazoline ring as 15a and 15b.
However, while preparing the in situ Rh(I)-catalyst, it was noticed that the solution did not turn red as
usually observed during the catalyst preparation. Due to steric hindrance the complexation of 15 may
be unfavourable as already proposed for other bulky oxazoline ligands.19 Hence, in three catalytic runs
with 15a (entry 5) excess of AgBF433 was added to remove the chloride from [Rh(cod)Cl]2 and to assist
in the formation of Rh(15a)-complexes. The yellow solutions of ligand and [Rh(cod)Cl]2 did in fact
change their colour to orange after AgBF4 had been added. The solutions turned immediately black
after the addition of diphenylsilane. Enantioselectivities up to 26.8% ee were obtained, depending on the
amount of AgBF4 added. The synthesised Rh(I)-complex 18 (entry 7) gave better chemical yields than
the corresponding in situ system with 15b (entry 6), but no stereoselectivity was found.
4. Experimental section
Chromatography: Merck silica gel 60 (63–200 mesh). Melting points (not corrected): Büchi SMP
1
20 (open capillaries). Elemental analyses: Microanalytical Laboratory, University of Regensburg. H
NMR: Bruker AW-80 (80 MHz, 31°C), AC-250 (250 MHz, 24°C) and ARX-400 (400 MHz, 21°C), 13
C
NMR: Bruker AC-250 (62.9 MHz, 24°C), TMS or the solvent itself as internal standard. For optimal
resolution some spectra were processed after recording using Bruker WIN NMR 5.0/5.1 software. The
abbreviations qC in the 13C NMR data represent quaternary carbon atoms. MS: Finnigan MAT 311 A
(EI, 70 eV) and MAT 95 (FD). High-resolution mass spectra were recorded on a Joel JMS-SX102A
(EI, 70 eV) at the Max–Planck–Institut für medizinische Forschung in Heidelberg. IR: Beckman IR
4240 (solids as KBr pellets, liquids as films between NaCl plates), only characteristic bands are listed.
Optical rotation: Perkin–Elmer polarimeter 241 (0.1 dm cuvettes). Commercially available reagents were
used without further purification if not stated otherwise. All anhydrous solvents were stored under
nitrogen. Abbreviations: cod=η4-1,5-cyclooctadiene, dppf=1,10-bis(diphenylphosphanyl)ferrocene, m-
cpba=m-chloroperbenzoic acid, men=menthyl, Ox=oxazoline, EA=ethyl acetate, PE=petroleum ether
(b.p. 40–60°C).
4.1. 1-(2-Ethoxycarbonyl-2-oxoethyl)pyridinium-bromide 1
Following the method of Hünig et al.13 dry pyridine (2.0 ml, 24.8 mmol) in dry ether (15 ml) was
added at 0°C to a stirred solution of 5.1 g (≥23.5 mmol) of ethyl bromopyruvate (>90%, Fluka) in dry
ether (15 ml) under nitrogen. Stirring in the ice bath (which was warming up) continued for 2 h. The
yellow precipitate was filtered off, carefully avoiding any contact with air. After washing with dry ether
(2×7 ml) the product was dried in vacuo. The light yellow salt (5.21 g, 19.0 mmol, 81% [lit.13: 89%])

H. Brunner et al. / Tetrahedron: Asymmetry 9 (1998) 407–422
413
was extremely hygroscopic and immediately became an orange oil if exposed to air. Even under argon it
can only be stored for a short while. 1H NMR (250 MHz, CD3OD); δ=1.34 (t, 3J=7.2 Hz, 3H, CH2CH3),
4.34 (q, 3J=7.2 Hz, 2H, CH2CH3), 4.73 (d, J=11.6 Hz), 4.91 (d, J=13.3 Hz), 5.02 (d, J=13.3 Hz), 5.14 (d,
J=11.6 Hz, together 2H, COCH2), 8.14 (‘dd’, 3J=7.9 Hz, 3J=6.8 Hz, 2H, H-3, H-5), 8.68 (‘tt’, 3J=7.9 Hz,
4J=1.4 Hz, 1H, H-4), 8.94 (‘dd’, 3J=6.8 Hz, 4J=1.4 Hz, 2H, H-2, H-6). 13C NMR (62.9 MHz, CD3OD);
δ=14.5 (CH3), 64.0 (CH2CH3), 66.8 (COCH2), 128.5 (C-3, C-5), 147.8 (C-4), 148.1 (C-2, C-6), 169.0
(COOEt). IR (film): ν (cm−1)=3140/3095 s, 2995 m (C–H), 1750 vs (C=O), 1270/1150/1105 s (C–O).
Kröhnke condensation of 1-(2-ethoxycarbonyl-2-oxoethyl)pyridinium-bromide 1 and (+)-pinocarvone
2: 5.27 g (max. 19.3 mmol) of 1, 8.9 g (115.4 mmol) of anhydrous ammonium acetate and 1.66 g
(11.0 mmol) of (+)-pinocarvone 230,34 were refluxed in dry methanol (17 ml) under nitrogen for 16
h. The solvent was evaporated and the brown residue was treated with water (30 ml). The solution was
extracted with CH2Cl2 (2×20 ml) and CHCl3 (2×20 ml). The combined organic layers were washed
with brine (20 ml), dried over MgSO4 and evaporated. The remaining oil was flash chromatographed
(SiO2, 11×3 cm, PE:EA 4:1): unidentified pinane derivatives were eluted first, followed by a mixture
of 5,6,7,8-tetrahydroquinoline compounds (yield: 23%). By a second flash chromatography (SiO2, 12×3
cm, PE:EA 5:1 -→ 3:2) this mixture was then separated into the following three products (in order of
elution):
4.2. Product: (−)-methyl (5R,7R)-5,6,7,8-tetrahydro-5,7-(9,9-dimethylmethano)quinoline-2-carboxyl-
ate 335
Light yellow liquid (383 mg, 1.7 mmol, 15%), Rf=0.52 (EA). 1H NMR (250 MHz, CD2Cl2); δ=0.63
2
3
(s, 3H, H-11), 1.26 (d, J=9.6 Hz, 1H, H-6endo), 1.41 (s, 3H, H-10), 2.39 (‘tt’, J7,6exo=4J7,5≈5.7
Hz, J7,8=2.9 Hz, 1H, H-7), 2.72 (dt, J=9.6 Hz, J6exo,5=3J6exo,7≈5.7 Hz, 1H, H-6exo), 2.85 (t,
3J5,6exo=4J5,7≈5.7 Hz, 1H, H-5), 3.15 (d, 3J8,7=2.9 Hz, 2H, H-8), 3.92 (s, 3H, COOCH3), 7.33 (d, 3J=7.7
Hz, 1H, H-4), 7.81 (d, 3J=7.7 Hz, 1H, H-3). 13C NMR (62.9 MHz, CD2Cl2); δ=21.3 (C-11), 26.1 (C-10),
31.9 (C-6), 36.9 (C-8), 39.7 (C-9), 40.6 (C-5), 47.2 (C-7), 52.5 (COOCH3), 122.7 (C-3), 133.7 (C-4),
145.7 (C-4a), 146.6 (C-2), 157.8 (C-8a), 166.4 (C=O). MS (EI): m/z (%)=231 (71) [M+], 230 (27), 216
(27) [M+−CH3], 189 (27), 188 (79) [M+−C3H7], 172 (26), 171 (34), 170 (40), 158 (21), 157 (39), 156
3
2
3
+
(46), 144 (43), 130 (28), 129 (63), 128 (100), 43 (30) [C3H7 ]. IR (film): ν (cm−1)=2960/2940/2920
s, 2885 m (C–H), 1740/1720 s (C=O). Specific rotation (c=1.1, CHCl3); [α]D22=−56, [α]57822=−58,
[α]54622=−66, [α]43622=−119.
4.3. Product: (−)-ethyl (5R,7R)-5,6,7,8-tetrahydro-5,7-(9,9-dimethylmethano)quinoline-2-carboxylate
435
Yellow liquid (22 mg, 0.1 mmol, 0.8%), Rf=0.49 (EA). 1H NMR (250 MHz, CD2Cl2); δ=0.63 (s, 3H,
H-11), 1.26 (d, 2J=9.6 Hz, 1H, H-6endo), 1.40 (t, 3J=7.1 Hz, 3H, CH2CH3), 1.41 (s, 3H, H-10), 2.39 (‘tt’,
3J7,6exo=4J7,5≈5.7 Hz, 3J7,8=2.9 Hz, 1H, H-7), 2.72 (dt, 2J=9.6 Hz, 3J6exo,5=3J6exo,7≈5.7 Hz, 1H, H-6exo),
3
3
3
2.85 (t, J5,6exo=4J5,7≈5.7 Hz, 1H, H-5), 3.16 (d, J8,7=2.9 Hz, 2H, H-8), 4.39 (q, 3H, J=7.1 Hz, 2H,
CH2CH3), 7.33 (d, 3J=7.7 Hz, 1H, H-4), 7.81 (d, 3J=7.7 Hz, 1H, H-3). 13C NMR (62.9 MHz, CD2Cl2);
δ=14.5 (CH2CH3), 21.3 (C-11), 26.1 (C-10), 31.9 (C-6), 37.0 (C-8), 39.7 (C-9), 40.6 (C-5), 47.2 (C-7),
61.6 (COOCH2), 122.7 (C-3), 133.6 (C-4), 146.0 (C-4a), 146.5 (C-2), 157.8 (C-8a), 165.9 (C=O). MS
(EI); m/z (%)=245 (65) [M+], 203 (25), 202 (80) [M+−C3H7], 173 (33), 171 (44), 170 (41), 158 (24), 157
+
(37), 156 (54), 130 (38), 129 (55), 128 (100), 43 (30) [C3H7 ], 41 (21). IR (film); ν (cm−1)=2985/2930

414
H. Brunner et al. / Tetrahedron: Asymmetry 9 (1998) 407–422
s, 2875 m (C–H), 1745/1720 s (C=O). Specific rotation (c=1.1, CHCl3); [α]D22=−44, [α]57822=−48,
[α]54622=−54, [α]43622=−103.
4.4. Product: (−)-(5R,7R)-5,6,7,8-tetrahydro-5,7-(9,9-dimethylmethano)quinoline-2-carboxamide 535
1
Yellow solid (160 mg, 0.7 mmol, 6.7%), Rf=0.43 (EA), m.p. 141–144°C. H NMR (250 MHz,
2
CDCl3); δ=0.64 (s, 3H, H-11), 1.27 (d, J=9.6 Hz, 1H, H-6endo), 1.42 (s, 3H, H-10), 2.39 (‘tt’,
3
2
3
3J7,6exo=4J7,5≈5.7 Hz, J7,8=2.9 Hz, 1H, H-7), 2.71 (dt, J=9.6 Hz, J6exo,5=3J6exo,7≈5.7 Hz, 1H, H-
3
6
exo), 2.84 (t, J5,6exo=4J5,7≈5.7 Hz, 1H, H-5), 3.10 (d, 3J8,7=2.9 Hz, 2H, H-8), 6.16 (br s, 1H, NHH0),
7.34 (d, 3J=7.7 Hz, 1H, H-4), 7.87 (br s, 1H, NHH0), 7.91 (d, 3J=7.7 Hz, 1H, H-3). 13C NMR (62.9 MHz,
CDCl3); δ=21.2 (C-11), 26.0 (C-10), 31.7 (C-6), 36.4 (C-8), 39.4 (C-9), 40.1 (C-5), 46.7 (C-7), 119.6
(C-3), 133.7 (C-4), 145.5 (C-4a), 147.0 (C-2), 155.9 (C-8a), 167.5 (C=O). MS (EI); m/z (%)=216 (74)
[M+], 174 (24), 173 (67) [M+−C3H7], 172 (32), 171 (25), 170 (35), 156 (45), 130 (26), 129 (55), 128
(100). IR (KBr): ν (cm−1)=3445 s, 3265 m, 3150 s (N–H), 2995/2980/2970 m, 2940/2930 s, 2910/2870
m (C–H), 1690 vs (C=O). Specific rotation (c=1.1, CHCl3); [α]D23=−61, [α]57823=−63, [α]54623=−72.
4.5. (−)-2-Cyano-(5R,7R)-5,6,7,8-tetrahydro-5,7-(9,9-dimethylmethano)quinoline 635
155 mg (0.7 mmol) of 5 and POCl3 (0.2 ml, 2.2 mmol) in CCl4 (4 ml) were refluxed for 18 h.
After cooling and evaporation the residue was treated with CHCl3 (20 ml) and half-saturated aqueous
NaHCO3 (20 ml). The organic layer was washed with water (10 ml) and brine (10 ml), dried over
MgSO4 and evaporated. Flash chromatography (SiO2, 7×2.5 cm, CH2Cl2) and recrystallisation from
1
PE led to 70 mg (0.35 mmol, 50%) of 6. Colourless crystals, Rf=0.26 (CH2Cl2), m.p. 60–62°C. H
2
NMR (250 MHz, CD2Cl2); δ=0.63 (s, 3H, H-11), 1.25 (d, J=9.8 Hz, 1H, H-6endo), 1.42 (s, 3H, H-
3
10), 2.39 (‘tt’, J7,6exo=4J7,5≈5.7 Hz, 3J7,8=2.9 Hz, 1H, H-7), 2.74 (dt, 2J=9.8 Hz, 3J6exo,5=3J6exo,7≈5.7
3
3
Hz, 1H, H-6exo), 2.86 (t, J5,6exo=4J5,7≈5.7 Hz, 1H, H-5), 3.12 (d, J8,7=2.9 Hz, 2H, H-8), 7.32 (d,
3J=7.7 Hz, 1H, H-4), 7.42 (d, J=7.7 Hz, 1H, H-3). 13C NMR (62.9 MHz, CD2Cl2); δ=21.3 (C-11),
3
26.0 (C-10), 31.7 (C-6), 36.8 (C-8), 39.7 (C-9), 40.3 (C-5), 47.3 (C-7), 118.3 (C≡N), 126.1 (C-3), 130.8
(C-4a), 133.6 (C-4), 147.1 (C-2), 159.9 (C-8a). MS (EI); m/z (%)=198 (32) [M+], 197 (25), 183 (44),
157 (15), 156 (41), 155 (100) [M+−C3H7], 154 (34), 143 (11), 142 (15), 128 (13), 41 (11). IR (KBr);
ν (cm−1)=2975/2945 s, 2875 m (C–H), 2230 m (C≡N). Specific rotation (c=1.1, CHCl3); [α]D24=−69,
[α]57824=−73, [α]54624=−83, [α]43624=−147, [α]36524=−237.
4.6. (−)-(5R,7R)-5,6,7,8-Tetrahydro-5,7-(9,9-dimethylmethano)quinoline-2-carboxylic acid 735
3 (100 mg, 0.4 mmol) was refluxed in 2 N NaOH (10 ml) for 1 h. The cooled solution was acidified
with conc. HCl and extracted with CHCl3 (3×10 ml). The combined organic layers were washed with
brine (10 ml), dried over MgSO4 and evaporated. Recrystallisation from PE:ether (1:1) gave 80 mg (0.37
mmol, 92%) of 7. Yellow solid, m.p. 158–162°C. 1H NMR (250 MHz, CD2Cl2): δ=0.63 (s, 3H, H-11),
2
3
3
1.27 (d, J=9.8 Hz, 1H, H-6endo), 1.43 (s, 3H, H-10), 2.41 (‘tt’, J7,6exo=4J7,5≈5.6 Hz, J7,8=2.8 Hz,
1H, H-7), 2.76 (dt, 2J=9.8 Hz, 3J6exo,5=3J6exo,7≈5.6 Hz, 1H, H-6exo), 2.85 (t, 3J5,6exo=4J5,7≈5.6 Hz, 1H,
H-5), 3.14 (d, 3J8,7=2.8 Hz, 2H, H-8), 7.46 (d, 3J=7.7 Hz, 1H, H-4), 7.89 (d, 3J=7.7 Hz, 1H, H-3), 9.28
(br s, 1H, COOH). 13C NMR (62.9 MHz, CD2Cl2); δ=21.3 (C-11), 26.0 (C-10), 31.9 (C-6), 36.4 (C-8),
39.8 (C-9), 40.4 (C-5), 47.2 (C-7), 121.1 (C-3), 135.2 (C-4), 143.8 (C-4a), 148.1 (C-2), 156.8 (C-8a),
164.8 (C=O). MS (EI); m/z (%)=217 (39) [M+], 216 (27), 175 (27), 174 (66) [M+−C3H7], 173 (32), 171
(25), 170 (35), 156 (40), 130 (37), 129 (59), 128 (100). IR (KBr): ν (cm−1)=2990 m, 2960/2930 s, 2870

H. Brunner et al. / Tetrahedron: Asymmetry 9 (1998) 407–422
415
m (C–H), 1740 s (C=O). Specific rotation (c=1.1, CHCl3); [α]D24=−57, [α]57824=−60, [α]54624=−69,
[α]43624=−121.
4.7. (−)-(5R,7R)-5,6,7,8-Tetrahydro-5,7-(9,9-dimethylmethano)quinoline-2-carboxylic acid chloride
835
240 mg (1.1 mmol) of 7 and thionylchloride (2.0 ml) were refluxed for 30 min. Excess thionylchloride
was removed and the light brown residue (254 mg, 1.1 mmol, 98%) was dried in vacuo. It was directly
used in the next reaction.
4.8. (−)-(4S)-Isopropyl-2-[(5R,7R)-5,6,7,8-tetrahydro-5,7-(9,9-dimethylmethano)quinolin-2-
yl]oxazoline 935
To a stirred solution of (S)-valinol (110 mg, 1.1 mmol) and triethylamine (130 mg, 1.3 mmol) in dry
CH2Cl2 (3 ml) was added 254 mg (1.08 mmol) of 8 in CH2Cl2 (5 ml) at 0°C under nitrogen. After stirring
for 16 h in an ice-bath which was warming up the solvent was removed and the residue treated with dry
toluene (4 ml) and thionylchloride (0.25 ml, 3.4 mmol) at 0°C. The temperature was stepwise increased to
100°C and stirring continued for 30 min. After evaporation of the solvent the residue was refluxed in dry
methanol (4 ml) and 245 mg (6.2 mmol) of NaOH for 4 h. To the cooled solution ether (25 ml), brine (5
ml) and the necessary amount of water to dissolve everything was added. The organic layer was washed
with brine (5 ml) and dried over MgSO4. Purification was performed by flash chromatography (SiO2,
11×3 cm, PE:EA 4:1 -→ 3:1). 151 mg (0.5 mmol, 49%) of 9 crystallised slowly from PE/ether at −20°C.
White solid, Rf=0.48 (EA), m.p. 75–76°C. 1H NMR (250 MHz, CDCl3); δ=0.64 (s, 3H, H-11), 0.94 (d,
0
3J=6.7 Hz, 3H, CH3), 1.06 (d, 3J=7.3 Hz, 3H, CH3 ), 1.26 (d, 2J=9.6 Hz, 1H, H-6endo), 1.41 (s, 3H, H-
10), 1.92 (‘sept’, 3J≈6.7 Hz, 1H, CHMe2), 2.38 (‘tt’, 3J7,6exo=4J7,5=5.9 Hz, 3J7,8=2.9 Hz, 1H, H-7), 2.69
2
(dt, J=9.6 Hz, 3J6exo,5=3J6exo,7≈5.9 Hz, 1H, H-6exo), 2.81 (t, 3J5,6exo=4J5,7≈5.9 Hz, 1H, H-5), 3.21 (d,
3J8,7=2.9 Hz, 2H, H-8), 4.10–4.24 (m, 2H, Ox–CHZHE and Ox–CH?), 4.50 (m, 1H, Ox–CHZHE?), 7.27
3
3
(d, J=7.70Hz, 1H, H-4), 7.72 (d, J=7.7 Hz, 1H, H-3). 13C NMR (62.9 MHz, CDCl3); δ=18.1 (CH3),
19.2 (CH3 ), 21.2 (C-11), 26.0 (C-10), 31.7 (C-6), 32.7 (CHMe2), 36.7 (C-8), 39.4 (C-9), 40.2 (C-5), 46.8
(C-7), 70.9 (Ox–CH2), 73.2 (Ox–CH), 121.1 (C-3), 133.2 (C-4), 144.2/144.5/157.2 (qC), 162.9 (C=N).
MS (EI); m/z (%)=284 (32) [M+], 243 (48) [M+−C3H5], 242 (29), 241 (100) [M+−C3H7], 213 (36), 157
(25), 155 (21). IR (film); ν (cm−1)=2950/2930 s, 2865 m (C–H), 1640 s (C=N). Specific rotation (c=1.1,
CHCl3); [α]D22=−137, [α]57822=−144, [α]54622=−165, [α]43622=−315, [α]36522=−583. C18H24N2O
(284.40): calcd C 76.02; H 8.51; N 9.85, found C 75.45; H 8.38; N 9.69%.
4.9. (−)-2-L-Menthylpyridine 11a
1.48 g (60.9 mmol) of magnesium turnings in dry THF (20 ml) were activated by stirring with a few
drops of 1,2-dibromoethane under nitrogen. After 5 min, 10 ml of a solution of freshly distilled (−)-L-
menthylchloride36 (10.0 ml, 53.8 mmol) in THF (60 ml) was added. Warming to ca. 50°C started the
reaction. Over a 45 min period the remaining (−)-L-menthylchloride solution was added dropwise and
stirring at 50°C continued for 16 h. After cooling unreacted magnesium was filtered off under nitrogen,
rinsed with THF (2×5 ml) and dried. By weighing the magnesium the theoretical amount of menthyl
Grignard 10a was estimated to be 47.7 mmol (89%). It was then added over 1 h to a stirred solution
21
of 2-bromopyridine (4.6 ml, 47.5 mmol) and 350 mg (0.48 mmol) of Pd(dppf)Cl2 in THF (20 ml) at
0°C under nitrogen. After 48 h stirring in an ice-bath, which was allowed to warm up, the solution was

416
H. Brunner et al. / Tetrahedron: Asymmetry 9 (1998) 407–422
quenched with saturated aqueous NH4Cl (230 ml) and diluted with enough water to dissolve precipitated
magnesium salts. The aqueous layer was extracted with ether (2×50 ml). The combined organic layers
were washed with brine (40 ml), dried over MgSO4 and the solvents evaporated. The remaining brown
oil was flash chromatographed (SiO2, 13×5 cm, CH2Cl2). Sequence of elution: uncharacterised menthyl
derivatives, unreacted 2-bromopyridine (Rf=0.4) and the crude product (Rf=0.27). By adding EA to the
eluent 2,20-bipyridine was isolated as the last fraction. Analytically pure 11a (950 mg, 4.4 mmol, 9.2%)
was obtained by kugelrohr distillation at 120–130°C/ca. 1 torr. 1H NMR (400 MHz, CDCl3); δ=0.70 (d,
3J=6.9 Hz, 3H, H-9 or H-10), 0.81 (d, 3J=6.9 Hz, 3H, H-10 or H-9), 0.90 (d, 3J=6.4 Hz, 3H, H-7), 1.07
(m, 1H, H-6), 1.19 (m, 1H, H-5), 1.30 (m, 1H, H-8), 1.32 (m, 1H, H-2), 1.50 (m, 1H, H-1), 1.71 (m, 1H,
H-4), 1.76 (m, 1H, H-50), 1.79 (m, 1H, H-20), 1.81 (m, 1H, H-60), 2.65 (dt, 3J=11.5 Hz, 3J=3.4 Hz, 1H,
3
H-3), 7.07 (ddd, 3J=7.7 Hz, 3J=4.9 Hz, 4J=1.2 Hz, 1H, Py–H-5), 7.10 (‘dt’, J=7.7 Hz, 4J=5J≈1.1 Hz,
3
4
3
4
5
1H, Py–H-3), 7.57 (dt, J=7.7 Hz, J=1.9 Hz, 1H, Py-H-4), 8.54 (ddd, J=4.9 Hz, J=1.9 Hz, J=1.0
Hz, 1H, Py-H-6). 13C NMR (62.9 MHz, CDCl3); δ=15.7/21.3 (C-9 and C-10), 22.4 (C-7), 24.6 (C-5),
27.9 (C-8), 33.0 (C-1), 35.1 (C-6), 43.5 (C-2), 46.5 (C-4), 49.9 (C-3), 120.8 (Py–C-5), 122.3 (Py–C-3),
136.0 (Py–C-4), 149.6 (Py–C-6), 165.8 (Py–C-2). MS (EI); m/z (%)=217 (33) [M+], 202 (10) [M+−CH3],
174 (29) [M+−C3H7], 106 (100) [(Py–C2H4)+], 93 (37) [C6H7N+]. IR (film); ν (cm−1)=2955/2920 vs,
2870 s (C–H). Specific rotation (c=3.25, EtOH); [α]D23=−36 (lit.18 [α]D21=−43.82), [α]57823=−38,
[α]54623=−43, [α]43623=−72, [α]36523=−109. C15H23N (217.35): calcd. C 82.89; H 10.67; N 6.44, found
C 82.76; H 10.48; N 6.26%.
4.10. (−)-2-L-Menthylpyridine-N-oxide 12a
250 mg (1.15 mmol) of 11a and 300 mg (≥1.39 mmol) of 80–90% m-cpba were stirred in CH2Cl2 (5
ml) at rt for 3 days. The solution was diluted with CHCl3 (10 ml) and extracted with 2 N NaOH (2×10
ml) and 10% aqueous K2CO3 (10 ml). The remaining organic layer was then washed with brine (10
ml), dried over MgSO4 and evaporated. Purification by flash chromatography (SiO2, 10×3 cm, acetone)
gave 240 mg of 12a (1.0 mmol, 89%), Rf=0.2 (acetone), b.p. 180–200°C/ca. 1 torr. 1H NMR (250 MHz,
3
C6D6); δ=0.65 (q, 3J=11.9 Hz, 1H, men–H), 0.80 (‘d’, J=6.7 Hz, 6H, H-9 and H-10), 0.89 (d, 3J=6.9
Hz, 3H, H-7), 1.03–1.75 (m, 7H, men–H), 1.95 (dd, J=12.4 Hz, J=2.0 Hz, 1H, men–H), 4.21 (dt, 3J=11.5
3
3
3
4
3
Hz, J=3.3 Hz, 1H, H-3), 6.17 (ddd, J=7.9 Hz, J=6.4 Hz, J=2.0 Hz, 1H, Py-H-5), 6.38 (dt, J=7.9
Hz, 4J=0.8 Hz, 1H, Py–H-4), 6.60 (dd, 3J=7.9 Hz, 4J=2.0 Hz, 1H, Py–H-3), 8.02 (dd, 3J=6.4 Hz, 4J=0.8
Hz, 1H, Py-H-6). 13C NMR (62.9 MHz, CD2Cl2); δ=16.5/21.6 (C-9 and C-10), 22.4 (C-7), 25.0 (C-5),
28.8 (C-8), 33.2 (C-1), 35.4 (C-6), 38.8 (C-3), 42.2 (C-2), 46.7 (C-4), 123.0 (Py–C-5?), 124.3 (Py–C-
4?), 125.5 (Py–C-3?), 139.9 (Py–C-6), 156.5 (Py–C-2). MS (EI); m/z (%)=233 (18) [M+], 216 (100)
[M+−OH], 190 (67) [M+−C3H7], 122 (54), 109 (51), 106 (40) [(Py-C2H4)+], 93 (27) [C6H7N+]. IR
(film): ν (cm−1)=2950/2920/2870 s (C–H), 1275 m, 1230 s (N–O). Specific rotation (c=1.1, CHCl3);
[α]D21=−70, [α]57821=−75, [α]54621=−84, [α]43621=−147, [α]36521=−223.
4.11. (−)-2-Cyano-6-L-menthylpyridine 13a
235 mg (1.0 mmol) of 12a and trimethylsilylcyanide (0.2 ml, 1.6 mmol) in dry CH2Cl2 (2.5 ml) were
stirred for 5 min under nitrogen. Then dimethylcarbamoylchloride (0.1 ml, 1.1 mmol) was added and
allowed to react for 3 days. After dilution with CH2Cl2 (8 ml) a solution of 10% aqueous K2CO3 (10 ml)
was added and stirring continued for 10 min., the organic layer was separated and the aqueous layer was
extracted with CH2Cl2 (2×5 ml). The combined organic layers were washed with brine (5 ml), dried over
MgSO4 and evaporated. The residue crystallised at −20°C from PE (1 ml) to give 190 mg (0.8 mmol,

H. Brunner et al. / Tetrahedron: Asymmetry 9 (1998) 407–422
417
1
3
78%) of 13a. Colourless crystals, m.p. 78–79°C. H NMR (250 MHz, CD2Cl2); δ=0.69 (d, J=6.9 Hz,
3
3
3H, H-9 or H-10), 0.81 (d, J=6.9 Hz, 3H, H-10 or H-9), 0.91 (d, J=6.5 Hz, 3H, H-7), 0.97–1.34 (m,
4H, H-6, H-5, H-8, H-2), 1.49 (m, 1H, H-1), 1.65–1.87 (m, 4H, H-4, H-50, H-20, H-60), 2.74 (dt, 3J=11.5
Hz, 3J=3.5 Hz, 1H, H-3), 7.36 (dd, 3J=7.8 Hz, 4J=1.0 Hz, 1H, Py–H-5), 7.51 (dd, 3J=7.8 Hz, 4J=1.0 Hz,
1H, Py–H-3), 7.73 (t, 3J=7.8 Hz, 1H, Py–H-4). 13C NMR (62.9 MHz, CD2Cl2); δ=15.9/21.5 (C-9 and C-
10), 22.6 (C-7), 24.9 (C-5), 28.6 (C-8), 33.3 (C-1), 35.4 (C-6), 43.6 (C-2), 46.9 (C-4), 50.2 (C-3), 118.2
(CN), 126.2/126.4 (Py–C-3 and C-5), 133.8 (Py–C-2), 137.5 (Py–C-4), 168.6 (Py–C-6). MS (EI); m/z
(%)=242 (27) [M+], 200 (12), 199 (38) [M+−C3H7], 146 (17), 145 (14), 132 (14), 131 (100), 118 (57), 41
(13). IR (KBr); ν (cm−1)=2960/2950/2940/2890/2870/2850 s (C–H), 2230 m (C≡N). Specific rotation
(c=1.1, CHCl3); [α]D24=−44, [α]57824=−46, [α]54624=−52, [α]43624=−90, [α]36524=−138. C16H22N2
(242.36): calcd C 79.29; H 9.15; N 11.56, found C 79.08; H 8.92; N 11.45%.
4.12. (−)-Methyl 6-L-menthylpyridine-2-carboximidate 14a
10 mg (0.4 mmol) of sodium were dissolved in dry methanol (7 ml) under nitrogen. 250 mg (1.0
mmol) of 13a was added and stirring was continued at rt for 3 days. After adding acetic acid (2 drops)
the solvent was removed in vacuo and the residue treated with warm ether (100 ml). Insoluble inorganic
salts were removed by filtration. Evaporation of the ether yielded 270 mg (0.98 mmol, 98%) of an oily
residue, which was used directly in the next reactions. IR (film); ν (cm−1)=3290 w (N–H), 2970/2915 s,
2870/2845 m (C–H), 1655 s (C=N).
4.13. (−)-6-L-Menthylpyridine-2-carboxamide 17
260 mg (0.95 mmol) of 14a and conc. HCl (3–4 drops) in dry chlorobenzene (20 ml) were heated at
80°C for 64 h with a gentle stream of nitrogen bubbling through. Direct flash chromatography (SiO2,
5.5×3 cm, CH2Cl2) yielded a small amount of an uncharacterised side-product. With ether, the main
product was eluted (Rf=0.25) and recrystallised from PE (15 ml) to give 100 mg (0.4 mmol, 40%) of 17.
3
Colourless crystals, m.p. 142–143°C. 1H NMR (250 MHz, CDCl3); δ=0.70 (d, J=6.9 Hz, 3H, H-9 or
H-10), 0.80 (d, 3J=6.9 Hz, 3H, H-10 or H-9), 0.92 (d, 3J=6.5 Hz, 3H, H-7), 1.00–1.35 (m, 4H, H-6, H-5,
H-8, H-2), 1.50 (m, 1H, H-1), 1.62–1.88 (m, 4H, H-4, H-50, H-20, H-60), 2.71 (dt, 3J=11.4 Hz, 3J=3.3 Hz,
1H, H-3), 6.14 (br s, 1H, NHH0), 7.26 (dd, 3J=7.5 Hz, 4J=1.2 Hz, 1H, Py–H-5), 7.75 (t, 3J=7.5 Hz, 1H,
4
Py–H-4), 7.99 (br s, 1H, NHH0), 8.01 (dd, 3J=7.5 Hz, J=1.2 Hz, 1H, Py–H-3). 13C NMR (62.9 MHz,
CDCl3); δ=15.7/21.3 (C-9 and C-10), 22.4 (C-7), 24.6 (C-5), 28.0 (C-8), 33.0 (C-1), 35.1 (C-6), 43.4
(C-2), 46.8 (C-4), 49.6 (C-3), 119.6 (Py–C-3), 125.2 (Py–C-5), 137.4 (Py–C-4), 149.0 (Py–C-2), 164.7
(C=O), 167.3 (Py–C-6). MS (EI); m/z (%)=260 (39) [M+], 245 (10) [M+−CH3], 217 (48) [M+−C3H7],
172 (13), 164 (19), 163 (14), 150 (11), 149 (100), 136 (39), 132 (15), 104 (21). IR (KBr); ν (cm−1)=3435
m, 3275/3195 w (N–H), 2950/2920 m, 2870 w (C–H), 1700 s (C=O). Specific rotation (c=1.1, CHCl3);
[α]D22=−39, [α]57822=−41, [α]54622=−45, [α]43622=−75, [α]36522=−111. C16H24N2O (260.38): calcd
C 73.81; H 9.29; N 10.76, found C 73.82; H 9.29; N 10.74%.
4.14. (−)-(4S)-Benzyl-2-(6-L-menthylpyridin-2-yl)oxazoline 15a
500 mg (1.8 mmol) of 14a, 280 mg (1.85 mmol) of (S)-phenylalaninol and conc. HCl (1 drop) were
dissolved in dry chlorobenzene (12 ml) and stirred at 80°C for 88 h with a gentle stream of nitrogen
bubbling through. The cooled solution was purified by flash chromatography (SiO2, 6.5×2.5 cm) with
CH2Cl2 as an eluent (Rf=0.07). Kugelrohr distillation at 250°C/ca. 1 torr gave 520 mg (1.4 mmol, 76%)

418
H. Brunner et al. / Tetrahedron: Asymmetry 9 (1998) 407–422
of the oxazoline 15a as a light yellow resin, which could not be crystallised. 1H NMR (250 MHz, CDCl3);
δ=0.71 (d, 3J=6.8 Hz, 3H, H-9 or H-10), 0.83 (d, 3J=6.9 Hz, 3H, H-10 or H-9), 0.88 (d, 3J=6.5 Hz, 3H,
H-7), 1.00–1.43 (m, 4H, H-6, H-2, H-5, H-8), 1.50 (m, 1H, H-1), 1.58–1.95 (m, 4H, H-4, H-50, H-60,
2
3
3
3
H-20), 2.74 (dd, J=13.7 Hz, J=9.2 Hz, 1H, CHAHBPh), 2.87 (dt, J=11.6 Hz, J=3.3 Hz, 1H, H-3),
2
3
2
3
3.31 (dd, J=13.7 Hz, J=4.8 Hz, 1H, CHAHBPh), 4.23 (dd, J=8.6 Hz, J=7.5 Hz, 1H, Ox–CHZHE),
4.42 (dd, 2J=8.6 Hz, 3J=9.4 Hz, 1H, Ox–CHZHE), 4.63 (dddd, 3J=9.4 Hz, 3J=9.2 Hz, 3J=7.5 Hz, 3J=4.8
3
Hz, 1H, Ox–CH), 7.19–7.36 (m, 6H, Ph–H and Py–H-5), 7.67 (t, J=7.5 Hz, 1H, Py–H-4), 7.88 (dd,
3J=7.5 Hz, 4J=1.2 Hz, 1H, Py–H-3). 13C NMR (62.9 MHz, CDCl3); δ=15.7/21.5 (C-9 and C-10), 22.4
(C-7), 24.7 (C-5), 28.1 (C-8), 32.9 (C-1), 35.1 (C-6), 41.8 (CH2Ph), 43.9 (C-2), 46.6 (C-4), 50.1 (C-3),
68.0 (Ox–CH), 72.5 (Ox–CH2), 121.6 (Py–C-3), 123.4 (Py–C-5), 126.5 (p-Ph–C), 128.6/129.3 (o- and
m-Ph–C), 136.5 (Py–C-4), 138.1 (qC of Ph), 146.4 (Py–C-2), 163.8 (C=N), 166.3 (Py–C-6). MS (EI);
m/z (%)=376 (18) [M+], calcd for C25H32N2O: 376.2515, found 376.2520, diff. +0.5 mmu/1.3 ppm, 286
+
(20), 285 (100) [M+−PhCH2], 259 (14), 257 (20), 91 (14) [PhCH2 ]. IR (film); ν (cm−1)=3065/3030 w,
2960/2925/2875 s (C–H), 1645 m (C=N). Specific rotation (c=1.1, CHCl3); [α]D16=−43, [α]57816=−48,
[α]54616=−51, [α]43616=−91, [α]36516=−169.
4.15. (+)-2-D-Menthylpyridine 11b
From 1.4 g (57.6 mmol) of magnesium turnings and freshly distilled (+)-D-menthylchloride36 (10.0
ml, 53.8 mmol) the Grignard 10b was prepared as described in the synthesis of 11a. According to
the theoretical amount of menthyl Grignard 10b (45.7 mmol, 85%) CuCN (2.05 g, 22.9 mmol) was
suspended in dry THF (50 ml) and at −78°C the menthyl Grignard solution was added dropwise. Stirring
was continued at −78°C for 20 min, then 2-bromopyridine (4.4 ml, 45.4 mmol) was added via a cannula.
After 2 h stirring was continued at rt for 17 h. A solution of 32% aqueous NH3 (50 ml) was added, the pH
was adjusted to 10 with 2 N NaOH and insoluble material was removed by filtration, followed by rinsing
with ether. The organic layer was separated and the aqueous layer was extracted with ether (2×20 ml).
The combined organic layers were washed with brine (20 ml), dried over MgSO4 and evaporated. By
a first flash chromatography (SiO2, 15×5 cm, CH2Cl2) the residue was separated into uncharacterised
menthyl derivatives and a 2-bromopyridine/product mixture. Separation of this mixture by a second flash
chromatography (SiO2, 20×5 cm) with PE:EA 9:1 as an eluent gave crude 11b (Rf=0.26), which was
finally purified by kugelrohr distillation at 120–130°C/ca. 1 torr yielding 3.59 g (16.5 mmol, 36%)
of 11b with spectroscopic properties identical with enantiomer 11a. Specific rotation (c=3.25, EtOH);
[α]D21=+29, [α]57821=+30, [α]54621=+35, [α]43621=+59, [α]36521=+93.
4.16. (+)-2-D-Menthylpyridine-N-oxide 12b
3.23 g (14.8 mmol) of 11b and 3.83 g (≥17.7 mmol) of 80–90% m-cpba in CH2Cl2 (60 ml)
were stirred at rt for 6 days. The precipitation of m-chlorobenzoic acid was completed at −20°C
for 4 h. The filtered solution was treated as described for 12a yielding 2.95 g (12.6 mmol, 85%) of
12b as a colourless oil. Specific rotation (c=1.1, CHCl3); [α]D21=+70, [α]57821=+71, [α]54621=+89,
[α]43621=+144, [α]36521=+220.
4.17. (+)-2-Cyano-6-D-menthylpyridine 13b
Synthesised from 2.95 g (12.5 mmol) of 12b, trimethylsilylcyanide (1.8 ml, 14.4 mmol) and dimethyl-
carbamoylchloride (1.15 ml, 12.5 mmol) in dry CH2Cl2 (25 ml) and reacted for 6 days as decribed

H. Brunner et al. / Tetrahedron: Asymmetry 9 (1998) 407–422
419
Table 2
Atomic coordinates and equivalent isotropic displacement coefficients
for 13a. After 40 and 64 h trimethylsilylcyanide (2×0.2 ml, 1.6 mmol) and dimethylcarbamoylchloride
(2×0.1 ml, 1.1 mmol) were replenished. Yield: 2.39 g (9.9 mmol, 79%) of 13b as colourless crystals. Spe-
cific rotation (c=1.1, CHCl3); [α]D21=+43, [α]57821=+46, [α]54621=+53, [α]43621=+90, [α]36521=+138.
4.18. X-Ray structure analysis of 13b
C16H22N2 (242.36); crystal dimensions 0.25×0.35×0.60 mm3; crystal system rhombic; space group
D2/4, P212121, (19); unit cell dimensions: a=9.119(3), b=9.725(3), c=16.599(5) Å, α=β=γ=90°,
V=1472(1) Å3, Z=4; density dcalcd=1.09 g/cm3, µ(Mo–Kα)=0.06 mm−1, 9.0°<2θ<27.0°; total no. of
reflections 2622, unique reflections 2395; F(000)=528; diffractometer Syntex R3. The structure was
solved by direct methods using the SHELXTL PLUS version 4.2/800 program system. Crystallographic
data have been deposited with the Cambridge Crystallographic Data Centre. Copies of the data can be
obtained free of charge on application to The Director, CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK, e-mail: teched@chemcrys.cam.ac.uk. (Table 2).
4.19. (+)-Methyl 6-D-menthylpyridine-2-carboximidate 14b
From 13b (2.38 g, 9.8 mmol) and sodium (23 mg, 1.0 mmol) in dry methanol (10 ml) as described for
14a. Purification by flash chromatography (SiO2, 10×3 cm, CH2Cl2) gave 2.11 g (7.7 mmol, 79%) of
14b (Rf=0.1), which was used directly in the next reactions.
4.20. (+)-(4S)-Benzyl-2-(6-D-menthylpyridin-2-yl)oxazoline 15b
1.1 g (4.0 mmol) of 14b, 610 mg (4.0 mmol) of (S)-phenylalaninol and conc. HCl (1 drop) in dry
chlorobenzene (20 ml) were stirred at 80°C for 67 h with a gentle stream of nitrogen bubbling through.
Purification by flash chromatography (SiO2, 8×3 cm, CH2Cl2) followed by kugelrohr distillation at
250°C/ca. 1 torr yielded 990 mg (2.6 mmol, 66%) of 15b (Rf=0.07), as a light yellow resin, which
1
3
could not be crystallised. H NMR (250 MHz, CDCl3); δ=0.72 (d, J=6.9 Hz, 3H, H-9 or H-10), 0.82

420
H. Brunner et al. / Tetrahedron: Asymmetry 9 (1998) 407–422
3
(d, J=6.9 Hz, 3H, H-10 or H-9), 0.89 (d, 3J=6.5 Hz, 3H, H-7), 1.05 (m, 1H, H-6), 1.18 (m, 1H, H-2),
1.22 (m, 1H, H-5), 1.33 (m, 1H, H-8), 1.51 (m, 1H, H-1), 1.63 (m, 1H, H-4), 1.74 (m, 1H, H-50), 1.81
(m, 1H, H-60), 1.87 (m, 1H, H-20), 2.76 (dd, 2J=13.9 Hz, 3J=9.1 Hz, 1H, CHAHBPh), 2.88 (dt, 3J=11.5
Hz, 3J=3.2 Hz, 1H, H-3), 3.28 (dd, 2J=13.9 Hz, 3J=5.2 Hz, 1H, CHAHBPh), 4.23 (dd, 2J=8.3 Hz, 3J=7.5
Hz, 1H, Ox–CHZHE), 4.42 (dd, 2J=8.3 Hz, 3J=9.1 Hz, 1H, Ox–CHZHE), 4.63 (dddd, 3J=9.1 Hz, 3J=9.1
3
3
Hz, J=7.5 Hz, J=5.2 Hz, 1H, Ox–CH), 7.19–7.33 (m, 5H, Ph–H), 7.23 (m, 1H, Py–H-5), 7.66 (t,
3J=7.5 Hz, 1H, Py–H-4), 7.88 (dd, 3J=7.5 Hz, 4J=1.2 Hz, 1H, Py–H-3). 13C NMR (62.9 MHz, CDCl3);
δ=15.8/21.4 (C-9 and C-10), 22.4 (C-7), 24.6 (C-5), 28.1 (C-8), 32.9 (C-1), 35.1 (C-6), 41.7 (CH2Ph),
43.7 (C-2), 46.7 (C-4), 50.1 (C-3), 68.0 (Ox–CH), 72.4 (Ox–CH2), 121.5 (Py–C-3), 123.3 (Py–C-5),
126.5 (p-Ph–C), 128.5/129.3 (o- and m-Ph–C), 136.5 (Py–C-4), 138.0 (qC of Ph), 146.4 (Py–C-2), 163.7
(C=N), 166.3 (Py–C-6). MS (EI); m/z (%)=376 (4) [M+], 285 (37) [M+−PhCH2], 275 (31), 260 (18),
233 (11), 232 (66), 179 (18), 178 (22), 172 (14), 165 (14), 164 (100), 151 (48), 132 (18), 130 (13), 105
+
(11), 104 (26), 91 (13) [PhCH2 ], 41 (11). IR (film); ν (cm−1)=3060/3025 w, 2950/2920 s, 2870/2850
m (C–H), 1645 m (C=N). Specific rotation (c=1.1, CHCl3); [α]D22=+51, [α]57822=+54, [α]54622=+62,
[α]43622=+116, [α]36522=+217. C25H32N2O (376.54): calcd. C 79.75; H 8.57; N 7.44, found C 78.82; H
8.37; N 7.17%.
4.21. (+)-2-(6-D-Menthylpyridin-2-yl)oxazoline 16
1.0 g (3.6 mmol) of 14b, 225 mg (3.6 mmol) of ethanolamine (dried over 4 Å molsieve) and conc.
HCl (1 drop) in dry chlorobenzene (20 ml) were stirred at 80°C for 70 h with a gentle stream of
nitrogen bubbling through. Purification by flash chromatography (SiO2, 6.5×3 cm, CH2Cl2) followed
by kugelrohr distillation at 250°C/1 torr yielded the oxazoline which solidified upon cooling. After
recrystallisation from PE (3 ml) 440 mg (43%) of 16 was obtained. White solid, Rf=0.05 (CH2Cl2),
m.p. 97–100°C. 1H NMR (250 MHz, CDCl3); δ=0.71 (d, 3J=6.9 Hz, 3H, H-9 or H-10), 0.81 (d, 3J=6.9
3
Hz, 3H, H-10 or H-9), 0.88 (d, J=6.5 Hz, 3H, H-7), 0.95–1.40 (m, 4H, H-6, H-2, H-5, H-8), 1.50 (m,
1H, H-1), 1.59–1.94 (m, 4H, H-4, H-50, H-60, H-20), 2.86 (dt, 3J=11.5 Hz, 3J=3.4 Hz, 1H, H-3), 4.11 (t,
3J=9.5 Hz, 2H, N–CH2), 4.51 (t, 3J=9.5 Hz, 2H, O–CH2), 7.23 (dd, 3J=7.9 Hz, 4J=1.2 Hz, 1H, Py–H-
3
3
4
5), 7.67 (t, J=7.9 Hz, 1H, Py–H-4), 7.84 (dd, J=7.9 Hz, J=1.2 Hz, 1H, Py–H-3). 13C NMR (62.9
MHz, CDCl3); δ=15.8/21.4 (C-9 and C-10), 22.4 (C-7), 24.6 (C-5), 28.1 (C-8), 32.9 (C-1), 35.0 (C-6),
43.7 (C-2), 46.5 (C-4), 50.1 (C-3), 55.1 (Ox–NCH2), 68.1 (Ox–OCH2), 121.3 (Py–C-3), 123.3 (Py–C-5),
136.4 (Py–C-4), 146.3 (Py–C-2), 164.3 (C=N), 166.3 (Py–C-6). MS (EI); m/z (%)=286 (23) [M+], 271
(21) [M+−CH3], 243 (80) [M+−C3H7], 229 (69), 217 (21), 175 (100), 164 (24), 162 (29), 149 (43), 136
(24), 104 (27). IR (KBr); ν (cm−1)=2950/2915 s, 2865/2840 m (C–H), 1645 s (C=N). Optical rotation
(c=1.1, CHCl3); [α]D22=+52, [α]57822=+56, [α]54622=+65, [α]43622=+117, [α]36522=+215. C18H26N2O
(286.42): calcd C 75.48; H 9.15; N 9.78, found C 75.04; H 8.96; N 9.60%.
4.22. (+)-(η4-1,5-Cyclooctadiene)[(4S)-benzyl-2-(6-D-menthylpyridin-2-yl)oxazoline-N,N0]rhodium(I)-
hexafluorophosphate 18
To a stirred solution of 15b (325 mg, 0.86 mmol) in dry CH2Cl2 (5 ml) were added 212 mg (0.43 mmol)
of [Rh(cod)Cl]2 in CH2Cl2 (5 ml) under nitrogen. The resulting yellow solution was stirred for 1.5 h, then
solid NH4PF6 (210 mg, 1.3 mmol) was added. After stirring for another 1.5 h, the inorganic salts were
filtered off and rinsed with CH2Cl2 (3×2 ml). The orange filtrate was evaporated and the residue dissolved
in benzene/PE. After cooling to −20°C for 24 h 400 mg (0.55 mmol, 64%) of 18 were collected. Orange
solid, m.p. >120°C (dec.). 1H NMR (250 MHz, CDCl3); δ=0.65–2.50 (m, 26H, men–H and cod–CH2),

H. Brunner et al. / Tetrahedron: Asymmetry 9 (1998) 407–422
421
2.83 (dd, 2J=13.7 Hz, 3J=7.0 Hz, 1H, CHAHBPh), 2.90–2.95 (m, 1H, H-3?), 2.99 (dd, 2J=13.7 Hz, 3J=4.8
2
Hz, 1H, CHAHBPh), 3.85–4.15 (m, 2H, cod–CH), 4.48–4.80 (m, 1H, Ox–CH?), 4.67 (dd, J=9.3 Hz,
2
3J=3.6 Hz, 1H, Ox–CHZHE?), 4.81 (‘t’, J=3J≈9.3 Hz, 1H, Ox–CHZHE?), 7.18–7.35 (m, 5H, Ph–H),
7.64 (dd, 3J=8.0 Hz, 4J=1.4 Hz, 1H, Py–H-3 or H-5), 7.72 (dd, 3J=7.6 Hz, 4J=1.4 Hz, 1H, Py–H-5 or H-
3), 8.07 (dd, 3J=8.0 Hz, 3J=7.6 Hz, 1H, Py-H-4). 13C NMR (62.9 MHz, CDCl3); δ=16.1/21.2 (C-9 and
C-10), 22.2 (C-7), 24.9 (C-5), 28.3 (C-8), 29.5/31.4 (cod–CH2), 31.9 (C-1), 34.6 (C-6), 41.4 (CH2Ph),
42.8 (C-2), 48.6 (C-4), 49.3 (C-3), 61.9 (Ox–CH), 76.0 (Ox–CH2), 79.2–81.0/83.4–84.4 (br, cod–CH),
124.1 (Py–C), 127.5 (p-Ph–C?), 127.8 (Py–C?), 128.7/130.1 (o- and m-Ph–C), 135.1 (qC of Ph), 141.0
(Py–C), 143.7 (Py–C-2), 169.5 (Py–C-6), 171.1 (C=N). MS (FD, CH2Cl2); m/z=587 [Rh(cod)15b+]. IR
(KBr): ν (cm−1)=2945/2915 s, 2860 m (CH), 1645 w (C=N), 890 vs, 555 s (PF). Specific rotation (c=1.1,
CHCl3); [α]D22=+93, [α]57822=+101, [α]54622=+123. C33H44F6N2OPRh·H2O (750.61): calcd. C 52.81;
H 6.18; N 3.73, found C 52.94; H 6.30; N 3.58%.
4.23. Asymmetric hydrosilylation of acetophenone
10 mg (0.02 mmol) of [Rh(cod)Cl]2 (0.04 mmol Rh) and ligand (0.2 mmol, if not otherwise stated)
were dissolved in acetophenone (1.0 ml, 8.5 mmol) under argon. 2.0 ml of CCl4 were added and the
solution was stirred at rt for 30 min (if AgBF4 was added, stirring was continued for another 30 min).
After cooling to 0°C for 30 min diphenylsilane (1.6 ml, 8.6 mmol) was added and stirring in the ice bath
which was warming up was continued for the period quoted.
To determine the amount of silylenol ether [III/(II+III)], the conversion of acetophenone (i.e. the
degree of hydrosilylation) [(II+III)/(I+II+III)] and the chemical yield of silylalkyl ether [II/(I+II+III)],
1
a sample was taken and a H NMR spectrum (CDCl3, 80 MHz) was recorded. The following integrals
were used for analysis: δ=5.70 ppm (s, Si–H, silylenol ether=IE), δ=5.40 (s, Si–H, silylalkyl ether=IA),
and δ=2.50 (s, CH3, acetophenone=IAP).
Calculations:
IE
III/(II + III)[%] =
100
IA + IE
(II + III)/(I + II + III)[%] =
3IE + 3IA
100
3IA + 3IE + IAP
3Ia
II/(I + II + III)[%] =
100 (reproducibility ꢀ 5%)
3Ia + 3Ie + Iap
Hydrolysis was performed by adding methanol (10 ml) and a few crystals of p-TosOH. After stirring
at rt for 30 min the solvents were evaporated and the residue was distilled in a kugelrohr apparatus at
100–120°C/ca. 1 torr. The enantiomeric excess was determined by injecting 0.4 µl of the diluted distillate
(3–4 drops in 1 ml of CH2Cl2) into a Fisons 8130 gas chromatograph (reproducibility ꢀ0.5%). Column:
Chrompack Chirasil-DEX CB (l=25 m, œ=0.25 mm), integrator: Varian 4290, retention times (118°C):
7.3–7.7 min [(R)-1-phenylethanol] and 8.0–8.3 min [(S)-1-phenylethanol].
Acknowledgements
We thank the Fonds der Chemischen Industrie and the BMBF for financial support.

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H. Brunner et al. / Tetrahedron: Asymmetry 9 (1998) 407–422
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