Enantioselective addition of diethylzinc to aldehydes using novel axially chiral 2-aminomethyl-1-(2'-hydroxyphenyl)naphthalene catalysts

Article abstract of DOI:10.1016/S0957-4166(98)00020-2

The synthesis of atropo-enantiomerically pure aminomethyl and hydroxymethyl substituted biaryls derivatives M-2 and M-3 (and, optionally, their enantiomers), by dynamic kinetic resolution of a racemic lactone precursor, is described. Their application as

Full text of DOI:10.1016/S0957-4166(98)00020-2

Pergamon
Tetrahedron: Asymmetry 9 (1998) 667–679
Enantioselective addition of diethylzinc to aldehydes using novel
axially chiral 2-aminomethyl-1-(20-hydroxyphenyl)naphthalene
catalysts1
Gerhard Bringmann ∗ and Matthias Breuning
Institut für Organische Chemie, Universität Würzburg, Am Hubland, D-97074 Würzburg, Germany
Received 22 December 1997; accepted 15 January 1998
Abstract
The synthesis of atropo-enantiomerically pure aminomethyl and hydroxymethyl substituted biaryls derivatives
M-2 and M-3 (and, optionally, their enantiomers), by dynamic kinetic resolution of a racemic lactone precursor,
is described. Their application as chiral catalysts in the asymmetric addition of diethylzinc to aldehydes leads to
excellent enantiomeric ratios of up to 99:1 and high chemical yields. © 1998 Elsevier Science Ltd. All rights
reserved.
1. Introduction
The discovery of asymmetric additions of diorganozinc reagents to aldehydes in the presence of
catalytic amounts of chiral auxiliaries,2 has initiated a search for other efficient chiral ligands for this
type of reaction.3 Besides β-amino thiols,4 β-amino thiocarboxylates,5 piperazines,6 oxazaborolidines,7
diols,8,9 and titanium complexes,10–12 especially N,N-dialkylated β-amino alcohols3 like DBNE 113,14 or
DAIB 415–17 have been used as chiral catalysts, often affording virtually enantiopure secondary alcohols.
C2-Symmetric axially chiral biaryl alcohols, however, often utilized as excellent chiral auxiliaries in
asymmetric synthesis,18 were found to give good ee’s as alkylation catalysts only in polymeric forms,19
in titanium complexes12 or as biscarboxamides 6b,20 while with the cheap BINOL 6a itself, no addition
of diethylzinc to benzaldehyde was observed.9
With this background in mind we have started to develop a new class of catalysts, which combine the
successfully used N,O- (or O,O-) functionalities with the biaryl axis as a stereogenic element. First efforts
in this field by Chan et al. with the axially chiral pyridylphenol 5, however, gave only moderate to good
enantioselectivities.21 In this paper we describe the directed synthesis of enantiopure 2-aminomethyl and
∗
Corresponding author. E-mail: bringman@chemie.uni-wuerzburg.de
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00020-2

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G. Bringmann, M. Breuning / Tetrahedron: Asymmetry 9 (1998) 667–679
Fig. 1. The novel biaryls 2 and 3 as a combination of structural elements of known chiral ligands in asymmetric synthesis
2-hydroxymethyl substituted 1-(20-hydroxy- or 20-alkoxyphenyl)naphthalene derivatives M-2 and M-3,
and their use as chiral catalysts in the asymmetric addition of diethylzinc to aldehydes (Fig. 1).
2. Results and discussion
2.1. Synthesis of the catalysts
As an efficient access to enantiopure, non C2-symmetric biaryl ligands, we chose the ‘lactone method-
ology’, previously developed in our group.22,23 Key intermediates in this procedure are helically distorted,
but configuratively unstable biaryl lactones like 7 (Scheme 1).22,24 Easily prepared by intramolecular
coupling,25 they can be cleaved such that one of the (now configuratively stable) atropisomeric ring
opened biaryl products is formed in high enantio- or diastereoselectivities — by dynamic kinetic resolu-
tion of the atropo-enantiomeric mixture, P-7zM-7.22,26–30
Scheme 1. Alternative pathways to M-2b, by atropo-diastereo- or -enantioselective cleavage of 7. Reaction conditions: (a)
NaH, 1R-menthol, diethyl ether, rt; (b) separation of diastereomers by column chromatography; (c) LiAlH4, THF, rt; (d) BnBr,
Cs2CO3, acetone, rt
An important intermediate in the synthesis of the envisaged catalysts is the biaryl alcohol M-2a.
Instead of its preparation by highly atropo-enantioselective oxazaborolidine·BH3 assisted reduction of 7
as described previously,27,29 we preferred a two-step procedure by atropo-diastereoselective cleavage
(dr 84:16) using 1R-menthol as a cheap reagent, allowing a facile separation from its (undesired)
diastereomer. Subsequent reduction of stereochemically pure M-8 gave enantiomerically homogeneous

G. Bringmann, M. Breuning / Tetrahedron: Asymmetry 9 (1998) 667–679
669
M-2a. The minor P-configured diastereomer of M-8 is not lost, but can be recycled into the process by
cyclization back to 722,23 — or can of course be used for the preparation of the enantiomeric reagents
(likewise synthesized, but not shown in Schemes 1 and 2). Mono-O-benzylation of M-2a gave M-2b.
Alternatively, M-8 can first be benzylated to afford M-9 and then be reduced. Despite the excellent yields
thus obtained, the former route from M-8 to M-2b via M-2a is preferable, due to the good crystallization
properties of this diol, which allow an additional enantiomeric enrichment.27,29
Scheme 2. Synthesis of the axially chiral amino alcohols M-3a, b, and c. Reaction conditions: (a) (CCl2Br)2, PPh3, CH2Cl2, rt;
(b) H2NMe, HNMe2, or HNnBu2; (c) 1. NaH, Ph(Me)NPPh3+I−, DMF, rt; 2. HNnBu2, 80°C; (d) BCl3, CH2Cl2, 0°C
The transformation of M-2b into the target biaryls, M-3a, b, and c, was straightforward, as shown
31
in Scheme 2: Hydroxy–halogen exchange with (CCl2Br)2/PPh3 gave M-10,32,33 which was converted
into M-11a, b, and c, respectively, by reaction in the amines as the solvents. Compound M-11c was
+ −
also prepared directly from M-2b, after activation of the OH group with Ph(Me)NPPh3 I (Murahashi’s
reagent),34 but this route was practical only for the high-boiling HNnBu2, because of the reaction
temperatures needed. The resulting oils of M-11a, b, and c were converted into white powders by
precipitation as hydrochlorides from diethyl ether:petroleum ether. Debenzylation gave the unprotected
amino alcohols M-3a, b, and c. These enantiopure biaryls are thus accessible from the racemic lactone
precursor 7 in five or six simple tranformations and good yields.
2.2. Application of the catalysts to the asymmetric addition of diethylzinc to aldehydes
In order to study the efficiency of the chiral biaryls as catalysts, we selected the asymmetric addition
of diethylzinc to benzaldehyde 12a in n-hexane at 20°C as a test reaction, using a 1:3:0.2 molar
ratio for 12a:diethylzinc:catalyst.3 The enantiomeric ratio of the product, 1-phenyl-1-propanol 13a, was
determined by HPLC analysis on a Chiracel OD-H column (for conditions, see Experimental Section).
Scheme 3. The asymmetric addition of diethylzinc to the aldehydes 12
In initial investigations, the biaryl alcohols M-2 and the amino alcohols M-3a and P-3b, c were tested
for their potentials as chiral catalysts. In contrast to the C2-symmetric BINOL 6a,9 the dialcohol M-
2a and its monobenzyl ether M-2b did catalyze the addition of diethylzinc to 12a (see Table 1, entries
1–3 and Scheme 3). The er’s of the product 13a, however, were only moderate. ‘Preheating’ of the
alcohol catalyst M-2a with 1.0 equivalents of diethylzinc according to Joshi et al.,9 which should lead
to a more rigid eight-membered cyclic monozinc dialkoxide structure and thus to more differentiated

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G. Bringmann, M. Breuning / Tetrahedron: Asymmetry 9 (1998) 667–679
diastereomeric transition states, gave slightly decreased asymmetric inductions, instead (entry 1 versus
2).
Table 1
Asymmetric addition of diethylzinc to benzaldehyde 12a catalyzed by 2 and 3
For the secondary amine M-3a, again a moderate enantiomeric ratio was obtained (entry 4). By
contrast, the tertiary amines P-3b and P-3c gave excellent er’s of up to 99:1 (entries 5 and 6).
Earlier investigations by Soai et al. with N,N-dialkylnorephedrines14 and by Noyori et al. with N,N-
dialkylaminoisoborneols17 as catalysts in the ethylation of 12a had shown a strong dependence of the
enantiomeric ratio on the substituents of the amino function. The optical purity of the product increased
with the length of the N-alkyl chains, with an optimum chain length of four carbon atoms.14 In accordance
with that report the catalytic properties of the di-n-butyl amine P-3c were even better than those of the
N,N-dimethyl compound P-3b (entry 5 versus 6).
Based on this promising first result with P-3c, the enantioselective addition of diethylzinc to 12a
catalyzed by P-3c was further optimized. Thus, reduction of the quantity of the catalyst P-3c showed that
even with 2 mol% no major loss of selectivity occurred (Table 2, entries 1–4). Disadvantages like the
required longer reaction times and the slightly diminished enantiomeric ratios were not observed when
upscaling the reaction (see Table 3, entry 1). Both a change of the solvent from n-hexane to toluene
(entry 5) and a variation of the temperature (entries 6 and 7) caused a decrease in enantiomeric excesses.
In previous reactions with DPMPM [diphenyl(10-methylpyrrolidin-20 -yl)methanol] as the catalyst, an
increase in enantioselectivity had been observed if the lithium alkoxide was taken instead of the β-amino
alcohol itself.35 Deprotonation of P-3c with n-butyllithium, however, resulted in a strong decrease of the
er (entry 8 versus 2). The addition of 0.50 equivalents of lithium chloride to the reaction mixture did
not give rise to a significant salt effect on the asymmetric induction as found recently for some β-amino
alcohols.36,37
In further investigations, the more easily available enantiomeric catalyst M-3c was used instead of
P-3c, now resulting in R-13a as the main product in the asymmetric ethylation of benzaldehyde 12a. In
contrast to the remarkable nonlinear relationship in the addition of diethylzinc to 12a catalyzed by DAIB
4, which, in the presence of, e.g., 8 mol% 4 of only 15% optical purity, led to 13a in 95% ee,3,16 a fully
linear relationship was observed for the use of M-3c as the catalyst (Fig. 2). Apparently, M-3c does not
form chemically stable, catalytically inactive meso zinc clusters as 4 does.
Finally, the use of M-3c as a catalyst in the addition of diethylzinc was extended to some other
aldehydes (Table 3). All reactions were carried out under optimized conditions with 1.0 mmol aldehyde,
2 mol% catalyst, M-3c, and 2.0 equivalents of diethylzinc in n-hexane at 20°C. The crude products were

G. Bringmann, M. Breuning / Tetrahedron: Asymmetry 9 (1998) 667–679
671
Table 2
Optimization of the ethylation of benzaldehyde 12a with P-3c as the chiral catalyst, to give S-13a
Table 3
Enantioselective addition of diethylzinc to aldehydes 12 catalyzed by 2.0 mol% of M-3c
Fig. 2. Linear correlation between the ee’s of the chiral auxiliary, M-3c, and the product, R-13a

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G. Bringmann, M. Breuning / Tetrahedron: Asymmetry 9 (1998) 667–679
purified by bulb-to-bulb distillation and the er’s were analyzed by HPLC on a Chiracel OD-H phase
or, for 3-nonanol 13d, by 19F NMR spectroscopy after esterification with S-Mosher acid chloride38 (for
conditions, see Experimental Section).
As illustrated in Table 3, M-3c catalyzed the asymmetric ethylation of various aldehydes 12, giving
the ethyl carbinols in more than 88% isolated yield, with high to excellent enantiomeric ratios of more
than 92:8, even for the sometimes problematic3 long-chain aliphatic aldehyde 12d.
In conclusion, the novel axially chiral biaryl amino alcohols M-3 prepared have been found to be
efficient catalysts in the asymmetric addition of diethylzinc to aldehydes 12. Especially M-3c catalyzes
the ethylation of various aldehydes in high yields with excellent enantiomeric ratios of up to 99:1. Thus,
M-3c represents the first non C2-symmetric, N,O-functionalized chiral biaryl catalyst to give comparably
good enantioselectivities as the well examined aliphatic β-amino alcohols. The preparation of further
non C2-symmetric axially chiral biaryls and the investigation of their use as catalysts in the addition of
various other organozinc reagents to aldehydes, are in progress.
3. Experimental
Melting points were determined with an Kofler hot plate apparatus and are uncorrected. IR spectra
were recorded on a Perkin–Elmer 1420 infrared spectrophotometer and are reported in wave numbers
1
(cm−1). H NMR, 13C NMR and 19F NMR spectra were taken on a Bruker AC 200 (200 MHz), AC
250 (250 MHz) or AMX 400 (400 MHz). Chemical shifts are given in parts per million (ppm) with the
deuterated solvent as an internal reference. Coupling constants, J, are given in hertz. In 13C NMR spectra,
sometimes not all quaternary Ar–C signals were detected due to their similar shifts and to their long T1
relaxation times. Mass spectra were recorded on a Finnigan MTA 8200 spectrometer at 70 eV in the EI
mode. Optical rotations were measured on a Perkin–Elmer 241 MC polarimeter. HPLC analyses were
carried out with a combination of a Waters M 510 pump, a Chiracel OD-H column (Daicel Chem. Ind.
Ltd, 4.6 mm×250 mm) and an ERC-7215 UV-detector.
Diethylzinc and S-Mosher acid chloride were purchased from Aldrich, 1R-menthol (>99% ee) from
Fluka. All aldehydes were distilled before use and stored under argon. NaH was washed with pentane
before use, gaseous methylamine and dimethylamine were prepared from the corresponding hydrochlo-
rides with KOH in a small amount of water. THF was freshly distilled from potassium. Diethyl ether,
toluene and n-hexane were distilled from sodium wire and stored over molecular sieves 4Å. All reactions
were carried out with dry glassware under an argon atmosphere. The Schlenk tube technique was used
for the asymmetric addition of diethylzinc to aldehydes.
3.1. Atropo-diastereoselective ring opening of lactone 7 with sodium 1R-mentholate
To 1R-menthol (5.06 g, 32.4 mmol) in diethyl ether (200 ml) NaH (778 mg, 32.4 mmol) was added
cautiously at room temperature. After gas evolution had ended and a further 30 min of stirring, the
lactone 7 (4.45 g, 16.2 mmol) was added to the cloudy reaction mixture, which was stirred until complete
conversion was detected by TLC (petroleum ether:diethyl ether 1:1). Water (200 ml) was added carefully,
the solution was acidified with 2 N HCl and extracted with diethyl ether (3×200 ml). The organic
phase was dried over MgSO4 and the solvent was removed in vacuo. Chromatographic separation of
the residue on silica gel (petroleum ether:diethyl ether 30:1-→3:1) yielded the diastereomeric menthyl
esters P-8 (1.08 g, 2.51 mmol, 15%, chromatographically more rapid) and M-8 (5.39 g, 12.5 mmol, 77%,

G. Bringmann, M. Breuning / Tetrahedron: Asymmetry 9 (1998) 667–679
673
chromatographically less rapid) as slightly yellow oils, which gave colorless crystals from petroleum
ether:diethyl ether.
100R-Menthyl P-1-(20-hydroxy-40,60-dimethylphenyl)-2-naphthoate P-8: mp 147–149°C; [α]D
20
1
−43.2 (c 0.31, EtOH); IR (KBr): ν 3300, 2940, 1650, 1600, 1310, 1130, 770; H NMR (250 MHz,
CDCl3): δ 0.53–1.83 (m, 8H, menthyl H), 0.67 (d, J=6.7 Hz, 3H, menthyl CH3), 0.81 (d, J=7.0 Hz, 3H,
menthyl CH3), 0.84 (d, J=6.7 Hz, 3H, menthyl CH3), 1.76 (s, 3H, 60-CH3), 2.38 (s, 3H, 40-CH3), 4.45
(s, 1H, OH), 4.74 (dt, J=10.7 Hz, J=4.3 Hz, 1H, 100-H), 6.72 (s, 2H, 30-H and 50-H), 7.40–7.52 (m, 2H,
Ar–H), 7.57 (mc, 1H, Ar–H), 7.90–8.00 (m, 3H, Ar–H); 13C NMR (63 MHz, CDCl3): δ 16.04, 19.68,
20.83, 21.30, 22.00 (CH and CH3), 23.14 (CH2), 25.99, 31.22 (CH and CH3), 34.19, 39.94 (CH2),
46.70 (CH or CH3), 75.21 (C-100), 113.8, 122.2, 123.0, 125.6, 126.5, 127.4, 127.8, 128.2, 128.7, 131.2,
132.5, 133.8, 134.9, 137.6, 138.8, 153.3 (Ar–C), 167.9 (C_O); MS: m/z (%) 430 (12) [M+], 292 (35)
+
[M+−C10H18 (menthene)], 274 (100) [C19H14O2 ], 231 (6), 202 (5). Anal. calcd for C29H34O3 (430.6):
C, 80.83; H, 7.96. Found: C, 80.84; H, 7.74.
20
100R-Menthyl M-1-(20-hydroxy-40,60-dimethylphenyl)-2-naphthoate M-8: mp 108°C; [α]D −84.5 (c
0.30, EtOH); IR (KBr): ν 3400, 2940, 1690, 1560, 1450, 1270, 1130, 760; 1H NMR (250 MHz, CDCl3):
δ 0.60–1.70 (m, 8H, menthyl H), 0.70 (d, J=7.0 Hz, 3H, menthyl CH3), 0.81, 0.85 (d, d, J=7.0 Hz each,
3H each, menthyl CH3), 1.80 (s, 3H, 60-CH3), 2.38 (s, 3H, 40-CH3), 4.45 (s, 1H, OH), 4.78 (dt, J=10.7
Hz, J=4.4 Hz, 1H, 100-H), 6.71, 6.74 (s, s, 1H each, 30-H and 50-H), 7.37–7.52 (m, 2H, Ar–H), 7.57 (mc,
1H, Ar–H), 7.93 (d, J=7.9 Hz, 1H, Ar–H), 7.97 (mc, 2H, Ar–H); 13C NMR (63 MHz, CDCl3): δ 15.88,
19.74, 20.94, 21.32, 21.97 (CH and CH3), 22.93 (CH2), 25.78, 31.25 (CH and CH3), 34.16, 40.07 (CH2),
46.75 (CH or CH3), 75.10 (C-100), 113.6, 122.1, 122.9, 125.8, 126.6, 127.3, 127.8, 128.1, 128.6, 130.8,
132.5, 134.1, 135.0, 137.8, 138.7, 153.1 (Ar–C), 167.7 (C_O); MS: m/z (%) 430 (13) [M+], 292 (36)
+
[M+−C10H18 (menthene)], 274 (100) [C19H14O2 ], 231 (6), 202 (5). Anal. calcd for C29H34O3 (430.6):
C, 80.83; H, 7.96. Found: C, 81.08; H, 8.25.
3.2. M-1-(20-Hydroxy-40,60-dimethylphenyl)-2-hydroxymethylnaphthalene M-2a
LiAlH4 (3.57 mg, 94.1 mmol) was added at room temperature cautiously to a solution of M-8 (4.05
g, 9.41 mmol) in THF (100 ml). After 1 h of stirring the reaction mixture was hydrolyzed carefully with
water (100 ml), acidified with 2 N HCl and extracted with diethyl ether (4×100 ml). The organic phase
was dried over MgSO4, the solvent was removed in vacuo and the remaining menthol was distilled off
in vacuo. Chromatography of the residue on silica gel (petroleum ether:diethyl ether 4:1-→1:2) afforded
the alcohol M-2a (2.51 g, 9.02 mmol, 96%) as a slightly yellow oil, which gave colorless crystals from
petroleum ether:diethyl ether (2.38 g, 8.55 mmol, 91%). HPLC analysis on a chiral phase [Chiracel OD-
H, solvent: n-hexane:i-PrOH 95:5, detection at 280 nm, flow rate 1.0 ml/min: tR=15 min (M), tR=23 min
(P)] gave >99.8:0.2 er. The spectroscopic data were identical to those of material previously obtained.27,29
Remark: Larger quantities of residual menthol, as remaining from the preparation of M-8, did not
disturb the reduction, if LiAlH4 was used in excess. Crystallization was found to be an excellent device
for the conversion of enantiomerically enriched M-2a (er>95:5) into virtually enantiopure material
(er>99.8:0.2).
3.3. 100R-Menthyl M-1-(20-benzyloxy-40,60-dimethylphenyl)-2-naphthoate M-9
The menthyl ester M-8 (1.01 g, 2.35 mmol), benzyl bromide (558 ml, 804 mg, 4.70 mmol) and Cs2CO3
(1.53 g, 4.70 mmol) were dissolved in acetone (50 ml) and stirred for 12 h at room temperature. The sol-
vent was removed in vacuo and the residual benzyl bromide was distilled off in vacuo. Chromatography

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G. Bringmann, M. Breuning / Tetrahedron: Asymmetry 9 (1998) 667–679
on silica gel (petroleum ether:diethyl ether 10:1) resulted in M-9 (1.17 g, 2.25 mmol, 96%) as a slightly
22
yellow oil: [α]D −58.6 (c 0.19, CHCl3); IR (film): ν 3040, 2930, 2910, 2850, 1690, 1600, 1560, 1270,
1
1125, 1095, 765; H NMR (250 MHz, CDCl3): δ 0.55 (q, J=11.0 Hz, 1H, menthyl H), 0.64 (d, J=7.0
Hz, 3H, menthyl CH3), 0.70–1.83 (m, 7H, menthyl H), 0.76 (d, J=6.7 Hz, 3H, menthyl CH3), 0.80 (d,
J=7.0 Hz, 3H, menthyl CH3), 1.86 (s, 3H, 60-CH3), 2.40 (s, 3H, 40-CH3), 4.72 (dt, J=10.7 Hz, J=4.3
Hz, 1H, 100-H), 4.83, 4.89 (d, d, J=12.8 Hz each, 1H each, OCH2Ph), 6.68, 6.79 (s, s, 1H each, 30-H and
50-H), 6.89 (mc, 2H, Ar–H), 7.11 (mc, 3H, Ar–H), 7.36 (mc, 1H, Ar–H), 7.46–7.55 (m, 2H, Ar–H), 7.90
(d, J=8.5 Hz, 2H, Ar–H), 8.05 (d, J=8.5 Hz, 1H, Ar–H); 13C NMR (63 MHz, CDCl3): δ 15.95, 19.79,
20.85, 21.71, 22.05 (CH and CH3), 23.02 (CH2), 25.81, 31.19 (CH and CH3), 34.27, 40.21 (CH2), 46.81
(CH or CH3), 69.69 (OCH2Ph), 74.31 (C-100), 110.8, 123.2, 125.4, 126.0, 126.3, 126.4, 127.0, 127.2,
127.9, 128.0, 129.1, 132.5, 134.9, 137.5, 137.7, 137.9, 138.1, 156.0 (Ar–C), 167.7 (C_O); MS: m/z (%)
+
+
520 (4) [M+], 382 (10) [M+−C10H18 (menthene)], 275 (13) [C19H15O2 ], 274 (35) [C19H14O2 ], 107
+
+
(26) [C7H7O+], 91 (100) [C7H7 ], 79 (21) [C6H7 ]; HR-MS: m/z calcd for C36H40O3: 520.298. Found:
520.299.
3.4. M-1-(20-Benzyloxy-40,60-dimethylphenyl)-2-hydroxymethylnaphthalene M-2b
From M-2a: In analogy to the benzylation of M-8, M-2a (2.00 g, 7.19 mmol) was stirred with benzyl
bromide (1.70 ml, 2.46 g, 14.4 mmol) and Cs2CO3 (4.68 g, 14.4 mmol) in acetone (100 ml) for 12 h at
room temperature. After removal of excessive benzyl bromide in vacuo, the residue was chromatographed
on silica gel (petroleum ether:diethyl ether 10:1-→1:1) to yield M-2b (2.57 g, 6.97 mmol, 97%) as a
slightly yellow oil, the spectroscopic data of which were identical to material previously obtained.28
From M-9: M-9 (1.17 g, 2.25 mmol) was reduced in THF (30 ml) at room temperature with LiAlH4
(853 mg, 22.5 mmol) as described in the preparation of M-2a. After removal of the menthol in vacuo,
chromatography of the residue on silica gel (petroleum ether:diethyl ether 4:1-→1:1) afforded M-2b (805
mg, 2.19 mmol, 97%) as a slightly yellow oil.
3.5. M-1-(20-Benzyloxy-40,60-dimethylphenyl)-2-bromomethylnaphthalene M-10
M-2b (600 mg, 1.63 mmol), PPh3 (854 mg, 3.26 mmol) and (CCl2Br)2 (1.06 g, 3.26 mmol) were
dissolved in dichloromethane (10 ml) and stirred for 30 min at room temperature. The solvent was
removed in vacuo and the residue was chromatographed on silica gel (petroleum ether:diethyl ether
23
10:1) to yield in M-10 (689 mg, 1.60 mmol, 98%) as a yellow oil: [α]D −83.0 (c 0.1, EtOH); CD:
∆ε213 −135.5, ∆ε217 −117.7, ∆ε224 −157.3, ∆ε239 +194.0, ∆ε273 −0.5, ∆ε295 −64.1; IR (KBr): ν
1
3040, 3020, 2940, 2900, 2840, 1600, 1560, 1090, 815, 750; H NMR (200 MHz, CDCl3): δ 1.96 (s,
3H, 60-CH3), 2.46 (s, 3H, 40-CH3), 4.46, 4.50 (d, d, J=11.2 Hz each, 1H each, CH2Br), 4.92, 4.99 (d, d,
J=16.2 Hz each, 1H each, OCH2), 6.78–7.00 (m, 4H, Ar–H), 7.14–7.20 (m, 3H, Ar–H), 7.32–7.56 (m,
3H, Ar–H), 7.71 (d, J=8.5 Hz, 1H, 3-H or 4-H), 7.90 (m, 1H, 8-H), 7.92 (d, J=8.5 Hz, 1H, 3-H or 4-H);
13C NMR (50 MHz, CD3OD): δ 19.98, 21.70 (CH3 at C-40 and CH3 at C-60), 33.14 (CH2Br), 69.86
(OCH2), 111.2, 123.4, 123.8, 126.1, 126.2, 127.2, 127.5, 128.0, 128.1, 132.5, 133.2, 133.4, 135.2, 137.4,
138.8, 156.2 (Ar–C); MS: m/z (%) 432/430 (6/6) [M+], 351 (4) [M+−Br], 260 (100) [M+−C7H7Br], 245
(17). Anal. calcd for C26H23BrO (431.4): C, 72.39; H, 5.37. Found: C, 71.99; H, 5.53.
Compound P-10 was prepared analogously from P-8 via P-2b.

G. Bringmann, M. Breuning / Tetrahedron: Asymmetry 9 (1998) 667–679
675
3.6. General procedure A for the preparation of the benzylated amines M-11 from M-10
A solution of M-10 in dichloromethane (2–4 ml/mmol M-10) was added to the amine (for the primary
amine H2NMe, also 2.00 equivalents of the amine hydrochloride were added) and stirred until complete
conversion was detected by TLC (deactivated silica gel, petroleum ether:acetone 6:1). The amine was
removed (for HNnBu2 in vacuo), the resulting oil was dissolved in diethyl ether and water (20 ml/mmol
M-10 each), alkalized with K2CO3 and exhaustively extracted with diethyl ether. The combined organic
layers were dried over MgSO4 and the solvent was removed in vacuo. For characterization, the resulting
oily M-11 was precipitated as a white solid from a solution in a little diethyl ether:petroleum ether
1:1, by passing HCl gas over the solution, and collected by filtration. A second crop was obtained by
concentration of the mother liquor.
3.7. M-1-(20-Benzyloxy-40,60-dimethylphenyl)-2-(N-methylaminomethyl)naphthalene M-11a
According to the general procedure A, M-10 (2.12 g, 4.91 mmol) and H3NMe+Cl− (644 mg, 9.82
mmol) were added to H2NMe (ca. 200 ml) in a three-necked flask with a dry ice condenser. After 1 h
of stirring at room temperature, the solution was worked up, yielding M-11a (1.85 g, 4.85 mmol, 99%).
20
For characterization a small amount M-11a·HCl was precipitated as a white solid: mp 82–87°C; [α]D
+20.4 (c 0.35, EtOH); IR (KBr): ν 3380, 3200–2200, 2920, 1595, 1555, 1440, 1085, 1065, 810, 740,
690; 1H NMR (250 MHz, CD3OD): δ 1.81 (s, 3H, 60-CH3), 2.44 (s, 6H, 40-CH3 and NCH3), 3.92, 4.19
(d, d, J=13.5 Hz each, 1H each, CH2N), 4.88, 5.00 (d, d, J=11.8 Hz each, 1H each, OCH2), 6.75–6.79
(m, 2H, 30-H and 50-H), 6.93–7.14 (m, 5H, Ar–H), 7.30 (br. d, J=7.9 Hz, 1H, Ar–H), 7.43, 7.57 (mc,
1H each, Ar–H), 7.64 (d, J=8.6 Hz, 1H, 3-H or 4-H), 7.99 (d, J=8.2 Hz, 1H, 8-H), 8.04 (d, J=8.6 Hz,
1H, 3-H or 4-H); 13C NMR (63 MHz, CD3OD): δ 19.86, 21.72 (CH3 at C-40 and CH3 at C-60), 33.03,
51.55, 71.47 (CH2N, NCH3 and OCH2), 113.2, 124.1, 125.4, 126.2, 127.2, 128.0, 128.1, 128.8, 129.3,
129.4, 129.9, 133.8, 135.3, 138.1, 139.6, 141.3, 157.4 (Ar–C); MS: m/z (%) 381 (37) [M+−HCl], 366
(14) [M+−CH4Cl], 350 (60) [M+−CH6ClN], 290 (100) [M+−C7H8Cl], 259 (69) [C19H15O+], 91 (30)
+
[C7H7 ]; HR-MS: m/z calcd for C27H27NO: 381.209. Found: 381.210.
3.8. P-1-(20-Benzyloxy-40,60-dimethylphenyl)-2-(N,N-dimethylaminomethyl)naphthalene P-11b
According to the general procedure A, P-10 (800 mg, 1.85 mmol) was added to HNMe2 (ca. 50 ml) in a
three-necked flask with a dry ice condenser. After 30 min of stirring at room temperature, the solution was
worked up and P-11b·HCl (621 mg, 1.44 mmol, 78%) was precipitated as a white solid: mp 89–91°C;
20
[α]D −23.7 (c 1.0, CHCl3); IR (KBr): ν 3600–3100, 2920, 2880, 2750–2100, 1590, 1555, 1435, 1300,
1
1080, 1065, 805, 745, 690; H NMR (250 MHz, CDCl3): δ 1.80 (s, 3H, 60-CH3), 2.41, 243 (s, s, 9H,
40-CH3 and N(CH3)2), 3.68, 3.96 (d, d, J=11.4 Hz each, 1H each, CH2N), 4.83, 4.88 (d, d, J=13.4 Hz
each, 1H each, OCH2), 6.70–6.77 (m, 2H, Ar–H), 6.79, 6.85 (s, s, 1H each, 30-H and 50-H), 7.04–7.16
(m, 3H, Ar–H), 7.26–7.39 (m, 2H, Ar–H), 7.49 (mc, 1H, Ar–H), 7.90 (d, J=8.2 Hz, 1H, 8-H), 7.96, 8.15
(d, d, J=8.5 Hz each, 1H each, 3-H and 4-H); 13C NMR (63 MHz, CDCl3): δ 19.79, 21.71 (CH3 at C-40
and CH3 at C-60), 43.58 (N(CH3)2), 59.41, 70.08 (NCH2 and OCH2), 111.4, 123.5, 124.1, 126.1, 126.3,
126.4, 126.5, 127.6, 128.2, 128.2, 128.6, 132.3, 133.5, 136.6, 138.5, 139.2, 156.1 (Ar–C); MS: m/z (%)
395 (44) [M+−HCl], 380 (14) [M+−CH4Cl], 350 (82) [M+−C2H8ClN], 304 (24) [M+−C7H8Cl], 259
+
(100) [C19H15O+], 91 (22) [C7H7 ], 58 (11) [C3H8N+]; HR-MS: m/z calcd for C28H29NO: 395.225.
Found: 395.226.

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G. Bringmann, M. Breuning / Tetrahedron: Asymmetry 9 (1998) 667–679
3.9. P-1-(20-Benzyloxy-40,60-dimethylphenyl)-2-(N,N-di-n-butylaminomethyl)naphthalene P-11c
According to the general procedure A, P-10 (784 mg, 1.82 mmol) was dissolved in HNnBu2 (10 ml)
and heated for 1 h at 120°C. Work up and precipitation gave P-11c·HCl (883 mg, 1.71 mmol, 94%) as a
20
white solid: mp 65–68°C; [α]D −29.0 (c 0.78, CHCl3); IR (KBr): ν 3600–3100, 2940, 2700–2100,
1
1595, 1555, 1440, 1085, 730, 690; H NMR (200 MHz, CDCl3): δ 0.61–0.93 (m, 8H, 2 CH2CH3,
CH2CH3), 1.14–1.63 (m, 6H, 3CH2CH2), 1.81 (s, 3H, 60-CH3), 2.44 (s, 3H, 40-CH3), 2.44–2.56 (m,
1H, NCHHCH2), 2.75–2.93 (m, 3H, NCHHCH2 and NCH2CH2), 3.90 (dd, J=13.2 Hz, J=7.1 Hz, 1H,
CHHN), 4.28 (dd, J=13.0 Hz, J=4.8 Hz, 1H, CHHN), 4.81, 4.87 (d, d, J=11.9 Hz, 1H each, OCH2),
6.62 (mc, 2H, Ar–H), 6.82 (s, 2H, 30-H and 50-H), 6.99–7.23 (m, 3H, Ar–H), 7.31–7.40 (m, 2H, Ar–H),
7.52 (mc, 1H, Ar–H), 7.93 (d, J=8.1 Hz, 1H, 8-H), 8.00 (d, J=8.7 Hz, 1H, 3-H or 4-H), 8.51 (d, J=8.6
Hz, 1H, 3-H or 4-H); 13C NMR (63 MHz, CDCl3): δ 13.42 (2 CH2CH3), 19.79 (CH3 at C-40 or CH3 at
C-60), 20.06 (2 CH2CH2), 21.64 (CH3 at C-40 or CH3 at C-60), 24.56, 25.50 (2 CH2CH2), 51.14, 52.64,
54.71 (2 NCH2CH2 and CH2N), 70.29 (OCH2), 111.6, 123.2, 124.2, 126.2, 126.4, 126.6, 127.1, 127.6,
128.2, 128.2, 128.9, 132.2, 133.6, 136.3, 138.5, 139.5, 156.0 (Ar–C); MS: m/z (%) 479 (28) [M+−HCl],
436 (91) [M+−C3H8Cl], 351 (34) [M+−C8H19ClN], 260 (57) [C19H16O+], 259 (100) [C19H15O+], 91
+
(54) [C7H7 ]; HR-MS: m/z calcd for C34H41NO: 479.319. Found: 479.319.
3.10. M-11c From M-2b
To M-2b (888 mg, 2.41 mmol) in DMF (20 ml), NaH (63.6 mg, 2.65 mmol) was added cautiously.
+ −
After 30 min of stirring at room temperature, Ph(Me)NPPh3 I (1.31 g, 2.65 mmol) was given to the
solution, which was stirred again for 30 min. HNnBu2 (963 µl, 739 mg, 4.82 mmol) was dropped in via
a syringe and the reaction mixture was heated for 2 h at 80°C. Water (50 ml) was added, the solution was
extracted with diethyl ether (5×50 ml) and the organic phase was dried over MgSO4. After removal of
the solvent in vacuo, the residue was chromatographed on deactivated silica gel (7.5% NH3, petroleum
ether:diethyl ether 6:1) to yield M-11b (1.04 g, 2.17 mmol, 90%) as a yellow oil, along with unreacted
starting material M-2b (44.5 mg, 121 µmol, 5%). For comparison of the NMR spectroscopic data of
those with P-11b·HCl, a small amount of M-11b was converted into M-11b·HCl as described above.
3.11. General procedure B for the debenzylation of the amines 11
To a solution of the amine 11 in dichloromethane (10 ml/mmol 11), 2.0 equivalents (3.0 equivalents for
the amine hydrochlorides 11·HCl) of a 1.0 M solution of BCl3 in hexane were added at 0°C. After 40 min
of stirring, the reaction mixture was hydrolyzed cautiously with water (15 ml/mmol 11), made alkaline
with K2CO3 and exhaustively extracted with dichloromethane. The combined organic layers were dried
over MgSO4 and the solvent was removed in vacuo. The resulting oily 3 was purified by chromatography.
3.12. M-1-(20-Hydroxy-40,60-dimethylphenyl)-2-(N-methylaminomethyl)naphthalene M-3a
According to the general procedure B, M-11a (1.85 g, 4.85 mmol) in dichloromethane (50 ml)
was debenzylated with 9.70 ml (9.70 mmol) of a 1.0 M BCl3 solution. Chromatography on deac-
tivated silica gel (7.5% NH3, diethyl ether:methanol 100:0-→5:1) and subsequent precipitation from
dichloromethane:diethyl ether:pentane gave M-3a (1.40 g, 4.80 mmol, 99%) as a white solid: mp
20
199–203°C; [α]D −13.8 (c 0.37, EtOH); IR (KBr): ν 3220, 2930, 2750, 2700, 1595, 1575, 1560,
1440, 1295, 810, 745; 1H NMR (250 MHz, CDCl3): δ 1.67 (s, 3H, 60-CH3), 2.24 (s, 3H, 40-CH3), 2.33

G. Bringmann, M. Breuning / Tetrahedron: Asymmetry 9 (1998) 667–679
677
(s, 3H, NCH3), 3.68, 3.84 (d, d, J=12.2 Hz each, 1H each, CH2N), 6.73, 6.91 (s, s, 1H each, 30-H and
50-H), 6.97 (br. s, 2H, NH and OH), 7.32 (mc, 2H, Ar–H), 7.40–7.48 (m, 1H, Ar–H), 7.60, 7.78 (d, d,
J=8.5 Hz each, 1H each, 3-H and 4-H), 7.79 (d, J=8.2 Hz, 1H, 8-H); 13C NMR (63 MHz, CDCl3): δ
19.91, 21.24 (CH3 at C-40 and CH3 at C-60), 33.77 (NCH3), 53.39 (CH2N), 116.3, 122.2, 123.2, 126.3,
126.5, 126.7, 127.5, 128.0, 128.2, 129.4, 132.7, 133.8, 136.5, 138.0, 139.4, 154.4 (Ar–C); MS: m/z (%)
291 (58) [M+], 276 (30) [M+−CH3], 260 (85) [C19H16O+], 259 (100) [C19H15O+], 245 (38), 215 (24);
HR-MS: m/z calcd for C20H21NO: 291.162. Found: 291.163.
3.13. P-1-(40,60-Dimethyl-20-hydroxyphenyl)-2-(N,N-dimethylaminomethyl)naphthalene P-3b
According to the general procedure B, P-11b·HCl (491 mg, 1.14 mmol) in dichloromethane (12 ml)
was debenzylated with 3.41 ml (3.41 mmol) of a 1.0 M BCl3 solution. Chromatography on deactivated
silica gel (7.5% NH3, petroleum ether:diethyl ether 2:1) afforded P-3b (261 mg, 1.86 mmol, 75%) as
20
a slighty yellow oil: [α]D +90.4 (c 0.82, CHCl3); IR (KBr): ν 3500–2000, 3010, 2920, 2800, 1595,
1440, 1300, 1035, 835, 800; 1H NMR (250 MHz, CDCl3): δ 1.65 (s, 3H, 60-CH3), 2.25, 2.38 (s, s, 9H,
40-CH3 and N(CH3)2), 3.13, 3.74 (d, d, J=11.8 Hz each, 1H each, CH2N), 5.30 (s, 1H, OH), 6.75, 6.86
(s, s, 1H each, 30-H and 50-H), 7.27–7.33 (m, 2H, Ar–H), 7.39–7.47 (m, 1H, Ar–H), 7.41 (d, J=8.2 Hz,
1H, 3-H or 4-H), 7.83 (d, J=8.5 Hz, 1H, 8-H), 7.85 (d, J=8.2 Hz, 1H, 3-H or 4-H); 13C NMR (63 MHz,
CDCl3): δ 20.14, 21.27 (CH3 at C-40 and CH3 at C-60), 44.34 (N(CH3)2), 63.29 (CH2N), 118.7, 123.2,
125.7, 125.8, 126.3, 126.4, 127.2, 127.9, 128.2, 133.3, 133.3, 133.5, 136.5, 137.8, 138.7, 156.0 (Ar–C);
MS: m/z (%) 305 (99) [M+], 304 (17) [M+−H], 290 (50) [M+−CH3], 260 (100) [C19H17O+], 259 (88)
[C19H16O+], 245 (45), 58 (19) [C3H8N+]. Anal. calcd for C21H23NO (305.4): C, 82.58; H, 7.59; N, 4.58.
Found: C, 82.19; H, 7.70; N, 4.29.
3.14. M-1-(40,60-Dimethyl-20-hydroxyphenyl)-2-(N,N-di-n-butylaminomethyl)naphthalene M-3c
According to the general procedure B, M-11c (988 mg, 2.08 mmol) in dichloromethane (40 ml) was
debenzylated with 5.20 ml (5.20 mmol) of a 1.0 M BCl3 solution. Chromatography on deactivated
silica gel (7.5% NH3, petroleum ether:diethyl ether 8:1) gave M-3c (794 mg, 2.04 mmol, 99%) as a
slighty yellow oil: [α]D20 +15.8 (c 1.2, CHCl3); IR (KBr): ν 3600–2100, 3010, 2930, 2840, 1595, 1440,
1
1300, 830, 805; H NMR (250 MHz, CDCl3): δ 0.61–0.93 (m, 6H, 2 CH2CH3), 1.10–1.50 (m, 8H, 4
CH2CH2), 1.65 (s, 3H, 60-CH3), 2.28–2.38 (m, 2H, NCH2CH2), 2.38 (s, 3H, 40-CH3), 2.55–2.68 (m, 2H,
NCH2CH2), 3.31, 3.75 (d, d, J=11.9 Hz each, 1H each, CH2N), 6.75, 6.83 (s, s, 1H each, 30-H and 50-H),
7.29–7.46 (m, 2H, Ar–H), 7.35–7.46 (m, 1H, Ar–H), 7.42 (d, J=8.2 Hz, 1H, 3-H or 4-H), 7.81 (d, J=8.5
Hz, 1H, 8-H), 7.85 (d, J=8.2 Hz, 1H, 3-H or 4-H); 13C NMR (63 MHz, CDCl3): δ 13.96 (2 CH2CH3),
20.11 (CH3 at C-40 or CH3 at C-60), 20.74 (2 CH2CH2), 21.24 (CH3 at C-40 or CH3 at C-60), 27.26 (2
CH2CH2), 52.39 (2 NCH2CH2), 58.82 (CH2N), 119.1, 123.2, 125.7, 125.9, 126.3, 126.4, 126.9, 127.8,
128.8, 133.3, 133.4, 133.7, 136.5, 137.6, 138.5, 155.7 (Ar–C); MS: m/z (%) 389 (20) [M+], 346 (50)
[M+−C3H7], 261 (100) [C19H17O+], 246 (19). Anal. calcd for C27H35NO (389.6): C, 83.24; H, 9.06; N,
3.60. Found: C, 82.59; H, 8.81; N, 3.61.
The analogous debenzylation of P-11c·HCl with 3.0 equivalents of a BCl3 solution afforded the
20
enantiomer P-3c in 86% yield: [α]D −13.2 (c 1.0, CHCl3).

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G. Bringmann, M. Breuning / Tetrahedron: Asymmetry 9 (1998) 667–679
3.15. General procedure for enantioselective addition of diethylzinc to aldehydes 12 catalyzed by chiral
biaryls
According to the reaction conditions (see Tables 1–3), 2.00–20.0 mol% of the biaryl catalyst (0.050
M in the used solvent) were treated with 2.00–3.00 equivalents of diethylzinc (1.00 M in n-hexane) at
room temperature. After 10 min of stirring the reaction mixture was adjusted to the given temperature
and 1.00 equivalent of the aldehyde 12 (100 µmol for optimation reactions, 1.00 mmol for alkylation of
various aldehydes) were added. Stirring was continued for 16–72 h, the reaction mixture was diluted with
diethyl ether (5 ml), hydrolyzed carefully with 3 ml 2 N HCl, and extracted with diethyl ether (3×5 ml).
After drying over MgSO4, the solvent was removed in vacuo. For reactions described in Tables 1 and
2, the resulting secondary alcohol 13a was only purified by TLC. In the other cases, the crude product
was bulb-to-bulb distilled. Er’s were determined by HPLC on chiral phase for aryl compounds [Chiracel
OD-H, detection at 254 nm, flow rate 1.0 ml/min]: 13a (solvent: n-hexane:i-PrOH 98:2): tR=15 min (S),
tR=17 min (R); 13b (solvent: n-hexane:i-PrOH 95:5): tR=14 min (S), tR=26 min (R); 13c (solvent: n-
hexane:i-PrOH 95:5): tR=14 min (R), tR=23 min (S). The absolute configurations were based on the sign
of their known optical rotations6b,35 or by 19F NMR after derivatization38 with S-Mosher acid chloride
for 13d.
Acknowledgements
This work has been supported by the Deutsche Forschungsgemeinschaft (SFB 347 ‘Selektive Reak-
tionen Metall-aktivierter Moleküle’) and by the Fonds der Chemischen Industrie (research funds and
a graduate research fellowship for M. B.). We gratefully acknowledge the help of Stephan Link for
experimental assistance.
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