Asymmetric Syntheses of 2-(1-Aminoethyl)phenols

Article abstract of DOI:10.1002/hlca.200490054

Three different routes were probed for the synthesis of enantiomerically enriched 2-(1-aminoethyl)phenols and their methyl ethers. The first route centers on diastereoselective nucleophile addition to chiral imines. The second route has as key steps the enantioselective reduction of a ketone followed by nucleophilic substitution, and the third route involves a diastereoselective imine reduction. The efficiency of the approach depends on the substrate substitution pattern. All three methods work well for the parent compound 2-(1-aminoethyl)phenol (1) but the third route is the most efficient, providing the compound with >96% enantiomer excess in three steps with an overall yield of 71%. Conversely, for the ortho-methyl analogue 2, the first method is best. For the t-Bu-substituted analogue 3, only moderate enantiomeric enrichment was achieved.

Full text of DOI:10.1002/hlca.200490054

Helvetica Chimica Acta Vol. 87 (2004)
561
Asymmetric Syntheses of 2-(1-Aminoethyl)phenols
by E. Peter K¸ndig*, Candice Botuha, Gilles Lemercier, Patrick Romanens, Lionel Saudan, and Sylvie Thibault
Department of Organic Chemistry, University of Geneva, 30 Quai Ernest Ansermet, CH-1211 Geneva 4
Three different routes were probed for the synthesis of enantiomerically enriched 2-(1-aminoethyl)phenols
and their methyl ethers. The first route centers on diastereoselective nucleophile addition to chiral imines. The
second route has as key steps the enantioselective reduction of a ketone followed by nucleophilic substitution,
and the third route involves a diastereoselective imine reduction. The efficiency of the approach depends on the
substrate substitution pattern. All three methods work well for the parent compound 2-(1-aminoethyl)phenol
(1) but the third route is the most efficient, providing the compound with > 96% enantiomer excess in three
steps with an overall yield of 71%. Conversely, for the ortho-methyl analogue 2, the first method is best. For the
t-Bu-substituted analogue 3, only moderate enantiomeric enrichment was achieved.
Introduction. Enantiomerically pure chiral a-amino alcohols have been exten-
sively used as chiral auxiliaries in asymmetric synthesis. They are abundant naturally
occurring compounds (e.g., norephedrine, ephedrine), or they are readily obtained
from a-amino acids. The presence of two different functionalities gives access to a large
variety of chiral derivatives such as oxazolidines [1], dihydrooxazoles [2], oxazolidi-
nones [3], formamidines [4], and 1,3,2-oxazaphospholidines [5]. All these groups have
found widespread use as chiral auxiliaries and chiral building blocks. Moreover, chiral
a-amino alcohols are ligands in their own right or are building blocks for chiral ligands
for transition-metal-mediated and catalyzed processes [6][7].
b-Amino alcohols on the other hand, while being important constituents of several
antibiotics [8] and other biologically active natural products [9], have not seen
extensive use as chiral auxiliaries or ligands [10][11] (for examples of chiral b-amino
alcohols as ligands for asymmetric synthesis, see [5][12]). The prime reason would
appear to be the lack of natural sources of these compounds. As part of a project aimed
at the use of chiral 2-(1-aminoalkyl)phenols as precursors to new ligands and reagents
[13], we present the results of a study of different asymmetric approaches to the
synthesis of the (1-arylethyl)amines 1 3 (the (R)-enantiomers are shown in the
Figure). We here describe three different routes that are complementary with respect
to yield, selectivity, and efficiency.
Chiral enantiomerically pure benzylamines are generally obtained either by
enzymatic [14] or chemical resolution [15] of racemic mixtures, or by asymmetric
synthesis with either a chiral organometallic catalyst [16] or chiral reagents [17][18].
For [(2-methoxyphenyl)alkyl]amines or [(2-hydroxyphenyl)alkyl]amines (ˆ2-(amino-
alkyl)phenols), most syntheses have relied on chemical resolution [13d][19][20].
These methods allowed to obtain the products with high enantiomer excess (ee), but in
the case of 1, they were often of low efficiency because multiple recrystallizations were
required. For example, amine (R)-1a was obtained in 28% yield and an ee > 98% after

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Helvetica Chimica Acta Vol. 87 (2004)
Figure. Chiral 2-(1-aminoethyl)phenols 1b, 2b and 3b, and their methyl ethers 1a, 2a, and 3a
five recrystallizations [19a]. Three asymmetric syntheses have been reported: in early
work, (R)-1a was prepared via Rh-catalyzed asymmetric hydrosilylation of a ketoxime
with 16.5% ee [16d]. More recently, (R)-1a and (R)-1b were synthesized in up to 77%
ee via nucleophilic addition of MeLi to chiral oxime ethers [21]. The synthesis of amine
(S)-1a by ring opening of a chiral 1,3-oxazolidine with an organomagnesium reagent
[22] is an efficient process, and this is an alternative route to those detailed in this
report.
Recently, chiral non-racemic benzylamines possessing o-hydroxy or o-methoxy
groups have found applications as chiral auxiliaries [23], chiral building blocks [13], or
as ligands for transition-metal catalysts [24][25]. Moreover, (S)-1a has been reported
to be a notably effective chiral auxiliary for the diastereoselective Lewis acid mediated
allylation of tricyclic N-acyl-N,O-acetals [26].
Amines 2 were chosen to probe the influence of aromatic substituents on the
conformation of the benzylic center. In ligands and auxiliaries containing a
dihydrooxazine ring derived from 2, and in metal chelates of ligand 2, the aromatic
Me group will enforce a pseudoaxial disposition of the benzylic Me group to avoid A(1,3)
strain [27]. Chiral amines 3 may be of interest as ligands or ligand building blocks with
the 3,5-di(tert-butyl) groups in place to guide incoming reagents to the chiral part of the
molecule [28][29].
Results and Discussion. 1. [1-(2-Methoxyphenyl)ethyl]amine ((R)-1a) and [1-(2-
Methoxy-6-methylphenyl)ethyl]amine ((S)-2a) via Diastereoselective Imine Alkylation
[30]: Method A. The amines (R)-1a and (S)-2a were synthesized by means of a method
previously described for the preparation of chiral non-racemic benzylamines via
alkylation of a chiral imine [31][32]. The synthetic route adopted by us for amine (R)-
1a is shown in Scheme 1. Condensation of (R)-phenylglycinol (ˆ(bR)-b-aminoben-
zeneethanol) with 2-methoxybenzaldehyde provided imine derivative (R)-4. Slow
addition of MeLi to a THF solution of (R)-4 at À 788 gave amino alcohol (R,R)-5 as an
orange oil. To achieve a high conversion (85% by GC) and chiral induction, the dark
blue mixture was stirred at À 788 for 24 h and subsequently at À 308 for another 24 h.
As judged by GC and 1H-NMR analysis of the crude mixture, a single diastereoisomer
was formed. Purification on deactivated silica gel gave amino alcohol (R,R)-5 in 59%

Helvetica Chimica Acta Vol. 87 (2004)
563
Scheme 1
a) (R)-Phenylglycinol, 4 ä molecular sieves, EtOH, r.t. b) MeLi, THF, À 788 to À 308. c) 1. Pb(OAc)4, K2CO3,
MeOH, 08; 2. aq. Na2CO3 soln. d) 1. Aq. AcOH soln., THF, r.t.; 2. aq. NaOH soln. e) Aq. NaOH soln., Et2O.
yield. Oxidative cleavage of the latter was performed by using a slight modification1) of
a literature procedure [33]. Imine (R)-6 was directly hydrolyzed in aq. AcOH/THF to
provide the crude amine (R)-1a (ee 96%). Purification by formation of the HCl salt
(R)-7 and recrystallization gave amine (R)-1a in 67% yield (from (R,R)-5) and with an
ee of 98%2) after basic extractive workup. The absolute configuration of amine (R)-1a
was established by 1H-NMR correlation of the amides obtained with both enantiomers
of Mosher×s acid [34] as described for other chiral amines [35].
The same reaction sequence, when applied to 2-methoxy-6-methylbenzaldehyde
(8) [36] and (S)-phenylglycinol, afforded via (S)-9, (S,S)-10, and (S)-11 the highly
enantiomerically enriched amine (S)-2a3) (Scheme 2).
The sequence of Schemes 1 and 2 was successfully applied on a 30-g scale of imine
derivative (R)-4 and a 12-g scale of imine derivative (S)-9 and provided with high
enantiomeric excess 6 g (34% over five steps) of amine (R)-1a and 2.4 g (46% over
four steps) of amine (S)-2a, respectively. Nevertheless, scale-up of this approach is
hampered by the high-dilution conditions required in the alkylation step (0.05m), and
the purification of the amino alcohol (R,R)-5 by chromatography (silica gel) prior to
the oxidative cleavage. Moreover, application of this methodology to the synthesis of
enantiomerically enriched amine 3a was not successful. A very poor yield was obtained
for the diastereoselective addition step. We, therefore, turned to other approaches.
1
)
Simultaneous addition of a soln. of (R,R)-5 and of Pb(OAc)4 in MeOH to a suspension of K2CO3 in MeOH
gave the lowest amount of oxazolidine formed between the amino alcohol and formaldehyde (see Exper.
Part and [33]).
2
3
)
The ee was determined by GC on a chiral stationary phase after formation of the trifluoroacetamide 16
(see below and Exper. Part).
The ee was determined by HPLC on a chiral stationary phase after formation of the naphthalene-1-
carboxamide with naphthalene-1-carbonyl chloride (see Exper. Part).
)

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Helvetica Chimica Acta Vol. 87 (2004)
Scheme 2
a) (S)-Phenylglycinol, 4 ä molecular sieves, EtOH, r.t. b) MeLi, THF, À 788, 48 h. c) 1. Pb(OAc)4, K2CO3,
MeOH, 08; 2. aq. Na2CO3 soln. d) 1. Aq. HCl soln., CH2Cl2, r.t.; 2. aq. NaOH soln.
2. [1-(2-Methoxyphenyl)ethyl]amine ((S)-1a), [1-(2-Methoxy-6-methylphenyl)-
ethyl]amine ((S)-2a), and {1-[3,5-Di(tert-butyl)-2-methoxyphenyl]ethyl}amine ((S)-
3a) via Enantioselective Ketone Reduction: Method B. In this second approach, amines
(S)-1a, (S)-2a, and (S)-3a were synthesized by using as key step the enantioselective
reduction of a prochiral ketone by the CoreyÀBakshiÀShibita (CBS) method [37 39].
The chiral benzyl alcohol was next substituted in a stereospecific SN2 reaction with
inversion of configuration by an N-nucleophile (Schemes 3 and 5).
Thus, alcohol (R)-14 was obtained in 99% yield and 96% ee4) from ketone 12
following a known procedure by using oxazaborolidine (S)-13 (20 mol-%) in THF
(0.4m) [40] (Scheme 3). Treatment of (R)-14 with diphenyl phosphorazidate (DPPA)
and 1,8-diazabicylo[5.4.0]undec-7-ene (DBU) in a THF solution at room temperature
gave the azide (S)-15 in 59% yield [41]. Hydrogenation of the latter over Pd/C gave
amine (S)-1a in 78% yield and with 93% ee5). The erosion of the ee from alcohol (R)-
14 to the amine (S)-1a is ascribed to the activated benzylic center in these compounds
[42]. Recrystallization of the trifluoroacetamide (S)-16 of amine (S)-1a from hexane/
AcOEt gave, after hydrolysis (K2CO3/MeOH/H2O), the amine (S)-1a with an ee
ꢀ 98%6).
The same reaction sequence was used for the preparation of amines (S)-2a and (S)-
3a starting from the ketones 21 and 20. The former was prepared following a literature
4
)
)
)
The ee was determined by 1H-and 19F-NMR after formation of the Mosher ester with (R)-Mosher chloride
(see Exper. Part).
The ee was determined by GC on a chiral stationary phase after formation of the trifluoroacetamide 16
(see Exper. Part).
The ee was determined by GC on a chiral stationary phase after formation of the trifluoroacetamide 16
(see Exper. Part).
5
6

Helvetica Chimica Acta Vol. 87 (2004)
565
Scheme 3
a) BH3 ¥ THF, THF, r.t. b) DPPA, DBU, THF, r.t. c) H2 (1 atm), Pd/C, EtOH, r.t. d) CF3COOH, THF. e)
1. Recryst. from hexane; 2. K2CO3, MeOH.
procedure in three steps from 2,3-dimethylanisole [36] and the latter from 17 via 18 and
19 as shown in Scheme 4. Alternatively, 19 is now accessible via an efficient TiCl4-
mediated phenol acetylation [43].
Scheme 4
a) MeMgBr, Et2O, reflux. b) MnO2, hexane, reflux. c) Me2SO4, K2CO3.

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Helvetica Chimica Acta Vol. 87 (2004)
The enantioselective reduction of ketones 20 and 21 turned out to be more difficult
than that of 2-methoxyacetophenone. Treatment of ketones 20 and 21 with borane ¥
THF complex in the presence of oxazaborolidine (S)-13 (20 mol-%) in THF (0.2m) at
room temperature gave the alcohols 23 and 25 with low enantioselectivity (23: 100%
yield, 43% ee; 25: 81% yield, 9% ee). Increasing the concentration (1m) resulted in
only a small improvement for alcohol 25 (86% yield, 31% ee). Better results were
achieved by using the preformed BH3 ¥ oxazaborolidine complex (S)-22 in dry CH2Cl2
at À 208 (0.7 1m) [44]. With a catalytic amount (5 mol-%) of (S)-22, alcohol (R)-23
was obtained from ketone 21 in 92% yield with 93% ee (Scheme 5). When applied to
ketone 20, alcohol (R)-25 was obtained in 74% yield with 90% ee. A stoichiometric
amount of the BH3 ¥ oxazaborolidine complex (S)-22 was required for the reduction of
ketone 19 to give alcohol (R)-18 (55% yield, 98% ee). The absolute configuration of
alcohols (R)-23, (R)-18, and (R)-25 as shown above, were determined by NMR
correlation after formation of the ester derived from Mosher×s acid [45].
Scheme 5
a) (S)-22 (5 mol-%), BH3 ¥ Me2S, CH2Cl2, À 208. b) DPPA, DBU, THF, r.t. c) H2 (1 atm), Pd/C, EtOH, r.t.
d) 4-NO2-DPPA, DBU, THF, r.t.
The reaction of alcohols (R)-23 (93% ee) and (R)-25 (90% ee) with DPPA and
DBU in THF solution at room temperature was very slow. The azides (S)-24 and (S)-26
were isolated in only 56 and 53% yield, respectively, and after long reaction times (24 h
for (R)-23, 72 h for (R)-25). Partial racemization was observed, as amines (S)-2a and

Helvetica Chimica Acta Vol. 87 (2004)
567
(S)-3a were obtained with a lower ee after hydrogenation of the azides: (S)-2a (51%
ee), and (S)-3a (77% ee). A better yield (85%) but slightly lower selectivity (69% ee)
was obtained for azide (S)-26 when the reaction was carried out with the more-reactive
bis(4-nitrophenyl) phosphorazidate (4-NO2-DPPA) [46] (Scheme 5).
This methodology was successfully applied to the synthesis of enantiomerically
enriched (S)-1a in an overall yield of 35% (5 steps). Despite the partial racemization
observed during the synthesis of amine (S)-1a by this Method B, scale-up was easier
than in the synthesis by Method A because the individual steps can be run at higher
concentrations. Nevertheless, it should be pointed out that the route via enantiose-
lective aryl alkyl ketones is limited because the selectivity drops for bulky alkyl groups.
i
t
Resolution is thus the method of choice for Pr or Bu analogs [13d]. Moreover, the
serious erosion of enantiomer purity of (S)-2a and (S)-3a obtained via this route makes
Method B of very limited use for these amines.
Amine (R)-1a was demethylated by treatment with AlBr3 [47] in benzene to
provide the aminophenol (R)-1b in 70% yield and 98% ee7). The use of BBr3,
previously successfully applied to the tert-butyl analog [13d], resulted here in partial
racemization. This procedure with AlBr3 could not be applied successfully for the
demethylation of (S)-3a because it resulted in partial loss of tert-butyl groups from the
aromatic ring.
3. 2-(1-Aminoethyl)phenols (R)-1b, (S)-2b, and (R)-3b via Diastereoselective Imine
Reduction: Method C. Hogeveen and co-workers have reported the highly diastereo-
selective reduction (Pd/H2) of chiral imines derived from ortho-methoxyacetophenone
and a-methylbenzylamine [48]. High diastereoselectivity was also reported for the
reductive amination of the imine derived from ortho-hydroxyacetophenone with
NaBH4 [25]. This approach could be a rapid and efficient route for the preparation of
2-(1-aminoethyl)phenols (R)-1b, (S)-2b, and (R)-3b, provided that a selective removal
of the chiral auxiliary could be found. The synthetic route to (1-aminoethyl)phenols
(R)-1b, (S)-2b, and (R)-3b via this approach is shown in Schemes 6 9.
Condensation of (R)-a-methylbenzylamine (99% ee) with ortho-hydroxyaceto-
phenone (27) afforded the corresponding imine derivative (R)-28. Addition of NaBH4
to a MeOH suspension of (R)-28 and CeCl3 ¥ 7 H2O at À 908 provided a diaster-
eoisomer mixture of amine (R,R)-29 and (S,R)-29 in a ratio of 96.5 :3.5 (93% de).
Recrystallization of the (R,R)-29 ¥ HCl salt in H2O followed by basic extractive workup
afforded amine (R,R)-29 in 82% yield and with a de > 96%. Selective cleavage of the
NÀC benzylic bond bearing the less-substituted aromatic ring was achieved by Pd-
catalyzed hydrogenolysis. Several conditions were tested with amine (R,R)-29, as
shown in the Table (cf. Scheme 7). A poor conversion was observed with Pd/C with
either H2 gas or under H-transfer conditions (NH4(HCO2); Entries 1 and 2).
Fortunately, the conversion was improved by using Pearlman×s catalyst (Pd(OH)2/C)
under acidic conditions (MeOH/AcOH) [49]. The highest yield was obtained under H2
pressure (4 atm) at room temperature, and this provided (R)-1b in 89% yield with an
ee > 96% (cleavage b, Entry 4). Increasing the temperature resulted in an internal
benzylic cleavage of amine 1b (Entry 5).
7
)
The ee was determined by GC after formation of the bis-Mosher ester (see Exper. Part).

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Helvetica Chimica Acta Vol. 87 (2004)
Scheme 6
a) (aR)-a-Methylbenzylamine, cat. TsOH, toluene, reflux. b) NaBH4, CeCl3 ¥ 7 H2O, MeOH, À 908 to r.t.
c) 1.5n HCl in Et2O recryst. from H2O. d) 1. 1m NaOH; 2. H2 (4 atm), Pd(OH)2/C, MeOH, AcOH, r.t.
Scheme 7
The imine derivatives (R)-33 and (R)-35 were obtained from the condensation of
(R)-a-methylbenzylamine with 2-hydroxy-6-methylacetophenone (32) [36b] and 3,5-
di(tert-butyl)-2-hydroxyacetophenone (19), respectively (Schemes 8 and 9, resp.).
Their reduction occurred with substantially lower diastereoselectivities than that of
imine derivative (R)-28. With NaBH4/CeCl3 in MeOH at À 908, the reduction of (R)-
33 gave a mixture of diastereoisomers (S,R)-34 and (R,R)-34 in a ratio of 59 :41 (18%

Helvetica Chimica Acta Vol. 87 (2004)
569
Scheme 8
a) (aR)-a-Methylbenzylamine, cat. TsOH, toluene, reflux. b) NaBH4, MeOH, À 788 to r.t. c) FC (SiO2).
d) NH4(HCO2), Pd(OH)2/C, MeOH, AcOH, reflux.
Scheme 9
a) (aR)-a-Methylbenzylamine, cat. TsOH, toluene, reflux. b) NaBH4, AcOH, THF, À 788 to r.t., then FC
(SiO2). c) H2 (4 atm), Pd(OH)2/C, MeOH, AcOH.
de). The same reaction with imine derivative (R)-35 afforded a mixture of (R,R)-36
and (S,R)-36 in a ratio of 79 :21 (58% de). For (R)-35, the use of NaBH4 in AcOH [25]
as reducing agent improved the diastereoselectivity somewhat (to 70% de). Purifica-

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Helvetica Chimica Acta Vol. 87 (2004)
Table. Effect of Catalysts and Hydrogen Sources on the Selectivity of the NÀC Cleavage of (R,R)-29a)
Entry
Hydrogen source
Conditions
(R)-1b/(R)-30/31ab)
Yield of 1b [%]
c
1
2
3
4
5
NH4(HCO2) (6 equiv.)
NH4(HCO2) (6 equiv.)
H2 (1 atm)d)
H2 (4 atm)
H2 (4 atm)
208, 40 h
708, 2 h
708, 16 h
208, 48 h
708, 20 h
42 : 17: 41
51 : 6 : 43
70 : 0 : 30
83 : 6 : 11
0 : 23 : 77
)
)
c
65e)
89f)
c
)
a) Reactions run with 2 mmol of substrate and Pd(OH)2/C (20 wt-%) in MeOH/AcOH. b) Ratio measured with
the crude mixture by GC (see Exper. Part). c) Not determined. d) 40 mol-% of Pd(OH)2/C. e) Isolated yield
after purification by distillation. f) Isolated yield after acidÀbase extractive workup.
tion by chromatography (silica gel) afforded amino alcohol (R,R)-36 in 51% yield with
a diastereomer ratio of 87:13 (74% de) (Scheme 9).
The reduction of imine derivative (R)-33 with NaBH4 in MeOH gave (S,R)-34 and
(R,R)-34 in a 86 :14 ratio (72% de; Scheme 8). Here, the two diastereoisomers could be
separated by chromatography (silica gel) to afford the highly diastereoisomerically
enriched amino alcohol (S,R)-34 (de > 96%) in a yield of 71%. Hydrogenolysis of
(S,R)-34 and (R,R)-36 in the presence of Pearlman×s catalyst under H-transfer
hydrogenation conditions and under 4 atm of H2, respectively, afforded the desired
amines (S)-2b in 76% yield with an ee > 96% and (R)-3b in 98% yield and 66% ee
(Schemes 8 and 9).
The absolute configuration of amines 2a and 3a and aminophenols 2b and 3b were
confirmed by using the 1H-NMR correlation of the amides obtained with both
enantiomers of Mosher×s acid as described for amine 1 [34][35].
In conclusion, we have described three different approaches for the synthesis of
enantiomerically enriched benzylamines bearing ortho-methoxy or ortho-hydroxy
groups. For 1b, Method C, based on earlier work by Hogeveen and co-workers [48] and
by Palmieri [25] is most efficient. In our hands, it provided (R)-1b (> 96% ee) in three
steps in an overall yield of 71%. For enantiomerically enriched amines 2, the route
based on Pridgen×s diastereoselective alkylation (Method A) proved to be best, and it
afforded (S)-2a (99% ee) in a four-step sequence in 46% yield. Problems persist to date
for the obtention of highly enantiomerically enriched 3, however; (R)-3b was obtained
with only 66% ee by Method C and (S)-3a in 69% ee via Method B. The methods
detailed in this report should prove useful in the synthesis of new chiral auxiliaries for
asymmetric synthesis and of chiral ligands based on 2-(1-aminoethyl)phenols.
Experimental Part
1. General. Reactions were carried out under N2, and the glassware was heat-dried prior to use. Solvents for
reactions were purified before use as follows: THF and Et2O were distilled from Na/benzophenone-ketyl
(ˆdiphenylketyl). CH2Cl2 and hexane were distilled from CaH2, and toluene and benzene from Na under N2.
Commercially available, solid chemicals were usually used without further purifiation, liquids were generally
freshly distilled. Chemicals were purchased from Fluka and Aldrich. The 2-methoxybenzaldehyde was washed
with sat. aq. NaHCO3 soln. and distilled from anh. MgSO4. The oxazaborolidine (S)-13, o-methoxyacetophe-
none (12), (‡)-(aR)-a-methylbenzylamine, 4-(tert-butyl)cyclohexanone, 3,5-di(tert-butyl)-2-hydroxybenzalde-
hyde (17), (À)-(R)-2-amino-2-phenylethanol (ˆ(À)-(bR)-b-aminobenzeneethanol) [50], 2-methoxy-6-meth-
ylbenzaldehyde (8) [36b], boraneÀoxazaborolidine complex (S)-22 [41], 1-(2-methoxy-6-methylphenyl)etha-

Helvetica Chimica Acta Vol. 87 (2004)
571
none (21) [36b], and 4-NO2-DPPA [46], were prepared by literature methods. MeLi was titrated following
Gilman×s method prior to use [51]. Pb(OAc)4 was placed under vacuum (0.2 mbar) for 30 min prior to use.
Hydrogenolysis was performed on a Parr apparatus No. 3916. Molecular sieves (4 ä) were activated at 1608
under vacuum (0.4 mbar) for 16 h. Flash column chromatography (FC): in air; silica gel Merck 60; the eluents
were distilled prior to use. GC: Hewlett-Packard 6890 chromatograph with FID detector; silicon capillary
column from Macherey-Nagel: Permabond OV-1-0.25 (25 m  0.32 mm i.d.) or Lipodex E (octakis(2,6-di-O-
pentyl-3-O-butyryl)-g-cyclodextrin; 25 m  0.25 mm i.d.); Chirasil DEX-CB capillary column; carrier gas He
(80 kPa); tR in min. HPLC: Daicel Chiralpack-AD and Chiracel-OD anal. columns; Jasco PU-980 chromato-
graph with UV detector; tR in min. M.p.×s: B¸chi 510 apparatus; uncorrected. Optical rotations: Perkin-Elmer
241 polarimeter; 10-cm cell. IR Spectra: films on NaCl windows or KBr press disks; Perkin-Elmer FT-IR-1650
instrument; n in cmÀ1. 1H-and 13C-NMR Spectra: Bruker 300, 400 or 500 or Varian XL-200 spectrometers; d in
ppm, J in Hz. MS: at 70 eV; Varian-CH4 or -SM1 instrument; in m/z (rel. %). Elemental analyses were
¬
¬
performed by Dr. H. J. Eder, Service de Microchimie, Departement de Chimie Pharmaceutique, Universite de
¡
Geneve.
2. Enantiomerically Enriched 1a and 1b: Method A. (À)-(bR)-b-{[(1E)-(2-Methoxyphenyl)methylene]-
amino}benzeneethanol ((R)-4). A soln. of (À)-(bR)-b-aminobenzeneethanol (22.2 g, 161.93 mmol) and 2-
methoxybenzaldehyde (22.0 g, 161.76 mmol) in EtOH (300 ml) was stirred for 26 h at r.t. with activated 4 ä
molecular sieves. This mixture was filtered through a pad of Celite and the filtrate evaporated. The white residue
obtained was washed with hexane and dried under vacuum: (R)-4 (37.20 g, 90%). White solid. M.p. 62 638.
20
‰aŠ ˆ À8.4 (c ˆ 2.19, EtOH). IR (CHCl3): 3593, 3030, 2939, 2887, 2841, 1635, 1601, 1488, 1466, 1438, 1383, 1287,
D
1
1251. H-NMR (C6D6, 400 MHz): 1.73 (br. s, 1 H); 3.22 (s, 3 H); 3.8 4.0 (m, 2 H); 4.42 (dd, J ˆ 8.1, 4.1, 1 H);
6.48 (d, J ˆ 8.5, 1 H); 6.91 (t, J ˆ 7.6, 1 H); 7.10 7.24 (m, 4 H); 7.46 (d, J ˆ 7.6, 2 H); 8.43 (dd, J ˆ 7.6, 1.8, 1 H);
9.03 (s, 1 H). 13C-NMR (C6D6, 50 MHz): 54.9; 68.2; 77.6; 111.1; 120.9; 125.1; 127.3 (2); 127.8; 128.0; 128.6 (2);
‡
132.1; 142.0; 158.2; 159.3. MS: 254 (2, [M À H] ), 224 (100), 209 (19), 180 (8), 91 (35), 77 (19). HR-MS:
‡
‡
254.1180 ([M À H] , C16H16NO2 ; calc. 254.1181). Anal. cal. for C16H17NO2 (255.32): C 75.27, H 6.71; found: C
75.01, H 6.72.
(À)-(bR)-b-{[(1R)-1-(2-Methoxyphenyl)ethyl]amino}benzeneethanol ((R,R)-5). A soln. of (R)-4 (28.90 g,
113.21 mmol) in THF (2 l) under N2 was cooled to À 788, 1.52m MeLi in Et2O (300 ml, 456 mmol) was added
dropwise. The resulting dark-blue soln. was stirred at À 788 for 24 h, the temperature allowed to reach À 308
within 6 h, and the mixture stirred at À 308 for 20 h. The reaction was quenched by addition of sat. aq. NH4Cl
soln. (250 ml) at À 308. The resulting yellow mixture was brought to r.t., the org. phase separated and
evaporated, the residue taken up in Et2O (200 ml), and the soln. washed with sat. aq. NaHCO3 soln. (100 ml).
The combined aq. phase was extracted with Et2O (3 Â 100 ml), the combined org. phase dried (Na2SO4) and
evaporated, and the crude orange oil (32 g) purified by FC (SiO2, hexane/Et2O 1 :2 ‡ 1% MeOH/sat. NH3):
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D
(R,R)-5 (18.19 g, 59%). Orange oil. ‰aŠ ˆ À32.1 (c ˆ 2.10, CH2Cl2). IR (CH2Cl2): 3612, 3443, 3344, 3029, 2964,
2872, 2838, 1600, 1586, 1492, 1464, 1403, 1369, 1278. 1H-NMR (CDCl3, 400 MHz): 1.41 (d, J ˆ 6.4, 3 H); 2.75 (br.
s, 2 H); 3.53 (dd, J ˆ 10.3, 7.4, 1 H); 3.69 (s, 3 H); 3.7 3.8 (m, 2 H); 4.13 (q, J ˆ 6.4, 1 H); 6.78 (d, J ˆ 8.4, 1 H);
6.92 (t, J ˆ 7.4, 1 H); 7.2 7.3 (m, 7 H). 13C-NMR (CDCl3, 100 MHz): 21.1; 50.8; 55.0; 61.6; 65.6; 110.6; 120.6;
‡
127.2 (2); 127.3; 127.8; 128.3 (2); 133.1; 141.5; 156.9. MS: 240 (46, [M À CH2OH] ), 135 (100), 106 (24), 91 (9),
‡
‡
77 (11). HR-MS: 240.1382 ([M À CH2OH] , C16H18NO ; calc. 240.1388).
(À)-[(1R)-1-(2-Methoxyphenyl)ethyl]amine Hydrochloride ((R)-7). A white suspension of anh. K2CO3
(55.02 g, 398.11 mmol) and MeOH (135 ml) was cooled to 08 with an ice bath. A soln. of (R,R)-5 (17.82 g,
65.67 mmol) in CH2Cl2 (250 ml) and a soln. of Pb(OAc)4 (34.73 g, 78.34 mmol) in CH2Cl2 (250 ml) were
simultaneously added dropwise within 12 min. After additional 3 min, the mixture was hydrolyzed with sat. aq.
Na2CO3 soln. (300 ml). The mixture was filtered through Celite and washed with CH2Cl2 (2 Â 100 ml) and sat.
aq. Na2CO3 soln. (2 Â 50 ml). The org. phase was washed with sat. aq. Na2CO3 soln. (250 ml). The combined aq.
phase was extracted with CH2Cl2 (2 Â 100 ml) and the combined org. phase dried (K2CO3) and evaporated:
imine derivative (R)-6 as an orange oil (15.46 g). The crude (R)-6 in THF (200 ml) was directly hydrolyzed in
30% aq. AcOH soln. (200 ml) for 20 h at r.t. The mixture was concentrated and the aq. phase extracted with
Et2O (3 Â 100 ml). The combined org. phase was washed with 30% aq. AcOH soln. (2 Â 100 ml). The combined
aq. phase was cooled to 08 and neutralized by addition of 6m aq. NaOH. The neutral aq. phase was washed with
Et2O (100 ml), cooled, and basified (pH 14) by addition of 6m NaOH. The basified aq. phase was extracted with
Et2O (4 Â 100 ml). The combined org. phase was dried (K2CO3) and evaporated and the residue purified by
bulb-to-bulb distillation (808/0.1 mbar): crude free amine (R)-1a (7.87 g, 52.1 mmol). Colorless oil. This was
taken up in Et2O (220 ml) and treated at 08 dropwise with 1.37n HCl in Et2O (48 ml, 65.76 mmol). The mixture
was stirred for 30 min at r.t. and the solvent evaporated to give a solid (9.70 g). This was dissolved in CH2Cl2

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Helvetica Chimica Acta Vol. 87 (2004)
(110 ml) and treated with hexane (220 ml). The precipitated white solid was filtered off, washed with hexane
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D
(50 ml), and dried under vacuum: (R)-7 (8.30 g, 67% from (R,R)-5). M.p. 174 1758. ‰aŠ ˆ À36.1 (c ˆ 1.00,
CHCl3). IR (CHCl3): 2972, 1605, 1496, 1465, 1384, 1292, 1252, 1084, 1029. 1H-NMR (CDCl3, 400 MHz): 1.69
(d, J ˆ 6.6, 3 H); 3.83 (s, 3 H); 4.69 (q, J ˆ 6.6, 1 H); 6.87 (d, J ˆ 8.0, 1 H); 6.95 (t, J ˆ 7.5, 1 H); 7.31 (td, J ˆ 8.0,
1.4, 1 H); 7.38 (dd, J ˆ 7.5, 1.4, 1 H); 8.6 (br. s, 3 H). 13C-NMR (CDCl3, 100 MHz): 18.5; 47.2; 55.4; 110.6; 120.9;
‡
125.9; 127.6; 129.9; 156.7. MS: 151 (3, [M À HCl] ), 136 (100), 121 (27), 107 (16), 91 (10), 77 (13). Anal. calc. for
C9H14ClNO (187.6690): C 57.60, H 7.52, N 7.46; found: C 57.72, H 7.52, N 7.44.
(‡)-[(1R)-1-(2-Methoxyphenyl)ethyl]amine ((R)-1a). To a suspension of (R)-7 (8.02 g, 42.77 mmol) in
Et2O (200 ml) at 08, 6n aq. NaOH (100 ml) was added, and the mixture was stirred at r.t. for 30 min. The aq.
phase was extracted with Et2O (3 Â 50 ml) and the combined org. phase dried (K2CO3) and evaporated: (R)-1a
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D
(6.82 g, 97%; 98% ee by GC of trifluoroacetamide (R)-16). Colorless oil. ‰aŠ ˆ ‡19.8 (c ˆ 2.22, EtOH). IR
(CHCl3): 3187, 3021, 3007, 2965, 2838, 1599, 1585, 1490, 1464, 1438, 1285, 1243. 1H-NMR (CDCl3, 400 MHz): 1.40
(d, J ˆ 6.8, 3 H); 1.90 (s, 2 H); 3.84 (s, 3 H); 4.35 (q, J ˆ 6.8, 1 H); 6.86 (d, J ˆ 8, 1 H); 6.94 (m, 1 H); 7.21 7.33
(m, 2 H). 13C-NMR (CDCl3, 100 MHz): 23.0; 45.9; 55.0; 110.4; 120.6; 125.6; 127.5; 135.4; 156.6. MS: 151 (1,
‡
‡
‡
M ), 150 (3), 138 (9), 136 (100), 121 (19), 107 (7), 77 (6). HR-MS: 151.0997 (M , C9H13NO ; calc. 151.0997).
The absolute configuration was confirmed to be (R) by comparison with literature data [19a].
(‡)-2,2,2-Trifluoro-N-[(1R)-1-(2-methoxyphenyl)ethyl]acetamide ((R)-16). To a soln. of (R)-1a (32.8 mg,
216.9 mmol) in THF (2 ml) was added (CF3CO)2O (250 ml, 1.79 mmol). The resulting soln. was stirred for 30 min
at r.t. and then evaporated. The residue was dissolved with CH2Cl2, the soln. filtered over a short column (1 Â
4 cm, SiO2), the column washed with CH2Cl2 (5 ml), and the solvent evaporated: (R)-16 (46.1 mg, 85%). White
solid. Chiral GC Lipodex E, H2, 50 kPa, 1208 isotherm; trifluoroacetamide: tR 15.9 ((À)-(S)-16; 0.8%); 17.5
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((‡)-(R)-16; 99.2%); ee 98%. M.p. 127 1288. ‰aŠ ˆ ‡138.1 (c ˆ 1.00, CH2Cl2). IR (CHCl3): 3422, 3028, 2980,
2841, 1720, 1603, 1588, 1533, 1494, 1465, 1241, 1169. 1H-NMR (CDCl3, 400 MHz): 1.53 (d, J ˆ 6.9, 3 H); 3.92
(s, 3 H); 5.22 (q, J ˆ 6.9, 1 H); 6.96 (t, J ˆ 7.8, 2 H); 7.2 7.3 (m, 2 H); 7.6 (br. s, 1 H). 13C-NMR (CDCl3,
100 MHz): 21.0; 48.8; 55.3; 111.3; 115.9 (q, J ˆ 36); 121.1; 128.4; 129.2; 155.9 (q, J ˆ 36); 156.9. MS: 247 (46,
‡
M ), 232 (79), 151 (6), 150 (58), 135 (25), 119 (12), 109 (11), 108 (11), 107 (100), 105 (18), 91 (30), 77 (28). HR-
‡
‡
MS: 247.0805 (M , C11H12NO2F3 ; calc. 247.0820). Anal. calc. for C11H12F3NO2: C 53.44, H 4.89, N 5.67; found: C
53.45, H 4.93, N 5.66.
(À)-2-[(1R)-1-Aminoethyl]phenol ((R)-1b). A soln. of (R)-1a (0.2 g, 1.32 mmol) in benzene (18 ml) was
added under N2 at r.t. to a soln. of AlBr3 (1.23 g, 4.6 mmol) in benzene (15 ml). The mixture was stirred for 20 h
at r.t. and then added to a sat. NaHCO3 soln. at 08 and stirred for 1 h. The mixture was extracted with AcOEt
(2 Â 10 ml), the combined org. phase washed with H2O, dried (K2CO3), and evaporated, and the residue
purified by bulb-to-bulb distillation: (R)-1b (126 mg, 70%; 98% ee by GC (OV17, He, 1008 for 1 min then 108/
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min to 2508; (R,R)-Mosher amide). White solid. M.p. 838. ‰aŠ ˆ À12.1 (c ˆ 0.60, EtOH). IR (KBr): 3448, 2979,
1594, 1447, 1275, 1150, 1110, 1180, 1040, 1000, 922, 748. 1H-NMR (CDCl3, 200 MHz): 1.49 (d, J ˆ 6.6, 3 H); 4.33
(q, J ˆ 6.6, 1 H); 6.7 7.2 (m, 4 H). 13C-NMR (CDCl3, 50 MHz): 23.6; 51.6; 117.0; 119.0; 127.2; 127.9; 128.5;
‡
‡
157.5. MS: 138 (3, [M ‡ 1] ), 137 (36, M ), 122 (72), 120 (100), 92 (19), 91 (68), 77 (19), 65 (15), 51 (12). Anal.
calc. for C8H11NO: C 70.05, H 8.08, N 10.21; found: C 70.06, H 8.04, N 10.08.
3. Enantiomerically Enriched 1a: Method B. (‡)-(aR)-2-Methoxy-a-methylbenzenemethanol ((R)-14). To
1m oxazaborolidine (S)-13 in toluene (40 ml, 0.04 mol) in THF (200 ml) 1m BH3 ¥ THF in THF (120 ml, 0.12 mol)
was added. Within 1 h, 1-(2-methoxyphenyl)ethanone (12; 27.58 ml, 0.1 mol) in THF (250 ml) was added slowly.
After 4 h, the reaction was stopped by adding MeOH (200 ml). The mixture was stirred for an additional 30 min
and then evaporated. The residue was dissolved in Et2O, the soln. washed with 1n HCl, sat. aq. Na2CO3 soln., and
brine, dried (Na2SO4), and evaporated, and the residue purified by FC (SiO2, cyclohexane/AcOEt 70 :30): (R)-
14 (30.3 g, 99%; 96% ee by 1H-NMR, integration of CHOH signal of the corresponding (R,R)-Mosher ester).
20
20
Colorless oil. ‰aŠ ˆ ‡25.6 (c ˆ 1.94, CHCl3) ([40]: ‰aŠ ˆ ‡32.3 (c ˆ 2.00, CHCl3)). IR (CHCl3): 3602, 3444,
D
D
3018, 2975, 2939, 2839, 1601, 1587, 1491, 1465, 1438, 1400, 1366, 2968, 1287, 1239, 1210. 1H-NMR (CDCl3,
400 MHz): 1.53 (d, J ˆ 6.5, 3 H); 2.30 (br. s, 1 H); 3.88 (s, 3 H); 5.12 (q, J ˆ 6.5, 1 H); 6.90 (d, J ˆ 8.1, 1 H); 6.98
(m, 1 H); 7.2 7.3 (m, 2 H). 13C-NMR (CDCl3, 100 MHz): 22.7; 55.1; 66.4; 110.3; 120.9; 126.0; 128.2; 133.3;
‡
156.4. MS: 152 (46, M ), 138 (16), 137 (100), 121 (25), 109 (52), 107 (83), 105 (18), 94 (22), 91 (21), 77 (49).
‡
‡
HR-MS: 152.0831 (M , C9H12O2 ; calc. 152.0837).
(À)-1-[(1S)-1-Azidoethyl]-2-methoxybenzene ((S)-15). Diphenylphosphoryl azide (ˆdiethyl phos-
phorazidate ˆ DPPA; 15.6 ml, 0.072 mol) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU; 10.8 ml,
0.072 mol) were added dropwise to a stirred soln. of (R)-14 (9.15 g, 0.060 mol) in THF (300 ml) at r.t. The
mixture was stirred for 12 h and then evaporated. H2O (100 ml) was added to the residue, the soln. extracted
with Et2O (3 Â 100 ml), the combined org. phase dried (MgSO4) and evaporated, and the residue purified by FC

Helvetica Chimica Acta Vol. 87 (2004)
573
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(SiO2, pentane/Et2O 80 :20): (S)-15 (6.3 g, 59%). Yellow oil. ‰aŠ ˆ À11.9 (c ˆ 2.12, CHCl3). IR (CHCl3): 3019,
2101, 1491, 1464, 1287, 1247, 1223. 1H-NMR (CDCl3, 400 MHz): 1.51 (d, J ˆ 6.8, 3 H); 3.86 (s, 3 H); 5.08 (q, J ˆ
6.8, 1 H); 6.92 (d, J ˆ 8.2, 1 H); 7.01 (t, J ˆ 7.5, 1 H); 7.2 7.4 (m, 2 H). 13C-NMR (CDCl3, 100 MHz): 20.0; 54.9;
‡
55.3; 110.5; 120.7; 126.5; 128.9; 129.0; 156.4. MS: 177 (10, M ), 136 (10), 135 (100), 119 (6), 105 (20), 91 (12), 77
‡
‡
(18). HR-MS: 177.0897 (M , C9H11N3O ; calc. 177.0902).
(À)-[(1S)-1-(2-Methoxyphenyl)ethyl]amine ((S)-1a). A mixture of (S)-15 (6.3 g, 35.5 mmol), EtOH
(130 ml), and the Pd/C catalyst (Degussa type 101 NE/W, 0.6 g) was purged with H2 (3Â), stirred under H2
(1 atm) at r.t. for 12 h, and then filtered through a pad of Celite. Evaporation gave crude (S)-1a as a yellow oil.
Purification by bulb-to-bulb distillation at 1208/2 Torr afforded pure (S)-1a (4.21 g, 78%). Colorless oil. Chiral
GC (Lipodex E, H2, 50 kPa, 1208 isotherm; trifluoroacetamide) tR 16.3 ((À)-(S)-16; 96.5%), 17.9 ((‡)-(R)-16;
3.5%); 93% ee. Enantiomerically pure amine (S)-1a (3.19 g, 76%) was obtained by recrystallization of (S)-16 in
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hexane/AcOEt followed by hydrolysis by K2CO3 in MeOH. ‰aŠ ˆ À18.2 (c ˆ 2.19, EtOH). Chiral GC (Lipodex
E, H2, 50 kPa, 1208 isotherm; trifluoroacetamide) tR 12.7 ((À)-(S)-16; > 98%), (R)-enantiomer not detected;
ee > 98%.
4. Enantiomerically Enriched 1b: Method C. (À)-2-{1-{[(1R)-1-Phenylethyl]imino}ethyl}phenol ((R)-28).
A mixture of 1-(2-hydroxyphenyl)ethanone (27; 4.08 g, 30.0 mmol), (‡)-(aR)-a-methylbenzylamine (3.63 g,
30.0 mmol; > 99% ee), TsOH (0.400 g, 3.0 mmol) and 4 ä molecular sieves (20 g) in dry toluene (40 ml) was
heated to reflux for 16 h. The soln. was filtered through a pad of Celite, and the filtrate was evaporated: crude
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(R)-28 (6.93 g, 29 mmol). Yellow oil. The product was used without further purification. ‰aŠ ˆ À275 (c ˆ 0.45,
CH2Cl2). IR (CHCl3): 3069, 3030, 2974, 2927, 1612, 1579, 1498, 1449, 1376, 1302, 1239, 1161, 1134, 1083. 1H-NMR
(C6D6, 400 MHz): 1.29 (d, J ˆ 6.6, 3 H); 1.54 (s, 3 H); 4.37 (q, J ˆ 6.6, 1 H); 6.59 (m, 1 H); 6.9 7.2 (m, 8 H);
16.29 (br. s, 1 H). 13C-NMR (C6D6, 100 MHz): 13.8; 25.0; 58.5; 116.9; 118.5; 119.8; 126.1; 126.8; 127.3; 127.6;
‡
128.1; 128.5; 132.1; 144.6; 163.7; 170.1. MS: 239 (41, M ), 148 (6), 135 (36), 121 (21), 105 (100), 91 (11), 77 (28).
‡
‡
HR-MS: 239.1324 (M , C16H17NO ; calc. 239.1310).
(‡)-2-{(1R)-1-{[(1R)-1-Phenylethyl]amino}ethyl}phenol ((R,R)-29). NaBH4 (2.28 g, 60 mmol) was added
in one portion to a mixture of (R)-28 (6.93 g, 29 mmol), CeCl3 ¥ 7 H2O (5.60 g, 15 mmol), and MeOH (100 ml) at
À 908. The temp. was allowed to rise slowly to r.t. (12 h), and CH2Cl2 (400 ml) was added, followed by sat. aq.
NH4Cl soln. (400 ml). The soln. was extracted with CH2Cl2 and the combined org. phase dried (MgSO4) and
evaporated. The resulting crude oily product was diluted in Et2O (200 ml) and the hydrochloride salt
precipitated by adding 1.5m HCl in Et2O (1 equiv.). The white precipitate was washed with H2O and dried:
(R,R)-29 ¥ HCl/(S,R)-29 ¥ HCl 20 :1 (by 1H-NMR; integration of MeCH signals). The white solid was
recrystallized in H2O: (R,R)-29 ¥ HCl (6.60 g, 82%; > 96% de, the other diastereoisomer was not detected).
20
M.p. 139 1418. ‰aŠ ˆ ‡56 (c ˆ 1.15, MeOH). IR (KBr): 3377, 3228, 2977, 2811, 2522, 1624, 1507, 1450, 1382,
D
1
1291, 1255, 1189, 1065. H-NMR ((D6)DMSO, 400 MHz): 1.43 (d, J ˆ 6.9, 3 H); 1.55 (d, J ˆ 6.7, 3 H); 3.96 (br.
s, 1 H); 4.14 (br. s, 1 H); 6.7 6.9 (m, 2 H); 7.13 (m, 1 H); 7.30 (s, 5 H); 7.47 (d, J ˆ 6.6, 1 H); 9.60 (br. s, 1 H);
9.80 (br. s, 2 H). 13C-NMR ((D6)DMSO, 100 MHz): 19.9; 20.9; 50.3; 56.1; 115.9; 119.6; 123.2; 128.1 (2); 128.2;
‡
128.9 (2); 129.0; 129.7; 137.1; 155.0. MS: 241 (13, [M À HCl] ), 226 (24), 136 (3), 122 (34), 120 (51), 106 (100),
‡
‡
91 (26), 77 (26). HR-MS: 241.1450 (M , C16H19NO ; calc. 241.1466).
Treatment of (R,R)-29 ¥ HCl with 1m aq. NaOH afforded the free amine (R,R)-29 (5.54 g, quant.). Colorless
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D
oil ‰aŠ ˆ ‡69 (c ˆ 0.11, CHCl3; > 96% ee) (25]: ‰aŠ ˆ ‡142 (c ˆ 1.66, CHCl3)). IR (CHCl3): 3322, 3005, 2988,
1
2927, 2869, 2730, 2638, 1588, 1487, 1452, 1406, 1377, 1257, 1193, 1144, 1106, 1029. H-NMR (CDCl3, 500 MHz):
1.43 (d, J ˆ 6.8, 3 H); 1.51 (d, J ˆ 6.8, 3 H); 3.69 (q, J ˆ 6.8, 1 H); 3.77 (q, J ˆ 6.8, 1 H); 6.78 (m, 2 H); 6.9 7.4
(m, 7 H). 13C-NMR (CDCl3, 100 MHz): 22.9; 23.4; 55.3; 56.1; 116.7; 119.1; 126.2 (2); 126.5; 127.4; 128.2 (2);
128.7 (2); 143.5; 157.5. MS: 241 (6, M ), 227 (10), 226 (39), 122 (16), 120 (16), 106 (37), 105 (29), 92 (33), 91
(100), 79 (11), 77 (13). HR-MS: 241.15 (M , C16H19NO ; calc. 241.1466).
‡
‡
‡
1
The absolute configuration was assigned (R,R) by comparison with H-NMR literature data [25].
(À)-2-[(1R)-1-Aminoethyl]phenol ((R)-1b): Best Procedure. A mixture of (R,R)-29 (5 g, 21 mmol),
MeOH (210 ml), AcOH (4 equiv., 4.8 ml, 84 mmol), and Pd(OH)2/C (20 wt-%, 2.1 g) was purged with H2 (3Â),
stirred under H2 (4 atm) at r.t. for 48 h, and then passed through a pad of Celite. The filtrate was evaporated:
(R)-1b/(R)-30/31a 83 :6 :11 (by GC (OV1, H2). The mixture was treated with 1n aq. HCl (100 ml) and extracted
with Et2O (2 Â 100 ml). The aq. phase (pH 1) was basified with 2n NaOH and extracted with Et2O (2 Â 100 ml).
The combined org. phase (pH 9) was dried (Na2SO4) and evaporated: (R)-1b (2.57 g, 89%; > 96% ee by
1H-NMR, integration of MeCH signal of the corresponding (R,S)-Mosher amide; the other diastereoisomer was
20
D
not detected). ‰aŠ ˆ À18 (c ˆ 1.85, CHCl3).
5. Enantiomerically Enriched 2a: Method A. (‡)-(bS)-b-{[(1E)-(2-Methoxy-6-methylphenyl)methylene]-
amino}benzeneethanol ((S)-9). A soln. of (‡)-(bS)-b-aminobenzeneethanol (5.90 g, 43.03 mmol) and 2-

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Helvetica Chimica Acta Vol. 87 (2004)
methoxy-6-methylbenzaldehyde (8; 5.90 g, 39.30 mmol) in EtOH (250 ml) was stirred for 26 h at r.t. with
activated 4 ä molecular sieves. The mixture was filtered through a pad of Celite which was washed with EtOH
(3 Â 20 ml). The solvent was evaporated and the residue washed with hexane and dried under vacuum: (S)-9
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(11.50 g, 99%). White solid. M.p. 58 608. ‰aŠ ˆ ‡18.8 (c ˆ 0.69, EtOH). IR (CH2Cl2): 3592, 3065, 3030, 2964,
2927, 2873, 2841, 1639, 1597, 1579, 1492, 1470, 1442, 1390, 1340, 1290. 1H-NMR (400 MHz, C6D6): 2.70 (s, 3 H);
3.25 (s, 3 H); 3.86 (m, 2 H); 4.38 (m, 1 H); 6.41 (d, J ˆ 8.3, 1 H); 6.79 (d, J ˆ 7.6, 1 H); 7.0 7.3 (m, 5 H); 7.47
(d, J ˆ 7.1, 2 H); 9.01 (s, 1 H). 13C-NMR (50 MHz, C6D6): 21.7; 55.7; 67.9; 77.9; 108.3; 123.7; 123.8; 126.9; 127.3;
‡
127.4; 128.5; 130.3; 130.3; 139.6; 140.9; 159.4; 160.9. MS: 269 (40, M ), 238 (100), 222 (11), 147 (18), 133 (17),
‡
‡
121 (4), 91 (38), 77 (23). HR-MS: 269.1408 (M , C17H19NO2 ; calc. 269.1415).
(‡)-(bS)-b-{[(1S)-1-(2-Methoxy-6-methylphenyl)ethyl]amino}benzeneethanol ((S,S)-10). A soln. of (S)-9
(11.50 g, 42.71 mmol) in THF (350 ml) under N2 was cooled to À 788, and 1.6m MeLi in Et2O (106 ml,
170 mmol) was added dropwise within 1.3 h under stirring. The resulting purple mixture was stirred at À 788 for
48 h. The reaction was stopped by addition of sat. aq. NH4Cl soln. (150 ml). The resulting yellow mixture was
allowed to warm to r.t. and the org. phase evaporated. Et2O (80 ml) was added and the soln. washed with sat. aq.
NaHCO3 soln. (50 ml). The combined aq. phase was extracted with Et2O (3 Â 50 ml), the combined org. phase
dried (Na2SO4) and evaporated, and the residue recrystallized in hexane/AcOEt: (S,S)-10 (8.23 g, 67% from
20
D
(S)-9). White solid. M.p. 123 1248. ‰aŠ ˆ ‡16.9 (c ˆ 0.93, CH2Cl2). IR (CH2Cl2): 3615, 3343, 3029, 2965, 2932,
2869, 2838, 1598, 1581, 1473, 1453, 1405, 1366, 1289, 1247. 1H-NMR (400 MHz, CDCl3): 1.44 (d, J ˆ 7.0, 3 H); 2.24
(s, 3 H); 3.5 3.6 (m, 2 H); 3.59 (s, 3 H); 3.6 3.7 (m, 1 H); 4.12 (q, J ˆ 7.0, 1 H); 6.53 (d, J ˆ 8.0, 1 H); 6.68
(d, J ˆ 8.0, 1 H); 6.98 (t, J ˆ 8.0, 1 H); 7.0 7.1 (m, 2 H); 7.1 7.2 (m, 3 H). 13C-NMR (100 MHz, CDCl3): 20.0;
‡
20.1; 51.7; 54.7; 62.3; 65.3; 108.9; 123.0; 127.0; 128.0; 130.6; 136.3; 141.9; 157.9. MS: 270 (14, [M À Me] ), 254
‡
(80), 238 (4), 149 (100), 134 (16), 119 (38), 106 (45), 91 (49), 77 (23). HR-MS: 270.1490 ([M À Me] ,
‡
C
17H20NO2 ; calc. 270.1494).
(À)-[(1S)-1-(2-Methoxy-6-methylphenyl)ethyl]amine ((S)-2a). A suspension of anh. K2CO3 (22.50 g,
160 mmol) in MeOH (60 ml) was cooled to 08. A soln. of (S,S)-10 (7.73 g, 27.11 mmol) in CH2Cl2 (100 ml) and a
soln. of Pb(OAc)4 (15.02 g, 33.89 mmol) in CH2Cl2 (100 ml) were added dropwise to the suspension at the same
time within 10 min. After an additional 3 min, the reaction was stopped by addition of sat. aq. Na2CO3 soln.
(150 ml). The brown-red mixture was filtered through a pad of Celite. CH2Cl2 (100 ml) was added, and the
mixture was washed with sat. aq. Na2CO3 soln. (2 Â 30 ml). The org. phase was extracted once more with sat. aq.
Na2CO3 soln. The org. phase was dried (K2CO3) and evaporated to afford the imine (S)-11 as a yellow oil which
solidified under vacuum (10À2 mbar). The solid was washed with hexane: (S)-11 (5.30 g) as a white solid. (S)-11
was directly hydrolyzed for 15 h by 0.05n HCl (400 ml) in CH2Cl2 (150 ml) at r.t. The soln. was decanted and the
org. phase washed with 0.05n HCl (70 ml). The combined aq. phase was extracted with Et2O (2 Â 20 ml) and
neutralized with 6n NaOH. The resulting aq. phase was extracted with Et2O (3 Â 20 ml) and basified (pH 9)
with 6n NaOH and extracted with Et2O (3 Â 20 ml). The combined org. phase was dried (MgSO4) and
evaporated and the crude yellow oil purified by bulb-to-bulb distillation at 608/0.4 mbar: (À)-(S)-2a (2.38 g,
70% from (S,S)-10). White solid. Chiral HPLC (corresponding N-[(1S)-1-(2-methoxy-6-methylphenyl)ethyl]-
i
naphthalene-1-carboxamide; Chiracel OD-H, 10% PrOH/hexane, 1 ml/min, l 300 nm): tR 12 min ((‡)-(R);
20
D
0.5%), ((À)-(S); 99.5%)); 99% ee. ‰aŠ ˆ À27.0 (c ˆ 1.21, EtOH). IR (CCl4): 3390, 3068, 2936, 2836, 1581, 1472,
1365, 1259, 1245. 1H-NMR (400 MHz, CDCl3): 1.47 (d, J ˆ 6.8, 3 H); 2.33 (s, 3 H); 2.38 (br. s, 2 H); 3.85 (s, 3 H);
4.31 (q, J ˆ 6.8, 1 H); 6.7 6.8 (m, 2 H); 7.08 (m, 1 H). 13C-NMR (50 MHz, CDCl3): 20.1; 22.2; 47.0; 55.1; 109.4;
‡
123.2; 126.9; 132.7; 135.6; 158.2. MS: 151 (10), 150 (100, [M À Me] ), 135 (24), 121 (12), 91 (8), 77 (6). HR-MS:
‡
‡
165.1152 (M , C10H15NO ; calc. 165.1153).
6. Enantiomerically Enriched 2a: Method B. (‡)-(aR)-2-Methoxy-a,6-dimethylbenzenemethanol ((R)-23).
To a soln. of boraneÀoxazaborolidine complex (S)-22 (265 mg, 0.913 mmol) in CH2Cl2 (0.5 ml; previously dried
over 4 ä molecular sieves) under N2, 10m BH3 ¥ SMe2 (1.70 ml, 18.27 mmol) was added. The mixture was cooled
to À 208, and 1m 21 (3 g, 18.27 mmol) in CH2Cl2 (18.3 ml; previously dried over 4 ä molecular sieves) was added
via a syringe pump within 5 h. After 36 h, MeOH (10 ml) was added to the soln. at À 208. The mixture was then
warmed to r.t. and evaporated. The residue was purified by FC (SiO2, cyclohexane/AcOEt 70 :30: (R)-23
(2.78 g, 92%; 93% ee by 1H-NMR, integration of Me-Ar signal of the corresponding (R,R)-Mosher ester).
20
Colorless oil. ‰aŠ ˆ ‡27.6 (c ˆ 1.30, CHCl3). IR (CHCl3): 3021, 2927, 1583, 1223. 1H-NMR (400 MHz, CDCl3):
D
1.52 (d, J ˆ 6.7, 3 H); 2.31 (s, 3 H); 3.6 (br. s, 1 H); 3.88 (s, 3 H); 5.06 (q, J ˆ 6.7, 1 H); 6.77 6.80 (m, 2 H); 7.10
(t, J ˆ 7.8, 1 H). 13C-NMR (100 MHz, CDCl3): 19.5; 23.0; 55.3; 67.2; 109.1; 123.5; 126.4; 130.9; 135.4; 157.4. MS:
‡
‡
‡
166 (74, M ), 164 (65), 151 (100), 149 (97), 212 (90), 91 (84). HR-MS: 166.0984 (M , C10H14O2 ; calc.
166.0993).

Helvetica Chimica Acta Vol. 87 (2004)
575
(‡)-2-[(1S)-1-Azidoethyl]-1-methoxy-3-methylbenzene ((S)-24). DPPA (0.724 ml, 3.3 mmol) followed by
DBU (0.473 ml, 3.3 mmol) were added at r.t. to a soln. of (R)-23 (464 mg, 2.8 mmol) in THF (8 ml). The mixture
was stirred at r.t. for 24 h. To the dark red soln., H2O (6 ml) and CH2Cl2 (6 ml) were added. The org. phase was
washed with H2O (2 Â 15 ml), dried (MgSO4), and evaporated and the residue purified by FC (SiO2,
20
D
cyclohexane/AcOEt 80 :20): (S)-24 (300 mg, 56%). Colorless oil. ‰aŠ ˆ ‡2.66 (c ˆ 1.24, CHCl3; 51% ee). IR
(CHCl3): 3020, 2936, 2839, 2116, 1583, 1489, 1472, 1373, 1262, 1206. 1H-NMR (400 MHz, CDCl3): 1.58 (s, J ˆ 7.1,
3 H); 2.41 (s, 3 H); 3.86 (s, 3 H); 5.17 (q, J ˆ 7.1, 1 H); 6.80 (d, J ˆ 7.6, 1 H); 7.18 (t, J ˆ 7.6, 2 H). 13C-NMR
‡
(100 MHz, CDCl3): 18.3; 20.0; 54.4; 55.5; 109.0; 120.9; 123.5; 126.6; 137.2; 157.9. MS: 191 (14, M ), 150 (11), 149
‡
‡
(100), 133 (12), 119 (19), 91 (20), 77 (13). HR-MS: 191.1074 (M , C10H13N3O ; calc. 191.1058).
(À)-[(1S)-1-(2-Methoxy-6-methylphenyl)ethyl]amine ((S)-2a). A mixture of (S)-24 (160 mg, 0.83 mmol),
EtOH (6 ml), and the Pd/C catalyst (Degussa type 101 NE/W, 10 mg) was purged with H2 (3Â), stirred under H2
(1 atm) at r.t. for 4 h, and then filtered through a pad of Celite. Evaporation gave a yellow oil, which was purified
by bulb-to-bulb distillation at 608/0.4 mbar: (S)-2a (132 mg, 96%). Chiral HPLC (N-[(1S)-1-(2-methoxy-6-
methylphenyl)ethyl]naphthalene-1-carboxamide; Chiracel OD-H, 10% iPrOH/hexane, 1 ml/min, l 300 nm): tR
20
D
12 ((‡)-(R); 24.5%); 18 ((À)-(S); 75.4%); 51% ee. ‰aŠ ˆ À14.5 (c ˆ 1.75, EtOH).
7. Enantiomerically Enriched 2b: Method C. (‡)-3-Methyl-2-{(1E)1-{[(1R)-1-phenylethyl]imino}-
ethyl}phenol ((R)-33). A mixture of 1-(2-hydroxy-6-methylphenyl)ethanone (32; 1.80 g, 12 mmol), (‡)-
(aR)-a-methylbenzylamine (1.45 g, 12 mmol; > 99% ee), a catalytic amount of TsOH (0.200 g), and 4 ä
molecular sieves (10 g) in dry toluene (20 ml) was refluxed for 20 h. The soln. was filtered through a pad of
Celite, and the filtrate was evaporated: crude (R)-33 (3.03 g, 12 mmol). Pale yellow solid. The product was used
20
D
1
without further purification. ‰aŠ ˆ ‡157 (c ˆ 0.35, EtOH). IR (CCl4): 2966, 1605, 1450, 1366, 1288. H-NMR
(400 MHz, CDCl3): 1.64 (d, J ˆ 6.5, 3 H); 2.33 (s, 3 H); 2.42 (s, 3 H); 4.89 (q, J ˆ 6.5, 1 H); 6.65 (d, J ˆ 7.4, 1 H);
6.81 (d, J ˆ 8.1, 1 H); 7.12 (t, J ˆ 7.8, 1 H); 7.26 (m, 2 H); 7.3 7.4 (m, 3 H). 13C-NMR (100 MHz, CDCl3): 20.8;
‡
23.4; 25.1; 58.9; 115.5; 121.9; 123.0; 126.4; 126.8; 128.7; 130.6; 136.9; 144.2; 160.3; 170.8. MS: 253 (25, M ), 238
‡
(11), 162 (6), 149 (20), 134 (10), 133 (6), 106 (11), 105 (100), 91 (4), 79 (18), 77 (26). HR-MS: 253.1457 (M ,
‡
C17H19NO ; calc. 253.1466).
(‡)-3-Methyl-2-{(1S)-1-{[(1R)-1-phenylethyl]amino}ethyl}phenol ((S,R)-34). To a soln. of 33 (506 mg,
2 mmol) in MeOH (10 ml) at À 788 was added NaBH4 (152 mg, 4 mmol). The mixture was allowed to warm to
r.t. and stirred for 12 h. The mixture was cooled to 08, and sat. NH4Cl soln. (5 ml) was added followed by CH2Cl2
(5 ml). The aq. phase was extracted with CH2Cl2 (5 ml) and the combined org. phase dried (MgSO4) and
evaporated: crude (S,R)-34/(R,R)-34 2.6 :1 (by 1H-NMR). Purification by FC (SiO2, pentane/Et2O/Et3N
20
4 :1:3) afforded (S,R)-34 (362 mg, 71%; > 96% de by 1H-NMR, integration of Me-Ar signal). ‰aŠ ˆ ‡18 (c ˆ
D
0.75, CHCl3). IR (CHCl3): 2970, 2922, 2855, 2744, 1605, 1583, 1465, 1444, 1378, 1272, 1234, 1108. 1H-NMR
(400 MHz, CDCl3): 1.40 (d, J ˆ 6.7, 3 H); 1.50 (d, J ˆ 6.7, 3 H); 2.22 (s, 3 H); 3.89 (q, J ˆ 6.7, 1 H); 4.36 (q, J ˆ 6.7,
1 H); 6.60 (d, J ˆ 7.5, 1 H); 6.69 (d, J ˆ 8.0, 1 H); 7.03 (t, J ˆ 8.0, 1 H); 7.26 7.36 (m, 5 H). 13C-NMR (100 MHz,
CDCl3): 19.4; 19.8; 21.3; 50.9; 54.3; 115.2; 121.1; 125.1; 126.3 (2); 127.4; 127.9; 128.6 (2); 135.4; 143.4; 157.9. MS:
‡
‡
‡
255 (31, M ), 240 (60), 134 (68), 120 (15), 106 (100), 91 (32), 79 (31). HR-MS: 255.1627 (M , C17H21NO ; calc.
255.1623).
20
D
A pure sample of (R,R)-34 (55 mg, 11%) was also obtained. M.p. 115 1178. ‰aŠ ˆ ‡55 (c ˆ 1.23, CHCl3).
IR (CHCl3): 2970, 2922, 2855, 2744, 1605, 1583, 1465, 1444, 1378, 1272, 1234, 1108. 1H-NMR (400 MHz, CDCl3):
1.31 (d, J ˆ 6.7, 3 H); 1.43 (d, J ˆ 6.8, 3 H); 1.92 (s, 3 H); 3.68 (q, J ˆ 6.8, 1 H); 3.90 (q, J ˆ 6.7, 1 H); 6.59 (d, J ˆ
7.4, 1 H); 6.72 (d, J ˆ 8.0, 1 H); 7.05 (t, 1 H); 7.15 (m, 2 H); 7.3 7.4 (m, 3 H). 13C-NMR (100 MHz, CDCl3): 19.0;
‡
20.7; 23.4; 51.1; 55.3; 114.9; 121.2; 124.0; 126.3 (2); 127.5; 127.8; 128.8 (2); 135.9; 143.6; 158.2. MS: 255 (22, M ),
241 (7), 240 (39), 136 (51), 135 (25), 134 (52), 133 (15), 120 (13), 106 (91), 105 (100), 91 (36), 77 (34). HR-MS:
‡
‡
255.1629 (M , C17H21NO ; calc. 255.1623).
(‡)-[(1S)-1-(2-Hydroxy-6-methylphenyl)ethyl]amine ((S)-2b). Hydrogenolysis of (S,R)-34 (1.02 g,
4 mmol) was performed in refluxing MeOH (40 ml) with AcOH (960 mg, 16 mmol), ammonium formate
(2.27 g, 24 mmol), and Pd(OH)2/C (20 wt.-%, 400 mg). The reaction was stopped after 24 h. The mixture was
filtered through a pad of Celite and the filtrate evaporated. The residue was dissolved in Et2O, the soln. washed
with sat. aq. NaHCO3 soln., dried (Na2SO4), and evaporated, and the residue recrystallized from hexane: (S)-2b
(460 mg, 76%; > 96% ee by 1H-NMR, integration of Me-Ar signal of the corresponding (S,R)-Mosher amide).
20
D
M.p. 110 1128. ‰aŠ ˆ ‡64 (c ˆ 0.9, CHCl3). IR (CHCl3): 3009, 2966, 2866, 2766, 1583, 1466, 1383, 1273, 1214,
1072. 1H-NMR (400 MHz, CDCl3): 1.43 (d, J ˆ 6.6, 3 H); 2.25 (s, 3 H); 4.65 (q, J ˆ 6.6, 1 H); 6.61 (d, J ˆ 7.5,
1 H); 6.70 (d, J ˆ 7.5, 1 H); 7.02 (t, J ˆ 7.5, 1 H). 13C-NMR (100 MHz, CDCl3): 19.3; 21.4; 47.7; 115.5; 121.1;
‡
125.8; 127.9; 135.1; 158.1. MS: 151 (50, M ), 136 (63), 134 ( 100), 119 (23), 105 (21), 91 (61), 77 (20). HR-MS:
‡
‡
151.0954 (M , C9H13NO ; calc. 151.0997).

576
Helvetica Chimica Acta Vol. 87 (2004)
8. Enantiomerically Enriched 3a: Method B. (Æ)-3,5-Di(tert-butyl)-2-hydroxy-a-methylbenzenemethanol
(18). MeMgBr (3m) in Et2O (8.33 ml, 25.0 mmol) was added within 30 min to a stirred soln. of 17 (2.34 g,
10.0 mmol) in Et2O (40 ml). The soln. was refluxed for 16 h. Sat. NH4Cl soln. (100 ml) was added and the
product extracted with Et2O (3 Â 40 ml). The combined org. phase was washed with H2O and brine, dried
(MgSO4), and evaporated: pure 18 (2.50 g, 100%). Colorless crystals. M.p. 62 648. IR (CHCl3): 3591, 3374,
2964, 2869, 1480, 1445, 1362, 1249, 1228, 1009, 881, 767. 1H-NMR (CDCl3, 400 MHz): 1.34 (s, 9 H); 1.48 (s, 9 H);
1.65 (d, J ˆ 6.8, 3 H); 2.47 (br. d, J ˆ 3.4 , 1 H); 5.06 (q, J ˆ 6.6, 1 H); 6.89 (d, J ˆ 2.4, 1 H); 7.30 (d, J ˆ 2.4 , 1 H);
8.20 (s, 1 H). 13C-NMR (CDCl3, 100 MHz): 23.0; 29.7; 31.6; 34.2; 35.1; 73.0; 121.2; 123.5; 136.0; 141.2; 152.5.
‡
‡
‡
MS: 250 (3, M ), 233 (33), 217 (100), 57 (26). HR-MS: 250.1927 (M , C16H26O2 ; calc. 250.1932).
1-[3,5-Di(tert-butyl)-2-hydroxyphenyl]ethanone (19). A soln. of 18 (2.50 g, 10.0 mmol), MnO2 (2.61 g,
30.0 mmol), and hexane (40 ml) was refluxed for 16 h. The soln. was filtered through a pad of Celite and the
filtrate evaporated: 19 (2.38 g, 96%). Pale yellow oil. IR (CHCl3): 3530, 2964, 2871, 1630, 1466, 1434, 1329, 1240,
1203, 1185, 1105, 974, 880, 822. 1H-NMR (CDCl3, 400 MHz): 1.35 (s, 9 H); 1.45 (s, 9 H); 2.67 (s, 3 H); 7.59
(q, J ˆ 2.5, 2 H); 13.01 (s, 1 H). 13C-NMR (CDCl3, 100 MHz): 27.0; 29.3; 31.3; 34.2; 35.0; 118.6; 124.3; 131.3;
‡
‡
‡
137.9; 140.0; 160.0; 205.2. MS: 248 (21, M ), 233 (100), 57 (12). HR-MS: 248.1774 (M , C16H24O2 ; calc.
248.1776).
1-[3,5-Di(tert-butyl)-2-methoxyphenyl]ethanone (20). A soln. of 19 (496 mg, 2.0 mmol), Me2SO4 (3.0 ml,
31 mmol), K2CO3 (5.0 g, 36 mmol), and acetone (20 ml) was refluxed for 4 h. After addition of 2n aq. NaOH
(100 ml), the product was extracted with CH2Cl2 (3 Â 50 ml), the combined org. phase dried (MgSO4) and
evaporated, and the crude product purified by FC (SiO2, Et2O/cyclohexane 1:4): 20 (449 mg, 85%). Colorless
crystals. M.p. 84 868. IR (CHCl3): 2965, 2870, 1678, 1595, 1477, 1425, 1364, 1266, 1244, 1102, 1008, 891. 1H-NMR
(CDCl3, 400 MHz): 1.33 (s, 9 H); 1.43 (s, 9 H); 2.65 (s, 3 H); 3.74 (s, 3 H); 7.32 (d, J ˆ 2.5, 1 H); 7.48 (d, J ˆ 2.5,
1 H). 13C-NMR (CDCl3, 100 MHz): 29.8; 30.8; 31.3; 34.5; 35.2; 63.1; 124.1; 127.3; 134.1; 142.2; 145.5; 156.6;
‡
‡
‡
203.6. MS: 262 (16, M ), 247 (100), 57 (22). HR-MS: 262.1935 (M , C17H26O2 ; calc. 262.1932).
(‡)-(aR)-3,5-Di(tert-butyl)-2-methoxy-a-methylbenzenemethanol ((R)-25). To a soln. of borane complex
(S)-22 (47 mg, 0.161 mmol) in CH2Cl2 (2 ml; previously dried over 4 ä molecular sieves) under N2 10m BH3 ¥
SMe2 (0.328 ml, 3.28 mmol) was added. The mixture was cooled to À 208 and 1m 20 (860 mg, 3.28 mmol) in
CH2Cl2 (3.3 ml; previously dried over 4 ä molecular sieves) was added via a syringe pump over 5 h. After 12 h,
MeOH (10 ml) was added to the soln. at À 208. The mixture was then warmed to r.t. and evaporated. The
residue was purified by FC (SiO2, cyclohexane/AcOEt 4 :1): (R)-25 (644 mg, 74%; 90% ee by 19F-NMR,
20
D
integration of CF3ÀC of the corresponding (R,R)-Mosher ester). Oil. ‰aŠ ˆ ‡24.7 (c ˆ 0.63, CHCl3). IR
(CHCl3): 3454, 2965, 2869, 1478, 1228, 1122, 1090, 1011, 922. 1H-NMR (CDCl3, 500 MHz): 1.33 (s, 9 H); 1.41
(s, 9 H); 1.58 (d, J ˆ 6.6, 3 H); 2.10 (br. s, 1 H); 3.82 (s, 3 H); 5.30 (q, J ˆ 6.6, 1 H); 7.27 (s, 1 H); 7.32 (s, 1 H).
13C-NMR (CDCl3, 125 MHz): 24.0; 31.5; 32.2; 34.7; 35.3; 62.8; 64.6; 121.5; 123.8; 138.1; 141.7; 146.2; 154.5. MS:
‡
‡
‡
264 (3, [M ‡ H] ), 246 (26), 232 (100), 57 (56). HR-MS: 264.2074 ([M ‡ H] , C17H28O2 ; calc. 264.2089).
(‡)-(aR)-3,5-Di(tert-butyl)-2-hydroxy-a-methylbenzenemethanol ((R)-18). To
a
soln. of borane-
Àoxazaborolidine complex (S)-22 (80 mg, 0.275 mmol) in CH2Cl2 (0.25 ml; previously dried over 4 ä
molecular sieves) under N2, 10m BH3 ¥ SMe2 (0.05 ml, 0.5 mmol) was added. The mixture was cooled to À 208
and 1m 19 (124 mg, 0.5 mmol) in CH2Cl2 (0.5 ml; previously dried over 4 ä molecular sieves) was added via a
syringe pump over 5 h. After 4 h, MeOH (5 ml) was added to the soln. at À 208. The mixture was then warmed
to r.t. and evaporated. The residue was purified by FC (SiO2, Et2O): (R)-18 (0.069 g, 55%). Chiral HPLC
(Chiracel OJ, 0.2% iPrOH/hexane, 0.3 ml/min, l 210 nm): tR 66.1 ((À)-(S); 1%), 80.1 ((‡)-(R); 99.0%; 98% ee.
20
D
‰aŠ ˆ ‡5.3 (c ˆ 1.2, CHCl3 ).
(À)-1-[(1S)-1-Azidoethyl]-3,5-di(tert-butyl)-2-methoxybenzene ((S)-26). To
a soln. of 25 (566 mg,
2.14 mmol) in THF (20 ml) was added 4-NO2-DPPA (1.17 g, 3.21 mmol). The suspension was stirred at r.t.
until the solid was dissolved. DBU (0.45 ml, 3.21 mmol) was added dropwise, and the yellow soln. was stirred for
2 h at r.t. H2O (10 ml) and CH2Cl2 (10 ml) were added to the deep yellow soln., the org. phase was washed with
H2O (2 Â 20 ml) and 2n HCl (2 Â 20 ml), dried (MgSO4), and evaporated and the residue purified by FC (SiO2,
20
cyclohexane/AcOEt 95 :05): (S)-26. Pale yellow crystals (530 mg, 85%). M.p. 55 568. ‰aŠ ˆ À17.3 (c ˆ 1.25,
D
1
CHCl3). IR (CH2Cl2): 3597, 2965, 2869, 2173, 1590, 1489, 1297, 1188, 1010, 965. H-NMR (CDCl3, 500 MHz):
1.34 (s, 9 H); 1.42 (s, 9 H); 1.58 (d, J ˆ 6.9, 3 H); 3.81 (s, 3 H); 5.03 (q, J ˆ 6.9, 1 H); 7.23 (d, J ˆ 2.5, 1 H); 7.33
(d, J ˆ 2.5, 1 H). 13C-NMR (CDCl3, 100 MHz): 21.4; 31.2; 31.5; 34.6; 35.4; 54.6; 63.1; 121.9; 124.3; 133.6; 142.0;
‡
‡
‡
146.3; 154.7. MS: 289 (14, M ), 247 (56), 231 (20), 57 (100). HR-MS: 289.2150 (M , C17H27ON3 ; calc. 289.2154).
(À)-{(1S)-1-[3,5-Di(tert-butyl)-2-methoxyphenyl]ethyl}amine ((S)-3a). A mixture of (S)-26 (450 mg,
1.55 mmol), EtOH (15 ml), and Pd/C catalyst (Degussa type 101 NE/W, 30 mg) was purged with H2 (3Â),
stirred under H2 (1 atm) at r.t. for 12 h, and then filtered through a pad of Celite. Evaporation gave (S)-3a

Helvetica Chimica Acta Vol. 87 (2004)
577
(394 mg, 96%; 69% ee by 19F-NMR, integration of CF3ÀC of the corresponding (S,R)-Mosher amide).
20
D
Colorless crystals. M.p. 77 788. ‰aŠ ˆ À13 (c ˆ 0.3, EtOH). IR (CHCl3): 3220, 2965, 2869, 1477, 1430, 1362,
1228, 1208, 1119, 1009, 882. 1H-NMR (CDCl3, 500 MHz): 1.33 (s, 9 H); 1.41 (s, 9 H); 1.44 (d, J ˆ 6.6, 3 H); 1.89
(br. s, 2 H); 3.80 (s, 3 H); 4.53 (q, J ˆ 6.6, 1 H); 7.25 (d, J ˆ 2.5, 1 H); 7.32 (d, J ˆ 2.5, 1 H). 13C-NMR (CDCl3,
‡
125 MHz): 25.0; 31.2; 31.5; 34.7; 35.4; 44.3; 62.7; 121.1; 122.9; 140.2; 141.7; 146.0; 154.4. MS: 263 (8, M ), 248
‡
‡
(100), 231 (23), 117 (10), 57 (62). HR-MS: 263.2237 (M , C17H29ON ; calc. 263.2249).
9. Enantiomerically Enriched 3b: Method C. (À)-2,4-Di(tert-butyl)-6-{(1E)-1-{[(1R)-1-phenylethyl]-
imino}ethyl}phenol ((R)-35). A mixture of 19 (2.48 g, 10.0 mmol), (‡)-(R)-a-methylbenzylamine (1.27 ml,
10.0 mmol), a catalytic amount of TsOH (0.095 g, 0.5 mmol) and 4 ä molecular sieves (5.0 g) in dry toluene
(15 ml) was refluxed for 16 h. The soln. was filtered and evaporated: crude (R)-35 (3.48 g, 99%). Yellow viscous
20
D
oil. ‰aŠ ˆ À155.0 (c ˆ 1.04, EtOH). IR (CHCl3): 3689, 3201, 2964, 2869, 1611, 1478, 1450, 1390, 1362, 1248, 1212,
1095, 1023, 878, 700. 1H-NMR (CDCl3, 500 MHz): 1.32 (s, 9 H); 1.49 (s, 9 H); 1.66 (d, J ˆ 6.6, 3 H); 2.35 (s, 3 H);
4.96 (q, J ˆ 6.6, 1 H); 7.41 7.16 (m, 7 H). 13C-NMR (CDCl3, 125 MHz): 15.2; 25.4; 29.5; 31.5; 34.2; 35.2; 58.5;
‡
118.0; 122.0; 126.4; 126.9; 127.0; 128.2; 128.6; 129.0; 137.6; 137.9; 144.6; 160.9; 171.1. MS: 351 (63, M ), 336 (28),
‡
‡
232 (59), 204 (19), 105 (100), 57 (28). HR-MS: 351.2538 (M , C24H33NO ; calc. 351.2562).
(‡)-2,4-Di(tert-butyl)-6-{(1R)-1-{[(1R)-1-phenylethyl]amino}ethyl}phenol ((R,R)-36). NaBH4 (1.15 g,
30 mmol) was slowly added to a soln. of AcOH (2 ml, 35 mmol) in THF (40 ml). The temp. of the soln. was
kept at 10 208 while H2 evolved (0.5 h). The soln. was then cooled to À 788, and (R)-35 (3.5 g, 10 mmol) in
THF (10 ml) was added in one portion and the temp. of the mixture was allowed to warm slowly to r.t. overnight.
The soln. was evaporated, the residue taken up in CH2Cl2 (100 ml), the soln. washed with sat. Na2CO3 soln.
1
(50 ml), dried (MgSO4), and evaporated, and the 2.4 :1 (by H-NMR) mixture (R,R)-36/(S,R)-36 purified by
20
D
1
FC (SiO2, pentane/CH2Cl2 1:1): (R,R)-36 (1.8 g, 51%; 74% de). Colorless viscous oil. ‰aŠ ˆ ‡35.0 (c ˆ 2.1,
CHCl3). IR (CHCl3): 3674, 3084, 2964, 2868, 1602, 1479, 1444, 1362, 1264, 1224, 1109, 882. H-NMR (CDCl3,
400 MHz; mixture of inseparable diastereoisomers): 1.26 1.27 (2s, 9 H); 1.35 1.46 (m, 18 H); 1.54 (2s, 9 H);
3.65 (2q, J ˆ 6.8, 6.5, each 1 H); 4.0 (2q, J ˆ 6.8, 6.5, each 1 H); 6.62 (d, J ˆ 2.5, 1 H); 6.75 (m, 1 H); 7.14 7.34
(m, 7 H). 13C-NMR (CDCl3, 100 MHz): 22.5; 23.2; 29.6; 31.7; 34.1; 35.5; 50.8; 55.2; 57.0; 122.3; 123.3; 125.5;
‡
126.4; 127.4; 128.6 (2); 135.8; 140.3; 143.8; 154.0. MS: 353 (34, M ), 338 (15), 232 (38), 217 (100), 175 (16), 105
‡
‡
(39), 84 (40), 69 (12), 57 (44). HR-MS: 353.2695 (M , C24H35NO ; calc. 353.2718).
(À)-2-[(1R)-1-Aminoethyl]-4,6-di(tert-butyl)phenol ((R)-3b). A mixture of 36 (1.41 g, 4 mmol), MeOH
(40 ml), AcOH (960 mg, 16 mmol), and Pd(OH)2/C (30 wt.-%, 850 mg) was purged with H2 (3Â), stirred under
H2 (4 atm) at r.t. for 16 h, and then passed through a pad of Celite. The filtrate was evaporated and the residue
taken up in Et2O (20 ml) and sat. NaHCO3 soln. (20 ml). The aq. phase was extracted with Et2O the combined
org. phase dried (MgSO4) and evaporated, and the residue purified by FC (pentane/Et2O/Et3N 95 :5 :3): (R)-3b
(976 mg, 98%; 66% ee by 19F-NMR, integration of CF3ÀC signal of the corresponding (R,S)-Mosher amide).
20
D
Pale yellow crystals. M.p. 80 828. ‰aŠ ˆ À3 (c ˆ 2.15, CHCl3). IR (CHCl3): 3689, 3392, 2964, 2869, 1601, 1480,
1440, 1362, 1223, 1161, 1129, 882. 1H-NMR (CDCl3, 500 MHz): 1.31 (s, 9 H); 1.44 (s, 9 H); 1.51 (d, J ˆ 6.6, 3 H);
4.34 (q, J ˆ 6.6, 1 H); 6.88 (d, J ˆ 2.5, 1 H); 7.22 (d, J ˆ 2.5, 1 H). 13C-NMR (CDCl3, 125 MHz): 23.5; 29.7; 31.6;
‡
34.2; 35.0; 52.4; 122.0; 122.8; 127.2; 136.6; 140.3; 154.1. MS: 249 (9, M ), 232 (33), 217 (100), 175 (13), 105 (14),
‡
‡
77 (14), and 57 (35). HR-MS: 249.2091 (M , C16H27NO ; calc. 249.2092).
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Received August 25, 2003