Further enantioselective syntheses of α-arylalkanamines via intermediate addition of Grignard reagents to a chiral hydrazone derived from (R)-(-)-2-aminobutan-1-ol

Article abstract of DOI:10.1016/S0957-4166(99)00146-9

Reaction of various aromatic aldehydes with the chiral hydrazine (R)-(- )-2, derived from 2-aminobutan-1-ol (R)-(-)-1, gave the corresponding hydrazones 5-12. Enantioselective addition of EtMgBr or n-BuMgBr to 5-8 gave the trisubstituted hydrazines 13a-f

Full text of DOI:10.1016/S0957-4166(99)00146-9

Pergamon
Tetrahedron: Asymmetry 10 (1999) 1579–1588
Further enantioselective syntheses of α-arylalkanamines via
intermediate addition of Grignard reagents to a chiral hydrazone
derived from (R)-(−)-2-aminobutan-1-ol
Patricia Bataille, Michel Paterne and Eric Brown ∗
Laboratoire de Synthèse Organique (ESA-CNRS 6011), Faculté des Sciences, Avenue Messiaen,
F-72085 Le Mans, Cedex 9, France
Received 26 March 1999; accepted 15 April 1999
Abstract
Reaction of various aromatic aldehydes with the chiral hydrazine (R)-(−)-2, derived from 2-aminobutan-1-ol
(R)-(−)-1, gave the corresponding hydrazones 5–12. Enantioselective addition of EtMgBr or n-BuMgBr to 5–8
gave the trisubstituted hydrazines 13a–f (d.e.s=100%). Catalytic hydrogenolysis (6 bar/Pd–C/110°C/5 h) of the
N–N bond of the latter afforded the enantiomerically enriched α-arylalkanamines (R)-(+)-14a–f (e.e.s=90–93%).
© 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
We recently described1 the synthesis of the chiral hydrazine (R)-(−)-2 in four steps from (R)-(−)-
2-aminobutan-1-ol 1, a readily available reagent (Scheme 1). Diastereoselective addition of Grignard
reagents to the benzenecarbaldehyde hydrazone (R)-(−)-3 derived from 2, followed by catalytic hy-
drogenolysis of the N–N bond of the resulting trisubstituted hydrazines (d.e.s=100%), afforded the
enantiomerically enriched (e.e.s=90–92%) (R)-(+)-α-phenylalkanamines 4a–g.
2. Results and discussion
We next applied the above reaction scheme to the syntheses of various ring-substituted α-aryl-
alkanamines. Thus, the hydrazones (R)-(−)-5–12 (pure anti-isomers) were prepared in 63–86% yields
∗
Corresponding author. E-mail: lso@lola.univ-lemans.fr
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00146-9

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Scheme 1.
from the hydrazine (R)-(−)-2 and the corresponding substituted aromatic aldehydes, using the ex-
perimental conditions (anhydrous MgSO4/TsOH/CH2Cl2/20°C/17 h) which we previously described
(Scheme 2).1
The addition of n-BuLi to the hydrazone 5 was attempted first. A total lack of reactivity was observed
when adding 2, 4 or 6 equivalents of n-BuLi to the hydrazone 5 in ether at 0°C for 17 h. However,
using 8 equivalents of n-BuLi did afford the expected trisubstituted hydrazine but in low yields (35%)
1
and with a low d.e. (41%, from H NMR). For this reason, we decided to limit ourselves to the use of
organomagnesium reagents. Thus, the addition of Grignard reagents to the hydrazones 5–12 was carried
out as previously described1 (10 equiv. RMgX/Et2O/reflux/17 h). The eight trisubstituted hydrazines
(R,R)-13a–h were thus obtained in 51–83% yields and with d.e.s=100% in all cases (as evidenced by
1H and 13C NMR). The addition of EtMgBr to the hydrazones 11 and 12 could not be carried out to
completion and gave inseparable mixtures of trisubstituted hydrazine and starting hydrazone.
None of the ring-substituted hydrazines 13a–h could be hydrogenolyzed under the conditions which
we previously developed for the hydrazines 4a–g (H2, 6 bar/HCl/EtOH/60°C/17 h).1 Increasing the
pressure to 25 bar at 60°C gave no better results. It was eventually found that the temperature was the
determining factor: indeed, hydrogenolysis of the hydrazines 13a–f at 110–120°C, in the presence of
a 10% Pd–C catalyst and conc. HCl in EtOH, under 6 bar for 5 h, afforded the corresponding (R)-α-
arylalkanamines (R)-(+)-14a–f in 35–47% yields after purification by chromatography. Under the same
conditions, hydrogenolysis of the hydrazines 13g and 13h gave inseparable mixtures. The e.e.s of the
three amines 14a,d,f were found to be within the range 90–93% by means of chiral GPC using a Restek
β dex column. The other three amines 14b,c,e could not be resolved using this and other chiral columns,
or by running the 1H NMR spectra in the presence of the shift reagent Eu(hfc)3. It can be assumed that
the e.e.s of the amines 14b,c,e are also in the range 90–93%, and that the six amines 14a–f all belong
to the R-series, analogously with the α-phenylalkanamines 4a–g, and in agreement with the addition
mechanism which we previously put forth.1 The α-arylalkanamines (R)-14a–d were known in racemic
form only. The amines (R)-14e,f are new compounds.
As early as 1979, Takahashi and his coworkers2 described a synthesis of α-phenylalkanamines, invol-
ving the enantioselective addition of Grignard reagents to the hydrazone derived from N-aminoephedrine
and benzaldehyde, followed by hydrogenolytic cleavage of the N–N bond of the resulting trisubstituted
hydrazine. Later on, Enders and his coworkers3 developed the chiral SAMP hydrazine, which they used
for the syntheses of aldehyde hydrazones of type 15 (Scheme 3). Diastereoselective addition of lithium
alkyls to 15 gave the corresponding trisubstituted hydrazines 16. Catalytic hydrogenolysis of the latter
using Raney nickel led to the corresponding amines 17 having e.e.s within the range 81–94%. A similar
study was carried out by Denmark and coworkers.4

P. Bataille et al. / Tetrahedron: Asymmetry 10 (1999) 1579–1588
1581
Scheme 2.
Scheme 3.
Our reaction scheme for the synthesis of enantiomerically enriched α-arylalkanamines is closely
related to that used by Enders.3 Some differences must be pointed out. We found that the presence of
a free OH group in the chiral fragment of arylhydrazones of type 5 is necessary for the addition reaction
to occur.1 Besides, the addition of organolithium reagents to the hydrazones of type 5 could not be carried
out using the experimental conditions described by Enders.3 In our experience, the best results in terms

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of chemical yields and diastereomeric excesses implied the use of a 10-fold excess of organomagnesium
reagents.
Since 2-aminobutan-1-ol 1 is readily available in both enantiomeric forms on the industrial scale, our
strategy can be applied to the syntheses of α-arylalkanamines belonging to both the R- and S-series.
3. Experimental
3.1. General
IR spectra were recorded with Nicolet 5DX and Genesis (Mattson) spectrophotometers. 1H NMR (400
MHz) and 13C NMR (100 MHz) spectra were recorded with a Bruker AC 400 spectrometer, using Me4Si
as an internal standard. HR mass spectra were recorded at the CRMPO (Université de Rennes I) using
a Varian Matt 311 spectrometer. Melting points were determined with a Reichert microscope. Optical
rotations were measured at 26°C with a Perkin–Elmer 343 micropolarimeter. Elemental analyses were
carried out at the I.C.S.N. (C.N.R.S., Gif-sur-Yvette). Chiral CPG experiments were carried out with a
Hewlett–Packard HP 6890 chromatograph equipped with a Restek β dex column. (R)-(−)-2-Aminobutan-
1-ol, [α]D −10.0 (neat), was kindly provided by SmithKline Beecham Laboratories (Mayenne).
3.2. 3,4,5-Trimethoxybenzenecarbaldehyde-N-[(1R)-1-(hydroxymethyl)propyl]-N-methylhydrazone
(R)-(−)-5
To a solution of hydrazine (R)-(−)-21 (1.10 g; 9.32 mmol) in anhydrous CH2Cl2 (30 ml), placed in a
100 ml flask equipped with a silica gel drying tube, 3,4,5-trimethoxybenzaldehyde (1.40 g; 7.17 mmol),
anhydrous MgSO4 (1.3 equiv.) and a catalytic amount of TsOH were added and the resulting mixture
was stirred for 17 h at 20°C. After filtration and evaporation of the filtrate, the residue thus obtained
was stirred with an aqueous solution of NaHSO3 for 1 h and the mixture was extracted with CH2Cl2
(3×20 ml). The combined organic phases were dried (MgSO4), evaporated under RP and the final residue
was chromatographed over silica gel (eluent cyclohexane:ether, 7:3, and elution gradient) to give the
hydrazone (R)-(−)-5 (1.51 g, 71.2%) as a viscous colourless oil, [α]D −17.0 (c 1.67, MeOH). Anal. calcd
for C15H24N2O4: C, 60.79; H, 8.16; N, 9.45. Found: C, 61.22; H, 8.13; N, 9.22. IR (film): 3440 (OH) and
1589 (C_N) cm−1; 1H NMR (CDCl3): δ 0.94 (t, J=7.5 Hz, 3H), 1.50–1.75 (m, 2H), 2.86 (t, J=5.9 Hz,
1H), 2.96 (d, J=0.6 Hz, 3H), 3.24–3.30 (m, 1H), 3.85 (s, 3H), 3.88 (s, 6H), 3.83–3.88 (m, 2H), 6.76 (s,
2H), 7.17 (s, 1H); 13C NMR (CDCl3): δ 10.97, 22.00, 36.71, 55.95, 60.85, 63.75, 69.58, 102.16, 130.69,
132.67, 137.46, 153.35.
3.3. 4-Methoxybenzenecarbaldehyde-N-[(1R)-1-(hydroxymethyl)propyl]-N-methylhydrazone (R)-(−)-6
Starting from 4-methoxybenzaldehyde (0.85 ml; 7.06 mmol), anhydrous MgSO4 (1.3 equiv.) and
TsOH (catalytic amount), and the hydrazine (R)-(−)-2 (1.0 g; 8.47 mmol) in anhydrous CH2Cl2 (30 ml),
the above procedure (see Section 3.2) led to hydrazone (R)-(−)-6 (1.33 g; 80.1%) as a viscous colourless
oil, [α]D −27.6 (c 1.3, MeOH). Anal. calcd for C13H20N2O2: C, 66.07; H, 8.53; N, 11.85. Found: C,
1
66.17; H, 8.52; N, 12.03. IR (film): 3413 (OH) and 1608 (C_N) cm−1; H NMR (CDCl3): δ 0.93 (t,
J=7.5 Hz, 3H), 1.40–1.70 (m, 2H), 2.93 (s, 3H), 3.02 (t, J=6.0 Hz, 1H), 3.16–3.22 (m, 1H), 3.81 (s, 3H),
3.84–3.87 (m, 2H), 6.87 (dt, J=2.4, 8.8 Hz, 2H), 7.23 (s, 1H), 7.44 (dt, J=2.4, 8.8 Hz, 2H); 13C NMR
(CDCl3): δ 11.01, 21.75, 36.95, 55.25, 63.74, 69.43, 113.97, 126.61, 129.77, 131.58, 159.07.

P. Bataille et al. / Tetrahedron: Asymmetry 10 (1999) 1579–1588
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3.4. 4-Fluorobenzenecarbaldehyde-N-[(1R)-1-(hydroxymethyl)propyl]-N-methylhydrazone (R)-(−)-7
Starting from 4-fluorobenzaldehyde (1.05 ml; 9.8 mmol), anhydrous MgSO4 (1.3 equiv.), TsOH
(catalytic amount) and the hydrazine (R)-(−)-2 (1.50 g; 13 mmol) in anhydrous CH2Cl2 (30 ml), the
above procedure (see Section 3.2) led to the hydrazone (R)-(−)-7 (1.60 g; 72.7%) as a colourless oil,
[α]D −18.6 (c 1.1, MeOH). Anal. calcd for C12H17FN2O: C, 64.26; H, 7.63, N, 12.49. Found: C, 64.46;
H, 7.77; N, 12.27. IR (film): 3409 (OH) and 1602 (C_N) cm−1; 1H NMR (CDCl3): δ 0.93 (t, J=7.5 Hz,
3H), 1.50–1.70 (m, 2H), 2.74 (s, 1H), 2.96 (s, 3H), 3.20–3.26 (m, 1H), 3.70–3.90 (m, 2H), 6.97–7.03 (m,
2H), 7.20 (s, 1H), 7.45–7.50 (m, 2H); 13C NMR (CDCl3): δ 11.04, 22.16, 36.95, 63.81, 69.75, 115.34,
115.55, 126.73, 126.81, 129.81, 133.24, 162.08.
3.5. 4-Methylbenzenecarbaldehyde-N-[(1R)-1-(hydroxymethyl)propyl]-N-methylhydrazone (R)-(−)-8
Starting from 4-methylbenzaldehyde (0.64 ml; 5.43 mmol), anhydrous MgSO4 (1.3 equiv.), TsOH
(catalytic amount) and the hydrazine (R)-(−)-2 (0.77 g; 6.52 mmol) in anhydrous CH2Cl2 (30 ml), the
above procedure (see Section 3.2) led to the hydrazone (R)-(−)-8 (0.875 g; 73.5%) as a colourless oil,
[α]D −25.8 (c 1.1, MeOH). Anal. calcd for C13H20N2O: C, 70.87; H, 9.15; N, 12.72. Found: C, 70.86;
H, 9.36; N, 12.65. IR (film): 3407 (OH) and 1583 (C_N) cm−1; 1H NMR (CDCl3): δ 0.93 (t, J=7.4 Hz,
3H), 1.50–1.80 (m, 2H), 2.33 (s, 3H), 2.94 (s, 3H), 3.20–3.30 (m, 1H), 3.80–3.90 (m, 2H), 7.12 (d, J=8.0
Hz, 2H), 7.22 (s, 1H), 7.40 (d, J=8.0 Hz, 2H); 13C NMR (CDCl3): δ 11.53, 21.73, 22.44, 37.49, 64.33,
70.01, 125.82, 129.73, 132.03, 134.18, 137.10.
3.6. 1,3-Benzodioxole-5-carbaldehyde-N-[(1R)-1-(hydroxymethyl)propyl]-N-methylhydrazone
(R)-(−)-9
Starting from piperonal (1.27 g; 8.46 mmol), anhydrous MgSO4 (1.3 equiv.), TsOH (catalytic amount)
and the hydrazine (R)-(−)-2 (1.30 g; 11 mmol) in anhydrous CH2Cl2 (30 ml), the above procedure (see
Section 3.2) led to the hydrazone (R)-(−)-9 (1.34 g; 63.2%) as a colourless oil, [α]D −22.7 (c 1.12,
MeOH). Anal. calcd for C13H18N2O3: C, 62.38; H, 7.25; N, 11.19. Found: C, 62.21; H, 7.41; N, 10.91.
1
IR (film): 3401 (OH) and 1565 (C_N) cm−1; H NMR (CDCl3): δ 0.91 (t, J=7.5 Hz, 3H), 1.50–1.75
(m, 2H), 2.92 (s, 3H), 3.17–3.23 (m, 1H), 3.78 (dd, J=3.6, 11.3 Hz, 1H), 3.84 (dd, J=7.3, 11.3 Hz, 1H),
5.93 (s, 2H), 6.75 (d, J=8.0 Hz, 1H), 6.87 (dd, J=7.9, 1.6 Hz, 1H), 7.13 (d, J=1.6 Hz, 1H), 7.17 (s, 1H);
13C NMR (CDCl3): δ 11.06, 22.02, 37.04, 63.74, 69.68, 100.99, 104.58, 108.15, 120.26, 131.18, 131.79,
147.04, 148.10.
3.7. 2-Naphthaldehyde-N-[(1R)-1-(hydroxymethyl)propyl]-N-methylhydrazone (R)-(−)-10
Starting from 2-naphthaldehyde (1.30 g; 8.42 mmol), anhydrous MgSO4 (1.3 equiv.), TsOH (catalytic
amount) and the hydrazine (R)-(−)-2 (1.0 g; 9.26 mmol) in anhydrous CH2Cl2 (30 ml), the above
procedure (see Section 3.2) led to the hydrazone (R)-(−)-10 (1.40 g; 65.1%) as pale-pink flakes, mp
80–82°C and [α]D −21.2 (c 1.13, MeOH). Anal. calcd for C16H20N2O: C, 74.97; H, 7.86; N, 10.93.
1
Found: C, 74.94; H, 8.01; N, 10.89; H NMR (CDCl3): δ 0.94 (t, J=7.44 Hz, 3H), 1.50–1.70 (m, 2H),
2.88 (s, 1H), 3.01 (s, 3H), 3.20–3.30 (m, 1H), 3.80–3.95 (m, 2H), 7.39–7.46 (m, 3H), 7.70–7.90 (m, 5H);
13C NMR (CDCl3): δ 11.0, 22.19, 36.99, 63.84, 69.77, 122.71, 125.06, 125.49, 126.14, 127.72, 127.75,
128.17, 131.02, 132.88, 133.60, 134.65.

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3.8. 2-Methoxybenzenecarbaldehyde-N-[(1R)-1-(hydroxymethyl)propyl]-N-methylhydrazone
(R)-(−)-11
Starting from 2-methoxybenzaldehyde (0.74 g; 5.43 mmol), anhydrous MgSO4 (1.3 equiv.), TsOH
(catalytic amount) and the hydrazine (R)-(−)-2 (0.77 g; 6.52 mmol) in anhydrous CH2Cl2 (30 ml), the
above procedure (see Section 3.2) led to the hydrazone (R)-(−)-11 (1.10 g; 85.9%) as a colourless oil,
[α]D −33 (c 1.78, MeOH). Anal. calcd for C13H20N2O2: C, 66.07; H, 8.53; N, 11.85. Found: C, 66.62; H,
8.22; N, 11.23. IR (film): 3409 (OH) and 1596 (C_N) cm−1; 1H NMR (CDCl3): δ 0.93 (t, J=7.5 Hz, 3H),
1.50–1.80 (m, 2H), 2.96 (s, 3H), 3.15–3.32 (m, 1H), 3.26 (s, 1H), 3.85 (s, 3H), 3.85–3.89 (m, 2H), 6.87
(d, J=8.2 Hz, 1H), 6.93 (t, J=7.5 Hz, 1H), 7.19 (td, J=1.6, 7.8 Hz, 1H), 7.54 (s, 1H), 7.69 (dd, J=1.6, 7.7
Hz, 1H); 13C NMR (CDCl3): δ 11.44, 22.32, 37.52, 55.79, 64.31, 69.90, 111.26, 121.21, 125.57, 125.75,
127.65, 128.51, 156.31.
3.9. 4-Hydroxybenzenecarbaldehyde-N-[(1R)-1-(hydroxymethyl)propyl]-N-methylhydrazone
(R)-(−)-12
Starting from 4-hydroxybenzaldehyde (0.86 g; 7.06 mmol), anhydrous MgSO4 (1.3 equiv.), anhydrous
TsOH (catalytic amount) and the hydrazine (R)-(−)-2 (1.0 g; 8.47 mmol) in anhydrous CH2Cl2 (30 ml),
the above procedure (see Section 3.2) led to the hydrazone (R)-(−)-12 (1.0 g; 63.7%) as a colourless
viscous oil, [α]D −34.8 (c 1.35, MeOH). MS calcd for C12H18N2O2: M, 222.1368. Found: M, 222.1379.
1
IR (film): 3413 (OH) and 1608 (C_N) cm−1; H NMR (CDCl3): δ 0.95 (t, J=7.4 Hz, 3H), 1.50–1.70
(m, 2H), 2.93 (s, 3H), 3.05–3.20 (m, 1H), 3.90–4.05 (m, 2H), 4.45 (s, 1H), 6.80 (dt, J=2.5, 8.6 Hz, 2H),
7.19 (s, 1H), 7.23 (s, 1H), 7.36 (dt, J=2.4, 8.6 Hz, 2H); 13C NMR (CDCl3): δ 11.55, 21.74, 38.05, 64.60,
69.03, 116.32, 127.56, 128.55, 156.59.
3.10. General procedure for the addition of alkyl Grignard reagents to the hydrazones 5–12: prepara-
tions of the trisubstituted hydrazines 13a–h
An alkyl bromide (10 equiv.) in dry ether was added to magnesium chips (10 equiv.). After refluxing
for 3 h, the mixture was cooled to −10°C and treated dropwise by the requisite hydrazone (1 equiv.) in dry
ether. After stirring under reflux for 16 h, the mixture was cooled to −10°C and hydrolyzed with brine.
After filtration through Celite, the aqueous phase was decanted and extracted three times more with ether.
The combined ethereal extracts were evaporated under reduced pressure and the residue was treated with
aqueous 50% HCl solution. The mixture was washed three times with pentane, then made basic with 32%
aqueous ammonia and finally extracted three times with ether. The combined ether extracts were dried
(MgSO4) and evaporated under reduced pressure, thus leading to the required trisubstituted hydrazine
which was used directly in the next hydrogenolysis step, without further purification. The hydrazines
13a–h are unstable colourless oils.
3.11. (2R)-2-{1-Methyl-2-[(1R)-1-(3,4,5-trimethoxyphenyl)propyl]hydrazino}butan-1-ol (R,R)-(+)-13a
Starting from magnesium (0.369 g; 15.2 mmol), bromoethane (1.13 ml; 15.2 mmol) in ether (20 ml)
and the hydrazone (R)-(−)-5 (0.3 g; 1.01 mmol) in ether (5 ml), the above procedure (see Section 3.10)
led to the hydrazine 13a (0.240 g; 72.9%) as a colourless oil, [α]D +13.4 (c 1.9, MeOH) and d.e.=100%
(1H and 13C NMR). 1H NMR (CDCl3): δ 0.80 and 0.86 (2t, J=7.4, 7.5 Hz, 6H), 1.20–2.00 (m, 4H), 2.47
(s, 3H), 2.47–2.52 (m, 1H), 3.48 (dd, J=7.6, 10.9 Hz, 1H), 3.61 (dd, J=4.9, 8.9 Hz, 1H), 3.68 (dd, J=2.7,

P. Bataille et al. / Tetrahedron: Asymmetry 10 (1999) 1579–1588
1585
11.0 Hz, 1H), 3.84 (s, 3H), 3.86 (s, 6H), 6.50 (s, 2H); 13C NMR (CDCl3): δ 10.39, 10.67, 17.14, 27.78,
40.22, 55.68, 55.76, 60.50, 62.86, 64.39, 67.91, 104.21, 137.10, 138.53, 153.08.
3.12. (2R)-2-{2-[(1R)-1-(4-Methoxyphenyl)propyl]-1-methylhydrazino}butan-1-ol (R,R)-(+)-13b
Starting from magnesium (0.412 g; 16.9 mmol), bromoethane (1.26 ml; 16.9 mmol) in ether (20 ml)
and the hydrazone (R)-(−)-6 (0.40 g; 1.69 mmol) in ether (5 ml), the above procedure (see Section 3.10)
led to the hydrazine 13b (0.323 g; 71.9%) as a colourless oil, [α]D +4.4 (c 1.34, MeOH) and d.e.=100%
(1H and 13C NMR). 1H NMR (CDCl3): δ 0.76 and 0.85 (2t, J=7.4, 7.4 Hz, 6H), 1.20–1.90 (m, 4H), 2.45
(s, 3H), 2.45–2.50 (m, 1H), 3.45 (dd, J=7.6, 10.8 Hz, 1H), 3.61–3.67 (m, 2H), 3.79 (s, 3H), 6.86 (d, J=8.4
Hz, 2H), 7.19 (d, J=8.6 Hz, 2H); 13C NMR (CDCl3): δ 10.67, 11.01, 17.21, 27.84, 40.55, 55.21, 63.27,
63.74, 68.15, 113.67, 128.86, 134.66, 153.86.
3.13. (2R)-2-{2-[(1R)-1-(4-Fluorophenyl)propyl]-1-methylhydrazino}butan-1-ol (R,R)-(+)-13c
Starting from magnesium (0.542 g; 22.3 mmol), bromoethane (1.66 ml; 22.3 mmol) in ether (20 ml)
and the hydrazone (R)-(−)-7 (0.50 g; 2.23 mmol) in ether (5 ml), the above procedure (see Section 3.10)
led to the hydrazine 13c (0.358 g; 63.4%) as a colourless oil, [α]D +16.8 (c 1.42, MeOH) and d.e.=100%
1
(1H and 13C NMR). H NMR (CDCl3): δ 0.76 and 0.83 (2t, J=7.4, 7.5 Hz, 6H), 1.20–1.90 (m, 4H),
2.44 (s, 3H), 2.40–2.50 (m, 1H), 3.37 (dd, J=7.9, 10.9 Hz, 1H), 3.60 (dd, J=2.9, 10.9 Hz, 1H), 3.67 (dd,
J=4.9, 9.0 Hz, 1H), 6.97–7.02 (m, 2H), 7.22–7.27 (m, 2H); 13C NMR (CDCl3): δ 9.84, 10.16, 17.09,
27.25, 39.51, 62.37, 62.97, 67.60, 114.24, 114.45, 128.55, 128.62, 138.49, 162.06.
3.14. (2R)-2-{[(1R)-1-(4-Fluorophenyl)pentyl]-1-methylhydrazino}butan-1-ol (R,R)-(+)-13d
Starting from magnesium (0.434 g; 17.8 mmol), n-bromobutane (1.9 ml; 17.8 mmol) in ether (20 ml)
and the hydrazone (R)-(−)-7 (0.40 g; 1.78 mmol) in ether (5 ml), the above procedure (see Section 3.10)
led to the hydrazine 13d (0.400 g; 79.4%) as a colourless oil, [α]D +11.2 (c 1.12, MeOH) and d.e.=100%
(1H and 13C NMR). 1H NMR (CDCl3): δ 0.82 and 0.84 (2t, J=7.2, 7.5 Hz, 6H), 1.00–1.90 (m, 8H), 2.43
(s, 3H), 2.43–2.50 (m, 1H), 3.34 (dd, J=8.0, 11.0 Hz, 1H), 3.60 (dd, J=2.9, 11.0 Hz, 1H), 3.75 (dd, J=5.2,
8.9 Hz, 1H), 6.98–7.02 (m, 2H), 7.22–7.27 (m, 2H); 13C NMR (CDCl3): δ 10.78, 13.81, 17.96, 22.67,
28.36, 34.80, 40.15, 62.11, 63.10, 68.26, 114.92, 115.13, 129.16, 129.24, 138.82, 163.18.
3.15. (2R)-2-{1-Methyl-2-[(1R)-1-(4-methylphenyl)propyl]hydrazino}butan-1-ol (R,R)-(+)-13e
Starting from magnesium (0.221 g; 9.1 mmol), bromoethane (0.68 ml; 9.1 mmol) in ether (20 ml) and
the hydrazone (R)-(−)-8 (0.20 g; 0.9 mmol) in ether (5 ml), the above procedure (see Section 3.10) led
to the hydrazine 13e (0.117 g; 51.5%) as a colourless oil, [α]D +3.5 (c 1.0, MeOH) and d.e.=100% (1H
and 13C NMR). 1H NMR (CDCl3): δ 0.76 and 0.85 (2t, J=7.4, 7.5 Hz, 6H), 1.10–2.0 (m, 4H), 2.32 (s,
3H), 2.44 (s, 3H), 2.45–2.48 (m, 1H), 3.45 (dd, J=7.5, 11.0 Hz, 1H), 3.62–3.67 (m, 2H), 7.11–7.17 (m,
4H); 13C NMR (CDCl3): δ 10.55, 10.94, 16.95, 20.99, 27.71, 40.26, 63.05, 63.97, 68.03, 127.62, 128.88,
136.77, 139.46.

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3.16. (2R)-2-{1-Methyl-2-[(1R)-1-(4-methylphenyl)pentyl]hydrazino}butan-1-ol (R,R)-(−)-13f
Starting from magnesium (0.442 g; 20 mmol), n-bromobutane (1.95 ml; 20 mmol) in ether (20 ml) and
the hydrazone (R)-(−)-8 (0.40 g; 1.82 mmol) in ether (5 ml), the above procedure (see Section 3.10) led
to the hydrazine 13f (0.422 g; 83.4%) as a colourless oil, [α]D −4.12 (c 1.07, MeOH) and d.e.=100% (1H
and 13C NMR). 1H NMR (CDCl3): δ 0.83 and 0.85 (2t, J=7.3, 7.5 Hz, 6H), 1.00–1.90 (m, 10H), 2.33 (s,
3H), 2.43 (s, 3H), 2.43–2.50 (m, 1H), 3.43 (dd, J=7.6, 10.9 Hz, 1H), 3.63–3.67 (m, 1H), 3.71 (dd, J=4.8,
9.1 Hz, 1H), 7.12 (d, J=8.0 Hz, 2H), 7.16 (d, J=8.1 Hz, 2H); 13C NMR (CDCl3): δ 11.03, 14.02, 18.04,
20.27, 21.97, 27.69, 33.91, 39.52, 61.86, 62.41, 67.35, 126.85, 128.18, 136.91, 139.99.
3.17. (2R)-2-{2-[(1R)-1-(1,3-Benzodioxol-5-yl)propyl]-1-methylhydrazino}butan-1-ol (R,R)-(+)-13g
Starting from magnesium (0.390 g; 16 mmol), bromoethane (1.19 ml; 16 mmol) in ether (20 ml) and
the hydrazone (R)-(−)-9 (0.40 g; 1.6 mmol) in ether (5 ml), the above procedure (see Section 3.10) led to
the hydrazine 13g (0.231 g; 51.6%) as a colourless oil, [α]D +15.0 (c 1.16, MeOH) and d.e.=100% (1H
and 13C NMR). 1H NMR (CDCl3): δ 0.77 and 0.86 (2t, J=7.4, 7.5 Hz, 6H), 1.20–1.90 (m, 4H), 2.44 (s,
3H), 2.46–2.49 (m, 1H), 3.43 (dd, J=7.8, 10.9 Hz, 1H), 3.60 (dd, J=4.8, 9.3 Hz, 1H), 3.64 (dd, J=2.9,
11.0 Hz, 1H), 5.94 (s, 2H), 6.70–6.79 (m, 3H); 13C NMR (CDCl3): δ 11.16, 11.59, 17.79, 28.46, 40.81,
63.55, 64.72, 68.80, 101.42, 108.31, 108.43, 121.77, 136.68, 146.69, 147.66.
3.18. (2R)-2-{1-Methyl-2-[(1R)-1-(2-naphthyl)propyl]hydrazino}butan-1-ol (R,R)-(−)-13h
Starting from magnesium (0.296 g; 12.2 mmol), bromoethane (0.91 ml; 12.2 mmol) in ether (20 ml)
and the hydrazone (R)-(−)-10 (0.30 g; 1.21 mmol) in ether (5 ml), the above procedure (see Section 3.10)
led to the hydrazine 13h (0.217 g; 65.5%) as a colourless oil, [α]D −2.1 (c 1.17, MeOH) and d.e.=100%
1
(1H and 13C NMR). H NMR (CDCl3): δ 0.79 and 0.83 (2t, J=7.4, 7.5 Hz, 6H), 1.20–2.10 (m, 4H),
2.47 (s, 3H), 2.47–2.55 (m, 1H), 3.44 (dd, J=7.6, 10.9 Hz, 1H), 3.64 (dd, J=2.8, 10.9 Hz, 1H), 3.86 (dd,
J=4.8, 9.2 Hz, 1H), 7.42–7.48 (m, 3H), 7.69 (s, 1H), 7.81–7.83 (m, 3H); 13C NMR (CDCl3): δ 9.66,
9.96, 16.34, 26.80, 39.55, 62.13, 63.63, 67.27, 124.42, 124.57, 124.92, 126.00, 126.63, 126.70, 127.09,
132.98, 133.28, 140.11.
3.19. General procedure for the hydrogenolysis of the hydrazines 13: preparation of the (R)-1-arylalkan-
amines 14
The trisubstituted hydrazine (13a–h) in ethanol was hydrogenolyzed in the presence of conc. HCl and
10% Pd–C under hydrogen (6 bar) at 110–120°C for 5 h. After filtration and evaporation, the residue was
treated with 32% aqueous ammonia until basic, and the mixture was extracted three times with ether. The
ethereal solutions were pooled, dried (MgSO4), filtered and evaporated, thus affording the crude amine
14 which was chromatographed over silica gel in the presence of triethylamine to prevent racemization
(eluent: cyclohexane:ether, 9:1, and elution gradient).
3.20. (R)-1-(3,4,5-Trimethoxyphenyl)propan-1-amine (R)-(+)-14a
Starting from the hydrazine (R,R)-(+)-13a (0.250 g; 0.77 mmol) in ethanol (15 ml), conc. HCl (0.16
ml) and 10% Pd–C (0.060 g), the above procedure (see Section 3.19) led to the pure amine (R)-(+)-14a
(0.060 g; 34.9%), [α]D +3.0 (c 1.85, EtOH) and e.e.=91.5% (chiral GPC). Lit.5 (racemic form); 1H NMR

P. Bataille et al. / Tetrahedron: Asymmetry 10 (1999) 1579–1588
1587
(CDCl3): δ 0.89 (t, J=7.4 Hz, 3H), 1.67 (quint., J=7.2 Hz, 2H), 1.85 (m, 2H), 3.76 (t, J=6.8 Hz, 1H),
3.84 (s, 3H), 3.87 (s, 6H), 6.55 (s, 2H).
3.21. (R)-1-(4-Methoxyphenyl)propan-1-amine (R)-(+)-14b
Starting from the hydrazine (R,R)-(+)-13b (0.256 g; 0.96 mmol) in ethanol (18 ml), conc. HCl (0.21
ml) and 10% Pd–C (0.074 g), the above procedure (see Section 3.19) led to the pure amine (R)-(+)-14b
(0.056 g; 35.2%), [α]D +13 (c 0.8, EtOH), which could not be resolved by chiral GPC. Lit.6 (racemic
form); 1H NMR (CDCl3): δ 0.85 (t, J=7.4 Hz, 3H), 1.51 (s, 2H), 1.60–1.72 (m, 2H), 3.76 (t, J=6.8 Hz,
1H), 3.80 (s, 3H), 6.55 (d, J=8.2 Hz, 2H), 7.22 (d, J=8.5 Hz, 2H).
3.22. (R)-1-(4-Fluorophenyl)propan-1-amine (R)-(+)-14c
Starting from the hydrazine (R,R)-(+)-13c (0.300 g, 1.18 mmol) in ethanol (24 ml), conc. HCl (0.25
ml) and 10% Pd–C (0.095 g), the above procedure (see Section 3.19) led to the pure amine (R)-(+)-14c
(0.072 g; 40.2%), [α]D +14 (c 0.85, EtOH), which could not be resolved by chiral GPC. Lit.7 (racemic
form); 1H NMR (CDCl3): δ 0.85 (t, J=7.4 Hz, 3H), 1.60–1.70 (m, 4H), 3.80 (t, J=6.8 Hz, 1H), 6.90–7.00
(m, 2H), 7.24–7.30 (m, 2H).
3.23. (R)-1-(4-Fluorophenyl)pentan-1-amine (R)-(+)-14d
Starting from the hydrazine (R,R)-(+)-13d (0.295 g; 1.05 mmol) in ethanol (20 ml), conc. HCl (0.22
ml) and 10% Pd–C (0.081 g), the above procedure (see Section 3.19) led to the pure amine (R)-(+)-
14d (0.089 g; 47.1%), [α]D +13.3 (c 1.05, EtOH) and e.e.=90% (chiral GPC). Lit.8 (racemic form); 1H
NMR (CDCl3): δ 0.86 (t, J=7.0 Hz, 3H), 1.00–1.70 (m, 8H), 3.86 (t, J=6.9 Hz, 1H), 6.98–7.02 (m, 2H),
7.25–7.29 (m, 2H).
3.24. (R)-1-(4-Methylphenyl)propan-1-amine (R)-(+)-14e
Starting from the hydrazine (R,R)-(+)-13e (0.190 g; 0.76 mmol) in ethanol (16 ml), conc. HCl (0.16
ml) and 10% Pd–C (0.063 g), the above procedure (see Section 3.19) led to the pure amine (R)-(+)-14e
(0.052 g; 46%), [α]D +9.5 (c 1.0, EtOH), which could not be resolved by chiral GPC. MS calcd for
1
(C10H14N_M–H)+: 148.126. Found: 148.113; H NMR (CDCl3): δ 0.85 (t, J=7.4 Hz, 3H), 1.60–1.70
(m, 2H), 1.80–1.90 (s, 2H), 2.33 (s, 3H), 3.76 (t, J=6.8 Hz, 1H), 7.13 (d, J=7.9 Hz, 2H), 7.19 (d, J=8.1
Hz, 2H); 13C NMR (CDCl3): δ 11.00, 21.04, 32.35, 57.53, 126.30, 129.07, 136.39, 143.41.
3.25. (R)-1-(4-Methylphenyl)pentan-1-amine (R)-(+)-14f
Starting from the hydrazine (R,R)-(−)-13f (0.314 g; 1.13 mmol) in ethanol (22 ml), conc. HCl (0.24
ml) and 10% Pd–C (0.088 g), the above procedure (see Section 3.19) led to the pure amine (R)-(+)-
14f (0.080 g; 40%), [α]D +2.9 (c 1.9, EtOH) and e.e.=93% (chiral GPC). MS calcd for C12H19N: M,
1
177.1517. Found: M, 177.1517; H NMR (CDCl3): δ 0.86 (t, J=7.1 Hz, 3H), 1.00–1.80 (m, 8H), 2.33
(s, 3H), 3.83 (t, J=6.9 Hz, 1H), 7.13 (d, J=8.0 Hz, 2H), 7.19 (d, J=8.1 Hz, 2H); 13C NMR (CDCl3): δ
13.59, 20.62, 22.26, 28.39, 39.95, 55.57, 125.79, 128.66, 136.36, 143.89.

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