Diastereoselective LiAlH4 reduction of chiral ketone hydrazones derived from (R)-(-)-2-aminobutan-1-ol

Article abstract of DOI:10.1016/S0957-4166(00)00044-6

Various chiral N,N-dialkylhydrazines were prepared in four to five steps from (R)-(-)-2-aminobutan-1-ol 6. They reacted with various prochiral ketones, thus giving the corresponding hydrazones. Reduction of the latter by means of LiAlH₄ afforded N,N,N'-trisubstituted hydrazines whose d.e.s were in the range 43-100%. Interestingly, LiAlH₄ reduction of the four N-trifluoroethylhydrazones 34 and 38-40 yielded the hydrazines 46 and 48-50, respectively, and with d.e.s=100% by ¹H and ¹³C NMR. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00044-6

Tetrahedron: Asymmetry 11 (2000) 1165±1181
Diastereoselective LiAlH4 reduction of chiral ketone
hydrazones derived from (R)-(±)-2-aminobutan-1-ol
Patricia Bataille, Michel Paterne and Eric Brown*
Á Â
Laboratoire de Synthese Organique (ESA-CNRS 6011), Faculte des Sciences, Avenue Olivier Messiaen,
F-72085 Le Mans Cedex 9, France
Received 22 December 1999; accepted 26 January 2000
Abstract
Various chiral N,N-dialkylhydrazines were prepared in four to ®ve steps from (R)-(±)-2-aminobutan-1-ol
6. They reacted with various prochiral ketones, thus giving the corresponding hydrazones. Reduction of
the latter by means of LiAlH4 a€orded N,N,N0-trisubstituted hydrazines whose d.e.s were in the range 43±
100%. Interestingly, LiAlH4 reduction of the four N-tri¯uoroethylhydrazones 34 and 38±40 yielded the
1
hydrazines 46 and 48±50, respectively, and with d.e.s=100% by H and 13C NMR. # 2000 Elsevier
Science Ltd. All rights reserved.
1. Introduction
As far as we know, only a few groups have examined the diastereoselective LiAlH4 reduction of
hydrazones derived from prochiral ketones and chiral hydrazines. Thus, starting from the SAMP
reagent 1, Enders1 prepared the ketone hydrazones 2 (Scheme 1). Reduction of the latter with
LiAlH4 or catecholborane yielded the corresponding trisubstituted hydrazines 3 whose d.e.s were
in the range 50±94%. LiAlH4 reduction a€orded the (S,S0)-hydrazine 3 as the major diastereomer,
whereas catecholborane led mainly to the (S,R0)-compounds. On the other hand, Takahashi et
al.2 described the condensation of acetophenone with N-aminoephedrine, which gave the hydra-
zone 4 as an 82:18 mixture of the E:Z isomers. LiAlH4 reduction of 4 furnished the trisubstituted
hydrazine 5 with a d.e.=30%.
The above authors remarked that the d.e.s of the ®nal hydrazines 3 and 5 were dependent upon
the proportions of E/Z geometrical isomers in the starting hydrazones 2 and 4, respectively. The
catalytic hydrogenation of chiral hydrazones was studied by Kiyooka et al.3 They found that the
asymmetric hydrogenolysis of the chiral hydrazones deriving from a few chiral amines and ethyl
pyruvate gave optically active alanine with e.e.s in the range 0.9±46.5%.
* Corresponding author.
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00044-6

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P. Bataille et al. / Tetrahedron: Asymmetry 11 (2000) 1165±1181
Scheme 1.
For some time now, we have used simple derivatives of 2-aminobutan-1-ol 6 as new chiral
auxiliaries in asymmetric synthesis.4,5 Indeed, racemic 6 is a low-molecular-weight compound
which can be easily resolved on the industrial scale. In this paper we describe the LiAlH4-medi-
ated asymmetric reduction of various hydrazones derived from the aminoalcohol (R)-( )-6
(Scheme 2).
Scheme 2.

P. Bataille et al. / Tetrahedron: Asymmetry 11 (2000) 1165±1181
1167
2. Results and discussion
We ®rst synthesized the hydrazone (R)-( )-8 in ca. 88% yield from acetophenone and 4-amino-
3-ethylmorpholine (R)-( )-7.4 However, all attempts with LiAlH4 failed to reduce the double
bond of (R)-( )-8. The acetophenone hydrazone (R)-( )-10 was next obtained from the N,N-
disubstituted hydrazine (R)-( )-9,4 as a 96:4 mixture of the E:Z geometrical isomers and in 62%
yield. The reduction of the hydrazone (R)-( )-10 using 15 molar equivalents of LiAlH4 in ether at
room temperature led to the trisubstituted hydrazine 11 in ca. 79% yield and with a d.e.=32%
(from 13C NMR).
We next extended our study to other hydrazines derived from aminobutanol (R)-( )-6, in order
to assess the in¯uence of the second N-substituent of the hydrazine on the diastereoselectivity of
the chemical reduction of the corresponding hydrazones made from various aromatic and
aliphatic ketones. The N-methylamine (R)-( )-14 was obtained by LiAlH4 reduction of the form-
amide (R)-(+)-13 resulting from the reaction of O-methylaminobutanol (R)-( )-126 with ethyl
formate. Treatment of the secondary amine (R)-( )-14 with aqueous nitrous acid smoothly
a€orded the N-nitrosoamine (R)-(+)-15 which was in turn transformed into the hydrazine (R)-
( )-16 upon reduction with LiAlH4 in ether. The secondary amine (R)-( )-17 was obtained by
N-alkylation of (R)-( )-12 with 1-bromopropane. N-Nitrosation of 17 gave the N-nitrosoamine
(R)-(+)-18 whose LiAlH4 reduction yielded the hydrazine (R)-(+)-19. N-Alkylation of amino-
butanol (R)-( )-6 by 2-bromoethanol led to the known aminodiol (R)-( )-20.7 N,O-Dimethyl-
ation of the latter was followed by nitrosation, thus yielding the intermediate (R)-( )-21 which was
next smoothly reduced with LiAlH4 into the hydrazine (R)-(+)-22. The N-tri¯uoroethylamine
(R)-( )-24 was obtained by LiAlH4 reduction of the tri¯uoroacetamide (R)-(+)-23 resulting from
the N-acylation of the amine 12 with tri¯uoroacetic anhydride. Nitrosation of the secondary
amine 24, followed by LiAlH4 reduction of the resulting intermediate (R)-(+)-25, a€orded the
N,N-disubstituted hydrazine (R)-(+)-26.
The hydrazines (R)-( )-16, (R)-(+)-19, (R)-(+)-22 and (R)-(+)-26 were treated with various
prochiral phenones and aliphatic ketones to give the 15 hydrazones 27±41 reported in Table 1.
The hydrazones 35±37 were obtained as mixtures of E/Z geometrical isomers, the former pre-
dominating (entries 9±11). The other 12 hydrazones were isolated as single E-isomers. LiAlH4
reduction of the CˆN bond of the hydrazones 27±41 was carried out next. The hydrazones 27,
28, 30, 33 and 35 gave the expected hydrazines 42, 43, 44, 45 and 47 with d.e.s in the range 43±
87% (entries 1, 2, 4, 7 and 9). Reduction of the hydrazones 29, 31 and 32 gave intractable mix-
tures of compounds (entries 3, 5 and 6). The a-tetralone hydrazone 41 could not be reduced
(entry 15). We did not e€ect the reduction of the E/Z hydrazones 36 and 37 (entries 10 and 11),
since they were not expected to give better results than the E/Z 35 (entry 9).
The hydrazones 34 and 38±40, deriving from the O-methyl-N-tri¯uoroethylhydrazine (R)-(+)-
26 and various phenones, were reduced with a ®fteen-fold molar excess of LiAlH4 at room tem-
perature, and a€orded the corresponding hydrazines 46 and 48±50 as single diastereomers
1
(d.e.s=100%). The d.e.s of these four hydrazines were determined from their H and 13C NMR
spectra, and their (R,S0) absolute con®guration was ascribed on the basis of the following tenta-
tive mechanism, which is analogous to that which we con®rmed in the case of the nucleophilic
addition of Grignard reagents to the CˆN bond of other similar chiral hydrazones4,5 (Scheme 3).
The present study does show that the N-tri¯uoroethyl group plays an important part in the
diastereoselectivity of the LiAlH4 reduction of the CˆN bond from the deriving chiral hydra-
zones. The reason for such a selectivity is not clear. Besides, and contrary to previous ®ndings, it

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P. Bataille et al. / Tetrahedron: Asymmetry 11 (2000) 1165±1181
Table 1
LiAlH4 reductions of the chiral hydrazones 27±41
appears that in the present case the OH group of the chiral auxiliary (R)-( )-6 must be protected
as a methyl ether in order to achieve diastereoselective LiAlH4 reduction of the corresponding
hydrazones. As far as we know, the formation of the four hydrazines 46 and 48±50 represents the
only reported examples of a totally diastereoselective reduction of the CˆN bond of chiral
hydrazones.

P. Bataille et al. / Tetrahedron: Asymmetry 11 (2000) 1165±1181
1169
Scheme 3.
3. Experimental
3.1. General
1
IR spectra were recorded with Nicolet 5DX and Genesis (Mattson) spectrophotometers. H
NMR (400 MHz) and 13C NMR (100 MHz) spectra were recorded with a Bruker AC 400 spec-
trometer, using Me4Si as an internal standard. HR mass spectra were recorded at the CRMPO
(Universite de Rennes I) using a Varian Matt 311 spectrometer. Melting points were determined
with a Reichert microscope. Optical rotations were measured at 26ꢀC with a Perkin±Elmer 343
micropolarimeter. Elemental analyses were carried out at the ICSN (CNRS, Gif-sur-Yvette).
Chiral GPC experiments were carried out with a Hewlett±Packard HP 6890 chromatograph
equipped with a Restek b dex column. (R)-( )-2-Aminobutan-1-ol, [ꢀ]D 10.0 (neat), was kindly
provided by SmithKline Beecham Laboratories (Mayenne).
3.2. General procedure for the preparation of ketone hydrazones
A solution of the hydrazine, the requisite ketone (1.05±1.50 equiv.) and TsOH (catalytic
amount) in dry toluene was re¯uxed under stirring for 12±20 h in a ¯ask equipped with a Dean±
Stark azeotropic water separator. After this the toluene was evaporated under reduced pressure
and the residue was, in certain cases, puri®ed by column chromatography on silica gel.
3.3. (3R)-3-Ethyl-N-[(E)-1-phenylethylidene]-1,4-oxazinan-4-amine (R)-( )-8
Starting from (R)-( )-4-amino-3-ethylmorpholine 7 (0.4 g, 3 mmol), acetophenone (0.24 ml, 2
mmol) and TsOH (catalytic amount) in dry toluene (30 ml), the above procedure led to hydra-
zone (R)-( )-8 as a colourless oil after chromatography (eluent: cyclohexane:ether, 95:5, then
elution gradient) (410 mg, 88.4%), [ꢀ]D 533 (c 1.2, MeOH). MS calcd for C14H20N2O: M,
1
232.1575. Found: 232.1567. IR (®lm): 1610 (CˆN) cm . 1H NMR (CDCl3) ꢁ: 0.85 (t, J=7.5 Hz,
3H), 1.20±1.70 (m, 2H), 2.38 (s, 3H), 2.63 (dt, J=2.5 and 11.3 Hz, 1H), 2.70 (td, J=3.4 and 11.2
Hz, 1H), 2.90±3.00 (m, 1H), 3.46 (t, J=10.8 Hz, 1H), 3.78 (td, J=2.6 and 11.1 Hz, 1H), 3.86±3.89
(m, 1H), 3.94 (dd, J=3.2 and 11.4 Hz, 1H), 7.37±7.78 (m, 5H). 13C NMR (CDCl3) ꢁ: 9.60, 15.45,
23.08, 53.45, 64.84, 66.26, 70.12, 126.44, 128.27, 129.47, 138.90, 164.66.
3.4. (R)-( )-2-[N0-(1-Phenylethylidene)-N-(2,2,2-tri¯uoroethyl)hydrazino]butan-1-ol (R)-( )-10
Starting from (R)-( )-2-[1-(2,2,2-tri¯uoroethyl)hydrazino]butan-1-ol 9 (3 g, 16 mmol), aceto-
phenone (1.69 ml, 14.4 mmol) and p-TsOH (catalytic amount) in dry toluene (25 ml), the above

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P. Bataille et al. / Tetrahedron: Asymmetry 11 (2000) 1165±1181
procedure led to hydrazone (R)-( )-10 as a yellow oil after chromatography (eluent: cyclo-
hexane:ether, 9:1, then elution gradient) (2.60 g, 62.2%), [ꢀ]D 16.9 (c 0.9, MeOH). Anal. calcd
for C14H19F3N2O: C, 58.32; H, 6.64; N, 9.72. Found: C, 58.44; H, 6.68; N, 9.57. IR (®lm): 3405
1
1
(OH) and 1614 (CˆN) cm . H NMR (CDCl3) ꢁ: 1.03 (t, J=7.4 Hz, 3H), 1.39±1.62 (m, 2H),
2.40 (s, 3H), 2.80±3.00 (m, 1H), 3.30±3.90 (m, 4H), 7.20±7.70 (m, 5H). 13C NMR (CDCl3) ꢁ:
11.40, 16.08, 21.84, 53.49, 63.45, 69.58, 123.92, 126.76, 128.07, 130.35, 137.75, 169.86. 19F NMR
ꢁ: 70.3 (96.3% of the E-isomer) and 70.9 (3.7% of the Z-isomer).
3.5. 2-[2-(1-Phenylethyl)-1-(2,2,2-tri¯uoroethyl)hydrazino]butan-1-ol 11
A suspension of LiAlH4 (394 mg, 10.4 mmol) in dry ether (50 ml) was cooled to 10ꢀC and
treated dropwise by the hydrazone (R)-( )-10 (200 mg, 0.69 mmol) in dry ether (10 ml). After
stirring at room temperature for 15 h, the mixture was quenched at 10ꢀC by methanol and
water (2 ml). After 30 min at room temperature, the suspension was ®ltered and the ®ltrate was
evaporated under reduced pressure. The aqueous residue was extracted three times with ether.
The organic extracts were pooled, dried (MgSO4) and evaporated under reduced pressure, thus
leading to the required hydrazine 11 as a colourless oil, which was used without further puri®ca-
tion (158 mg, 78.6%), d.e.=31% determined by 13C NMR. MS calcd for C14H21F3N2O: M,
1
1
290.1605. Found: 290.1592. IR (®lm): 3409 (OH) and 3033 (CHˆ) cm . H NMR (CDCl3) ꢁ
major diastereomer: 0.90 (t, J=7.4 Hz, 3H), 1.25±1.52 (m, 2H), 1.31 (d, J=6.6 Hz, 3H), 2.56±2.64
(m, 1H), 3.32±3.41 (m, 2H), 3.58 (dd, J=7.6 and 11.2 Hz, 1H), 3.72 (dd, J=3.1 and 11.3 Hz, 1H),
3.91 (q, J=6.5 Hz, 1H), 7.29±7.32 (m, 5H); minor diastereomer: 0.84 (t, J=7.4 Hz, 3H), 1.25±
1.52 (m, 2H), 1.39 (d, J=6.4 Hz, 3H), 2.65±2.70 (m, 1H), 3.15±3.42 (m, 4H), 3.91 (q, J=6.3 Hz,
1H), 7.23±7.28 (m, 5H). 13C NMR (CDCl3) ꢁ major diastereomer: 11.14, 19.41, 21.03, 55.90,
57.32, 62.86, 66.98, 124.42, 126.63, 127.37, 128.31, 143.68; minor diastereomer: 11.06, 17.44,
20.67, 55.90, 57.51, 62.42, 66.98, 124.42, 126.63, 127.37, 128.31, 143.28.
3.6. (2R)-2-Formamido-1-methoxybutane (R)-(+)-13
A mixture of (2R)-1-methoxybutan-2-amine (R)-( )-126 (13.6 g, 132 mmol) and ethyl formate
(50 ml, 620 mmol) was stirred under re¯ux for 18 h, then the excess ester was evaporated under
reduced pressure. Vacuum distillation of the residue gave the formamide (R)-(+)-13 as a colourless
liquid (12 g, 69.4%): b.p.20=120±124ꢀC and [ꢀ]D +28.3 (c 2.06, MeOH). MS calcd for C6H13NO2:
1
1
M, 131.0942. Found: 131.0946. IR (®lm): 1681 (CˆO) cm . H NMR (CDCl3) (200 MHz) ꢁ:
0.90±1.00 (m, 3H), 1.40±1.70 (m, 2H), 3.35 (s, 3H), 3.30±3.50 (m, 2H), 3.90±4.20 (m, 1H), 5.80±6.00
(s, 1H), 8.19 (s, 1H). 13C NMR (200 MHz) (CDCl3) ꢁ: 10.43, 24.67, 49.16, 59.07, 73.55, 160.98.
3.7. (2R)-1-Methoxy-N-methylbutan-2-amine (R)-( )-14
A suspension of LiAlH4 (9.28 g, 242 mmol) in dry ether (150 ml) was cooled to 0ꢀC and treated
dropwise by the formamide (R)-(+)-13 (7 g, 53.4 mmol) in dry ether (150 ml). After stirring
under re¯ux for 8 h, the mixture was quenched at 20ꢀC by methanol (33 ml), followed by water
(47 ml) at 15ꢀC. After 30 min at room temperature, the suspension was ®ltered and the solids
were extracted several times with ether. The ®ltrate was dried (MgSO4) and distilled under
atmospheric pressure, thus giving amine (R)-( )-14 as a colourless liquid (3.25 g, 52%),
b.p.=127ꢀC and [ꢀ]D 27 (c 1.0, MeOH). MS calcd for C6H15NO [M OCH3] : M, 86.0969.
+
.

P. Bataille et al. / Tetrahedron: Asymmetry 11 (2000) 1165±1181
1171
Found: 86.0971. 1H NMR (CDCl3) (200 MHz) ꢁ: 0.90 (t, J=7.5 Hz, 3H), 1.20±1.50 (m, 2H), 2.30
(s, 1H), 2.42 (s, 3H), 2.45±2.65 (m, 1H), 3.21±3.45 (m, 2H), 3.36 (s, 3H). 13C NMR (200 MHz)
(CDCl3) ꢁ: 10.49, 23.98, 34.26, 59.19, 60.76, 74.80.
3.8. (2R)-1-Methoxy-N-methyl-N-nitrosobutan-2-amine (R)-(+)-15
Sodium nitrite (5.6 g, 82 mmol) in water (10 ml) was added dropwise at 0ꢀC to a mixture of the
amine (R)-( )-14 (3.2 g, 27 mmol), concentrated hydrochloric acid (4 ml) and crushed ice (15 g).
After stirring for 17 h at room temperature, the mixture was extracted with dichloromethane (20
ml), the aqueous phase was saturated with NaCl then extracted three times more with dichloro-
methane (3Â20 ml). The combined organic extracts were dried (MgSO4), ®ltered and evaporated
under reduced pressure, thus giving the nitrosoamine (R)-(+)-15 as a yellow oil (3.4 g, 86.3%),
[ꢀ]D +16.9 (c 1.3, MeOH), which was used in the next step without further puri®cation. MS calcd
1
for C6H14N2O2: M, 146.1055. Found: 146.1045. IR (®lm): 1436 (NO) cm . 1H NMR (CDCl3) ꢁ:
0.95 (t, J=7.4 Hz, 3H), 1.60±1.80 (m, 2H), 3.00 (s, 3H), 3.36 (s, 3H), 3.62 (dd, J=4.0 and 10.4 Hz,
1H), 3.68 (dd, J=7.8 and 10.4 Hz, 1H), 4.60±4.70 (m, 1H). 13C NMR (CDCl3) ꢁ: 9.48, 21.23,
27.96, 57.91, 63.56, 72.05.
3.9. 1-[(1R)-1-(Methoxymethyl)propyl]-1-methylhydrazine (R)-( )-16
A suspension of LiAlH4 (0.91 g, 23.9 mmol) in dry ether (80 ml) was cooled to 0ꢀC and treated
dropwise with the N-nitrosoamine (R)-(+)-15 (1.0 g, 6.8 mmol) in dry ether (20 ml). After stirring
overnight at room temperature, the excess hydride was destroyed by addition of methanol (3 ml)
and water (5 ml). The suspension was ®ltered and the solids were extracted several times with
dichloromethane. The combined organic extracts were dried (MgSO4) and evaporated under
reduced pressure, thus a€ording the hydrazine (R)-( )-16 (0.9 g, 99.5%), [ꢀ]D 6.0 (c 1.1,
1
MeOH), which was used in the next step without further puri®cation. H NMR (200 MHz)
(CDCl3) ꢁ: 0.95 (t, J=7.4 Hz, 3H), 1.20±1.70 (m, 2H), 2.56 (s, 3H), 2.50±2.60 (m, 1H), 2.90±3.20
(m, 2H), 3.36 (s, 3H), 3.40±3.60 (m, 2H). 13C NMR (200 MHz) (CDCl3) ꢁ: 11.69, 20.58, 46.13,
59.29, 67.79, 73.00.
3.10. (2R)-1-Methoxy-N-propylbutan-2-amine (R)-( )-17
1-Bromopropane (4.4 ml, 48.5 mmol) in THF (25 ml) was added to (2R)-1-methoxybutan-2-
amine (R)-( )-126 (5 g, 48.5 mmol) in THF (25 ml). After heating under re¯ux for 18 h, solid
Na2CO3 (5.14 g, 48.5 mmol) was added. After re¯uxing for a further 18 h, the mixture was
®ltered and the ®ltrate was distilled under an atmospheric pressure, thus leading to amine (R)-
( )-17 as a colourless oil (3 g, 42.8%), b.p.=130±150ꢀC, [ꢀ]D 14.8 (c 1.1, MeOH). MS calcd for
1
C8H19NO: M, 145.1466. Found: 145.1469. H NMR (200 MHz) (CDCl3) ꢁ: 0.90 (t, J=7.4 Hz,
3H), 0.92 (t, J=7.2 Hz, 3H), 1.20±1.50 (m, 4H), 2.00±2.80 (m, 4H), 3.35 (s, 3H), 3.10±3.60 (m,
2H). 13C NMR (200 MHz) (CDCl3) ꢁ: 10.60, 12.21, 23.94, 24.58, 49.76, 59.11, 75.28.
3.11. (2R)-1-Methoxy-N-nitroso-N-propylbutan-2-amine (R)-(+)-18
Sodium nitrite (2.85 g, 41.4 mmol) in water (10 ml) was added dropwise at room temperature
to a mixture of amine (R)-( )-17 (2 g, 13.8 mmol), concentrated hydrochloric acid (2 ml) and

1172
P. Bataille et al. / Tetrahedron: Asymmetry 11 (2000) 1165±1181
crushed ice (8 g). After stirring for 17 h at room temperature, the mixture was extracted with
dichloromethane (20 ml), the aqueous phase was saturated with NaCl then extracted several times
with dichloromethane. The combined organic extracts were dried (MgSO4), ®ltered and evapo-
rated under reduced pressure. The crude product was puri®ed by column chromatography on
silica gel (eluent: cyclohexane:ether, 9:1, then elution gradient), thus giving the nitrosoamine (R)-
(+)-18 as a yellow oil (1.4 g, 58.4%), [ꢀ]D +0.4 (c 1.1, MeOH). MS calcd for C8H18N2O2: M,
1
1
174.1368. Found: 174.1365. IR (®lm): 1450 (NO) cm . H NMR (CDCl3) ꢁ major conformer
(79%): 0.90 (t, J=7.4 Hz, 3H), 0.94 (t, J=7.5 Hz, 3H), 1.30±1.90 (m, 4H), 3.34 (s, 3H), 3.40±3.70
(m, 4H), 4.35±4.45 (m, 1H); minor conformer (21%): 0.85 (t, J=7.4 Hz, 3H), 1.00 (t, J=7.4 Hz,
3H), 1.30±1.90 (m, 4H), 3.28 (s, 3H), 3.40±3.70 (m, 4H), 4.80±4.95 (m, 1H). 13C NMR (CDCl3) ꢁ
major conformer: 10.51, 11.60, 19.65, 23.10, 45.64, 58.74, 64.74, 73.81; minor conformer: 10.75,
11.27, 21.36, 22.98, 51.52, 54.26, 58.59, 71.32.
3.12. 1-[(1R)-1-(Methoxymethyl)propyl]-1-propylhydrazine (R)-(+)-19
A suspension of LiAlH4 (760 mg, 20.1 mmol) in dry ether (80 ml) was cooled to 0ꢀC and
treated dropwise with the N-nitrosoamine (R)-(+)-18 (1 g, 5.75 mmol) in dry ether (20 ml). After
stirring at room temperature for 17 h, the excess hydride was destroyed by addition of methanol
and water (4 ml). After 30 min at room temperature, the suspension was ®ltered and the solids
were extracted several times with dichloromethane. The combined organic extracts were dried
(MgSO4) and evaporated under reduced pressure, thus leading to the hydrazine (R)-(+)-19 (900
mg, 97.8%), [ꢀ]D +3 (c 3, MeOH), which was used in the next step without further puri®cation.
1H NMR (200 MHz) (CDCl3) ꢁ: 0.91 (t, J=7.3 Hz, 3H), 0.95 (t, J=7.2 Hz, 3H), 1.20±1.60
(m, 4H), 2.50±2.80 (m, 3H), 3.34 (s, 3H), 3.40 (dd, J=4.0 and 10.0 Hz, 1H), 3.59 (dd, J=7.0 and
10.0 Hz, 1H). 13C NMR (200 MHz) (CDCl3) ꢁ: 11.87, 12.01, 21.22, 21.49, 59.24, 60.09, 73.42,
66.62.
3.13. (2R)-1-Methoxy-N-(2-methoxyethyl)-N-nitrosobutan-2-amine (R)-( )-21
A suspension of sodium hydride (60% in oil, 2.8 g, 70 mmol) (previously washed with pentane)
in dry ether (50 ml) was treated dropwise by (2R)-2-[(2-hydroxyethyl)amino]butan-1-ol (R)-( )-
207 (4.2 g, 32 mmol) in dry ether (20 ml). After stirring under re¯ux for 15 h, a solution of methyl
iodide (4.32 ml, 64 mmol) in dry ether (20 ml) was added. The mixture was stirred under re¯ux
for a further 5 h then quenched at 10ꢀC by brine. The aqueous phase was decanted and
extracted three times with ether (3Â100 ml). The organic extracts were pooled, dried (MgSO4)
and evaporated under reduced pressure. The colourless residue (3 g, 18.6 mmol) was directly
treated with concentrated hydrochloric acid (2.7 ml), crushed ice (10.9 g) and sodium nitrite (3.9
g, 56 mmol) in water (5 ml) and the mixture was stirred for 17 h at room temperature. Extraction
with dichloromethane and puri®cation of the residue by column chromatography on silica gel
(eluent: cyclohexane:ether, 9:1, and elution gradient) led to nitrosoamine 21 as a yellow oil (1.6 g,
24%), [ꢀ]D 11.0 (c 1.1, MeOH). MS calcd for C8H18N2O3: M, 160.1337. Found: 160.1345. IR
1
1
(®lm): 1450 (NO) cm . H NMR (CDCl3) ꢁ major conformer (88.5%): 0.94 (t, J=7.4 Hz, 3H),
1.80±2.00 (m, 2H), 3.30 and 3.34 (2s, 6H), 3.80±3.90 (m, 6H), 4.45±4.53 (m, 1H); minor con-
former: 0.84 (t, J=7.4 Hz, 3H), 1.50±1.70 (m, 2H), 3.29 and 3.38 (2s, 6H), 3.38±4.20 (m, 6H),
4.80±4.90 (m, 1H). 13C NMR (CDCl3) ꢁ major conformer: 10.47, 23.12, 44.00, 58.54, 58.60, 65.07,
68.35, 73.84; minor conformer: 10.67, 21.27, 49.15, 58.54, 58.72, 54.15, 70.92, 71.18.

P. Bataille et al. / Tetrahedron: Asymmetry 11 (2000) 1165±1181
1173
3.14. 1-(2-Methoxyethyl)-1-[(1R)-1-(methoxymethyl)propyl]hydrazine (R)-(+)-22
Starting from LiAlH4 (1.0 g, 26.7 mmol) in dry ether (100 ml) and the N-nitrosoamine (R)-( )-
21 (1.45 g, 7.63 mmol) in dry ether (30 ml), the above procedure [see (R)-(+)-19)] led to hydrazine
(R)-(+)-22 as a colourless oil (1.3 g, 97.0%), [ꢀ]D +4.5 (c 1, MeOH), which was used in the next
step without further puri®cation. 1H NMR (CDCl3) ꢁ: 0.95 (t, J=7.5 Hz, 3H), 1.32±1.58 (m, 2H),
2.69±2.75 (m, 1H), 2.78±2.90 (m, 2H), 3.34 and 3.36 (2s, 6H), 3.45 (dd, J=3.6 and 10.0 Hz, 1H),
3.56±3.61 (m, 3H). 13C NMR (CDCl3) ꢁ: 11.39, 21.10, 56.41, 58.76, 58.85, 67.00, 71.70, 72.90.
3.15. (1R)-N-[1-(Methoxymethyl)propyl]tri¯uoroacetamide (R)-(+)-23
Tri¯uoroacetic anhydride (34.3 ml, 243 mmol) in dry ether (120 ml) was added dropwise at
10ꢀC to (R)-1-methoxybutan-2-amine (R)-( )-126 (25.0 g, 243 mmol) in dry ether (120 ml) for 1
h. At the end of addition, solid Na2CO3 (43.2 g, 407 mmol) was added. After stirring for 1 h at
10ꢀC and 2 h to reach room temperature, the mixture was ®ltered through Celite, the solid
material was extracted with ether and the combined organic phases were pooled, dried (MgSO4)
and evaporated under reduced pressure. Vacuum distillation of the residue gave the amide (R)-
(+)-23 as a colourless oil (39.4 g, 82.5%), b.p.90=117±119ꢀC, [ꢀ]D+23.5 (c 1.55, MeOH). Anal.
calcd for C7H12F3NO2: C, 42.21; H, 6.07; N, 7.03. Found: C, 42.94; H, 6.05; N, 7.11. IR (®lm):
1
1704 (CˆO) cm . 1H NMR (CDCl3) ꢁ: 0.94 (t, J=7.5 Hz, 3H), 1.55±1.75 (m, 2H), 3.37 (s, 3H),
3.20±3.50 (m, 2H), 3.90±4.00 (m, 1H), 6.51 (s, 1H). 13C NMR (CDCl3) ꢁ: 10.28, 24.34, 51.36,
59.10, 72.50, 115.89, 156.85. 19F NMR ꢁ: 76.5.
3.16. (2R)-1-Methoxy-N-(2,2,2-tri¯uoroethyl)butan-2-amine (R)-( )-24
A suspension of LiAlH4 (9.92 g, 261 mmol) in dry ether (200 ml) was cooled to 10ꢀC and
treated dropwise by the amide (R)-(+)-23 (17.2 g, 86 mmol) in dry ether (50 ml). After stirring for
1 h at room temperature then 10 h under re¯ux, the mixture was quenched at 15ꢀC by methanol
(34 ml), followed by water (50 ml). After stirring for 30 min at room temperature, the suspension
was ®ltered through Celite and the solid material was extracted several times with ether. The
®ltrate was dried (MgSO4) and distilled under atmospheric pressure. The residue was distilled
under reduced pressure, thus giving amine (R)-( )-24 as a colourless oil (12.9 g, 80.9%),
b.p.40=54±56ꢀC and [ꢀ]D 9.4 (c 1.3, MeOH). Anal. calcd for C7H14F3NO: C, 45.40; H, 7.62; N,
1
7.56. Found: C, 45.39; H, 7.61; N, 7.49. H NMR (CDCl3) ꢁ: 0.92 (t, J=7.5 Hz, 3H), 1.30±1.50
(m, 2H), 2.71±2.77 (m, 1H), 3.10±3.32 (m, 2H), 3.35 (s, 3H), 3.36±3.50 (m, 2H). 13C NMR
(CDCl3) ꢁ: 10.02, 24.13, 48.18, 57.97, 58.87, 74.92, 125.62. 19F NMR ꢁ: 72.6.
3.17. (2R)-1-Methoxy-N-nitroso-N-(2,2,2-tri¯uoroethyl)butan-2-amine (R)-(+)-25
Sodium nitrite (24.0 g, 348 mmol) in water (20 ml) was added dropwise at room temperature to
a mixture of amine (R)-( )-24 (21.5 g, 116 mmol), concentrated hydrochloric acid (17 ml) and
crushed ice (52.2 g). After stirring for 17 h at room temperature, the mixture was extracted with
dichloromethane (20 ml), the aqueous phase was saturated with NaCl then extracted several times
with dichloromethane. The combined organic extracts were dried (MgSO4), ®ltered and evapo-
rated under reduced pressure, thus a€ording the nitrosoamine (R)-(+)-25 (22.7 g, 91.5%), [ꢀ]D
+2.14 (c 1.2, MeOH), which was used in the next step without further puri®cation. A sample was

1174
P. Bataille et al. / Tetrahedron: Asymmetry 11 (2000) 1165±1181
chromatographed (eluent: cyclohexane:ether, 9:1, then elution gradient) for elemental analysis.
Anal. calcd for C7H13F3N2O2: C, 39.25; H, 6.12; N, 13.08. Found: C, 39.16; H, 5.99; N, 12.93. IR
1
(®lm): 1475 (NO) cm . 1H NMR (CDCl3) ꢁ major conformer: 0.99 (t, J=7.4 Hz, 3H), 1.80±2.10
(m, 2H), 3.32 (s, 3H), 3.60±3.75 (m, 2H), 3.92 (dd, J=9.1 and 14.8 Hz, 1H), 4.30±4.43 (m, 1H),
4.67 (dd, J=9.0 and 14.8 Hz, 1H); minor conformer: 0.86 (t, J=7.4 Hz, 3H), 1.50±1.70 (m, 2H),
3.29 (s, 3H), 3.60±3.75 (m, 2H), 3.86±3.98 (m, 1H), 4.61±4.74 (m, 1H), 4.75±4.86 (m, 1H). 13C
NMR (CDCl3) ꢁ major conformer: 10.46, 23.38, 44.31, 58.99, 65.55, 75.45, 122.51. 19F NMR ꢁ:
69.0 (88.1%), 70.2 (11.9%).
3.18. 1-[(1R)-1-(Methoxymethyl)propyl]-1-(2,2,2-tri¯uoroethyl)hydrazine (R)-(+)-26
A suspension of LiAlH4 (1.9 g, 50 mmol) in dry ether (100 ml) was cooled to 0ꢀC and treated
dropwise with the N-nitrosoamine (R)-(+)-25 (4.28 g, 20 mmol) in dry ether (100 ml). After
stirring at room temperature for 6 h, the excess hydride was destroyed at 10ꢀC by methanol (5
ml) and water (10 ml). After 30 min at room temperature, the suspension was ®ltered and the
solids were extracted several times with dichloromethane. The combined organic extracts were
dried (MgSO4) and evaporated under reduced pressure, thus leading to the hydrazine (R)-(+)-26
(2.8 g, 70%), [ꢀ]D +7.4 (c 1.4, MeOH), which was used in the next step without further pur-
i®cation. 1H NMR (CDCl3) ꢁ: 0.96 (t, J=7.3 Hz, 3H), 1.19±1.52 (m, 2H), 2.60±2.80 (m, 1H), 3.34
(s, 3H), 3.30±3.46 (m, 4H). 13C NMR (CDCl3) ꢁ: 10.76, 21.93, 58.67, 60.37, 67.38, 72.94, 125.51.
19F NMR ꢁ: 71.6.
3.19. Acetophenone-N-[(1R)-1-(methoxymethyl)propyl]-N-methylhydrazone (R)-( )-27
Starting from (R)-( )-16 (0.5 g, 3.78 mmol), acetophenone (0.29 ml, 2.52 mmol) and TsOH
(catalytic amount) in anhydrous toluene (20 ml), the above procedure (see Section 3.2) led to
hydrazone (R)-( )-27 as a yellow oil after chromatography (eluent: cyclohexane then elution
gradient: cyclohexane:ether) (405 mg, 68.8 %), [ꢀ]D 166.6 (c 1.1, MeOH). MS calcd for
1
1
C14H22N2O: M, 234.1732. Found: 234.1737. IR (®lm): 1608 (CˆN) cm . H NMR (CDCl3) ꢁ:
0.95 (t, J=7.4 Hz, 3H), 1.50±1.70 (m, 2H), 2.32 (s, 3H), 2.58 (s, 3H), 2.80±2.90 (m, 1H), 3.36 (s,
3H), 3.50 (dd, J=5.4 and 9.7 Hz, 1H), 3.77 (dd, J=5.3 and 9.8 Hz, 1H), 7.20±7.40 (m, 3H), 7.70±
7.80 (m, 2H). 13C NMR (CDCl3) ꢁ: 11.25, 15.77, 23.19, 41.55, 59.13, 68.12, 73.53, 126.37, 127.27,
128.26, 139.47, 160.46.
3.20. 2-Hydroxyacetophenone-N-[(1R)-1(methoxymethyl)propyl]-N-methylhydrazone (R)-( )-28
Starting from (R)-( )-16 (0.75 g, 5.68 mmol), 2-hydroxyacetophenone (0.45 ml, 3.79 mmol)
and TsOH (catalytic amount) in anhydrous toluene (20 ml), the above procedure (see Section 3.2)
led to hydrazone (R)-( )-28 as a yellow liquid after chromatography (eluent: cyclohexane) (890
mg, 94.4%), [ꢀ]D 201.8 (c 1.1, MeOH). MS calcd for C14H22N2O2: M, 250.1681. Found:
1
1
250.1674. IR (®lm): 3361 (OH) and 1602 (CˆN) cm . H NMR (CDCl3) ꢁ: 0.96 (t, J=7.4 Hz,
3H), 1.50±1.70 (m, 2H), 2.45 (s, 3H), 2.63 (s, 3H), 2.80±2.90 (m, 1H), 3.35 (s, 3H), 3.48 (dd, J=4.8
and 9.9 Hz, 1H), 3.66 (dd, J=5.9 and 10.0 Hz, 1H), 6.86 (td, J=1.0 and 7.9 Hz, 1H), 6.95 (dd,
J=1.0 and 8.3 Hz, 1H), 7.26 (td, J=1.6 and 7.7 Hz, 1H), 7.48 (dd, J=1.5 and 7.9 Hz, 1H), 13.92
(s, 1H). 13C NMR (CDCl3) ꢁ: 10.68, 13.85, 21.90, 41.53, 58.43, 66.94, 72.20, 116.96, 117.62,
119.63, 127.44, 130.59, 160.26, 168.27.

P. Bataille et al. / Tetrahedron: Asymmetry 11 (2000) 1165±1181
1175
3.21. Acetophenone-N-[(1R)-1-(methoxymethyl)propyl]-N-propylhydrazone (R)-( )-29
Starting from (R)-(+)-19 (0.56 g, 3.5 mmol), acetophenone (0.27 ml, 2.33 mmol) and TsOH
(catalytic amount) in anhydrous toluene (20 ml), the above procedure (see Section 3.2) led to
hydrazone (R)-( )-29 as a yellow oil after chromatography (eluent: cyclohexane) (466 mg,
76.3%), [ꢀ]D 220 (c 1.3, MeOH). MS calcd for C16H26N2O: M, 262.2045. Found: 262.2044. IR
1
1
(®lm): 1616 (CˆN) cm . H NMR (CDCl3) ꢁ: 0.90 (t, J=7.4 Hz, 3H), 0.98 (t, J=7.4 Hz, 3H),
1.42±1.65 (m, 4H), 2.36 (s, 3H), 2.71±3.00 (m, 3H), 3.34 (s, 3H), 3.45 (dd, J=6.5 and 9.5 Hz, 1H),
3.76 (dd, J=4.6 and 9.5 Hz, 1H), 7.34±7.37 (m, 2H), 7.73±7.76 (m, 3H). 13C NMR (CDCl3) ꢁ:
11.44, 11.71, 16.03, 21.68, 23.28, 55.12, 58.90, 65.24, 73.28, 126.34, 128.15, 129.00, 139.44, 163.43.
3.22. 2-Hydroxyacetophenone-N-[(1R)-1-(methoxymethyl)propyl]-N-propylhydrazone (R)-( )-30
Starting from (R)-(+)-19 (0.40 g, 2.5 mmol), 2-hydroxyacetophenone (0.2 ml, 1.66 mmol) and
TsOH (catalytic amount) in anhydrous toluene (20 ml), the above procedure (see Section 3.2) led
to hydrazone (R)-( )-30 as a yellow liquid after chromatography (eluent: cyclohexane) (142 mg,
30.7%), [ꢀ]D 268 (c 1.0, MeOH). MS calcd for C16H26N2O2: M, 278.1994. Found: 278.2004. IR
1
1
(®lm): 3361 (OH) and 1602 (CˆN) cm . H NMR (CDCl3) ꢁ: 0.90 (t, J=7.4 Hz, 3H), 0.99 (t,
J=7.4 Hz, 3H), 1.40±1.60 (m, 4H), 2.50 (s, 3H), 2.70±2.90 (m, 3H), 3.33 (s, 3H), 3.41 (dd, J=5.7
and 9.5 Hz, 1H), 3.62 (dd, J=5.4 and 9.7 Hz, 1H), 6.83±6.87 (m, 1H), 6.95 (dd, J=1.1 and 8.3
Hz, 1H), 7.25±7.29 (m, 1H), 7.49 (dd, J=1.6 and 8.0 Hz, 1H), 14.33 (s, 1H). 13C NMR (CDCl3) ꢁ:
10.81, 10.90, 14.06, 20.65, 21.73, 54.86, 58.23, 64.88, 71.95, 116.92, 117.32, 118.42, 127.56, 130.60,
160.81, 171.13.
3.23. 2-Methoxyacetophenone-N-[(1R)-1-(methoxymethyl)propyl]-N-propylhydrazone (R)-( )-31
Starting from (R)-(+)-19 (0.6 g, 3.75 mmol), 2-methoxyacetophenone (0.34 ml, 2.49 mmol)
and TsOH (catalytic amount) in anhydrous toluene (20 ml), the above procedure (see Section 3.2)
led to hydrazone (R)-( )-31 as a yellow liquid after chromatography (eluent: cyclohexane:ether,
9:1, then elution gradient) (480 mg, 65.7 %), [ꢀ]D 48.8 (c 0.8, MeOH). MS calcd for
1
1
C17H28N2O2: M, 292.2150. Found: 292.2155. IR (®lm): 1600 (CˆN) cm . H NMR (CDCl3) ꢁ:
0.91 (t, J=7.4 Hz, 3H), 1.00 (t, J=7.4 Hz, 3H), 1.46 (sex, J=7.4 Hz, 2H), 1.61 (quint, J=7.2 Hz,
2H), 2.31 (s, 3H), 2.70±2.90 (m, 3H), 3.38 (s, 3H), 3.40±3.50 (m, 1H), 3.72 (dd, J=4.4 and 9.6 Hz,
1H), 3.81 (s, 3H), 6.88±7.31 (m, 4H).
3.24. Acetophenone-N-(2-methoxyethyl)-N-[(1R)-1-(methoxymethyl)propyl]hydrazone (R)-( )-32
Starting from (R)-(+)-22 (0.6 g, 3.41 mmol), acetophenone (0.26 ml, 2.27 mmol) and TsOH
(catalytic amount) in anhydrous toluene (20 ml), the above procedure (see Section 3.2) led to
hydrazone (R)-( )-32 as a yellow liquid after chromatography (eluent: cyclohexane:ether, 9:1,
then elution gradient) (330 mg, 52.3%), [ꢀ]D 220 (c 1.0, MeOH). MS calcd for C16H26N2O2: M,
1
278.1994. Found: 278.2004. IR (®lm): 1608 (CˆN) cm . 1H NMR (CDCl3) ꢁ: 0.98 (t, J=7.4 Hz,
3H), 1.59 (quint, J=7.4 Hz, 2H), 2.37 (s, 3H), 2.87 (quint, J=6.1 Hz, 1H), 3.05±3.20 (m, 2H),
3.33 (s, 6H), 3.37±3.50 (m, 3H), 3.74 (dd, J=4.8 and 9.7 Hz, 1H), 7.35±7.78 (m, 5H). 13C NMR
(CDCl3) ꢁ: 11.38, 15.99, 23.06, 52.63, 58.77, 58.86, 66.19, 71.37, 73.07, 126.36, 128.15, 129.16,
139.14, 164.08.

1176
P. Bataille et al. / Tetrahedron: Asymmetry 11 (2000) 1165±1181
3.25. 2-Hydroxyacetophenone-N-(2-methoxyethyl)-N-[(1R)-1-(methoxymethyl)propyl]hydrazone
(R)-( )-33
Starting from (R)-(+)-22 (0.6 g, 3.41 mmol), 2-hydroxyacetophenone (0.27 ml, 2.27 mmol) and
TsOH (catalytic amount) in anhydrous toluene (20 ml), the above procedure (see Section 3.2) led to
hydrazone (R)-( )-33 as a yellow liquid after chromatography (eluent: cyclohexane:ether, 95:5, then
elution gradient) (470 mg, 70.5%), [ꢀ]D 183 (c 1.2, MeOH). MS calcd for C16H26N2O3: M, 294.194.
1 1
Found: 294.195. IR (®lm): 1602 (CˆN) cm . H NMR (CDCl3) ꢁ: 0.99 (t, J=7.4 Hz, 3H), 1.50±1.60
(m, 2H), 2.51 (s, 3H), 2.89±2.95 (m, 1H), 3.08±3.21 (m, 2H), 3.32 and 3.33 (2s, 6H), 3.38±3.47 (m, 3H),
3.62 (dd, J=5.7 and 9.8 Hz, 1H), 6.86 (td, 1.1 and 7.5 Hz, 1H), 6.96 (dd, J=1.1 and 8.2 Hz, 1H), 7.26±
7.32 (m, 1H), 7.50 (dd, J=1.5 and 8.0 Hz, 1H), 14.14 (s, 1H). 13C NMR (CDCl3) ꢁ: 10.97, 14.31,
21.93, 52.87, 58.27, 58.44, 65.95, 70.31, 72.10, 117.17, 117.64, 119.31, 127.93, 131.00, 160.75, 172.04.
3.26. N-(1-Methoxymethyl)propyl-N0-(1-phenylethylidene)-N-(2,2,2-tri¯uoroethyl)-hydrazone (R)-
( )-34
Starting from (R)-(+)-26 (2.11 g, 10 mmol), acetophenone (1.1 ml, 9.5 mmol) and p-TsOH
(catalytic amount) in anhydrous toluene (20 ml), the above procedure (see Section 3.2) led to
hydrazone (R)-( )-34 as a yellow oil (2.9 g, 97.5%), [ꢀ]D 151.3 (c 1.1, MeOH), which was used
in the next step without further puri®cation. Anal. calcd for C15H21F3N2O: C, 59.59; H, 7.00; N,
1 1
9.27. Found: C, 60.02; H, 7.03; N, 9.12. IR (®lm): 1614 (CˆN) cm . H NMR (CDCl3) ꢁ: 1.02 (t,
J=7.4 Hz, 3H), 1.61 (quint, J=7.3 Hz, 2H), 2.40 (s, 3H), 2.75±2.83 (m, 1H), 3.33 (s, 3H), 3.52
(dd, J =4.5 and 9.7 Hz, 1H), 3.61 (dd, J=4.7 and 9.8 Hz, 1H), 3.63±3.69 (m, 2H), 7.74±7.77 (m,
3H), 7.37±7.39 (m, 2H). 13C NMR (CDCl3) ꢁ: 11.36, 16.11, 22.33, 54.42, 58.97, 67.64, 72.35,
125.24, 126.70, 128.28, 129.71, 138.69, 167.54. 19F NMR ꢁ: 70.9.
3.27. 4-Phenylbutan-2-one-N-[(1R)-(1-methoxymethyl)propyl]-N-(2,2,2-tri¯uoroethyl)hydrazone
(R)-( )-35
Starting from (R)-(+)-26 (2 g, 10 mmol), 4-phenylbutan-2-one (1.35 ml, 9 mmol) and TsOH
(catalytic amount) in anhydrous toluene (20 ml), the above procedure (see Section 3.2) after 4
days under re¯ux, led to hydrazone (R)-( )-35 as a yellow±orange oil after chromatography
(eluent: cyclohexane then elution gradient: cyclohexane:ether) (2.5 g, 84.2%), [ꢀ]D 46.8 (c 1.1,
MeOH). Presence of two isomers (E:Z, 86.5:13.5). Anal. calcd for C17H25F3N2O: C, 61.80; H,
1
7.63; N, 8.48. Found: C, 61.66; H, 7.29; N, 8.42. IR (®lm): 1604 (CˆN) cm . 1H NMR (CDCl3)
ꢁ major isomer: 0.90±1.00 (m, 3H), 1.40±1.50 (m, 2H), 1.97 (s, 3H), 2.40±2.90 (m, 5H), 3.33 (s,
3H), 3.30±3.60 (m, 4H), 7.00±7.30 (m, 5H); minor isomer: 0.90±1.00 (m, 3H), 1.50±1.52 (m, 2H),
2.00 (s, 3H), 2.40±2.90 (m, 5H), 3.34 (s, 3H), 3.30±3.60 (m, 4H), 7.00±7.30 (m, 5H). 13C NMR
(CDCl3) ꢁ major isomer: 11.21, 17.70, 22.00, 32.63, 40.04, 54.01, 58.80, 67.23, 71.87, 125.00,
125.95, 128.13, 141.10, 172.38. 19F NMR ꢁ: 70.9 (86.5%) and 70.7 (13.5%).
3.28. 1-Phenylbutan-1-one-N-[(1R)-(1-methoxymethyl)propyl]-N-(2,2,2-tri¯uoroethyl)hydrazone
(R)-( )-36
Starting from (R)-(+)-26 (1 g, 5 mmol), butyrophenone (667 mg, 4.5 mmol) and TsOH (catalytic
amount) in anhydrous toluene (20 ml), the above procedure (see Section 3.2) led to hydrazone

P. Bataille et al. / Tetrahedron: Asymmetry 11 (2000) 1165±1181
1177
(R)-( )-36 as an orange oil (1.37 g, 92.6%), [ꢀ]D 108.9 (c 1.05, MeOH), which was used in the
next step without further puri®cation. Presence of two isomers (E:Z, 82:18). Anal. calcd for
C17H25F3N2O: C, 61.80; H, 7.63; N, 8.48. Found: C, 62.14; H, 7.67; N, 8.25. IR (®lm): 1689
1
(CˆN) cm . 1H NMR (CDCl3) ꢁ major isomer: 0.91 (t, J=7.3 Hz, 3H), 1.05 (t, J=7.4 Hz, 3H),
1.37±1.80 (m, 4H), 2.49±2.97 (m, 3H), 3.33 (s, 3H), 3.54±3.77 (m, 4H), 7.29±7.70 (m, 5H); minor
isomer: 0.86±1.06 (m, 6H), 1.56±1.80 (m, 4H), 2.49±2.97 (m, 3H), 3.34 (s, 3H), 3.54±3.77 (m, 4H),
7.30±8.20 (m, 5H). 19F NMR ꢁ: 70.7 (82%) and 70.6 (18%).
3.29. 1-Phenylpropan-1-one-N-[(1R)-(1-methoxymethyl)propyl]-N-(2,2,2-tri¯uoroethyl)hydrazone
(R)-( )-37
Starting from (R)-(+)-26 (1 g, 5 mmol), propiophenone (600 mg, 4.5 mmol) and TsOH (cata-
lytic amount) in anhydrous toluene (20 ml), the above procedure (see Section 3.2) led to hydra-
zone (R)-( )-37 as an orange oil (1.27 g, 89.4%), [ꢀ]D 96 (c 1.04, MeOH), which was used in the
next step without further puri®cation. Presence of two isomers (E:Z, 85.5:14.5). MS calcd for
1
C16H23F3N2O: M, 316.1762. Found: 316.1759. IR (®lm): 1691 (CˆN) cm . 1H NMR (CDCl3) ꢁ
major isomer: 1.01 and 1.04 (2t, J=7.5 and 7.3 Hz, 6H), 1.59±1.66 (m, 2H), 2.50±3.00 (m, 3H),
3.33 (s, 3H), 3.41±3.77 (m, 4H), 7.29±7.68 (m, 5H); minor isomer: 0.96±1.08 (m, 6H), 1.54±1.59
(m, 2H), 2.50±3.00 (m, 3H), 3.34 (s, 3H), 3.41±3.77 (m, 4H), 7.29±7.68 (m, 5H). 19F NMR ꢁ:
70.7 (85.5%) and 70.6 (14.5%).
3.30. 4-Methoxyacetophenone-N-[(1R)-1-(methoxymethyl)propyl]-N-(2,2,2-tri¯uoroethyl)hydrazone
(R)-( )-38
Starting from (R)-(+)-26 (480 mg, 2.4 mmol), 4-methoxyacetophenone (240 mg, 1.6 mmol)
and TsOH (catalytic amount) in anhydrous toluene (20 ml), the above procedure (see Section 3.2)
led to hydrazone (R)-( )-38 as a colourless oil after chromatography (eluent: cyclohexane then
elution gradient: cyclohexane:ether) (0.4 g, 75.3%), [ꢀ]D 121 (c 0.95, MeOH). Anal. calcd for
C16H23F3N2O2: C, 57.82; H, 6.98; N, 8.43. Found: C, 57.91; H, 7.04; N, 8.42. IR (®lm): 1602
1
1
(CˆN) cm . H NMR (CDCl3) ꢁ: 1.02 (t, J=7.4, 3H), 1.55±1.63 (m, 2H), 2.37 (s, 3H), 2.70±
2.80 (m, 1H), 3.33 (s, 3H), 3.52 (dd, J=4.8 and 9.7 Hz, 1H), 3.58±3.65 (m, 3H), 3.83 (s, 3H),
6.90 (d, J=8.9 Hz, 2H), 7.73 (d, J=8.9 Hz, 2H). 13C NMR (CDCl3) ꢁ: 11.33, 15.74, 22.28,
54.47, 54.92, 58.92, 67.64, 72.30, 113.54, 125.48, 128.13, 131.21, 160.95, 167.10. 19F NMR ꢁ:
70.9.
3.31. 2-Acetonaphthone-N-[(1R)-1-(methoxymethyl)propyl]-N-(2,2,2-tri¯uoroethyl)hydrazone
(R)-( )-39
Starting from (R)-(+)-26 (480 mg, 2.4 mmol), 2-acetylnaphthalene (272 mg, 1.6 mmol) and
TsOH (catalytic amount) in anhydrous toluene (20 ml), the above procedure (see Section 3.2) led
to hydrazone (R)-( )-39 as a viscous yellow oil after chromatography (eluent: cyclohexane then
elution gradient: cyclohexane:ether) (275 mg, 49%), [ꢀ]D 153 (c 0.8, MeOH). Anal. calcd for
C19H23F3N2O: C, 64.76; H, 6.58; N, 7.95. Found: C, 64.63; H, 6.71; N, 7.95. IR (®lm): 1608
1
1
(CˆN) cm . H NMR (CDCl3) ꢁ: 1.05 (t, J=7.4 Hz, 3H), 1.64 (quint, J=7.3 Hz, 2H), 2.52 (s,
3H), 2.80±2.88 (m, 1H), 3.35 (s, 3H), 3.56 (dd, J=4.4 and 9.8 Hz, 1H), 3.64 (dd, J=4.5 and 9.7
Hz, 1H), 3.67±3.74 (m, 2H), 7.48±7.54 (m, 2H), 7.70±7.90 (m, 3H), 8.04 (d, J=8.7 Hz, 1H), 8.10

1178
P. Bataille et al. / Tetrahedron: Asymmetry 11 (2000) 1165±1181
(s, 1H). 13C NMR (CDCl3) ꢁ: 11.36, 15.96, 22.35, 54.48, 58.98, 67.66, 72.39, 123.98, 126.24,
126.73, 126.76, 127.61, 127.79, 128.63, 132.98, 134.04, 136.14, 166.96. 19F NMR ꢁ: 70.9.
3.32. 2-Acetylfuran-N-[(1R)-1-(methoxymethyl)propyl]-N-(2,2,2-tri¯uoroethyl)hydrazone (R)-
( )-40
Starting from (R)-(+)-26 (300 mg, 1.5 mmol), 2-acetylfurane (0.1 ml, 1 mmol) and TsOH
(catalytic amount) in anhydrous toluene (20 ml), the above procedure (see Section 3.2) led to
hydrazone (R)-( )-40 as a yellow oil after chromatography (eluent: cyclohexane:ether. 9:1, then
elution gradient) (182 mg, 62.3%), [ꢀ]D 139 (c 2, MeOH). Anal. calcd for C13H19F3N2O2:
1
C, 53.42; H, 6.55; N, 9.58. Found: C, 53.94; H, 6.61; N, 9.79. IR (®lm): 1602 (CˆN) cm .
1H NMR (CDCl3) ꢁ: 1.01 (t, J=7.4 Hz, 3H), 1.58±1.66 (m, 2H), 2.32 (s, 3H), 2.72±2.78 (m, 1H),
3.32 (s, 3H), 3.55 (t, J=4.7 Hz, 2H), 3.63±3.70 (AB, J=9.4 Hz, 2H), 6.45 (dd, J=1.7 and 3.4 Hz,
1H), 6.77 (d, J=3.4 Hz, 1H), 7.50 (d, J=1.6 Hz, 1H). 13C NMR (CDCl3) ꢁ: 11.22, 15.06,
22.14, 54.18, 58.89, 67.80, 72.09, 111.32, 118.86, 125.38, 144.18, 152.05, 159.18. 19F NMR ꢁ:
71.1.
3.33. 3,4-Dihydro(2H)naphthalen-1-one-N-[(1R)-1-(methoxymethyl)propyl]-N-(2,2,2-tri¯uoro-
ethyl)hydrazone (R)-( )-41
Starting from (R)-(+)-26 (480 mg, 2.4 mmol), a-tetralone (234 mg, 1.6 mmol) and TsOH
(catalytic amount) in anhydrous toluene (15 ml), the above procedure (see Section 3.2) after 4
days under re¯ux, led to hydrazone (R)-( )-41 as a yellow oil after chromatography (eluent:
cyclohexane) (219 mg, 41.7%), [ꢀ]D 136 (c 0.7, MeOH). Anal. calcd for C17H23F3N2O: C, 62.18;
1
1
H, 7.06; N, 8.53. Found: C, 62.29; H, 6.84; N, 8.32. IR (®lm): 1616 (CˆN) cm . H NMR
(CDCl3) ꢁ: 1.01 (t, J=7.4 Hz, 3H), 1.55±1.63 (m, 2H), 1.85±1.94 (m, 2H), 2.70±2.78 (m, 2H), 2.83
(t, J=6.1 Hz, 2H), 2.94±3.00 (m, 1H), 3.33 (s, 3H), 3.50 (dd, J=4.7 and 9.6 Hz, 1H), 3.61 (dd,
J=4.7 and 9.6 Hz, 1H), 3.62±3.68 (m, 2H), 7.13 (d, J=7.7 Hz, 1H), 7.17±7.23 (m, 1H), 7.26±7.31
(td, J=1.2 and 7.4 Hz, 1H), 8.17 (d, J=7.8 Hz, 1H). 13C NMR (CDCl3) ꢁ: 11.36, 22.32, 22.48,
27.87, 29.83, 54.47, 58.94, 67.58, 72.49, 125.12, 125.33, 126.10, 128.65, 128.85, 132.80, 140.39,
166.59. 19F NMR ꢁ: 70.0.
3.34. 1-[(1R)-1-(Methoxymethyl)propyl]-1-methyl-2-(1-phenylethyl)hydrazine 42
A suspension of LiAlH4 (126 mg, 3.3 mmol) in dry ether (30 ml) was cooled to 10ꢀC and
treated dropwise by hydrazone (R)-( )-27 (54 mg, 0.22 mmol) in dry ether (10 ml). After stirring
under re¯ux for 72 h, the mixture was quenched at 10ꢀC by methanol and water. After 30 min
at room temperature, the suspension was ®ltered and the ®ltrate was evaporated under reduced
pressure. The aqueous residue was extracted three times with ether (3Â10 ml). The organic
extracts were pooled, dried (MgSO4) and evaporated under reduced pressure, thus leading to the
hydrazine 42 as a colourless and unstable oil, without further puri®cation (28 mg, 52%),
1
d.e.=43% (1H NMR). H NMR (200 MHz) (CDCl3) ꢁ major diastereomer: 0.83 (t, J=7.3 Hz,
3H), 1.10±1.60 (m, 2H), 1.29 (d, J=6.4 Hz, 3H), 2.49 (s, 3H), 2.50±2.80 (m, 1H), 3.24 (s, 3H), 3.32
(dd, J=5.5 and 10.3 Hz, 1H), 3.52 (dd, J=7.6 and 9.7 Hz, 1H), 3.94 (q, J=6.5 Hz, 1H), 7.00±7.40
(m, 5H); minor diastereomer: 0.80 (m, 3H), 1.10±1.60 (m, 5H), 2.47 (s, 3H), 2.50±2.80 (m, 1H),
3.33 (s, 3H), 3.28±3.57 (m, 2H), 3.89±3.99 (m, 1H), 7.00±7.40 (m, 5H).

P. Bataille et al. / Tetrahedron: Asymmetry 11 (2000) 1165±1181
1179
3.35. N-[(1R)-1-(Methoxymethyl)propyl]-N-methyl-N0-[1-(2-hydroxyphenyl)ethyl]hydrazine 43
A suspension of LiAlH4 (455 mg, 12 mmol) in dry ether (40 ml) was cooled to 10ꢀC and
treated dropwise by hydrazone (R)-( )-28 (200 mg, 0.8 mmol) in dry ether (20 ml). After stirring
at room temperature for 20 h, the mixture was quenched at 10ꢀC by methanol and water. After
30 min at room temperature, the suspension was ®ltered and the ®ltrate was evaporated under
reduced pressure. The aqueous residue was extracted three times with ether. The organic extracts
were pooled, dried (MgSO4) and evaporated under reduced pressure, thus leading to the hydra-
zine 43 as a colourless and unstable oil, without further puri®cation (200 mg, quantitative),
1
d.e.=61.9% (1H NMR). H NMR (CDCl3) ꢁ major diastereomer: 0.82 (t, J=7.4 Hz, 3H), 1.20±
1.40 (m, 2H), 1.37 (d, J=6.8 Hz, 3H), 2.51 (s, 3H), 2.84±2.91 (m, 1H), 3.28 (s, 3H), 3.34±3.40 (m,
1H), 3.53 (t, J=8.9 Hz, 1H), 4.14 (q, J=6.7 Hz, 1H), 6.76 (t, J=7.4 Hz, 1H), 6.81 (d, J=8.0 Hz,
1H), 6.98 (d, J=7.2 Hz, 1H), 7.11 (t, J=7.7 Hz, 1H), 10.66 (s, 1H); minor diastereomer: 0.85 (t,
J=7.4 Hz, 3H), 1.20±1.40 (m, 2H), 1.34 (d, J=6.8 Hz, 3H), 2.45 (s, 3H), 2.97±2.98 (m, 1H), 3.33
(s, 3H), 3.34±3.40 (m, 1H), 3.62 (t, J=9.8 Hz, 1H), 4.10 (q, J=6.7 Hz, 1H), 6.76 (t, J=7.4 Hz,
1H), 6.81 (d, J=8.0 Hz, 1H), 6.96 (d, J=7.2 Hz, 1H), 7.11 (t, J=7.7 Hz, 1H), 10.92 (s, 1H). 13C
NMR (CDCl3) ꢁ major diastereomer: 10.24, 18.27, 21.14, 37.54, 56.07, 57.91, 63.31, 72.41,
115.84, 118.15, 127.04, 127.21, 129.25, 157.70; minor diastereomer: 10.53, 18.50, 20.55, 37.05,
56.01, 57.97, 62.31, 72.68, 115.77, 118.09, 127.04, 127.21, 129.25, 157.70.
3.36. N-[(1R)-1-(Methoxymethyl)propyl]-N-propyl-N0-[1-(2-hydroxyphenyl)ethyl]hydrazine 44
A suspension of LiAlH4 (47.8 mg, 1.25 mmol) in dry ether (20 ml) was cooled to 10ꢀC and
treated dropwise by hydrazone (R)-( )-30 (70 mg, 0.25 mmol) in dry ether (10 ml). After stirring
at room temperature for 20 h, the mixture was quenched at 10ꢀC by methanol and water. After
30 min at room temperature, the suspension was ®ltered and the ®ltrate was evaporated under
reduced pressure. The aqueous residue was extracted three times with ether. The organic extracts
were pooled, dried (MgSO4) and evaporated under reduced pressure, thus leading to the hydra-
zine 44 as a colourless and unstable oil, without further puri®cation (50 mg, 71.4%), d.e.=87%
(1H NMR). 1H NMR (CDCl3) ꢁ major diastereomer: 0.93±0.94 (2t, J=7.4 and 7.4 Hz, 6H), 1.10±
1.70 (m, 4H), 1.38 (d, J=6.7 Hz, 3H), 2.40±3.20 (m, 3H), 3.24 (s, 3H), 3.26±3.66 (m, 2H), 4.12 (q,
J=6.5 Hz, 1H), 6.78 (t, J=7.3 Hz, 1H), 6.83 (d, J=7.9 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 7.14 (t,
J=7.6 Hz, 1H). 13C NMR (CDCl3) ꢁ major diastereomer: 11.67, 11.85, 18.89, 21.32, 22.63, 56.84,
58.93, 61.07, 65.80, 74.19, 116.82, 119.12, 128.05, 128.32, 156.87, 128.23.
3.37. 2-[1-(2-Hydroxyphenyl)ethyl]-1-(2-methoxyethyl)-1-[(1R)-1-(methoxymethyl)propyl]hydra-
zine 45
A suspension of LiAlH4 (194 mg, 5 mmol) in dry ether (20 ml) was cooled to 10ꢀC and
treated dropwise by hydrazone (R)-( )-33 (0.1 g, 0.34 mmol) in dry ether (5 ml). After stirring at
room temperature for 20 h, the mixture was quenched at 10ꢀC by methanol and water. After 30
min at room temperature, the suspension was ®ltered and the ®ltrate was evaporated under
reduced pressure. The aqueous residue was extracted three times with ether. The organic extracts
were pooled, dried (MgSO4) and evaporated under reduced pressure, thus leading to the hydra-
zine 45 as a colourless and unstable oil, without further puri®cation (40 mg, 40%), d.e.=48.7%
(1H NMR). 1H NMR (CDCl3) ꢁ major diastereomer: 0.95 (t, J=7.3 Hz, 3H), 1.25±1.33 (m, 2H),

1180
P. Bataille et al. / Tetrahedron: Asymmetry 11 (2000) 1165±1181
1.38 (d, J=6.6 Hz, 3H), 2.81±2.87 (m, 2H), 2.95±3.05 (m, 1H), 3.24 and 3.36 (2s, 6H), 3.35±3.70
(m, 4H), 4.09 (q, J=6.6 Hz, 1H), 6.70±7.20 (m, 5H); minor diastereomer: 0.88 (t, J=7.3 Hz, 3H),
1.25±1.33 (m, 2H), 1.35 (d, J=6.9 Hz, 3H), 2.81±2.87 (m, 2H), 2.95±3.05 (m, 1H), 3.17 and 3.22
(2s, 6H), 3.35±3.70 (m, 4H), 4.07 (q, J=6.9 Hz, 1H), 6.70±7.20 (m, 5H).
3.38. N-[(1R)-1-(Methoxymethyl)propyl]-N0-(1-methyl-3-phenyl)propyl-N-(2,2,2-tri¯uoroethyl)-
hydrazine 47
A suspension of LiAlH4 (354 mg, 9.1 mmol) in dry ether (50 ml) was cooled to 10ꢀC and
treated dropwise by hydrazone (R)-( )-35 (200 mg, 0.6 mmol) in dry ether (20 ml). After stirring
at room temperature for 15 h, the mixture was quenched at 10ꢀC by methanol (1.1 ml) and
water (1.7 ml). After 30 min at room temperature, the suspension was ®ltered and the ®ltrate was
evaporated under reduced pressure. The aqueous residue was extracted three times with ether.
The organic extracts were pooled, dried (MgSO4) and evaporated under reduced pressure. The
residue was puri®ed by column chromatography on silica gel (eluent: cyclohexane:ether, 9:1, and
elution gradient), thus leading to the hydrazine 47 as a colourless oil (110 mg, 54.7 %), [ꢀ]D
+33.3 (c 0.9, MeOH), 71%<d.e.<75% determined by 13C NMR. Anal. calcd for
C17H27F3N2O: C, 61.43; H, 8.19; N, 8.43. Found: C, 61.47; H, 8.47; N, 8.13. 1H NMR (CDCl3) ꢁ
major diastereomer: 0.95 (t, J=7.3 Hz, 3H), 1.07 (d, J=6.0 Hz, 3H), 1.10±1.30 (m, 2H), 1.40±1.60
(m, 2H), 2.60±2.65 (m, 2H), 2.79±2.88 (m, 2H), 2.82 (q, J=6.0 Hz, 1H), 3.08 (dd, J=9.7 and 15.2
Hz, 1H), 3.32 (s, 3H), 3.37 (dd, J=3.9 and 9.9 Hz, 1H), 3.51 (AB system, J=9.7 Hz, 2H), 7.17±
7.29 (m, 5H); minor diastereomer: 0.91 (m, 3H), 1.01 (d, J=6.3 Hz, 3H), 1.10±1.30 (m, 2H), 1.40±
1.60 (m, 2H), 2.60±2.65 (m, 2H), 2.79±2.88 (m, 2H), 3.04±3.10 (m, 1H), 3.35±3.41 (m, 1H), 3.44±
3.54 (m, 2H), 7.17±7.29 (m, 5H). 13C NMR (CDCl3) ꢁ major diastereomer: 11.17, 18.93, 22.58,
32.12, 37.02, 51.43, 59.05, 63.28, 74.52, 125.39, 125.74, 125.79, 128.19, 142.36.
3.39. 1-[(1R)-1-(Methoxymethyl)propyl]-2-[(1R)-1-phenylethyl]-1-(2,2,2-tri¯uoroethyl)hydrazine
(R,S)-(+)-46
Starting from LiAlH4 (1.9 g, 49.6 mmol) in dry ether (100 ml) and (R)-( )-34 (1 g, 3.3 mmol) in
dry ether (50 ml), the above procedure (see Section 3.38), without chromatography, led to
hydrazine 46 as a yellow oil (854 mg, 85.4%), [ꢀ]D +57.4 (c 0.6, EtOH), d.e.=100% determined
by 13C NMR and 1H NMR. Anal. calcd for C15H23F3N2O: C, 59.20; H, 7.62; N, 9.20. Found: C,
1
59.54; H, 7.94; N, 9.43. H NMR (CDCl3) ꢁ: 0.96 (t, J=7.3 Hz, 3H), 1.16±1.23 (m, 2H), 1.33 (d,
J=6.4 Hz, 3H), 2.85±2.91 (m, 1H), 3.14 (dd, J=9.7 and 15.1 Hz, 1H), 3.25 (s, 3H), 3.35 (dd,
J=4.1 and 9.9 Hz, 1H), 3.50±3.57 (m, 2H), 3.68 (s, 1H), 3.91 (q, J=6.4 Hz, 1H), 7.22±7.35 (m,
5H). 13C NMR (CDCl3) ꢁ: 11.20, 21.12, 22.85, 55.90, 57.16, 58.83, 63.90, 74.39, 126.02, 127.13,
127.26, 128.32, 144.00.
3.40. N-[(1R)-1-(Methoxymethyl)propyl)-N0-[1-(4-methoxyphenyl)ethyl]-N-(2,2,2-tri¯uoroethyl)-
hydrazine (R,S)-(+)-48
Starting from LiAlH4 (438 mg, 11 mmol) in dry ether (50 ml) and (R)-( )-38 (256 mg, 0.77
mmol) in dry ether (10 ml), the above procedure (see Section 3.38), with chromatography (eluent:
cyclohexane), led to hydrazine 48 as a colourless oil (130 mg, 50.6%), [ꢀ]D +40.7 (c 1.4, MeOH),
d.e.=100% (13C NMR and 1H NMR). Anal. calcd for C16H25F3N2O2: C, 57.47; H, 7.54; N, 8.38.

P. Bataille et al. / Tetrahedron: Asymmetry 11 (2000) 1165±1181
1181
1
Found: C, 57.63; H, 7.55; N, 8.35. H NMR (CDCl3) ꢁ: 0.97 (t, J=7.3 Hz, 3H), 1.15±1.25 (m,
2H), 1.31 (d, J=6.3 Hz, 3H), 2.85±2.95 (m, 1H), 3.10±3.16 (m, 1H), 3.25 (s, 3H), 3.34 (dd, J=4.2
and 9.9 Hz, 1H), 3.49±3.63 (m, 3H), 3.79 (s, 3H), 3.86 (q, J=6.4 Hz, 1H), 6.85 (d, J=8.6 Hz, 2H),
7.25 (d, J=8.5 Hz, 2H). 13C NMR (CDCl3) ꢁ: 11.22, 21.07, 22.84, 55.22, 55.79, 56.36, 59.00,
63.83, 74.39, 113.65, 125.43, 128.27, 136.85, 158.69.
3.41. N-[(1R)-1-(Methoxymethyl)propyl)-N0-[1-(naphthalen-2-yl)ethyl]-N-(2,2,2-tri¯uoroethyl)-
hydrazine (R,S)-(+)-49
Starting from LiAlH4 (356 mg, 9.38 mmol) in dry ether (50 ml) and (R)-( )-39 (220 mg, 0.62
mmol) in dry ether (10 ml), the above procedure (see Section 3.38), without chromatography, led
to hydrazine 49 as a yellow oil (177 mg, 80%), [ꢀ]D +26.8 (c 1.05, MeOH), d.e.=100% deter-
1
mined by 13C NMR and H NMR. Anal. calcd for C19H25F3N2O: C, 64.39; H, 7.11; N, 7.90.
1
Found: C, 64.83; H, 7.19; N, 7.95. H NMR (CDCl3) ꢁ: 0.96 (t, J=7.3 Hz, 3H), 1.20±1.40 (m,
2H), 1.42 (d, J=6.3 Hz, 3H), 2.90±3.10 (m, 1H), 3.17 (dd, J=9.7 and 15.2 Hz, 1H), 3.21 (s, 3H),
3.31±3.36 (m, 1H), 3.50±3.70 (m, 2H), 4.08 (q, J=6.3 Hz, 1H), 7.41±7.80 (m, 7H). 13C NMR
(CDCl3) ꢁ: 11.20, 21.60, 22.87, 55.60, 57.31, 58.95, 63.85, 74.44, 125.52 to 127.96, 126.74, 132.87,
133.41, 142.16.
3.42. N-[1-(Furan-2-yl)ethyl]-N-[(1R)-(methoxymethyl)propyl]-N-(2,2,2-tri¯uoroethyl)hydrazine
(R,S)-(+)-50
Starting from LiAlH4 (325 mg, 8.56 mmol) in dry ether (50 ml) and (R)-( )-40 (167 mg, 0.57
mmol) in dry ether (10 ml), the above procedure (see Section 3.38), without chromatography, led
to hydrazine 50 as a colourless oil (113 mg, 67.3%), [ꢀ]D +31.4 (c 0.35, MeOH), d.e.=100%
determined by 13C NMR and 1H NMR. Anal. calcd for C13H21F3N2O2: H, 7.19; N, 9.52. Found:
H, 7.09; N, 9.68. 1H NMR (CDCl3) ꢁ: 0.94 (t, J=7.3 Hz, 3H), 1.00±1.30 (m, 2H), 1.36 (d, J=6.5
Hz, 3H), 2.75±2.83 (m, 1H), 3.09±3.15 (m, 1H), 3.31 (s, 3H), 3.37 (dd, J=4.0 and 9.9 Hz, 1H),
3.46±3.51 (AB, J=9.4 Hz, 2H), 3.98 (q, J=6.5 Hz, 1H), 6.15 (d, J=3.4 Hz, 1H), 6.29 (dd, J=1.8
and 3.1 Hz, 1H), 7.33 (d, J=1.6 Hz, 1H). 13C NMR (CDCl3) ꢁ: 11.65, 18.29, 23.44, 51.60, 55.48,
59.60, 64.39, 74.87, 106.30, 110.57, 125.45, 141.31, 157.10.
References
1. Enders, D. Current Trends in Organic Synthesis; Nozaki, H., Ed.; 1982, pp. 151±168.
2. Takahashi, H.; Tomita, K.; Noguchi, H. Chem. Pharm. Bull. 1981, 29, 3387±3391.
3. Kiyooka, S.; Takeshima, K.; Yamamoto, H.; Suzuki, K. Bull. Chem. Soc. Jpn. 1976, 49, 1897±1900.
4. Bataille, P.; Paterne, M.; Brown, E. Tetrahedron: Asymmetry 1998, 9, 2181±2192.
5. Bataille, P.; Paterne, M.; Brown, E. Tetrahedron: Asymmetry 1999, 10, 1579±1588.
Â
6. (a) Ruault, T. Memoire de D.R.S.U.M.; University of Le Mans, 1989; pp. 46±47; (b) Filoche, B. These de
Doctorat, University of Le Mans, 1992, p. 71.
Â
7. Penfornis, A. Memoire de D.R.S.U.M.; University of Le Mans, 1991; pp. 30±31.