Synthesis of chiral non-racemic 1,2-diamines from O-acetyl mandelic acid: Application in enantioselective deprotonation of epoxides and diethylzinc addition to aldehydes

Article abstract of DOI:10.1016/S0040-4020(02)00376-9

A variety of 1,2-diamines were synthesized from readily available O-acetyl mandelic acid. These diamines were used in the synthesis of key intermediates for the preparation of (-)-utenone A and carbovir involving enantioselective deprotonation of epoxides. The addition of Et₂Zn catalysed by some of these diamines was also studied and although ees were not high, some interesting observations were made in the outcome of the stereochemistry of the product.

Full text of DOI:10.1016/S0040-4020(02)00376-9

TETRAHEDRON
Pergamon
Tetrahedron 58 -2002) 4693±4706
Synthesis of chiral non-racemic 1,2-diamines from O-acetyl
mandelic acid: application in enantioselective deprotonation of
epoxides and diethylzinc addition to aldehydes
P. Saravanan, Alakesh Bisai, S. Baktharaman, M. Chandrasekhar and Vinod K. Singhp
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India
Received 13 December 2001; accepted 13 February 2002
AbstractÐA variety of 1,2-diamines were synthesized from readily available O-acetyl mandelic acid. These diamines were used in the
synthesis of key intermediates for the preparation of -2)-utenone A and carbovir involving enantioselective deprotonation of epoxides. The
addition of Et2Zn catalysed by some of these diamines was also studied and although ees were not high, some interesting observations were
made in the outcome of the stereochemistry of the product. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
metric dihydroxylation, and amino-hydroxylation allowed
access to various enantiomerically pure diols and amino
alcohols. The diol derivatives when activated as mesylates,
cyclic sul®tes, and sulfates showed a good electrophilic
behaviour towards various nitrogen nucleophiles and have
been used for the synthesis of optically active C2 symmetric
vicinal diamines.15,16
Vicinal diamines are very important in organic synthesis,
especially in medicinal chemistry1 and asymmetric syn-
thesis.2 Diamines have extensively been used as chiral
ligands in a variety of asymmetric transformations such as
Mukiyama aldol reactions,3 Michael additions,4 Sharpless
dihydroxylation,5 chiral Lewis acid-based reactions,6 acyl-
ation of alcohols,7 protonation of enolates,8 conjugate
addition9 and desymmetrization of meso ketones10 and
epoxides.11 Due to the usefulness of such chiral non-racemic
1,2-diamines, numerous studies have been aimed at the
design of ef®cient diastereo- and enantioselective synthetic
routes for their acquisition.12 Conceptually, the simplest
procedure for the generation of the 1,2-diamino unit is the
amminolysis of the corresponding vicinal dihalides.
However, this method, which was applied at the beginning
of this century for the preparation of ethylenediamine,
mainly yielded elimination products in more complex
systems.13 Although enantiopure 1,2-disubstituted diamines
have been frequently obtained through resolution,14 other
methods were increasingly employed in their synthesis.
For example, the ef®ciency and scope of sharpless asym-
In the past several years we have been involved in the
enantioselective deprotonation of epoxides using chiral
lithium amide bases derived from diamines 1 -Fig. 1)
which were rationally designed in our laboratory by taking
cyclohexene oxide as a model substrate.17 Using these
diamines, we were able to synthesize a prostaglandin inter-
mediate 2 in as high as 97% ee.17a Following on from our
work, O'Brien and coworkers carried out a study on the
enantioselective deprotonation of epoxides using diamine
1a and synthesized some important chiral intermediates.18
Similar chiral diamines have been used by others for a
variety of enantioselective reactions.19,20 The most
frequently used synthetic route to these diamines starts
with phenylglycine and involves N-protection, amide
formation and reduction. There is, however, a racemization
Figure 1.
Keywords: chiral 1,2-diamines; O-acetyl mandelic acid; enantioselective deprotonation; epoxides; diethylzinc addition; aldehydes.
Corresponding author. Fax: 91-512-597436; e-mail: vinodks@iitk.ac.in
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020-02)00376-9

4694
P. Saravanan et al. / Tetrahedron 58 '2002) 4693±4706
Scheme 1.
problem at the coupling step to an amide which has already
been studied in detail and the problem has been minimized
to a great extent by using 1-hydroxybenzotriazole -HOBT)
in conjunction with DCC and CuCl2.17a However, there still
remained a need for a ¯exible and practical synthesis of
diamines of type 1.
on the opening of an aziridinium ion generated from
1,2-amino alcohol.9 Later on, O'Brien et al. reported a
one-pot method for the synthesis of diamines of type 1
from -R)-styrene oxide.18a In this method, -R)-styrene
oxide was subjected to ring opening with pyrrolidine
under Rossiter's condition to give a mixture of regio-
isomeric amino alcohols in a 70:30 ratio. Since both the
amino alcohols were going to provide the same aziridinium
Rossiter et al. described the synthesis of diamine 1b relying
Table 1. Chiral non-racemic b-acyloxy amides
Entry
Chiral non-racemic amides
Isolated yield -%)
Entry
7
Chiral non-racemic amides
Isolated yield -%)
1
74
70
2
3
86
89
8
9
98
90
4
87
10
11
89
94
5
6
71
92

P. Saravanan et al. / Tetrahedron 58 '2002) 4693±4706
4695
Table 2. Chiral non-racemic b-amino alcohols
Entry
Chiral b-amino alcohols
Isolated yield -%)
Entry
7
Chiral b-amino alcohols
Isolated yield -%)
1
77
89
2
3
96
73
8
9
98
91
4
86
10
11
98
88
5
6
79
95
ion, separation of the major regioisomer was not required.
Therefore, the ring-opened crude product was directly
subjected to mesylation followed by reaction with aqueous
methylamine to obtain the chiral non-racemic diamine 1a in
good yield. However, the one-pot method was only success-
ful when reactive amines such as pyrrolidine and piperidine
were used in the ®rst step. Besides this, the synthesis of
-S)-diamines necessitates the use of expensive -S)-styrene
oxide. So in a further improvement, they showed that
phenylglycinol, which is commercially available in both
enantiomeric forms, can be used as a precursor to synthesize
different N,N-disubstituted diamines.18b The approach is
simple, but the cost factor of phenylglycinol makes it less
practical. In this paper, we describe full details of a more
¯exible method for the synthesis of vicinal diamines of type
1 from a cheap and readily available material.21 The appli-
cation of these diamines in the asymmetric synthesis of
intermediates for natural product synthesis where the key
step would be enantioselective deprotonation of epoxides
and the use of some of the vicinal diamines in enantio-
selective addition of Et2Zn to aldehydes are also described.
-S)-O-acetyl mandelic acid 3 as a white crystalline material
in near quantitative yield. Treatment of 3 with various
amines -primary and secondary) using DCC as condensing
reagent and HOBT/CuCl2 as a deracemizing additive, gave
the desired amides 4a±4k in good yields -Table 1). The
amides were treated with lithium aluminum hydride in
tetrahydrofuran -THF) under re¯ux conditions to provide
amino alcohols 5a±5k in very good yields -Table 2). During
the reduction, both amide and acetate groups were reduced
in one step without racemization and the resulting products
were pure enough for further reactions. Thus, the b-amino
alcohols obtained from reactions with secondary amines
were converted into various diamines using O'Brien's
one-pot method.18a Treatment of b-amino alcohols 5 with
methanesulfonyl chloride in the presence of Et3N in diethyl
ether led to the formation of aziridinium ion 7b, which was
opened with various aliphatic and aromatic amines at
room temperature to provide diamines in excellent yields.
Initially, aqueous solutions of methylamine and ammonia
were used for the opening of aziridinium ion. Later, it
was realized that the presence of water -5±10 equiv.) was
essential for a successful ring opening reaction. So, in all of
the cases studied, some water was added just before addition
of the amine. It was assumed that water might be respon-
sible for dissolving the aziridinium ion. It was also neces-
sary to use a large excess of low boiling amines
-methylamine, ammonia, and tert-butylamine). In the case
of high boiling amines, 1.0±5.0 equiv. of amines was
enough for completion of the reaction.
2. Results and discussion
We have developed a synthesis of chiral non-racemic
diamines from mandelic acid, a starting material which is
cheap and commercially available in both enantiomeric
forms. The synthetic route for the preparation of vicinal
diamines is depicted in Scheme 1. -S)-Mandelic acid was
treated with neat acetyl chloride at room temperature to give
The presence of a benzylic position in the aziridinium ion

4696
P. Saravanan et al. / Tetrahedron 58 '2002) 4693±4706
Scheme 2.
7b increases the regio- and stereoselectivity towards various
nucleophiles during the ring opening reaction -Scheme 2).
In the case of aziridinium ion opening with primary amines,
products 1, that contain deprotonable proton at one of the
amine sites -protic b-diamines) were obtained -Table 3).
Similarly, secondary amines gave aprotic diamines 6
-Table 4). Even less nucleophilic amines such as aniline,
b-naphthylamines, and other aromatic amines gave
diamines in good yield -Table 3, entries 7, 8, 11, 12and
16). Even hindered amines opened the aziridinium ion in an
ef®cient manner -Table 3, entries 7 and 13). The ring
opening was smooth for acyclic and cyclic amines -Table 4).
of aziridinium ions has also been postulated in substitution
reactions of amino tosylates and in the Mitsunobu reactions
of amino alcohols.23 In order to prove the regio- and stereo-
speci®city in the opening of aziridinium ion 7b, it was
allowed to react with -R)-a-methylbenzylamine to provide
the diamine 1j. The absence of the -R,R) diastereomeric
peak in the 1H NMR spectrum indicated that the ring
opening reaction was stereospeci®c -Table 3, entry 10).
Comparison of the speci®c rotation value of the diamine
25
-S)-1a {[a]D ˆ197.5 -cˆ2.7, CHCl3)} with the literature
25
value17a {[a]D ˆ291.6 -cˆ1.8, CHCl3) for -R)-1a} indi-
cated that there was no racemization during the synthesis of
the diamines, and this was also con®rmed by chiral HPLC
analysis. The net retention of con®guration observed in
these substitution reactions suggested the neighbouring
The postulation of an aziridinium ion intermediate is based
on literature precedent of similar reactions.22 The existence
Table 3. Chiral non-racemic protic b-diamines
Entry
Chiral non-racemic diamines
Yield -%)
Entry
9
Chiral non-racemic diamines
Yield -%)
1
80
80
2
3
4
96
88
90
10
11
12
87
88
95
5
6
80
85
13
14
96
92
7
8
80
77
15
16
88
87

P. Saravanan et al. / Tetrahedron 58 '2002) 4693±4706
4697
Table 4. Chiral non-racemic aprotic b-diamines
Entry
Chiral non-racemic diamines
Yield -%)
Entry
10
Chiral non-racemic diamines
Yield -%)
1
96
94
2
3
6211
99
87
71
12
4
5
6
7
73
60
78
80
13
14
15
16
75
75
75
74
8
9
80
99
group participation by the tertiary amine functionality in the
amino alcohol 5 -Scheme 2) followed by nucleophilic attack
of the external amine at the benzylic position. This was in
contrast to episelenium and episulfonium ions, which
partially racemize during Ritter type substitution reac-
tions.24 Thus, we have developed a convenient approach
to amino alcohols and diamines of type 1 and 6 starting
from mandelic acid.
Recently, we discovered17 that the CNLA base derived
from diamine 1a was an excellent chiral base for enantio-
selective deprotonation of epoxides. In order to extend its
scope further, we report here the application of both the
enantiomers of the chiral diamine 1 in the synthesis of
important cyclopentanoid intermediates -Fig. 2). Enantio-
selective deprotonation of epoxide 826 with a base derived
from diamine -R)-1a under Asami's conditions26b was
carried out to give 9 in 83% yield and 94% ee. Allylic
alcohol 9 is an intermediate26b in the synthesis of utenone
A 1027 which is an antileukemic and considered to be a
biosynthetic precursor of other marine natural products.28
Similarly, we have extended the application of our chiral
base chemistry in the synthesis of -2)-carbovir 11, an
The enantioselective deprotonation of symmetrical epoxides
to give optically active allylic alcohols using non-enzymatic
methods, where enantiotopic proton selection takes place by
means of a chiral non-racemic lithium amide -CNLA) base,
is a very challenging area in asymmetric synthesis.25

4698
P. Saravanan et al. / Tetrahedron 58 '2002) 4693±4706
Figure 2.
Scheme 3.
anti-HIV agent. Enantioselective deprotonation of epoxide
1229 with -S)-1a in THF gave an intermediate 13 in 20%
yield and 80% ee.30 The change of solvent to benzene lowered
the yield to 14% and the enantioselectivity to 40%. The
synthetic utility of 13 has already been shown in the literature
by converting it into the anti-HIV agent 1130c Since the trans-
isomer of the epoxide 12 is also known to be converted into
-2)-carbovir,30a we studied the enantioselective deprotonation
of the trans-epoxide with -R)-1a and observed a poor enantio-
selectivity -27% ee). This is not surprising in view of our
previous experience in this area.17
on this chiral diamine failed to give any asymmetric
induction.
We then changed our attention to study the addition of
diethylzinc to aldehydes catalysed by chiral non-racemic
diamines of the type 1. For the initial studies, the reaction
of benzaldehyde was examined in different solvents using
diamine -R)-1a, and it was found that cyclohexane was a
better solvent than hexane and toluene. Under these con-
ditions, -S)-1-phenyl-1-propanol was obtained in 47% ee.
The reaction with other aldehydes is summarized in Table
5. In all cases, ligand -R)-1a gave alcohols of -S)-con®gu-
ration.36 It was observed that aromatic aldehydes with
electron withdrawing groups gave slightly higher enantio-
selectivity -Table 5; entries 5 and 6).
The catalytic enantioselective addition of diethylzinc to
aldehydes is an important method for preparing chiral
secondary alcohols.31 Most of the successful results have
been obtained by using b-amino alcohols as chiral ligands.32
Although diamines were also reported to show catalytic
activity, there are only a few examples.33 Asami,34 and
recently Brunel et al.35 have used proline-based diamines
in this type of reaction and reported a maximum of 80% ee
for the diethylzinc addition to benzaldehyde.
The effect of other chiral diamines was then examined under
the same reaction conditions using p-chlorobenzaldehyde as
a model substrate, and the results are summarized in Table
6. Although the enantioselectivity remained modest, the
stereochemical outcome of the reaction was quite unprece-
dented. The absolute stereochemistry of the products
depended upon the steric size substituent on the nitrogen
attached to the chiral centre. In diamines with a N±Me
group, the absolute stereochemistry of the newly formed
hydroxyl group was opposite to that of the ligand
We were interested to examine the effectiveness of diamines
1 in the addition of diethylzinc to enones and aldehydes. At
the outset, a conjugate addition to chalcone using 1.8 equiv.
of diethylzinc in the presence of Ni-acac)2 and diamine
-R)-1a -20 mol%) was carried out. The product was
obtained in good yield, but there was no asymmetric induc-
tion in the reaction -Scheme 3). Changing the substituents
Table 6. Enantioselective addition of Et2Zn to 4-chlorobenzaldehyde cata-
lysed by -R)- or -S)-1
Table 5. Enantioselective addition of Et2Zn to aldehydes catalysed by -R)-
1a
Entry
Diamine
Yield -%)
ee -%)a
1
2
3
4
5
6
7
8
9
10
-R)-1a
-R)-1b
-R)-1c
-S)-1d
-S)-1e
-S)-1f
-S)-1h
-S)-1j
-S)-1m
-S)-1o
88
9266 -
81
826 -
94
83
74
87
95
80
53 -S)
S)
65 -S)
R)
50 -R)
44 -R)
2- S)
68 -S)
58 -S)
4 -S)
Entry
1
Substrate
67
4-Methoxybenzaldehyde
4-Methylbenzaldehyde
4-Chlorobenzaldehyde
4-Fluorobenzaldehyde
Ferrocenealdehyde
Yield -%)
ee -%)a
Benzaldehyde
84
47
,4,6-Trim2e2thylbenzaldehyde
46
3
4
5
6
7
9237
76
88
77
65
38
53
54
71
a
a
Ee -%) was determined by analysis of 400 MHz 1H NMR spectrum of
Mosher esters.
Ee -%) was determined by analysis of 400 MHz 1H NMR spectrum of
Mosher esters.

P. Saravanan et al. / Tetrahedron 58 '2002) 4693±4706
4699
Figure 3.
stereochemistry -Table 6, entries 1±6). However, for sub-
stituents sterically larger than a N±Me group, the reverse
was true -Table 6, entries 7±10).
organic extracts were dried over anhydrous sodium sulfate.
Evaporation of solvents was performed at reduced pressure.
THF and diethyl ether were distilled from sodium
benzophenone ketyl under nitrogen. Benzene and dichloro-
methane were distilled from CaH2. N,N-Dimethylforma-
mide -DMF) was distilled from CaH2 at reduced pressure.
Pyridine was distilled from CaH2 at atmospheric pressure.
The sense of asymmetric induction in the diethylzinc
addition reaction can be explained by favourable transition
state models as depicted in Fig. 3. If R is Me group, it orients
itself cis to the phenyl group at the chiral centre. Then,
Et2Zn coordinates to the N atom trans to the phenyl
group. The aldehyde then approaches the metal in the
most appropriate manner -si face attack). Thus the product
with opposite stereochemistry, as compared to the ligand
con®guration, is obtained. In the case of ligands when R
is larger than a Me group, the R-group prefers to orientate
itself in a trans fashion with respect to the phenyl group at
the chiral centre. In this kind of situation, the re face of the
aldehyde will be preferred for the addition reaction, thus
giving the product with the same stereochemistry as the
chiral ligand.
4.1.1. 0S)-O-Acetyl mandelic acid 03). -S)-Mandelic acid
-25 g, 165 mmol) was added to acetyl chloride -59 mL,
825 mmol) portionwise -®ve times) at rt and stirred over-
night. The volatile materials were removed in vacuo.
Crystallization of the crude material from benzene gave
the pure product as a white crystalline powder -30 g,
94%); mp 96±988C -lit.37 mp 95±97.58C).
4.2. General procedure for couplingof 0 S)-O-acetyl
mandelic acid with various amines
To a mixture of -S)-O-acetyl mandelic acid -5 g, 25 mmol),
anhydrous CuCl2 -4 g, 30 mmol), and HOBT -4.1 g,
30 mmol) in dry DMF -100 mL) was added dropwise a
solution of DCC -6.2g, 30 mmol) in DMF -15 mL) at
08C, and the mixture was stirred for 30 min. Amine
-50 mmol) was added and the stirring was continued for
24 h -08C, rt). The reaction mixture was diluted with
EtOAc -100 mL) and washed with cold 0.1N HCl, saturated
NaHCO3, and brine. The organic layer was dried over
anhydrous sodium sulfate, and the solvent was evaporated
in vacuo. The crude material was puri®ed by column
chromatography on silica gel using petroleum ether±
EtOAc as eluent to give the pure amides 4 -Table 1).
3. Conclusion
In conclusion, we have presented a versatile and practical
method for the synthesis of -S)-chiral diamines from
-S)-O-acetyl mandelic acid. A variety of amino alcohols
and diamines were synthesized in high yields. We have
shown application of some of the diamines in the synthesis
of key intermediates for natural products and drug
compounds. We have also studied Et2Zn addition reactions
catalysed by some of the diamines. Although ees were not
high, some interesting observations were made in the
outcome of the stereochemistry of the product.
4.2.1. S01)-N-Isopropyl-O-acetyl mandelamide 04a).
Yield 74% as a white solid; mp 94±988C; Rf 0.60 -50%
25
4. Experimental
4.1. General
EtOAc in petroleum ether); [a]D ˆ194.7 -cˆ1.0,
CHCl3); IR -KBr) 1620, 1730 cm21 1H NMR -CDCl3,
;
400 MHz) d 1.07 -d, Jˆ6 Hz, 6H), 2.09 -s, 3H),
3.98±4.05 -m, 1H), 5.94±6.07 -m, 2H), 7.20±7.45 -m, Ph,
5H). Anal. calcd for C13H17NO3: C, 66.38; H, 7.23; N, 5.95;
found: C, 66.42; H, 7.18; N, 5.98.
1H NMR spectra were recorded on 60, 300, and 400 MHz
Jeol spectrometers. Chemical shifts are expressed in part per
million down®eld from TMS as an internal standard, and
coupling constants are reported in hertz. Routine monitoring
of reactions was performed using silica gel-G obtained from
Acme. All the column chromatographic separations were
done by using silica gel -Acme's, 60±120 mesh). Petroleum
ether used was of boiling range 60±808C. Reactions which
needed anhydrous conditions were run under an atmosphere
of dry nitrogen or argon using ¯ame-dried glassware. The
4.2.2. S01)-N-tert-Butyl-O-acetyl mandelamide 04b).
Yield 86% as a white solid; mp 74±798C; Rf 0.65 -50%
25
EtOAc in petroleum ether); [a]D ˆ169.7 -cˆ6.25,
CHCl3); IR -KBr) 1710 cm21
;
1H NMR -CDCl3,
400 MHz) d 1.48 -s, 9H), 2.10 -s, 3H), 5.85±5.92 -m,
2H), 7.41±7.48 -m, Ph, 5H). Anal. calcd for C14H19NO3:
C, 67.46; H, 7.63; N, 5.62; found: C, 67.24; H, 7.83; N, 5.68.

4700
P. Saravanan et al. / Tetrahedron 58 '2002) 4693±4706
4.2.3.
S01)-N-[O-0Acetyl)mandelyl]THF-2-yl-methyl-
calcd for C14H17NO4: C, 63.87; H, 6.46; N, 5.32; found: C,
63.80; H, 6.24; N, 5.38.
amine 04c). Yield 89% -mixture of diastereomers) as a
viscous liquid; Rf 0.70 -50% EtOAc in petroleum ether);
IR -neat) 3010, 1730, 1625, 1220, 830 cm21; H NMR
1
4.2.10. 0S)-1-[O-0Acetyl)mandelyl]tetrahydroisoquino-
line 04j). Yield 89% as a white solid; mp 104±1068C; Rf
-CCl4, 60 MHz) d 1.82-m, 4H), 2.12-s, 3H), 2.78 -m,
1H), 3.30 -m, 1H), 3.72-m, 3H), 6.05 -s, 1H), 7.40 -s, 5H,
Ph). Anal. calcd for C15H19NO4: C, 64.98; H, 6.85; N, 5.05;
found: C, 65.12; H, 6.89; N, 5.18.
25
0.50 -25% EtOAc in petroleum ether); [a]D ˆ1190.8
-cˆ1.0, CHCl3); IR -KBr) 3030, 1720, 1630, 1200 cm21
;
1H NMR -CDCl3) d 2.18 -s, 3H), 2.30±2.90 -m, 2H),
3.50±3.90 -m, 2H), 4.60±4.90 -m, 2H), 6.34 -s, 1H),
7.04±7.47 -m, 9H); MS -CI, m/z): 310 -M111), 250, 222
-base peaks). Anal. calcd for C19H19NO3: C, 73.78; H, 6.14;
N, 4.53; found: C, 73.63; H, 6.26; N, 4.68.
4.2.4. S01)-N-Benzyl-O-acetyl mandelamide 04d). Yield
86% as a white solid; Rf 0.90 -50% EtOAc in petroleum
25
ether); [a]D ˆ1120.3 -cˆ4.7, CHCl3); IR -KBr) 2960,
1730, 1620, 850, 720 cm21; H NMR -CCl4, 60 MHz) d
1
4.2.11. 0S)01)-N-[0R)-a-Methylbenzyl]-O-acetyl mandel-
amide 04k). Yield 94% as a white solid; mp 126±1288C; Rf
2.20 -s, 3H), 4.20 -d, Jˆ6 Hz, 2H), 5.96 -s, 1H), 7.1±7.58
-m, 10H, Ph). Anal. calcd for C17H17NO3: C, 72.08; H, 6.01;
N, 4.95; found: C, 71.83; H, 6.10; N, 4.98.
25
0.70 -50% EtOAc in petroleum ether); [a]D ˆ1282
-cˆ1.0, CHCl3); IR -KBr) 3320, 1730, 1650, 1220 cm21
;
1H NMR -CDCl3, 300 MHz) d 1.49 -d, Jˆ6.9 Hz, 3H),
2.16 -s, 3H), 5.18 -quintet, Jˆ7 Hz, 1H), 6.08 -s, 1H),
6.32±6.34 -bd, Jˆ7 Hz, 1H, ±NH), 7.29±7.36 -m, 10H);
MS -CI, m/z): 298 -M111) -base peak), 238. Anal. calcd
for C18H19NO3: C, 72.71; H, 6.39; N, 4.71; found: C, 72.64;
H, 6.26; N, 4.68.
4.2.5. S01)-N,N-Diallyl-O-acetyl mandelamide 04e).
Yield 71% as a white solid; mp 68±708C; Rf 0.80 -25%
25
EtOAc in petroleum ether); [a]D ˆ1157 -cˆ1.0,
CHCl3); IR -KBr) 3010, 1720, 1630 cm21 1H NMR
;
-CDCl3, 300 MHz) d 2.15 -s, 3H), 3.70±3.90 -m, 3H),
4.17 -dd, Jˆ15, 6 Hz, 1H), 5.0±5.21 -m, 4H), 5.50±5.61
-m, 1H), 5.61±5.80 -m, 1H), 6.18 -s, 1H), 7.39±7.50 -m,
Ph, 5H); MS -CI, m/z): 274 -M1). Anal. calcd for
C16H19NO3: C, 70.32; H, 6.95; N, 5.12; found: C, 70.46;
H, 6.73; N, 5.34.
4.3. General procedure for LAH reduction of
0S)-O-acetyl mandelamides
To a suspension of LAH -20 mmol) in THF -50 mL), was
added amide 4 -5 mmol) in THF -10 mL) at rt and it was
re¯uxed for 12h. Excess LAH was destroyed by addition of
EtOAc -0.5 mL). After cooling to 08C, water was added
-0.5 mL), followed by the 4N NaOH -0.5 mL). After
5 min, 1.5 mL water was added and the mixture was stirred
for 15 min. Resulting white precipitate was ®ltered through
celite, ®ltrate was dried over anhydrous sodium sulfate, and
solvent was removed in vacuo. The resulting crude material
was pure enough for further reaction. In a few cases it was
necessary to purify. For analytical purpose, most of the
samples were puri®ed over silica gel column chroma-
tography using petroleum ether±EtOAc as eluent to afford
the pure amino alcohols 5 -Table 2).
4.2.6. 0S)-1-[O-0Acetyl)mandelyl]pyrrolidine 04f). Yield
92% as white solid; mp 116±1188C; Rf 0.40 -50% EtOAc
25
in petroleum ether); [a]D1 ˆ1146.9 -cˆ4.2, CHCl3); IR
-KBr) 1710, 1620 cm21; H NMR -CDCl3, 300 MHz) d
1.65±2.0 -m, 4H), 2.15 -s, 3H), 3.0±3.15 -m, 1H), 3.36±
3.44 -m, 1H), 3.53±3.66 -m, 2H), 6.02 -s, 1H), 7.36±7.59
-m, Ph, 5H); MS -CI, m/z): 248 -M111), 188 -base peak).
Anal. calcd for C14H17NO3: C, 68.01; H, 6.88; N, 5.66;
found: C, 68.26; H, 6.88; N, 5.64.
4.2.7. 0S)-1-[O-0Acetyl)mandelyl]-2-[0S)-methoxymethyl]-
pyrrolidine 04g). Yield 70% as a white solid; mp
96±1008C; Rf 0.60 -50% EtOAc in petroleum ether);
25
[a]D ˆ170.76 -cˆ1.0, CHCl3); IR -KBr) 1720,
1
1060 cm21; H NMR -CDCl3, 300 MHz) d 1.70±1.95 -m,
4.3.1. 0S)-2-0isopropylamino)-1-phenylethanol 05a). Yield
77% as a white solid; mp 68±728C; Rf 0.20 -50% EtOAc in
2H), 2.15 -s, 3H), 3.10±3.62 -m, 4H), 3.20 -s, 3H), 4.30 -m,
3H), 6.0 -s, 1H), 7.30±7.60 -m, Ph, 5H); MS -CI, m/z): 292
-M111). Anal. calcd for C16H21NO4: C, 65.97; H, 7.21; N,
4.81; found: C, 65.67; H, 7.46; N, 4.79.
25
petroleum ether); [a]D ˆ152.5 -cˆ4.0, CHCl3); IR -KBr)
3450, 3340, 860 cm21; 1H NMR -CDCl3, 400 MHz) d 0.96
-d, Jˆ9 Hz, 6H), 2.49±2.65 -m, 2H), 3.40±3.53 -m, 1H),
4.01 -bs, 1H, OH), 4.58±4.65 -m, 1H), 7.33 -m, 5H, Ph).
Anal. calcd for C11H17NO: C, 73.74; H, 9.49; N, 7.82;
found: C, 73.34; H, 9.41; N, 7.72.
4.2.8. 0S)-1-[O-0Acetyl)mandelyl]piperidine 04h). Yield
98% as a white solid; mp 107±1088C; Rf 0.60 -50%
25
EtOAc in petroleum ether); [a]D ˆ1119 -cˆ3.0,
CHCl3); IR -KBr) 1710, 1620, 1220 cm21 1H NMR
;
4.3.2. 0S)-2-0tert-Butylamino)-1-phenylethanol) 05b).
Yield 96% as a white solid; mp 69±718C; Rf 0.20 -50%
-CDCl3, 300 MHz) d 1.38±1.80 -m, 6H), 2.15 -s, 3H),
3.20±3.75 -m, 4H), 6.20 -s, 1H), 7.30±7.50 -m, Ph, 5H);
MS -CI, m/z): 262 -M111). Anal. calcd for C15H19NO3: C,
68.96; H, 7.27; N, 5.36; found: C, 68.92; H, 7.34; N, 5.30.
25
EtOAc in petroleum ether); [a]D ˆ145.1 -cˆ1.75,
1
CHCl3); IR -KBr) 3500, 3010, 2930, 760 cm21; H NMR
-CDCl3, 400 MHz) d 1.08 -s, 9H), 2.20±2.74 -m, 2H),
3.49±3.66 -bs, 1H, OH), 4.58±4.66 -m, 1H), 7.28 -m, 5H,
Ph). Anal. calcd for C12H19NO: C, 74.61; H, 9.84; N, 7.25;
found: C, 74.48; H, 9.78; N, 7.30.
4.2.9. 0S)-1-[O-0Acetyl)mandelyl]morpholine 04i). Yield
90% as a white solid; mp 92±938C; Rf 0.50 -50% EtOAc
25
in petroleum ether); [a]D1 ˆ1118.4 -cˆ4.6, CHCl3); IR
-KBr) 1725, 1620 cm21; H NMR -CDCl3, 300 MHz) d
2.16 -s, 3H), 3.15±3.78 -m, 8H), 6.20 -s, 1H), 7.40 -s, Ph,
5H); MS -CI, m/z): 264 -M111), 176 -base peak); Anal.
4.3.3.
0S)-1-Phenyl-2-[0tetrahydrofuran-2-ylmethyl)-
amino]-ethanol 05c). Yield 73% as a viscous liquid; Rf
0.30 -50% EtOAc in petroleum ether); IR -neat) 3450,

P. Saravanan et al. / Tetrahedron 58 '2002) 4693±4706
4701
1220, 830, 750 cm21; 1H NMR -CDCl3, 400 MHz) d 1.09±
1.89 -m, 4H), 2.54±2.73 -m, 3H), 3.56±3.87 -m, 5H),
4.67 -m, 1H), 7.35 -m, 5H, Ph). Anal. calcd for
C13H19NO2: C, 70.58; H, 8.59; N, 6.33; found: C, 70.72;
H, 8.62; N, 6.29.
4.3.10. 0S)-2-0Tetrahydroisoquinolin-1-yl)-1-phenyletha-
nol 05j). Yield 98% as a white solid; mp 75±778C; Rf 0.80
25
-50% EtOAc in petroleum ether); [a]D ˆ164.0 -cˆ1.0,
;
CHCl3); IR -KBr) 3350, 3020, 830 cm21 1H NMR
-CDCl3, 400 MHz) d 2.60±2.80 -m, 4H), 2.90±3.10 -m,
2H), 3.68 -d, Jˆ14 Hz, 1H), 3.94 -d, Jˆ14 Hz, 1H), 4.86
-dd, Jˆ9.0, 3.0 Hz, 1H), 7.35 -m, 9H, aromatics); MS -m/z):
254 -M111) -base peak), 236. Anal. calcd for C17H19NO: C,
80.63; H, 7.50; N, 5.53; found: C, 80.61; H, 7.46; N, 5.62.
4.3.4. 0S)-2-0Benzylamino)-1-phenylethanol 05d). Yield
86% as a white solid; Rf 0.5 -50% EtOAc in petroleum
25
ether); [a]D ˆ159.7 -cˆ1.0, CHCl3); IR -KBr) 3470,
1
3020, 2950, 760 cm21; H NMR -CCl4, 60 MHz) d 3.65
4.3.11. 0S)-2-[0R)-a-Methylbenzylamino)]-1-phenyl-
ethanol 05k). Yield 88% as white solid; mp 124±1308C;
-m, 4H), 4.72-m, 1H), 7.34 -m, 10H, Ph).). Anal. calcd
for C15H17NO: C, 79.79; H, 7.49; N, 6.17; found: C,
79.90; H, 7.56; N, 6.18.
25
Rf 0.80 -50% EtOAc in petroleum ether); [a]D ˆ1134.0
-cˆ1.45, CHCl3) {lit.38 [a]D ˆ2111.0 -cˆ1, CHCl3) for
25
R,S isomer}.
4.3.5. 0S)-2-0N,N-Diallylamino)-1-phenylethanol 05e).
Yield 79% as a viscous liquid; Rf 0.80 -25% EtOAc in
25
4.4. General procedure for synthesis of diamine 118
petroleum ether); [a]D ˆ158.6 -cˆ4.12, CHCl3); IR
-neat) 3420, 3020, 1420 cm21 1H NMR -CDCl3, 400
;
MHz) d 2.40±2.60 -m, 3H), 3.10±3.40 -m, 3H), 4.60±
4.75 -m, 1H), 5.15±5.20 -m, 4H), 5.80±6.0 -m, 2H), 7.35
-m, 5H, Ph); MS -m/z): 219 -M112), 218 -M111), 202
-base peak), 200. Anal. calcd for C14H19NO: C, 77.41; H,
8.75; N, 6.45; found: C, 77.52; H, 8.64; N, 6.89.
To a stirred solution of amino alcohol 5 -5 mmol) in dry
ether -20 mL) was added Et3N -2mL, 15 mmol) at rt. It was
cooled to 08C, and methanesulfonyl chloride -0.465 mL,
6 mmol) was added dropwise. The resulting reaction
mixture became dif®cult to stir. After 30 min, more Et3N
-1.4 mL, 10 mmol) and the corresponding amine -1±50
equiv. was used; see Section 2), and water -10 equiv.)
were added and the resulting biphasic reaction mixture
was stirred at 08C to rt for 20 h. The organic and aqueous
layers were separated, and the aqueous layer was extracted
with diethyl ether -three times). The combined ether extracts
were washed with saturated NaHCO3 and brine. The organic
layer was dried over anhydrous sodium sulfate and concen-
trated in vacuo. Methyl amine substituted diamines -Table
3; entries 1±6) were puri®ed by Kugelrohr distillation.
Other diamines -Table 3; entries 7±16) were puri®ed by
column chromatography over silica gel using EtOAc±
petroleum ether as eluent to afford the pure diamines 1.
4.3.6. 0S)-2-0Pyrrolidin-1-yl)-1-phenylethanol 05f). Yield
95% as a white solid; mp 68±698C; Rf 0.20 -50% EtOAc in
25
petroleum ether); [a]D ˆ151.5 -cˆ1.3, CHCl3) {lit.31b
27
[a]D
143.88 -cˆ0.96, MeOH)}; IR -KBr) 3500,
1100 cm21; H NMR -CDCl3, 400 MHz) d 1.70±1.85 -m,
4H), 2.45±2.55 -m, 3H), 2.73±2.78 -m, 3H), 4.70 -dd, Jˆ9,
3 Hz, 1H), 7.34 -m, 5H, Ph); MS -m/z): 192-M 111), 174.
Anal. calcd for C12H17NO: C, 75.39; H, 8.90; N, 7.32;
found: C, 75.42; H, 8.76; N, 7.62.
1
4.3.7. 0S)-2-[0S)-20-Methoxymethylpyrrolidin-1-yl)]-1-
phenylethanol 05g). Yield 89% as a viscous liquid; Rf
25
0.60 -50% EtOAc in petroleum ether); [a]D ˆ194.2
-cˆ6.8, CHCl3); IR -neat) 3450, 1120 cm21
;
1H NMR
Aprotic diamines 6 were prepared as per the general pro-
cedure mentioned above, except that the reactions with the
amines were carried out for 48 h at rt. All the aprotic
diamines were puri®ed by column chromatography over
silica gel using EtOAc±petroleum ether as eluent -Table 4).
-CCl4, 60 MHz) d 1.50±1.85 -m, 4H), 2.20±3.10 -m, 6H),
3.40 -s, 3H), 3.45 -m, 1H), 4.0 -bs, 1H, OH), 4.75 -m, 1H),
7.33 -m, 5H, Ph); MS -m/z): 236 -M111), 218. Anal. calcd
for C14H21NO2: C, 71.48; H, 8.93; N, 5.95; found: C, 71.93;
H, 8.74; N, 6.02.
4.4.1. 0S)-N-Methyl-1-phenyl-2-0pyrrolidin-1-yl)ethana-
mine 01a). Yield 80% as a yellow viscous liquid; bp
4.3.8. 0S)-2-0Piperdin-1-yl)-1-phenylethanol 05h).31b
Yield 99% as a white solid; mp 84±858C; Rf 0.60 -50%
25
1188C -1 mm); Rf 0.70 -10% MeOH in DCM); [a]D
ˆ
25
25
182.5 -cˆ5.5, CHCl3) {lit.17 [a]D ˆ264.0 -cˆ1.4,
EtOH) for R enantiomer}.
EtOAc in petroleum ether); [a]D ˆ181.4 -cˆ1.0,
CHCl3); 1H NMR -CDCl3, 400 MHz) d 1.40±1.75 -m,
6H), 2.35±2.50 -m, 4H), 2.60±2.80 -m, 2H), 4.71 -dd,
Jˆ12, 4 Hz, 1H), 7.34 -m, 5H, Ph).
4.4.2. 0S)-N-Methyl-1-phenyl-2-0piperidin-1-yl)ethana-
mine 01b). Yield 96% as a colourless oil; Rf 0.80 -10%
25
MeOH in DCM); [a]D ˆ197.5 -cˆ2.7, CHCl3) {lit.17
4.3.9. 0S)-2-0Morpholin-1-yl)-1-phenylethanol 05i). Yield
91% as a white solid; mp 96±988C; Rf 0.50 -50% EtOAc
in petroleum ether); 96% ee -chiracel OD column 0.46£
25
[a]D ˆ291.6 -cˆ1.8, CHCl3) for R enantiomer}.
2
2 5 cm, solvent: hexane/isopropanol ratio 90:10; ¯ow rate
4.4.3. 0S)-N-Methyl-1-phenyl-2-0morpholin-1-yl)ethana-
mine 01c). Yield 88% as a colourless liquid; Rf 0.75 -10%
0.5 mL/min; UV 254 nm; RT: 15.6 min for S-enantiomer
25
MeOH in DCM); [a]D ˆ193.1 -cˆ2.9, CHCl3) {lit.17
25
and 14.65 min for R-enantiomer); [a]D ˆ161.8 -cˆ2.7,
CHCl3); IR -KBr) 3450, 3030, 760 cm21
;
1H NMR
25
[a]D ˆ292.0 -cˆ1.2, CHCl3) for R enantiomer}.
-CDCl3, 400 MHz) d 2.40±2.61 -m, 6H), 2.75 -bs, 1H,
OH), 3.70±3.80 -m, 4H), 4.75 -dd, Jˆ9, 3.5 Hz, 1H), 7.33
-m, 5H, Ph); MS -m/z) 208 -M111), 190 -base peak). Anal.
calcd for C12H17NO2: C, 69.56; H, 8.21; N, 6.76; found: C,
69.82; H, 8.24; N, 6.84.
4.4.4. 0S)-N-Methyl-1-phenyl-2-0N,N-diallylamino)ethana-
mine 01d). Yield 90% as a viscous liquid; Rf 0.70 -5%
25
MeOH in DCM); [a]D ˆ183.1 -cˆ4.9, CHCl3); IR
-neat) 3330, 3020, 2960, 1680, 750 cm21
;
1H NMR

4702
P. Saravanan et al. / Tetrahedron 58 '2002) 4693±4706
-CDCl3, 400 MHz) d 2.28 -s, 3H), 2.32±2.70 -m, 3H),
2.90±3.10 -m, 2H), 3.20±3.40 -m, 2H), 3.53±3.62 -m,
1H), 5.10±5.22 -m, 4H), 5.79±5.92 -m, 2H), 7.20±7.40
-m, 5H, Ph); MS -CI, m/z) 232 -M112), 231 -M111),
200. Anal. calcd for C15H22N2: C, 78.26; H, 9.56; N,
12.17; found: C, 78.34; H, 9.42; N, 12.24.
63±648C; Rf 0.70 -10% EtOAc in petroleum ether);
25
[a]D ˆ17.2- cˆ6.5, CHCl3); IR -KBr) 3350, 3030,
1
2920, 2800, 1600, 820 cm21; H NMR -CDCl3, 400 MHz)
d 1.40±1.62 -m, 6H), 2.20±2.40 -bs, 2H), 2.42±2.60 -m,
4H), 4.29 -dd, Jˆ7.5, 2.5 Hz, 1H), 5.34 -bs, 1H, ±NH), 6.55
-d, Jˆ7.6 Hz, 2H), 6.68 -t, Jˆ7 Hz, 1H), 7.10 -t, Jˆ7 Hz,
2H), 7.25±7.28 -m, 1H), 7.35 -t, Jˆ8 Hz, 2H), 7.44 -d,
Jˆ7.5 Hz, 2H); MS -CI, m/z): 282 -M112), 281 -M111),
279, 250. Anal. calcd for C19H24N2: C, 81.42; H, 8.57; N,
10.00; found: C, 81.72; H, 8.63; N, 10.12.
4.4.5. 0S)-N-Methyl-1-phenyl-2-[0S)-20-0methoxymethyl-
pyrrolidin-1-yl)ethanamine 01e). Yield 82% as a viscous
25
liquid; Rf 0.80 -10% MeOH in DCM); [a]D ˆ116.0
-cˆ1.75, CHCl3); IR -neat) 3420, 1150, 860 cm21
;
1H
NMR -CCl4, 60 MHz) d 1.40±1.92-m, 4H), 2.30±3.02
4.4.12.
0S)-N-b-Naphthyl-1-phenyl-2-0piperidin-1-
-m, 7H), 3.30 -s, 3H), 3.95 -s, 1H, ±NH), 4.72-m, 1H),
7.26 -m, 5H, Ph); MS -CI, m/z): 250 -M112), 249
-M111), 218 -base peak). Anal. calcd for C15H24N2O: C,
72.58; H, 9.67; N, 11.29; found: C, 72.64; H, 9.82; N, 11.46.
yl)ethanamine 01l). Yield 95% as a white solid; mp 90±
928C; Rf 0.70 -10% EtOAc in petroleum ether);
25
[a]D ˆ131.2- cˆ7.6, CHCl3); IR -KBr) 3300, 3020,
2910, 2800, 1620, 830, 750 cm21 1H NMR -CDCl3,
;
400 MHz) d 1.48 -m, 2H), 1.62 -m, 4H), 2.34 -bs, 2H),
2.6 -m, 4H), 4.41 -dd, Jˆ7, 2.5 Hz, 1H), 5.51 -s, 1H,
±NH), 6.56 -d, Jˆ2Hz, 1H), 7.01 -dd, Jˆ9, 2Hz, 1H),
7.15 -t, Jˆ6.0 Hz, 1H), 7.27 -t, Jˆ7.5 Hz, 2H), 7.36 -t,
Jˆ7.5 Hz, 2H), 7.41 -d, Jˆ7 Hz, 1H), 7.49 -d, Jˆ7.5 Hz,
2H), 7.62 -d, Jˆ9 Hz, 1H), 7.66 -d, Jˆ9 Hz, 1H). Anal.
calcd for C23H26N2: C, 83.64; H, 7.88; N, 8.48; found: C,
83.88; H, 7.92.
4.4.6. 0S)-N-Methyl-1-phenyl-2-0tetrahydroisoquinolin-
1-yl)ethanamine 01f). Yield 85% as a viscous liquid; Rf
25
0.9 -5% MeOH in DCM); [a]D ˆ141.3 -cˆ7.2, CHCl3);
IR -neat) 3350, 3020 cm21; 1H NMR -CDCl3, 400 MHz) d
2.30 -s, 3H), 2.50±3.20 -m, 7H), 3.57 -d, Jˆ16 Hz, 1H),
3.76 -dd, Jˆ10, 3 Hz, 1H), 3.87 -d, Jˆ16 Hz, 1H), 7.12±
7.41 -m, 9H, aromatics); MS -CI, m/z): 268 -M112), 267
-M111), 265, 236. Anal. calcd for C18H22N2: C, 81.20; H,
8.27; N, 10.52; found: C, 81.34; H, 8.29; N, 10.56.
4.4.13. 0S)-N-01,1-Dimethylethyl)-1-phenyl-2-0piperidin-
1-yl)ethanamine 01m). Yield 96% as a viscous liquid; Rf
25
4.4.7. 0S)-N-a-Naphthyl-1-phenyl-2-0pyrrolidin-1-
yl)ethanamine 01g). Yield 80% as a yellow viscous oil;
0.90 -10% EtOAc in petroleum ether); [a]D ˆ188 -cˆ7.0,
25
CHCl3) {lit.18h [a]D ˆ277 -cˆ1, CHCl3) for R enantiomer}.
25
Rf 0.40 -10% EtOAc in petroleum ether); [a]D ˆ2115
-cˆ4.0, CHCl3); IR -neat) 3450, 3320, 3200, 3020, 2800,
4.4.14. 0S)-N-Tetrahydrofuranylmethyl-1-phenyl-2-
0piperidin-1-yl)ethanamine 01n). Yield 92% as a viscous
1
820 cm21; H NMR -CDCl3, 400 MHz) d 1.78±1.83 -m,
25
4H), 2.63±2.80 -m, 5H), 3.14 -t, Jˆ9 Hz, 1H), 4.48 -d,
Jˆ11 Hz, 1H), 6.20 -bs, 1H, ±NH), 6.27 -d, Jˆ6 Hz, 1H),
7.10±8.20 -m, 11H). Anal. calcd for C22H24N2: C, 83.54; H,
7.59; N, 8.86; found: C, 83.92; H, 7.64.
liquid; Rf 0.80 -50% EtOAc in petroleum ether); [a]D
175.7 -cˆ6.0, CHCl3); IR -neat) 3500, 3310, 3020, 2920,
2800, 1590, 830 cm21 1H NMR -CDCl3, 400 MHz) d
ˆ
;
1.35±1.42-m, 3H), 1.40±1.62-m, 4H), 1.80±2.0 -m, 3H),
2.20±2.42 -m, 4H), 2.40±2.62 -m, 6H), 3.65±4.10 -m, 3H),
7.20±7.38 -m, 5H, Ph). Anal. calcd for C18H28N2O: C,
75.00; H, 9.72; N, 9.72; found: C, 74.72; H, 9.84.
4.4.8. 0S)-N-ortho-Anisyl-1-phenyl-2-0pyrrolidin-1-
yl)ethanamine 01h). Yield 77% as a viscous liquid; Rf
25
0.45 -10% EtOAc in petroleum ether); [a]D ˆ228.7
-cˆ3.5, CHCl3); IR -neat) 3450, 3400, 3050, 2950, 2800,
4.4.15. 0S)-N-Cyclohexyl-1-phenyl-2-0piperidin-1yl)etha-
namine 01o). Yield 88% as yellow crystals; mp 58±608C; Rf
1
1600, 830 cm21; H NMR -CDCl3, 400 MHz) d 1.80 -m,
25
4H), 2.40±2.61 -m, 5H), 2.90 -t, Jˆ12Hz, 1H), 3.92-s, 3H),
4.26 -dd, Jˆ12, 4 Hz, 1H), 5.61 -bs, 1H, ±NH), 6.23 -m,
1H), 6.62 -m, 2H), 6.78 -m, 1H), 7.22 -m, 1H), 7.31 -t,
Jˆ6.5 Hz, 2H), 7.42 -d, Jˆ6 Hz, 2H). Anal. calcd for
C19H24N2O: C, 77.03; H, 8.11; N, 9.46; found: C, 77.32;
H, 8.14; N, 9.40.
0.65 -10% EtOAc in petroleum ether); [a]D ˆ193 -cˆ7.0,
CHCl3); IR -KBr) 3450, 2950 cm21 1H NMR -CDCl3,
;
400 MHz) d 0.95±1.20 -m, 5H), 1.38±1.80 -m, 11H),
1.95±2.20 -m, 2H), 2.20±2.35 -m, 4H), 2.37 -t, Jˆ12Hz,
1H), 2.60 -bs, 1H), 3.94 -dd, Jˆ10, 3 Hz, 1H), 7.20±7.43
-m, 5H, Ph). Anal. calcd for C19H30N2: C, 79.72; H, 10.49;
N, 9.79; found: C, 79.52; H, 10.54.
4.4.9. 0S)-N-Benzyl-1-phenyl-2-0piperidin-1-yl)ethana-
mine 01i). Yield 80% as white crystals; mp 62±638C; Rf
4.4.16. 0S)-N-03,5-Dimethylphenyl)-1-phenyl-2-0piperi-
din-1-yl)ethanamine 01p). Yield 87% as a yellow viscous
liquid; Rf 0.95 -10% EtOAc in petroleum ether);
25
0.60 -10% EtOAc in petroleum ether); [a]D ˆ1114
-cˆ6.3, CHCl3) {lit.18 [a]D ˆ2108.6 -cˆ2, CHCl3) for R
25
25
enantiomer}.
[a]D ˆ110.1 -cˆ4.5, CHCl3); IR -neat) 3450, 3340,
1
3010, 2920, 1590 cm21; H NMR -CDCl3, 400 MHz) d
4.4.10. 01S)-N-[01R)-Phenylethyl]-1-phenyl-2-0piperidin-
1yl)ethanamine 01j). Yield 87% as a colourless viscous
liquid; Rf 0.75 -10% EtOAc in petroleum ether);
1.40±1.62 -m, 6H), 2.18 -s, 6H), 2.20±260 -m, 6H), 4.26
-dd, Jˆ10, 4 Hz, 1H), 5.42-bs, 1H, ± NH), 6.17 -s, 2H), 6.34
-s, 1H), 7.24±7.42 -m, 5H). Anal. calcd for C21H28N2: C,
81.82; H, 9.09; N, 9.09; found: C, 81.62; H, 9.14.
25
25
[a]D ˆ1134.9 -cˆ7.5, CHCl3) {lit.18h [a]D ˆ241.6
-cˆ1, CHCl3) for RR isomer}.
4.4.17. 0S)-N,N-Diethyl-1-phenyl-2-0diallylamino)ethan-
amine 06a). Yield 96% as a viscous liquid; Rf 0.80 -10%
4.4.11. 0S)-N-Phenyl-1-phenyl-2-0piperidin-1-yl)ethana-
mine 01k). Yield 88% as a white crystalline solid; mp
25
EtOAc in petroleum ether); [a]D ˆ14.4 -cˆ4.3, CHCl3);

P. Saravanan et al. / Tetrahedron 58 '2002) 4693±4706
4703
IR -neat) 3020, 2960, 730 cm21
;
1H NMR -CDCl3,
300 MHz) d 1.22±1.28 -m, 2H), 1.38±1.45 -m, 4H),
1.66±1.77 -m, 4H), 2.32±2.36 -m, 4H), 2.52±2.69 -m,
5H), 2.95±3.01 -m, 1H), 3.43 -t, Jˆ6 Hz, 1H), 7.21±7.38
-m, 5H, Ph); MS -CI, m/z): 259 -M111) -base peak), 188,
128. Anal. calcd for C17H26N2: C, 79.06; H, 10.07; N, 10.85;
found: C, 79.26; H, 10.24; N, 10.38.
300 MHz) d 1.03 -t, Jˆ9 Hz, 6H), 2.60±3.23 -m, 10H),
4.01 -t, Jˆ6 Hz, 1H), 5.12-m, 4H), 5.79 -m, 2H), 7.31
-m, 5H, Ph). Anal. calcd for C18H28N2: C, 79.41; H,
10.29; N, 10.29; found: C, 79.32; H, 10.44.
4.4.18. 0S)-N-[1-phenyl-2-0pyrrolidin-1-yl)ethyl]piperi-
dine 06b). Yield 62% as a viscous liquid; Rf 0.40 -50%
4.4.24. 0S)-N-[1-Phenyl-2-0piperidin-1-yl)ethyl]morpho-
line 06h). Yield 80% as a colourless viscous oil; Rf 0.60
25
EtOAc in petroleum ether); [a]D ˆ13.8 -cˆ2.9, CHCl3);
1
25
IR -neat) 1210, 770 cm21; H NMR -CDCl3, 300 MHz) d
-50% EtOAc in petroleum ether); [a]D ˆ16.0 -cˆ2.0,
1.25±1.34 -m, 2H), 1.50±1.58 -m, 4H), 1.62±1.70 -m, 4H),
2.36±2.39 -m, 4H), 2.48±2.60 -m, 3H), 2.90±3.07 -m, 3H),
3.69 -t, Jˆ5 Hz, 1H), 7.19±7.38 -m, 5H, Ph); MS -CI, m/z):
259 -M111) -base peak), 174. Anal. calcd for C17H26N2: C,
79.06; H, 10.07; N, 10.09; found: C, 78.96; H, 10.32; N,
10.14.
CHCl3); IR -neat) 1120, 780 cm21 1H NMR -CDCl3,
;
300 MHz) d 1.28±1.40 -m, 2H), 1.41±1.58 -m, 4H),
2.36±2.46 -m, 6H), 2.48±2.61 -m, 3H), 2.86 -dd, Jˆ14,
6 Hz, 1H), 3.51 -t, Jˆ5 Hz, 1H), 3.65 -t, Jˆ6 Hz, 4H),
7.20±7.39 -m, 5H, Ph). Anal. calcd for C17H26N2O: C,
74.45; H, 9.49; N, 10.22; found: C, 74.52; H, 9.54.
4.4.19. 0S)-N-[1-Phenyl-2-0diallylamino)ethyl]tetrahydro-
isoquinoline 06c). Yield 71% as a viscous liquid; Rf 0.80
4.4.25. 0S)-N,N-Diethyl-1-phenyl-2-0morpholin-4-yl)-
ethanamine 06i). Yield 99% as a viscous liquid; Rf 0.60
25
25
-50% EtOAc in petroleum ether); [a]D ˆ11.3 -cˆ3.0,
-10% EtOAc in petroleum ether); [a]D ˆ111.6 -cˆ2.5,
CHCl3); IR -neat) 3010, 750 cm21
;
1H NMR -CDCl3,
CHCl3); IR -neat) 1310, 810 cm21 1H NMR -CDCl3,
;
300 MHz) d 2.65±2.89 -m, 6H), 3.05±3.10 -m, 4H), 3.60
-d, Jˆ14 Hz, 1H), 3.71 -t, Jˆ6 Hz, 1H), 3.76 -d, Jˆ14 Hz,
1H), 5.06±5.14 -m, 4H), 5.68±5.79 -m, 2H), 6.92±7.16 -m,
4H), 7.21±7.38 -m, 5H, aromatics); MS -CI, m/z): 333
-M111), 200.
300 MHz) d 1.03 -t, Jˆ9 Hz, 6H), 2.37±2.44 -m, 4H),
2.44±2.51 -m, 2H), 2.63±2.72 -m, 4H), 3.63 -t, Jˆ4.5 Hz,
4H), 3.92-t, Jˆ6 Hz, 1H), 7.26±7.32 -m, 5H, Ph); MS -CI,
m/z): 263 -M111), 190. Anal. calcd for C16H26N2O: C,
73.28; H, 9.92; N, 10.68; found: C, 73.29; H, 9.68; N, 10.72.
4.4.20. 0S)-N,N-Diethyl-1-phenyl-2-0piperdin-1-yl)ethana-
mine 06d). Yield 73% as a viscous liquid; Rf 0.60 -20%
4.4.26. 0S)-N-[1-Phenyl-2-0morpholin-4-yl)ethyl]pyrro-
lidine 06j). Yield 94% as a yellow viscous liquid; Rf 0.40
25
25
EtOAc in petroleum ether); [a]D ˆ14.2- cˆ2.4, CHCl3);
-50% EtOAc in petroleum ether); [a]D ˆ110.9 -cˆ3.2,
1
2
IR -neat) 1360, 780 cm21; H NMR -CDCl3, 300 MHz) d
CHCl3); 98% ee -chiracel OD column 0.46£2 5 cm,
1.01 -t, Jˆ6 Hz, 6H), 1.32±1.40 -m, 2H), 1.42±1.58 -m,
4H), 2.28±2.49 -m, 6H), 2.58±2.82 -m, 4H), 3.91 -t,
Jˆ6.5 Hz, 1H), 7.18±7.36 -m, 5H, aromatics); MS -CI,
m/z): 262 -M112), 188 -base peak). Anal. calcd for
C17H28N2: C, 78.46; H, 10.76; N, 10.38; found: C, 78.42;
H, 10.24; N, 10.38.
solvent: hexane/isopropanol ratio 90:10; ¯ow rate 0.5 mL/
min; UV 254 nm; RT: 7.87 min for S-enantiomer and
15.25 min for R-enantiomer); IR -neat) 1120, 760 cm21
;
1H NMR -CDCl3, 300 MHz) d 1.70±1.74 -m, 4H), 2.37±
2.45 -m, 6H), 2.59±2.66 -m, 3H), 2.88±2.94 -m, 1H), 3.36
-dd, Jˆ7.5, 3 Hz, 1H), 3.56 -t, Jˆ4.5 Hz, 4H), 7.18±7.39
-m, 5H, aromatics). MS -CI, m/z): 261 -M111) -base peak),
190. Anal. calcd for C16H24N2O: C, 73.84; H, 9.23; N,
10.76; found: C, 74.26; H, 9.36; N, 10.89.
4.4.21. 0S)-N,N-Diallyl-1-phenyl-2-0piperidin-1-yl)ethana-
mine 06e). Yield 60% as a viscous liquid; Rf 0.80 -50%
25
EtOAc in petroleum ether); [a]D ˆ115.7 -cˆ1.9,
CHCl3); IR -neat) 3040, 920 cm21
;
1H NMR -CDCl3,
4.4.27. 0S)-N-[1-Phenyl-2-0morpholin-4-yl)ethyl]piperi-
dine 06k). Yield 99% as a viscous liquid; Rf 0.40 -10%
300 MHz) d 1.38 -m, 2H), 1.52 -m, 4H), 2.41 -m, 4H),
2.71 -m, 1H), 2.80±2.92 -m, 3H), 3.26 -dd, Jˆ15, 6 Hz,
2H), 4.02 -t, Jˆ6 Hz, 1H), 5.08±5.19 -m, 4H), 5.78±5.92
-m, 2H), 7.19±7.36 -m, 5H, Ph); MS -CI, m/z): 286
-M112), 188, 119.
25
EtOAc in petroleum ether); [a]D ˆ116.0 -cˆ6.2,
CHCl3); IR -neat) 1210, 750 cm21 1H NMR -CDCl3,
;
300 MHz) d 1.22±1.38 -m, 2H), 1.42±1.58 -m, 4H),
2.38±2.42 -m, 6H), 2.46±2.58 -m, 2H), 2.69±2.76 -m,
1H), 2.92 -dd, Jˆ14, 6 Hz, 1H), 3.57±3.66 -m, 5H), 7.21±
7.36 -m, 5H, Ph); MS -CI, m/z) 275 -M111) -base peak),
190. Anal. calcd for C17H26N2O: C, 74.45; H, 9.48; N,
10.21; found: C, 75.02; H, 9.76; N, 10.19.
4.4.22. 0S)-N-benzyl-N-Methyl-1-phenyl-2-0piperidin-1-
yl)ethanamine 06f). Yield 78% as a colourless viscous
25
liquid; Rf 0.80 -10% EtOAc in petroleum ether); [a]D
ˆ
119.2- cˆ4.0, CHCl3); IR -neat) 1220, 750 cm21; 1H NMR
-CDCl3, 300 MHz) d 2.14 -s, 3H), 2.21±2.48 -m, 4H), 2.68
-q, Jˆ6 Hz, 1H), 3.01 -q, Jˆ6 Hz, 1H), 3.39 -d, Jˆ14 Hz,
1H), 3.63 -d, Jˆ14 Hz, 1H), 3.66 -t, Jˆ6.0 Hz, 6H), 3.85 -t,
Jˆ6.5 Hz, 1H), 7.20±7.40 -m, 10H, Ph); MS -CI, m/z): 311
-M113) -base peak), 190. Anal. calcd for C21H28N2: C,
81.81; H, 9.09; N, 9.05; found: C, 81.76; H, 9.16; N, 9.24.
4.4.28. 0S)-N,N-Diethyl-1-phenyl-2-0tetrahydroisoquino-
lin-2-yl)ethanamine 06l). Yield 87% as a viscous liquid;
25
Rf 0.70 -10% EtOAc in petroleum ether); [a]D ˆ15.0
-cˆ1.4, CHCl3); IR -neat) 1215, 760 cm21
;
1H NMR
-CDCl3, 300 MHz) d 1.05 -t, Jˆ9 Hz, 6H), 2.38±2.46 -m,
2H), 2.62±2.94 -m, 7H), 3.10±3.16 -m, 1H), 3.64 -d,
Jˆ14 Hz, 1H), 3.73 -d, Jˆ14 Hz, 1H), 4.04 -t, Jˆ6.5 Hz,
1H), 6.92±7.41 -m, 9H, aromatics).
4.4.23. 0S)-N-[1-Phenyl-2-0piperidin-1-yl)ethyl]pyrro-
lidine 06g). Yield 80% as a yellow viscous liquid; Rf 0.40
25
-50% EtOAc in petroleum ether); [a]D ˆ17.9 -cˆ2.2,
4.4.29. 0S)-N,N-Diallyl-1-phenyl-2-0tetrahydroisoquino-
lin-2-yl)ethanamine 06m). Yield 75% as viscous liquid;
CHCl3); IR -neat) 1220, 760 cm21 1H NMR -CDCl3,
;

4704
P. Saravanan et al. / Tetrahedron 58 '2002) 4693±4706
25
Rf 0.70 -10% EtOAc in petroleum ether); [a]D ˆ115.6
15 min stirring, the epoxide 12 -230 mg, 1.0 mmol) was
added and the mixture was stirred for 48 h. Most of the
THF was removed in vacuo at 08C, and the crude material
was taken up in diethyl ether -20 mL). It was washed with
aqueous tartaric acid, water, brine, and dried. Solvent was
removed under reduced pressure and the crude material was
puri®ed on silica gel column to provide the pure allylic
alcohol 13 -62mg, 27%) as a colourless liquid; Rf 0.50
-cˆ2.3, CHCl3); IR -neat) 3010, 1440, 780 cm21
;
1H
NMR -CDCl3, 300 MHz) d 2.64±2.96 -m, 8H), 3.12±3.16
-m, 1H), 3.21±3.34 -m, 1H), 3.70 -d, Jˆ4.5 Hz, 2H), 4.16
-t, Jˆ6 Hz, 1H), 5.10±5.21 -m, 4H), 5.79±5.94 -m, 2H),
6.95±7.41 -m, 9H, aromatics); MS -CI, m/z): 333
-M111), 236, 132. Anal. calcd for C23H28N2: C, 83.12; H,
8.41; N, 8.43; found: C, 83.26; H, 8.48; N, 8.68.
25
-10% EtOAc in petroleum ether); [a]D ˆ236.8 -cˆ1.85,
25
4.4.30. 0S)-N-[1-Phenyl-2-0tetrahydroisoquinolin-2-yl)-
ethyl]pyrrolidine 06n). Yield 75% as viscous liquid; Rf
CHCl3) {lit.30a,c [a]D ˆ244.3 -cˆ1.5, CHCl3) for -1S)
25
isomer with 95% ee, [a]D ˆ133.2- cˆ0.78, CHCl3) for
25
0.80 -50% EtOAc in petroleum ether); [a]D ˆ124.5
-1R) isomer with 72% ee}.
-cˆ3.15, CHCl3); IR -neat) 1210, 1090, 750 cm21
;
1H
NMR -CDCl3, 300 MHz) d 1.71±1.78 -m, 4H), 2.45±2.50
-m, 2H), 2.64±2.69 -m, 4H), 2.71±2.83 -m, 3H), 3.13 -q,
Jˆ5 Hz, 1H), 3.43 -t, Jˆ6 Hz, 1H), 3.56 -d, Jˆ14 Hz, 1H),
3.64 -d, Jˆ14 Hz, 1H), 6.92±6.98 -m, 1H), 7.01±7.18 -m,
3H), 7.20±7.42 -m, 5H, aromatics); MS -CI, m/z): 307
-M111) -base peak), 236. Anal. calcd for C21H26N2: C,
82.35; H, 8.49; N, 9.15; found: C, 82.42; H, 8.44; N, 9.26.
4.5. General procedure for the enantioselective addition
of diethylzinc to aldehydes catalysed by vicinal diamines
To a ¯ame dried ¯ask, carbonyl compound -1 mmol) and
diamine 1a -40 mg, 0.2mmol, 20 mol%) were added,
dissolved in dry cyclohexane -8 mL) and stirred for
20 min. The reaction mixture was cooled to 08C. Diethyl-
zinc -2mL, 2mmol, and 1 M hexane solution) was added
over a period of 5 min. The reaction mixture was stirred for
20 h at 08C to room temperature. Saturated NH4Cl -5 mL)
and 1N HCl -5 mL) were added to quench the reaction and
the mixture was extracted with EtOAc -three times). The
combined organic layers were washed with water, brine and
dried over Na2SO4. The solvent was removed under reduced
pressure and the resulting oily substrate was puri®ed by
silica gel column chromatography using EtOAc±petroleum
ether as eluent to give pure alcohols 14.
4.4.31. 0S)-N-[1-Phenyl-2-0tetrahydroisoquinolin-2-yl)-
ethyl]morpholine 06o). Yield 94% as a yellow viscous
25
liquid; Rf 0.60 -10% EtOAc in petroleum ether); [a]D
ˆ
115.7 -cˆ3.5, CHCl3); IR -neat) 1200, 740 cm21; 1H NMR
-CDCl3, 300 MHz) d 2.41±2.64 -m, 6H), 2.66±2.82 -m,
4H), 3.17 -dd, Jˆ11, 4 Hz, 1H), 3.59±3.72-m, 6H), 6.94±
1
7.39 -m, 9H, aromatics); MS -CI, m/z) 32 3 -M 11) -base
peak), 236. Anal. calcd for C21H26N2O: C, 78.26; H, 8.07; N,
8.69; found: C, 78.34; H, 8.56; N, 8.72.
4.4.32. 0S)-N-[1-Phenyl-2-0tetrahydroisoquinolin-2-yl)-
ethyl]piperidine 06p). Yield 74% as a yellow viscous
25
4.6. Determination of enantiomeric purity of optically
active alcohols39
liquid; Rf 0.70 -10 EtOAc in petroleum ether); [a]D
;
ˆ
114.1 -cˆ3.2, CHCl3); IR -neat) 1220, 790 cm21
1H
NMR -CDCl3, 300 MHz) d 1.24±1.40 -m, 2H), 1.43±1.61
-m, 4H), 2.18±2.26 -m, 4H), 2.72±2.84 -m, 4H), 2.82±2.86
-m, 1H), 3.12±3.17 -m, 1H), 3.65 -d, Jˆ14 Hz, 2H), 3.73 -t,
Jˆ6 Hz, 1H), 6.96±7.10 -m, 1H), 7.11±7.16 -m, 3H), 7.21±
7.38 -m, 5H, aromatics); MS -CI, m/z): 321 -M111) -base
peak), 236. Anal. calcd for C22H28N2: C, 82.50; H, 8.75; N,
8.73; found: C, 82.72; H, 8.36; N, 8.42.
General procedure for making MTPA ester of -S)-14e. To
a solution of -S)-14e -5 mg), Et3N -3 equiv.) and a crystal
of DMAP in dichloromethane -0.5 mL) was added
-S)-MTPACl -1.5 equiv., 98% ee) at room temperature.
Reaction mixture was allowed to stand until the starting
material was fully consumed. If necessary, some more
amount of MTPACl and Et3N were added to make sure
that the reaction was complete. Reaction mixture was
®ltered through a short silica gel column to get the mixture
of two diastereomeric MTPA esters; 1H NMR -CDCl3,
400 MHz) d 0.93 -t, Jˆ9 Hz, 3H), 1.79±2.01 -m, 2H),
3.54 -s, 3H), 5.77 -dd, Jˆ9, 3 Hz, 1H) -for SS from major
-S)-1-hydroxy-propyl-4-chloro)benzene), 5.85 -dd, Jˆ9,
3 Hz, 1H) -for RS from minor -R)-1-hydroxy-propyl-
-4-chloro)benzene), 7.12±7.40 -m, 9H, aromatics). Based
on above 400 MHz NMR data, the enantiomeric excess
of -S)-1-hydroxy-propyl-4-chloro)benzene was 66.5%.
The optical purity of the -R)-Mosher acid was 98%.
So, corrected value of the optical purity was 68% using
diamine 1j.
4.4.33.
cis-01S,4R)-4-Hexadecyl-4-trimethylsiloxy-2-
cyclopentene-1-ol 09). n-BuLi -E-Merck, 1.74 M in hexane,
1.15 mL, 2.0 mmol) was added to a solution of -R)-diamine
1a -480 mg, 2.2 mmol) in toluene -10 mL) at 08C. After
15 min stirring, the epoxide 8 -400 mg, 1.0 mmol) was
added and the mixture stirred -08C, rt) for 24 h. The reaction
mixture was taken up in diethyl ether -30 mL) followed by
washing with aqueous tartaric acid, water, brine. The
organic layer was dried, and removal of the solvent under
reduced pressure gave the crude product. The crude material
was puri®ed on silica gel column using EtOAc±petroleum
ether as eluent provide the pure allylic alcohol 9 -328 mg,
83%) as a colourless oil; Rf 0.50 -10% EtOAc in petroleum
25
25
ether); [a]D ˆ220.8 -cˆ1.25, CHCl3) {lit.26b [a]D
ˆ
218.1 -cˆ1.02, CHCl3) for 89% ee}.
Acknowledgements
4.4.34. cis-01R,4S)-4-tert-Butyldimethylsiloxymethyl-2-
cyclopenten-1-ol 013). n-BuLi -E-Merck 1.74 M in hexane,
1.15 mL, 2.0 mmol) was added to a solution of diamine
-S)-1a -480 mg, 2.2 mmol) in THF -10 mL) at 08C. After
V. K. S. thanks DST -Government of India) for the Swar-
najayanti Fellowship -1998).

P. Saravanan et al. / Tetrahedron 58 '2002) 4693±4706
4705
P. J. Chem. Soc., Perkin Trans. I 1998, 1483. -d) O'Brien, P.;
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-g) O'Brien, P.; Pilgram, C. D. Tetrahedron Lett. 1999, 40,
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