A concise method for the functionalisation of ethanolamine α to nitrogen using free radical methodology

Article abstract of DOI:10.1016/S0040-4020(00)01123-6

A method is described for the free radical functionalisation of ethanolamine at the carbon atom α to nitrogen. The key step of the methodology is a 1,5-hydrogen atom abstraction to produce an α-aminoalkyl radical at C-4 of a 1,3-oxazolidine.

Full text of DOI:10.1016/S0040-4020(00)01123-6

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 1399±1410
A concise method for the functionalisation of ethanolamine
a to nitrogen using free radical methodology
Rajendra Gosain, Andrew M. Norrish and Mark E. Woodp
School of Chemistry, University of Exeter, Stocker Road, Exeter, Devon EX4 4QD, UK
Received 2 October 2000; revised 9 November 2000; accepted 23 November 2000
AbstractÐA method is described for the free radical functionalisation of ethanolamine at the carbon atom a to nitrogen. The key step of the
methodology is a 1,5-hydrogen atom abstraction to produce an a-aminoalkyl radical at C-4 of a 1,3-oxazolidine. q 2001 Elsevier Science
Ltd. All rights reserved.
We recently reported preliminary studies into the free±
radical functionalisation of b-amino alcohols at the carbon
atom a to nitrogen,1 using 1,5-hydrogen atom abstraction as
the key a-aminoalkyl radical2 generating step. In
developing this procedure, our aim was to produce a general
method which would facilitate carbon±carbon bond
formation at this carbon atom without the need for prior
functionalisation. The methodology should also be com-
patible with a wide variety of functional groups to minimise
the need for complex protection strategies, hence the choice
of free radical based techniques. The experiments described
herein concentrate on the functionalisation of ethanolamine
1 (Scheme 1) as a model system for more complex amino
alcohols.
Ethanolamine derived 1,3-oxazolidines of general structure
2 containing an N-2-halobenzyl or N-2-halobenzoyl pro-
tecting±radical translocating (PRT) group,3 when subjected
to standard tin hydride mediated free radical generating
conditions, represent a synthetically viable source of
a-aminoalkyl radicals 3. These radicals are produced via
1,5-hydrogen atom transfer and can be trapped with appro-
priate radicalphiles (Scheme 1). The lack of a hydrogen
substituent at C-2 ensures that hydrogen atom abstraction
Scheme 1. Overall methodology.
Keywords: amino alcohols; oxazolidines; radicals.
* Corresponding author. Tel.: 144-1392-263450; fax: 144-1392-263434; e-mail: m.e.wood@exeter.ac.uk
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01123-6

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R. Gosain et al. / Tetrahedron 57 (2001) 1399±1410
Scheme 2. Reagents and conditions: NaBH4, EtOH (6, 89%; 7, 91%).
Scheme 3. Reagents and conditions: see Table 1.6,7
Table 1. Results for Scheme 3 (a, RCOCH3, TsOH (cat.), C6H6, D (2H2O);
Ê
b, EtO2CCOCH3, 4 A mol. sieves, THF, RT)
any possible amide con®gurational problems which could
affect the ef®ciency of the 1,5-hydrogen atom abstraction in
the corresponding N-2-halobenzoyl derivatives (2, Xˆ
CˆO).5 N-2-Halobenzoyl derivatives (2, XˆCˆO) were,
however, also prepared for comparative purposes.
Substrate
Hal
R
Method
Product
Yield (%)
6
6
6
7
7
Br
Br
Br
I
Ph-
a
a
a
a
b
8
9
10
11
12
83
100
72
61
65
4-NO2-C6H4-
4-pyridyl-
4-pyridyl-
EtO2C-
Firstly, the PRT group was introduced via a reductive
amination procedure, leading to both the N-2-bromobenzyl
6 and N-2-iodobenzyl 7 derivatives as starting materials for
ring closure (Scheme 2).
I
can only occur at C-4 as required and also gives an alkylated
product 4 from which the functionalised, N-protected
b-amino alcohol 5 can be obtained by mild hydrolytic
cleavage.
Condensation of 6 with acetophenone under Dean±Stark
dehydrating conditions gave 1,3-oxazolidine 8 in good
yield (83%, Scheme 3 and Table 1) but the heterocycle
was found to be highly susceptible towards acidolytic
cleavage, with repeated chromatography on silica gel result-
ing in substantial decomposition. Stability could be
improved by the incorporation of an electron withdrawing
group into the C-2 aromatic substituent, the 4-nitro deriva-
tive 9 proving to be stable towards chromatography on silica
gel, but as expected, it proved to be incompatible with tin
hydride mediated free radical procedures. It was found,
however, that a 4-pyridyl or ethyl ester substituent at C-2
conferred adequate stability on compounds 10, 11 and 12
which were used in preliminary studies.
For more complex amino alcohols, already possessing an
alkyl substituent a to nitrogen, the chiral centre in this
starting material should offer the possibility for stereo-
control at C-2 during the 1,3-oxazolidine formation and,
ultimately, transfer of stereochemical information back to
C-4 during the intermediate radical trapping process,
following Seebach's principle of self-reproduction of
chirality.4
A variety of 1,3-oxazolidines 2 were prepared by two-step
methods to investigate the structural features required to
give them suf®cient stability towards the typical reaction
conditions and puri®cation methods encountered in standard
tin hydride based free radical procedures. N-2-Halobenzyl
PRT groups (2, XˆCH2) were chosen initially to eliminate
N-2-Iodobenzoyl 1,3-oxazolidine 13 was also prepared for
comparative purposes. For this example, the best yield
(58%) was obtained by ®rstly condensing ethanolamine
1 with acetophenone under Dean±Stark dehydrating
Scheme 4. Reagents and conditions: i, PhCOCH3, C6H6, D (2H2O); ii, 2-iodobenzoyl chloride, Et3N, C6H6, 08C (58% over 2 steps).
Scheme 5. Reagents and conditions: see Table 2.

R. Gosain et al. / Tetrahedron 57 (2001) 1399±1410
1401
Table 2. Results for Scheme 5 (a, Bu3SnD, AIBN, C6H6, D; b, Bu3SnD,
Et3B, O2, C6H6, RT)
Two radicalphiles, tert-butyl acrylate and acrylonitrile,
were then introduced into the system in an attempt to
form carbon±carbon bonds at C-4. Scheme 6 and Table 3
show the optimised results for these studies.
Substrate Hal
X
R
Method Products (ratio) Yield (%)
10
11
13
13
Br CH2 4-pyridyl-
a
a
a
b
14, 15 (1: 2)
14, 15 (1: 2)
16, 17 (1: 1)
16, 17 (1: 1)
74
92
64
100
I
I
I
CH2 4-pyridyl-
Slow addition of tributyltin hydride (3 eq.) and AIBN to a
benzene solution of the C-2 4-pyridyl derivative 11 under
re¯ux, in the presence of a 3-fold excess of tert-butyl acryl-
ate, gave a reasonable (50%) isolated yield of the required
product 18a/b as an inseparable 2:1 diastereoisomer
mixture.8 Photochemical AIBN cleavage at room tempera-
ture resulted in a signi®cant reduction in the number of
minor side-products for the same process, using tert-butyl
acrylate (5 eq.), whilst maintaining a comparable isolated
yield (54%) of alkylated products 18a/b. Most importantly,
however, it was found, under these conditions, that slow
addition of tributyltin hydride/AIBN was not necessary,
despite the excess of tin hydride which was found to be
required for optimal results. Similarly, the use of triethyl-
borane/oxygen initiation gave rise to a very `clean' reaction
which gave a comparable yield of 18a/b with an identical
ratio of diastereoisomers. These results were echoed with
acrylonitrile as the radicalphile with an isolated yield of
51% of 19a/b as an inseparable 2:1 diastereoisomer mixture
being obtained.
CˆO
Ph-
Ph-
CˆO
conditions, followed by acylation of the crude reaction
product with 2-iodobenzoyl chloride in the presence of
triethylamine (Scheme 4). As expected, this derivative
proved to be highly stable towards silica gel chromato-
graphy, particularly when compared with the corresponding
N-2-iodobenzyl derivative 11. Unfortunately, NMR spectra
of 13 recorded at room temperature were complicated by the
presence of amide rotamers.
In order to obtain a qualitative insight into the ef®ciency of
the proposed hydrogen atom transfer step for both classes of
PRT group equipped 1,3-oxazolidine, reductions of deriva-
tives 10, 11 and 13 were carried out using tributyltin deuter-
ide under different initiation conditions. In all cases, all of
the required tributyltin deuteride was added at the start of
the reaction, resulting in conditions which would be
expected to disfavour 1,5-hydrogen atom abstraction.
Pleasingly, in all cases, signi®cant levels of deuterium
incorporation were found at C-4 in both of the ®nal products
15 and 17. The optimised results for these experiments are
summarised in Scheme 5 and Table 2.
Ethyl pyruvate derived 1,3-oxazolidine 12 gave lower yields
of alkylated products 20a/b and 21a/b with tert-butyl acryl-
ate and acrylonitrile respectively (triethylborane/oxygen
initiation), although with a slightly improved diastereo-
isomer ratio of 3:1 in both cases. The acrylonitrile trapped
products 21a and 21b proved to be separable, allowing the
assignment of relative stereochemistry using NOESY9
experiments. The major stereoisomer proved to be that in
which the newly introduced C-4 substituent and the C-2
ethyl ester were cis relative to each other. The key
NOESY results obtained are summarised in Fig. 1. (Note:
all other NOE enhancements support these stereochemical
assignments.)
N-2-Iodobenzyl derivative 11 could be reduced more
cleanly and ef®ciently than the corresponding bromide 10,
hence this derivative was used in all future experiments.
Both 10 and 11 gave a 1: 2 ratio of deuterated products 14
and 15 (determined by 2H NMR), in favour of the required
C-4 deuterio derivative 15, which was produced as a 1:1
mixture of diastereoisomers. 13 gave a 1:1 mixture of
deuterated products 16 and 17 with quantitative reduction
occurring under triethylborane/oxygen mediated initiation
conditions. Mass spectrometry con®rmed the presence of
only one deuterium atom in all of the products 14±17.
(Note: all spectra were compared with the corresponding
unlabelled samples.)
A possible explanation for the observed stereochemistry is
that the intermediate a-aminoalkyl radical 22 could
preferentially adopt an envelope conformation in which
the C-2 ethyl ester is pseudo-equatorial and the methyl
Scheme 6. Reagents and conditions: CH2ˆCH-Y (2.2±7.4 equiv.), Bu3SnH, initiator (see Table 3), C6H6.
Table 3. Results for Scheme 6 (a, AIBN, D (slow addition); b, AIBN, hn, RT (no slow addition); c, Et3B, O2 (no slow addition))
Substrate
R
Y
Method
Isolated yield (%)
Products (dr8)
t
-CO2 Bu
11
11
11
11
11
12
12
4-pyridyl-
4-pyridyl-
4-pyridyl-
4-pyridyl-
4-pyridyl-
EtO2C-
a
b
c
b
c
c
c
50
54
42
51
51
41
26
18a/b (2:1)
18a/b (2:1)
18a/b (2:1)
19a/b (2:1)
19a/b (2:1)
20a/b (3:1)
21a/b (3:1)
t
-CO2 Bu
t
-CO2 Bu
-CN
-CN
t
-CO2 Bu
-CN
EtO2C-

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R. Gosain et al. / Tetrahedron 57 (2001) 1399±1410
Figure 1. Key NOESY results.
group pseudo-axial (Fig. 2). Approach of the acrylonitrile
radicalphile on the least hindered face, away from the
methyl group, would give rise to the stereochemistry
observed in the major product.
Similar NOESY experiments carried out on the mixture of
diastereoisomers of 20a and 20b again suggested that the
major diastereoisomer obtained was that in which the C-4
substituent was cis to the C-2 ethyl ester (12a).
Figure 2. Possible explanation for observed diastereoselectivity.
Signi®cantly improved yields were observed for analogous
reactions using the N-2-iodobenzoyl 1,3-oxazolidine 13.
The optimised results, summarised in Scheme 7 and Table
4, were obtained under slow addition conditions using a 2.8
fold excess of tert-butyl acrylate and an 8.5 fold excess of
acrylonitrile to give products 23a/b and 24a/b respectively.
24a/b was obtained as a 2.5:1 mixture of diastereoisomers
(70% yield) and 24a/b as a 1.7:1 mixture (59% yield),
neither of which proved to be readily separable. Again,
NMR spectra were complicated by the presence of amide
rotamers which unfortunately prevented de®nitive assign-
ments of C-2/C-4 relative stereochemistry by NOE studies.
Scheme 7. Reagents and conditions: CH2ˆCH-Y (2.8±8.5 equiv.),
Bu3SnH, AIBN (see Table 4).
Table 4. Results for Scheme 7 (a, Bu3SnH, AIBN, C6H6, D (slow addition);
d, Bu3SnCl (15 mol%), NaBH3CN, AIBN, tBuOH, D)
The improvement in isolated yield here can, to some extent,
be attributed to the enhanced stability of the N-benzoylated
1,3-oxazolidine moiety compared with its N-benzylated
counterpart towards silica gel chromatography.
Substrate
R
Y
Method Isolated yield (%) Products (dr8)
t
13
13
13
13
Ph- -CO2 Bu
Ph- -CN
Ph- -CO2 Bu
Ph- -CN
a
a
d
d
70
59
75
61
23a/b (2.5:1)
24a/b (1.7:1)
23a/b (2.0:1)
24a/b (1.8:1)
t
Importantly, it was also found that the reaction conditions
using N-2-iodobenzoyl substrate 13 could be modi®ed to
replace the excess of tributyltin hydride from the earlier
experiments with a catalytic quantity (15 mol%) of tributyl-
tin chloride and in situ reduction to the hydride using
sodium cyanoborohydride. Good yields of 23a/b and 24a/
b were obtained (75% and 61% respectively) with similar
diastereoisomeric ratios to those obtained in the earlier
experiments and a simpli®ed puri®cation procedure could
now be employed. (Note: these conditions proved unsuit-
able with N-2-iodobenzyl substrate 11, where reductive
ring-opening of the 1,3-oxazolidine10 proved to be the
major competing reaction pathway.)
Scheme 8. Reagents and conditions: i, see Table 5; ii, neutral alumina (for
products 26 and 27 only).
Table 5. Conditions and results for Scheme 8 (a, HCl, H2O, THF, RT; b, Amberlitew IR-120 (H1 form), CH3CN, RT)
Substrate
X
R
Y
Method
Isolated yield (%)
Product
t
18a/b
19a/b
20a/b
21a/b
23a/b
24a/b
CH2
CH2
CH2
CH2
4-pyridyl-
4-pyridyl-
EtO2C-
EtO2C-
Ph-
-CO2 Bu
-CN
-CO2 Bu
a
a
a
a
b
b
99
99
84
48
76
89
26
27
26
27
28
29
t
-CN
-CO2 Bu
-CN
t
CˆO
CˆO
Ph-

R. Gosain et al. / Tetrahedron 57 (2001) 1399±1410
1403
All of the alkylated products could be cleaved ef®ciently to
the corresponding alkylated, N-protected b-amino alcohols
under mild acidolytic conditions (Scheme 8). Diastereo-
isomer mixtures 18a/b, 19a/b and 20a/b and major dia-
stereoisomer 21a were all cleaved using aqueous
hydrochloric acid in dilute tetrahydrofuran solutions to
give the corresponding b-amino alcohols 26 and 27.
(Note: signi®cant degradation of nitrile containing product
27 was observed with prolonged exposure to the hydrolysis
conditions.) The free amines in each case could be released
from their hydrochloride salts by chromatography using a
neutral alumina stationary phase.11
Chemical shifts are quoted in ppm relative to tetramethyl-
silane as reference, assignments being derived from DEPT9
editing.
2H NMR spectra were obtained using a BruÈker Advance
DRX400 spectrometer operating at 61.4 MHz. Chemical
shifts are quoted in ppm relative to tetramethylsilane with
internal referencing to deuteriochloroform.
Mass spectra were determined using a Kratos Pro®le HV3
instrument, a Thermoquest Finnigan TRACE 2000 GC-MS
instrument or by the EPSRC National Mass Spectrometry
Service Centre, Swansea, UK in electron impact (EI),
ammonia chemical ionisation (CI) and positive ion electro-
spray (ES1) modes.
N-Benzoyl derivatives 23a/b and 24a/b were hydrolysed
using a suspension of Amberlitew IR-120 (H1 form) ion
exchange resin in acetonitrile solution, the acetophenone
produced in these reactions being removed under high
vacuum. Again, the hydrolysis procedure proved to be
ef®cient, products 28 and 29 being obtained in 76%
and 89% yields respectively. The results of all of these
hydrolyses are summarised in Scheme 8 and Table 5.
Analytical thin layer chromatography was carried out using
glass or aluminium backed plates coated with Merck Kiesel-
gel 60 F254, with developed plates being visualised by
quenching of u.v. ¯uorescence or by staining with iodine
or potassium permanganate as appropriate. Flash chroma-
tography was carried out using BDH silica gel with particle
size 40±63 mm.
In summary, we have developed a viable, mild method for
the functionalisation of ethanolamine at the carbon a to the
nitrogen which does not require prior functionalisation of
the b-amino alcohol. The key step in this synthetic pro-
cedure is an ef®cient 1,5-hydrogen atom transfer using a
nitrogen protecting, radical translocating (PRT) group and
we are currently developing extensions of this methodology
for the functionalisation of more complex b-amino
alcohols, particularly those already containing one alkyl
substituent a to nitrogen, where signi®cant possibilities
for stereocontrol exist. The methodology has the potential
for development into a useful synthetic approach towards
highly substituted amine derivatives including a,a-disub-
stituted a-amino acids.
Solvents and reagents were used as supplied or puri®ed
using standard procedures as described in Perrin, D. D.;
Armarego, W. L. F., Puri®cation of Laboratory Chemicals,
3rd edition, Pergamon Press, Oxford, 1988 as appropriate.
Petroleum ether refers to the fraction of light petroleum
ether boiling between 40 and 608C.
Solvents were removed under reduced pressure using a
BuÈchi R110 Rotavapor equipped with a water or dry ice
condenser as appropriate.
1.1.1. N-(2-Bromobenzyl)-2-aminoethanol (6). A mixture
of ethanolamine 1 (1.28 cm3, 21.3 mmol), 2-bromobenzal-
dehyde (3.90 g, 21.1 mmol) and anhydrous potassium
carbonate (3.00 g, 21.7 mmol) in ethanol (10 cm3) was
heated under re¯ux for 1 h. After cooling to room tempera-
ture, the reaction mixture was ®ltered and sodium boro-
hydride (960 mg, 25.4 mmol) was added, the resulting
mixture being stirred at room temperature for 3 h. The
reaction mixture was then concentrated in vacuo and the
residue cooled in an ice bath before acidi®cation by drop-
wise addition of hydrochloric acid (2 M). The resulting
aqueous solution was extracted with ethyl acetate
(2£15 cm3) and concentrated in vacuo to a thick paste to
which was added saturated aqueous sodium bicarbonate
(30 cm3). The resulting aqueous solution was extracted
with ethyl acetate (3£20 cm3) and the combined extracts
were dried (magnesium sulfate), ®ltered and evaporated in
vacuo to give the title compound as a colourless oil (4.30 g,
89%); Rf 0.15 (4:1 v/v EtOAc:petroleum ether); nmax/cm21
(thin ®lm) 3520-3075brs (N-H, O-H), 2980±2730s (C-H),
1591w, 1568w, 1468s, 1441s, 1109m, 1053s, 1026s, 752s
and 658m; dH (400 MHz; CDCl3) 2.78 (2H, t, J 5, CH2NH),
3.67 (2H, t, J 5, CH2OH), 3.88 (2H, s, ArCH2), 7.12 (1H, dt,
J 8 and 1 Ar-H), 7.26±7.37 (2H, m, Ar-H) and 7.54 (1H, d, J
8, Ar-H); dC (100 MHz; CDCl3) 50.3 (CH2NH), 53.2
(CH2OH), 61.0 (ArCH2), 124.1 (ArCBr), 127.5, 128.8,
130.4 (ArCH), 132.9 (ArCH) and 138.7 (AripsoCCH2); m/z
(CI) 232 (MH1, 100%), 230 (MH1, 100), 152 (61), 62 (17)
1. Experimental
1.1. General
Melting points were determined using a Gallenkamp
MPD350 apparatus and are uncorrected.
Infrared spectra were recorded using a Nicolet Magna 550
spectrometer with major absorbances being quoted using
the abbreviations: w, weak; m, medium; s, strong and br,
broad. Thin ®lm samples were prepared by evaporation of a
dilute chloroform solution of the compound on a sodium
chloride plate.
1H NMR spectra were obtained using either BruÈker AM300
or BruÈker Advance DRX400 spectrometers at operating
frequencies of 300 and 400 MHz respectively. Chemical
shifts are quoted in ppm relative to tetramethylsilane as
reference with coupling constants being given to the nearest
0.5 Hz. The abbreviations: s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet; and br, broad are used.
13C NMR spectra were obtained using either a BruÈker
ACF300 or BruÈker Advance DRX400 spectrometer at
operating frequencies of 75 and 100 MHz, respectively.

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R. Gosain et al. / Tetrahedron 57 (2001) 1399±1410
and 52 (20); m/z (EI) 200 (72%), 198 (70), 171 (100), 169
(98), 118 (25), 91 (52), 90 (52), 89 (66), 63 (40) and 51 (25);
(Found MH1 (ES1) 230.0182, C9H1379BrNO requires
230.0180).
(C-H), 1605w, 1521s, 1496w, 1456w, 1349s, 1279w,
1211w, 1082m, 1015w, 847m, 756w, 738w and 699m; dH
(300 MHz; CDCl3) 1.72 (3H, s, CH3C), 2.76, 2.93 (2£1H,
2£m, NCH2CH2), 3.70±3.81, 4.02±4.12 (2£2H,
2£complex, CH2CH2O and ArCH2), 7.19 (1H, t, J 7, Ar-
H), 7.37 (1H, t, J 7, Ar-H), 7.59 (2H, t, J 7, Ar-H) and 7.84,
8.21 (2£1H, AA0BB0, J 9, Ar-H of 4-NO2Ph-); dC (75 MHz;
CDCl3) 24.3 (CH3C), 50.2 (NCH2CH2), 53.0 (CH2CH2O),
63.0 (ArCH2), 98.6 (CH3C), 123.5 (ArC-H), 124.5
(ArC-Br), 127.1, 127.5, 128.8, 130.7, 133.0 (ArC-H),
138.3 (AripsoC, 2-I-Ph-), 147.4 (ArC-NO2) and 153.2
(AripsoC, 4-NO2Ph-); m/z (EI) 363 ([M2CH3]1, 36%), 361
([M2CH3]1, 38), 256 (27), 254 (29), 171 (98), 169 (100),
90 (42) and 77 (17).
1.1.2. N-(2-Iodobenzyl)-2-aminoethanol (7). Using the
procedure described above for the preparation of N-(2-
bromobenzyl)-2-aminoethanol 6, with ethanolamine 1 (690
ml, 11.5 mmol), 2-iodobenzaldehyde (2.30 g, 9.9 mmol),
anhydrous potassium carbonate (3.00 g, 21.7 mmol) and
sodium borohydride (470 mg, 12.4 mmol), the title
compound was prepared as a colourless oil (2.50 g, 91%);
Rf 0.14 (4:1 v/v EtOAc:petroleum ether); nmax/cm21 (thin
®lm) 3500±3080brs (N-H, O-H), 3000±2750s (C-H),
1603w, 1588w, 1562w, 1455s, 1434s, 1107s, 1015s and
748s; dH (400 MHz; CDCl3) 2.75 (2H, brs, NH, OH), 2.79
(2H, m, CH2NH), 3.68 (2H, d, J 5, CH2OH), 3.83 (2H, s,
ArCH2), 6.95 (1H, m, Ar-H), 7.31 (2H, m, Ar-H) and 7.82
(1H, dd, J 8 and 1, Ar-H); dC (100 MHz; CDCl3) 50.3
(CH2NH), 57.6 (CH2OH), 61.0 (ArCH2), 99.7 (ArCI),
128.4, 129.0, 129.8 (ArCH), 139.6 (ArCH) and 141.7
(AripsoCCH2); m/z (CI) 278 (MH1, 31%), 134 (100), 108
(90) 106 (50) and 62 (29); m/z (EI) 277 (M1, 4%), 246
(89), 217 (100), 118 (29), 91 (62), 90 (48) and 89 (44);
(Found MH1 (CI) 278.0045, C9H13INO requires 278.0042).
1.1.5. 4-(3-(2-Bromobenzyl)-2-methyl-oxazolidin-2-yl)-
pyridine (10).
A solution of N-(2-bromobenzyl)-2-
aminoethanol 6 (3.73 g, 16.2 mmol), 4-acetylpyridine
(1.94 g, 16.0 mmol) and 4-toluenesulfonic acid mono-
hydrate (10 mg, 0.05 mmol) in benzene (50 cm3) was heated
under re¯ux, using a Dean±Stark water separator for 6 h.
The solvent was evaporated in vacuo and the residue was
puri®ed by ¯ash chromatography on silica gel (eluting with
1:1 v/v petroleum ether: ethyl acetate) to give the title
compound as a yellow oil (3.83 g, 72%); Rf 0.40 (1:1 v/v
petroleum ether:EtOAc); nmax/cm21 (thin ®lm) 3114±
2767m (C-H), 1594m, 1562w, 1466m, 1439s, 1404w,
1367w, 1334w, 1155w, 1207m, 1156m, 1080s, 1025s,
815m and 751s; dH (400 MHz; CDCl3) 1.64 (3H, s,
CH3C), 2.75 (1H, m, NCH2CH2), 2.90 (1H, m,
NCH2CH2), 3.74 (1H, m, CH2CH2O), 3.75, 4.00 (2£1H,
ABq, JAB 14, ArCH2), 4.03 (1H, ca. q, J 7.5, CH2CH2O),
7.12 (1H, t, J 7.5, Ar-H), 7.30 (1H, t, J 7.5, Ar-H), 7.48-7.58
(4H, complex, 2£Ar-H and 2£pyridine CH) and 8.59 (2H,
part of AA0BB0, J 5, pyridine CH); dC (100 MHz; CDCl3)
23.9 (CH3C), 50.2 (NCH2CH2), 53.0 (CH2CH2O), 63.1
(ArCH2), 97.9 (CH3C), 121.1 (pyridine CH), 124.4
(ArCBr), 127.4, 128.7, 130.6, 133.0 (ArCH), 138.4
(AripsoCCH2), 149.8 (pyridine CH) and 154.4 (pyridineipsoC);
m/z (CI) 335 (MH1, 100%), 333 (MH1, 100%), 256 (5) and
254 (5); m/z (EI) 319 (28%), 317 (29), 256 (67), 254 (70),
171 (100), 169 (100), 90 (55), 78 (40), 51 (40) and 43 (25);
(Found MH1 (ES1) 333.0604, C16H1779BrN2O requires
333.0602).
1.1.3. 2-Phenyl-2-methyl-3-(2-bromobenzyl)-oxazolidine
(8). A solution of N-(2-bromobenzyl)-2-aminoethanol 6
(1.42 g, 6.2 mmol), acetophenone (800 mg, 6.7 mmol) and
4-toluenesulfonic acid monohydrate (53 mg, 0.28 mmol) in
benzene (50 cm3) was heated under re¯ux using a Dean±
Stark water separator for 12 h. The solvent was evaporated
in vacuo and the residue was puri®ed by ¯ash chromato-
graphy on silica gel (eluting with 3:1 v/v hexane: ethyl
acetate) to give the title compound as a colourless oil
(1.70 g, 83%); Rf 0.30 (3:1 v/v hexane:EtOAc); nmax/cm21
(thin ®lm) 3127±2758m (C-H), 1653w, 1596s, 1559m,
1495m, 1456s, 1407m, 1375m, 1282w, 1210m, 1156m,
1065s, 1025s, 821s, 741w, 698s and 668w; dH (400 MHz;
CDCl3) 1.69 (3H, s, CH3C), 2.87 (2H, m, NCH2CH2), 3.76,
3.95 (2£1H, ABq, JAB 14, ArCH2), 3.81 (1H, m, CH2O),
4.02 (1H, ca. q, J 7.5, CH2O), 7.13 (1H, dt, J 6 and 1, Ar-H),
7.25 (4H, complex, Ar-H and Ph-H), 7.56 (1H, dd, J 8 and 1,
Ar-H) and 7.61±7.69 (3H, complex, Ar-H and Ph-H); dC
(75MHz; CDCl3) 24.2 (CH3C), 50.3 (NCH2CH2), 53.1
(ArCH2), 98.7 (CH3C), 124.3 (ArCBr), 126.1, 127.4,
128.0, 128.4, 130.6, 132.8 (ArCH and PhCH) and 138.9,
145.3 (AripsoC and PhipsoC); m/z (EI) 318 ([M2CH3]1,
99%), 316 ([M2CH3]1, 100), 256 (44), 254 (45), 171
(90), 169 (91), 132 (12), 105 (27), 91 (51), 34 (77) and 51
(12).
1.1.6. 4-(3-(2-Iodobenzyl)-2-methyl-oxazolidin-2-yl)-pyri-
dine (11). Using the procedure described above for the
preparation of 4-(3-(2-bromobenzyl)-2-methyl-oxazolidin-
2-yl)-pyridine 10, with N-(2-iodobenzyl)-2-aminoethanol 7
(1.90 g, 6.90 mmol), 4-acetylpyridine (1.03 g, 8.50 mmol)
and p-toluenesulfonic acid (52 mg, 0.27 mmol), the title
compound was prepared as a colourless oil (1.61 g, 61%);
Rf 0.40 (1:1 v/v hexane:EtOAc); nmax/cm21 (thin ®lm)
3105-2765m (C-H), 1595m, 1559m, 1461m, 1439m,
1408m, 1375m, 1271m, 1218w, 1209m, 1147w, 1092w,
1058w, 1023s, 823m, 751s, 669m and 654m; dH
(400 MHz; CDCl3) 1.67 (3H, s, CH3C), 2.74 (1H, m,
NCH2CH2), 2.89 (1H, m, NCH2CH2), 3.68, 3.96 (2£1H,
ABq, JAB 14, ArCH2), 3.73 (1H, m, CH2O), 4.03 (1H, ca.
q, J 7.5, CH2O), 6.97 (1H, dt, J 8 and 1.5, Ar-H), 7.35 (1H, t,
J 8, Ar-H), 7.53 (1H, d, J 8, Ar-H), 7.55, 8.58 (2£2H,
AA0BB0, J 6, pyridine CH) and 7.86 (1H, dd, J 8 and 1,
Ar-H); dC (100 MHz; CDCl3) 24.1 (CH3C), 50.0
1.1.4. 2-(4-Nitrobenzyl)-2-methyl-3-(2-bromobenzyl)-oxa-
zolidine (9). A solution of N-(2-bromobenzyl)-2-amino-
ethanol
6
(2.33 g, 10.1 mmol), 4-nitroacetophenone
(1.67 g, 10.1 mmol) and 4-toluenesulfonic acid mono-
hydrate (2 crystals) in benzene (50 cm3) was heated under
re¯ux using a Dean±Stark water separator for 12 h. The
solvent was evaporated in vacuo and the residue was
puri®ed by ¯ash chromatography on silica gel (eluting
with 2:1 v/v hexane:ethyl acetate) to give the title compound
as a yellow oil (3.83 g, 100%); Rf 0.30 (10:9:1 v/v/v
hexane:EtOAc:Et3N); nmax/cm21 (thin ®lm) 3131±2761m

R. Gosain et al. / Tetrahedron 57 (2001) 1399±1410
1405
(NCH2CH2), 57.6 (CH2CH2O), 63.0 (ArCH2), 97.9 (CH3C),
100.2 (ArCI), 121.1 (pyridine CH), 128.2, 128.9, 130.3,
139.7 (ArCH), 141.2 (AripsoCCH2), 149.9 (pyridine CH)
and 154.4 (pyridineipsoC); m/z (CI) 381 (MH1, 100%), 255
(63), 139 (37), 134 (81), 122 (97) and 108 (24); m/z (EI) 365
(37), 302 (81), 217 (100), 91 (57), 90 (49), 89 (33), 78 (28),
51 (29) and 43 (19); (Found MH1 (ES1) 381.0476,
C16H18IN2O requires 381.0464).
1585m, 1559w, 1404s, 1226m, 1071m, 1046m, 766m,
698m and 639m; dH (400 MHz; CDCl3) 2.20 (3H, s,
CH3C), 2.29-2.54 (2H, brm, NCH2), 3.85 (1H, ca. q, J 7,
NCH2), 4.07 (1H, m, CH2O), 7.09 (1H, dt, J 8 and 2, Ar-H),
7.24±7.46 (5H, complex, Ph-H), 7.68 (2H, brs, ArC-H) and
7.84 (1H, d, J 8, ArC-H); dC (100 MHz; CDCl3) 25.1 (br,
CH3), 48.4 (CH2N), 63.5 (CH2O), 91.3 (CH3C), 96.8 (ArCI),
126.0, 126.6, 128.2, 128.9, 130.3, 139.4 (ArCH and PhCH),
1
143.7 (PhipsoC) and 167.3 (CˆO); m/z (CI) 411 (MNH4
,
1.1.7. 3-(2-Iodobenzyl)-2-methyl-oxazolidine-2-carboxylic
acid ethyl ester (12). Ethyl pyruvate (540 ml, 4.86 mmol)
was added dropwise to a vigorously stirred mixture of N-(2-
iodobenzyl)-2-aminoethanol 7 (1.15 g, 4.15 mmol) and
17%), 394 (MH1, 15), 285 (43), 268 (100), 165 (35), 148
(29), 138 (26), 120 (22), 86 (8) and 61 (5); m/z (EI) 378
(32%), 316 (13), 231 (100), 203 (21), 117 (12), 105 (52), 77
(76), 76 (39), 51 (22) and 43 (14); (Found MH1 (ES1)
394.0303, C17H17INO2 requires 394.0304).
Ê
powdered 4 A molecular sieves (3.00 g) in tetrahydrofuran
(40 cm3). After stirring at room temperature overnight, the
molecular sieves were removed by ®ltration and the solvent
removed in vacuo. The residue was puri®ed by ¯ash
chromatography on silica gel (eluting with dichloro-
methane) to give the title compound as a yellow oil
(1.01 g, 65%); Rf 0.40 (CH2Cl2); nmax/cm21 (thin ®lm)
3070±2750m (C-H), 1732s (CˆO), 1564w, 1437m,
1375m, 1248s, 1200s, 1126s, 1109s, 1026s, 1013s, 901w,
752s and 650w; dH (400 MHz; CDCl3) 1.36 (3H, t, J 7,
CH3CH2), 1.59 (3H, s, CH3C), 2.92 (1H, ca. q, J 8,
CH2N), 3.04 (1H, m, CH2N), 3.63, 3.90 (2£1H, ABq, JAB
14, ArCH2), 4.02 (1H, ca. q, J 4, CH2CH2O), 4.14 (1H, m,
CH2CH2O), 4.26 (2H, m, CH3CH2), 6.95 (1H, m, Ar-H),
7.33 (1H, m, Ar-H), 7.45 (1H, m, Ar-H) and 7.82 (1H, dd,
J 8 and 1, Ar-H); dC (100 MHz; CDCl3) 14.6 (CH3CH2),
21.3 (CH3C), 49.8 (CH2N), 57.5 (CH2OCN), 60.9 (ArCH2),
65.8 (CH3CH2O), 94.5 (NCO), 99.4 (ArCI), 128.3, 128.9,
129.8, 139.5 (ArCH), 140.6 (AripsoCCH2) and 171.3 (CˆO);
m/z (CI) 376 (MH1, 38%), 250 (32), 134 (100), 108 (39),
106 (63), 86 (43) and 61 (33); m/z (EI) 302 (100%), 217
(44), 91 (100) and 43 (93); (Found MH1 (ES1) 376.0415,
C14H19INO3 requires 376.0409).
1.1.9. 4-(3-(2-Deuteriobenzyl)-2-methyl-oxazolidin-2-yl)-
pyridine (14) and 4-(4-deuterio-3-benzyl-2-methyl-oxa-
zolidin-2-yl)-pyridine (15). A de-gassed solution of 4-(3-
(2-iodobenzyl)-2-methyl-oxazolidin-2-yl)-pyridine 11 (380
mg, 1.00 mmol), tributyltin deuteride (554 ml, 2.05 mmol)
and 2,20-azobisisobutyronitrile (12 mg, 0.07 mmol) in
benzene (25 cm3) was heated under re¯ux for 2 h. After
cooling to room temperature, the reaction mixture was
diluted with ethyl acetate (15 cm3) and the resulting solution
was stirred with aqueous sodium hydroxide solution (1.0 M,
5.0 cm3) for 20 min before the separated organic phase was
dried (sodium sulfate), ®ltered and evaporated to give a
residue which was puri®ed by ¯ash chromatography on
silica gel (eluting with 3:1 v/v hexane: ethyl acetate). This
gave the title compound mixture (1:2, 14:15) as a yellow oil
(234 mg, 92%); Rf 0.40 (1:1 v/v hexane:EtOAc); dD
(61.4 MHz; CCl4) 2.66 (0.33D, s, NCHDCH2), 2.78
(0.33D, s, NCHDCH2) and 7.31 (0.33D, s, Ph-D); m/z (CI)
256 (MH1, 24%), 153 (30), 122 (70), 121 (60), 109 (28),
108 (100), 106 (50) and 80 (33).
Key comparative data for unlabelled 4-(3-benzyl-2-methyl-
oxazolidin-2-yl)-pyridine: nmax/cm21 (thin ®lm) 3111±
2755w (C-H), 1595m, 1551w, 1495w, 1453m, 1407m,
1375w, 1281w, 1210w, 1156w, 1065w, 1023m, 822m,
736w, 699m and 667w; dH (400 MHz; CDCl3) 1.62 (3H,
s, CH3C), 2.76, 2.87 (2£1H, 2£m, NCH2CH2), 3.60, 3.91
(2£1H, ABq, JAB 13, PhCH2), 3.75 (1H, m, CH2CH2O), 3.98
(1H, ca. q, J 7.5, CH2CH2O), 7.22±7.45 (5H, complex,
Ph-H), and 7.52, 8.59 (2£1H, AA0BB0, J 6, pyridine CH);
dC (100 MHz; CDCl3) 23.6 (CH3C), 50.2 (NCH2CH2), 53.5
(CH2CH2O), 63.3 (PhCH2), 97.4 (CH3C), 121.1 (pyridine
CH), 127.1, 128.3, 128.4 (PhCH), 139.4 (PhipsoC), 149.8
(pyridine CH) and 154.4 (pyridineipsoC); m/z (CI) 255
(MH1, 100%), 176 (5), 152 (5), 122 (4) and 108 (6); m/z
(EI) 254 (M1, 1%), 239 (42), 176 (65), 133 (10), 91 (100)
and 65 (23); (Found MH1 (ES1) 255.1502, C16H19N2O
requires 255.1497).
1.1.8. (2-Iodo-phenyl)-(2-phenyl-2-methyl-oxazolidin-3-
yl)-methanone (13). A solution of ethanolamine 1 (593
ml, 9.82 mmol) and acetophenone (940 mg, 7.82 mmol) in
benzene (100 cm3) was heated under re¯ux using a Dean
and Stark water separator for 24 h. The dark residue
obtained from evaporation of the solvent in vacuo was
dissolved in ethyl acetate (30 cm3) and the resulting solution
was washed with water (2£15 cm3), dried (sodium sulfate),
®ltered and evaporated in vacuo. A solution of the residue in
dichloromethane (10 cm3) was added dropwise over 30 min
to a stirred solution of 2-iodobenzoyl chloride (2.050 g,
7.69 mmol) and triethylamine (2.50 cm3, 17.94 mmol) in
benzene at 08C under a nitrogen atmosphere. The stirred
reaction mixture was allowed to attain room temperature
over 3 h and after stirring at this temperature for a further
3 h, a saturated aqueous solution of sodium bicarbonate
(15 cm3) was added and the resulting biphasic mixture
stirred for a further 30 min. The separated aqueous phase
was extracted with dichloromethane (3£15 cm3) and the
combined organic extracts were dried (sodium sulfate),
®ltered and evaporated in vacuo. The residue was puri®ed
by ¯ash chromatography on silica gel (eluting with 3:1 v/v
hexane:ethyl acetate) to give the title compound as a yellow
oil which crystallised on standing to a yellow solid (1.740 g,
58%); m.p. 122±1248C; Rf 0.36 (3:1 v/v hexane:EtOAc);
1.1.10. (2-Deuteriophenyl)-(2-phenyl-2-methyl-oxazoli-
din-3-yl)-methanone (16) and (2-phenyl)-(4-deuterio-2-
phenyl-2-methyl-oxazolidin-3-yl)-methanone (17). Tri-
ethylborane (1.0 M solution on tetrahydrofuran, 100 ml,
0.1 mmol) was added to a solution of (2-iodo-phenyl)-
(2-phenyl-2-methyl-oxazolidin-3-yl)-methanone 13 (71.5 mg,
0.18 mmol) and tributyltin deuteride (148 ml, 0.55 mmol) in
benzene (8 cm3) at room temperature. After stirring for 12 h,
aqueous sodium hydroxide solution (1.0 M, 20 cm3) was
n
max/cm21 (thin ®lm) 3138±2826w (C-H), 1653s (CˆO),

1406
R. Gosain et al. / Tetrahedron 57 (2001) 1399±1410
added and the biphasic mixture was stirred for 20 min before
the separated organic phase was dried (sodium sulfate), ®ltered
and evaporated in vacuo. The residue was puri®ed by ¯ash
chromatography on silica gel (eluting with 5:2 v/v petroleum
ether:ethyl acetate) to give the title compound mixture (1:1,
16:17) as a colourless oil (48.5 mg, 100%); Rf 0.31 (3:1 v/v
hexane:EtOAc); dD (61.4 MHz; CCl4) 3.57 (0.25D, s,
NCHDCH2), 3.69 (0.25D, s, NCHDCH2) and 7.47 (0.5H, s,
part of AA0BB0,
J 6, pyridine CH minor); dC
(100 MHz; CDCl3) 23.9 (CH3C major), 26.4 (CH3C
t
and CH2CH2CO2 Bu minor), 28.0 ((CH3)3C major and
t
(CH3)3C, CH2CH2CO2 Bu minor), 29.5 (CH2CH2CO2 Bu
t
t
major), 32.1 (CH2CH2CO2 Bu major), 50.6 (PhCH2
minor), 55.6 (PhCH2 major), 61.3 (NCH minor), 64.1
(NCH major), 68.8 (CHCH2O major), 70.0 (CHCH2O
minor), 80.1 ((CH3)3C major), 80.4 ((CH3)C minor),
97.1 (CH3C minor), 97.9 (CH3C major), 121.3, 124.2,
126.1, 127.0, 127.9, 128.3, 128.7, 128.8 (PhCH and
pyridine CH both), 139.6 (PhipsoC major), 140.1 (PhipsoC
minor), 149.7 (pyridine CH both), 152.1 (pyridineipsoC
1
Ph-D); m/z (CI) 286 (MNH4 , 32%), 269 (MH1, 100), 268
(27) and 149 (19).
Key comparative data for unlabelled (2-phenyl)-(2-phenyl-
max/cm21 (thin
t
2-methyl-oxazolidin-3-yl)-methanone:
n
minor), 155.6 (pyridineipsoC major), 172.2 (CO2 Bu minor)
and 172.3 (CO2 Bu major); m/z (CI) 383 (MH1, 100%), 291
t
®lm) 3140±2833s (C-H), 1640s (CˆO), 1602m, 1578m,
1494m, 1446m, 1403s, 1370m, 1272m, 1228m, 1176w,
1096w, 1071m, 1041m, 1028m, 869w, 764m, 699m, 726s
and 657m; dH (400 MHz; CDCl3) 2.12 (3H, brs, CH3C),
3.70 (1H, brm, NCH2CH2), 3.77 (1H, brm, NCH2CH2),
3.87 (1H, m, CH2CH2O), 4.04 (1H, m, CH2CH2O) and
7.25±7.59 (10H, complex, Ph-H); dC (100 MHz; CDCl3)
24.9 (CH3C), 49.0 (NCH2), 63.3 (CH2O), 96.4 (CH3C),
125.9, 126.4, 128.4, 128.3, 128.5, 129.8 (PhCH), 137.7
(PhipsoC), 141.8 (PhipsoC) and 168.3 (CˆO); m/z (CI) 285
(MNH41, 37%), 268 (MH1, 100) and 148 (18); m/z (EI) 267
(M1, 13%), 253 (21), 252 (65, 190 (40), 147 (12), 117 (39),
105 (90) and 77 (100); (Found MH1 (ES1) 268.1336,
C17H18NO2 requires 268.1337).
(13), 122 (76), 108 (85), 106 (41) and 80 (32); m/z (EI) 253
(10%), 91 (100), 57 (52) and 41 (49); (Found MH1 (ES1)
383.2336, C23H31N2O3 requires 383.2334).
1.1.12.
4-(2-tert-Butoxycarbonyl-ethyl)-3-benzyl-2-(4-
(18a/b)Ðmethod b.
pyridyl)-2-methyl-oxazolidine
Tributyltin hydride (1.488 cm3, 5.53 mmol) and 2,20-azo-
bisisobutyronitrile (36 mg, 0.22 mmol) were added to a
de-gassed solution of 4-(3-(2-iodobenzyl)-2-methyl-oxa-
zolidin-2-yl)-pyridine 11 (700 mg, 1.84 mmol) and tert-
butyl acrylate (1.257 cm3, 8.58 mmol) in benzene
(60 cm3). After irradiation with a medium pressure mercury
vapour lamp at room temperature under a nitrogen
atmosphere for 6 h, the solvent was evaporated in vacuo
and the reaction was worked-up as described in method a
above to give the title compound (pale yellow oil) as an
inseparable 2:1 mixture of diastereoisomers (378 mg,
54%); data as reported above in method a.
1.1.11.
4-(2-tert-Butoxycarbonyl-ethyl)-3-benzyl-2-(4-
pyridyl)-2-methyl-oxazolidine (18a/b)Ðmethod a. A
de-gassed solution of tributyltin hydride (2.230 cm3,
7.65 mmol) and 2,20-azobisisobutyronitrile (28 mg, 0.17
mmol) in benzene (120 cm3) was added dropwise over
8 h, to a stirred solution of 4-(3-(2-iodobenzyl)-2-methyl-
oxazolidin-2-yl)-pyridine 11 (940 mg, 2.47 mmol) and tert-
butyl acrylate (1.017 cm3, 6.94 mmol) in benzene (100 cm3)
under re¯ux and under a nitrogen atmosphere. The solvent
was removed in vacuo and the residue was taken up in ethyl
acetate (10 cm3), the resulting solution being washed with
saturated aqueous sodium ¯uoride solution (15 cm3)
followed by aqueous ammonia (2 M, 2£20 cm3). The
organic phase was dried (sodium sulfate), ®ltered and
evaporated in vacuo, the residue being puri®ed by ¯ash
chromatography on silica gel (eluting with 3:2 v/v hexane:
ethyl acetate) to give the title compound (pale yellow oil) as
an inseparable 2:1 mixture of diastereoisomers (472 mg,
50%); Rf 0.42 (1:1 v/v hexane: EtOAc); nmax/cm21 (thin
®lm) 3124±2757m (C-H), 1731s (CˆO), 1690w, 1593m,
1438w, 1419m, 1256m, 1194m, 1150m, 1039m, 835w and
769m; dH (400 MHz; CDCl3) 1.33 (6H, s, (CH3)3C major
1.1.13.
4-(2-tert-Butoxycarbonyl-ethyl)-3-benzyl-2-(4-
pyridyl)-2-methyl-oxazolidine (18a/b)Ðmethod c. Tri-
ethylborane (1.0 M solution in tetrahydrofuran, 100 ml,
0.1 mmol) was added to a de-gassed solution of 4-(3-(2-
iodobenzyl)-2-methyl-oxazolidin-2-yl)-pyridine 11 (340 mg,
0.90 mmol), tributyltin hydride (481 ml, 1.79 mmol) and
tert-butyl acrylate (263 ml, 1.80 mmol) in benzene
(50 cm3). The reaction ¯ask was opened to the air and the
mixture was stirred at room temperature for 12 h before
removal of the solvent in vacuo and work-up as described
in method a above. This gave the title compound (pale
yellow oil) as an inseparable 2:1 mixture of diastereo-
isomers (143 mg, 42%); data as reported above in method a.
1.1.14. 4-(2-Cyano-ethyl)-3-benzyl-2-(4-pyridyl)-2-methyl-
oxazolidine (19a/b)Ðmethod b. Tributyltin hydride (832
ml, 3.09 mmol) and 2,20-azobisisobutyronitrile (24 mg,
0.15 mmol) were added to a de-gassed solution of 4-(3-(2-
iodobenzyl)-2-methyl-oxazolidin-2-yl)-pyridine 11 (487
mg, 1.28 mmol) and acrylonitrile (186 ml, 2.83 mmol) in
benzene (50 cm3). After irradiation with a medium pressure
mercury vapour lamp at room temperature under a nitrogen
atmosphere overnight, the solvent was evaporated in vacuo
and the residue was puri®ed by ¯ash chromatography on
silica gel (eluting with 1:3 hexane:ethyl acetate) to give
the title compound (colourless oil) as an inseparable 2:1
mixture of diastereoisomers (200 mg, 51%); Rf 0.25 (2:3
v/v hexane:EtOAc); nmax/cm21 (thin ®lm) 3120±2797w
(C-H), 2228s (CN), 1608s, 1503m, 1453m, 1410s, 1372m,
1339w, 1282w, 1206m, 1120w, 1092s, 1014m, 900w and
t
diastereoisomer), 1.35±1.47 (2H, complex, CH2CH2CO2 Bu
both diastereoisomers), 1.38 (3H, s, (CH3)3C minor dia-
stereoisomer), 1.56 (2H, s, CH3C major), 1.73 (1H, s,
CH3C minor), 1.89 (1.34H, m, CH2CO2 Bu major), 2.14
t
t
(0.67H, m, CH2CO2 Bu minor), 3.11 (0.33H, m, NCH
minor), 3.20 (0.67H, m, NCH major), 3.35 (0.67H, dd, J 8
and 7, CHCH2O major), 3.49, 3.61 (2£0.33H, ABq, JAB 14,
PhCH2 minor), 3.67 (0.67H, part of ABq, JAB 14.5, PhCH2
major), 3.76 (0.33H, ca. t, J 8, CH2CH2O minor), 4.11±4.20
(1.67H, complex, PhCH2 and CH2CH2O major and
CH2CH2O minor), 7.20±7.38 (5.67H, complex, Ph-H
both and pyridine CH minor), 7.47, 8.54 (2£1.34H,
AA0BB0, J 6, pyridine CH major) and 8.59 (0.67H,

R. Gosain et al. / Tetrahedron 57 (2001) 1399±1410
1407
839s; dH (400 MHz; CDCl3) 1.61 (2H, s, CH3C major
diastereoisomer), 1.65 (1H, s, CH3C minor), 1.65±1.95
(4H, complex, CH2CH2CN both diastereoisomers), 3.22±
3.38 (2.33H, complex, NCH both, PhCH2 minor, CH2O
both), 3.61 (0.67H, part of ABq, JAB 13, PhCH2 major),
4.19±4.33 (2H, complex, PhCH2 both, CH2O both), 7.23±
7.42 (5.67H, complex, Ph-H both and pyridine CH minor),
7.49, 8.59 (2£1.34H, AA0BB0, J 6, pyridine CH major) and
8.62 (0.67H, part of AA0BB0, pyridine CH minor); dC
(100 MHz; CDCl3) major diastereoisomer: 13.6
(CH2CH2CN), 24.6 (CH3C), 30.1 (CH2CH2CN), 55.9
(PhCH2), 63.0 (NCH), 68.2 (CH2O), 98.5 (CH3C), 119.1
(CN), 120.9, 127.8, 128.6, 129.2, 149.9 (PhCH and pyridine
CH), 139.0 (PhipsoC) and 155.4 (pyridineipsoC); m/z (CI) 308
(MH1, 94%), 187 (21), 139 (20), 122 (92), 108 (100), 106
(46) and 80 (34); m/z (EI) 292 (3%), 229 (9), 91 (100), 78
(20), 65 (21), 51 (23) and 43 (12); (Found MH1 (ES1)
308.1766, C19H22N3O requires 308.1763).
4.30 (3.25H, complex, PhCH2 minor, CHCH2O both,
CH3CH2O both) and 7.18±7.36 (5H, Ph-H both); dC
(100 MHz; CDCl3) major diastereoisomer: 14.5 (CH3CH2),
t
22.9 (CH3C), 28.0 ((CH3)3C), 28.1 (CH2CH2CO2 Bu), 31.3
(CH2CO2 Bu), 52.1 (PhCH2), 60.7 CH3CH2), 62.0 (NCH),
t
71.0 (CHCH2O), 80.2 ((CH3)3C), 96.2 (NCO), 126.9, 127.0,
128.1, 128.2 (PhCH), 139.9 (PhipsoC) and 171.4, 172.5
(CˆO); dC (100 MHz; CDCl3) minor diastereoisomer:
t
14.1 (CH3CH2), 20.0 (CH3C), 27.3 (CH2CH2CO2 Bu), 28.1
t
((CH3)3C), 31.7 (CH2CO2 Bu), 52.5 (PhCH2), 61.0
CH3CH2), 62.0 (NCH), 70.2 (CHCH2O), 80.2 ((CH3)3C),
95.2 (NCO), 126.9, 127.0, 128.1, 128.2 (PhCH), 139.9
(PhipsoC) and 171.4, 172.5 (CˆO); m/z (CI) 378 (MH1,
100%), 304 (8) 214 (10), 134 (16) and 106 (19); m/z (EI)
304 (10%), 248 (25), 91 (100), 57 (22) and 43 (18); (Found
MH1 (ES1) 378.2281, C21H31NO5 requires 378.2280).
1.1.17. 4-(2-Cyano-ethyl)-3-benzyl-2-methyl-oxazolidine-
2-carboxylic acid ethyl ester (21a/b)Ðmethod c. Acrylo-
nitrile (260 ml, 3.95 mmol) was added to a stirred solution of
3-(2-iodobenzyl)-2-methyl-oxazolidine-2-carboxylic acid
ethyl ester 12 (500 mg, 1.33 mmol) and tri-n-butyltin
hydride (1.230 cm3, 4.57 mmol) in benzene (45 cm3) at
room temperature. Triethylborane (1.0 M solution in tetra-
hydrofuran, 100 ml, 0.1 mmol) was added and after stirring
overnight, the solvent was evaporated in vacuo. A solution
of the resulting oil in ethyl acetate (30 cm3) was stirred
vigorously with an aqueous solution of sodium ¯uoride
(20% w/v, 50 cm3) for 2 h, after which, the separated
organic phase was dried (magnesium sulfate), ®ltered and
evaporated in vacuo to give a yellow oil. (Note: 1H NMR of
the crude product indicated a 3:1 mixture of diastereo-
isomers of the title compound.) The product was puri®ed
by ¯ash chromatography on silica gel (eluting with
dichloromethane) to give the title compound as two dia-
stereoisomers; major diastereoisomer: yellow oil (86 mg,
1.1.15. 4-(2-Cyano-ethyl)-3-benzyl-2-(4-pyridyl)-2-methyl-
oxazolidine (19a/b)Ðmethod c. Triethylborane (1.0 M
solution in tetrahydrofuran, 100 ml, 0.1 mmol) was added
to a de-gassed solution of 4-(3-(2-iodobenzyl)-2-methyl-
oxazolidin-2-yl)-pyridine 11 (175 mg, 0.46 mmol), tributyl-
tin hydride (250 ml, 0.93 mmol) and acrylonitrile (223 ml,
3.39 mmol) in benzene (25 cm3). The reaction ¯ask was
opened to the air and the mixture was stirred at room
temperature for 6 h before removal of the solvent in vacuo
and work-up as described in method a above. This gave the
title compound (colourless oil) as an inseparable 2:1 mixture
of diastereoisomers (72 mg, 51%); data as reported above in
method b.
1.1.16. 4-(2-tert-Butoxycarbonyl-ethyl)-3-benzyl-2-methyl-
oxazolidine-2-carboxylic acid ethyl ester (20a/b)Ðmethod
c. tert-Butyl acrylate (230 ml, 1.57 mmol) was added to a
stirred solution of 3-(2-iodobenzyl)-2-methyl-oxazolidine-
2-carboxylic acid ethyl ester 12 (200 mg, 0.53 mmol) and
tri-n-butyltin hydride (490 ml, 1.82 mmol) in benzene
(45 cm3) at room temperature. Triethylborane (1.0 M
solution in tetrahydrofuran, 100 ml, 0.1 mmol) was added
and, after stirring overnight, the solvent was evaporated in
vacuo. A solution of the resulting oil in ethyl acetate
(30 cm3) was stirred vigorously with an aqueous solution
of sodium ¯uoride (20% w/v, 50 cm3) for 2 h, after which,
the separated organic phase was dried (magnesium sulfate),
®ltered and evaporated in vacuo to give a yellow oil. The
product was puri®ed by ¯ash chromatography on silica gel
(eluting with dichloromethane) to give the title compound
(yellow oil) as an inseparable 3:1 mixture of diastereo-
isomers (81 mg, 41%); Rf 0.22 (CH2Cl2); nmax/cm21 (thin
®lm) 3100±2800m (C-H), 1730s (CˆO), 1456m, 1367m,
1257m, 1213m, 1153s, 1028w and 701w; dH (400 MHz;
CDCl3) 1.24 (0.75H, t, J 7, CH3CH2 minor diastereoisomer),
1.32 (2.25H, t, J 7, CH3CH2 major diastereoisomer), 1.37
(2.25H, s, (CH3)3C minor), 1.38 (6.75H, s, (CH3)3C major),
1.44 (2.25H, s, CH3C major), 1.49 (0.75H, s, CH3C minor)
21%): Rf 0.40 (3:2 v/v petroleum ether:EtOAc); nmax
/
cm21 (thin ®lm) 3100±2780m (C-H), 2445w (CN), 1730s
(CˆO), 1456m, 1377m, 1254s, 1213s, 1171s, 1128s, 899w,
746m and 701m; dH (400 MHz; CDCl3) 1.33 (3H, t, J 7,
CH3CH2), 1.37 (1H, m, CH2CH2CN), 1.53 (3H, s, CH3C),
1.57 (1H, m, CH2CH2CN), 2.15 (2H, m, CH2CN), 3.46 (1H,
m, CHN) 3.51, 3.93 (2£1H, ABq, JAB 14, PhCH2), 3.69 (1H,
dd, J 8 and 5, CHCH2O), 4.24 (2H, ca. dq, J 7 and 2,
CH3CH2), 4.38 (1H, ca. t, J 8, CHCH2O) and 7.24±7.36
(5H, complex, Ph-H); dC (100 MHz; CDCl3) 12.1
(CH2CN), 14.4 (CH3CH2), 22.6 (CH3C), 22.8 (CH2CH2CN),
53.0 (PhCH2), 61.0 (CH3CH2), 61.5 (NCH), 70.5
(CHCH2O), 96.5 (NCO), 119.6 (CN), 127.6, 128.2, 128.6
(PhCH), 139.1 (PhipsoC) and 170.9 (CˆO); m/z (CI) 303
(MH1, 100%), 139 (40) and 106 (16); m/z (EI) 229 (15%),
91 (100), 65 (12) and 43 (18); (Found MH1 (ES1) 303.1710,
C17H23N2O3 requires 303.1708); minor diastereoisomer:
yellow oil (18 mg, 5%); Rf 0.23 (3:2 v/v petroleum ether:
EtOAc); nmax/cm21 (thin ®lm) 3120±2770m (C-H), 2445w
(CN), 1736s (CˆO), 1497w, 1454m, 1375m, 1263m,
1211m, 1173m, 1124s, 1026m, 743w and 701m; dH
(400 MHz; CDCl3) 1.30 (3H, t, J 7, CH3CH2), 1.45 (1H,
m, CH2CH2CN), 1.55 (1H, s, CH3C), 1.61 (1H, m,
CH2CH2CN), 2.10 (2H, m, CH2CN), 3.26 (1H, m, NCH),
3.67, 4.21 (2£1H, ABq, JAB 14, PhCH2), 3.77 (1H, dd, J 8
and 7, CHCH2O, 4.14 (1H, dd, J 8 and 7, CHCH2O), 4.20
(2H, m, CH3CH2) and 7.22±7.35 (5H, complex, Ph-H); dC
t
1.63±1.74 (2H, complex, CH2CH2CO2 Bu both diastereo-
isomers), 2.01±2.16 (2H, complex, CH2CO2 Bu both),
t
3.15 (0.25H, m, NCH minor), 3.35 (0.75H, ca. dq, J 8 and
3, NCH major), 3.62, 3.86 (2£0.75H, ABq, JAB 15, PhCH2
major), 3.69 (0.75H, dd, J 7 and 8, CHCH2O major), 3.74±
3.80 (0.5H, complex, PhCH2 and CHCH2O minor), 4.06±

1408
R. Gosain et al. / Tetrahedron 57 (2001) 1399±1410
(100 MHz; CDCl3) 12.9 (CH2CN), 14.2 (CH3CH2), 19.8
(CH3C), 28.3 (CH2CH2CN), 53.7 (PhCH2), 61.3 (CH3CH2),
61.6 (NCH), 69.1 (CHCH2O), 95.9 (NCO), 119.5 (CN),
127.5, 128.4, 128.5 (PhCH), 139.1 (PhipsoC) and 172.2
(CˆO); m/z (CI) 303 (MH1, 45%), 139 (100) and 106 (67);
m/z (EI) 229 (27%), 91 (100), 65 (12) and 43 (17); (Found
MH1 (ES1) 303.1706, C17H23N2O3 requires 303.1708).
1446s, 1396s, 1372s, 1271m, 1237s, 1075s, 1027m, 765s,
700s and 660m; dH (400 MHz; d8 toluene; 1008C) 1.12±
1.61 (4H, complex, CH2CH2CN both diastereoisomers),
1.87 (1.11H, s, CH3C minor diastereoisomer), 1.96
(1.89H, s, CH3C major diastereoisomer), 3.24 (0.37H, ca.
dd, J 9 and 5, CH2O minor), 3.35 (0.63H, ca. dd, J 9 and 3,
major), 3.63 (0.63H, ca. dd, J 9 and 6, CH2O major), 3.82
(0.37H, ca. dd, J 9 and 7, CH2O minor), 3.91±4.02 (1H,
complex, NCH both) and 6.93±7.60 (10H, complex, Ph-H
both); dC (100 MHz; d8 toluene; 1008C) major diastereo-
isomer: 13.0 (CH2CN), 26.4 (CH3C), 29.5 (CH2CH2CN,
57.6 (NCH), 66.6 (CH2O), 96.8 (CH3C), 117.6 (CN),
PhCH region obscured by overlap with solvent peaks,
138.2, 142.6 (2£PhipsoC) and 168.5 (CˆO); dC (100 MHz;
d8 toluene; 1008C) minor diastereoisomer: 13.2 (CH2CN),
26.1 (CH3C), 29.6 (CH2CH2CN), 57.8 (NCH), 67.5 (CH2O),
97.6 (CH3C), 117.3 (CN), PhCH region obscured by overlap
with solvent peaks, 137.9, 143.4 (2£PhipsoC) and 168.5
(CˆO); m/z (CI) 338 (MNH41, 100%), 321 (MH1, 47),
201 (46), 139 (22), 82 (22) and 52 (18); m/z (EI) 305
(10%), 105 (100), 77 (70) and 51 (16); (Found MH1
(ES1) 321.1605; C20H21N2O2 requires 321.1603).
1.1.18. 3-(3-Benzoyl-2-phenyl-2-methyl-oxazolidin-4-yl)-
propionic acid tert-butyl ester (23a/b)Ðmethod a. A de-
gassed solution of tributyltin hydride (924 ml, 3.44 mmol),
2,20-azobisisobutyronitrile (18 mg, 0.11 mmol) and tert-
butyl acrylate (690 ml, 4.71 mmol) in benzene (18 cm3)
was added dropwise over 6 h to a stirred, de-gassed solution
of (2-iodo-phenyl)-(2-phenyl-2-methyl-oxazolidin-3-yl)-
methanone 13 (660 mg, 1.68 mmol) in benzene (20 cm3)
under re¯ux under a nitrogen atmosphere. After heating
under re¯ux for a further 3 h, the cooled reaction mixture
was diluted with ethyl acetate (10 cm3) and the resulting
solution was stirred with aqueous sodium hydroxide solu-
tion (2.0 M, 10 cm3) for 30 min before being dried (sodium
sulfate), ®ltered and evaporated in vacuo. The residue was
puri®ed by ¯ash chromatography on silica gel (eluting with
2:1 v/v hexane:ethyl acetate) to give the title compound
(colourless oil) as an inseparable 2.5:1 mixture of dia-
stereoisomers (461 mg, 70%); Rf 0.40 (3:1 v/v hexane:
EtOAc); nmax/cm21 (thin ®lm) 3123±2833m (C-H), 1728
(CˆO), 1695m, 1681w, 1648s, 1633s, 1451m, 1438m,
1395s, 1364s, 1241m, 1154s, 1073w, 1025w, 876w, 759m
and 701s; dH (400 MHz; d8 toluene; 1008C) 1.23 (2.6H, s,
(CH3)3C minor diastereoisomer), 1.31 (6.4H, s, (CH3)3C
major diastereoisomer), 1.45±2.15 (4H, complex,
1.1.20. 3-(3-Benzoyl-2-phenyl-2-methyl-oxazolidin-4-yl)-
propionic acid tert-butyl ester (23a/b)Ðmethod d.. A de-
gassed solution of (2-iodo-phenyl)-(2-phenyl-2-methyl-
oxazolidin-3-yl)-methanone 13 (260 mg, 0.66 mmol), tert-
butyl acrylate (447 ml, 3.12 mmol), tributyltin chloride (27
ml, 0.1 mmol), sodium cyanoborohydride (82 mg, 1.31
mmol) and 2,20-azobisisobutyronitrile (8 mg, 0.05 mmol)
in tert-butanol (25 cm3) was heated under re¯ux for 2 h
under a nitrogen atmosphere. The solvent was removed in
vacuo and the residue was dissolved in ethyl acetate
(40 cm3), the resulting solution being washed with water
(2£10 cm3). The separated organic phase was dried (sodium
sulfate), ®ltered and evaporated in vacuo and the residue
was puri®ed by ¯ash chromatography on silica gel (eluting
with 2:1 v/v hexane:ethyl acetate) to give the title compound
(colourless oil) as an inseparable 2.0:1 mixture of diaster-
eoisomers (280 mg, 75%); data as reported above in
method a.
t
CH2CH2CO2 Bu both diastereoisomers), 1.98 (0.86H, s,
CH3C minor), 2.09 (2.14H, s, CH3C major), 3.42 (0.29H,
ca. dd, J 9 and 5.5, CH2O minor), 3.55 (0.71H, ca. dd, J 9
and 3, CH2O major), 3.73 (0.71H, ca. dd, J 9 and 6, CH2O
major), 3.91 (0.29H, ca. dd, J 9 and 7, CH2O minor) 4.02±
4.12 (1H, complex, NCH both) and 6.95±7.76 (10H,
complex, Ph-H); dC (100 MHz; CDCl3) principal peaks
for major diastereoisomer only, 26.2 (CH3C), 28.0
t
t
((CH3)3C), 28.1 (CH2CH2CO2 Bu), 32.0 (CH2CH2CO2 Bu),
58.5 (NCH), 67.2 (CHCH2O), 80.6 ((CH3)3C), 125.8, 126.3,
126.5, 127.1, 128.2, 128.6, 131.6, 137.8 (PhCH and PhipsoCH),
1.1.21. 3-(3-Benzoyl-2-phenyl-2-methyl-oxazolidin-4-yl)-
propionitrile (24a/b)Ðmethod d. A de-gassed solution of
(2-iodo-phenyl)-(2-phenyl-2-methyl-oxazolidin-3-yl)-metha-
none 13 (460 mg, 1.17 mmol), acrylonitrile (645 ml,
9.80 mmol), tributyltin chloride (48 ml, 0.18 mmol), sodium
cyanoborohydride (145 mg, 2.31 mmol) and 2,20-
azobisisobutyronitrile (8 mg, 0.05 mmol) in tert-butanol
(25 cm3) was heated under re¯ux for 2 h under a nitrogen
atmosphere. The solvent was removed in vacuo and
the residue was dissolved in ethyl acetate (40 cm3) and the
resulting solution was washed with water (2£10 cm3). The
separated organic phase was dried (sodium sulfate), ®ltered
and evaporated in vacuo and the residue was puri®ed by
¯ash chromatography on silica gel (eluting with 2:1 v/v
hexane:ethyl acetate) to give the title compound (colourless
oil) as an inseparable 1.8:1 mixture of diastereoisomers
(160 mg, 61%); data as reported above in method a.
t
171.7 (PhC(O)N) and 174.1 (CO2 Bu); m/z (CI) 396 (MH1,
100%), 276 (62) and 139 (13); m/z (EI) 219 (21%), 202 (28),
105 (100), 77 (46), 57 (27) and 41 (16); (Found MH1 (ES1)
396.2176, C24H30NO4 requires 396.2175).
1.1.19. 3-(3-Benzoyl-2-phenyl-2-methyl-oxazolidin-4-yl)-
propionitrile (24a/b)Ðmethod a. A de-gassed solution of
tributyltin hydride (600 ml, 2.23 mmol), 2,20-azobisiso-
butyronitrile (15 mg, 0.09 mmol) and acrylonitrile (498
ml, 7.56 mmol) in benzene (15 cm3) was added dropwise
over 6 h to a stirred, de-gassed solution of (2-iodo-phenyl)-
(2-phenyl-2-methyl-oxazolidin-3-yl)-methanone 13 (350 mg,
0.89 mmol) in benzene (15 cm3) under re¯ux under a nitro-
gen atmosphere. After heating under re¯ux for a further 6 h,
work-up as described for 3-(3-benzoyl-2-phenyl-2-methyl-
oxazolidin-4-yl)-propionic acid tert-butyl ester (23a/b)
above gave the title compound (colourless oil) as an insepar-
able 1.7:1 mixture of diastereoisomers (168 mg, 59%); Rf
0.30 (1:1 v/v hexane: EtOAc); nmax/cm21 (thin ®lm) 3135±
2790m (C-H), 2246w (CN), 1636s (CˆO), 1601m, 1493m,
1.1.22. 4-Benzylamino-5-hydroxy-pentanoic acid-tert-
butyl ester (26)Ðfrom 4-(2-tert-butoxycarbonyl-ethyl)-
3-benzyl-2-(4-pyridyl)-2-methyl-oxazolidine
(18a/b).

R. Gosain et al. / Tetrahedron 57 (2001) 1399±1410
1409
Aqueous hydrochloric acid (2.0 M, 2 drops) was added to
a stirred solution of 4-(2-tert-butoxycarbonyl-ethyl)-3-
benzyl-2-(4-pyridyl)-2-methyl-oxazolidine 18a/b (54 mg,
0.14 mmol) in tetrahydrofuran (5 cm3) at room temperature.
After stirring for 3 h, the reaction mixture was evaporated to
dryness in vacuo and the residue was applied to a neutral
alumina chromatography column in chloroform. After
elution of the by-product, 4-acetylpyridine with chloroform,
elution with 9:1 v/v chloroform:methanol gave the title
compound as a colourless oil (39 mg, 99%); Rf 0.30 (19:1
v/v CHCl3:CH3OH); nmax/cm21 (thin ®lm) 3580±3140brw
(N-H, O-H), 3090±2770m (C-H), 1728s (CˆO), 1456m,
1392m, 1367s, 1256m, 1153s, 1049m, 847w and 700m;
dH (400 MHz; CDCl3) 1.43 (9H, s, (CH3)3C), 1.74, 1.85
(50 cm3). After stirring overnight, the reaction mixture
was evaporated to dryness in vacuo, the ®nal traces of
water being removed by co-evaporation with benzene.
The residue was puri®ed by chromatography on neutral
alumina, eluting with 9:1 v/v chloroform:methanol, giving
the title compound as a yellow oil (63 mg, 84%); data as
reported above.
1.1.25. 4-Benzylamino-5-hydroxy-pentanenitrile (27)Ð
from 4-(2-cyano-ethyl)-3-benzyl-2-methyl-oxazolidine-
2-carboxylic acid ethyl ester (21a). Aqueous hydrochloric
acid (2 M, 2 cm3) was added, at room temperature, to a
stirred solution of the major diastereoisomer of 4-(2-
cyano-ethyl)-3-benzyl-2-methyl-oxazolidine-2-carboxylic
acid ethyl ester 21a (73 mg, 0.24 mmol) in tetrahydrofuran
(50 cm3). After stirring overnight, the reaction mixture was
evaporated to dryness in vacuo, the ®nal traces of water
being removed by co-evaporation with benzene. The residue
was puri®ed by chromatography on neutral alumina, eluting
with 9:1 v/v chloroform:methanol, giving the title
compound as a yellow oil (24 mg, 48%); data as reported
above.
t
t
(2£1H, 2£m, CH2CH2CO2 Bu), 2.28 (2H, m, CH2CO2 Bu),
2.73 (1H, m, NCH), 2.82 (2H, brs, NH, OH), 3.39 (1H, dd,
J 11 and 6, CHCH2O), 3.66 (1H, dd, J 11 and 4, CHCH2O),
3.82, 3.86 (2£1H, ABq, JAB 13, PhCH2) and 7.20±7.41
(5H, complex, Ph-H); dC (100 MHz; CDCl3) 26.2
t
t
(CH2CH2CO2 Bu), 28.1 ((CH3)3C), 31.9 (CH2CO2 Bu), 50.8
(PhCH2), 57.8 (NCH), 62.4 (CH2OH), 80.6 ((CH3)3C), 127.3,
128.3, 128.5 (PhCH), 139.3 (PhipsoC) and 172.8 (CˆO); m/z
(CI) 280 (MH1, 100%), 108 (37) and 106 (22); m/z (EI) 91
(100%), 57 (43) and 41 (46); (Found MH1 (CI) 280.1909,
C16H26NO3 requires 280.1912).
1.1.26. 4-Benzoylamino-5-hydroxy-pentanoic acid tert-
butyl ester (28). Amberlitew IR-120 (H1 form, ca. 5 mg)
was added to a stirred solution of 3-(3-benzoyl-2-phenyl-2-
methyl-oxazolidin-4-yl)-propionic acid tert-butyl ester 23a/
b (220 mg, 0.56 mmol) in acetonitrile (5 cm3) at room
temperature. After stirring at this temperature for 12 h, the
ion-exchange resin was removed by ®ltration and the
solvent was removed in vacuo. The residue was puri®ed
by ¯ash chromatography on silica gel (eluting with 3:7
v/v hexane:ethyl acetate) to give the title compound as a
colourless oil (124 mg, 76%); Rf 0.20 (1:1 v/v hexane:
EtOAc); nmax/cm21 (thin ®lm) 3612±3135brm (N-H,
O-H), 3090±2791m (C-H), 1727s (ester CˆO), 1641
(amide CˆO), 1579w, 1539m, 1489m, 1392w, 1368m,
1293m, 1255m, 1152s, 713w and 694w; dH (400 MHz;
CDCl3) 1.40 (9H, s, (CH3)3C), 1.94 (2H, ca. q, J 7,
1.1.23. 4-Benzylamino-5-hydroxy-pentanenitrile (27)Ð
from 4-(2-cyano-ethyl)-3-benzyl-2-(4-pyridyl)-2-methyl-
oxazolidine (19a/b). Aqueous hydrochloric acid (2.0 M, 2
drops) was added to a stirred solution of 4-(2-cyano-ethyl)-
3-benzyl-2-(4-pyridyl)-2-methyl-oxazolidine 19a/b (94 mg,
0.31 mmol) in tetrahydrofuran (5 cm3) at room temperature.
After stirring for 3 h, the reaction mixture was evaporated to
dryness in vacuo and the residue was applied to a neutral
alumina chromatography column in chloroform. After
elution of the by-product, 4-acetylpyridine with chloroform,
elution with 9:1 v/v chloroform:methanol gave the title
compound as a colourless oil (62 mg, 99%); Rf 0.53 (9:1
v/v CHCl3: CH3OH); nmax/cm21 (thin ®lm) 3570±3120brm
(N-H, O-H), 3040±2780s (C-H), 2247w (CN), 1456m,
1217m, 1053m, 756s and 700m; dH (400 MHz; CDCl3)
1.82 (2H, m, CH2CH2CN), 2.46 (2H, ca. dt, J 7 and 2,
CH2CN), 2.82 (1H, m, NCH), 3.48 (1H, ca. dd, J 11 and
5, CH2O), 3.72 (1H, ca. dd, J 11 and 4, CH2O), 3.80, 3.83
(2£1H, ABq, JAB 13, PhCH2) and 7.20±7.41 (5H, complex,
Ph-H). (Note: N-H and O-H signals were broadened to a
degree such that their chemical shifts could not be readily
determined); dC (100 MHz, CDCl3) 13.9 (CH2CN), 27.6
(CH2CH2CN), 51.1 (PhCH2), 56.9 (NCH), 62.4 (CH2OH),
119.7 (CN), 127.3, 128.1, 128.6 (PhCH) and 140.0
(PhipsoC); m/z (CI) 205 (MH1, 100%), 173 (27), 108 (22)
and 52 (60); m/z (EI) 173 (19%), 91 (100), 65 (20) and 41
(23); (Found MH1 (CI) 205.1338, C12H17N2O requires
205.1341).
t
t
CH2CH2CO2 Bu), 2.38 (2H, m, CH2CH2CO2 Bu), 3.40
(1H, brs, OH), 3.70 (2H, m, CH2OH), 4.11 (1H, m, NCH),
7.02 (1H, brd, J 7.5, NH), 7.39 (2H, ca. t, J 8, Ph-H), 7.47
(1H, ca. t, J 8, Ph-H) and 7.79 (2H, ca. d, J 8, Ph-H); dC
t
(100 MHz; CDCl3) 25.4 (CH2CH2CO2 Bu), 28.0 ((CH3)3C),
32.1 (CH2CH2CO2 Bu), 52.5 (NCH), 65.2 (CH2OH), 81.1
t
((CH3)3C), 127.1, 128.5, 131.6 (PhCH) and 174.0
(CO2 Bu); m/z (CI) 294 (MH1, 100%), 264 (15), 238 (26),
t
237 (42), 220 (33) and 139 (73); m/z (EI) 206 (7%), 105
(100), 77 (73), 57 (50), 43 (30) and 41 (46); (Found MH1
(ES1) 294.1710, C16H24NO4 requires 294.1705).
1.1.27. N-(3-Cyano-1-hydroxymethyl-propyl)-benzamide
(29). Amberlitew IR-120 (H1 form, ca. 5 mg) was added
to a stirred solution of 3-(3-benzoyl-2-phenyl-2-methyl-
oxazolidin-4-yl)-propionitrile 24a/b (120 mg, 0.38 mmol)
in acetonitrile (5 cm3) at room temperature. After stirring
at this temperature for 12 h, the ion-exchange resin was
removed by ®ltration and the solvent and acetophenone
were removed in vacuo. The residue was puri®ed by ¯ash
chromatography on silica gel (eluting with 3:7 v/v hexane:
ethyl acetate) to give the title compound as a yellow
1.1.24. 4-Benzylamino-5-hydroxy-pentanoic acid-tert-
butyl ester (26)Ðfrom 4-(2-tert-butoxycarbonyl-ethyl)-
3-benzyl-2-methyl-oxazolidine-2-carboxylic acid ethyl
ester (20a/b). Aqueous hydrochloric acid (2 M, 2 cm3)
was added at room temperature to a stirred solution of the
3:1 mixture of diastereoisomers of 4-(2-tert-butoxycarbo-
nyl-ethyl)-3-benzyl-2-methyl-oxazolidine-2-carboxylic acid
ethyl ester 20a/b (100 mg, 0.27 mmol) in tetrahydrofuran
oil (74 mg, 89%); Rf 0.30 (1:4 v/v hexane: EtOAc); nmax
/
cm21 (thin ®lm) 3544±3141brm (N-H, O-H), 3010±2816w

1410
R. Gosain et al. / Tetrahedron 57 (2001) 1399±1410
2. Renaud, P.; Giraud, L. Synthesis 1996, 913±926.
3. Snieckus, V.; Cuevas, J.-C.; Sloan, C. P.; Liu, H.; Curran, D. P.
J. Am. Chem. Soc. 1990, 112, 896±898. For examples related
to this work, see also: Undheim, K.; Williams, L. J. Chem.
Soc., Chem. Commun. 1994, 883±884; Curran, D. P.; Yu, H.;
Liu, H. Tetrahedron, 1994, 51, 7343±7366; Williams, L.;
Booth. S. E.; Undheim, K. Tetrahedron 1994, 48, 13697±
13708; Booth, S. E.; Benneche, T.; Undheim, K. Tetrahedron
1995, 51, 3665±3674.
(C-H), 2228w (CN), 1636s (CˆO), 1586s, 1540s, 1462m,
1424m, 1306m, 1165w, 1066m, 1015m and 747m; dH
(300 MHz; CDCl3) 2.05 (2H, ca. q, J 7, CH2CH2CN), 2.25
(1H, brs, OH), 2.48 (2H, ca. t, J 7, CH2CN), 3.78 (2H, m,
CH2OH), 4.23 (1H, m, NCH), 6.77 (1H, brd, J 8, NH), 7.42
(2H, dt, J 7 and 1.5, Ph-H), 7.51 (1H, dt, J 7 and 1.5, Ph-H)
and 7.78 (2H, dd, J 7 and 1.5, Ph-H); dC (75 MHz; CDCl3)
14.4 (CH2CN), 27.5 (CH2CH2CN), 50.9 (NCH), 64.0
(CH2OH), 127.1, 128.6, 133.8 (PhC-H), 137.0 (PhipsoC)
and 168.4 (CˆO); m/z (CI) 236 (MNH41, 100%), 219
(MH1, 38), 206 (16) and 139 (45); m/z (EI) 146 (13%),
105 (100), 77 (85) and 51 (35); (Found MH1 (ES1)
219.1130, C12H15N2O2 requires 219.1133).
4. Seebach, D.; Sting, A. R.; Hoffmann, M. Angew. Chem., Int.
Ed. Engl. 1996, 35, 2708±2748.
5. For a discussion of this problem in amide systems, see: Jones,
K.; Storey, J. M. D. J. Chem. Soc., Chem. Commun. 1992,
1766±1767.
6. Typical conditions for 1,3-oxazolidine preparation from
b-amino alcohols are described in: Maury, C.; Gharbaoui,
T.; Royer, J.; Husson, H.-P. J. Org. Chem. 1996, 61, 3687±
3693.
Acknowledgements
The authors gratefully acknowledge the Leverhulme Trust
for a postdoctoral fellowship to R. G., Dr V. Sik, Exeter, UK
for NMR spectroscopy and the EPSRC National Mass
Spectrometry Service Centre, Swansea, UK for mass
spectrometric work.
7. All structural formulae illustrating chiral molecules represent
racemic mixtures.
8. Diastereoisomer ratios were determined from 1H NMR spectra
of crude reaction products.
9. Derome, A. E. Modern NMR Techniques for Chemistry
Research; Pergamon Press: Oxford, 1987.
References
10. Page, P. C. B.; Heaney, H.; Rassias, G. A.; Reignier, S.;
Sampler, E. P.; Talib, S. Synlett 2000, 104±106.
11. Kumar, S. D. Aldrichimica Acta 1993, 26, 34.
1. Gosain, R.; Norrish, A. M.; Wood, M. E. Tetrahedron Lett.
1999, 40, 6673±6676.