Remarkable dependence of the regioselectivity of free radical additions to 3-cinnamoyloxazolidin-2-ones on the stability of the intermediate adduct-radical, electrophilicity of the adding radicals and the conditions for their generation

Article abstract of DOI:10.1039/a701154g

Electrophilic (CCl₃) and nucleophilic radicals (Prⁱ) are found to add at 80°C to the C=C bond of 3-(E)-cinnamoyl-4-phenyloxazolidin-2-one 1a and 3-(E)-cinnamoyl-4-benzyloxazolidin-2-one 1b predominantly at the α-position of the bond. While for the CCl₃ radical no product of β-addition has been found, for the Prⁱ radical such a path constitutes up to 40% of the whole process at 80°C. An interplay between the stability of the intermediate adduct radicals and the electrophilicity or nucleophilicity of the radicals undergoing addition are invoked to rationalize the observation. At a low temperature (-23°C) β-addition of the Prⁱ radical becomes the dominant process (up to 75%).

Full text of DOI:10.1039/a701154g

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Remarkable dependence of the regioselectivity of free radical
additions to 3-cinnamoyloxazolidin-2-ones on the stability of the
intermediate adduct-radical, electrophilicity of the adding radicals
and the conditions for their generation
Vitali I. Tararov, Nikolai Yu. Kuznetzov, Vladimir I. Bakhmutov,
Nikolai S. Ikonnikov, Yuri N. Bubnov, Victor N. Khrustalev,
Tatiana F. Saveleva and Yuri N. Belokon*
A. N. Nesmeyanov Institute of Organoelement Compounds, Academy of Sciences,
117813 Moscow, Russian Federation
Electrophilic (CCl ) and nucleophilic radicals (Pri) are found to add at 80 ЊC to the C᎐C bond of 3-(E)-
᎐
3
cinnamoyl-4-phenyloxazolidin-2-one 1a and 3-(E)-cinnamoyl-4-benzyloxazolidin-2-one 1b predominantly
at the á-position of the bond. While for the CCl3 radical no product of â-addition has been found, for the
Pri radical such a path constitutes up to 40% of the whole process at 80 ЊC. An interplay between the
stability of the intermediate adduct radicals and the electrophilicity or nucleophilicity of the radicals
undergoing addition are invoked to rationalize the observation. At a low temperature (Ϫ23 ЊC)
â-addition of the Pri radical becomes the dominant process (up to 75%).
established by single crystal X-ray analysis.3 Isomer 2, having a
greater Rf value on SiO2, was found to have an αS,βR,4R-
configuration† whilst isomer 3 had an αR,βS,4R-configuration.
The compounds arose from primary attack of the CCl3 radical
Introduction
In recent years there has been tremendous progress in the stereo-
selective synthesis of organic compounds via radical addition to
the olefinic bond. It has been documented that steric models
(Felkin, chelate etc.), developed earlier for heterolytic reactions,
work well in the cases of homolytic reactions also.1 Much less
explored and still a somewhat obscure process is the regioselec-
at the α-position of the C᎐C bond of 1a. The next stage of
᎐
C᎐Br formation in the chain transfer reaction proceeded with
very high diastereoselection to give the products of anti-
configuration (see Scheme 1 and Fig. 1). The A-strain model1d
can be invoked to rationalize the observed stereoselectivity of
the bromine atom transfer in both peroxide and Fe(CO)5 pro-
moted reactions (see Fig. 1). Preliminary results of BrCCl3 add-
ition to (R)-1b indicated that here too only two isomers were
formed.
The first conclusion derived from the results is that chelation
control effects were absent for both C-CCl3 and C-Br formation
stages with initiation by Fe(CO)5 [or other Fe(CO)5-derived Fe-
containing particles].4 If this were not so, the stereoselectivities
of the peroxide or the metal-redox processes would have been
different since oxazolidinone substrates of similar structure are
known to be greatly influenced when undergoing diastereoselec-
tive nucleophilic radical addition by the complexation with
metal ions and stabilization of the syn-(s)-conformation of the
tivity of radical addition to RC᎐CR bonds.2 Generally, such
᎐
factors as stability of the intermediate reactive adducts, so
important in the carbanion chemistry with its late transition
state situation, seem to be of minor importance in exothermic,
earlier transition state radical addition chemistry.2
We have now studied the addition of both electrophilic
(CCl ) and nucleophilic (Pri) radicals to the C᎐C bond of
᎐
3
3-(E)-cinnamoyl-4-phenyloxazolidin-2-one 1a and 3-(E)-
cinnamoyl-4-benzyloxazolidin-2-one 1b (see Schemes 1 and 2),
to find out if the stability of the intermediate radical adducts A
and B, or the relative electrophilicity of the attacking radicals,
was responsible for the regioselectivity of the attack. Although
as expected, we found that the regioselectivity of the radical
addition was influenced by the relative electrophilicity of the
attacking radicals, it was also necessary to take into account the
stability of the intermediate adduct-radical as being a more
important factor in rationalizing the radical addition pattern at
high temperatures. Unexpectedly, we discovered that the α-/β-
regioselectivity of the addition of the nucleophilic radical was
reversed by changing the conditions under which the radical
was generated.
substrate in which the α- and β-positions of the C᎐C bond are
᎐
shielded by the 4-substituent of the heterocycle.5
Another salient feature of the reaction is the primary attack
of the CCl radical at the α-position of the C᎐C bond. Two
᎐
3
explanations may account for this: (a) A positive charge local-
ized at the β-position of the C᎐C bond of 1a influences the
᎐
electrophilic CCl3 radical to attack preferentially the α-position
of the cinnamoyl moiety and thus avoid electrostatic repulsion
at the β-position. (b) The primary α-attack is directed by the
relative stability of the intermediate adduct-radical A, as com-
pared to radical B. The stability of the benzyl-type radical A is
greater than that of B (at least 7 kcal molϪ1, as assessed by the
corresponding energies of C᎐H bond dissociation of toluene6
Results and discussion
Compounds 1a [both racemic and of the (R)-configuration] and
(R)-1b were synthesized, as described in the Experimental sec-
tion. The addition of BrCCl3 to (R)-1a was initiated either by
benzoyl peroxide (BP) or Fe(CO)5 at 80 ЊC. Out of eight pos-
sible isomers which might be formed only 2 and 3 (see Scheme
1) were recovered from the reaction mixture and separated by
TLC (SiO2). The structure of these and their ratio (close to 1:1,
see Table 1, runs 1 and 2) were unaffected by the use of peroxide
or redox initiation. The structures of the compounds were
† For convenience, the terms α and β have been used for the two pos-
itions of the cinnamoyl double bond (see formula 1a). However, in the
Experimental section, where the products prepared have been named,
these positions, the double bond having been reduced, are referred to as
2Ј and 3Ј.
J. Chem. Soc., Perkin Trans. 1, 1997
3101

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Table 1 Regio- and diastereo-selectivity of the addition of CCl3 and Pri radicals to (R)-3-(E)-cinnamoyl-4-benzyloxazolidin-2-one (R)-1b and
rac- or (R)-3-(E)-cinnamoyl-4-phenyloxazolidin-2-one rac-1a, or (R)-1a*
Run
RHal
Substr.
Initiator
T/ЊC
t/h
α:βa
Ratio of α-isomersa
Ratio of β-isomersa
c.y.b
1.3 (3):1(2)d
1.2 (3):1(2)d
4.1 (5a):1(4a)
1.8 (5a):1(4a)
1.5 (5b):1(4b)
1.4 (5a):1(4a)
1.3 (5a):1(4a)
–
–
58
28
83
65
74
51
20
c
1
2
3
4
5
6
7
CCl3Br
CCl3Br
PriI
(R)-1a
(R)-1a
rac-1a
rac-1a
(R)-1b
rac-1a
rac-1a
Fe(CO)5
PBc
80
80
80
80
80
20
0.3
30
2.5
17
15
2.5
3
α only
α only
2.3:1
1.6:1
3:1
1:3
1:2.4
Pr3Bc
AIBNc
AIBNc
Pr3Bf
2.7 (7a):1(6a)
1.2 (7a):1(6a)
e
1.6 (7a):1(6a)
1.4 (7a):1(6a)
PriI
PriI
PriI
PriI
Pr3Bf
Ϫ23
* Runs 3–7 were performed with Bu3SnH. a The ratios of diastereoisomers and α/β ratios were established from the 1H NMR spectra of the mixtures
or by weighing the fractions. b Isolated yield of diastereoisomeric mixture of products. c In PhH. d Only anti-product. e Not determined. f In CH2Cl2.
Ph
Ph
H
H
O
N
O
O
N
O
PriI + Bu3SnH
+
BrCCl3
+
O
α
O
β
Ph
Ph
1a
R = Ph = 1a
R = Bn = 1b
Fe(CO)5 or
(C6H5COO)2
at 80 °C
AlBN at 80 °C, PhH
Pr3B + O2 at 80 °C, PhH
Pr3B + O2 at 20 °C or – 20 °C, CH2Cl2
in PhH
Ph
Ph
Ph
H
H
H
O
Ph
Ph
Ph
H
H
H
O
N
O
O
N
O
N
O
+
O
N
O
O
N
O
O
N
O
O
CCl3
O
CCl3
CCl3
O
+
O
O
Pri
O
Ph
Ph
Ph
B-type adduct-radicals
Pri
Pri
A-type adduct-radicals
Ph
Ph
Ph
A-type adduct-radicals
B-type adduct-radicals
Ph
H
Ph
TLC (SiO2)
Bu3SnH
H
O
N
O
O
N
O
Ph
Ph
Ph
+
H
H
H
Br
O
Br
O
CCl3
CCl3
O
N
O
O
N
O
O
N
O
Ph
Ph
+
+
H
H
O
H
H
O
Pri
O
(αS,βR,4R)-2
(αS,βR,4R)-3
Pri
Pri
Ph
Ph
Ph
Only anti-addition, low de
Scheme 1
α-addition
β-addition
and ethyl acetate7) and, as a result, no β-primary attack
occurred in the system.
(αR,4R)-isomers
(αS,4R)-isomers
(βR,4R)/(βS,4R)
R = Ph = 4a
R = Bn = 4b
5a
5b
6a/7a
The data available from the literature indicated that for sim-
ilar types of substrate, nucleophilic Pri radicals added intermol-
Scheme 2
ecularly at the β-position of the C᎐C bond of their cinnamoyl
᎐
moieties at a low temperature (Ϫ78 ЊC).8,9 Thus, it seemed that
the main reason for the greater degree of α-attack with the CCl3
radical was a result of its electrophilicity [hypothesis (a)].
Unfortunately, the conditions under which the experiments
were conducted [Ϫ78 ЊC and Bu3SnH in case of refs. 8 and 9
and 80 ЊC, (PhCO2)2 in our case] were insufficiently close to
make this kind of reasoning convincing. It was therefore neces-
sary to obtain experimental results on the regioselectivity of Pri
radical addition to our substrates at 80 ЊC.
were conducted in PhH at 80 ЊC. Unexpectedly, the reaction
mixture was found to consist of, at least, four isomeric products
of Pri- and H-addition to the C᎐C bonds of both 1a and 1b (see
᎐
Scheme 2, products 4–7). The reaction mixtures were purified
on SiO2 (hexane) to remove all the Sn-containing products and
the isomers were separated by preparative TLC. One of the
isomers, derived from rac-1a (second in its Rf values), formed
good quality crystals and its structure, as determined by the
X-ray single crystal analysis, was found to be that of rac-
(αR*,4R*)-3-α-isopropylhydrocinnamoyl-4-phenyloxazolidin-
2-one 4a. In other words, at least one of the isomers resulted
The additions of PriI (see Scheme 2) in the presence of
Bu3SnH (AIBN or Pr3B ϩ O2 as initiators) to rac-1a and (R)-1b
3102
J. Chem. Soc., Perkin Trans. 1, 1997

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Br-donor
Br-donor
i C6H5CHO
ii PriMgBr, THF
iii KOH, MeOH
Me
Me
CO2H
CO2Et
EtO2C
H
H
ROC
H
ROC
Ph
Ph
Ph
H
i PriBr, EtONa, EtOH
ii PhCH2Cl, NaH, THF
iii KOH, MeOH
9
A
B
CCl3
Favourable
CCl3
Unfavourable
transition state
CH2Ph
transition state
Ph
CO2H
Ph
COCl
Me
H
SOCl2
+
HN
O
Me
Me
Me
O
ROC
Cl3C
Br
Ph
ROC
Cl3C
Br
Ph
8
10
NaH, MeCN
syn-
anti-
Fig. 1
TLC (SiO2, Et2O–C6H14–PhH, 1:4:1)
from the α-addition which was clearly observed at 80 ЊC even in
CH2Ph
CH2Ph
H
H
the case of nucleophilic radical addition to the C᎐C bond of the
᎐
cinnamoyl moiety. Still the question remained as how much of
α- and β-addition was really occurring.
O
O
N
O
+
N
O
Ph
Ph
In order to answer this, model compounds were synthesized,
starting with the malonic ester (see Scheme 3). A mixture of
racemic α-isopropylhydrocinnamic acid 8 and β-isopropyl-
hydrocinnamic acid 9, synthesized in this way, were found to
be easily separated and analyzed by GLC as their methyl
esters.
O
O
Me
Me
Me
Me
4b
5b
Scheme 3
Thus, we were able to establish which isomer, recovered
from the reaction mixtures, had come from α- or β-addition by
simply hydrolyzing it and analyzing the corresponding iso-
propylhydrocinnamic acid. For the isomers derived from both
1a and 1b, the first two diastereoisomers, having greater Rf
values (Scheme 2, products 4 and 5), were found to come from
the α-addition and other two isomers having smaller Rf values
(Scheme 2, products 6 and 7) came from the β-addition.
The absolute configurations of the diastereoisomers were
established in the following way. The condensation of acid 8
with (R)-4-benzyloxazolidin-2-one 10 (see Scheme 3) gave a
mixture of two diastereoisomers which were separated by TLC.
The structure of one of these isomers (that with the greater
Rf value) was established (X-ray) as (αS,4R)-N-α-isopropyl-
hydrocinnamoyl-4-benzyloxazolidin-2-one 5b. Thus, the assign-
ment of configuration of the α-products from 1b was made
by comparing the 1H NMR spectra of the two diastereoisomers
with those of the model isomer. The configuration of the
diastereoisomers originating from α-addition to 1a was estab-
lished by X-ray analysis, as indicated above whilst the con-
figurations of the β-products 6a and 7a, were established by
Still unexplained however was the 100% β-regioselectivity of
the Pri radical addition to the cinnamoyl moiety of other 3-
cinnamoyloxazolidin-2-ones at low temperatures.8,9 To resolve
this apparent contradiction we studied the addition of the Pri
radical to 1a and 1b at 20 and Ϫ20 ЊC, using a Pr3B ϩ O2
initiation system. The results are summarized in Table 1 (runs
6,7). Since, as can be seen from the data, it was the β-addition
which clearly prevailed at the low temperatures, it is tempting to
suggest that there were some complexes derived from Pr3B (or
other boron-derived compounds in the reaction mixture) and
the substrates that had much more electrophilic C᎐C bonds
᎐
than those in the initial 1a or 1b. Thus, the electrophilicity of
the bond in the complexes might be increased concomitantly
with the rate of the nucleophilic radical attack at the β-position
relative to the α-attack. But the comparison of runs 3 and 4 of
Table 1 indicated that both AIBN and Pr3B initiations gave
similar α:β ratio patterns at 80 ЊC.
Another Lewis acid, Bu3SnI, formed in the reaction mixture,
might be the next candidate for the role of the chelating agent,
and increasing the relative proportion of the β-isomer in the
reaction mixture. In a recent publication by Sibi and co-workers
this Sn-derivative was shown to affect (as postulated by the
authors via chelation) the relative rates of reduction versus
intramolecular cyclization, and favouring the latter in enoyl-
oxazolidinones, bearing a bromo (or iodo)methyl group at 4-
position of the heterocycle.5 We believe that kind of influence
highly unlikely on the following grounds: (a) according to ref.
5, the effect should be observed (or most pronounced) at 80 ЊC.
In fact, we observed a predominance of α-attack of the Pri
radical at the temperature, (b) The diastereoselectivities of the
Bu3SnH initiated β-additions were low at all the temperatures
studied. Had the chelation been responsible for the increased
proportion of the β-addition products at low temperatures, the
de of the addition would have been much higher.5,8,9
1
comparing their H NMR spectra with those described in the
literature.10
Finally, we established the ratio of α to β addition of the Pri
radical to either 1a or 1b at 80 ЊC and the diastereoisomeric
ratio of the α-addition simply by analyzing the 1H NMR spec-
tra of the reaction mixtures or by weighing the fractions con-
taining the corresponding isomers. The results, summarized in
Table 1 (runs 3–5), indicated unequivocally that it was the α-
attack of the nucleophilic Pri radicals which prevailed at 80 ЊC
for both 1a and 1b. As can be seen from the data, the simple
picture of electrostatic effects being mainly responsible for the
direction of α- versus β-attack, was insufficient to account for
the experimental observations. On the contrary, it is the greater
stability of the intermediate radical adducts A versus B which
seemed to govern the process [hypothesis (b)]. It seemed that the
electrophilicity of the radicals also played a part because a sig-
nificant portion of the addition product (30–40%) came from
the β-addition path. No such products were found in the elec-
trophilic CCl3 radical addition to either 1a or 1b.
A further hypothetical mechanism for the reaction is pos-
sible, based on the assumption that the reactions of alkyl
halides initiated by Bu3SnH proceed by two different mechan-
isms, one of which, being typically radical, predominates at
high temperatures and gives the α-addition products and the
other, ionic or metal-organic, playing an important role at the
J. Chem. Soc., Perkin Trans. 1, 1997
3103

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range of low temperatures and giving rise to the β-addition
products.
CHCl3) [lit.,14c for the (S)-isomer, mp 128–130 ЊC, [α]D25 ϩ58 (c 1,
CHCl3)].
The extension of these studies and investigation of the add-
rac-4-Phenyloxazolidin-2-one. This compound, obtained in
the same manner (85%), had mp 137–138 ЊC (EtOH) (lit.,13 mp
137–138 ЊC) (Found: C, 66.18; H, 5.56; N, 8.50. C9H9NO2
requires C, 66.24; H, 5.56; N, 8.58%); δH(CDCl3) 7.30 (5 H, m),
6.51 (1 H, br d), 4.73–5.04 (1 H, m), 4.73–4.54 (1 H, m) and
4.30–4.02 (1 H, m).
ition of electrophilic radicals to the C᎐C bond of 1a and 1b at
᎐
low temperatures and similar substrates are underway.
Experimental
General
(R)-3-(E)-Cinnamoyl-4-benzyloxazolidin-2-one (R)-1b. NaH
(60% suspension in oil; 0.28 g, 7.11 mmol) was added to 10 (0.9
g, 5.08 mmol) in MeCN (15 cm3) with stirring and cooling to
0 ЊC. When the evolution of H2 stopped, a solution of cin-
namoyl chloride (1.18 g, 7.11 mmol) in MeCN (5 cm3) was
added dropwise to the mixture. Stirring was continued for a
further 1 h, after which the reaction mixture was acidified (to
pH < 7) with 10% aq. AcOH. The mixture was then extracted
with PhMe–ether (3:1; 8 cm3 × 3), and the combined extracts
were dried (K2CO3) and evaporated in vacuo. The residue was
recrystallised from EtOH to give the product (1.42 g, 91%), mp
129–130 ЊC; [α]D25 Ϫ57.83 (c 1, CHCl3) (Found: C, 74.23; H, 5.52;
N, 4.35. C19H17NO3 requires C, 74.24; H, 5.57; N, 4.56%);
δH(CDCl3) 7.58 (2 H, m), 7.37–7.30 (10 H, m), 4.75–4.71 (1 H,
m), 4.20–4.13 (2 H, m), 3.32 (1 H, dd, J 3.0 and 13.4) and 2.80
(1 H, dd, J 9.5 and 13.3).
All reactions requiring anhydrous conditions were performed in
oven-dried glassware under argon. All transfers of solutions
and solvents were performed by syringe techniques. Chemicals
and solvents were purified by standard procedures. Melting
points are uncorrected. Kieselgel 60 (Merck) was used for
column chromatography and silica gel 60 F254 pre-coated
plates (Merck) were used for TLC. Preparative TLC was car-
ried out with glass plates on silica gel (Chemapol) LSL254
1
5/40. H NMR spectra were recorded on Bruker 200 and 400
MHz instruments. The optical rotations were measured with
a Perkin-Elmer M241 polarimeter and were recorded as 10Ϫ1
deg cm2 gϪ1. The chemical shifts are given in δ (ppm) relative
to SiMe4 as an internal standard. The analyses of α-isopropyl-
hydrocinnamic acid and β-isopropylhydrocinnamic acid,
were conducted by CGLC of their methyl esters on a model
3700-00 gas chromatograph equipped with a flame ionisation
detector, and SE-54 fused silica capillary column 25 m × 0.20
mm i.d., 0.20 µm film; col. temp. 140 ЊC; carrier gas He at 1.5
bar.
(R)-3-(E)-Cinnamoyl-4-phenyloxazolidin-2-one (R)-1a. This
compound, synthesized in the same manner (70%), had mp
170–171 ЊC, [α]D25 Ϫ4.1 (c 1, CHCl3) [lit.,14c for the (S)-isomer, mp
169–171 ЊC, [α]D25 ϩ3.4].
rac-3-(E)-Cinnamoyl-4-phenyloxazolidin-2-one rac-1a. This
compound, prepared analogously, had mp 179–181 ЊC (Found:
C, 73.76; H, 5.22; N, 4.94. C18H17NO3 requires C, 73.70; H,
5.16; N, 4.78%); δH(CDCl3) 7.94 (1 H, d, J 15.7), 7.76 (1 H, d, J
15.7), 7.52–7.60 (2 H, m), 7.25–7.45 (8 H, m), 5.53 (1 H, dd, J
3.8 and 8.6), 4.69 (1 H, t, J 8.6) and 4.27 (1 H, dd, J 3.8 and 8.6).
Preparation of starting compounds
(R)-2-Amino-3-phenylpropan-2-ol. This compound was pre-
pared by a modified literature procedure.11 To a stirred solution
of (R)-phenylalanine (2.2 g, 13 mmol) in THF (20 cm3) was
added LiBH4 (0.88 g, 39 mmol) followed by a solution of
H2SO4 (99.5%; 1.04 cm3, 19.5 mmol) in THF (1 cm3), added
dropwise. The mixture was stirred at the ambient temperature
for 24 h after which it was treated with MeOH (15 cm3) with
continued stirring until a clear solution was formed. Aq. NaOH
(4 ; 20 cm3) was then added dropwise to it. The resulting
precipitate was filtered off and the filtrate evaporated in vacuo.
The residue was extracted with PhMe (10 cm3 × 3). The com-
bined extracts were evaporated in vacuo to give the amino alco-
hol which was vacuum dried: yield 1.73 g (88%); mp 86–88 ЊC,
[α]D25 ϩ22.1 (c 1.5 EtOH) {lit.,12 mp 88–90 ЊC, [α]D25 ϩ22.0 (c 1.5
EtOH}.
Preparation of model compounds
rac-2-Benzyl-3-methylbutanoic acid 8. This compound was
obtained by a double alkylation of ethyl malonate. The first
alkylation of the ester with PriBr was carried out in EtOH in the
presence of EtONa, as described in the literature.15a The prod-
uct (without prior purification) was alkylated further with
PhCH2Cl in THF in the presence of NaH under reflux (3 h).
The corresponding benzyl(isopropyl)malonic ester (60% yield)
was obtained after distillation in vacuo 122 ЊC/0.7 mmHg, nD20
1.4893 (lit.,15b 109–112 ЊC/0.5 mmHg, nD20 1.4890). The target
compound 8 was obtained by hydrolysis and decarboxylation
of the initial diester, as described in the literature15b (Found: C,
74.68; H, 8.43. C12H16O2 requires C, 74.96; H, 8.39%);
δH(CDCl3) 7.28–7.10 (5 H, m), 2.80 (2 H, br d, J 6.5), 2.56–2.48
(1 H, m), 2.04–1.83 (1 H, m) and 1.09–1.03 (6 H, m).
rac-4-Methyl-3-phenylpentanoic acid 9. This compound was
synthesized, starting with the malonic ester condensation with
benzaldehyde to give a benzylidene-malonic ester, according to
a literature procedure.16a The purified (by distillation) inter-
mediate was then added to an isopropylmagnesium bromide
solution in THF, as described in the literature for phenylmag-
nesium bromide addition16b (no cuprous salts were added). The
target acid 9, obtained after the hydrolysis and decarboxylation
at 140–180 ЊC in an oil-bath of the intermediate substituted
malonic acid as indicated above, was distilled in vacuo and had
bp 133 ЊC/0.7 mmHg (Found: C, 74.23; H, 7.88. C12H16O2
requires C, 74.96; H, 8.39%); δH(CDCl3) 7.26–7.11 (5 H, m),
2.93–2.62 (3 H, m), 1.93–1.84 (1 H, m), 0.92 (3 H, d, J 6.7) and
0.74 (3 H, d, J 6.7).
(R)-2-Amino-2-phenylethanol. This compound was obtained
from -phenylglycine in the same manner and was used further
without purification.
rac-2-Amino-2-phenylethanol. This compound was obtained
from ,-phenylglycine in the same manner (87%), mp 75–
77 ЊC (lit.,13 mp 76–77 ЊC).
(R)-4-Benzyloxazolidin-2-one 10. Methyl chloroformate (1.92
g, 20 mmol, 1.6 cm3) in toluene (10 cm3) was added dropwise to
a mixture of a solution of (R)-2-amino-3-phenylpropan-1-ol
(1.6 g, 10 mmol) in toluene (20 cm3) and aq. KOH [1.12 g, 20
mmol in water (7.8 cm3)]. Vigorous stirring was continued for 1
h after which the organic layer was separated and the aqueous
layer was extracted with PhMe (10 cm3 × 2). The combined
extracts were dried (MgSO4) and refluxed over K2CO3 (0.1 g)
for 3 h, the reaction being monitored by TLC (PhH–C6H14–
Et2O, 2:1:1). Finally, the mixture was evaporated in vacuo and
the residue allowed slowly to crystallize. Subsequent recrystal-
lisation from hexane–ether (8:1) gave the product 10 (1.57 g,
84%), mp 86–88 ЊC, [α]D20 Ϫ4.58 (c 1.1 EtOH) [lit.,14a mp 87–
88.5 ЊC, for (S)-isomer [α]D25 ϩ4.9 (c 1.1 EtOH)] (Found: C,
66.77; H, 6.26; N, 7.90. C10H11NO2 requires C, 66.22; H, 6.56;
N, 7.82%); δH[(CD3)2CO] 7.20 (m, 5 H), 5.64 (1 H, br d), 3.88
(1 H, m), 3.45 (2 H, m), 3.00 (1 H, br d) and 2.85 (1 H, t, J 7.2).
(R)-4-Phenyl-2-oxazolidinone. This compound, obtained by a
literature procedure,14b had mp 130–131 ЊC, [α]D25 Ϫ55 (c 1,
(2ЈR,4R)-4b and (2ЈS,4R)-3-(2Ј-Isopropyl-3Ј-phenylpropion-
yl)-4-benzyloxazolidin-2-one 5b. A mixture of 4b and 5b was
prepared by the condensation of 8 (as its acyl chloride) with 10
in the same manner, as described for the synthesis of 1b. Pure
5b was isolated by preparative TLC (SiO2, C6H14–PhH–Et2O,
4:1:1) as a fraction, having the highest Rf value. The crystals
3104
J. Chem. Soc., Perkin Trans. 1, 1997

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of the isomer for the X-ray single-crystal analysis were grown
from an ethanol solution and had mp 100–101 ЊC; [α]D25 Ϫ100.19
(c, 1.04, CHCl3) (Found: C, 75.03; H, 7.22; N, 3.95. C22H25NO3
requires C, 75.18; H, 7.17; N, 3.98%); δH(CDCl3) 7.45–7.05 (10
H, m), 4.23 (1 H, m), 4.04 (1 H, m), 3.95 (1 H, dd, J 2.1 and 8.9),
3.59 (1 H, t, J 8.9), 3.27 (1 H, dd, J 3.3 and 13.3), 3.04 (1 H, dd,
J 4.8 and 13.0), 2.85 (1 H, t, J 13.0), 2.65 (1 H, t, J 13.3), 2.09–
2.06 (1 H, m) and 0.98–1.05 (6 H, m).
Compound 4b, recovered as the second fraction (lowest Rf
value), had mp 126–127 ЊC; [α]D25 Ϫ19.47 (c, 0.99 in CHCl3)
(Found: C, 75.05; H, 7.21; N, 3.95. C22H25NO3 requires C,
75.18; H, 7.17; N, 3.98%); δH(CDCl3) 7.27–7.16 (8 H, m), 6.92–
6.88 (2 H, m), 4.61–4.56 (1 H, m), 4.29–4.24 (1 H, m), 4.04 (1 H,
t, J 8.8), 3.95 (1 H, dd, J 5.8 and 8.8), 3.00 (1 H, dd, J 4.9 and
13.3), 2.94 (1 H, t, J 13.3, 1 H), 2.77 (1 H, dd, J 3.3 and 13.6,
1 H), 2.12 (1 H, dd, J 9.4 and 13.6), 2.07–1.99 (1 H, m) and
1.09–1.04 (6 H, m).
65%) which were separated by preparative TLC (SiO2, EtOAc–
Cl3CH–C6H14, 1:8:15). The two isomers with the highest Rf
values, 4a and 5a, were each decomposed (see below) to give the
acid 8 (GLC) which indicated that they were α-diastereo-
isomers. One of the α-isomers with the lower Rf value, 4a, pro-
duced good quality crystals (EtOH) suitable for X-ray crystal
analysis. The determined configuration was rac-(αR*,4R*)
which indicated that the other isomer (of higher Rf) 5a had a
rac-(αS*,4R*) configuration.
rac-(2ЈS*,4R*)-3-(2Ј-Isopropyl-3Ј-phenylpropionyl)-4-
phenyloxazolidin-2-one 4a (highest Rf). Mp 106.5–107.5 ЊC
(Found: C, 74.61; H, 6.90; N, 4.14. C21H23NO3 requires C,
74.75; H, 6.87; N, 4.15%); δH(CDCl3) 7.45–7.12 (10 H, m), 5.08
(1 H, dd, J 3.2 and 8.2), 4.19–4.01 (3 H, m), 2.85 (1 H, dd, J 4.6
and 11.1), 2.76 (1 H, t, J 11.1), 2.05–1.95 (1 H, m) and 0.95 (6
H, dd, J 6.7 and 12.6).
rac-(2ЈR*,4R*)-3-(2Ј-Isopropyl-3Ј-phenylpropionyl)-4-
phenyloxazolidin-2-one 5a (lowest Rf). Mp 96.5–97.5 ЊC
(Found: C, 75.01; H, 6.75; N, 4.18. C21H23NO3 requires C,
74.75; H, 6.87; N, 4.15%); δH(CDCl3) 7.25–7.00 (8 H, m), 6.75–
6.72 (2 H, m), 5.32 (1 H, dd, J 4.3 and 8.6), 4.52 (1 H, t, J 8.6),
4.26 (1 H, m), 4.04 (1 H, dd, J 4.2 and 8.5), 2.83 (2 H, m), 2.03–
1.97 (1 H, m) and 1.05 (6 H, br d, J 6.8).
Addition of BrCCl3 to (R)-1a
Benzoyl peroxide (BP) initiation. A solution of (R)-1a (1.37 g,
4.7 mmol), BrCCl3 (1.86 g, 9.4 mmol) and BP (0.03 g, 0.12
mmol) in anhydrous benzene (6.5 cm3) was refluxed for 15 h
with, every 3 h, a fresh portion of BP (0.02 g, 0.085 mmol)
being introduced. After the addition of 4 portions of BP the
solution was refluxed for a further 15 h. The reaction was mon-
itored by TLC (SiO2, C6H14–PhH–Et2O, 4:1:1). The reaction
mixture was cooled, and the precipitate was filtered off and
washed with benzene to afford the starting material (R)-1a (0.47
g, 20.3%). The filtrate was evaporated to dryness to give a mix-
ture of initial (R)-1a (1.3 g) and diastereoisomeric products (2.3
g, 28%). The ratio of αR,βS,4R:αS,βR,4R was estimated to be
1.2:1 (1H NMR spectra of initial mixture). Isomers were separ-
ated by preparative TLC (SiO2, C6H14–PhH–Et2O, 4:1:1).
Samples of the diastereoisomers were additionally purified by
recrystallization from a benzene–hexane mixture. The absolute
configuration of the isomers were assigned by a single-crystal
X-ray analysis.3
The other two diastereoisomers (with lower Rf values) 6a and
7a were also decomposed (see below) and found to contain the
acid 9 (GLC); thus, their structures could be assigned as those
of the β-isomers. The absolute configuration of the β-isomers
1
could also be easily established by comparing their H NMR
spectra with those reported in the literature (ref. 10) for the
compounds whose structures were determined by X-ray
analysis.
rac-(3ЈR*,4R*)-3-(3Ј-Isopropyl-3Ј-phenylpropionyl)-4-
phenyloxazolidin-2-one 6a (lower Rf) δH(CDCl3) 7.25–7.10 (8
H, m), 6.75 (2 H, m), 5.28 (1 H, dd, J 4.1 and 8.7), 4.55 (1 H, t,
J 8.7), 4.07 (1 H, dd, J 4.1 and 8.7), 3.73 (1 H, dd, J 9.9 and
15.8), 3.13 (1 H, t, J 15.8), 2.95 (1 H, m), 1.88 (1 H, m), 0.96 (3
H, d, J 6.7) and 0.74 (3 H, d, J 6.7).
(2ЈR,3ЈS,4R)-3-(3Ј-Bromo-2Ј-trichloromethyl-3Ј-phenyl-
propionyl)-4-phenyloxazolidin-2-one 2. Highest Rf; mp 154–
155 ЊC; [α]D25 Ϫ122.4 (c, 1.9, PhH) (Found: C, 46.47; H, 3.04; N,
2.65. C19H15BrCl3NO3 requires C, 46.42; H, 3.08; N, 2.84%);
δH(CDCl3) 7.48–7.62 (2 H, m), 7.21–7.41 (8 H, m), 6.52 (1 H, d,
J 10.6), 5.57 (1 H, d, J 10.6), 5.54 (1 H, dd, J 3.6 and 8.7), 4.76
(1 H, t, J 8.7) and 4.38 (1 H, dd, J 3.6 and 8.7).
(2ЈS,3ЈR,4R)-3-(3Ј-Bromo-2Ј-trichloromethyl-3Ј-phenyl-
propionyl)-4-phenyloxazolidin-2-one 3. Lowest Rf; mp 120–
124 ЊC; δH(CDCl3) 7.1–8.7 (10 H, m), 6.51 (1 H, d, J 10.6), 5.52
(1 H, dd, J 3.7 and 8.7), 5.47 (1 H, d, J 10.6), 4.73 (1 H, t, J 8.7)
and 4.38 (1 H, dd, J 3.7 and 8.7).
Fe(CO)5 initiation. A glass tube was charged with (R)-1a
(0.13 g, 0.44 mmol), Fe(CO)5 (8.6 mg, 0.044 mmol), BrCCl3
(1.78 g, 9.0 mmol) and anhydrous benzene (1 cm3). The mixture
was cooled to Ϫ78 ЊC, evacuated in vacuo, and filled with Ar.
The procedure was repeated twice and finally the tube was
sealed and placed in a thermostat (80 ЊC) for 4 h. After this, the
reaction mixture was separated by preparative TLC to afford a
mixture of diastereoisomers 2 and 3 (0.7 g, 32%) in 1:1 ratio, as
estimated from the 1H NMR spectra of the mixture.
rac-(3ЈS*,4R*)-3-(3Ј-Isopropyl-3Ј-phenylpropionyl)-4-
phenyloxazolidin-2-one 7a (Higher Rf of the two β-isomers)
δH(CDCl3) 7.32–7.12 (10 H, m), 5.16 (1 H, dd, J 3.5 and 8.7),
4.43 (1 H, t, J 8.7), 4.17 (1 H, dd, J 3.5 and 8.7), 3.58 (1 H, dd, J
10.4 and 16.6), 3.16 (1 H, dd, J 16.6 and 4.3), 2.95 (1 H, m), 1.83
(1 H, m), 0.93 (3 H, d, J 6.7) and 0.73 (3 H, d, J 6.7).
The reaction with (R)-1b was performed in the same way to
give a mixture of four diastereoisomers (0.13 g, 74%) which
were separated by preparative TLC (C6H14–PhH–Et2O, 4:1:1).
The decomposition of each isomer established that the first two
isomers (higher Rf) were α-isomers and other two (lower Rf)
were β-isomers. The absolute configuration of the α-isomers
were assigned by comparing their parameters (1H NMR and
mp) with those of the model compounds (see above). The first
fraction (higher Rf) contained 5b and the next fraction (lower
Rf) contained 4b.
(b) Pr3B ؉ O2 initiation at 80 ЊC. To a refluxing solution of
rac-1a (0.23 g, 0.78 mmol) and PriI (0.78 cm3, 7.8 mmol) in PhH
(9 cm3), were added simultaneously, by two syringes, Bu3SnH
(1.71 cm3, 2.9 mmol) and Pr3B (1.05 cm3, 5.85 mmol). Dry air (5
cm3) was bubbled through the reaction mixture. After 1.5 h
further portions of Bu3SnH (0.6 cm3) and Pr3B (0.3 cm3) were
added to the reaction mixture; then further air (5 cm3) was
passed through it. The solution was refluxed for a further 1 h,
the reaction being monitored by TLC (see above). Work-up of
the reaction mixture and separation of the isomers were con-
ducted as described above. The ratios of the isomers (0.21 g,
The addition of PriI to rac-1a and (R)-1b in the presence of
Bu3SnH
(a) AIBN initiation. To a solution of rac-1a (0.15 g, 0.5 mmol)
and PriI (0.1 cm3, 1.0 mmol) in PhH (10 cm3) was added a
solution of Bu3SnH (0.22 cm3, 0.75 mmol) and AIBN (0.03 g,
0.15 mmol) by syringe within a period of 17 h at 80 ЊC. The
reaction was stopped when the starting material had been con-
sumed (TLC control). The reaction mixture was evaporated
and then flash chromatographed on SiO2, first with hexane, to
separate the Sn derivatives, and then with PhH. The benzene
fraction was evaporated to give the mixture of the isomers (1 g,
1
83% total) were determined from H NMR spectral measure-
ments of the reaction mixture and comparison of the integral
intensities of the proton resonances at 5.08 ppm (for αS,4R-5a),
5.32 ppm (αR,4R-4a), 5.16 ppm (βS,4R-7a) and 5.28 ppm
(βR,4R-6a).
(c) Pr3B ؉ O2 initiation at low temperatures. To a solution of
J. Chem. Soc., Perkin Trans. 1, 1997
3105

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rac-1a (0.15 g, 0.5 mmol) and PriI (0.5 cm3, 5.0 mmol) in
CH2Cl2 (4 cm3), were added Bu3SnH (0.5 cm3, 1.7 mmol) and
Pr3B (0.5 cm3, 2.77 mmol) at Ϫ23 ЊC (CCl4–solid CO2); dry air
(5 cm3) was then bubbled through the mixture via a syringe for 2
h with stirring. Further portions of Bu3SnH (0.23 cm3, 0.8
mmol) and Pr3B (0.4 cm3, 2.23 mmol) were added to the mix-
ture and stirring was continued for a further 1 h at Ϫ23 ЊC. The
reaction mixture was then cooled to Ϫ75 ЊC and put on a SiO2
column (jacketted at Ϫ78 ЊC); washing of the column with
cooled hexane removed all the Sn- and boron-derivatives. The
column was then warmed to ambient temperature and washed
with PhH. Evaporation of the benzene solution afforded a res-
idue consisting of a mixture of isomers (0.03 g, 20%) which
were separated by preparative TLC (EtOAc–CHCl3–C6H14,
1:8:15). A reaction at ambient temperature was conducted in a
similar manner (0.08 g, 51%), the only difference being that
cooling of the column was unnecessary.
wR2 = 0.107 for all 1901 unique reflections. A small contribu-
tion for anomalous scatterers (three oxygen atoms with Mo
radiation) did not allow us to determine the absolute configur-
ation merely on the basis of X-ray experiment. Nevertheless,
the presence of the chiral centre at C(4) with the authentic
known configuration—(R) made it possible to assign unam-
biguously the configuration of the newly formed chiral centre at
the C(7) atom that was of S-configuration.
All calculations were carried out with SHELXTL PLUS and
SHELXL-93 programs. Atomic coordinates, bond lengths,
bond angles and thermal parameters have been deposited at the
Cambridge Crystallographic Data Centre [see Notice to
Authors, (1997), J. Chem. Soc., Perkin Trans 1, 1997, Issue 1].
Any requests for this material should be accompanied by a full
bibliographic citation for this work together with the reference
number 207/134.
Acknowledgements
The work was supported by RFFI (Russian Fund for Fund-
amental Research Grant No. 96-03-33430). The authors thank
Professor D. Curran for helpful discussions.
Hydrolysis of the diastereoisomeric 3-(2Ј-isopropyl-3Ј-phenyl-
propionyl)-4-benzyl(or phenyl)oxazolidin-2-ones and recovery of
4 methyl-3-phenylpentanoic acids
To a solution of an isomer (0.11 g, 0.33 mmol), in a mixture of
THF (5 cm3) and water (5 cm3) was added aq. H2O2 (30%; 0.08
cm3, 2.64 mmol) and LiOH (0.03 g, 1.32 mmol). The reaction
mixture was stirred at 20 ЊC for 3 h. After completion of the
reaction (TLC), most of the THF was removed by evaporation
to leave an aqueous solution (pH 12) which was extracted with
CH2Cl2 (3 × 10 cm3); work-up of the extracts gave recovery of
4-benzyl-(or phenyl)oxazolidin-2-ones. The aqueous solution
was acidified with aq. HCl (3 ) to pH 1 and then again
extracted with CH2Cl2 (4 × 15 cm3). The combined extracts
were dried (MgSO4) and concentrated to yield a 4-methyl-3-
phenylpentanoic acid. The acid was esterified by MeOH (with
SOCl2) and the ester was used for the analysis by GLC method.
References
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Carbon Bond, Pergamon, Oxford, 1986; (b) C. P. Jasperse and D. P.
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X-Ray diffraction analysis
Crystal data for (3ЈR*,4R*)-3-(2Ј-isopropyl-3Ј-phenylpropion-
yl)-4-phenyloxazolidin-2-one: C21H23NO3, M = 337.40, mono-
clinic, space group C2/c, at 20 ЊC: a = 28.216(7), b = 6.284(2),
c = 21.509(6) Å, β = 102.08(2)Њ, V = 3729(2) Å3, Z = 8, Dc =
1.202 g cmϪ3. Unit cell parameters and 3247 reflections were
measured with an automated 4-circle Siemens P3/PC diffract-
ometer [293 K, λ(Mo-Kα), graphite monochromator, θ/2θ-
scan, θmax = 25Њ]. The structure was solved by direct methods
and refined by the full-matrix least-squares technique in aniso-
tropic approximation for non-hydrogen atoms. Hydrogen atoms
in the geometrically calculated positions were included in
refinement with fixed positional and isotropic thermal (‘riding’
model) parameters. The final discrepancy factors are R1 = 0.066
for 1493 unique reflections with I > 2σ(I) and wR2 = 0.152 for
3121 unique reflections.
Crystal data for (2ЈS,4R)-3-(2Ј-isopropyl-3Ј-phenylpropion-
yl)-4-benzyloxazolidin-2-one: C22H25NO3, M = 351.43, ortho-
rhombic, space group P212121, at 20 ЊC: a = 6.350(2), b =
9.420(2), c = 32.806(8) Å, V = 1962.3(8) Å3, Z = 4, Dc = 1.190 g
cmϪ3. Unit cells parameters and 1944 reflections for the sample
were measured analogously. The final discrepancy factors are
R1 = 0.058 for 1237 unique reflections with I > 2σ(I) and
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Paper 7/01154G
Received 18th February 1997
Accepted 18th June 1997
3106
J. Chem. Soc., Perkin Trans. 1, 1997