Axially chiral N-(o-aryl)-4-hydroxy-2-oxazolidinone derivatives from diastereoselective reduction of N-(o-aryl)-2,4-oxazolidinediones: Thermally interconvertible atropisomers via ring-chain-ring tautomerization

Article abstract of DOI:10.1002/chir.20811

The reduction of the axially chiral N-(o-aryl)-5,5-dimethyl-2,4- oxazolidinediones by NaBH₄ yielded axially chiral N-(o-aryl)-4-hydroxy-5,5-dimethyl-2-oxazolidinone enantiomers having a chiral center at C-4, with 100% diastereoselectivity as has been shown by their ¹H and ¹³C NMR spectra and by enantioselective HPLC analysis. The resolved enantiomeric isomers were found to interconvert thermally through an aldehyde intermediate formed upon ring cleavage via a latent ring-chain-ring tautomerization. It was found that the rate of enantiomerization depended on the size and the electronic effect of the ortho substituent present on the aryl ring bonded to the nitrogen of the heterocycle.

Full text of DOI:10.1002/chir.20811

CHIRALITY 22:641–654 (2010)
Axially Chiral N-(o-aryl)-4-Hydroxy-2-oxazolidinone Derivatives
from Diastereoselective Reduction of N-(o-aryl)-
2,4-oxazolidinediones: Thermally Interconvertible
Atropisomers via Ring-Chain-Ring Tautomerization
_
ˇ
¨
*
OZNUR DEMIR-ORDU AND ILKNUR DOGAN
_
Department of Chemistry, Bogazic¸i University, Bebek, 34342, Istanbul, Turkey
ˇ
ABSTRACT
The reduction of the axially chiral N-(o-aryl)-5,5-dimethyl-2,4-oxazoli-
dinediones by NaBH4 yielded axially chiral N-(o-aryl)-4-hydroxy-5,5-dimethyl-2-oxazoli-
dinone enantiomers having a chiral center at C-4, with 100% diastereoselectivity as has
1
been shown by their H and 13C NMR spectra and by enantioselective HPLC analysis.
The resolved enantiomeric isomers were found to interconvert thermally through an
aldehyde intermediate formed upon ring cleavage via a latent ring-chain-ring tautomeri-
zation. It was found that the rate of enantiomerization depended on the size and the
electronic effect of the ortho substituent present on the aryl ring bonded to the nitrogen
C
VV
of the heterocycle. Chirality 22:641–654, 2010.
2009 Wiley-Liss, Inc.
KEY WORDS: axial chirality;
diastereoselective
reduction;
ring-chain-ring
tautomerization; enantioselective HPLC; enantiomer separation;
barrier to enantiomerization; 2,4-oxazolidinediones; temperature-
dependent NMR
INTRODUCTION
oxazolidinediones (6)1–6 to yield axially chiral hemiami-
nal type compounds, N-(o-aryl)-4-hydroxy-5,5-dimethyl-2-
oxazolidinones 7–12, having also a chiral center at C-4
which were found to racemize by a latent10 ring-chain-ring
The heterocyclic analogs of biphenyls of the type N-(o-
aryl)-2,4-oxazolidinediones (6)1–6 (Scheme 1) have
ground states where the two rings are orthogonal to each
other and are thus axially chiral.1–3 The enantiomers of
these compounds are known to racemize thermally via
rotation around the Nsp2-Caryl bond,2,3 through a planar
transition state (Scheme 1). In fact the activation barriers
determined for these2,3 and structurally similar systems4
revealed that there is a linear relationship between the van
der Waals radius of the ortho halogen substituent and the
activation barrier to hindered rotation.
tautomerization rather than by rotation around the Nsp2
-
Caryl bond (see Fig. 1). The barriers to enantiomerization
of the N-(o-aryl)-4-hydroxy-5,5-dimethyl-2-oxazolidinone
enantiomers have been determined by either enantioselec-
tive HPLC by following the interconversion of one
resolved enantiomer peak to the other or by temperature
dependent 1H NMR.
The reduction of unsymmetrical anhydrides5 and cyclic
amides with NaBH4 are known to be regioselective.6 The
hydride attack takes place on the carbonyl group that is vic-
EXPERIMENTAL
General Methods
1H and 13C NMR spectra of all compounds were
inal to the most substituted carbon. We therefore expect recorded on a Varian-Mercury VX-400 MHz-BB (308C). IR
the regioselective reduction at C-4 carbon in compounds analyses were performed on a Mattson Genesis II FTIR
(6)1–6 which will result in the synthesis of the axially chi- using KBr discs. Liquid chromatography analyses with UV
ral N-(o-aryl)-4-hydroxy-5,5-dimethyl-2-oxazolidinones (see detector (k 5 254 nm) were performed using CHIRALCEL
Fig. 1) having a chiral center at C-4 of the ring. The synthe- OD-H column (particle size: 5 lm, column size: 250 3 4.6
sis of these compounds, their chromatographic resolutions mm2), CHIRALPAK AD column (partical size: 5 lm, col-
and study of their barriers to enantiomerization carried out umn size: 250 3 4.6 mm2), CHIRALPAK IB column (par-
in this work are considered important because such com- tical size: 5 lm, column size: 250 3 4.6 mm2) or CHIRAL-
pounds may have a potential to be used as axially chiral
non-biaryl auxiliaries7 and bidentate ligands8 with suitable
ortho substituents. For example, the N-(o-hydroxyphenyl)
*Correspondence to: I. Dogan, Bogazic¸i University, Department of Chem-
istry, Bebek, 34342, Istanbul, Turkey. E-mail: dogan@boun.edu.tr
Contract grant sponsor: Bogazic¸i University Research Fund (BAP);
substituted N-(o-aryl)-4-hydroxy-5,5-dimethyl-2-oxazolidi-
nones would be analogous to the well known BINOL.9
This article describes the regio and diastereoselective
NaBH4 reduction of racemic N-(o-aryl)-5,5-dimethyl-2,4-
C
Contract grant number: 08B507
Received for publication 15 June 2009; Accepted 30 September 2009
DOI: 10.1002/chir.20811
Published online 10 December 2009 in Wiley InterScience
(www.interscience.wiley.com).
VV
2009 Wiley-Liss, Inc.

642
DEMIR-ORDU AND DOGAN
(1.00 g, 99%), mp 96-988C (ethyl acetate-/n-hexane); 1H
NMR (400 MHz; CDCl3, Me4Si): d 1.40 and 1.48 (6H, 2 3
s, 2 3 CH3), 2.23 (3H, s, oꢀꢀCH3), 3.32 (1H, d, J 7.4, OH),
4.90 (1 H, d, J 7.4, CꢀꢀH), 7.17–7.29 (4H, m, 4 3 CꢀꢀH);
13C NMR (100 MHz; CDCl3, Me4Si): d 151.8 (C ¼¼ O),
132.9 (C), 130.2 (C), 127.4 (CꢀꢀH), 125.4 (CꢀꢀH), 124.9
(CꢀꢀH), 123.1 (CꢀꢀH), 84.3 (CꢀꢀH), 78.8 (C), 22.9
(oꢀꢀCH3), 17.0 (CH3), 14.3 (CH3); elemental analysis:
Found: C, 65.4; H, 7.1; N, 6.2; calculated for C12H15NO3:
C, 65.1; H, 6.8; N, 6.3%; IR Data (mmax (KBr)/cm21): 3262
(OꢀꢀH), 1714 (C¼¼O).
N-(a-naphthyl)-4-hydroxy-5,5-dimethyl-2-oxazolidinone
(8). The compound was prepared according to the gen-
eral procedure using 0.50 g (1.96 mmole) compound (6)2
in 6 ml THF (0,33 M), 0.30 g (7.84 mmole) sodium boro-
hydride in 1.8 ml water (4,35 M). After extraction with
ethyl acetate, the product was obtained as a white solid
(0.36 g, 71%), mp 124–1268C (ethyl acetate-hexane); 1H
NMR (400 MHz; CDCl3, Me4Si): d1.48 and 1.64 (6H, 23s,
23CH3), 3.80 (1H, br s, OH), 5.02 (1 H, s, C–H), 7.40–8.00
(7H, m, 7 3 CꢀꢀH); 13C NMR (100 MHz; CDCl3, Me4Si):
d 156.3 (C¼¼O), 134.8 (C), 131.5 (C), 130.9 (C), 129.4
(CꢀꢀH), 128.9 (CꢀꢀH), 127.5 (CꢀꢀH), 127.3 (CꢀꢀH), 126.7
(CꢀꢀH), 125.8 (CꢀꢀH), 122.4 (CꢀꢀH), 88.5 (CꢀꢀH), 82.9
(C), 27.2 (CH3), 21.1 (CH3); elemental analysis: Found: C,
70.1; H, 5.7; N, 5.7; calculated for C15H15NO3: C, 70.0; H,
5.9; N, 5.4%; IR Data (mmax (KBr)/cm21): 3337 (OꢀꢀH),
1704 (C¼¼O).
Scheme 1. The compounds subjected to reduction reaction by
NaBH4, T1 and T2 represent the transition states.
N-(o-fluorophenyl)-4-hydroxy-5,5-dimethyl-2-oxazolidi-
none (9). The compound was prepared according to the
general procedure using 0.25 g (1.12 mmole) compound
(6)3 in 3.5 ml THF (0,32 M), 0.17 g (4.48 mmole) sodium
borohydride in 1.1 ml water (4,00 M). After extraction
with ethyl acetate, the product was obtained as a white
PAK IC column (partical size: 5 lm, column size: 250 3
4.6 mm2). Separations were done at T 5 280 K. Reactions
were followed by TLC using silica gel 60-F254. Elemental
analyses were performed on Thermo Scientific Flash EA
1112 CHNS analyzer. Melting points were recorded using
Electrothermal 9100 melting point apparatus.
1
solid (0.25 g, 65%), mp 85-868C (ethyl acetate-hexane); H
NMR (400 MHz; CDCl3, Me4Si): d 1.48 and 1.55 (6H, 2 3
s, 2 3 CH3), 3.32 (1H, br s, OH), 5.15 (1 H, s, CꢀꢀH),
7.16–7.57 (4H, m, 4 3 CꢀꢀH); 13C NMR(100 MHz; tolu-
ene-d8, Me4Si): d 155.3 (C¼¼O), 130.3 (CꢀꢀH), 129.0 (C),
127.4 (C), 124.3 (CꢀꢀH), 116.2 (CꢀꢀH), 115.9 (CꢀꢀH), 88.0
(CꢀꢀH), 82.8 (C), 25.8 (CH3), 20.2 (CH3); elemental analy-
sis: Found: C, 58.4; H, 5.3; N, 6.4; calculated for
C11H12NO3F: C, 58.7; H, 5.4; N, 6.2%; %; IR Data (mmax
(KBr)/cm21): 3367 (OꢀꢀH), 1752 (C¼¼O).
Synthesis of Compounds (6)1–6
Compounds (6)1–6, N-(o-aryl)-5,5-dimethyl-2,4-oxazoli-
dinediones were prepared according to the procedures
given in Refs. 2 and 3.
Synthesis of Compounds 7–12
General procedure for the reduction reactions with
sodium borohydride.11 To a mixture of the starting ma-
terial (1 eq) in THF was added a solution of sodium boro-
hydride (4 eq.) in water at a rate to maintain the internal
temperature at 20–258C. The mixure was stirred at room
temperature for 1–7 h, and the completion of the reaction
N-(o-chlorophenyl)-4-hydroxy-5,5-dimethyl-2-oxazolidinone
(10). The compound was prepared according to the gen-
eral procedure using 0.20 g (0.84 mmole) compound (6)4
in 2.6 ml THF (0,32 M), 0.13 g (3.34 mmole) sodium boro-
was monitored by TLC. To the reaction mixture was added hydride in 0,8 ml water (4,00 M). After extraction with
ethyl acetate, the product was obtained as a white solid
2 M HCl (5 eq.) at a rate to maintain the internal tempera-
ture at 20–258C. The reaction mixture was extracted with
(0.19 g, 93%), mp 110–1128C (ethyl acetate-hexane); 1H
ethyl acetate. The combined organic layers were washed NMR (400 MHz; CDCl3, Me4Si): d 1.40 and 1.53 (6H, 2 3
s, 2 3 CH3), 3.63 (1H, br s, OH), 5.04 (1 H, s, CꢀꢀH),
with brine, dried with MgSO4 and purified by ethyl ace-
tate-hexane.
N-(o-tolyl)-4-hydroxy-5,5-dimethyl-2-oxazolidinone
(7). The compound was prepared according to the gen-
eral procedure using 1.00 g (4,56 mmole) compound (6)1
7.22–7.46 (4H, m, 43CꢀꢀH); 13C NMR(100 MHz; CDCl3,
Me4Si): d 156.0 (C¼¼O), 133.0 (C), 132.7 (C), 131.9
(CꢀꢀH), 130.4 (CꢀꢀH), 130.0 (CꢀꢀH), 127.9 (CꢀꢀH), 87.7
(CꢀꢀH), 83.9 (C), 26.6 (CH3), 20.9 (CH3); elemental analy-
in 14 ml THF (0,33 M), 0.69 g (18,25 mmole) sodium boro- sis: Found: C, 54.4; H, 5.0; N, 5.6; calculated for
C11H12NO3Cl: C, 54.7; H, 5.0; N, 5.8%); IR Data (mmax
hydride in 4,5 ml water (4,05 M). After extraction with
ethyl acetate, the product was obtained as a white solid
Chirality DOI 10.1002/chir
(KBr)/cm21): 3338 (OꢀꢀH), 1708 (C¼¼O).

THERMALLY INTERCONVERTIBLE ATROPISOMERS
643
Fig. 1. The reaction of compounds (6)1-6 with NaBH4, (i) NaBH4, THF-H2O, room temperature. The reaction yielded the thermodynamic product
by 100% diastereoselectivity.
N-(o-bromophenyl)-4-hydroxy-5,5-dimethyl-2-oxazolidi-
(C), 87.5 (CꢀꢀH), 83.5 (C), 26.7 (CH3), 21.0 (CH3); ele-
none (11). The compound was prepared according to mental analysis: Found: C, 45.8; H, 4.3; N, 5.1; calculated
the general procedure using 0.30 g (1.06 mmole) com- for C11H12NO3Br C, 46.1; H, 4.2; N, 4.9%; IR Data (mmax
pound (6)5 in 3.5 ml THF (0,30 M), 0.16 g (4.22 mmole) (KBr)/cm21): 3342 (OꢀꢀH), 1708 (C¼¼O).
sodium borohydride in 1.0 ml water (4,22 M). After extrac-
N-(o-iodophenyl)-4-hydroxy-5,5-dimethyl-2-oxazolidi-
tion with ethyl acetate, the product was obtained as a none (12). The compound was prepared according to
white solid (0.24 g, 79%), mp 154–1568C (ethyl acetate-hex- the general procedure using 0.20 g (0.60 mmole) com-
1
ane); H NMR (400 MHz; CDCl3, Me4Si): d1.42 and 1.56 pound (6)6 in 1.9 ml THF (0,32 M), 0.091 g (2.42 mmole)
(6H, 2 3 s, 2 3 CH3), 3.42 (1H, d, J 8.0, OH), 5.09 (1 H, d, sodium borohydride in 0.6 ml water (4,00 M). After extrac-
J 8.0, CꢀꢀH), 7.16–7.60 (4H, m, 4 3 CꢀꢀH); 13C NMR(100 tion with ethyl acetate, the product was obtained as a
MHz; CDCl3, Me4Si): d 155.6 (C¼¼O), 134.2 (C), 133.6 white solid (0.13 g, 66%), mp 148–1508C (ethyl acetate-hex-
1
(CꢀꢀH), 132.2 (CꢀꢀH), 130.3 (CꢀꢀH), 128.6 (CꢀꢀH), 123.4 ane); H NMR (400 MHz; CDCl3, Me4Si): d 1.50 and 1.69
Chirality DOI 10.1002/chir

644
DEMIR-ORDU AND DOGAN
TABLE 1. Reduction of compounds (6)1–6 by NaBH4
Table 1). The ring structures of compounds 7–12 were
determined by 1H and 13C NMR in CDCl3 (see Fig. 2).
A second hydride transfer that would result in ring
opening did not take place probably due to the steric hin-
drance of the 5,5-dimethyl groups.
Starting materials
Product no
Yield (%)
Reduction timea
(6)1
(6)2
(6)3
(6)4
(6)5
(6)6
7
8
9
10
11
12
99
71
65
93
79
66
3 h 30 min
7 h
4 h
4 h 30 min
4 h 30 min
6 h 30 min
1
The H NMR spectra of the hemiaminals 7–12 showed
diastereotopic splittings for the C-5 methyl groups like the
precursor compounds (6)1–6 which have been discussed
previously in detail.2,3 Because of the formation of a chiral
center on C-4 in compounds 7–12, in addition to the chi-
ral axis, the chemical shift difference between the diaster-
eotopic geminal dimethyl protons for these compounds
were found to increase by 0.06 ppm compared with those
of (6)1–6.
aReduction times were determined by following the reaction with TLC
using chloroform or ethylacetate: n-hexane mixture (1:2) as an eluent.
Samples were taken at 30 min intervals.
(6H, 2 3 s, 2 3 CH3), 3.36 (1H, d, J 7.0, OH), 5.16 (1 H, d,
J 7.0, CꢀꢀH), 7.08–7.93 (4H, m, 4 3 C–H); 13C NMR(100
MHz; CDCl3, Me4Si): dC 155.6 (C¼¼O), 140.0 (CꢀꢀH),
137.3 (C), 131.9 (CꢀꢀH), 130.6 (CꢀꢀH), 129.6 (CꢀꢀH), 99.3
(C), 87.5 (CꢀꢀH), 83.6 (C), 27.0 (CH3), 21.2 (CH3) ; ele-
mental analysis: Found: C, 39.5; H, 3.8; N, 4.3; calculated
for C11H12NO3I: C, 39.7; H, 3.6; N, 4.2%); IR Data (mmax
(KBr)/cm21): 3334 (OꢀꢀH), 1709 (C¼¼O).
Stereoselectivity (Diastereoselectivity) in Reduction
of Compounds (6)1–6
The reaction of NaBH4 with compounds (6)1–6 can in
principle be expected to form four stereoisomers due to
the formation of a new chiral center on C-4: two enantio-
meric (S-M/R-P, S-P/R-M) and two diastereomeric pairs
1
(S-M/S-P, R-M/R-P) (see Fig. 1). However the H and 13C
NMR of the reduction products 7–12 showed the pres-
ence of only one of these diastereomeric pairs (S-M/R-P
pair as has been proved by NOESY and will be explained
later in the text) (see Fig. 2) and the enantioselective
HPLC on the columns Chiralcel OD-H, Chiralpak AD-H,
RESULTS AND DISCUSSION
Reaction with NaBH411
The reduction reactions of compounds (6)1–6 were IB and/or IC showed only one enantiomeric pair.
carried out by four molecular equivalents of NaBH4 in The observation of only one enantiomeric pair for com-
THF. It was observed that the reaction took place regiose- pounds 7–12 led us consider the possibility of a stereose-
lectively reducing only the C-4 carbonyl and not the C-2, to lective reduction. As boron in NaBH4 is tetracoordinated,
yield N-(o-aryl)-4-hydroxy-5,5-dimethyl-2-oxazolidinones in the attack of the hydride, the Felkin-Anh model is usu-
with 100% diastereoselectivity (compounds 7–12) (Fig. 1, ally invoked.5 The attack of the hydride takes place anti to
Fig. 2. 400 MHz 1H NMR spectrum of compound 12 in CDCl3. S:Solvent.
Chirality DOI 10.1002/chir

THERMALLY INTERCONVERTIBLE ATROPISOMERS
645
Fig. 3. The NOESY spectrum of compound 7 in CDCl3. [Color figure can be viewed in the online issue, which is available at www.interscience.
wiley.com.]
the most bulky or the polar group, i.e., the ortho substitu- quite unstable products where the hydroxyl and the ortho
ent in our case, resulting in a facial selectivity for the car- substituents are syn with respect to each other (kinetic
bonyl group. Thus, the attack of a hydride on prochiral C-4 products) (see Fig. 1).
carbonyl group can be accomplished either on the Re or Si
NOESY spectra for compounds 7 and 12 were taken to
face of the carbonyl. Because of the presence of an ortho elucidate the stereochemistry of the reduction products
substituent that is very close to the reaction site, a selectiv- (Figs. 3 and 4). The observed crosspeaks between the C-4
ity for the attack from the opposite side of the ortho sub- carbinyl hydrogen and the ortho methyl protons of com-
stituent could be expected. However, this would form pound 7 revealed that these protons are on the same side,
Chirality DOI 10.1002/chir

646
DEMIR-ORDU AND DOGAN
Fig. 4. The NOESY spectrum of compound 12 in CDCl3. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]
Ring-Chain-Ring Tautomerism: Mechanism and Kinetics
of the Interconversion Between the N-(o-aryl)-4-Hydroxy-
5,5-dimethyl-2-oxazolidinone Enantiomers, (7–12)
( S-M$R-P/R-M$S-P)
Ring-chain tautomerization has been shown to occur in
a number of heterocyclic compounds.10,12–20 The tautom-
erism results from an interconversion of the chain and the
ring isomers.
indicating that they are the thermodynamic products, (S-
M) and (R-P) (see Fig. 3). The spatial proximity between
the carbinyl hydrogen and one of the C-5 methyl groups
could also be seen in this spectrum. In the NOESY spec-
trum of compound 12 (see Fig. 4), the crosspeak
observed between ortho hydrogen and C-4 hydroxyl group
also showed that the isomers have conformations where
C-4 hydroxyl group and iodine atom are on opposite sides
(Thermodynamic products, (S-M) and (R-P)).
Chirality DOI 10.1002/chir

THERMALLY INTERCONVERTIBLE ATROPISOMERS
647
Scheme 2. Racemization of compounds 7–12 through an aldehyde intermediate.
For compounds 7–12, the two enantiomers (S-M) and
Having in hand the enantiomerization barriers for com-
(R-P) (see Fig. 1) were found to be resovable by chiral pounds 7–12, we could clearly see that the barriers for
chromatography and the separated enantiomer was found the ortho-fluoro, chloro, bromo and iodo derivatives did
to thermally interconvert to its counterpart with time and not show a linearity depending on the size of the ortho-sub-
finally racemized. This fact pointed to a ring-chain-ring tau- stituent (Fig. 6a). The barriers to rotation for the ortho-flu-
tomerization where the hemiaminal7–12 opened to give the oro, chloro, bromo and iodo derivatives of the correspond-
corresponding aldehyde (Scheme 2) which then reclosed ing oxazolidinediones [(6)1–6] on the other hand where
by either a Re or Si face attack of the nitrogen to give (S- the enantiomerization was due to the hindered rotation2
M) and (R-P) products.
around the Nsp2-Caryl bond did show a linearity depending
To clarify the mechanism of enantiomerization between on the o-halogen substituent (Fig. 6b).2 This was taken as
the enantiomeric pairs (S-M/R-P pair), one of the enan- a proof for the existence of a different mechanism for the
tiomers of compounds 7–12 was collected microprepara- enantiomerization for these compounds. Previously a ring
tively by HPLC using a chiral column (Table 2). The etha- opening-ring closure mechanism has been proposed for
nol solution of the collected enantiomer was kept at six-membered N-o-aryl substituted heterocyclic com-
308C,10–12 at 508C (7, 8) or at 788C (9) in a constant tem- pounds.22
perature bath and its interconversion to the other enan-
The interconversion of (S-M) to (R-P) for compounds 7–
tiomer was followed by taking an aliquot of ethanol solu- 12 could proceed via an aldehyde intermediate formed
tion at certain time intervals and analyzing them by HPLC. from a ring cleavage (Scheme 2) as has been observed for
Considering the interconversion follows a first order reac- structurally related compounds.23,24 However, such an in-
tion kinetics, the slope of the line ln ([enantiomer]t- 50/ termediate was not observed in the NMR time scale in
[enantiomer]0-50) 5 22 kt, where [enantiomer]t is the per CDCl3. Taking the NMR spectra in d6-DMSO in the ab-
cent composition of an enantiomer at time t, [enantiomer]0 sence or presence of trifluoroacetic acid-d or pyridine-d5,
is the starting per cent composition of the enantiomer and which could stabilize the aldehyde intermediate10,12 did
50 is the equilibrium composition,21 gave the rate constant not exhibit its existence as well. With the aim of trapping
(see Fig. 5) and hence the activation barrier for intercon- the aldehyde intermediate as an imine, the compound 10
version.21 The kinetic and chromatographic data pertinent was treated with benzyl amine in toluene under reflux for
to enantiomerizations are given in Table 2.
one day as has been described in Ref. 10. Analysis of the
Chirality DOI 10.1002/chir

648
DEMIR-ORDU AND DOGAN
TABLE 2. The kinetic and chromatographic data for racemization of compounds 7-12, determined by HPLC
Eluent
composition
(% v, n-Hexane:
% v, Ethanol)
Flow
Rate/ml
min21
Capacity
Factors,
k1&k2
Rate
Constant,
Activation Barrier,
t1/2/min
(303 K)
Entries
7
Column
Selectivity, a
k/sec21
DG#/kJ mol21
b
Chiralpak
IB
Chiralcel
OD-H
Chiralpak
IB
Chiralpak
IB
Chiralcel
OD-H
Chiralcel
OD-H
90:10
80:20
95:5
0.7
0.4
0.6
0.7
0.6
0.6
2.33
2.53
1.19
1.91
3.18
3.89
2.09
2.36
1.53
2.08
1.89
3.11
1.09
5.00 3 1025,a
1.67 3 1025,a
5.75 3 1025,d
8.00 3 1025,f
1.53 3 1024,f
1.58 3 1024,f
105.92 6 0.7
108.86 6 0.7
114.94 6 0.7
98.02 6 0.7
96.38 6 0.7
96.30 6 0.7
–
c
8
9
1.61
1.22
1.13
1.36
1.65
–
e
–
10
11
12
90:10
90:10
90:10
72
42
36
aAt 50 6 28C.
bThe interconversion was too slow at 303 K to determine the kinetics (3% interconversion in 100 min at 313 K).
cThe interconversion was too slow at 303 K to determine the kinetics (2% interconversion in 106 min at 313 K).
dAt 78 6 28C.
eThe interconversion did not take place at 303 K.
fAt 30 6 28C.
Fig. 5. The HPLC chromatograms taken to follow the racemization and the plot of ln ([enantiomer]t- 50/[enantiomer]0-50) versus time (min) at 308C
for compound 10.
Chirality DOI 10.1002/chir

THERMALLY INTERCONVERTIBLE ATROPISOMERS
649
Fig. 6. The dependance of the enantiomerization barriers on the van der Waal’s radius of the ortho substituents (a) for compounds 9–12 (b) for
compounds 3–6.2 [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]
1H and 13C NMR spectra of the crude product from this in this series (Scheme 2).12,13 It has been observed that,
reaction showed the presence of a cyclic aminal structure the rate of enantiomerization for compounds 9–12
(13) formed probably by an attack of NH to the formed depended on both the nature of the ortho substituent and
imine (Scheme 3, Fig. 7). This was taken as a proof that its size (Table 2). As can be seen from Table 2 compound
the enantiomerization took place through an aldehyde in- 12 has the highest enantiomerization rate. This fact was
termediate.
attributed to the large van der Waals radius of iodine that
Comparison of the activation barriers for enantiomeriza- caused a more rapid ring opening than the other halogen
tion for compounds 7–12 (Table 2) revealed that the ortho ortho substituents. Also because of the lowest electronega-
substituents had an effect on the rate of tautomerization as tivity of iodine atom compared with the other halogens an
has been observed before.25,26 It is known that electron increase in the nucleophilicity of the N can be expected.
donating groups on phenyl ring favors the ring formation, Thus the hemiaminal ring 12 could more rapidly open
whereas the electron withdrawing groups leads to the for- and then close compared with 9–11. Because of the small-
mation of open chain.12,13 After the attack of an hydride to est van der Waals radius of florine atom, at 308C com-
the C-4 carbonyl selectively to form the (R-M) and (S-P) pound 9 could not form an aldehyde intermediate as will
isomers (Scheme 2), the formed hydroxy lactam might be explained further in the text.
turn into an aldehyde via ring opening due to the steric in-
The 1H NMR spectrum of compound 9 although
terference caused by the syn-orientation of the hydroxyl showed the presence of only one diastereomer at 308C,
and Z groups. In fact, the unstable (R-M) isomer could be when the toluene-d8 solution of the compound was cooled
stabilized by two ways: first, by the rotation around the from 308C to 2708C in the NMR probe (see Fig. 8) the
chiral axis or second by ring opening. The most important other diastereomer appeared at 2538C. Also, it was
factor that results in ring opening is that during rotation, observed that the chemical shift of the hydroxyl proton
the ortho substituents orient the lone pair electrons on ox- was deshielded remarkably from approximately 3.7 to 6.1
ygen towards the C-4 carbonyl, assiting the formation of ppm revealing that there was a hydrogen bonding2,3
an aldehyde. After ring opening, either due to the gem-di- between the hydroxyl hydrogen and the fluorine atom.
methyl effect (Thorpe-Ingold effect),27 and/or the nucleo- The appearance of the other isomer at 2538C was attrib-
philicity of N, the molecule favors the intramolecular cycli- uted to a slow rotation around the CꢀꢀN bond axis. There-
zation as the two reacting sites are close to each other fore, it was concluded that the rotation around the CꢀꢀN
(Compounds 7–12). The fact that the rate of enantiomeri- single bond of compound 9 was so fast at room tempera-
zation increases from fluorine to iodine derivatives could ture making the resulting isomers enantiomeric having
also be explained by the increased nucleophilicity of the N only (S) and (R) configurations on C-4. The existence of
Scheme 3. Trapping of the aldehyde intermediate of compound 10 as an aminal 13.
Chirality DOI 10.1002/chir

650
DEMIR-ORDU AND DOGAN
Fig. 7. The 400 MHz 1H NMR spectrum of a crude product containing 10 and 13 in CDCl3.
enantiomers was proven by the 1H NMR spectrum of com- was too slow at 508C and 658C (2% decrease in concentra-
pound 9 in the presence of (S)-(1)-1-(9-anthryl)-2,2,2-tri- tion after 138 min at 508C, 4.4% decrease in concentration
fluoro ethanol (see Fig. 9), by observing splitting of the after 136 min at 658C), and could only be followed at 788C.
peaks due to the formation of diastereomeric association This observation proved the importance of the magnitude
complexes.2,3,28
of the van der Waals radius on tautomerization assisting
At temperatures below 2508C the hydroxy proton at C-4 the ring opening and formation of an aldehyde intermedi-
can form a stronger hydrogen bond with ortho fluorine, ate. Because of the smallest van der Waals radius of fluo-
yielding (R-M) and (S-P) enantiomers in addition to their rine and the lowest nucleophilicty of N carrying the o-fluo-
diastereomers (S-M) and (R-P). The separation in Hertz rophenyl, ring opening and closure was difficult resulting
between the signals of the diastereomers in the absence of in a highest activation barrier in the series (Table 2).
rapid rotation could be achieved at 2538C (220 K) and
found as 12 Hz for 400 MHz NMR instrument. The coales-
cence of the signals took place at 2538C (see Fig. 8). By
using the Eyring Equation,29 the activation barrier to hin-
dered rotation was found as 47.3 6 0.05 kJ/mol which was
lower than that of compound (6)3 (57.3 kJ/mol).2 This
decrease in the activation barrier was explained in terms
of the stability of also the transition state of 9 during rota-
tion via hydrogen bonding. As the hydroxyl and ortho fluo-
rine groups are very close to each other in space in the
transition state, they should be capable of forming a stron-
ger hydrogen bond that will stabilize the transition state.
The enantiomers of compound 9 could be resolved by
enantioselective HPLC on Chiralpak IC column at 78C.
Because of the absence of the M and P atropisomerism
resulting from the fast rotation around the CꢀꢀN single
bond, the two chromatographic peaks observed were
attributed to the (R) and (S) enantiomers of compound 9.
One of the enantiomers was resolved micropreparatively
to determine the rate of its conversion to its counterpart.
However their interconversion did not take place at 308C,
Chirality DOI 10.1002/chir
Fig. 8. 400 MHz low temperature dynamic NMR study of compound 9
in toluene-d8.

THERMALLY INTERCONVERTIBLE ATROPISOMERS
651
Fig. 9. Part of the 1H NMR spectrum of compound 9 showing the signals of diastereotopic methyl protons on C-5 in the (a) absence and (b) pres-
ence of chiral auxiliary (S)-(1)-1-(9-anthryl)-2,2,2-trifluro ethanol.
The tolyl and naphthyl derivatives (7 and 8) opened by 3% in 100 min and by 2% in 106 min, at 408C for 7 and
very slowly at 308C as revealed by the fact that the 8, respectively. At 508C, however, the oxazolidinone ring
resolved enantiomer interconverted to its counterpart only of 7 and 8 opened because high temperatures generally
Fig. 10. The chromatograms taken to follow the thermal equilibration of the diastereomeric rotational isomers of 12, (a) t 5 0 min, (b) t 5 97 min,
(c) t 5 2117 min, (d) t 5 5451 min, (e) t 5 6332 min (equilibrium), column: Chiralcel OD-H, eluent: 90%:10% (n-hexane:ethanol, v/v), Flow: 0.5 ml/min,
k: 254 nm, a: 1.29 and 1.87 for the minor and major enantiomeric pairs, respectively.
Chirality DOI 10.1002/chir

652
DEMIR-ORDU AND DOGAN
Scheme 4. Interconversion of enantiomeric and diastereomeric isomers of N-(o-aryl)-4-hydroxy-5,5-dimethyl-2-oxazolidinones 7–12 through an alde-
hyde intermediate.
favor the formation of the open chain,12 and then, due to enantiomeric pair in small amount revealed that they were
the higher nucleophilicity of N, together with the gem-di- the (S-P) and (R-M), the initial kinetic products. It was
methyl effect the ring was reformed immediately.
proved that the hemiaminal ring opens and tautomerizes
through an aldehyde intermediate (Scheme 2), and the N
in the aldehyde form favors the less hindered attack to
form more stable isomers (S-M) and (R-P) at 308C. How-
ever, at higher temperatures (788C) sufficient energy
could have been supplied for the attack of N from the
other side to form the less stable (S-P) and (R-M) isomers
MECHANISM OF THE INTERCONVERSION BETWEEN
THE DIASTEREOMERIC N-(O-ARYL)-4-HYDROXY-5,5-
DIMETHYL-2-OXAZOLIDINONES (7–12)
(S-M$S-P/R-P$R-M)
When the product 12 (Fig. 10a) was injected to the (Scheme 4). Therefore upon reflux at 788C in ethanol, the
Chiralcel OD-H column only two isomers (50% each) expected four isomers could be observed. The equilibrium
which were interpreted as enantiomers of each other, compositions of the diastereomeric pairs for compounds
were detected. However, after keeping the solution of 12 7–12 are given in Table 3.
at 788C for 97 min the other pair, minor in amount (Fig.
The diastereomer ratios given in Table 3 revealed the
9b) could be observed. Equilibrium for this interconver- importance of the size of the ortho substituents also on the
sion was reached after 6332 min at 788C (Fig. 9e) having a diastereomer interconversion and thus the steric interfer-
ratio of 94.09%:5.91%. The observation of the newly formed ence between the groups on N and the site to be attacked.
Chirality DOI 10.1002/chir

THERMALLY INTERCONVERTIBLE ATROPISOMERS
653
TABLE 3. The equilibrium compositions of diastereomers of compounds 7-12
Eluent composition,
v/v (n-hexane%:ethanol%)
Flow Rate/
ml min21
Diastereomer ratio at
equilibrium (S-M/R-P%:R-M/S-P%)
Entries
Column
7a
Chiralpak IB
Chiralcel OD-H
–
Chiralpak IB
Chiralcel OD-H
Chiralcel OD-H
90:10
70:30
–
90:10
90:10
90:10
0.7
0.3
–
0.7
0.5
0.5
90.1:9.9
94.8:5.2
50:50
68.0:32.0
94.5:5.5
94.1:5.9
8a
9b
10a
11a
12a
aThe diastereomer interconversion was done at 788C and followed by chiral HPLC.
bThe diastereomer interconversion was followed by temperature dependent NMR.
As chlorine (compound 10) has a smaller van der Waals The interconversion between diastereomeric hemiaminals
radius than bromine and iodine in the halogen series, the (interconversion of (S-M)/(R-P) to (R-M)/(S-P)) took place
attack of N is less hindered compared to other attacks, at higher temperatures (788C) and was found to be affected
forming the less stable isomers in relatively higher equilib- by the size of the ortho substituents.
rium amounts (Table 3). The fixed orientation of the peri
hydrogen of the a-naphthyl for compound 8, probably
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Chirality DOI 10.1002/chir