Dynamic helical chirality of an intramolecularly hydrogen-bonded bisoxazoline

Article abstract of DOI:10.1021/jo026496f

The synthesis and conformational properties of 2,6-bis-[2-((4S)-4-methyl-4,5-dihydro-1,3-oxazol-2- yl)phenyl]carbam oylpyridines, 2, have been described. Bisoxazoline 2a was prepared in five steps from 2-nitrobenzoyl chloride in an overall yield of 71%. In contrast to related structures such as 1, bisoxazoline 2a exhibits a highly biased P-type helical conformation in solution and in the solid state. In the crystal lattice, 2a further assembles into a left-handed helical superstructure aligned along the crystallographic c axis. The barrier to helical interconversion, as measured by line-shape analysis of the temperature-dependent ¹H NMR spectra of thiobenzyl derivative 2b, was determined to be quite low (ΔG? = 12.3 kcal/mol), indicating the presence of a highly dynamic helical chirality.

Full text of DOI:10.1021/jo026496f

Dyn a m ic Helica l Ch ir a lity of a n In tr a m olecu la r ly
Hyd r ogen -Bon d ed Bisoxa zolin e†
Adam J . Preston, Gideon Fraenkel, Albert Chow, J udith C. Gallucci, and J on R. Parquette*
Department of Chemistry, The Ohio State University, Columbus, Ohio 43210
parquett@chemistry.ohio-state.edu
Received September 30, 2002
The synthesis and conformational properties of 2,6-bis-[2-((4S)-4-methyl-4,5-dihydro-1,3-oxazol-2-
yl)phenyl]carbam oylpyridines, 2, have been described. Bisoxazoline 2a was prepared in five steps
from 2-nitrobenzoyl chloride in an overall yield of 71%. In contrast to related structures such as 1,
bisoxazoline 2a exhibits a highly biased P-type helical conformation in solution and in the solid
state. In the crystal lattice, 2a further assembles into a left-handed helical superstructure aligned
along the crystallographic c axis. The barrier to helical interconversion, as measured by line-shape
1
analysis of the temperature-dependent H NMR spectra of thiobenzyl derivative 2b, was determined
to be quite low (∆Gq ) 12.3 kcal/mol), indicating the presence of a highly dynamic helical chirality.
In tr od u ction
ity based on the presence of a dynamic and highly biased
conformational equilibrium have potential to serve as
molecular scaffolds upon which to build structural adapt-
ability into functional materials.
The helix represents an important example of confor-
mational chirality that is ubiquitous in the structure of
biomolecules1 and extensively exploited in asymmetric
catalysis.2 Conformational chirality has been observed
primarily in compounds displaying atropisomerism such
as helicenes,3 substituted biphenyls,4 1,1′-bi-2-binaphyls,5
molecular propellers,6 “gela¨nder” molecules,7 transition-
metal complexes,8 and cyclophanes.9 Occasionally, com-
pounds having chiral conformations with low barriers to
racemization spontaneously resolve during crystallization
into a single conformational enantiomer but racemize in
solution.10 Although the use of highly rigid, preorganized
structures in functional materials and supramolecular
chemistry has been a successful design strategy, it has
recently been suggested that overly constrained synthetic
catalysts and receptors are less effective, because in these
rigid systems binding affinity and specificity are inter-
dependent.11 Therefore, molecules exhibiting helical chiral-
Pyridine-2,6-dicarboxamides exist primarily in the
syn,syn conformation, because this conformation places
the amide NH groups in close proximity to the pyridine-
N, which permits intramolecular hydrogen-bonding in-
teractions to occur. Further, this orientation of the
amides minimizes the repulsive electrostatic interactions
between the amide oxygens.12 This conformational pref-
erence has been exploited as a scaffold to create helical
structures, because groups linked through the carbox-
amides are constrained in a manner that positions them
above and below the plane of the pyridine moiety,
resulting in a local helical structure.13 However, inter-
conversion between the helical antipodes is fast relative
to the NMR time scale, and chiral derivatives have not
exhibited a significant helical diastereomic bias in solu-
tion.14
Structure 1 folds into a helical conformation due to
hydrogen-bonding of the amide N-H’s with the pyr-N
and carbonyl oxygens (Chart 1). In solution, we observed
† Dedicated to the honor and memory of Prof. Henry Rapoport.
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10.1021/jo026496f CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/04/2002
22
J . Org. Chem. 2003, 68, 22-26

Dynamic Helical Chirality of a Bisoxazoline
CHART 1
low temperature, the methylene hydrogens of the thioben-
zyl group appear as a well-defined AB quartet due to the
global helical conformation of the molecule. Interestingly,
at temperatures where the rate of helical interconversion
was slow on the NMR time scale, only a single helical
diastereomer was evident, indicating an extremely biased
conformational equilibrium. Increasing temperature
caused the AB quartet to gradually coalesce into a singlet,
consistent with the progressive averaging of the two
protons undergoing A-B exchange due to an MSP
helical interconversion. However, both the A and B
proton chemical shifts as well as the difference between
them (δA - δB) varied with temperature. Therefore, to
calculate the rate constants for interconversion it was
necessary to estimate the intrinsic δA - δB at a temper-
ature where signal averaging was observed.18 This was
done by plotting the observed δA - δB values over the
temperature range in which an AB spectrum could be
discerned (-90 f -20 °C) and then extrapolating to a
temperature at which A-B averaging takes place
(-10 °C). A-B line shapes were then calculated as a
function of k1, the rate constant for helical interconver-
sion, using the extrapolated δA - δB value and the ob-
served J A-B coupling constant (12.76 Hz).18 Matching the
experimental and calculated NMR spectra provided the
first-order rate constant for helical interconversion (k1
) 345 s-1). This rate constant corresponds to a ∆Gq value
of 12.3 kcal for the barrier to helical interconversion.
Therefore, the helical diastereomers rapidly interconvert
at ambient temperature.
Cir cu la r Dich r oism . Absolu te Ster eoch em istr y of
Helica l Str u ctu r e. The stereochemistry of the helical
bias in solution was determined by circular dichroism
(CD) spectroscopy (Figure 2). The ultraviolet (UV) spec-
trum of 2a in acetonitrile displayed absorptions at 216,
253, and 309 nm. Accordingly, the CD spectrum of 2a in
acetonitrile showed a positive Cotton effect (CE) at 216
nm, a negative CE at 253 nm, and a bisignet couplet
having a negative CE at 300 nm, a positive CE at 328,
and a zero-crossing at 309 nm. The peaks at 216 and 253
nm are simple CEs associated with the corresponding
transitions in the UV spectra at 216 and 256 nm,
respectively. The bisignet couplet centered at 309 nm
shows excitonic splitting with positive chirality, as
defined by Nakanishi and Harada.19
a chiral helical bias only when this structure was
incorporated as a peripheral unit in dendrimers rigidified
through hydrogen bonding.15 The conformational chirality
that occurs in dendrimers, but not in the monomer 1, was
attributed to the correlated molecular motion that occurs
at the periphery of the dendrimers, which increased the
energetic difference between the helical antipodes. The
goal of the current research was directed at developing
low molecular weight molecules displaying dynamically
biased, helical conformations, which also may potentially
serve as ligands for transition metals. We reasoned that
rigidifying the helical conformation by replacing the
amide carbonyls, which interact with the N-H’s via a
relatively weak dO‚‚‚H-N H-bond, with oxazoline moi-
eties capable of stronger dN‚‚‚H-N H-bonding interac-
tions, as shown in structure 2, would lead to greater
helical bias. Furthermore, molecular modeling studies
suggested that in the lowest energy conformation, the
methyl substituents of the oxazoline groups interact more
strongly in the M than in the P helical conformation.16
Resu lts a n d Discu ssion
Syn th esis. Bisoxazoline 2a was prepared in five steps
with an overall yield of 71% from 2-nitrobenzoyl chloride
(Scheme 1). Synthesis proceeded by amidation of 2-ni-
trobenzoyl chloride with L-alaninol followed by chlorina-
tion of the resultant alcohol, 4a , with thionyl chloride
affording chloride 4b. Ring closure with sodium hydride
to oxazoline 5a , reduction of the nitro function by
hydrogenation over Pd-C, and final reaction with 4-chlo-
N-[2-(4-Methyl-4,5-dihydrooxazol-2-yl)phenyl]aceta-
mide (6) also exhibited a transition in the UV spectrum
at 309 nm, indicating that this chromophore was respon-
sible for the transition at 309 nm for 2a . Time-dependent
density-functional (TDDFT) methods20 were applied to
6, using the three-parameter Lee-Yang-Parr (B3LYP)
functional21 and the 6-31g* basis set, to model the
2-acylaminophenyl oxazoline moieties of 2a responsible
for the transition at 309 nm (Figure 3). Prior to perform-
ing the TDDFT electronic structure calculations, the
geometry of 6 was optimized using the B3LYP functional
also employing the 6-31g* basis set.22 The lowest energy
transition corresponded to a πfπ* transition at 296 nm,
in reasonable agreement with the experimental value of
1
ropyridine-2,6-dicarbonyl dichloride afforded 2a . The H
NMR spectrum of 2a in CDCl3 was consistent with the
presence of stronger hydrogen-bonding interactions be-
tween the N-H’s and the dN of the oxazolines relative
to the dO of the carbonyls in 1. Whereas for 1 a single
resonance was observed for the N-H’s at 12.7 ppm,17 2a
exhibited a low-field resonance for the N-H’s at 13.7
ppm.
Solu tion Str u ctu r e. Helica l In ter con ver sion Ba r -
r ier . The fluxional nature of the molecule was evident
1
in the H NMR spectrum of 2b in THF-d8 (Figure 1). At
(15) (a) Recker, J .; Tomcik, D. J .; Parquette, J . R. J . Am. Chem. Soc.
2000, 122, 10298.(b) Huang, B.; Parquette, J . R. J . Am. Chem. Soc.
2001, 123, 2689.
(16) A Monte Carlo conformational search using the MM2* force
field as implemented in Macromodel 6.0 predicted that the P helical
conformation was favored over the M helix by 0.8 kcal/mol.
(17) Huang, B.; Parquette, J . R. Org. Lett. 2000, 2, 239.
(18) Kaplan, J . I.; Fraenkel, G. NMR of Chemically Exchanging
Systems; Academic Press: New York, 1960; pp 101-104.
(19) Harada, N.; Nakanishi, K. O. Circular Dichroic Spectroscopy:
Exciton Coupling in Organic Stereochemistry; University Science
Books: Mill Valley, CA, 1983.
J . Org. Chem, Vol. 68, No. 1, 2003 23

Preston et al.
SCHEME 1a
a
Reagents: (a) (S)-2-amino-1-propanol, CH2Cl2, (C2H5)3N. (b) SOCl2, CHCl3, reflux. (c) NaH, THF. (d) H2/Pd-C, EtOAc. (e) Ac2O,
CH2Cl2, (C2H5)3N, DMAP (cat.). (f) 4-Chloropyridine-2,6-dicarbonyl dichloride, Pyr-CH2Cl2. (g) PhCH2SH, NaH, THF.
F IGURE 2. UV (arbitrary scale) and molar CD spectra of 2a
in acetonitrile.
F IGURE 1. Temperature-dependent 1H NMR spectra of 2b
in THF-d8.
this electronic absorption. Inspection of the excitations
that contribute to the transition at 296 nm indicates that
the transition is dominated by an excitation that pro-
motes an electron from a π molecular orbital (MO 58) to
F IGURE 3. Molecular orbitals and electric transition dipole
moment of the πfπ* transition at 309 nm, calculated by
TDDFT using the 6-31g* basis set.
(20) The TDDFT-B3LYP calculations were run as implemented in
M. J . Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb,
J . R. Cheeseman, V. G. Zakrzewski, J . A. Montgomery, J r., R. E.
Stratmann, J . C. Burant, S. Dapprich, J . M. Millam, A. D. Daniels, K.
N. Kudin, M. C. Strain, O. Farkas, J . Tomasi, V. Barone, M. Cossi, R.
Cammi, B. Mennucci, C. Pomelli, C. Adamo, S. Clifford, J . Ochterski,
G. A. Petersson, P. Y. Ayala, Q. Cui, K. Morokuma, D. K. Malick, A.
D. Rabuck, K. Raghavachari, J . B. Foresman, J . Cioslowski, J . V. Ortiz,
A. G. Baboul, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I.
Komaromi, R. Gomperts, R. L. Martin, D. J . Fox, T. Keith, M. A. Al-
Laham, C. Y. Peng, A. Nanayakkara, M. Challacombe, P. M. W. Gill,
B. J ohnson, W. Chen, M. W. Wong, J . L. Andres, C. Gonzalez, M. Head-
Gordon, E. S. Replogle, and J . A. Pople, Gaussian 98, Revision A.7.;
Gaussian, Inc.: Pittsburgh, PA, 1998.
a π* orbital (MO 59). The electric transition dipole
moment runs approximately along the axis containing
C-3 and C-6 of 6, as shown in Figure 3. Therefore, the
(21) (a) Bauernschmitt, R.; Ahlrichs, R. Chem. Phys. Lett. 1996, 256,
454. (b) Stratmann, R. E.; Scuseria, G. E.; Frisch, M. J . J . Chem. Phys.
1998, 109, 8218. (c) Foresman, J . B.; Head-Gordon, M.; Pople, J . A.;
Frisch, M. J . J . Phys. Chem. 1992, 96, 135.
(22) Hehre, W. J .; Radom, L.; Schleyer, P. V. R.; Pople, J . A. Ab initio
Molecular Orbital Theory; J ohn Wiley & Sons: New York, 1986.
24 J . Org. Chem., Vol. 68, No. 1, 2003

Dynamic Helical Chirality of a Bisoxazoline
Exp er im en ta l Section
Gen er a l. Melting points were determined in open capillar-
ies and are uncorrected. 1H NMR spectra were recorded at 400
MHz and 13C NMR spectra at 100 MHz. Electrospray mass
spectra were recorded at The Ohio State University Chemical
Instrument Center. Circular dichroism (CD) measurements
were carried out using optical grade solvents and quartz glass
cuvettes with a 10 mm path length. All reactions were per-
formed under an argon or nitrogen atmosphere. Dimethylfor-
mamide (DMF) was dried by distillation from activated 4 Å
sieves; THF was distilled from sodium/benzophenone ketyl;
pyridine, triethylamine, and dichloromethane were distilled
from calcium hydride; and CHCl3 was distilled from CaCl2.
Chromatographic separations were performed on silica gel 60
(230-400 mesh, 60 Å) using the indicated solvents.
N-(2-H yd r oxy-(1S)-1-m et h ylet h yl)-2-n it r ob en za m id e
(4a ). 2-Nitrobenzoyl chloride was prepared by adding oxalyl
chloride (1.27 g, 0.87 mL, 10.0 mmol) to a solution of 2-ni-
trobenzoic acid (0.84 g, 5.00 mmol) and DMF (2 drops) in CH2-
Cl2 (10 mL). After stirring for 2 h, the solution became
homogeneous and was concentrated in vacuo. The residue was
dissolved in CH2Cl2 (2 × 5 mL) and added over the course of
1 h to a solution of S-(+)-2-amino-1-propanol (0.45 g, 467 µL,
6.00 mmol), Et3N (1.5 g, 2.1 mL, 15.0 mmol), and 4 Å molecular
sieves (ca 0.5 g) in CH2Cl2 (20 mL) at 0 °C. The reaction was
allowed to warm to ambient temperature over 2 h. The
molecular sieves were removed by filtration, and the solution
was concentrated. The resultant residue was purified by
column chromatography on silica using 50% CH2Cl2/EtOAc.
Product was isolated as a white crystalline solid (1.06 g, 4.73
mmol, 94%): mp 90-91 °C (CH2Cl2); 1H NMR (CDCl3) δ 1.32
(d, J ) 6.9 Hz, 3H), 2.24 (t, J ) 5.6 Hz, 1H), 3.68 (m, 1H),
3.87 (m, 1H), 4.29 (m, 1H), 6.00 (s, 1H), 7.56 (td, J ) 1.5, 5.8
Hz, 1H), 7.60 (dd, J ) 1.4, 8.1 Hz, 1H), 7.69 (td, J ) 1.2, 7.45
Hz, 1H), 8.09 (dd, J ) 1.1, 8.2 Hz1H); 13C NMR (CDCl3) δ 16.6,
48.2, 65.9, 124.5, 128.8, 130.4, 133.0, 133.8, 146.2, 166.7;
HRMS (ES) m/z [Na]+ 247.0689 (calcd for C10H12N2O4Na+
247.0689).
N-(2-Ch lor o-(1S)-1-m eth yleth yl)-2-n itr oben zam ide (4b).
To a solution of 4a (0.99 g, 4.39 mmol) in CHCl3 (24 mL) was
added SOCl2 (1.05 g, 641 µL, 8.79 mmol). The reaction was
heated at reflux for 30 min. The reaction was cooled to room
temperature and concentrated under vacuum. The resultant
residue was purified by column chromatography on silica using
2% EtOAc/CH2Cl2, affording the product as a white solid (1.03
g, 4.24 mmol, 97%): mp 113-114 °C (CH2Cl2); 1H NMR
(CDCl3) δ 1.39 (d, J ) 6.7 Hz, 3H), 3.70 (dd, J ) 3.4, 11.2 Hz,
1H), 3.88 (dd, J ) 4.2, 11.2 Hz, 1H), 4.58 (m, 1H), 6.00 (d, J )
6.3 Hz, 1H) 7.53 (dd, J ) 1.4, 7.5 Hz, 1H) 7.60 (td, J ) 1.5, 7.8
Hz, 1H), 7.69 (td, J ) 1.2, 7.5 Hz, 1H), 8.09 (dd, 1.0, 8.2 Hz,
1H); 13C NMR (CDCl3) δ 17.5, 46.1, 48.9, 124.6, 128.7, 130.6,
132.7, 133.8, 146.3, 166.0; HRMS (ES) m/z [Na]+ 265.0367
(calcd for C10H11ClN2O3Na+ 265.0350).
F IGURE 4. Interconversion between M and P helical confor-
mations: the relative orientation of electric transition moments
(positive chirality) indicates P helical conformational bias.
absolute sense of helical chirality relating the 2-acylami-
nophenyl oxazoline chromophores in solution can be
assigned to be P, as shown in Figure 4 using the exciton
chirality method pneumonic. The insensitivity of the
couplet to temperature indicates that a highly biased
helical secondary structure is present in 2a .
Solid -Sta te Con for m a tion . A clear, tetragonal crys-
tal in space group P41 was obtained for 2a by crystal-
lization from CH2Cl2/EtOAc.23 X-ray diffraction showed
that the asymmetric unit was composed of two virtually
identical molecules exhibiting P helical chirality, in
agreement with the CD studies (Figure 5). This helical
conformation is induced by four hydrogen-bonding inter-
actions between the pyridyl amide NH’s and both the
pyridine-N, with an average N-N distance of 2.685 Å,
and the oxazoline-N’s with an average N-N distance of
2.704 Å. These hydrogen-bonding interactions force the
oxazoline rings to be placed in a face-to-face stacked
arrangement that projects the methyl substituents above
and below the plane of the helix, resulting in a P helical
chirality. In the crystal lattice, 2a further assembles into
a left-handed helix aligned along the crystallographic c
axis.24 The helical superstructure is primarily stabilized
by edge-to-face stacking interactions between the 2-acyl-
aminophenyl rings of adjacent asymmetric units, with
an average Cedge-Cface distance of 3.74 Å. Presumably for
electrostatic reasons, the two molecules of the asym-
metric unit are packed in an arrangement orienting the
C-Cl bond of one molecule antiparallel to a pyridyl amide
CdO bond of the other molecule having (Cl)C‚‚‚O(dC)
and (C)Cl‚‚‚C(dO) distances of 3.463 and 3.622 Å,
respectively.
Con clu sion
(4S )-4-Me t h yl-2-(2-n it r op h e n yl)-4,5-d ih yd r o-1,3-ox-
a zole (5a ). To a suspension of NaH (0.34 g, 8.50 mmol, 60%
dispersion in oil) in THF (11 mL) was slowly added a solution
of 4b (1.03 g, 4.25 mmol) in THF (10 mL). The reaction was
stirred at room temperature for 1 h and then filtered to remove
salts and concentrated. The resultant residue was purified by
column chromatography on silica using 2% EtOAc/CH2Cl2,
affording the product as a colorless oil (0.80 g, 3.87 mmol,
91%): 1H NMR (CDCl3) δ 1.37 (d, J ) 6.6 Hz, 3H), 3.97 (t, J
) 7.8 Hz, 1H), 4.39 (m, 1H), 4.51 (dd, J ) 8.0, 9.2 Hz, 1H),
7.59 (td, J ) 1.8, 7.7 Hz, 1H), 7.63 (td, J ) 1.6, 7.5 Hz, 1H),
7.81 (dd, J ) 1.8, 7.6 Hz, 1H), 7.84 (dd, J ) 1.7, 7.7 Hz, 1H);
13C NMR (CDCl3) δ 20.9, 62.3, 75.0, 123.4, 123.8, 130.9, 131.3,
132.4, 149.1, 160.9; HRMS (ES) m/z [Na]+ 229.0571 (calcd for
We conclude that the increased structural rigidity
imparted to bisoxazoline 2 by the stronger intramolecular
dN‚‚‚H-N H-bonding interactions, relative to 1, causes
a highly biased helical equilibrium to develop at low
molecular weights. Although the low barrier to helical
interconversion produces a highly dynamic conforma-
tional equilibrium at ambient temperature, a strong bias
for the P helical sense is present in solution and in the
solid state. We are currently investigating the confor-
mational and catalytic properties of associated metal
complexes of 2.
C
10H10N2O3Na+ 229.0584).
(23) Crystallographic information: T ) 150(2) K; P41, a ) 8.951(1)
Å, c ) 61.611(1) Å.; V ) 4935.9(8) Å3; Z ) 8; 8656 unique data; R1(F)
) 0.029, wR2(F2) ) 0.053; GOF ) 1.044.
2-[(4S)-4-Meth yl-4,5-dih ydr o-1,3-oxazol-2-yl]an ilin e (5b).
To a solution of 5a (0.77 g, 3.72 mmol) in EtOAc (18.6 mL)
was added Pd/C (0.08 g). The reaction was placed under an
(24) For related, solid-state helical superstructures, see ref 14a,f.
J . Org. Chem, Vol. 68, No. 1, 2003 25

Preston et al.
F IGURE 5. X-ray crystal structure of 2a (left) and stereodepiction of associated crystal lattice (right).
atmosphere of H2 (balloon) and stirred for 20 h. The reaction
was filtered through Celite to remove Pd/C and concentrated.
The resultant residue was purified by column chromatography
on silica using 5% EtOAc/hexanes, affording the product as a
colorless oil (0.58 g, 3.31 mmol, 89%): 1H NMR (CDCl3) δ 1.35
(d, J ) 6.5 Hz, 3H), 3.85 (m, 1H), 4.43 (m, 2H,), 6.08 (bs, 2H),
6.66 (ddd, J ) 1.1, 7.3, 8.1 Hz, 1H), 6.70 (dd, J ) 0.9, 8.2 Hz,
1H), 7.20 (ddd, J ) 1.6, 7.2, 8.5 Hz, 1H), 7.69 (dd, J ) 1.5, 7.9
Hz, 1H); 13C NMR (CDCl3) δ 21.7, 62.1, 72.2, 109.2, 115.6,
116.0, 129.5, 131.9, 148.5, 163.5; HRMS (ES) m/z [H]+ 177.1028
(calcd for C10H13N2O+ 177.1022).
purified by column chromatography on silica with 10% EtOAc/
hexanes, affording the product as a white glassy solid (44.0
mg, 0.073 mmol, 72%): mp 174-175 °C (CH2Cl2); 1H NMR
(CDCl3) δ 1.00 (d, J ) 6.6 Hz, 6H), 3.67 (t, J ) 8.2 Hz, 2H),
3.95 (m, 2H), 4.24 (dd, J ) 8.1, 1.1 Hz, 2H), 4.38 (s, 2H), 7.17
(td, J ) 1.0, 7.6 Hz, 2H), 7.30 (bt, J ) 7.3 Hz, 1H), 7.37 (t, J
) 7.4 Hz, 2H), 7.48 (d, J ) 7.3 Hz, 2H), 7.56 (td, J ) 1.5, 7.9
Hz, 2H), 7.89 (dd, J ) 1.5, 7.9 Hz, 2H), 8.25 (s, 2H), 8.92 (dd,
J ) 0.6, 8.3 Hz, 2H), 13.62 (s, 2H); 13C NMR (CDCl3) δ 20.9,
35.8, 62.1, 72.7, 115.0, 120.6, 121.4, 123.1, 127.9, 128.9, 129.2,
132.2, 135.0, 139.0, 150.0, 153.3, 162.0, 163.3; HRMS (ES) m/z
[Na]+ 628.1998 (calcd for C34H31N5O4SNa+, 628.1989).
4-Ch lor o-2,6-bis[2-((4S)-4-m eth yl-4,5-dih ydr o-1,3-oxazol-
2-yl)p h en yl]ca r ba m oylp yr id in e (2a ). To a stirred solution
of 5b (0.16 g, 0.92 mmol) in CH2Cl2 (4 mL) and pyridine (1
mL) with activated 4 Å sieves was added 4-chloropyridine-
2,6-dicarbonyl chloride (0.11 g, 0.46 mmol). The reaction was
stirred at room temperature for 3 h and then filtered to remove
sieves and concentrated. The resultant residue was dissolved
in CH2Cl2 (50 mL) and washed with saturated NaHCO3 (50
mL). The aqueous layer was back-extracted with CH2Cl2 (2 ×
25 mL), and the organic phases were combined, dried over
MgSO4, filtered, and concentrated, affording product as a white
crystalline solid (0.23 g, 0.44 mmol, 96%). The crude product
was determined to be of high purity by TLC (10% EtOAc/
hexanes) and 1H NMR (further purification can be achieved
by column chromatography on silica using 10% EtOAc/hex-
N-[2-((4S)-4-Meth yl-4,5-d ih yd r ooxa zol-2-yl)p h en yl]a c-
eta m id e (6). To a solution of 5b (36 mg, 0.21 mmol), DMAP
(3.0 mg, 0.025 mmol), and Et3N (6.2 mg, 86 µL, 0.62 mmol) in
CH2Cl2 (1 mL) at 0 °C was added acetic anhydride (42.0 mg,
39 µL, 0.41 mmol). The reaction warmed to room temperature
over 27 h and then was concentrated in vacuo. The resultant
residue was purified by column chromatography on silica
with 10% EtOAc/hexanes, affording the product as a white
crystalline solid (17.0 mg, 0.078 mmol, 38%): mp 70-71 °C
(CH2Cl2); 1H NMR (CDCl3) δ 1.39 (d, J ) 6.5 Hz, 3H), 2.22 (s,
3H), 3.92 (m, 1H), 4.48 (m, 2H), 7.07 (td, J ) 1.2, 7.6 Hz, 1H),
7.46 (td, J ) 1.6, 7.9 Hz, 1H) 7.84 (dd, J ) 1.6, 7.9 Hz, 1H),
8.72 (dd, J ) 0.85, 8.5 Hz, 1H), 12.24 (s, 1H); 13C NMR (CDCl3)
δ 21.6, 25.3, 62.0, 72.0, 113.0, 119.6, 122.1, 129.1, 132.5, 140.0,
163.4, 169.2; HRMS (ES) m/z [Na]+ 241.0941 (calcd for
1
anes): mp 161-162 °C (CH2Cl2); H NMR (CDCl3) δ 1.00 (d,
C
12H14N2O2Na+, 241.0947).
J ) 6.6 Hz, 6H), 3.70 (t, J ) 8.2 Hz, 2H), 3.95 (m, 2H), 4.26 (t,
J ) 8.7 Hz, 2H), 7.19 (t, J ) 7.7 Hz, 2H), 7.57 (td, J ) 1.6, 7.9
Hz, 2H), 7.89 (dd, J ) 1.5, 7.8 Hz, 2H), 8.40 (s, 2H) 8.92 (d, J
) 8.3 Hz, 2H), 13.72 (s, 2H); 13C NMR (CDCl3) δ 20.9, 62.1,
72.7, 115.0, 120.6, 123.3, 125.5, 129.3, 132.4, 138.9, 147.5,
151.9, 162.1, 162.4; HRMS (ES) m/z [Na]+ 540.1404 (calcd for
Ack n ow led gm en t. This work was supported by the
National Science Foundation NSE program (CHE-
0103133). Acknowledgment is also made to the donors
of the Petroleum Research Fund, administered by the
American Chemical Society for partial support of this
work.
C
27H24ClN5O4Na+, 540.1410). Anal. Calcd for C27H24ClN5O4:
C, 62.61; H, 4.67; N, 13.52. Found: C, 62.37; H, 4.72; N, 13.33.
4-Th ioben zyl-2,6-bis[2-((4S)-4-m eth yl-4,5-d ih yd r o-1,3-
oxa zol-2-yl)p h en yl]ca r ba m oylp yr id in e (2b). To a suspen-
sion of NaH (24 mg, 0.59 mmol, 60% dispersion in oil) in THF
(0.5 mL) was added benzyl mercaptan (50.0 mg, 47 µL, 0.40
mmol). The reaction was stirred for 30 min, then a solution of
2a (52.0 mg, 0.10 mmol) in THF (0.5 mL) was added and the
reaction heated to 50 °C for 14 h. The reaction was filtered to
remove salts and concentrated. The resultant residue was
Su p p or tin g In for m a tion Ava ila ble: Tables of X-ray
structural data and ORTEP diagrams for 2a , Gaussian output
for the TDDFT calculations of 6, and 1H NMR spectra for all
new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
J O026496F
26 J . Org. Chem., Vol. 68, No. 1, 2003