Synthesis, copper(II) complexes and catalytic activity of substituted 6-(1,3-oxazolin-2-yl)pyridine-2-carboxylates

Article abstract of DOI:10.1007/s11243-010-9336-3

The optically pure 6-(4-alkyl-4,5-dihydro-1,3-oxazol-2-yl)pyridine-2- carboxylates have been prepared from 6-methoxycarbonylpyridine-2-carboxylic acid by a sequence of three reactions with the overall yield of 40-50%. Some of these compounds form stable complexes with Cu(II) ions in non-aqueous medium. Their polymeric structure was determined in the solid phase by X-ray diffraction analysis. The Cu(II) complexes were also used as catalysts for addition reactions of terminal alkynes to imines giving substituted propargylamines with maximum yield 64% and 37% ee. Springer Science+Business Media B.V. 2010.

Full text of DOI:10.1007/s11243-010-9336-3

Transition Met Chem (2010) 35:363–371
DOI 10.1007/s11243-010-9336-3
Synthesis, copper(II) complexes and catalytic activity
of substituted 6-(1,3-oxazolin-2-yl)pyridine-2-carboxylates
•
Pavel Drabina Petr Funk Ales Ruzicka
•
•
ˇ
˚ ˇ ˇ
•
Jirı Hanusek Milos Sedlak
ˇ´
ˇ
´
Received: 25 November 2009 / Accepted: 4 February 2010 / Published online: 18 February 2010
Ó Springer Science+Business Media B.V. 2010
Abstract The optically pure 6-(4-alkyl-4,5-dihydro-1,3-
oxazol-2-yl)pyridine-2-carboxylates have been prepared
from 6-methoxycarbonylpyridine-2-carboxylic acid by a
sequence of three reactions with the overall yield of 40–
50%. Some of these compounds form stable complexes
with Cu(II) ions in non-aqueous medium. Their polymeric
structure was determined in the solid phase by X-ray dif-
fraction analysis. The Cu(II) complexes were also used as
catalysts for addition reactions of terminal alkynes to
imines giving substituted propargylamines with maximum
yield 64% and 37% ee.
The aim of this work is to prepare such analogues of
pybox ligands, in which one of the oxazoline rings is
replaced by the carboxylic group (Scheme 1). These new
tridentate oxazoline ligands 2a–e and 3a–c should form
stable complexes containing covalent and coordina-
tion bonds with transition metal ions. Therefore such
complexes should be more stable in comparison with
common pybox complexes. It is well known the stability
of a complex is a very significant factor that fundamen-
tally affects its enantioselectivity in asymmetric syntheses
[1–8].
Therefore we have also studied the coordination proper-
ties of 3a–c with Cu(II), because such complexes can be used
as enantioselective catalysts [12, 13]. Finally this work
represents a continuation and supplementation of our pre-
vious studies concerning Cu(I)/Cu(II) complexes of 4,5-
dihydro-1H-imidazol-5-ones, which were used as homoge-
neous catalysts in some asymmetric reactions [14–17].
Introduction
The oxazoline derivatives prepared from chiral optically
pure amino alcohols belong among the best known ligands
applied in enantioselective catalysis [1–6]. The most fre-
quently used oxazoline-based N,N,N-tridentate ligands are
so-called ‘‘pyboxes’’ [7, 8] in which two oxazoline rings
are bound to the pyridine at the 2- and 6-positions. These
ligands exhibit the C2 symmetry predominantly. Literature
[9–11] describes only a few derivatives in which two
substituted oxazoline rings carrying different substituents
are bound to the pyridine ring.
Results and discussion
Preparation and characterization of 6-(4,5-dihydro-1,
3-oxazolin-2-yl)pyridine-2-carboxylates
The starting 6-methoxycarbonylpyridine-2-carboxylic acid
was prepared by a procedure suggested by Schmuck [18] in
a good yield (75%). After activation of the 6-methox-
ycarbonylpyridine-2-carboxylic acid with ethyl chlorofor-
mate in the presence of triethylamine, we carried out
acylation of corresponding chiral 2-aminoalcohols to give
the respective amides 1a–e. In our case it was necessary to
change the order of addition of the reactants, as compared
with the classical procedure [19] in which the respective
amine is added to an excess of activated acid. The reverse
´
P. Drabina (&) ꢀ P. Funk ꢀ J. Hanusek ꢀ M. Sedlak
Institute of Organic Chemistry and Technology,
Faculty of Chemical Technology, University of Pardubice,
´
Studentska 573, 53210 Pardubice, Czech Republic
e-mail: pavel.drabina@upce.cz
ˇ
˚ˇ
A. Ruzicka
Department of General and Inorganic Chemistry,
Faculty of Chemical Technology, University of Pardubice,
´
Studentska 573, 53210 Pardubice, Czech Republic
123

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Transition Met Chem (2010) 35:363–371
Scheme 1 For 1–2: R = Et (a);
i-Pr (b); i-Bu (c); t-Bu (d); Ph
(e). X = Cl (a); Br (b). For 3:
M = Li (a); Na (b); K (c)
procedure [20], in which the activated acid is slowly added
to a slight excess of 2-aminoalcohol at low temperature,
prevents undesirable acylation of the hydroxyl group.
The amides 1a–e prepared in this way were then sub-
mitted to ring closure reaction which gave the oxazolines
2a–e. References [7, 8, 21–31] describe many synthetic
procedures using various reagents, however, these reagents
sometimes fail in oxazoline synthesis. For example fre-
quently used thionyl chloride [21, 24, 26, 27] provides the
respective chloro derivative which unfortunately does not
undergo required intramolecular ring closure reaction in
our case. The ring closure reaction of 1a–e was successful
only after activation of hydroxyl group with mesyl chloride
(1.3 equivalent) in combination with excess triethylamine
(ca 5 equivalents) [20]. In order to achieve full conversion,
it was necessary to reflux the reaction mixture in dichlo-
romethane for 3 days. Recrystallization from cyclohexane
gave oxazolines 2a–e in yields of ca 70%.
Fig. 1 ORTEP representation of structure of compound 2a
N-benzylideneaniline (Scheme 2). This reaction belongs
among C–C couplings producing chiral propargylamines
which represent important intermediates in synthesis of
various chiral nitrogen compounds (heterocyclic, in par-
ticular) [32–36]. It is well known [37] that Cu(I) complexes
are highly efficient catalysts in this reaction. The chemical
and optical yield of this addition reaction is also affected
by the solvent used. Therefore, our studies were focused
not only on mutual comparison of enantioselective prop-
erties of individual derivatives 2a–e, but also on finding a
suitable solvent affording acceptable chemical/optical
yield.
The last step in the synthesis of 3a–c was alkaline
hydrolysis of ester 2b in methanolic solutions of alkali
hydroxides (LiOH, NaOH, KOH). The carboxylates 3a–c
were obtained in quantitative yields. The free carboxylic
acid prepared by subsequent acidification of 3a–c is very
unstable and undergoes fast acid-catalyzed solvolysis of
the oxazoline ring.
All the prepared substances 1–3 were characterized by
melting points, elemental analyses, 1H and 13C NMR
spectroscopy, and specific optical rotation. Compounds 1–2
were also characterized by mass spectrometry, and the
structure of compound 2a in the solid phase was deter-
mined by X-ray diffraction analysis (Fig. 1).
A survey of all the experiments performed is presented
in Table 1. It was found that the reaction does not take
place in N-coordinating solvents (DMF and MeCN)
(entries 1 and 2) probably preventing necessary coordina-
tion of reactants to the chiral Cu(I) complex. In O-coor-
dinating solvents (MeOH, THF, MTB) (entries 3–5), the
reaction gives low chemical as well as optical yields (4–
14% ee). On the other hand, in non-coordinating solvents
(CH2Cl2, CHCl3, toluene), the chemical yields were
increased and also the enantiomeric excess (entries 6–8)
was better. Moreover in all the non-coordinating solvents
Enantioselective addition of phenylacetylene to
N-benzylideneaniline
Chiral ligands 2a–e were tested as enantioselective cata-
lysts for asymmetric addition of phenylacetylene to
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Transition Met Chem (2010) 35:363–371
365
Scheme 2 Asymmetric
addition of phenylacetylene to
N-benzylideneaniline catalyzed
by 2a–e/CuOTf complexes
Table 1 Results of catalytic experiments
carboxylate. Unfortunately no catalytic activity of 3a–c
complexes was observed during addition of phenylacety-
lene to N-benzylideneaniline. Therefore we extended our
studies of enantioselectivity to Henry reaction of 4-nitro-
benzaldehyde and nitromethane which is usually catalyzed
by Cu(II) complexes [43–47]. Although the chemical yield
of this reaction was almost quantitative with Cu(II) com-
plexes of 3a–c, no enantiomeric excess was obtained.
Therefore we have studied coordination properties of 3a–c.
Elemental analysis showed that compounds 3a–c forms
complexes with copper(II) halides in the ratio 1:1 and only
one halogen atom is present in the complex molecule. This
suggests that only one halogen atom is substituted by the
carboxylate. The same results were obtained with two
equivalents of ligands 3a–c per one equivalent of cop-
per(II) halogenide.
Entry Ligand Solvent
Time [d] Yield % ee %
1
2b
2b
2b
2b
2b
2b
2b
2b
2a
2c
2d
2e
MeCN
14
14
–
–
–
–
2
DMF
3
MeOH
4.5
22
43
31
33
40
64
21
40
24
38
-4
4
THF
5
2
2
7
6
4
6
6
6
-14
-8
5
MTB/THF 4:1
CH2Cl2/toluene 1:1
CHCl3
6
?18
?22
?37
?2
7
8
CH2Cl2
9
CH2Cl2
10
11
12
CH2Cl2
?11
-6
CH2Cl2
CH2Cl2
?31
Complexes 4a–b were prepared from 3a–c and cop-
per(II) chloride or bromide in isopropyl alcohol as solvent.
In the case of 3b–c where the less soluble sodium or
potassium bromides and chlorides precipitate from iso-
propyl alcohol, addition of corresponding crown ether was
necessary (‘‘Experimental section’’).
the predominant enantiomer of the product had opposite
configuration (as also observed in Ref. [38–42]) as com-
pared with O-coordinating solvents. Dichloromethane was
found to be the most appropriate solvent: the absolute
values of enantiomeric excess reached 37% ee.
Single crystals of 4a–b were obtained from their satu-
rated methanolic solutions by very slow precipitation with
ethyl acetate. The ORTEP diagrams of complexes 4a–b
(Fig. 2) show that both complexes have almost the same
arrangement. The copper atom is coordinated with five
ligands (not four as expected for a single complex mole-
cule) to form a slightly deformed tetragonal pyramid
(SPY), whose top is occupied by a halogen atom of the
neighboring complex molecule. A linear polymeric struc-
ture then results in this way, i.e. complex molecules are
mutually connected by the halogen bridges.
Further subsequent experiments were focused on com-
parison of catalytic properties of the individual derivatives
2a–e. The addition reaction was performed in dichloro-
methane with 10 mol % of catalyst (entries 9–12). It is well
known that the bulkiness of a group attached to the oxaz-
oline ring strongly affects enantioselectivity of this reaction
[37]. Therefore, it was not surprising that derivative 2a
(R = Et) gave virtually racemic product (?2% ee). How-
ever, the derivatives 2c–e carrying bulkier R-substituents
were also less efficient in their enantioselectivity as com-
pared with 2b (R = iPr). In the case of derivative 2d
(R = t-Bu) the isolated product contained predominantly
the opposite enantiomer (-6% ee).
We have also tried to obtain single crystal from aqueous
solution because both complexes are well soluble in water.
Unfortunately the single crystals obtained in this way were
identified as copper(II) pyridine-2,6-dicarboxylate dehy-
drate [48, 49]. This shows that both complexes 4a,b are
unstable in aqueous solution; they undergo hydrolysis of
the oxazoline ring to give a carboxylate. This behavior can
be explained by the Cu(II) atom properties, i.e. Cu(II) atom
acts as a Lewis acid facilitating nucleophilic addition of
water [50–55] (Scheme 3).
Preparation and characterization of Cu(II) complexes of
(S)-6-(4-isopropyl-4,5-dihydro-1,3-oxazolin-2-
yl)pyridine-2-carboxylates (4a,b)
From enantioselectivity studies it was found that the
complex of 2b (R = i-Pr) with Cu(I) exhibits the highest
enantiomeric excess during addition of phenylacetylene to
N-benzylideneaniline. Therefore we have prepared ligands
3a–c for which we expected better enatioselectivity due to
the presence of a covalent bond between copper and
The course of hydrolysis of complex 4b was monitored
spectrophotometrically: a dilute methanolic solution of
complex 4b was injected into a cell containing redistilled
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Transition Met Chem (2010) 35:363–371
Fig. 2 ORTEP representations
of structures of complexes
4a (left) and 4b (right side)
Scheme 3 Hydrolysis of
complex 4a–b
2a–e show some enantioselectivity in addition of phenyl-
acetylene to N-benzylideneaniline (up to 37% ee). Com-
pounds 3a–c form polymeric complexes with copper(II)
chloride and bromide in which the copper is pentacoordi-
nated (SPY) but their enantioselectivity in the above
mentioned reaction is negligible.
Experimental section
General
Fig. 3 Spectral record for 4b solvolysis in aqueous medium
6-Methoxycarbonylpyridine-2-carboxylic acid was pre-
pared according to the method described by Schmuck and
Machon [18]. Other reagents for the syntheses were
obtained from commercial sources (Sigma–Aldrich, Acros
Organics—reagent grade) and were used without further
water (Fig. 3). Under such experimental conditions, the
spectral record probably corresponds to hydrolysis of the
oxazoline ring (s1/2 * 600 s) to give an amide. Sub-
sequent hydrolysis of this amide is much slower (by orders
of magnitude) [56, 57].
1
purification. The H and 13C NMR spectra were recorded
on a Bruker Avance 500 spectrometer at 500.13 (1H) and
1
125.76 MHz (13C) in CDCl3. The H and 13C chemical
Conclusion
shifts were referenced to the central peaks of solvent
(d = 2.55 and 39.60, respectively). The mass spectra were
recorded on instrument set from Agilent Technologies (gas
chromatograph 6890N with mass detector 5973 Network).
The elemental analyses were performed on a Fisons
These 6-(4-alkyl-4,5-dihydro-1,3-oxazol-2-yl)pyridin-2-
carboxylates 2a–e and 3a–c represent new oxazoline
ligands which can catalyze various reactions. The ligands
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Transition Met Chem (2010) 35:363–371
367
Instruments EA 1108 CHN. The optical rotation was
measured on a Perkin-Elmer 341 instrument, concentration
c is given in g/100 mL. The optical purity of N-(1,3-
diphenylpropyn-2-yl)aniline was determined by HPLC
using a Chiralcel OD-H column (Daicel) (95/5 hexane/
propane-2-ol, 0.5 mL/min, 254 nm). The UV/VIS spectra
were measured on a HP UV/VIS 8453 Diode Array
apparatus.
125 MHz, d ppm): 165.1; 163.7; 150.1; 146.0; 138.1;
126.8; 125.2; 63.0; 57.1; 52.9; 29.5; 19.5; 18.7; EI-MS: m/z
235 (100%), 223, 217, 205, 191, 181, 164, 157, 136, 105,
92; Anal. calcd. for C13H18N2O4: C, 58.6; H, 6.8; N, 10.5.
Found: C, 58.5; H, 6.7; N, 10.8.
Methyl (S)-6-[N-(1-hydroxy-4-methylpent-2-
yl)carbamoyl]pyridine-2-carboxylate (1c)
20
Yield 68%; mp 80–82 °C; ½aꢁD ¼ ꢃ64:4ꢂ (c 1.07, CH3OH);
General procedure for preparation of compounds 1a–e
1H NMR (CDCl3-d, 500 MHz, d ppm): 8.44 (d, 3J =
8.4 Hz, 1H, NH), 8.19 (d, J = 7.7 Hz, 1H, PyH), 8.12 (d,
3
A cold mixture (0 °C) of 6-methoxycarbonylpyridine-2-
carboxylic acid (1.82 g, 10 mmol) and triethylamine
(1.4 mL, 10 mmol) in CH2Cl2 (20 mL) was treated with
ethyl chloroformate (0.96 mL, 10 mmol). The solution
obtained was gradually added after 30 min into a solution
of 2-aminoalcohol (1 eq., 10 mmol) and triethylamine
(1.4 mL, 10 mmol) in 20 mL CH2Cl2 with continuous
cooling. The reaction mixture was stirred at room tem-
perature for 1 day, then washed first with 13% acetic acid
(5 mL/40 mL H2O) and finally with saturated solution of
NaHCO3 (ca 1 g/40 mL H2O). The organic layer was dried
with anhydrous Na2SO4, and CH2Cl2 was evaporated under
reduced pressure. The obtained yellow oil was crystallized
from ethyl acetate/cyclohexane (1:10) to give a white
crystalline solid.
3
3J = 7.2 Hz, 1H, PyH), 7.89 (t, J = 7.7 Hz, 1H, PyH),
4.27 (m, 1H, CH), 3.99 (s, 3H, CH3), 3.84 (m, 1H,
3
CH2OH), 3.71 (m, 1H, CH2OH), 1.69 (sp, J = 7.2 Hz,
2H, CH2), 1.56 (m, 1H, CH), 1.44 (m, 1H, CH), 0.93 (m,
6H, 2 9 CH3); 13C NMR (CDCl3-d, 125 MHz, d ppm):
165.3; 163.9; 150.4; 146.4; 138.5; 127.2; 125.6; 65.8; 53.2;
50.6; 40.7; 25.1; 23.2; 22.5; EI-MS: m/z 280, 249 (100%),
231, 223, 207, 205, 193, 181, 164, 157, 136, 105, 92; Anal.
calcd. for C14H20N2O4: C, 60.0; H, 7.2; N, 10.0. Found: C,
60.1; H, 7.2; N, 10.1.
Methyl (S)-6-[N-(1-hydroxy-3,3-dimethylbut-2-
yl)carbamoyl]pyridine-2-carboxylate (1d)
20
Yield 69%; mp 118–120 °C; ½aꢁD ¼ ꢃ7:6ꢂ (c 0.96, CH3OH);
Methyl (R)-6-[N-(1-hydroxybut-2-
yl)carbamoyl]pyridine-2-carboxylate (1a)
1H NMR (CDCl3-d, 500 MHz, d ppm): 8.75 (d, 3J = 9.0 Hz,
3
3
1H, NH), 8.10 (d, J = 7.8 Hz, 1H, PyH), 8.13 (d, J =
7.8 Hz, 1H, PyH), 7.82 (t, 3J = 7.8 Hz, 1H, PyH), 4.06 (m,
1H, CH),4.01(s, 3H, CH3),3.73(m,2H, CH2OH), 1.00(s, 9H,
3 9 CH3); 13C NMR (CDCl3-d, 125 MHz, d ppm): 165.3;
164.4; 150.3; 146.4; 138.3; 127.0; 125.4; 62.3; 60.0; 53.2;
34.4; 27.1; EI-MS: m/z 249 (100%), 223, 205, 191, 181, 164,
136, 105; Anal. calcd. for C14H20N2O4: C, 60.0; H, 7.2; N,
10.0. Found: C, 60.2; H, 7.2; N, 9.7.
20
Yield 72%; mp 71–73 °C; ½aꢁD ¼ þ20:9ꢂ (c 1.08, CH3OH);
1H NMR (CDCl3-d, 500 MHz, d ppm): 8.52 (d, 3J =
8.0 Hz, 1H, NH), 8.10 (dd, J = 8.0 Hz, J = 1 Hz, 1H,
3
4
3
PyH), 8.07 (dd, J = 8.0 Hz, J = 1 Hz, 1H, PyH), 7.84
4
3
(t, J = 8.0 Hz, 1H, PyH), 3.98 (m, 1H, CH), 3.95 (s, 3H,
CH3), 3.83 (m, 1H, CH2OH), 3.72 (m, 1H, CH2OH), 1.64
(m, 2H, CH2CH3), 0.93 (t, 3J = 7.5 Hz, 3H, CH2CH3); 13
C
NMR (CDCl3-d, 125 MHz, d ppm): 165.0; 163.6; 150.2;
146.0; 138.1; 126.8; 125.2; 64.4; 53.4; 52.9; 24.3; 10.5; EI-
MS: m/z 221 (100%), 205, 189, 177, 164, 150, 136, 105,
92; Anal. calcd. for C12H16N2O4: C, 57.1; H, 6.4; N, 11.1.
Found: C, 57.0; H, 6.4; N, 11.3.
Methyl (R)-6-[N-(1-hydroxy-2-phenyl-2-
ethyl)carbamoyl]pyridine-2-carboxylate (1e)
20
Yield 66%; mp 118–119 °C; ½aꢁD ¼ þ107:9ꢂ (c 0.97,
1
CH3OH); H NMR (CDCl3-d, 500 MHz, d ppm): 9.65 (d,
3
3J = 7.0 Hz, 1H, NH), 8.05 (d, J = 7.7 Hz, 1H, PyH),
Methyl (S)-6-[N-(1-hydroxy-3-methylbut-2-
yl)carbamoyl]pyridine-2-carboxylate (1b)
3
3
7.88 (d, J = 7.7 Hz, 1H, PyH), 7.74 (t, J = 7.7 Hz, 1H,
PyH), 7.38 (m, 2H, Ph), 7.23 (m, 3H, Ph), 5.28 (m, 1H,
CH), 4.10–3.96 (m, 2H, CH2OH), 4.03 (s, 3H, CH3); 13C
NMR (CDCl3-d, 125 MHz, d ppm): 165.7; 163.6; 150.5;
146.2; 139.8; 138.2; 128.8; 127.7; 127.2; 127.1; 125.5;
66.1; 56.4; 53.4; EI-MS: m/z 269 (100%), 207, 191, 181,
164, 136, 105, 77; Anal. calcd. for C16H16N2O4: C, 64.0;
H, 5.4; N, 9.3. Found: C, 64.1; H, 5.6; N, 9.4.
20
Yield 79%; mp 89–90 °C; ½aꢁD ¼ ꢃ27:7ꢂ (c 1.02, CH3OH);
1H NMR (CDCl3-d, 500 MHz, d ppm): 8.65 (d, 3J =
3
8.5 Hz, 1H, NH), 8.07 (dd, J = 8.0 Hz, 2H, PyH), 7.83
(t, 3J = 8.0 Hz, 1H, PyH), 3.97 (s, 3H, CH3), 3.91 (m, 1H,
CH), 3.89 (m, 1H, CH2OH), 3.79 (m, 1H, CH2OH), 1.99
(sp, 2H, iPrCH), 0.95 (m, 6H, iPrCH3); 13C NMR (CDCl3-d,
123

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Transition Met Chem (2010) 35:363–371
General procedure for preparation of compounds 2a–e
CH), 1.71 (m, 1H, CH2), 1.38 (m, 1H, CH2), 0.95 (m, 6H,
2 9 CH3); 13C NMR (CDCl3-d, 125 MHz, d ppm): 165.4;
162.0; 148.1; 147.3; 137.9; 127.2; 126.8; 74.0; 65.6; 53.1;
45.5; 25.6; 22.8; EI-MS: m/z 262, 247, 219, 205 (100%),
191, 177, 151, 137, 117, 103; Anal. calcd. for C14H18N2O3:
C, 64.1; H, 6.9; N, 10.7. Found: C, 64.4; H, 6.8; N, 10.6.
A cold solution (0 °C) of compound 1 (4 mmol) and tri-
ethylamine (3 mL, 20 mol) in CH2Cl2 (15 mL) was treated
with methansulfonyl chloride (0.5 mL, 6 mmol). After 3-
day reflux, the solvent was evaporated under reduced
pressure. The residue was suspended in ethyl acetate
(5 mL), filtered through a silica gel plug (1 cm), and
washed with ethyl acetate (ca 60 mL). Then, the yellowish
solution was extracted with water (2 9 40 mL) and dried
with anhydrous Na2SO4. Evaporation of the solvent under
reduced pressure gave a yellowish oil, which was crystal-
lized from cyclohexane (ca 50 mL).
Methyl (S)-6-(4-tert-butyl-4,5-dihydro-1,3-oxazol-2-
yl)pyridine-2-carboxylate (2d)
20
Yield 64%; mp 112–114 °C; ½aꢁD ¼ ꢃ63:4ꢂ (c 0.99,
1
CH3OH); H NMR (CDCl3-d, 500 MHz, d ppm): 8.31 (d,
3
3J = 7.4 Hz, 1H, PyH), 8.19 (d, J = 7.8 Hz, 1H, PyH),
3
7.91 (t, J = 7.8 Hz, 1H, PyH), 4.46 (t, J = 9.0 Hz, 1H,
3
3
3
Methyl (R)-6-(4-ethyl-4,5-dihydro-1,3-oxazol-2-
yl)pyridine-2-carboxylate (2a)
OxCH2), 4.31 (t, J = 8.7 Hz, 1H, OxCH), 4.10 (t, J =
8.8 Hz, 1H, OxCH2), 3.98 (s, 3H, CH3), 0.94 (s, 9H,
3 9 CH3); 13C NMR (CDCl3-d, 125 MHz, d ppm): 165.5;
162.0; 148.1; 147.4; 137.8; 127.5; 126.8; 76.6; 69.7; 53.2;
34.1; 26.1; EI-MS: m/z 247, 205, 191 (100%), 177, 146,
137, 105; Anal. calcd. for C14H18N2O3: C, 64.1; H, 6.9; N,
10.7. Found: C, 64.3; H, 7.1; N, 10.4.
20
Yield 67%; mp 61–63 °C; ½aꢁD ¼ þ49:5ꢂ (c 1.04, CH3OH);
1H NMR (CDCl3-d, 500 MHz, d ppm): 8.18 (m, 2H, PyH),
7.91 (t, J = 7.5 Hz, 1H, PyH), 4.57 (t, J = 8.0 Hz, 1H,
3
3
3
OxCH2), 4.26 (m, 1H, OxCH), 4.13 (t, J = 8.0 Hz, 1H,
OxCH2), 3.96 (s, 3H, CH3), 1.75 (m, 1H, CH2CH3), 1.60
(m, 1H, CH2CH3), 0.94 (t, 3J = 7.5 Hz, 3H, CH2CH3); 13
C
Methyl (R)-6-(4-phenyl-4,5-dihydro-1,3-oxazol-2-
yl)pyridine-2-carboxylate (2e)
NMR (CDCl3-d, 125 MHz, d ppm): 165.3; 162.0; 147.9;
147.0; 137.8; 127.1; 126.7; 73.0; 68.3; 28.5; 10.2; EI-MS:
m/z 219, 205 (100%), 177, 163, 150, 131, 117, 103; Anal.
calcd. for C12H14N2O3: C, 61.5; H, 6.0; N, 12.0. Found: C,
61.5; H, 6.3; N, 11.7.
20
Yield 71%; mp 107–108 °C; ½aꢁD ¼ þ55:2ꢂ (c 1.02,
CH3OH); 1H NMR (CDCl3-d, 500 MHz, d ppm): 8.37
(d, 3J = 7.8 Hz, 1H, PyH), 8.24 (d, 3J = 7.7 Hz, 1H, PyH),
7.94 (t, 3J = 7.8 Hz, 1H, PyH), 7.26–7.36 (m, 5H, Ph), 5.44
(t, 3J = 9.8 Hz, 1H, OxCH), 4.91 (t, 3J = 9.6 Hz, 1H,
Methyl (S)-6-(4-isopropyl-4,5-dihydro-1,3-oxazol-2-
yl)pyridine-2-carboxylate (2b)
3
OxCH2), 4.40 (t, J = 8.7 Hz, 1H, OxCH2), 4.00 (s, 3H,
CH3); 13C NMR (CDCl3-d, 125 MHz, d ppm): 165.4; 163.4;
148.2; 147.1; 141.7; 138.0; 129.0; 128.0; 127.6; 127.1;
126.9; 75.7; 70.5; 53.2; EI-MS: m/z 282, 267, 252, 192
(100%), 179, 165, 118; Anal. calcd. for C16H14N2O3: C,
68.1; H, 5.0; N, 9.9. Found: C, 68.0; H, 5.3; N, 9.9.
20
Yield 75%; mp 95–98 °C; ½aꢁD ¼ ꢃ60:2ꢂ (c 1.07, CH3OH);
1H NMR (CDCl3-d, 500 MHz, d ppm): 8.25 (d, 3J = 8.0 Hz,
1H, PyH), 8.17 (d, J = 8.0 Hz, 1H, PyH), 7.89 (t, J =
3
3
3
8.0 Hz, 1H, PyH), 4.50 (t, J = 8.5 Hz, 1H, OxCH2), 4.12
3
(t, J = 8.5 Hz, 1H, OxCH2), 4.11 (m, 1H, OxCH), 3.94
(s, 3H, CH3), 1.85 (sp, 3J = 6.5 Hz, 1H, iPrCH), 0.99
General procedure for preparation of compounds 3a–c
3
3
(d, J = 6.5 Hz, 3H, iPrCH3), 0.98 (d, J = 6.5 Hz, 3H,
iPrCH3); 13C NMR (CDCl3-d, 125 MHz, d ppm): 165.2;
161.8; 147.8; 147.0; 137.6; 127.1; 126.6; 72.8; 71.0; 52.9;
32.7; 18.9; 18.2; EI-MS: m/z 248, 233, 217, 205 (100%), 191,
177, 150, 136, 117, 103; Anal. calcd. for C13H16N2O3: C,
62.9; H, 6.5; N, 11.3. Found: C, 62.7; H, 6.7; N, 11.6.
Compound 2b (1.05 mmol) was dissolved in one equivalent
of methanolic solution of the respective alkali hydroxide
(1 mol L-1). After 24-h stirring at room temperature, the
solvent was removed under reduced pressure and the residue
was suspended in diethylether. The obtained suspension was
filtered, and the solid was thoroughly washed with diethyl-
ether (3 9 20 mL).
Methyl (S)-6-(4-isobutyl-4,5-dihydro-1,3-oxazol-2-
yl)pyridine-2-carboxylate (2c)
Lithium (S)-6-(4-isopropyl-4,5-dihydro-1,3-oxazol-2-
yl)pyridine-2-carboxylate (3a)
20
Yield 72%; mp 74–75 °C; ½aꢁD ¼ ꢃ64:4ꢂ (c 1.07, CH3OH);
1H NMR (CDCl3-d, 500 MHz, d ppm): 8.21 (m, 2H, PyH),
7.91 (t, J = 7.8 Hz, 1H, PyH), 4.60 (t, J = 8.2 Hz, 1H,
3
3
20
Yield 95%; mp [ 300 °C; ½aꢁD ¼ ꢃ52:6ꢂ (c 1.03, CH3
3
OxCH2), 4.38 (m, 1H, OxCH), 4.08 (t, J = 8.2 Hz, 1H,
3
OxCH2), 3.98 (s, 3H, CH3), 1.83 (sp, J = 6.6 Hz, 1H,
OH); 1H NMR (CDCl3-d, 500 MHz, d ppm): 8.12 (d, 3J =
7.0 Hz, 1H, PyH), 8.00 (m, 2H, PyH), 4.33 (t, 3J = 9.0 Hz,
123

Transition Met Chem (2010) 35:363–371
369
3
1H, OxCH2), 4.01 (m, 1H, OxCH), 3.94 (m, J = 8.5 Hz,
1H, OxCH2), 1.67 (sp, 3J = 6.5 Hz, 1H, iPrCH), 0.88
the mixture was stirred at room temperature for 1 day. The
obtained green precipitate was filtered off, washed with
isopropyl alcohol (3 9 5 mL) and dried under reduced
pressure.
3
3
(d, J = 6.5 Hz, 3H, iPrCH3), 0.81 (d, J = 6.5 Hz, 3H,
iPrCH3); 13C NMR (CDCl3-d, 125 MHz, d ppm): 166.9;
161.3; 156.0; 144.2; 138.6; 125.4; 123.9; 72.0; 70.2; 32.2;
18.5; 18.2; Anal. calcd. for C12H13LiN2O3: C, 60.0; H, 5.5;
N, 11.7. Found: C, 59.9; H, 5.3; N, 11.8.
Complex 4a
Yield: Method A 85%; Method B 92%; mp 257–260 °C;
20
½aꢁD ¼ ꢃ67:7ꢂ (c = 0.13, CH3OH). Anal. calcd. for C12
Sodium (S)-6-(4-isopropyl-4,5-dihydro-1,3-oxazol-2-
yl)pyridine-2-carboxylate (3b)
H13N2O3CuCl: C, 43.4; H 3.9; N, 8.4; Cl, 10.7. Found: C,
43.0; H 4.0; N, 8.2; Cl, 10.8.
20
Yield 94%; mp [ 300 °C; ½aꢁD ¼ ꢃ24:9ꢂ (c 1.01, CH3OH);
1H NMR (CDCl3-d, 500 MHz, d ppm): 8.30 (d, 3J = 7.0 Hz,
1H, PyH), 8.16 (t, 3J = 8,0 Hz, 1H, PyH), 8.06 (d,
3J = 7.0 Hz, 1H, PyH), 4.62 (t, 3J = 9.0 Hz, 1H, OxCH2),
4.28 (t, 3J = 9.0 Hz, 1H, OxCH2), 4.18 (m, 1H, OxCH), 1.86
Complex 4b
Yield: Method A 88%; Method B 87%; mp 243–245 °C;
20
½aꢁD ¼ ꢃ52:7ꢂ (c = 0.40, CH3OH). Anal. calcd. for
3
3
(sp, J = 7.0 Hz, 1H, iPrCH), 1.05 (d, J = 7.0 Hz, 3H,
iPrCH3), 0.98 (d, 3J = 7.0 Hz, 3H, iPrCH3); 13C NMR
(CDCl3-d, 125 MHz, d ppm): 166.8; 161.5; 157.3; 144.7;
138.0; 125.8; 123.7; 72.2; 70.6; 32.3; 18.9; 18.3; Anal. calcd.
for C12H13N2NaO3: C, 56.3; H, 5.1; N, 10.9. Found: C, 56.0;
H, 5.1; N, 11.0.
C12H13N2O3CuBr: C, 38.3; H 3.5; N, 7.4; Br, 21.2. Found:
C, 38.5; H 3.7; N, 7.7; Br, 21.0.
General procedure for enantioselective addition of
phenylacetylene to N-benzylideneaniline catalyzed by
ligand 2-Cu(OTf) complex
Potassium (S)-6-(4-isopropyl-4,5-dihydro-1,3-oxazol-2-
yl)pyridine-2-carboxylate (3c)
Ligand 2a–e (0.06 mmol), copper(I) triflate benzene com-
plex (0.05 mmol of copper) and N-benzylideneaniline
(0.5 mmol) were dissolved in the respective anhydrous sol-
vent (2 mL). After ca 15 min, phenylacetylene (1 mmol)
was added, and the mixture formed was stirred at room
temperature. The course of the reaction was monitored by
GC/MS. Then the reaction mixture was chromatographed on
a silica gel using EtOAc/hexane (1:6) mixture as an eluent.
The product was isolated as a yellow crystalline solid, whose
optical purity was determined by HPLC (chiral column
Daicel Chiralcel OD-H (hexane/isopropyl alcohol = 95/5,
flow rate = 0.5 mL/min, k = 254 nm), tR1 = 17.8 min,
tR2 = 20.9 min).
20
Yield 82%; mp [ 300 °C; ½aꢁD ¼ ꢃ36:8ꢂ (c 1.14, CH3
OH); 1H NMR (CDCl3-d, 500 MHz, d ppm): 8.06 (d,
3
3J = 7.0 Hz, 1H, PyH), 7.88 (m, 2H, PyH), 4.42 (t, J =
3
8.5 Hz, 1H, OxCH2), 4.08 (t, J = 8.5 Hz, 1H, OxCH2),
3
4.01 (m, 1H, OxCH), 1.70 (sp, J = 6.5 Hz, 1H, iPrCH),
3
3
0.88 (d, J = 6.5 Hz, 3H, iPrCH3), 0.81 (d, J = 6.5 Hz,
3H, iPrCH3); 13C NMR (CDCl3-d, 125 MHz, d ppm):
167.8; 162.5; 158.0; 144.8; 137.8; 126.1; 123.6; 72.3; 70.7;
32.5; 19.0; 18.6; Anal. calcd. for C12H13KN2O3: C, 52.9;
H, 4.8; N, 10.3. Found: C, 53.1; H, 4.7; N, 10.4.
Preparation of copper(II) complexes 4a–b (Method A)
X-ray
Lithium salt 3a (48.0 mg, 0.2 mmol) was suspended in dry
isopropyl alcohol (2 mL) and anhydrous CuCl2 or CuBr2
(0.2 mmol) was added. After ca 1 h, the suspension
changed to a dark green solution, which was stirred at room
temperature for 1 day. The precipitate formed was filtered
off, washed with isopropyl alcohol (3 9 5 mL) and dried
under reduced pressure.
The crystallographic data (excluding structure factors) for
structures 2a, 4a and 4b have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC 746798 2a; CCDC 746799 4a and
CCDC 746800 4b. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/conts/retrieving.html or
from the Cambridge Crystallographic Data Centre, 12,
Union Road, Cambridge, CB2 1EZ, UK; fax: ?44 1223
336033 or deposit@ccdc.cam.ac.uk. The X-ray data were
collected on a Nonius KappaCCD diffractometer fitted
Preparation of copper(II) complexes 4a–b (Method B)
˚
A suspension of ligand 3b or 3c (0.2 mmol) in dry iso-
propyl alcohol (2 mL) was mixed with anhydrous CuCl2 or
CuBr2 (0.2 mmol) and crown-ether (15-crown-5 ether for
ligand 3b; 18-crown-6 ether for ligand 3c) (0.2 mmol), and
with MoKa radiation (k = 0.71073 A) at 150(1) K. The
absorption correction was performed using a Gaussian
procedure [58], the structure was solved by direct methods
(SIR92 [59]), and full-matrix least-squares refinements on
123

370
Transition Met Chem (2010) 35:363–371
F2 were carried out using the program SHELXL97 [60].
Flack parameter [61] was optimized to zero value with
known chemical absolute configuration R for structure 2a.
Hydrogen atoms were mostly localized on a difference
Fourier map; however, to ensure uniformity of treatment,
all hydrogen atoms were recalculated into idealized posi-
tions (riding model) and assigned temperature factors
Acknowledgments The authors wish to acknowledge the financial
support of the Ministry of Education, Youth and Sports (MSM 002
162 7501) and Grant Agency of the Czech Republic (Grant No. 203/
08/P010).
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