Novel C 2-symmetric bis-oxazoline ligands

Article abstract of DOI:10.1007/s11172-012-0307-z

Two novel C ₂-symmetric bis-oxazoline ligands were synthesized and their complexes with Cu(OAc)₂ were studied as catalysts in the enantioselective Henry reaction of 4-nitrobenz-aldehyde with nitromethane giving high yield of nitro al

Full text of DOI:10.1007/s11172-012-0307-z

Russian Chemical Bulletin, International Edition, Vol. 61, No. 11, pp. 2180—2182, November, 2012
2180
Novel C2ꢀsymmetric bisꢀoxazoline ligands
V. V. Veselovsky, A. V. Lozanova, and E. A. Mistryukov
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Eꢀmail: ves@ioc.ac.ru
Two novel C2ꢀsymmetric bisꢀoxazoline ligands were synthesized and their complexes with
Cu(OAc)2 were studied as catalysts in the enantioselective Henry reaction of 4ꢀnitrobenzꢀ
aldehyde with nitromethane giving high yield of nitro aldol with ee up to 40%.
Key word: C2ꢀsymmetric bisꢀoxazoline ligands, copper complexes, enantioselective Henry
reaction.
Scheme 1
C2ꢀSymmetric chiral bisꢀoxazoline ligands are the
components of known effective catalysts of many enantioꢀ
selective processes,1 including aldol and eneꢀcarbonyl conꢀ
densations, the Michael addition, carbo and hetero cycloꢀ
addition,2 and nitro aldol Henry reaction.3 At the same
time, the search for new compounds of this series the most
suitable for a particular reaction is still urgent (see, for
example, Ref. 3b). Present work is devoted to the synthesis
of two novel enantiomerically pure C2ꢀsymmetric bisꢀoxazolꢀ
ine ligands 1 and 2 based on available starting compounds.
Reagents and conditions: i. NaOAc, H2O, THF, 20 C; ii. Ph3P,
(NCO2Et)2, THF, –5—20 C.
1ꢀol (6) and diethyl oxalate. The reaction of compound 6
and diethyl oxalate led to diamide 7 in moderate yield.
Refluxing of diamide 7 with SOCl2 afforded chloroꢀderivꢀ
ative 8 (Scheme 2). The latter underwent ring closure unꢀ
der heating with NaOH in MeOH giving target compound
2 in 82% yield.
Earlier unknown diamide 5 and bisꢀoxazoline 1 were
characterized by combination of the spectroscopic methꢀ
ods. Structures of amide 7, chloride 8, and bisꢀoxazoline 2
were confirmed by 1H NMR spectroscopy and by a comꢀ
parison of their physicochemical properties with those of
the corresponding optical antipodes.4
The starting compounds for the synthesis of bisꢀoxꢀ
azoline 1 were amino diol 3, the known intermediate in
the synthesis of chloroamphenicol, and 2,2ꢀdiethylmalonyl
chloride (4). Reaction between these compounds in the
presence of a saturated aqueous NaOAc solution resulted
in Nꢀacylation product 5 in moderate yield (Scheme 1).
Intramolecular ring closure of the latter under the
Mitsunobu conditions proceeds with formation of two
oxazoline cycles to give bisꢀoxazoline 1 in 76% yield.
Bisꢀoxazoline 2 was synthesized similarly to its optical
antipode4 from commercially available 2(R)ꢀaminobutanꢀ
Catalytic performance of complexes of bisꢀoxazolines
1 and 2 with Cu(OAc)2 were tested in a model reaction,
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2163—2165, November, 2012.
1066ꢀ5285/12/6111ꢀ2180 © 2012 Springer Science+Business Media, Inc.

Bisꢀoxazoline ligands
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 11, November, 2012 2181
Scheme 2
of PriOH in hexane, flow rate of 1 mL min–1. Retentions times
are 22 and 29 min for (R)ꢀ9 and (S)ꢀ9, respectively (cf. Ref. 3b).
Sonication was performed with an ultrasonic bath UZVꢀ1/100ꢀTN.
The solvents were purified and dried following the standard proꢀ
cedures. Commercially available amino alcohols 3, 6, NaOAc,
Ph3P, (NCO2Et)2, SOCl2, Cu(OAc)2 (Acros Organics), and diꢀ
ethylmalonic acid (Aldrich) were used. 2.2ꢀDiethylmalonyl
dichloride (4) was synthesized by a known procedure.5
(1S,1´S,2S,2´S)ꢀN,N´ꢀBis[1,3ꢀdihydroxyꢀ1ꢀ(4ꢀnitrophenꢀ
yl)propꢀ2ꢀyl)]diethylmalonamide (5). To a stirred solution of
amine 3 (2.12 g, 10 mmol) in THF, saturated aqueous NaOAc
(50 mL) was added at 20 C following by additon of chloride 4
(1 g, 0.5 mmol). The reaction mixture was stirred for 1 h, the
organic layer was separated, washed twice with brine, dried with
NaSO4, and concentrated in vacuo. Column chromatography
(SiO2 stabilized with EtOAc, gradient elution from EtOAc to
EtOAc—10% MeOH) afforded 2 g of the product with Rf 0.28
(MeCN), recrystallization of which from MeCN gave diamide 5
in the yield of 1.2 g (44%), colorless crystals, m.p. 189.5—190.5 C,
Reagent and conditions: i. (CO2Et)2, PhMe, reflux, 2 h; ii. SOCl2,
PhMe, DMF (cat.), reflux, 3 h; iii. NaOH, MeOH, reflux, 2 h.
26
[]D +26.6 (c 1.0, EtOH). MS (ESI), m/z: found 549.2187,
viz., nitro aldol condensation of nitromethane and 4ꢀniꢀ
571.2005; calculated for C25H32N4O10, m/z: 549.2191 [M + H]+,
571.2011 [M + Na]+. IR (dispersion in Nujol), /cm–1: 712,
720, 811, 820, 857, 868, 951, 1002, 1012, 1045, 1072, 1101,
1191, 1222, 1250, 1329, 1351, 1468, 1521, 1606, 1649, 2855,
2928, 3408. 1H NMR (CDCl3—CD3OD), : 0.12 (t, 6 H, 2 Me,
J = 7.2 Hz); 1.41 (dd, 2 H, CH2, J = 13.0 Hz, J = 7.2 Hz); 1.51
(dd, 2 H, CH2, J = 13.0 Hz, J = 7.2 Hz); 3.50 (dd, 2 H, CH2OH,
J = 10.8 Hz, J = 5.1 Hz); 3.58 (dd, 2 H, CH2OH, J = 10.8 Hz,
J = 6.4 Hz); 4.05 (m, 2 H, 2 CHN); 5.01 (d, 2 H, 2 CHO,
J = 2.3 Hz); 7.43 (d, 4 H, 4 HCAr, J = 8.7 Hz); 8.00 (d, 4 H,
4 HCAr, J = 8.7 Hz).
trobenzaldehyde (Scheme 3).
Scheme 3
2,2´ꢀ(Pentaneꢀ3,3ꢀdiyl)bis{4(S)ꢀ[1(S)ꢀhydroxyꢀ1(S)ꢀ(4ꢀnitroꢀ
phenyl)methyl]ꢀ4,5ꢀdihydrooxazole} (1). To a stirred solution of
diamine 5 (1.18 g, 2.15 mmol) and Ph3P (1.35 g, 5.16 mmol) in
THF (12 mL), a solution of diethyl azodicarboxylate (0.9 g,
0.8 mL, 5.16 mmol) in THF (5 mL) was added over 5 min at
–5 C under argon. The reaction mixture was stirred at 0 C for 1 h
and then kept at 20 C for 15 h. The solvent was removed in vacuo,
and the residue was dissolved in hot CH2Cl2. The precipiꢀ
tate (0.7 g) formed on cooling was filtered off and washed
with CH2Cl2 (0.7 g). The filtrate was concentrated in vacuo.
Column chromatography (SiO2, gradient elution with CH2Cl2,
CH2Cl2—EtOAc, EtOAc, EtOAc—5% MeOH) afforded bisꢀoxꢀ
azoline 1 in the yield of 0.84 g (76%), m.p. 95—97 C,
Reagents and conditions: Cu(OAc)2/L (10 mol.%, L = 1 or 2),
PriOH.
In both cases, scalemic nitro alcohol 9 was obtained in
high yield, however, enantiomeric excess of the reaction
products was low (ee 18 and 40%, respectively, HPLC
data), which is lower than the best ee value of 81% providꢀ
ed by the ligands of this type.3b Nevertheless, we continue
the search for more promising ligands.
Experimental
26
[]D +94.5 (c 1.0, EtOH). MS (ESI), m/z: found 513.1974,
535.1790; calculated for C25H28N4O8, m/z: 513.1980 [M + H]+,
535.1799 [M + Na]+. IR (dispersion in Nujol), /cm–1: 707,
751, 763, 849, 958, 982, 1023, 1043, 1081, 1110, 1128, 1142,
1227, 1248, 1346, 1364, 1465, 1524, 1607, 1642, 2669, 2855,
Melting points were measured on a Koffler apparatus.
IR spectra were recorded on a Bruker ALPHAꢀT instrument.
1H NMR spectra were recorded on a Bruker ACꢀ200 spectromeꢀ
ter at 298 K, the chemical shifts are given in the  scale relative
to the residual solvent signals ( 7.27). High resolution mass
spectra (ESI) were recorded on a Bruker micrOTOF II spectroꢀ
meter at capillary voltage of 4.5 kV using direct inlet (via syringe
pump) with MeOH as a solvent (a flow rate of 3 L min–1
operating on a positive ions mode (the mass range 500—3000 Da),
rate of the main nitrogen flow is 4 L min–1 (180 C). Optical
rotation was measured on a Jasco DIP polarimeter. Column
chromatography was performed using Silica gel 60 (0.04—0.06 mm,
Fluka); Rf values were measured using the precoated plates Siluꢀ
fol. For HPLC (UV detection at 254), a chiral phase Kromasil 3
CelluCoat (column 4.6×150 mm) was used, elution with 10 vol.%
1
2924, 3004, 3160. H NMR (CDCl3—CD3OD (4 : 1)), : 0.83
(t, 6 H, 2 Me, J = 7.5 Hz); 1.78—2.05 (m, 4 H, 2 CH2); 4.06
(d, 2 H, 2 OH, J = 5.8 Hz); 4.28 (d, 4 H, 2 CH2O, J = 8.2 Hz);
4.51 (ddd, 2 H, 2 CHN, J = 8.2 Hz, J = 8.2 Hz, J = 4.8 Hz); 4.74
(dd, 2 H, 2 CHO, J = 5.8 Hz, J = 4.8 Hz); 7.55 (d, 4 H, 4 HCAr,
J = 8.8 Hz); 8.21 (d, 4 H, 4 HCAr, J = 8.8 Hz).
)
N,N´ꢀBis[(1R)ꢀ1ꢀ(hydroxymethyl)propyl]ethanediamide (7).
A solution of amino alcohol 6 (8.91 g, 100 mmol) and diethyl
oxalate (7.31 g, 50 mmol) in toluene (50 mL) was refluxed for 2 h
under argon and concentrated in vacuo. Recrystallization of the
residue from EtOH afforded diamide 7 in the yield of 9.29 g
25
(80%), m.p. 212—213.5 C (MeOH), []D +54.60 (c 0.5,

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Russ.Chem.Bull., Int.Ed., Vol. 61, No. 11, November, 2012
Veselovsky et al.
EtOH) (cf. Ref. 4 for (1S,1´S)ꢀenantiomer: m.p. 211—213 С,
[]D24 –46 (c 0.5, EtOH)). 1H NMR (CDCl3—CD3OD (4 : 1)),
: 0.93 (t, 6 H, 2 Me, J = 7.4 Hz); 1.39—1.81 (m, 4 H, 2 CH2);
3.58 (d, 4 H, 2 CH2O, J = 5.2 Hz); 3.81 (m, 2 H, 2 CHN).
N,N´ꢀBis((2R)ꢀ1ꢀchlorobutꢀ2ꢀyl)ethanediamide (8). To a soꢀ
lution of diamide 7 (4.91 g, 21.14 mmol), SOCl2 (25 g, 0.21 mol)
and toluene (30 ml), DMF (0.1 mL) was added at 20 C. The
reaction mixture was refluxed for 3 h, cooled to room temperaꢀ
ture, filtrated and the volatiles were removed in vacuo. Recrysꢀ
tallization of the residue from CH2Cl2 afforded chloride 8 in the
yield of 3.17 g (56%), colorless crystals, m.p. 205—207.5 C
(CHCl3), []D25 +87.40 (c 0.5, CHCl3) (cf. Ref. 4 for (1S,1´S)ꢀ
The mixture was sonicated for 10 min, then to a light blue soluꢀ
tion formed, 4ꢀnitrobenzaldehyde (151 mg, 1 mmol) and MeNO2
(610 mg, 10 mmol) were added. The reaction mixture was kept
for 20 h (TLC monitoring) and concentrated in vacuo. Column
chromatography on SiO2 (elution with CHCl3) afforded scalemꢀ
ic nitro alcohol 9 in the yield of 203 mg (96%) (18% ee, HPLC
1
data). H NMR (CDCl3), : 3.47 (br.s, 1 H, OH); 4.58—4.62
(m, 2 H, CH2O); 5.61 (dd, 1 H, CHO, J = 7.4 Hz, J = 5.0 Hz);
7.62 (d, 2 H, 2 HAr, J = 8.7 Hz); 8.23 (d, 2 H, 2 HAr, J = 8.7 Hz)
(cf. Ref. 3b).
B. Similar reaction carried out with ligand 2 gave scalemic
nitro alcohol 9 in 94% yield (40% ee, HPLC data).
24
enantiomer: m.p. 191—193 C, []D –47 (c 0.5, MeOH)).
1H NMR (CDCl3—CD3OD), : 0.98 (t, 6 H, 2 Me, J = 7.4 Hz);
1.53—1.90 (m, 4 H, 2 CH2); 3.67 (d, 4 H, 2 CH2Cl, J = 4.1 Hz);
4.10 (m, 2 H, 2 CHN); 7.54 (br.s, 2 H, 2 HN, J = 7.7 Hz).
(4R,4´R)ꢀ4,4´ꢀDiethylꢀ4,4´,5,5´ꢀtetrahydroꢀ2,2´ꢀbiꢀ1,3ꢀoxꢀ
azole (2). A suspension of chloride 8 (2.5 g, 9.29 mmol) and
NaOH (0.88 g, 22.0 mmol) in MeOH (20 mL) was refluxed for
2 h. Then the reaction mixture was cooled, the precipitate was
filtered off and washed with MeOH, the filtrate was concentratꢀ
ed in vacuo, and the residue was extracted with EtOAc (5×10 mL).
Removal of the solvent in vacuo and vacuum distillation of the
residue afforded bisꢀoxazoline 2 in the yield of 1.5 g (82%),
viscous liquid, b.p 99—102 C (0.08 Torr), []D25 +167.20 (c 0.5,
EtOH) (cf. Ref. 4 for (1S,1´S)ꢀenantiomer: b.p. 121 C (0.1 Torr),
[]D –172 (without solvent)). H NMR (CDCl3—CD3OD),
: 0.97 (t, 6 H, 2 Me, J = 7.4 Hz); 1.45—1.85 (m, 4 H, 2 CH2);
4.03 (dd, 2 H, 2 CHO, J = 8.5 Hz, J = 7.7 Hz); 4.22 (m, 2 H,
2 CHN); 4.49 (dd, 2 H, 2 CH´O, J = 9.4 Hz, J = 7.7 Hz).
(1R)ꢀ1ꢀ(4ꢀNitrophenyl)ꢀ2ꢀnitroethanꢀ1ꢀol (9). A. The reacꢀ
tion flask dried at 100 C and cooled down to 20 C under nitroꢀ
gen stream was charged with bisꢀoxazoline 1 (51 mg, 0.1 mmol),
Cu(OAc)2 (16 mg, 0.09 mmol), and anhydrous PriOH (1.5 mL).
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 10ꢀ03ꢀ00089).
Referenses
1. E. Schulz, in Topics in Organometallic Chemistry, Eds M. Leꢀ
maire, P. Mangeney, Springer, Berlin—Heidelberg—New
York, 2005, vol. 15, p. 93.
2. J. Johnson, D. Evans, Acc. Chem. Res., 2000, 33, 325.
3. (a) D. A. Evans, D. Seidel, M. Rueping, H. W. Lam, J. T.
Shaw, C. W. Downey, J. Am. Chem. Soc., 2003, 125, 12692;
(b) S. K. Ginotra, V. K. Singh, Org. Biomol. Chem., 2007,
5, 3932.
24
1
4. I. Butula, G. Karlovic´, Liebigs Ann. Chem., 1976, 1455.
5. J. Büchi, G. Enézian, H. Eichenberger, R. Lieberherr, Helv.
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Received October 2, 2012