A convenient synthesis of chiral 2-alkynyl-1,3-oxazolines

Article abstract of DOI:10.1016/S0957-4166(00)00409-2

A general, high-yielding, two-step synthesis of chiral 2-alkynyl-1,3-oxazolines starting from 2-alkynoic acids and 2-aminoalcohols is disclosed. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00409-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 4407–4416
A convenient synthesis of chiral 2-alkynyl-1,3-oxazolines
Alexandre Cevallos, Ramon Rios, Albert Moyano,* Miquel A. Perica`s* and Antoni Riera
Unitat de Recerca en S´ıntesi Asime`trica (URSA), Departament de Qu´ımica Orga`nica, Universitat de Barcelona,
c/Mart´ı i Franque`s, 1-11, 08028 Barcelona, Spain
Received 2 October 2000; accepted 11 October 2000
Abstract
A general, high-yielding, two-step synthesis of chiral 2-alkynyl-1,3-oxazolines starting from 2-alkynoic
acids and 2-aminoalcohols is disclosed. © 2000 Published by Elsevier Science Ltd.
1. Introduction
Chiral oxazolines have been extensively used in asymmetric synthesis, as both auxiliaries and
ligands.1 In the context of our study of the Pauson–Khand reaction of chiral, electron-deficient
alkynes,2 we needed to prepare a set of chiral 2-alkynyl-1,3-oxazolines. 2-Alkynyl-1,3-oxazolines,
however, appear to be a practically unexplored class of compounds, and only a few examples of
achiral or homochiral 2-alkynyl-1,3-oxazolines have been described.3,4 Up to now, the only
preparation of a chiral, alkyne-substituted oxazoline is the synthesis of t-leucinol-derived
2-alkynyl-1,3-oxazolines reported by Meyers and Kovachek.4 This method requires the genera-
tion of the corresponding 2-hydro-1,3-oxazoline, which after metallation with t-butyl lithium is
treated with dibromotetrafluoroethane to give an unstable 2-bromo-1,3-oxazoline. Palladium(0)-
promoted coupling of this compound with a trimethylstannylacetylene finally affords the
2-alkynyl-1,3-oxazoline, in a process that takes place in overall moderate yields (25–28%) from
the starting homochiral 2-aminoalcohol. We wish to report here a high-yield, convenient and
general synthesis of homochiral 2-alkynyl-1,3-oxazolines that takes place in only two steps from
a 2-aminoalcohol and a 2-alkynoic acid.
2. Results and discussion
Taking into account the ready availability of 2-alkynoic acids, we envisaged obtaining
2-alkynyl-1,3-oxazolines by the two-step process summarized in Scheme 1, involving the
* Corresponding authors. E-mail: amoyano@qo.ub.es; mapericas@qo.ub.es
0957-4166/00/$ - see front matter © 2000 Published by Elsevier Science Ltd.
PII: S0957-4166(00)00409-2

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preparation of a 2-alkynoyl-derived b-hydroxyamide I and its subsequent cyclization to the
corresponding oxazoline II: although this process is based on a well-established route for the
preparation of chiral oxazolines from carboxylic acids,5 it had up to now not been applied to
2-alkynoic acids.
Scheme 1.
After some experimentation,6 we found that the most convenient conditions to perform the
first step relied on the use of in situ generated N-hydroxysuccinimide esters7 (Scheme 2 and
Table 1). The reaction took place in very mild conditions (formation of the active ester and
stirring with the aminoalcohol at room temperature), and the yields were generally high. The
generation of the N-hydroxysuccinimide ester was performed by treatment of the 2-alkynoic
acid, in 1,4-dioxane or in tetrahydrofuran, with N-hydroxysuccinimide and N,N%-dicyclohexyl-
carbodiimide and stirring for 2.5 h. After the addition of the homochiral aminoalcohol, stirring
was maintained until total consumption of the starting products, and after filtering out the
dicyclohexylurea the crude was purified by column chromatography. In this way, the b-hydrox-
yamides derived from phenylpropiolic acid 1a, trimethylsilylpropiolic acid 1b and tetrolic acid 1c
were obtained in excellent yields (84–93%). Somewhat lower yields were achieved with 9-decen-
2-ynoic acid 1d, and the hydroxyamide 3eii could not be isolated from the reaction of propiolic
acid 1e with (S)-phenylglycynol 2ii, probably owing to polymerization of the acid in the reaction
medium.
Scheme 2.
Two different sets of conditions were developed for the cyclization of the hydroxyamides 3 to
the corresponding oxazolines 4 (Scheme 3 and Table 2).
Oxazolines 4ai, 4aii, 4cii and 4dii were best obtained under Mitsunobu reaction conditions5f
(1.5 equiv. PPh3, 1.5 equiv. DEAD, toluene, reflux; conditions A). The yield of the (S)-tert-leu-
cinol-derived oxazoline 4aiii was much improved by treatment of 3aiii with tosyl chloride and
triethylamine in the presence of DMAP in refluxing dichloroethane5d (conditions B). In this way,
the overall yield (from 2iii) for 4aiii is 75%, three times higher than that previously described.4
Conditions B, which involve the generation and in situ cyclization of the hydroxyamide tosylate,
also led to somewhat better yields of oxazoline 4cii. It is worth noting that fluoride-induced

A. Ce6allos et al. / Tetrahedron: Asymmetry 11 (2000) 4407–4416
4409
Table 1
b-Hydroxyamides 3 from 2-alkynoic acids 1 and b-aminoalcohols 2
2-Alkynoic acid (R1)
b-Aminoalcohol (R2)
b-Hydroxiamide, % yield
1a (Ph)
1a (Ph)
1a (Ph)
1b (Si(CH3)3)
1c (CH3)
2i (CH2CH(CH3)2)
2ii (CH2Ph)
2iii (C(CH3)3)
2ii (CH2Ph)
2ii (CH2Ph)
2ii (CH2Ph)
3ai, 87
3aii, 84
3aiii, 92
3bii, 93
3cii, 93
3dii, 63
3eii, 0
1d ((CH2)5CHꢀCH2)
1e (H)
2ii (CH2Ph)
Scheme 3.
Table 2
2-Alkynyl-1,3-oxazolines 4 from N-(2-alkynoyl)hydroxyamides 3
b-Hydroxyamide
Reaction conditionsa
Oxazoline (R1, R2)
Yield (%)
3ai
A
A
A
B
A
B
A
B
A
4ai (Ph, CH2CH(CH3)2)
4aii (Ph, CH2Ph)
4aiii (Ph, C(CH3)3)
81
87
23
82
60
75
72
67
60
3aii
3aiii
3aiii
3bii
3bii
3cii
3cii
3dii
4aiii (Ph, C(CH3)3)
4bii (Si(CH3)3, CH2Ph)
4bii (Si(CH3)3, CH2Ph)
4cii (CH3, CH2Ph)
4cii (CH3, CH2Ph)
4dii ((CH2)5CHꢀCH2, CH2Ph)
a See Scheme 3.
desilylation of this compound afforded the 2-ethynyloxazoline 4eii in 91% yield, thus overcom-
ing the lack of accessibility of the b-hydroxyamides derived from propiolic acid (Scheme 4).
In summary, we have developed a practical and general route to 2-alkynyl-1,3-oxazolines,
taking place in only two steps from readily available 2-alkynoic acids and 2-aminoalcohols.
Preliminary experiments show that chiral 2-alkynyl-1,3-oxazolines readily participate in inter-
molecular Pauson–Khand reactions, leading regioselectively and in high yields to 3-(2-oxa-
zolinyl)-2-cyclopentenones as chromatographically separable diastereomer mixtures; in contrast,
intramolecular Pauson–Khand cycloadditions appear to be highly disfavoured for this kind of
substrate. These results shall be reported in due time. We hope that other applications of
2-alkynyl-1,3-oxazolines will develop as a result of the present ready availability of these
hitherto almost unknown homochiral substrates.

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Scheme 4.
3. Experimental
3.1. General methods
Optical rotations were measured at room temperature (23°C) on a Perkin–Elmer 241 MC
polarimeter (concentration in g/100 ml). Melting points were determined on a Gallenkamp
apparatus and have not been corrected. Infrared spectra were recorded on a Nicolet 510 FT-IR
instrument. NMR spectra were acquired on Varian-Gemini 200 or Varian Unity 300 instruments
in CDCl3. 1H NMR spectra were obtained at 200 or 300 MHz (s=singlet, d=doublet, t=triplet,
q=quartet, h=heptuplet, m=multiplet and b=broad) using tetramethylsilane (TMS) as an
internal standard in CDCl3, and 13C NMR spectra were obtained at 50.3 or 75.3 MHz,
referenced to residual CHCl3 (l=77.00 ppm) in CDCl3. Carbon multiplicities (CH3, CH2, CH,
Cq) have been assigned by DEPT experiments. Low-resolution mass spectra were recorded on
a Hewlett–Packard 5988 A spectrometer; ammonia was used for chemical ionization (CI).
High-resolution mass spectra were performed by the ‘Unidade de Espectrometria de Masas de
la Universidade de Santiago de Compostela’, using the FAB+ technique. Elemental analyses
were performed by the ‘Servei d’Ana`lisis Elementals del CSIC de Barcelona’. Chromatographic
separations were carried out using SiO2 (230–400 mesh) eluting with hexanes–ethyl acetate
mixtures. Chromatographic analyses were performed on a Helwett–Packard 1050 HPLC instru-
ment equipped with a Nucleosil 120 C18 (20 cm) column. Dichloromethane, 1,2-dichloroethane
,
and dioxane were distilled over calcium hydride and preserved on 4 A molecular sieves.
Tetrahydrofuran was distilled over sodium benzophenone ketyl before use. Toluene was distilled
over sodium immediately prior to use. Triethylamine was distilled over calcium hydride and
preserved on KOH pellets. 8-Nonen-2-ynoic acid 1d was prepared as previously described,2c and
(S)-2-amino-3-phenyl-1-propanol 2ii was obtained from the corresponding amino acid according
to the methodology of McKennon and Meyers.8 All of the remaining starting materials were
obtained from commercial suppliers and used without purification. Reactions were generally
performed in flame- or oven-dried glassware under nitrogen.
3.2. Preparation of N-(2-hydroxyethyl)ynamides 3
3.2.1. N-[(1S)-2-Hydroxy-1-(2-methylpropyl)ethyl]-3-phenylprop-2-ynamide, 3ai
To a stirred solution of 2.67 g (18.3 mmol) of phenylpropiolic acid 1a in 120 ml of anhydrous
dioxane, 2.12 g (18.4 mmol) of N-hydroxysuccinimide and 3.79 g (18.4 mmol) of N,N%-dicyclo-
hexylcarbodiimide were added sequentially. After 2.5 h of stirring at room temperature, 2.10 ml
(1.92 g, 16.3 mmol) of (S)-(+)-leucinol 2i were added via a syringe; stirring was maintained for
an additional 5 h until completion of the reaction (TLC monitoring). After this time, the

A. Ce6allos et al. / Tetrahedron: Asymmetry 11 (2000) 4407–4416
4411
precipitated N,N%-dicyclohexylurea was filtered off, and the solvent was eliminated at reduced
pressure. The residue was taken up in 100 ml of ethyl acetate, and the solution was washed twice
with 30 ml of a saturated NaCl solution. After extracting the aqueous phase with ethyl acetate
(20 ml), the combined organic extracts were dried over sodium sulfate and the solvents removed
in vacuo. The crude product was purified by column chromatography (hexane/ethyl acetate
70/30) to give 3.49 g (87% yield) of 3ai as a colourless solid. Colourless crystals, mp 102–3°C.
[h]2D3=−44.4 (c 1.26 CHCl3). IR (KBr) 3250, 2950, 2217, 1630 cm−1. H NMR (300 MHz)
1
l=7.55–7.27 (m, 5H), 6.20 (d, J=8.8 Hz, 1H), 4.18 (m, 1H), 3.65 (m, 2H), 2.58 (b, 1H), 1.70
(m, 1H), 1.40 (m, 2H), 0.96 (d, J=6.9 Hz, 6H). 13C NMR (75 MHz) l=153.8 (Cq), 132.4 (CH),
129.9 (CH), 128.5 (CH), 120.0 (Cq), 85.2 (Cq), 82.9 (Cq), 65.1 (CH2), 50.3 (CH), 39.9 (CH2),
24.8 (CH), 23.0 (CH3), 22.2 (CH3). MS (CI-NH3) m/e=246 ([M+1]+, 100%). Elemental analysis:
calculated for C15H19NO2: C, 73.43%; H, 7.81%; N, 5.71%; found: C, 73.63%; H, 7.84%; N,
5.66%.
3.2.2. N-[(1S)-1-Benzyl-2-hydroxyethyl]-3-phenylprop-2-ynamide, 3aii
To a stirred solution of 3.29 g (22.5 mmol) of phenylpropiolic acid (1a) in 120 ml of
anhydrous dioxane, 2.41 g (20.9 mmol) of N-hydroxysuccinimide and 4.26 g (20.7 mmol) of
N,N%-dicyclohexylcarbodiimide were added sequentially. After 2.5 h of stirring at room temper-
ature, 3.05 g (20.2 mmol) of (S)-(−)-2-amino-3-phenyl-1-propanol (2ii) were added in one single
portion; stirring was maintained for 8 h until completion of the reaction (TLC monitoring).
After this time, the precipitated N,N%-dicyclohexylurea was filtered off, and the solvent was
eliminated at reduced pressure. The residue was taken up in 100 ml of ethyl acetate, and the
solution was washed twice with 30 ml of a saturated NaCl solution. After extracting the aqueous
phase with ethyl acetate (20 ml), the combined organic extracts were dried over sodium sulfate
and the solvents removed in vacuo. The crude product was purified by column chromatography
(hexane/ethyl acetate 65/35) to give 4.76 g (84% yield) of 3aii as a colourless solid. Colourless
crystals, mp 113–4°C. [h]2D3=−68.8 (c 1.65 CHCl3). IR (KBr) 3287, 2950, 2217, 1630, 1329, 1055,
1
758, 692 cm−1. H NMR (200 MHz) l=7.50–7.21 (m, 10H), 6.67 (d, J=8.0 Hz, 1H), 4.25 (m,
1H), 3.95 (b, 1H), 3.60 (m, 2H), 2.93 (d, J=7.4 Hz, 2H). 13C NMR (50 MHz) l=153.7 (Cq),
137.3 (Cq), 132.5 (CH), 129.2 (CH), 128.6 (CH), 128.5 (CH), 128.4 (CH), 126.2 (CH), 120.0
(Cq), 85.4 (Cq), 82.9 (Cq), 62.9 (CH2), 53.1 (CH), 36.8 (CH2). MS (CI-NH3) m/e=280 ([M+1]+,
100%), 297 ([M+18]+, 39%). Elemental analysis: calculated for C18H17NO2: C, 77.43%; H, 6.09%;
N, 5.02%; found: C, 77.25%; H, 6.18%; N, 4.85%.
3.2.3. N-[(1S)-1-(tert-Butyl)-2-hydroxyethyl]-3-phenylprop-2-ynamide, 3aiii
Obtained by the method described above starting from 0.438 g (3.00 mmol) of phenylpropiolic
acid 1a, 0.450 g (3.91 mmol) of N-hydroxysuccinimide, 0.713 g (3.46 mmol) of N,N%-dicyclo-
hexylcarbodiimide and 0.390 g (3.33 mmol) of (S)-tert-leucinol 2iii in 30 ml of anhydrous
dioxane. The reaction was complete after 15 h of stirring at room temperature. Working up and
column chromatography (hexane/ethyl acetate 3/1) afforded 0.677 g (92% yield) of hydrox-
yamide 3aiii. Colourless crystals, mp 119–21°C. [h]2D3=−20.6 (c 1.63 CHCl3). IR (KBr) 3226,
1
3064, 2965, 2213, 1632, 1329, 1310, 1053, 754 cm−1. H NMR (200 MHz) l=7.56–7.37 (m, 5H),
6.32 (d, J=9.0 Hz, 1H), 4.00–3.50 (m, 3H), 2.60 (b, 1H), 1.00 (s, 9H). 13C NMR (50 MHz)
l=154.0 (Cq), 132.4 (CH), 129.9 (CH), 128.4 (CH), 120.0 (Cq), 85.7 (Cq), 82.5 (Cq), 62.4
(CH2), 59.8 (CH), 33.9 (Cq), 26.9 (CH3). MS (CI-NH3) m/e=246 ([M+1]+, 100%), 263 ([M+18]+,
36%).

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3.2.4. N-[(1S)-1-Benzyl-2-hydroxyethyl]-3-trimethylsilylprop-2-ynamide, 3bii
Obtained by the method described above starting from 0.235 g (1.65 mmol) of trimethyl-
silylpropiolic acid 1b, 0.242 g (2.10 mmol) of N-hydroxysuccinimide, 0.406 g (1.97 mmol) of
N,N%-dicyclohexylcarbodiimide and 0.285 g (1.88 mmol) of (S)-(−)-2-amino-3-phenyl-1-
propanol 2ii in 30 ml of anhydrous dioxane. The reaction was complete after 15 h of stirring
at room temperature. Working up and column chromatography (hexane/ethyl acetate 70/30)
afforded 0.424 g (93% yield) of hydroxyamide 3bii. Colourless crystals, mp 85–87°C. [h]2D3=
−49.6 (c 1.10 CHCl3). IR (KBr) 3208, 3060, 2185 (very weak), 1624, 1312, 1252, 1051, 847
1
cm−1. H NMR (200 MHz) l=7.10–7.00 (m, 5H), 6.08 (d, J=7.8 Hz, 1H), 4.00 (m, 1H), 3.40
(m, 2H), 2.69 (d, J=7.0 Hz, 2H), 0.00 (s, 9H). The signal corresponding to the OH group
could not be identified. 13C NMR (50 MHz) l=153.7 (Cq), 137.9 (Cq), 129.8 (CH), 129.3
(CH), 127.3 (CH), 98.0 (Cq), 92.7 (Cq), 63.5 (CH2), 53.6 (CH), 37.4 (CH2), 0.0 (CH3). MS
(CI-NH3) m/e=276 ([M+1]+, 100%), 293 ([M+18]+, 72%).
3.2.5. N-[(1S)-1-Benzyl-2-hydroxyethyl]but-2-ynamide, 3cii
Obtained by the method described above starting from 0.128 g (1.52 mmol) of tetrolic acid
1c, 0.175 g (1.52 mmol) of N-hydroxysuccinimide, 0.361 g (1.75 mmol) of N,N%-dicyclohexyl-
carbodiimide and 0.285 g (1.88 mmol) of (S)-(−)-2-amino-3-phenyl-1-propanol (2ii) in 30 ml
of anhydrous dioxane. The reaction mixture was stirred overnight at room temperature.
Working up and column chromatography (hexane/ethyl acetate 40/60) afforded 0.307 g (93%
yield) of hydroxyamide 3cii. Colourless crystals, mp 70–72°C. [h]2D3=−67.6 (c 1.13 CHCl3). IR
1
(KBr) 3287, 2963, 2251, 1636, 1302, 1049 cm−1. H NMR (200 MHz) l=7.32–7.21 (m, 5H),
6.10 (m, 1H), 4.20 (m, 1H), 3.60 (m, 2H), 2.89 (d, J=7.4 Hz, 2H), 2.50 (b, 1H), 1.93 (s, 3H).
13C NMR (50 MHz) l=149.9 (Cq), 133.5 (Cq), 125.4 (CH), 124.9 (CH), 122.9 (CH), 86.0
(Cq), 80.2 (Cq), 59.3 (CH2), 49.1 (CH), 32.9 (CH2), 3.9 (weak, CH3). MS (CI-NH3) m/e=218
([M+1]+, 100%), 235 ([M+18]+, 97%).
3.2.6. N-[(1S)-1-Benzyl-2-hydroxyethyl]oct-7-en-2-ynamide, 3dii
Obtained by the method described above starting from 0.612 g (4.03 mmol) of 8-nonen-2-
ynoic acid 1d, 0.525 g (4.57 mmol) of N-hydroxysuccinimide, 0.930 g (4.50 mmol) of N,N%-
dicyclohexylcarbodiimide and 0.680 g (4.50 mmol) of (S)-(−)-2-amino-3-phenyl-1-propanol
(2ii) in 40 ml of anhydrous tetrahydrofuran. The reaction mixture was stirred overnight at
room temperature. Working up and column chromatography (hexane/ethyl acetate 70/30)
afforded 0.715 g (63% yield) of hydroxyamide 3dii. Colourless solid, mp=71–72°C. [h]2D3=−
1
44.8 (c 1.02 CHCl3). IR (KBr) 3284, 2932, 2247, 1624, 1327, 1283, 1030, 700 cm−1. H NMR
(200 MHz) l=7.31–7.21 (m, 5H), 6.11 (d, J=6.8 Hz, 1H), 5.80 (m, 1H), 5.00 (m, 2H), 4.18
(m, 1H), 3.60 (m, 2H), 2.50 (s, 1H), 2.90 (d, J=7.4 Hz, 2H), 2.26 (m, 2H), 2.05 (m, 2H),
1.60–1.40 (m, 4H). 13C NMR (50 MHz) l=154.0 (Cq), 138.1 (CH), 137.2 (Cq), 129.2 (CH),
128.6 (CH), 126.6 (CH), 114.8 (CH2), 88.0 (Cq), 75.7 (Cq, 63.2 (CH2), 52.9 (CH), 36.7 (CH2),
33.2 (CH2), 28.0 (CH2), 27.1 (CH2), 18.5 (CH2). MS (CI-NH3) m/e=286 ([M+1]+, 100%), 303
([M+18]+, 25%).

A. Ce6allos et al. / Tetrahedron: Asymmetry 11 (2000) 4407–4416
4413
3.3. General procedures for the cyclization of N-(2-hydroxyethyl)ynamides 3 to
2-alkynyl-1,3-oxazolines 4
3.3.1. Method A
To a stirred solution of the ynamide 3 (1.0 mmol) and triphenylphosphine (1.5 mmol) in
anhydrous toluene (10 ml), 1.5 mmol of diethyl azodicarboxylate (DEAD) were added at room
temperature. The resulting mixture was heated to reflux until the disappearance of the starting
amide (TLC monitoring), cooled and submitted directly to purification by column chromatogra-
phy, eluting with hexane/ethyl acetate mixtures.
3.3.2. Method B
To a stirred solution of the ynamide 3 (1.0 mmol), triethylamine (5.0 mmol) and 4-(dimethyl-
amino)pyridine (4-DMAP, 0.05 mmol) in 1,2-dichloroethane (4 ml), 1.4 mmol of p-toluenesul-
fonyl chloride (TsCl) were added at room temperature. The resulting mixture was heated to
reflux until the disappearance of the starting amide (TLC monitoring). After cooling, the solvent
and the excess triethylamine were eliminated at reduced pressure, and the residue was purified
by column chromatography, eluting with hexane/ethyl acetate mixtures.
3.3.3. (4S)-4-(2-Methylpropyl)-2-(2-phenylethynyl)-1,3-oxazoline, 4ai
Prepared according to general method A, starting from 0.494 g (2.01 mmol) of hydroxyamide
3ai, 0.809 g (3.09 mmol) of triphenylphosphine and 0.47 ml (0.520 g, 3.00 mmol) of DEAD in
20 ml of anhydrous toluene. After heating to reflux for 24 h and chromatographic purification
(92/8 hexane/ethyl acetate), 0.370 g (81% yield) of oxazoline 4ai were obtained. Colourless
crystals, mp 72–3°C. [h]2D3=−84.1 (c 1.17 CHCl3). IR (KBr) 2954, 2234, 1628, 1362, 1163, 972,
1
762, 688 cm−1. H NMR (200 MHz) l=7.58–7.34 (m, 5H), 4.40 (m, 2H), 3.90 (m, 1H), 1.90 (h,
J=6.6 Hz, 1H), 1.65 (m, 1H), 1.30 (m, 1H), 0.97 (d, J=6.6 Hz, 3H), 0.95 (d, J=6.6 Hz, 3H).
13C NMR (50 MHz) l=149.5 (Cq), 132.4 (CH), 129.9 (CH), 128.4 (CH), 120.3 (Cq), 97.0 (Cq),
89.0 (Cq), 73.0 (CH2), 65.3 (CH), 45.2 (CH2), 25.3 (CH), 23.0 (CH3), 22.4 (CH3). MS (CI-NH3)
m/e=228 ( [M+1]+, 100%). Elemental analysis: calculated for C15H17NO: C, 79.30%; H, 7.49%;
N, 6.17%; found: C, 79.18%; H, 7.78%; N, 5.97%.
3.3.4. (4S)-4-Benzyl-2-(2-phenylethynyl)-1,3-oxazoline, 4aii
Prepared according to general method A, starting from 0.558 g (2.00 mmol) of hydroxyamide
3aii, 0.785 g (3.00 mmol) of triphenylphosphine and 0.47 ml (0.520 g, 3.00 mmol) of DEAD in
20 ml of anhydrous toluene. After heating to reflux for 24 h and chromatographic purification
(92/8 hexane/ethyl acetate), 0.454 g (87% yield) of oxazoline 4aii were obtained. Colourless
crystals, mp 75–6°C. [h]2D3=+15.3 (c 1.08 CHCl3). IR (KBr) 2950, 2232, 1624, 1358, 1161, 970,
762, 689 cm−1. 1H NMR (200 MHz) l=7.55–7.26 (m, 10H), 4.60 (m, 1H), 4.30 (m, 1H), 4.10 (m,
1H), 3.17 (dd, J=13.6 Hz, J%=6.0 Hz, 1H), 2.73 (dd, J=13.6 Hz, J%=8.0 Hz, 1H). 13C NMR
(50 MHz) l=150.0 (Cq), 137.4 (Cq), 132.4 (CH), 130.0 (CH), 129.1 (CH), 128.6 (CH), 128.4
(CH), 126.6 (CH), 120.3 (Cq), 89.7 (Cq), 71.7 (CH2), 70.0 (CH), 41.4 (CH2). The signal around
97–98 ppm corresponding to the acetylenic carbon vicinal to the oxazoline ring was very weak
and could not be observed. MS (CI-NH3) m/e=262 ( [M+1]+, 100%). Elemental analysis:
calculated for C18H15NO: C, 82.73%; H, 5.79%; N, 5.36%; found: C, 82.37%; H, 5.62%; N,
5.50%.

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3.3.5. (4S)-4-(tert-Butyl)-2-(2-phenylethynyl)-1,3-oxazoline, 4aiii4
(a) Prepared according to general method A, starting from 0.150 g (0.61 mmol) of hydroxy-
amide 3aiii, 0.478 g (1.82 mmol) of triphenylphosphine and 0.30 ml (0.332 g, 1.93 mmol) of
DEAD in 6 ml of anhydrous toluene. After heating to reflux for 24 h and chromatographic
purification (97/3 hexane/ethyl acetate), 0.032 g (23% yield) of oxazoline 4aiii were obtained. (b)
Following the general method B, 0.175 g (0.92 mmol) of TsCl were added to a solution of 0.128
g (0.52 mmol) of hydroxyamide 3aiii, 0.35 ml (0.254 g, 2.5 mmol) of triethylamine and 0.006 g
(0–05 mmol) of 4-DMAP in 2 ml of 1,2-dichloroethane. After heating to reflux for 24 h and
chromatographic purification, 0.097 g (82% yield) of oxazoline 4aiii were obtained. Colourless
solid, mp 57–9°C. [h]2D3=−69.3 (c 1.19 CHCl3). IR (KBr) 2959, 2869, 2230, 1634, 1354, 1163,
1
978, 756 cm−1. H NMR (200 MHz) l=7.56–7.35 (m, 5H), 4.40–4.00 (m, 3H), 0.96 (s, 9H). 13C
NMR (50 MHz) l=149.2 (Cq), 132.4 (CH), 129.9 (CH), 128.4 (CH), 120.5 (Cq), 89.0 (Cq), 76.4
(CH), 68.6 (CH2), 33.8 (Cq), 25.9 (CH3). The signal around 97–98 ppm corresponding to the
acetylenic carbon vicinal to the oxazoline ring was very weak and could not be observed. MS
(CI-NH3) m/e=228 ([M+1]+, 100%), 245 ([M+18]+, 1%).
3.3.6. (4S)-4-Benzyl-2-(2-trimethylsilylethynyl)-1,3-oxazoline, 4bii
(a) Prepared according to general method A, starting from 0.424 g (1.50 mmol) of hydroxy-
amide 3bii, 0.610 g (2.33 mmol) of triphenylphosphine and 0.36 ml (0.398 g, 2.30 mmol) of
DEAD in 15 ml of anhydrous toluene. After heating to reflux for 15 h and chromatographic
purification (99/1 hexane/ethyl acetate), 0.230 g (60% yield) of oxazoline 4bii were obtained. (b)
Following the general method B, 0.470 g (2.47 mmol) of TsCl were added to a solution of 0.446
g (1.60 mmol) of hydroxyamide 3bii, 1.20 ml (0.871 g, 8.65 mmol) of triethylamine and 0.006 g
(0.05 mmol) of 4-DMAP in 8 ml of 1,2-dichloroethane. After heating to reflux for 3 h and
chromatographic purification, 0.310 g (75% yield) of oxazoline 4bii were obtained. Colourless
oil. [h]2D3=−6.9 (c 1.08 CHCl3). IR (NaCl film)=2961, 1624, 1346, 1252, 1221, 935, 847, 762, 700
1
cm−1. H NMR (200 MHz) l=7.00–6.99 (m, 5H), 4.20 (m, 1H), 4.00 m, 1H), 3.76 (m, 1H), 2.90
(dd, J=14.0 Hz, J%=5.4 Hz, 1H), 2.43 (dd, J=14.0 Hz, J%=8.4 Hz, 1H), 0.00 (s, 9H). 13C NMR
(50 MHz) l=150.0 (Cq), 138.0 (Cq), 129.8 (CH), 129.3 (CH), 127.3 (CH), 98.0 (Cq), 92.7 (Cq),
72.4 (CH2), 68.6 (CH), 42.0 (CH2), 0.0 (CH3). MS (CI-NH3) m/e=258 ([M+1]+, 100%). HRMS
(FAB+): calculated for C15H19NOSi: 257.1236; found: 257.1223.
3.3.7. (4S)-4-Benzyl-2-(prop-1-ynyl)-1,3-oxazoline, 4cii
(a) Prepared according to general method A, starting from 0.187 g (0.86 mmol) of hydroxy-
amide 3cii, 0.436 g (1.66 mmol) of triphenylphosphine and 0.26 ml (0.288 g, 1.62 mmol) of
DEAD in 10 ml of anhydrous toluene. After heating to reflux for 24 h and chromatographic
purification (7/1 hexane/ethyl acetate), 0.124 g (72% yield) of oxazoline 4cii were obtained. (b)
Following the general method B, 0.366 g (1.92 mmol) of TsCl were added to a solution of 0.271
g (1.25 mmol) of hydroxyamide 3cii, 1.00 ml (0.726 g, 7.22 mmol) of triethylamine and 0.006 g
(0.05 mmol) of 4-DMAP in 6 ml of 1,2-dichloroethane. After heating to reflux for 12 h and
chromatographic purification, 0.167 g (67% yield) of oxazoline 4cii were obtained. Colourless
solid, mp=38–40°C. [h]2D3=−17.4 (c 1.10 CHCl3). IR (NaCl film)=3029, 2921, 2247, 1630, 1352,
1
1273, 1246, 1024, 955, 700 cm−1. H NMR (200 MHz) l=7.27–7.23 (m, 5H), 4.40 (m, 1H), 4.20
(m, 1H), 4.00 (m, 1H), 3.11 (dd, J=13.4 Hz, J%=5.6 Hz, 1H), 2.67 (dd, J=13.4 Hz, J%=8.4 Hz,
1H), 2.00 (s, 3H). 13C NMR (50 MHz) l=149.9 (Cq), 137.4 (Cq), 129.1 (CH), 128.5 (CH), 126.5
(CH), 88.4 (Cq), 71.5 (CH2), 67.6 (CH), 41.3 (CH2), 4.1 (CH3). The signal corresponding to the

A. Ce6allos et al. / Tetrahedron: Asymmetry 11 (2000) 4407–4416
4415
acetylenic carbon vicinal to the oxazoline ring was very weak and could not be observed. MS
(CI-NH3) m/e=200 ([M+1]+, 100%). HRMS (FAB+): calculated for C13H14NO: 200.1075;
found: 200.1071.
3.3.8. (4S)-4-Benzyl-2-(oct-7-en-1-ynyl)-1,3-oxazoline, 4dii
Prepared according to general method A, starting from 0.695 g (2.43 mmol) of hydroxyamide
3dii, 1.067 g (4.07 mmol) of triphenylphosphine and 0.57 ml (0.630 g, 3.60 mmol) of DEAD in
25 ml of anhydrous toluene. After heating to reflux for 32 h and chromatographic purification
(98/2 hexane/ethyl acetate), 0.389 g (60% yield) of oxazoline 4dii were obtained. Colourless
dense oil. [h]2D3=−3.8 (c 1.07 CHCl3). IR (NaCl film)=2929, 2245, 1630, 1352, 1242, 1028 cm−1.
1H NMR (200 MHz) l=7.25–7.17 (m, 5H), 5.80 (m, 1H), 5.00 (m, 2H), 4.40 (m, 1H), 4.20 (m,
1H), 3.95 (m, 1H), 3.10 (dd, J=14.0 Hz, J%=5.6 Hz, 1H), 2.65 (dd, J=14.0 Hz, J%=8.4 Hz,
1H), 2.31 (m, 2H), 2.05 (m, 2H), 1.54 (m, 4H). 13C NMR (50 MHz) l=149.8 (Cq), 138.1 (CH),
137.4 (Cq), 129.0 (CH), 128.5 (CH), 126.5 (CH), 114.8 (CH2), 92.3 (Cq), 71.5 (CH2), 69.6 (Cq),
67.7 (CH), 41.3 (CH2), 33.1 (CH2), 27.9 (CH2), 27.1 (CH2), 18.8 (CH2). MS (CI-NH3) m/e=268
([M+1]+, 100%). HRMS (FAB+): calculated for C18H21NO: 267.1623; found: 267.1622.
3.3.9. (4S)-4-Benzyl-2-ethynyl-1,3-oxazoline, 4eii
To a stirred solution of 0.106 g (0.40 mmol) of the 2-(trimethylsilylethynyl)-1,3-oxazoline 4bii
in 1 ml of tetrahydrofuran, 0.01 ml (0.01 mmol) of a 1.0 M solution of tetrabutylammonium
fluoride in tetrahydrofuran and 0.05 ml (2.78 mmol) of distilled water were added sequentially
via a syringe, at room temperature. After 30 min, the reaction mixture was diluted with 20 ml
of dichloromethane and washed with 20 ml of a saturated NaCl solution. The aqueous phase,
after separation, was washed with dichloromethane (2×20 ml). The combined organic phase was
dried over Na2SO4, and the solvent was removed at reduced pressure. The crude product was
purified by column chromatography (1/1 hexane/ethyl acetate), to give 0.067 g (91% yield) of the
2-ethynyl-1,3-oxazoline 4eii. Colourless solid, mp=53–7°C. [h]2D3=−62.5 (c 1.58 CHCl3). IR
1
(NaCl film)=3178, 3023, 2915, 2120, 1628, 1350, 1211, 976, 700 cm−1. H NMR (200 MHz)
l=7.28–7.22 (m, 5H), 4.45 (m, 1H), 4.25 (m, 1H), 4.00 (m, 1H), 3.12 (dd, J=13.8 Hz, J%=6.0
Hz, 1H), 2.95 (s, 1H), 2.70 (dd, J=13.8 Hz, J%=8.4 Hz, 1H). 13C NMR (50 MHz) l=149.0 (Cq,
137.1 (Cq), 129.1 (CH), 128.5 (CH), 126.6 (CH), 78.3 (Cq), 71.9 (CH), 71.8 (CH2), 67.8 (CH),
41.1 (CH2). MS (CI-NH3) m/e=186 ([M+1]+, 100%). HRMS (FAB+): calculated for C12H11NO:
185.0841; found: 185.0843.
Acknowledgements
Financial support from DGES (PB97-0939 and PB98-1246) is gratefully acknowledged.
Ramon Rios thanks the Ministerio de Educacio´n y Cultura for a predoctoral fellowship.
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