Novel synthesis of 2-trichloromethyl-4-vinyloxazoline and its derivatization by ring cleavage reactions

Article abstract of DOI:10.1007/s10593-012-1077-0

A novel efficient and eco-friendly method for the synthesis of 2-trichloromethyl-4-vinyloxazoline is presented that involves Lewis acid-catalyzed cyclization of bisimidate derived from but-3-ene-1,2-diol. The derivatization potential of 2-trichloromethyl-4-vinyloxazoline is demonstrated by ring opening reactions with water, hydrobromic acid, hydrochloric acid, and acetic acid leading to allylamine derivatives.

Full text of DOI:10.1007/s10593-012-1077-0

Chemistry of Heterocyclic Compounds, Vol. 48, No. 6, September, 2012 (Russian Original Vol. 48, No. 6, June, 2012)
NOVEL SYNTHESIS OF 2-TRICHLOROMETHYL-
4-VINYLOXAZOLINE AND ITS DERIVATIZATION
BY RING CLEAVAGE REACTIONS*
L. Grigorjeva1, A. Maleckis1, K. Klimovica1, M. Skvorcova1,
N. Ivdra1, G. Leitis1, and A. Jirgensons1**
A novel efficient and eco-friendly method for the synthesis of 2-trichloromethyl-4-vinyloxazoline is
presented that involves Lewis acid-catalyzed cyclization of bisimidate derived from but-3-ene-1,2-diol.
The derivatization potential of 2-trichloromethyl-4-vinyloxazoline is demonstrated by ring opening
reactions with water, hydrobromic acid, hydrochloric acid, and acetic acid leading to allylamine
derivatives.
Keywords: allyl amine, Lewis acids, oxazoline, trichloroacetimidate, cyclization.
2-Trichloromethyl-4-vinyloxazoline (2) is an attractive multifunctional building block with high
derivatization potential. The synthesis of 2-trichloromethyl-4-vinyloxazoline (2) using Pd(II)-catalyzed
cyclization of bistrichloroacetimidate Z-1 derived from (Z)-but-2-ene-1,4-diol was first reported by Sabat and
Johnson [1]. They have also demonstrated the transformation of vinyloxazoline 2 to protected vinylglycinol,
which was further used for the synthesis of unnatural amino acids. Asymmetric synthesis of vinyloxazoline 2
from both bistrichloroacetimidate isomers E-1 and Z-1 catalyzed by cationic Pd(II) complex was later developed
in our group [2].
Cl3C
H2C
CCl3
O
cat. Pd(II)
O
NH
N
HN
O
CCl3
E,Z-1
2
Recently, we reported that vinyloxazolines could also be obtained by Lewis acid (LA)-catalyzed
cyclization of bistrichloroacetimidates derived from substituted 1,4-butenediols [3, 4]. Compared to palladium
catalysis, this method offers a cheaper and more eco-friendly alternative for the synthesis of vinyloxazolines as
amino acid and amino alcohol precursors. Unfortunately, cyclization of the simplest analog – bistrichloroacet-
_______
*Dedicated to professor Ivars Kalvinsh on the occasion of his 65th birthday.
**To whom correspondence should be addressed, e-mail: aigars@osi.lv.
1Latvian Institute of Organic Synthesis, 21 Aizkraukles St., Riga LV-1006, Latvia.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, 989-994, June, 2012. Original article
submitted March 12, 2012.
0009-3122/12/4806-0919©2012 Springer Science+Business Media New York
919

imidate E-1 – to vinyloxazoline 2 by the use of FeCl3 or AlCl3 as catalysts was problematic due to the formation
1
of side products to a considerable extent (one major unidentified side product >20%, by GC/MS and H NMR
spectroscopy). In addition, we observed relatively slow formation of product 2 from bistrichloro-
CCl3
10 mol% LA
H2C
CH2Cl2, rt
Cl3CCN
O
CCl3
NH
H2C
OH
2
O
cat. DBU
85%
OH
3
NH
4
TABLE 1. Yield of Vinyloxazoline 2 in Lewis Acid-catalyzed Cyclization
of Bistrichloroacetimidate 4
Entry
Catalyst
Time, min
Yield, %
1
2
3
4
AlCl3
FeCl3
BF3·OEt2
TMSOTf
5
10
1
95
94
96
93
1
acetimidate E-1 compared to its higher homologs [3, 4]. A reason for that could be slower ionization of acid-
complexed imidate derived from primary alcohol in compound E-1 to give carbenium ion, which is the proposed
reactive intermediate for this reaction type [3, 4].
We anticipated that clean and efficient synthesis of the vinyloxazoline 2 could be achieved from
bistrichloroacetimidate 4 as the starting material, since the more facile ionization of the secondary imidate group
in compound 4 would lead to fast formation of the allylic cation intermediate and thus side reactions would be
diminished. Indeed, bistrichloroacetimidate 4, regioisomeric to compound 1, derived from commercially available
but-3-ene-1,2-diol (3) underwent rapid cyclization when exposed to Lewis acid catalysts. The reaction provided
the desired vinyloxazoline 2 in excellent yields with all the catalysts studied (Table 1).
To expand the utility of vinyloxazoline 2, its ring cleavage reactions were investigated. As reported
previously, hydrolysis of vinyloxazoline 2 under strongly acidic conditions leads to vinylglycinol 5 [1, 2, 5].
Partial hydrolysis of vinyloxazoline 2 was achieved by literature protocol using TsOH in aqueous pyridine to
give N-trichloroacetyl glycinol 6 in excellent yield [6-8]. There are several literature precedents demonstrating
that protonation of the oxazoline ring makes it susceptible for ring cleavage with nucleophiles [9-12]. Based on
this, we explored ring cleavage of vinyloxazoline 2 with acids containing a nucleophilic counterion. The
reaction of vinyloxazoline 2 with HBr and HCl provided allyl amine derivatives 7 and 8 in good yields. In a
similar way, heating of oxazoline 2 in a mixture of acetic acid and acetic anhydride gave O-acylated
H2C
OAc
O
Ac2O–AcOH
aq. HCl
H2C
H2C
OH
2·HCl
HN
60°C
70%
EtOH, rt
70% [2]
NH
5
CCl3
9
2
OH
O
H2C
Cl
O
HBr
AcOH
rt
HCl
TsOH
Py–H2O, 80°C
91%
HN
HN
Et2O, rt
70%
CCl3
6
CCl3
95%
8
H2C
Br
HN
O
CCl3
7
920

vinylglycinol 9. Next, we demonstrated that acidic conditions can be used also for cleavage of chiral
vinyloxazoline 2 without inducing racemization. For this purpose, the enantiomerically enriched substrate (R)-2
[2] (ee 82%) was transformed to bromide (R)-7 according to previously established conditions. Bromide (R)-7
was then subjected to K2CO3 which regenerated vinyloxazoline (R)-2 (ee 82%) with complete conservation of
enantiomeric purity.
Bromomethylallyl amine 7 could be potentially used as alkylating agent by replacement of bromine
with nucleophiles. We found that this transformation is limited to very good nucleophiles, such as azide ion,
thioacetate, and phenylthiolate, to give azide 10 and thiol derivatives 11a,b. An attempt to achieve the
alkylation with other nucleophiles such as phenoxide, alkoxide, potassium phthalimide malonate anion, or
Meldrum's acid anion resulted in cyclization regenerating vinyloxazoline 2.
H2C
N3
O
H2C
SR
O
NaN3
KSR
HN
HN
7
DMF, rt
73%
DMF, rt
CCl3
CCl3
11a,b
10
11 a R = Ac (89%), b R = Ph (84%)
In summary, we have developed a new synthesis of vinyloxazoline by Lewis acid-catalyzed cyclization
of bisimidate derived from but-3-ene-1,2-diol. This constitutes an efficient and environmentally friendly method
for the synthesis of a multifunctional building block. Ring cleavage reactions of vinyloxazoline were studied
and it was shown that these can provide access to a variety of vinylamine derivatives. We believe that our
research presented in this article will enable the use of vinyloxazoline as intermediate for the synthesis of
pharmaceutically relevant compounds and natural products.
EXPERIMENTAL
1
The IR spectrum was recorded on a Shimadzu IR Prestige 21 spectrometer in nujol. H and 13C NMR
spectra were obtained on a Varian Mercury 400 spectrometer (400 and 100 MHz, respectively) in CDCl3 using
the residual solvent signal as internal standard (δН 7.26 and δС 77.2 ppm). HRMS were obtained using a Q-TOF
micro high resolution mass spectrometer with ESI. Optical rotation was measured on a Perkin Elmer 141
polarimeter. Chiral gas chromatography was performed on an Agilent Technologies 6890N Network GC
System chromatograph, chiral stationary phase, column: 6-TBDMS-2,3-Me-β-CD 50%, 25 m; program 60°C,
5 min, then 60–210°C, 8°C/min; injection: split less 250°C; injection volume 1 μl; sample concentration 1
mg/ml, FID detector. Melting points were determined on an OptiMelt Automated Melting Point System. Flash
chromatography was carried out using Merck Kieselgel (230-400 mesh). Thin-layer chromatography was
performed on silica gel and was visualized by staining with KMnO4. Reagents and starting materials were
obtained from commercial sources and used as received. The solvents were purified and dried by standard
procedures prior to use; petroleum ether of boiling range 60–80°C was used.
But-1-ene-3,4-diylbis(trichloroacetimidate) (4). 4 Å Molecular sieves were added to a solution of but-
3-ene-1,2-diol (3) (0.25 g, 2.84 mmol) in CH2Cl2 (25 ml). The reaction mixture was cooled to 0°C and then
DBU (0.09 ml, 0.57 mmol, 20 mol %) was added. The solution was stirred at 0°C for 30 min. Then
trichloroacetonitrile (1.13 ml, 11.30 mmol) was added, and the reaction mixture was stirred until TLC showed
complete conversion (0.5 h). The solvent was removed under reduced pressure and the residue was purified by
flash column chromatography using petroleum ether–EtOAc, 8:1, as an eluent to give compound 4. Yield 0.90 g
(85%). Colorless oil. 1H NMR spectrum, , ppm (J, Hz): 4.47 (1H, dd, J = 11.7, J = 7.4) and 4.56 (1H, dd, J = 11.7,
J = 3.5, CH2O); 5.38 (1H, d, J = 11.0) and 5.54 (1H, d, J = 17.2, CH2=CH); 5.79–5.84 (1H, m, HCO); 5.94 (1H,
13
ddd, J = 17.2, J = 11.0, J = 6.7, CH2=CH); 8.36 (1H, br. s, NH); 8.42 (1H, br. s, NH). C NMR spectrum, ,
921

ppm: 69.0 (CH2O); 76.0 (HCO); 91.0 (CCl3); 91.3 (CCl3); 119.3 (CH2=C); 131.1 (C=CH); 161.6 (C=NH);
162.5 (C=NH). Unstable in conditions for high-resolution mass spectrum.
2-Trichloromethyl-4-vinyloxazoline (2). 4 Å Molecular sieves and Lewis acid catalyst (0.053 mmol,
10 mol%) were added to a stirred solution of but-1-ene-3,4-diyl(bistrichloroacetimidate) (4) (0.200 g, 0.53 mmol)
in CH2Cl2 (10 ml) at room temperature. After the reaction was complete (TLC control in the first minute of the
reaction), Et3N (50 mol%, 37 l, 0.27 mmol) was added to the reaction mixture and then the solvent was
removed under reduced pressure. The residue was purified by chromatography on a short silica gel column
using petroleum ether–EtOAc, 8:1, as an eluent to give compound 2 as a colorless oil (see Table 1).
Spectroscopic characterization matched with literature data [1, 2].
N-[1-(Hydroxymethyl)prop-2-en-1-yl]trichloroacetamide (6). p-TsOH·H2O (2.18 g, 11.5 mmol) was
added to a solution of 2-trichloromethyl-4-vinyloxazoline (2) (2.24 g, 10.4 mmol) in a mixture of pyridine and
water (4:1, 150 ml). The mixture was heated at 80°C for 2.5 h and then cooled to room temperature. Pyridine
was removed in vacuo and the residue partitioned between EtOAc (100 ml) and 5% aq. KHSO4 (100 ml). The
aqueous phase was separated and extracted repeatedly with EtOAc (2100 ml). The combined organic phase
was washed with brine (100 ml) and dried over Na2SO4. The extract was filtered and the solvent was removed in
vacuo to give compound 6. Yield 2.21 g (91%). Colorless crystalline material. Physicochemical and spectral
data of the obtained compound matched with literature data [13].
N-(1-Bromobut-3-en-2-yl)trichloroacetamide (7). HBr (33%) in AcOH (2.5 ml) was added to a
solution of 2-trichloromethyl-4-vinyloxazoline (2) (1.03 g, 4.8 mmol) in CH2Cl2 (10 ml). The reaction mixture
was stirred at room temperature for 4 h and then poured into saturated aq. NaHCO3 (30 ml). The mixture was
extracted with EtOAc (340 ml), the combined organic phase was washed with brine, dried over Na2SO4,
filtered and the solvent was removed in vacuo. The residue was purified on silica gel column (eluent EtOAc–
light petroleum ether, gradient 1:8 to 1:3) to give compound 7. Yield 1.34 g (95%). Colorless crystalline
1
material; mp 58-60°C. H NMR spectrum, , ppm (J, Hz): 3.53 (1H, dd, J = 10.6, J = 4.5) and 3.67 (1H, dd,
J = 10.6, J = 4.3, CH2Br); 4.77 (1H, m, CHN); 5.30-5.42 (2H, m, CH2=CH); 5.86 (1H, ddd, J = 15.7, J = 10.2,
J = 5.1, CH2=CH); 6.96 (1H, s, NH). 13C NMR spectrum, , ppm: 35.6 (CH2Br); 52.8 (CHN); 92.3 (CCl3);
118.7 (CH=CH2); 133.6 (CH=CH2); 161.3 (C=O). Found, m/z: 293.8853 [M+H]+. C6H8BrCl3NO. Calculated,
m/z: 293.8855.
Enantiomerically enriched (R)-N-(1-bromobut-3-en-2-yl)trichloroacetamide R-(7) was prepared from
(R)-2-trichloromethyl-4-vinyloxazoline R-(2) [2] (ee 82%, chiral GC). [α]D20 +26.98° (c 5.5, CH2Cl2).
Anhydrous K2CO3 (25.5 mg, 0.185 mmol) was added to a solution of compound R-(7) (11.0 mg, 0.037
mmol) in DMF (1 ml). The reaction mixture was stirred at room temperature overnight and then poured into
saturated aq. NaCl (25 ml). The mixture was extracted with EtOAc (325 ml), the combined organic phase was
washed with brine, dried over Na2SO4, filtered, and the solvent was removed in vacuo to give compound (R)-2
(ee 82%) as colorless oil.
N-(1-Chlorobut-3-en-2-yl)trichloroacetamide (8). HCl (2.5 M) in Et2O (2.5 ml) was added to a
solution of 2-trichloromethyl-4-vinyloxazoline (2) (0.30 g, 1.4 mmol) in CH2Cl2 (5 ml). The reaction mixture
was stirred at room temperature for 4 h and poured into saturated aq. NaHCO3 (15 ml). The mixture was
extracted with EtOAc (315 ml), combined organic phase was washed with brine, dried over Na2SO4, and the
solvent was evaporated in vacuo. The residue was purified by flash chromatography on silica gel (eluent
EtOAc–light petroleum ether, gradient 1:8 to 1:3) to give compound 8. Yield 0.25 g (70%). White crystalline
1
material, mp 56-57°C. H NMR spectrum, , ppm (J, Hz): 3.72 (1H, dd, J = 10.6, J = 4.5) and 3.81 (1H, dd,
J = 10.6, J = 4.3, CH2Cl); 4.79 (1H, m, CHN); 5.32–5.44 (2H, m, CH2=CH); 5.89 (1H, ddd, J = 15.8, J = 10.6,
J = 5.5, CH2=CH); 6.97 (1H, s, NH). 13C NMR spectrum, , ppm: 46.5 (CH2Cl); 53.4 (CHN); 92.3 (CCl3); 118.8
(CH=CH2); 132.9 (CH=CH2); 161.4 (C=O). Found, m/z: 249.9416 [M+H]+. C6H8Cl4NO. Calculated, m/z:
249.9360.
2-[(Trichloroacetyl)amino]but-3-en-1-yl Acetate (9). AcOH (1 ml) was mixed with Ac2O (1 ml) and
kept at room temperature for 2 h. In this mixture, 2-trichloromethyl-4-vinyloxazoline (2) (0.30 g, 1.4 mmol) was
922

dissolved. The mixture was heated at 60°C for 2 h and then cooled to room temperature. The reaction mixture
was poured into saturated aq. NaHCO3 (25 ml) and agitated for 30 min, then extracted with EtOAc (320 ml).
The combined organic phase was washed with brine and dried over Na2SO4. The extract was filtered, the
solvent was evaporated, and the residue was purified by flash chromatography on silica gel (eluent EtOAc–light
petroleum ether, gradient 1:8 to 1:3) to give compound 9. Yield 0.27 g (70%). Colorless oil. 1H NMR spectrum, ,
ppm (J, Hz): 2.05 (3H, s, CH3); 3.42 (1H, dd, J = 11.0, J = 4.7) and 4.47 (1H, dd, J = 11.0, J = 5.1, CH2OAc);
4.93 (1H, m, CHN); 5.21-5.44 (2H, m, CH2=CH); 5.75 (1H, s, NH); 5.83 (1H, ddd, J = 16.2, J = 10.6, J = 5.9,
CH2=CH). 13C NMR spectrum, , ppm: 23.2 (CH3C=O); 50.3 (CHN); 69.4 (CH2OAc); 92.9 (CCl3); 118.3
(CH=CH2); 132.9 (CH=CH2); 161.9 (CCl3C=O); 170.1 (CH3C=O). Found, m/z: 273.9807 [M+H]+.
C8H11Cl3NO3. Calculated, m/z: 273.9805.
N-(1-Azidobut-3-en-2-yl)trichloroacetamide (10). NaN3 (0.195 g, 3 mmol) was added to a solution of
N-(1-bromobut-3-en-2-yl)trichloroacetamide (7) (0.300 g, 1 mmol) in DMF (3 ml). The reaction mixture was
stirred at room temperature for 12 h and then poured into water (30 ml). The mixture was extracted with EtOAc
(60 ml), and the organic phase was washed with brine and dried over Na2SO4. The extract was filtered, the
solvent was evaporated, and the residue was purified by flash chromatography on silica gel (eluent EtOAc–light
petroleum ether, gradient 1:8 to 1:3) to give compound 10. Yield 0.192 g (73%). Colorless oil. IR spectrum, ,
cm-1: 2103 (N3), 1696 (C=O). 1H NMR spectrum, , ppm (J, Hz): 3.56 (1H, dd, J = 12.5, J = 4.7) and 3.62 (1H,
dd, J = 12.5, J = 4.7, CH2N3); 4.61 (1H, m, CHN); 5.34-5.44 (2H, m, CH=CH2); 5.86 (1H, ddd, J = 15.7, J = 10.2,
J = 5.5, CH=CH2); 6.83 (1H, s, NH). 13C NMR spectrum, , ppm: 52.7 (CH2N3); 53.8 (CHN); 92.3 (CCl3);
118.6 (CH=CH2); 133.2 (CH=CH2); 161.4 (C=O).
S-{2-[(Trichloroacetyl)amino]but-3-en-1-yl} Thioacetate (11a). Potassium thioacetate (0.34 g, 3 mmol)
was added to a solution of N-(1-bromobut-3-en-2-yl)trichloroacetamide (7) (0.30 g, 1 mmol) in DMF (3 ml). The
reaction mixture was stirred at room temperature for 12 h and then poured into water (30 ml). The mixture was
extracted with EtOAc (60 ml), and the organic phase was washed with brine and dried over Na2SO4. The extract
was filtered, the solvent was evaporated, and the residue was purified by flash chromatography on silica gel
(eluent EtOAc–light petroleum ether, gradient 1:8 to 1:3) to give compound 11a. Yield 0.26 g (89%). Colorless
oil. 1H NMR spectrum, , ppm (J, Hz): 2.37 (3H, s, CH3C=O); 3.10 (1H, dd, J = 14.5, J = 9.0) and 3.25 (1H, dd,
J = 14.5, J = 4.3, CH2S); 4.56 (1H, m, CHN); 5.27 (1H, dt, J = 10.2, J = 0.8) and 5.31 (1H, dt, J = 16.0, J = 0.8,
13
CH=CH2); 5.81 (1H, ddd, J = 16.0, J = 10.2, J = 5.5, CH=CH2); 7.05 (1H, s, NH). C NMR spectrum, , ppm:
30.5 (CH3C=O); 32.3 (CH2S); 54.1 (CHN); 92.4 (CCl3); 117.5 (CH=CH2); 134.6 (CH=CH2); 161.6 (CCl3C=O);
196.8 (CH3C=O). Found, m/z: 289.9490 [M+H]+. C8H11Cl3NO2S. Calculated, m/z: 289.9576.
N-[1-(Phenylsulfanyl)but-3-en-2-yl]trichloroacetamide (11b). Thiophenol (0.330 g, 0.31 ml, 3 mmol)
and K2CO3 (0.138 g, 1 mmol) were added to a solution of N-(1-bromobut-3-en-2-yl)trichloroacetamide (7)
(0.300 g, 1 mmol) in DMF (3 ml). The reaction mixture was stirred at room temperature for 4 h and then poured
into water (30 ml). The mixture was extracted with EtOAc (60 ml), and the organic phase was washed with
brine (640 ml). The extract was dried over Na2SO4, and the solvent was evaporated. The residue was purified
by flash chromatography on silica gel (eluent EtOAc–light petroleum ether, gradient 1:20 to 1:8) to give
1
compound 11b. Yield 0.280 g (84%). Colorless oil. H NMR spectrum, , ppm (J, Hz): 3.21 (2H, m, CH2S);
4.62 (1H, m, CHN); 5.32-5.45 (2H, m, CH=CH2); 5.85 (1H, ddd, J = 15.5, J = 10.2, J = 5.5, CH=CH2); 6.92
(1H, s, NH); 7.15-7.35 (3H, m, H Ph); 7.40 (2H; m, H Ph). 13C NMR spectrum, , ppm: 38.5 (CH2S); 52.8
(CHN); 92.4 (CCl3); 117.5 (CH=CH2); 127.1 (Ph); 129.3 (Ph); 130.5 (C Ph); 134.7 (CH=CH2); 134.7 (C Ph);
161.2 (C=O). Found, m/z: 323.9778 [M+H]+. C12H13NOSCl3. Calculated, m/z: 323.9783.
This work was carried out with the financial support of the European Social Fund
(No. 2009/0203/1DP/1.1.2.0/09/APIA/VIAA/023).
923

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