Enantioselective formal [2+2] cycloaddition of ketenes with nitroso compounds catalyzed by N-heterocyclic carbenes

Article abstract of DOI:10.1039/c0ob00249f

Chiral N-heterocyclic carbenes were found to be efficient catalysts for the formal [2+2] cycloaddition reaction of alkyl(aryl)ketenes and nitroso compounds to give the corresponding 1,2-oxazetidin-3-ones in moderate to good yields with high enantioselecti

Full text of DOI:10.1039/c0ob00249f

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Enantioselective formal [2+2] cycloaddition of ketenes with nitroso
compounds catalyzed by N-heterocyclic carbenes†
Tong Wang, Xue-Liang Huang and Song Ye*
Received 13th June 2010, Accepted 11th August 2010
DOI: 10.1039/c0ob00249f
Chiral N-heterocyclic carbenes were found to be efficient catalysts for the formal [2+2] cycloaddition
reaction of alkyl(aryl)ketenes and nitroso compounds to give the corresponding 1,2-oxazetidin-3-ones
in moderate to good yields with high enantioselectivities. Reductive ring-opening of the oxazetidinones
give the corresponding a-hydroxy acid derivatives in good yields.
Introduction
Optically active a-hydroxy acids and their derivatives are impor-
tant building blocks for asymmetric synthesis of natural products
and biologically interesting compounds.1 As a consequence,
numerous efforts have been made to their asymmetric synthesis.2
Scheme 1 Chiral NHC precursors derived from L-pyroglutamic acid.
In the subtype of tertiary a-hydroxy acid derivatives, several
efficient routes have been developed. Representative approaches
include the a-alkylation of oxazolidin-2,4-diones,3 hydroxylation
of enolates,2a dihydroxylation of ketene acetals,4 addition of
organometallic reagents or nitromethane to a-ketoesters,5 allylic
alkylation of 1,2-enediol carbonates or related compounds,6 and
cyanosilylation of ketones.7
The asymmetric cycloaddition reaction of ketenes provided an
interesting approach to masked chiral a-hydroxy acids. Lectka
reported an enantioselective [4+2] cycloaddition of monosubsti-
tuted ketenes and o-quinones to give the corresponding chiral
secondly a-hydroxy acid derivatives.8 We recently reported an
enantioselective [4+2] cycloaddition of disubstituted ketenes and
o-quinones, but the transformation of the resulted cycloadduct to
a-hydroxy acid failed.9 Interestingly, Fu et al. reported the planar-
chiral DMAP derivative-catalyzed cycloaddition of disubstituted
ketenes and nitroso compounds and the corresponding tertiary
a-hydroxy acid derivatives were obtained in good yields and high
enantioselectivities. However, aryl(methyl)ketenes wherein the aryl
group is unhindered, lead to low enantioselectivties (3–13% ee).10
During the preparation of this manuscript, Chatterjee et al.
reported a copper-catalyzed enantioselective [2+2] cycloaddition
of 2-nitrosopyridine with ketenes.11
Results and discussion
Initially, the cycloaddition of phenyl(ethyl)ketene 2a and ni-
trosobenzene catalyzed by NHCs was investigated. However,
only trace of desired cycloadduct was detected for these NHCs-
catalyzed reactions. According to literatures, two regioisomers,
1,2-oxazetidin-4-ones (A) and 1,2-oxazetidin-3-ones (B) could
be formed for the uncatalyzed reaction of ketenes and nitroso
compounds, while the cycloadducts B are unstable and further
decarboxylate to imines (Scheme 2).16
Scheme 2 Regioisomers for the cycloaddition of ketenes and nitroso
compounds.
During our investigation of the NHC-catalyzed reaction,
The use of N-heterocylic carbenes (NHC) as organocatalysts
has been received great attentions in the past decades.12 In the line
of our research on NHC-catalyzed reactions,13 we, simultaneously
with Smith et al.,14 found that NHCs are efficient catalysts for the
reactions of ketenes. The easy preparation of the NHCs 1¢ derived
from L-pyrogultamic acid15 and the high enantioselectivities of the
catalytic reactions promoted us to investigate the cycloaddtion
of ketenes and nitroso compounds using NHCs 1¢ as catalysts
(Scheme 1).
Fu et al. reported that nitroso compound
3 with a 2-
trifluoromethylphenyl group was the best choice for their chiral
DMAP derivative-catalyzed reaction.10 Thus, the NHC-catalyzed
reaction of ketenes and nitroso compounds was re-investigated by
using nistroso compound 3 as the reagent (Table 1).
It was found that the NHC 1a¢ could catalyze the reaction of
ketene 2a and nitroso compound 3 to give the desired cycloadduct
of 1,2-oxazetidin-3-one 4a in good yield with high enantioselectiv-
ity (entry 1).17 Solvent screening revealed that THF is the solvent
of choice (entries 1–4). It is interesting that the reaction at -20 ◦C
gave the best result. Lowering or elevating the reaction temperature
resulted in inferior yields and enantioselectivities (entries 1 vs.
5–8).
Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory
of Molecular Recognition and Function, Institute of Chemistry, Chinese
Academy of Sciences, Beijing 100190, China. E-mail: songye@iccas.ac.cn
† Electronic supplementary information (ESI) available: Copy of 1H
NMR, 13C NMR and CD spectra. See DOI: 10.1039/c0ob00249f
The NHCs synthesized from different aryl hydrazines were then
investigated.15,18 NHC 1b¢ and 1c¢ with an electron-donating group
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Table 1 Optimization of reaction conditions
Table 2 Enantioselecitive [2+2] cycloaddition reaction of ketenes and
nitroso compound 3 catalyzed by chiral NHC 1a¢
Entry
2
Ar
R
4
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
Ph
Et
Et
Et
Et
Et
Et
Et
Me
Me
n-Pr
n-Bu
4a
4b
4c
4d
4e
4f
4g
4h
4i
88
54
80
57
80
82
81
35
43
83
86
94
79
95
72
94
90
85
70
95
88
95
4-ClC6H4
4-MeC6H4
4-MeOC6H4
3-MeC6H4
2-ClC6H4
1-Naphthyl
Ph
3-MeC6H4
Ph
Ph
Entry
NHCa
Solvent
T/◦C
Yieldb (%)
eec,d (%)
1
2
3
4
5
6
7
8
1a¢
1a¢
1a¢
1a¢
1a¢
1a¢
1a¢
1a¢
1b¢
1c¢
1d¢
1e¢
1f¢
THF
DME
DCM
ether
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
-20
-20
-20
-20
-10
0
-30
-40
-20
-20
-20
-20
-20
-20
88
79
23
14
89
35
83
46
85
90
80
Trace
45
7
94
83
40
46
91
79
87
72
91
92
93
/
9
10
11
2j
2k
4j
4k
a See note a in Table 1. b Isolated yields. c Determined by chiral HPLC.
9
10
11
12
13
14
82
-55
1g¢
a NHCs 1a¢–g¢ were generated from their precursors 1a–g (10 mol%) and
Cs2CO3 (10 mol%) at room temperature for 20 min, and used immediately.
b Isolated yields. c Determined by chiral HPLC. d The minus value indicates
an opposite enantioselectivity observed.
Scheme 3 Synthesis of a-hydroxy amides.
In conclusion, chiral N-heterocyclic carbenes were found to
be efficient catalysts for the cycloaddition of aryl(alkyl)ketenes
and a nitroso compound. Ketenes with methyl, ethyl, n-propyl
and n-butyl subsitutent all worked well to give the corresponding
1,2-oxazetidin-3-ones in moderate to good yields with high
enantioselectivities.
(Ar2 = 4-MeOC6H4 or 2-i-PrC6H4)19 afforded comparable results
(entries 1 and 9–10). NHC 1d¢ with a N-benzyl group20 gave
cycloadduct in 80% yield with 93% ee (entry 11). NHCs with a free
hydroxy group were also examined (entries 12–14).21 Although the
NHC 1e¢ (Ar1 = Ar2 = Ph, R = H) gave only trace cycloadduct,
NHC 1f¢ (Ar1 = 3,5-(CF3)2C6H3, Ar2 = Ph, R = H) showed some
catalytic activity for the reaction. The NHC 1g¢ with bulky mesity
group and a free hydoxy group gave the cycloadduct in very low
yield but with opposite enantioselectivity (entry 1 vs. 14).11d
Several other aryl(alkyl)ketenes were then tested for cycloaddi-
tion with nitroso compound 3 (Table 2). Aryl(ethyl)ketenes 2a–
d with either electron-withdrawing (4-Cl) or electron-donating
groups (4-Me, 4-MeO) gave the cycloadduct in good to high
yield with good to excellent enantioselectivity (entries 2–4).
Aryl(alkyl)ketenes with ortho- or meta-substituted aryl group
(3-MeC6H4, 2-ClC6H4) (2e–f) and 1-naphthyl(ethyl) ketene (2g)
worked well (entries 5–7). For phenyl(methyl)ketene, which gave
cycloadduct in 72% yield with 13% ee in Fu’s report,10 low yield
but good enantioselectivity (70% ee) was observed in the NHC-
catalyzed reaction (entry 8). Another aryl(methyl)ketene 2i (Ar =
3-MeC6H4) gave product in 43% yield with 95% ee (entry 9).
Phenyl(n-alkyl)ketene (2j–k, R = n-Pr, n-Bu) worked well (entries
10–11).
Experimental
Unless otherwise indicated, all starting materials were obtained
from commercial supplies and used as received. Anhydrous ether,
DME and THF were distilled from sodium and benzophenone.
Anhydrous CH2Cl2 was distilled from CaH2. Chiral triazoliums
1a–g and ketenes were synthesized according to our previous
reports.13 1-Nitroso-2-(trifluoromethyl)benzene was prepared ac-
cording to literature.10 All reactions utilizing air or moisture
sensitive reagents were performed in oven-dried glasswares with
magnetic stirring under nitrogen atmosphere. Column chromato-
graph was performed with silica gel 200~300 mesh.
General procedure for the [2+2] cycloaddition of ketenes with
1-nitroso-2-(trifluoromethyl)benzene catalyzed by NHC
To an oven-dried 50 mL Schlenk tube equipped with a stir bar
was charged with triazolium salt 1a (28.5 mg, 0.05 mmol) and
anhydrous Cs2CO3 (16.3 mg, 0.05 mmol). This tube was closed
with a septum, evacuated, and back-filled with nitrogen. To this
mixture was added freshly distilled THF (5 mL) and stirred for
20 min at room temperature. The resulting solution was cooled
to -20 ◦C, and 1-nitroso-2-(trifluoromethyl)benzene (131.3 mg,
The resulted optically active 1,2-oxazetidin-3-ones are valuable
in organic synthesis.22 For examples, a-hydroxy amides could be
easily prepared by the reductive cleavage of the N–O bond of
1,2-oxazetidin-3-ones 4a and 4c (Scheme 3).
5008 | Org. Biomol. Chem., 2010, 8, 5007–5011
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0.75 mmol) was added in one portion, followed by slow addition of
the ketene (0.5 mmol). After stirring for 24 h, the reaction mixture
was diluted with ethyl acetate and passed through a short silica
pad. The solvent was removed under reduced pressure and the
residue was purified by chromatography on silica gel (petroleum
ether/ethylacetate, typically 100 : 1) to give the desired product.
Racemic samples for the standard of chiral HPLC spectra were
prepared using racemic NHC precursor rac-1a, prepared from
racemic pyroglutamic acid, as catalyst.
7.4 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d 168.9, 160.0, 134.5 (q,
J = 1.5 Hz), 132.8, 130.2, 127.9, 127.7, 127.3 (q, J = 5.3 Hz), 126.4,
124.0, 123.7 (q, J = 32.3 Hz), 122.8 (q, J = 271.5 Hz), 114.2, 55.3,
29.5, 7.9; HRMS (ESI) calcd for C18H17F3NO3 [M+H]+ 352.1161,
found 352.1152; IR (KBr): n 2925, 1798, 1605, 1513, 1454, 1318,
1253, 1175, 1139, 1057, 1035, 834, 763 cm-1; [a]D20 -33.4 (CHCl3,
c = 1.0); H◦PLC analysis: 72% ee [Daicel CHIRALPAK AD-H
column; 20 C; 1.0 mL min-1; solvent system: 2-propanol/hexane =
1 : 99; retention times: 11.0 min (major), 16.8 min (minor)].
(-)-4-Ethyl-4-phenyl-2-(2-(trifluoromethyl)phenyl) -1,2-oxaze-
tidin-3-one (4a)10. Yield: 141 mg, 88%; colorless oil; Rf 0.35
(petroleum ether/ethyl acetate = 20 : 1); H NMR (CDCl3, 300
(-)-4-Ethyl-4-m-tolyl-2-(2-(trifluoromethyl)phenyl)-1,2-oxaze-
tidin-3-one (4e)10. Yield: 133 mg, 80%; colorless oil; Rf 0.35
(petroleum ether/ethyl acetate = 20 : 1); H NMR (CDCl3, 300
1
1
MHz): d 7.72 (d, J = 7.8 Hz, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.60–
7.55 (m, 3H), 7.49–7.36 (m, 4H), 2.44–2.20 (m, 2H), 1.16 (t, J =
7.2 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d 168.7, 135.8, 134.5,
132.9, 128.9, 128.8, 128.1, 127.5 (q, J = 5.3 Hz), 124.9, 124.2,
123.8 (q, J = 32.3 Hz), 122.9 (q, J = 271.5 Hz), 101.9, 30.0, 7.9;
[a]D20 -47.8 (CHCl3, c = 1.0; literature:10 [a]D20 -39, CHCl3, c = 0.30);
HPLC analysis: 94% ee [Daicel CHIRALPAK AD-H column;
20 ◦C; 1.0 mL min-1; solvent system: 2-propanol/hexane = 1 : 99;
retention times: 5.9 min (major), 7.4 min (minor)].
MHz): d 7.72 (d, J = 7.8 Hz, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.58
(t, J = 7.5 Hz, 1H), 7.43–7.30 (m, 4H), 7.20–7.18 (m, 1H), 2.40 (s,
3H), 2.40–2.19 (m, 2H), 1.16 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3,
75 MHz): d 168.8, 138.7, 135.8, 134.6 (q, J = 1.5 Hz), 132.9, 129.6,
128.8, 128.0, 127.5 (q, J = 5.25 Hz), 125.5, 124.2, 123.8 (q, J =
32.3 Hz), 122.9 (q, J = 271.5 Hz), 122.0, 102.0, 30.1, 21.6, 7.9;
[a]D20 -47.8 (CHCl3, c = 1.0; literature:10 [a]D20 -36, CHCl3, c = 0.36);
HPLC analysis: 94% ee [Daicel CHIRALPAK AD-H column;
20 ◦C; 1.0 mL min-1; solvent system: 2-propanol/hexane = 1 : 99;
retention times: 5.4 min (major), 6.7 min (minor)].
(-)-4-(4-Chlorophenyl)-4-ethyl-2-(2-(trifluoromethyl)phenyl)-
1,2-oxazetidin-3-one (4b). Yield: 96 mg, 54%; colorless oil; Rf
(-)-4-(2-Chlorophenyl)-4-ethyl-2-(2-(trifluoromethyl)phenyl)-
1,2-oxazetidin-3-one (4f). Yield: 147 mg, 82%; colorless oil; Rf
1
0.30 (petroleum ether/ethyl acetate = 20 : 1); H NMR (CDCl3,
1
300 MHz): d 7.73 (d, J = 7.8 Hz, 1H), 7.66–7.56 (m, 2H), 7.51–
7.47 (m, 2H), 7.45–7.40 (m, 3H), 2.41–2.16 (m, 2H), 1.15 (t, J =
7.4 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d 168.2, 134.8, 134.3,
134.2 (q, J = 0.75 Hz), 132.9, 129.0, 128.3, 127.5 (q, J = 5.3
Hz), 126.3, 124.3, 124.0 (q, J = 32.3 Hz), 122.8 (q, J = 271.5
Hz), 101.2, 29.8, 7.8; HRMS (ESI) calcd for C17H14ClF3NO2
[M+H]+ 356.0665, found 356.0667; IR (KBr): n 3459, 2922, 1798,
1634, 1492, 1454, 1318, 1270, 1174, 1141, 1093, 1057, 1036,
1015, 896, 830, 763, 657, 635 cm-1; [a]D20 -37.4 (CHCl3, c = 1.0);
HPLC analysis: 79% ee [Daicel CHIRALPAK AD-H column;
20 ◦C; 1.0 mL min-1; solvent system: 2-propanol/hexane = 1 : 99;
retention times: 7.6 min (major), 10.6 min (minor)].
0.38 (petroleum ether/ethyl acetate = 20 : 1); H NMR (CDCl3,
300 MHz): d 7.77–7.65 (m, 3H), 7.58 (t, J = 7.5 Hz, 1H), 7.48–
7.38 (m, 2H), 7.36–7.30 (m, 2H), 2.62–2.39 (m, 2H), 1.18 (t, J =
7.5 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d 167.2, 134.2 (q, J = 1.5
Hz), 133.5, 132.9, 131.9, 131.3, 130.1, 128.2, 127.5 (q, J = 5.25 Hz),
127.3, 126.9, 124.3, 124.0 (q, J = 32.3 Hz), 122.9 (q, J = 271.5 Hz),
102.0, 28.7, 8.2; HRMS (ESI) calcd for C17H14ClF3NO2 [M+H]+
356.0665, found 356.0657; IR (KBr): n 3460, 1797, 1603, 1453,
1318, 1267, 1139, 1056, 1037, 759 cm-1; [a]D20 -36.0 (CHCl3, c = 1.0);
HPLC analysis: 90% ee [Daicel CHIRALPAK AD-H column; 20
◦C; 1.0 mL min-1; solvent system: 2-propanol/hexane = 1 : 99;
retention times: 6.7 min (minor), 7.6 min (major)].
(-)-4-Ethyl-4-p-tolyl-2-(2-(trifluoromethyl)phenyl)-1,2-oxaze-
tidin-3-one (4c). Yield: 135 mg, 80%; colorless oil; Rf 0.35
(petroleum ether/ethyl acetate = 20 : 1); H NMR (CDCl3, 300
(-)-4-Ethyl-4-(naphthalen-1-yl)-2-(2-(trifluoromethyl)phenyl)-
1,2-oxazetidin-3-one (4g)10. Yield: 150 mg, 81%; colorless oil; Rf
0.35 (petroleum ether/ethyl acetate = 20 : 1); H NMR (CDCl3,
1
1
MHz): d 7.72 (d, J = 7.8 Hz, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.57
(t, J = 7.8 Hz, 1H), 7.45–7.37 (m, 3H), 7.26–7.24 (m, 2H), 2.38
(s, 3H), 2.42–2.19 (m, 2H), 1.16 (t, J = 7.4 Hz, 3H); 13C NMR
(CDCl3, 75 MHz): d 168.9, 138.7, 134.5 (q, J = 1.5 Hz), 132.9,
132.8, 129.5, 128.0, 127.4 (q, J = 5.3 Hz), 124.9, 124.1, 123.7 (q,
J = 32.3 Hz), 122.9 (q, J = 271.5 Hz), 101.9, 29.8, 21.2, 7.8; HRMS
(ESI) calcd for C18H17ClF3NO2 [M+H]+ 336.1211, found 336.1210;
IR (KBr): n 3501, 1798, 1603, 1491, 1454, 1318, 1269, 1173, 1138,
1057, 1036, 893, 810, 763, 661 cm-1; [a]D20 -32.4 (CHCl3, c = 1.0);
HPLC analysis: 95% ee [Daicel CHIRALPAK AD-H column;
20 ◦C; 1.0 mL min-1; solvent system: 2-propanol/hexane = 1 : 99;
retention times: 6.6 min (major), 9.2 min (minor)].
300 MHz): d 8.22 (d, J = 8.1 Hz, 1H), 7.91–7.86 (m, 3H), 7.72
(d, J = 8.1 Hz, 1H), 7.65 (d, J = 8.1 Hz, 1H), 7.56–7.47 (m,
4H), 7.38 (t, J = 7.5 Hz, 1H), 2.59–2.50 (m, 2H), 1.21 (t, J =
7.4 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d 167.4, 133.4 (q,
J = 1.5 Hz), 133.3, 131.8, 131.1, 128.7, 128.4, 127.9, 127.0, 126.4
(q, J = 5.25 Hz), 125.4, 125.2, 124.4, 123.9, 123.2, 122.8 (q, J =
32.3 Hz), 122.1, 121.9 (q, J = 271.5 Hz), 102.8, 29.9, 7.4; [a]D20
-27.4 (CHCl3, c = 1.0; literature:10 [a]D20 +36, CHCl3, c = 0.27);
HPLC analysis: 85% ee [Daicel CHIRALPAK AD-H column;
20 ◦C; 0.5 mL min-1; solvent system: 2-propanol/hexane = 1 : 99;
retention times: 13.7 min (minor), 16.1 min (major)].
(-)-4-Methyl-4-phenyl-2-(2-(trifluoromethyl)phenyl)-1,2-oxaze-
tidin-3-one (4h)10. Yield: 53 mg, 35%; colorless oil; Rf 0.25
(-)-4-Ethyl-4-(4-methoxyphenyl)-2-(2-(trifluoromethyl)phenyl)-
1,2-oxazetidin-3-one (4d). Yield: 95 mg, 57%; colorless oil; Rf
1
(petroleum ether/ethyl acetate = 20 : 1); H NMR (CDCl3, 300
1
0.20 (petroleum ether/ethyl acetate = 20 : 1); H NMR (CDCl3,
MHz): d 7.76–7.69 (m, 2H), 7.64–7.57 (m, 3H), 7.49–7.37 (m,
4H), 2.07 (s, 3 H); 13C NMR (CDCl3, 75 MHz): d 169.2, 136.3,
134.5, 132.9, 129.0, 128.9, 128.2, 127.4 (q, J = 5.3 Hz), 124.9,
124.4, 124.1 (q, J = 32.3 Hz), 122.8 (q, J = 271.5 Hz), 98.3, 22.4;
300 MHz): d 7.72 (d, J = 7.8 Hz, 1H), 7.67 (d, J = 8.1 Hz, 1H),
7.58 (t, J = 7.8 Hz, 1H), 7.60–7.45 (m, 2H), 7.40 (t, J = 7.8 Hz,
1H), 6.99–6.94 (m, 2H), 3.83 (s, 3H), 2.42–2.19 (m, 2H), 1.16 (t, J =
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[a]D20 -6.9 (CHCl3, c = 1.0; literature:10 [a]D20 -8.1, CHCl3, c = 0.28);
HPLC analysis: 70% ee [Daicel CHIRALPAK AD-H column;
20 ◦C; 1.0 mL min-1; solvent system: 2-propanol/hexane = 1 : 99;
retention times: 7.6 min (major), 9.8 min (minor)].
Celite. The filtrate was concentrated under reduced pressure to
give the desired product without further purification.
(+)-2-Hydroxy-2-phenyl-N-(2-(trifluoromethyl)phenyl)butana-
◦
mide (5a). Yield: 111 mg, 99%; m.p. 109 C; Rf 0.6 (petroleum
1
ether/ethyl acetate = 5 : 1); H NMR (CDCl3, 300 MHz): d 9.11
(-)-4-Methyl-4-m-tolyl-2-(2-(trifluoromethyl)phenyl)-1,2-oxa-
zetidin-3-one (4i). Yield: 69 mg, 43%; colorless oil; Rf 0.25
(br s, 1H), 8.23 (d, J = 8.1 Hz, 1 H), 7.67–7.64 (m, 2H), 7.59 (d,
J = 7.5 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.39 (t, J = 7.5 Hz,
1H), 7.34–7.29 (m, 2H), 7.19 (t, J = 7.5 Hz, 1H), 2.89 (s, 1H),
2.52–2.40 (m, 1H), 2.23–2.11 (m, 1H), 0.99 (t, J = 7.5 Hz, 3H);
13C NMR (CDCl3, 75 MHz): d 172.5, 141.8, 135.0 (q, J = 1.5 Hz),
132.8, 128.5, 128.0, 126.0 (q, J = 5.2 Hz), 125.2, 124.3, 124.0
((q, J = 271.5 Hz), 123.5, 120.1 (q, J = 30.0 Hz), 79.8, 32.1,
7.7; HRMS (EI) calcd for C17H16F3NO2 [M]+ 323.1133, found
323.1137; IR (KBr): n 3488, 1653, 1635, 1590, 1532, 1300, 1286,
1172, 1117, 1059, 1034, 811, 763, 651 cm-1; [a]D20 +8.8 (CHCl3,
c = 1.0); H◦PLC analysis: 93% ee [Daicel CHIRALPAK AD-H
column; 20 C; 1.0 mL min-1; solvent system: 2-propanol/hexane =
5 : 95; retention times: 12.0 min (major), 15.1 min (minor)].
1
(petroleum ether/ethyl acetate = 20 : 1); H NMR (CDCl3, 300
MHz): d 7.75–7.68 (m, 2H), 7.6 (t, J = 7.8 Hz, 1H), 7.45–7.31
(m, 4H), 7.20 (d, J = 7.2 Hz, 1H), 2.40 (s, 3 H), 2.07 (s, 3 H);
13C NMR (CDCl3, 75 MHz): d 169.3, 138.7, 136.2, 134.6 (q, J =
1.5 Hz), 132.9, 129.8, 128.8, 128.2, 127.4 (q, J = 5.3 Hz), 125.4,
124.3, 124.0 (q, J = 32.3 Hz), 122.8 (q, J = 271.5 Hz), 121.9,
98.4, 22.4, 21.5; HRMS (ESI) calcd for C17H15F3NO2 [M+H]+
322.1055, found 322.1049; [a]2D0 -55.3 (CHCl3, c = 1.0); IR (KBr):
n 3500, 1807, 1644, 1455, 1319, 1267, 1177, 1139, 764, 741 cm-1;
HPLC analysis: 95% ee [Daicel CHIRALPAK AD-H column;
20 ◦C; 1.0 mL min-1; solvent system: 2-propanol/hexane = 1 : 99;
retention times: 7.4 min (major), 9.5 min (minor)].
(+)-2-Hydroxy-2-p-tolyl-N-(2-(trifluoromethyl)phenyl) butana-
mide (5c). 1,2-oxazetidin-3-one 4c (100 mg, 0.3 mmol; 90%ee;
prepared from 1.5 mmol p-tolyl(ethyl)ketene) was used. Yield:
100 mg, 99%; colorless oil; Rf 0.5 (petroleum ether/ethyl acetate =
(-)-4-Phenyl-4-propyl-2-(2-(trifluoromethyl)phenyl)-1,2-oxaze-
tidin-3-one (4j). Yield: 139 mg, 83%; colorless oil; Rf 0.35
(petroleum ether/ethyl acetate = 20 : 1); H NMR (CDCl3, 300
1
MHz): d 7.70 (d, J = 7.2 Hz, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.57–
7.52 (m, 3H), 7.46–7.34 (m, 4H), 2.36–2.16 (m, 2H), 1.74–1.47 (m,
2H), 0.99 (t, J = 7.5 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d 168.9,
136.1, 134.6 (q, J = 1.5 Hz), 132.9, 128.9, 128.8, 128.1, 127.5 (q,
J = 5.3 Hz), 124.9, 124.1, 123.8 (q, J = 32.3 Hz), 122.9 (q, J = 271.5
Hz), 101.5, 38.9, 17.0, 14.1; HRMS (ESI) calcd for C18H17F3NO2
[M+H]+ 336.1211, found 336.1208; IR (KBr): n 3500, 1806,
1495, 1454, 1318, 1267, 1173, 1138, 1057, 1036, 763, 708 cm-1;
[a]2D0 -45.0 (CHCl3, c = 1.0); HPLC analysis: 88% ee [Daicel
1
5 : 1); H NMR (CDCl3, 300 MHz): d 9.11 (br s, 1H), 8.23 (d,
J = 8.1 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.53–7.48 (m, 3H),
7.21–7.16 (m, 3H), 2.87 (s, 1H), 2.49–2.40 (m, 1H), 2.38 (s, 3H),
2.19–2.08 (m, 1H), 0.99 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3,
75 MHz): d 172.7, 138.9, 137.7, 135.0 (q, J = 1.5 Hz), 132.8,
129.2, 126.1 (q, J = 5.2 Hz), 125.5, 124.3, 124.1 (q, J = 270.7 Hz),
123.5, 120.0 (q, J = 30.0 Hz), 79.7, 32.0, 21.0, 7.7; HRMS (EI)
calcd for C18H18F3NO2 [M]+ 337.1290, found 337.1293; IR (KBr):
n 3445, 1680, 1635, 1590, 1525, 1457, 1320, 1286, 1172, 1117,
1059, 1034, 993, 811, 763, 651 cm-1; [a]D20 +4.5 (CHCl3, c = 1.0);
HPLC analysis: 90% ee [Daicel CHIRALPAK AD-H column;
20 ◦C; 1.0 mL min-1; solvent system: 2-propanol/hexane = 5 : 95;
retention times: 11.9 min (major), 18.0 min (minor)].
◦
CHIRALPAK AD-H column; 20 C; 0.5 mL min-1; solvent
system: 2-propanol/hexane = 1 : 99; retention times: 16.2 min
(major), 18.7 min (minor)].
(-)-4-Butyl-4-phenyl-2-(2-(trifluoromethyl)phenyl)-1,2-oxaze-
tidin-3-one (4k). Yield: 150 mg, 86%; colorless oil; Rf 0.35
1
(petroleum ether/ethyl acetate = 20 : 1); H NMR (CDCl3, 300
Acknowledgements
MHz): d 7.72 (d, J = 8.1 Hz, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.60–
7.54 (m, 3H), 7.47–7.37 (m, 4H), 2.33–2.23 (m, 2H), 1.60–1.50 (m,
2H), 1.46–1.36 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3,
75 MHz): d 168.7, 135.9, 134.4 (q, J = 1.5 Hz), 132.8, 128.8, 128.7,
128.0, 127.4 (q, J = 5.3 Hz), 124.8, 124.1, 123.7 (q, J = 32.3 Hz),
122.8 (q, J = 271.5 Hz), 101.4, 36.4, 25.4, 22.6, 13.8; HRMS (ESI)
calcd for C19H19F3NO2 [M+H]+ 350.1368, found 350.13568; IR
(KBr): n 3497; 2965, 1799, 1651, 1603, 1557, 1504, 1494, 1455,
1318, 1267, 1137, 1057, 1035, 762, 696 cm-1; [a]D20 -43.6 (CHCl3,
c = 0.5); H◦PLC analysis: 95% ee [Daicel CHIRALPAK AD-H
column; 20 C; 0.5 mL min-1; solvent system: 2-propanol/hexane =
1 : 99; retention times: 13.2 min (major), 14.7 min (minor)].
Financial support from National Science Foundation of China
(20872143, 20932008), the Ministry of Science and Technology of
China (2009ZX09501-018) and the Chinese Academy of Sciences
are greatly acknowledged.
Notes and references
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5010 | Org. Biomol. Chem., 2010, 8, 5007–5011
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