Stereoselective one-pot synthesis of oxazolines

Article abstract of DOI:10.1021/jo8003937

(Chemical Equation Presented) Treatment of alkenes with NBS, a nitrile, NaHCO₃ and water in the presence of Cu(OTf)₂ or Zn(OTf)₂ is reported to furnish oxazolines in one pot and good yields. The reaction is equally applica

Full text of DOI:10.1021/jo8003937

SCHEME 1. Synthesis of Oxazolines via Haloamidation
Reaction
Stereoselective One-Pot Synthesis of Oxazolines
Saumen Hajra,* Sukanta Bar, Debarshi Sinha, and
Biswajit Maji
Department of Chemistry, Indian Institute of Technology,
Kharagpur 721302, India
shajra@chem.iitkgp.ernet.in
ReceiVed February 18, 2008
TABLE 1. Synthesis of Oxazoline 3a from Stilbene 1a
Treatment of alkenes with NBS, a nitrile, NaHCO3 and water
in the presence of Cu(OTf)2 or Zn(OTf)2 is reported to
furnish oxazolines in one pot and good yields. The reaction
is equally applicable to chalcones.
entry
MLn
none
conv (%)a
yield of 3a (%)a
1
2
0
0
0
0
NiCl2
3
MgCl2
0
0
4
5
6
7
8
9
10
11
12
13
Mg(OTf)2
Cu2Cl2
0
0
<5
<5
<10
<15
<15
40 (35)
40 (35)
66 (15)
67 (15)
10
25
30
32
35
100
100
100
100
Oxazolines are frequently found in biologically active natural
products and pharmaceuticals.1,2 Their chiral derivatives are
widely used as ligands or chiral pools in asymmetric synthesis.3
Achiral oxazolines are also valuable intermediates in organic
synthesis4 and polymer chemistry.5 Consequently, many meth-
ods exist in the literature for their synthesis.6– 8 The majority
Sm(OTf)3
Yb(OTf)3
Y(OTf)3
Sc(OTf)3
FeCl3
CuCl2
Zn(OTf)2
Cu(OTf)2
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a Determined from the 1H NMR spectra of the crude reaction mixture
with succinic anhydride as an internal standard; yields in the parentheses
refer to the yield of dibromide of trans-stilbene.
of the methods involve prior preparation of precursor 1,2-amino
alcohols.6 Recently, multicomponent reactions have been re-
ported for the synthesis.7 Alternatively, oxazolines are prepared
by cyclization of ꢀ-haloamides 2, which in turn are obtained
by haloamidation reaction of alkenes 1 (Scheme 1). However,
selective haloamidation reactions of alkenes are little explored.9
Recently, an efficient method for the haloamidation of cyclo-
hexenes was reported.10A one-pot synthesis11 of oxazolines from
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10.1021/jo8003937 CCC: $40.75 2008 American Chemical Society
Published on Web 05/07/2008

TABLE 2. Cu(OTf)2-Catalyzed Bromoamidation Reaction and
One-Pot Synthesis of Oxazolinesa
TABLE 3. One-Pot Synthesis of Oxazolines from Chalconesa
entry R1 R2 R3 time (h) convb (%) product yield of 7c (%)
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
OMe
OMe
OMe
H
H
F
Me
Ph
Me
Ph
12
7
14
8
16
6
8
5
5
5
72
100
70
100
72
100
71
100
100
100
(()-7a
(()-7b
(()-7c
(()-7d
(()-7e
(()-7f
(()-7g
(()-7h
(()-7i
(()-7j
65
68
66
69
68
71
69
74
78
76
F
Cl Me
Cl Ph
H
H
F
Me
Ph
Ph
10 OMe Cl Ph
a One-pot synthesis of oxazoline from chalcone 6 (1.0 equiv) was
performed with Zn(OTf)2 (0.05 equiv), 1.2 equiv of NBS, 1.2 equiv of
NaHCO3 and 1.2 equiv of H2O in different nitriles at 20-25 °C.
b Determined from the 1H NMR spectra of the crude reaction mixture
with succinic anhydride as internal standard. c Isolated yield of the
respective oxazoline 7 after column chromatography based on 100%
conversion of the alkenes; 8–12% dibromide and 5–10% bromohydrin
also formed.
Based on our previous experience,12 we envisioned that metal
triflates might catalyze both the haloamidation of alkenes and
the subsequent cyclization to the oxazolines (Scheme 1).
Accordingly, we first studied the reaction of stilbene 1a with
NBS in aqueous CH3CN in the presence of a variety of Lewis
acids, and the results are presented in Table 1.
Among the Lewis acids examined, Zn(OTf)2 and Cu(OTf)2
were found to be most effective for the formation of oxazolines
(entries 12 and 13). The best result was obtained when substrate
1a was treated with 0.05 equiv of Cu(OTf)2 [or Zn (OTf)2], 1.2
equiv of NBS, 1.2 equiv of H2O, and 1.2 equiv of NaHCO3 in
CH3CN at 25 °C, for 8 h. The use of NaHCO3 gave cleaner
reactions. Limiting the amount of water to 1.2 equiv was
required to minimize the competing formation of bromohydrin.
Shorter reaction time led to the formation of a mixture of
bromoamide and oxazoline.
To establish the generality of the reaction, we investigated
different combinations of alkenes and two nitriles, i.e., aceto-
nitrile and benzonitrile (Table 2). trans-Stilbene, styrene, dihy-
dronaphthalene, indene, and ꢀ-propylstyrene directly provided
the oxazolines 3 with both of the nitriles (entries 1–8). On the
other hand, cyclohexene and cis-cyclooctene exclusively yielded
the bromoamides 2 in good yields, which did not cyclize to
give the oxazolines, even on prolonged reaction time (entries
9–12). Treatment with DBU and Et3N transformed the bromo-
amides to the corresponding oxazolines.9 Reactions with ben-
zonitrile were, in general, faster than those with acetonitrile.
a Cu(OTf)2 (0.05 equiv)-catalyzed one-pot synthesis of oxazoline was
performed with 1.0 equiv of alkene, 1.2 equiv of NBS, 1.2 equiv of
NaHCO3, and 1.2 equiv of H2O in different nitriles at 20–25 °C.
b Isolated yield of pure oxazoline/haloamide after column chromato-
graphy; 10-15% dibromide and 5-10% bromohydrin were obtained.
c Alkenes were used in excess (5.0 equiv), and NBS was used as a
limiting reagent.
(10) Yeung, Y.-Y.; Gao, X.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 9644–
9645.
(11) Minakata, S.; Morino, Y.; Ide, T.; Oderaotoshi, Y.; Komatsu, M. Chem.
Commun. 2007, 3279–3281.
(12) (a) Hajra, S; Maji, B.; Bar, S. Org. Lett. 2007, 9, 2783–2786. (b) Hajra,
S.; Bhowmick, M.; Maji, B.; Sinha, D. J. Org. Chem. 2007, 72, 4872–4876. (c)
Hajra, S.; Sinha, D.; Bhowmick, M. J. Org. Chem. 2007, 72, 852–1855. (d)
Hajra, S.; Bhowmick, M.; Sinha, D. J. Org. Chem. 2006, 71, 9237–9240
(e) Hajra, S.; Sinha, D.; Bhowmick, M. Tetrahedron Lett. 2006, 47, 7017–7019.
(f) Hajra, S.; Bhowmick, M.; Karmakar, A. Tetrahedron Lett. 2005, 46, 3073–
3077.
alkenes and amides using t-BuOI was reported while our study
was in progress. Here, we describe a one-pot stereoselective
synthesis of oxazolines based on metal triflate catalyzed
haloamidation reaction of alkenes with NBS, a nitrile, and water.
J. Org. Chem. Vol. 73, No. 11, 2008 4321

127.4, 126.7 (2C), 125.6 (2C), 88.9, 78.9. Anal. Calcd for
C21H17NO: C, 84.25; H, 5.72; N, 4.68. Found: C, 84.39; H, 5.43;
N, 4.49.
In order to increase the scope of the reaction, we opted to
study the reactivities of the supposedly less nucleophilic alkenes,
i.e., chalcones 6 (Table 3). Moreover, haloamidations of R,ꢀ-
unsaturated ketones are little studied.
2-Methyl-3a,4,5,9b-tetrahydronapthol[1,2-d]oxazole (3e): gum-
1
my liquid; 0.147 g (51%); H NMR (CDCl3, 400 MHz) δ 7.43
When chalcones 6 were subjected to the Zn(OTf)2-catalyzed
reaction with NBS (1.2 equiv), H2O (1.2 equiv) in CH3CN, or
PhCN at 20–25 °C, oxazolines 7 were obtained in moderate to
good yields (Table 3). Reactions with acetonitrile were slower,
with incomplete conversion even after 12–16 h (entries 1, 3, 5,
and 7), whereas reactions in benzonitrile were complete (100%
conversion) in 5–8 h (entries 2, 4, 6, and 8–10).
(1H, d, J ) 7.2 Hz), 7.24 (1H, d, J ) 6.8 Hz), 7.17 (1H, t, J ) 7.2
Hz), 7.11 (1H, d, J ) 7.2 Hz), 5.15 (1H, d, J ) 9.6 Hz), 5.04–5.0
(1H, m), 2.77–2.69 (1H, m), 2.60–2.54 (1H, m), 2.18–2.08 (1H,
m), 1.97 (3H, s), 1.92–1.81(1H, m); 13C NMR (CDCl3, 100 MHz)
δ 164.9, 137.9, 134.9, 129.5, 128.2, 127.1, 127.0, 78.4, 66.9, 28.1,
24.4, 13.9. Anal. Calcd for C12H13NO: C, 76.98; H, 7.00; N, 7.48.
Found: C, 77.18; H, 6.91; N, 7.29.
(2-Methyl-4-phenyl-4,5-dihydrooxazol-5-yl)phenylmethanone
(7a): colorless liquid; 0.119 g (65%); 1H NMR (CDCl3, 400 MHz)
δ 7.85 (2H, d, J ) 8.0 Hz), 7.26 (1H, t, J ) 7.6 Hz), 7.45 (2H, t,
J ) 8.0 Hz), 7.40–7.33 (3H, m), 7.25 (2H, t, J ) 1.2 Hz), 5.55
(1H, d, J ) 6.8 Hz), 5.23 (1H, d, J ) 6.4 Hz), 2.23 (3H, s); 13C
NMR(CDCl3, 100 MHz) δ 199.4, 169.3, 139.6, 134.3, 133.2, 129.1
(2C), 128.8 (2C), 128.5 (2C), 127.9, 126.9(2C), 75.4, 54.6, 22.9.
Anal. Calcd for C17H15NO2: C, 76.96; H, 5.70; N, 5.28. Found: C,
76.71; H, 5.89; N, 5.61.
In summary, a general and efficient method is described for
one-pot synthesis of oxazolines based on haloamidation of
alkenes with NBS and stoichiometric amount of water. This
process is catalyzed by Lewis acids. Cu(OTf)2 and Zn(OTf)2
are most effective for the reactions. Chalcones are also suitable
for the transformations. Further applications of 1,2-halofunc-
tionalization of alkenes are currently under investigation in our
laboratory.
(2,4-Diphenyl-4,5-dihydrooxazol-5-yl)phenylmethanone (7b): col-
1
orless liquid; 0.213 g (68%); H NMR (CDCl3, 400 MHz) δ 8.1
(2H, d, J ) 7.2 Hz), 7.94 (2H, d, J ) 7.2 Hz), 7.64 (1H, t, J ) 7.2
Hz), 7.56–7.31 (10H, m), 5.71 (1H, d, J ) 6.4 Hz), 5.52 (1H, d, J
) 6.4 Hz); 13C NMR(CDCl3, 100 MHz) δ 194.4, 163.8, 140.9,
134.0, 131.7, 129.1 (2C), 129.0 (2C), 128.8 (2C), 128.7 (2C),
128.54, 128.44 (2C), 128.18, 127.0 (2C), 126.8, 86.7, 73.6. Anal.
Calcd for C22H17NO2: C, 80.71; H, 5.23; N, 4.28. Found: C, 80.91;
H, 5.15; N, 4.51.
Experimental Section
General Procedure for One-Pot Synthesis of Oxazolines
from Alkenes. To a well-stirred solution of an alkene (1.0 equiv)
and nitrile (5 mL/mmol), Cu(OTf)2 or Zn(OTf)2 (0.05 equiv), and
NBS (1.2 equiv) were added NaHCO3 (1.2 equiv) and H2O (1.2
equiv) and the mixture allowed to stir at rt (20 to 25 °C) under an
argon atmosphere. Progress of the reaction was monitored by TLC.
On completion, solvent was evaporated under reduced pressure.
The crude reaction mixture was subjected to purification by flash
column chromatography using EtOAc/petroleum ether (60-80 °C)
as an eluent.
Acknowledgment. We thank DST, New Delhi, for providing
financial support and Prof. D. Mal for helpful suggestions. S.B.
and D.S. thank CSIR, New Delhi, and B.M. thanks UGC, New
Delhi, for their fellowships.
2,4,5-Triphenyl-4,5-dihydrooxazole (3b): gummy liquid; 0.215
g (65%); 1H NMR (CDCl3, 400 MHz) δ 8.07 (2H, d, J ) 7.2 Hz),
7.53–7.15 (13H, m), 5.35 (1H, d, J ) 7.6 Hz), 5.16 (1H, d, J )
7.6 Hz); 13C NMR (CDCl3, 100 MHz) δ 164.0, 141.9, 140.4, 131.7,
128.93 (2C), 128.87 (2C), 128.59 (2C), 128.53 (2C), 128.51, 127.7,
Supporting Information Available: Spectral data and spectra
of oxazolines 3 and 7. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO8003937
4322 J. Org. Chem. Vol. 73, No. 11, 2008