Diastereoselective cycloadditions of a soluble polymer-supported substituted allyl alcohol derived from Baylis-Hillman reaction with nitrile oxides

Article abstract of DOI:10.1016/j.tet.2008.04.002

A diastereoselective cycloaddition of a soluble polymer-supported Baylis-Hillman adduct with nitrile oxides is described. The reaction has shown to proceed with moderate diastereoselectivity, favoring the syn isomer of the resulting 3,5-substituted isoxazolines. The stereochemistry of the products has been assigned using ¹H NMR studies. The structure of one of the diastereomers has been determined by single-crystal X-ray crystallographic analysis.

Full text of DOI:10.1016/j.tet.2008.04.002

Tetrahedron 64 (2008) 5779–5783
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Diastereoselective cycloadditions of a soluble polymer-supported substituted
allyl alcohol derived from Baylis–Hillman reaction with nitrile oxides
*
Yongjia Shang , Zhijun Feng, Lili Yuan, Shaowu Wang
Anhui Key Laboratory of Functional Molecular Solids, College of Chemistry and Materials Science, Anhui Normal University, Wuhu 241000, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A diastereoselective cycloaddition of a soluble polymer-supported Baylis–Hillman adduct with nitrile
oxides is described. The reaction has shown to proceed with moderate diastereoselectivity, favoring the
syn isomer of the resulting 3,5-substituted isoxazolines. The stereochemistry of the products has been
assigned using 1H NMR studies. The structure of one of the diastereomers has been determined by
single-crystal X-ray crystallographic analysis.
Received 14 January 2008
Received in revised form 29 March 2008
Accepted 1 April 2008
Available online 8 April 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
phase methods (use of excess reagents, easy isolation, and purifi-
cation of products). So, the synthetic approaches that utilize sol-
7
1
,3-Dipolar cycloaddition reactions of nitrile oxides to alkenes
uble polymer have been developed by many workers in the past
7,8
are widely used in organic synthesis due to the generally high
regioselectivity and stereoselectivity of these reactions and the
synthetic versatility of the corresponding isoxazolines. The iso-
xazoline ring system is of particular interest since it is a component
of various pharmaceutical agents and also a precursor to useful
synthetic intermediates for the construction of a variety of 1,3-
difunctionalized compounds, such as
amino alcohols. If a chiral alkene is used as the dipolarophile, two
diastereoisomers could be formed by 1,3-dipolar cycloaddition.
Control of diastereoselectivity in these cycloadditions is important
for economical syntheses of intermediates and natural products.
So, cycloaddition of nitrile oxide with chiral alkenes in solution
phase have been thoroughly studied.
allow the prediction of the main diastereomer, have been published
and theoretical calculations have given insights into the origins of
decades. We are interested in the development of the liquid-
phase stereoselective strategy for the synthesis of isoxazolines,
which can be applied to combinatorial synthesis of small poly-
functional heterocycle libraries.
1
As mentioned above, coupled with our previous work on the
liquid-phase synthesis of isoxazol(in)es through the nitrile oxide
9
b-hydroxycarbonyls and
g-
cycloaddition, we turn our attention to the substituted allyl alco-
2
6,10
hols 3 by using Baylis–Hillman reaction
on the soluble resin. We
3
predicted that the OH group at the allylic stereocenter of the chiral
adduct 3 would play an important role in controlling the diaster-
eoselectivity in the cycloaddition of nitrile oxides with the soluble
polymer-supported adduct 3. Our attempts to obtain the diaster-
eoselectivity in these reactions were successful. And they also
provide the first examples of the liquid-phase diastereoselective
cycloadditions of nitrile oxides to chiral alkenes. Herein, we would
like to describe the details of the reactions.
4
3
,5a–h
Several models, which
5
their selectivities. It has been found that diastereoselectivity of the
cycloadditions depends mainly upon the nature of dipole and
dipolarophile, and electrostatic factors play a major role in con-
trolling the stereoselectivity of these reactions. Furthermore,
a number of cycloadditions of nitrile oxides to alkenes carried out
2
. Results and discussion
As shown in Scheme 1, we chose to perform our reactions on the
6
on solid supports have also been reported in the last few years.
soluble poly(ethylene glycol) 4000 (PEG4000). The polymeric acryl-
ate was prepared by treatment of dihydroxyl-PEG4000
MW¼4000 g/mol) 1 with acryloyl chloride in the presence of Et N in
However, few examples of diastereoselective cycloadditions of ni-
trile oxides to chiral alkenes on soluble solid supports have been
reported. Soluble polymer-supported organic synthesis, termed
2
(
3
refluxing dichloromethane. Then the reaction of benzaldehyde with
the polymeric acrylate 2 in the presence of a catalytic amount of 3-
quinuclidinol in absolute ethanol gave the polymer-supported race-
mic mixture of Baylis–Hillman adduct 3. After precipitation with
diethyl ether, the resin 3 was treated with 4 equivof aldoximine4 and
N-chlorosuccinimide (NCS) in dichloromethane in a one-pot pro-
cedure. Successively, triethylamine was added slowly over a period of
‘
liquid-phase’ organic synthesis (LPOS), couples the advantages of
traditional homogeneous solution chemistry (high reactivity, lack
of diffusion phenomena, and ease of analysis) with those of solid
*
Corresponding author. Fax: þ86 553 3883517.
E-mail address: shyj@mail.ahnu.edu.cn (Y. Shang).
0
040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.04.002

5780
Y. Shang et al. / Tetrahedron 64 (2008) 5779–5783
OH
O
O
Cl
O
O
O
a
b
+
O
O
OH
R
O
1
2
(
+)3
Ar
N
O
R
R
H
OH
H
OH
H
HO
N
Ar
c
Ar
O
+
N
+
H
OH
3
4a-h
5a-h, syn
5a'-h', anti
d
d
O
O
Ar
N
O
OMe
OMe
OH
H
OH
H
N
Ar
O
6a-h, syn
7a-h, anti
O
O
R=
Scheme 1. Reagents and conditions: (a) Et
,
= PEG resin
O
ꢀ
3
N, CH
2
Cl
2
, 24 h; (b) benzaldehyde, 3-quinuclidinol, absolute ethanol, 50 C, 96 h; (c) NCS, Et
3
N, rt, 16 h; (d) NaOCH
3
, CH
3
OH.
2
h to generate the nitrile oxide and the resulting mixture was stirred
atroom temperature overnight. The triethylaminehydrochloride was
removed by precipitation with benzene. The solution was concen-
trated and the polymer-supported isoxazolines 5 were precipitated
out by adding diethyl ether. Substrate cleavage was accomplished by
treating 5 with 5% MeONa in methanol at room temperature. Then,
the diastereomeric mixture of cycloproducts 6 and 7 was obtained
and purified by flash column chromatography. Yields and di-
astereoisomeric ratios are summarized in Table 1.
It was observed the syn-diastereoisomer was the major product
withmoderate diastereoselectivityinallcases. The diastereoisomeric
ratio of the resulting cycloadducts 6a–h, 7a–h was determined by
HPLC and the isomers purified by flash column chromatography. The
relative stereochemistry of the major isomer was assigned by
Figure 1. Single-crystal X-ray structure of 6a.
1
examination of the H NMR chemical shifts of the proton attached to
Ar
0
N
Ar
N
C-5 (see Section 4). In all cases examined above, the chemical shift of
O
O
0
the C-5 proton of the major syn isomer occurred at higher field than
that of the anti, analogous to those reported in the literature.5b,h
H
H
R H
O
H
H
R H
O
H
Ph
Table 1
Ph
H
Results of diastereoselective cycloaddition products
A syn- (favored)
B anti-
2
3 Ar
N
1
O
4
Figure 2. Model for the transition state of the 1,3-DC reaction of nitrile oxides to
alkenes.
H CO
5'
3
5
O
OH
In addition, the structure of a diastereomer 6a, which is a race-
Product 6 and 7
mic mixture, has been determined directly by the single-crystal X-
11
ray diffraction studies (Fig. 1). It could also confirm that 6a is the
syn isomer.
Product
Ar–
Yielda (%)
Ratiob 6/7
6a, 7a
6b, 7b
6c, 7c
6d, 7d
6e, 7e
4-MePh–
Ph–
4-MeOPh–
3-NO Ph–
4-ClPh–
O
O
83
81
85
56
62
72:28
63:37
79:21
76:24
70:30
The observed syn selectivity in these reactions are probably due
to hydrogen bonding of OH group with the incoming nitrile oxide
oxygen and the steric repulsion between the substituent at the
2
1
d
chiral alkene stereocenter and the allylic proton (Fig. 2). However,
the small phenyl group at the allylic stereocenter affects the effect
of steric factors; and the electrostatic repulsion due to the nega-
tively charged oxygen of the incoming nitrile oxide determines that
6f, 7f
85
78:22
5
,12
6
6
g, 7g
h, 7h
2,4-ClPh–
3,4-MeOPh–
79
74
60:40
61:39
the syn selectivity is moderate.
The experimental data also show
a dependence of the amount of diastereoselectivity on the nature of
the nitrile oxide; in particular, it seems to correlate with the
amount of negative charge present on the nitrile oxide oxygen.
a
Combined yield of both isomers.
b
2
Determined by HPLC (silica gel, LC-18; MeOH/H O).

Y. Shang et al. / Tetrahedron 64 (2008) 5779–5783
5781
3
. Conclusion
In summary, we have accomplished the diastereoselective cy-
4.3.1. Compound 3
1
H NMR (300 MHz, CDCl
CH
), 7.28–7.36 (m, 5H, ArH).
3
):
d
3.39–3.86 (m, PEG-H), 4.25 (t, 2H,
PEGOCH
1H, ]CH
2
2 2
OCO), 5.58 (s, 1H, –CHOH), 5.83 (s, 1H, ]CH ), 6.36 (s,
cloadditions of nitrile oxides to a soluble polymer-supported
substituted allyl alcohols derived from the Baylis–Hillman reaction
with a moderate diastereoselectivity. Thus, we have provided the
liquid-phase diastereoselective synthesis of the 3,5-substituted
isoxazolines through 1,3-dipolar cycloaddition of nitrile oxides
with chiral alkenes. On the basis of this work, we expect to improve
the diastereoselectivity by changing the structures of the Baylis–
Hillman adducts and nitrile oxides. Extension of the work is now in
progress in our laboratory.
2
4.4. General procedure for the synthesis of poly(ethylene
glycol)-supported isoxazolines 5
To a solution of N-chlorosuccinimide (NCS, 2 mmol) in 5 mL dry
CH
was over, the polymer-supported Baylis–Hillman adduct
(0.5 mmol) was added in one portion. The reaction mixture was
stirred at room temperature for 30 min, and then Et N (2 mmol) in
mL CH Cl was added dropwise over 2 h and the mixture was
2 2
Cl was added the aldoxime (2 mmol). After the chlorination
3
3
4
2
2
4
4
. Experimental
stirred overnight at room temperature. Then, a three-fold excess of
dry benzene was added to remove the triethylamine hydrochloride
formed. The mixture was filtered and the filtrate was concentrated.
.1. General
2
Addition of Et O to the residue precipitated the resin, which was
then filtered and washed with Et O to afford the polymer-sup-
2
ported isoxazolines 5.
All chemicals and resin were commercially available and the
preparation of the acryloyl chloride and aldoximes was made
according to previously described procedures. IR spectra were
1
recorded on KBr pellets on a PTIR-8400S spectrometer. H NMR
0
4
.4.1. Compounds 5a, 5a
spectra were recorded at 300 MHz on a Bruker Avance DMX300
spectrometer and 13C NMR spectra at 75 MHz on the same spec-
trometer in deuteriochloroform solutions. All chemical shifts are
reported in parts per million from TMS as an internal standard. Mass
spectra (EI) were performed on a HP-5989 instrument with ioniza-
tion energy maintained at 70 eV. Elemental analyses were carried
out on an EA-1110 elemental analyzer. Column chromatography was
carried out on Merck Kieselgel (particle size 0.300–0.400 mm) and
solvents were distilled before use. X-ray crystallographic data were
determined on a SMART APEX II X-ray diffractometer. Crystal of 6a
were obtained by slow evaporation of a solution in diethyl ether/
hexane. The results of the structural analyses are illustrated in
Figure 1.
1
H NMR (300 MHz, CDCl
3
):
d
3
2.38 (s, 3H, CH ), 3.48–3.78 (m,
PEG-H), 4.28 (t, 2H, J¼4.7, PEGOCH
2
CH
2
OCO), 5.25 (d, 1H, J¼5.8,
CHOH), 5.36 (d, 1H, J¼3.5, CHOH), 7.15 (d, 2H, J¼7.7, ArH), 7.27–7.35
(m, 5H, ArH), 7.49 (d, 2H, J¼7.7, ArH). Yield: 95%.
0
4
.4.2. Compounds 5b, 5b
1
3
H NMR (300 MHz, CDCl ): d 3.45–3.78 (m, PEG-H), 4.34 (t, 2H,
J¼4.7, PEGOCH
2
CH
2
OCO), 5.18 (d, 1H, J¼6.3, CHOH), 5.31 (d, 1H,
J¼3.9, CHOH), 7.22–7.31 (m, 8H, ArH), 7.60 (m, 2H, ArH). Yield: 97%.
0
4
.4.3. Compounds 5c, 5c
1
3
H NMR (300 MHz, CDCl ): d 3.48–3.80 (m, PEG-H), 4.35 (t, 2H,
J¼4.8, PEGOCH
2
CH
2
OCO), 5.23 (d, 1H, J¼6.5, CHOH), 5.35 (s, 1H,
CHOH), 6.91 (d, 2H, J¼8.7, ArH), 7.27–7.51 (m, 5H, ArH), 7.60 (d, 2H,
J¼8.7, ArH). Yield: 95%.
4
.2. General procedure for the synthesis of poly(ethylene
glycol)-supported acrylate 2
0
4
.4.4. Compounds 5d, 5d
1
3
H NMR (300 MHz, CDCl ): d 3.45–3.85 (m, PEG-H), 4.34 (t, 2H,
To
.5 mmol) in CH
the mixture was cooled to 0 C. Subsequently, acryloyl chloride
a
solution of dihydroxy-PEG4000 1 (10 g,
M
W
¼4000,
J¼4.7, PEGOCH
2
CH
2
OCO), 5.42 (d, 1H, J¼3.6, CHOH), 5.43 (d,
2
2
2
Cl (50 mL) was added triethylamine (2.8 mL) and
ꢀ
1H, J¼3.8, CHOH), 7.27–7.39 (m, 5H, ArH), 7.60 (m, 1H, ArH), 8.10 (d,
1
H, J¼7.2, ArH), 8.23 (d, 1H, J¼7.8, ArH), 8.59 (s, 1H, ArH). Yield: 96%.
(
1.6 mL, 20 mmol) was added dropwise within 30 min. The reaction
ꢀ
mixture was stirred at 0 C for 1 h and then at room temperature
for 24 h. Then, a three-fold excess of anhydrous benzene was added
to the reaction mixture to remove the triethylamine hydrochloride
formed. The mixture was filtered and the filtrate was concentrated.
0
4.4.5. Compounds 5e, 5e
1
H NMR (300 MHz, CDCl
3
): d 3.48–3.82 (m, PEG-H), 4.32 (t, 2H,
J¼4.8, PEGOCH
2
CH
2
OCO), 5.18 (d, 1H, J¼3.8, CHOH), 5.37 (d, 1H,
J¼3.8, CHOH), 7.27–7.38 (m, 5H, ArH), 7.43 (d, 2H, J¼8.5, ArH), 7.65
2
Addition of Et O to the residue precipitated the resin, which
was then filtered and washed with Et O to afford the polymer-
2
(
d, 2H, J¼8.5, ArH). Yield: 96%.
supported acrylate 2 in 97% yield.
0
4
.4.6. Compounds 5f, 5f
1
3
H NMR (300 MHz, CDCl ): d 3.45–3.85 (m, PEG-H), 4.34 (t, 2H,
4
.2.1. Compound 2
1
J¼4.8, PEGOCH
2
CH
2
OCO), 5.22 (d, 1H, J¼6.3, CHOH), 5.35 (d, 1H,
O), 6.80 (d, 1H, J¼8.0, ArH), 7.03 (d,
H, J¼8.0, ArH), 7.12–7.48 (m, 6H, ArH). Yield: 95%.
H NMR (300 MHz, CDCl
3
):
d
3.64–3.87 (m, PEG-H), 4.31 (t, 2H,
), 6.12 (m, 1H,
J¼3.8, CHOH), 5.99 (s, 2H, OCH
2
PEGOCH
COCH]CH
2
CH
2
OCO), 5.84 (d, 1H, J¼10.1, –COCH]CH
2
1
2
), 6.42 (d, 1H, J¼15.9, –COCH]CH
2
).
0
.4.7. Compounds 5g, 5g
4
1
4
.3. General procedure for the synthesis of poly(ethylene
H NMR (300 MHz, CDCl
3
): d 3.48–3.80 (m, PEG-H), 4.25 (t, 2H,
glycol)-supported Baylis–Hillman adduct 3
J¼4.7, PEGOCH
2
CH
2
OCO), 5.26 (d, 1H, J¼5.3, CHOH), 5.32 (s, 1H,
CHOH), 7.08–7.50 (m, 8H, ArH). Yield: 95%.
A solution of the polymeric acrylate 2 (10 g, 2.5 mmol), benz-
0
aldehyde (25 mmol), and 3-quinuclidinol (2.5 mmol) in 50 mL ab-
4.4.8. Compounds 5h, 5h
ꢀ
1
solute ethanol was stirred at 50 C for 96 h. Then, 500 mL Et
2
O was
H NMR (300 MHz, CDCl
3
): d 3.45–3.85 (m, PEG-H), 4.34 (t, 2H,
added to precipitate the resin, which was then filtered and washed
with Et O to afford the polymer-supported Baylis–Hillman adduct 3
in 95% yield.
J¼4.7, PEGOCH
2
CH
2
OCO), 5.24 (d, 1H, J¼5.8, CHOH), 5.31 (d, 1H,
2
J¼3.8, CHOH), 6.82 (s, 1H, ArH), 7.06 (s, 1H, ArH), 7.28–7.39 (m, 6H,
ArH). Yield: 97%.

5782
Y. Shang et al. / Tetrahedron 64 (2008) 5779–5783
4
.5. General procedure for the synthesis of isoxazolines 6 and 7
2H, J¼8.8, ArH), 7.26–7.36 (m, 5H, ArH), 7.48 (d, 2H, J¼8.8, ArH). 13C
NMR (75 MHz, CDCl
3
):
d
39 (N]CCH
2
), 53 (COOCH
3
), 55 (PhOCH
and
). EIMS m/z¼342 [M] . Anal.
19 5
H O N: C, 66.86; H, 5.57; N, 4.11. Found: C, 66.98; H,
3
),
The cleavage of the polymer support was accomplished by
treating 5 with CH ONa in CH OH at room temperature for 8 h. Et
was added to the mixture and the organic phase was separated.
Removal of Et O gave the desired isoxazolines 6 and 7, which were
75 (CHOH), 91 (CH
), 156 (N]CCH
Calcd for C19
5.81; N, 4.36.
2 6 5
CON), 114, 120, 126, 128, 137 and 161 (C H
), 170 (COOCH
2 3
þ
3
3
2
O
C
6
H
4
2
separated by the column chromatography on silica gel (EtOAc/
hexane).
4.5.4. 3-(3-Nitrophenyl)-5-(1-phenyl-hydroxymethyl)-5-
methoxycarbonyl isoxazoline
4
.5.1. 3-(4-Methylphenyl)-5-(1-phenyl-hydroxymethyl)-5-
Compound 6d: pale yellow solid. IR (KBr):
n
max 3509, 1728,
2.89 (d, 1H, J¼3.8, CHOH),
), 5.43 (d, 1H, J¼3.8, CHOH),
7.25–7.39 (m, 5H, ArH), 7.64 (t, 1H, ArH), 8.05 (d, 1H, J¼7.8, ArH),
ꢁ
1 1
methoxycarbonyl isoxazoline
1605 cm . H NMR (300 MHz, CDCl
3
): d
ꢁ
1
Compound 6a: white solid. IR (KBr):
n
max 3308, 1736, 1605 cm
), 3.02 (d, 1H, J¼3.5,
), 5.36 (d, 1H, J¼3.4,
CHOH), 7.19 (d, 2H, J¼7.7, ArH), 7.27–7.37 (m, 5H, ArH), 7.55 (d, 2H,
.
3.77 (s, 2H, N]CCH ), 3.83 (s, 3H, OCH
2
3
1
H NMR (300 MHz, CDCl
3
):
d
2.38 (s, 3H, CH
3
13
CHOH), 3.66 (s, 2H, N]CCH
2
), 3.79 (s, 3H, OCH
3
8.29 (d, 1H, J¼7.1, ArH), 8.44 (s, 1H, ArH). C NMR (75 MHz, CDCl
39 (N]CCH ), 53 (OCH ), 74 (CHOH), 93 (CH CON), 124, 126, 128,
130, 131, 132, 137 and 148 (C and C ), 156 (CH C]NO), 171
). EIMS m/z¼357 [M] . Anal. Calcd for C18 : C,
60.67; H, 4.49; N, 7.87. Found: C, 60.91; H, 4.70; N, 7.96.
Compound 7d: pale yellow solid. IR (KBr): max 3509, 1728,
2.88 (d, 1H, J¼3.9, CHOH),
), 3.81 (d, 1H, J¼9.0, N]CCH ), 3.84 (s,
), 5.42 (d, 1H, J¼3.6, CHOH), 7.27–7.39 (m, 5H, ArH), 7.63 (t,
1H, ArH), 8.05 (d,1H, J¼7.2, ArH), 8.28 (d,1H, J¼7.8, ArH), 8.43 (s,1H,
3
):
d
2
3
2
13
J¼7.7, ArH). C NMR (75 MHz, CDCl
OCH ), 73 (CHOH), 93 (CH CON), 125, 126, 127, 128, 129, 137 and
40 (C and C ), 157 (N]CCH ), 170 (COOCH
). EIMS m/z¼326
MþH] . Anal. Calcd for C19 N: C, 70.15; H, 5.85; N, 4.31.
Found: C, 70.37; H, 5.90; N, 4.52.
Compound 7a: white solid. IR (KBr):
H NMR (300 MHz, CDCl ): 2.36 (s, 3H, CH
CHOH), 3.65 (d, 1H, J¼17.5, N]CCH ), 3.74 (s, 3H, OCH
J¼17.5, N]CCH ), 5.24 (d, 1H, J¼5.8, CHOH), 7.16 (d, 2H, J¼7.8, ArH),
.28–7.35 (m, 5H, ArH), 7.49 (d, 2H, J¼7.8, ArH). C NMR (75 MHz,
CDCl ): 21 (CH ), 40 (N]CCH ), 53 (OCH ), 74 (CHOH), 91
CON), 125, 126, 127, 128, 129, 137 and 140 (C
3
):
d
21 (CH
3
), 37 (N]CCH
2
), 53
6
H
5
6
H
4
2
þ
(
1
[
3
2
(COOCH
3
16 6 2
H O N
6
H
5
6
H
4
2
3
þ
H
19
O
4
n
ꢁ
1 1
1605 cm . H NMR (300 MHz, CDCl
3.72 (d, 1H, J¼9.0, N]CCH
3H, OCH
3
): d
ꢁ1
n
max 3308, 1736, 1605 cm
), 2.87 (d, 1H, J¼5.8,
), 3.78 (d, 1H,
.
2
2
1
3
d
3
3
2
3
1
3
2
ArH). C NMR (75 MHz, CDCl
(CHOH), 92 (CH CON),124,126,128,130, 131,132,137 and 148 (C
and C ), 156 (CH
Anal. Calcd for C18
3 2 3
): d 40 (N]CCH ), 53 (OCH ), 75
13
7
2
6 5
H
þ
3
d
3
2
3
6
H
4
2
C]NO), 171 (COOCH
3
). EIMS m/z¼357 [M] .
(
(
CH
N]CCH
2
6
H
5
and C
6
H
4
), 156
H
16 6 2
O N : C, 60.67; H, 4.49; N, 7.87. Found: C,
þ
2
), 170 (COOCH
3
). EIMS m/z¼326 [MþH] . Anal. Calcd for
60.91; H, 4.70; N, 7.96.
C
4
19 19 4
H O N: C, 70.15; H, 5.85; N, 4.31. Found: C, 70.37; H, 5.90; N,
.52.
4.5.5. 3-(4-Chlorophenyl)-5-(1-phenyl-hydroxymethyl)-5-
methoxycarbonyl isoxazoline
ꢁ
1
4
.5.2. 3-Phenyl-5-(1-phenyl-hydroxymethyl)-5-methoxycarbonyl
isoxazoline
Compound 6b: white solid. IR (KBr):
H NMR (300 MHz, CDCl ):
3.17 (d, 1H, J¼3.8, CHOH), 3.59 (s, 2H,
N]CCH ), 3.68 (s, 3H, OCH
), 5.28 (d, 1H, J¼3.8, CHOH), 7.22–7.31
m, 8H, ArH), 7.56 (d, 2H, J¼7.5, ArH). C NMR (75 MHz, CDCl
N]CCH ), 53 (OCH ), 74 (CHOH), 91 (CH CON), 126, 127, 128, 129,
30 and 137 (C and C ), 156 (N]CCH ), 170 (COOCH ). EIMS
N: C, 69.45; H, 5.47; N,
Compound 6e: white solid. IR (KBr):
H NMR (300 MHz, CDCl ):
2.94 (d, 1H, J¼3.8, CHOH), 3.64 (s, 2H,
N]CCH ), 3.80 (s, 3H, OCH
), 5.38 (d,1H, J¼3.8, CHOH), 7.26–7.38 (m,
5H, ArH), 7.40 (d, 2H, J¼8.5, ArH), 7.60 (d, 2H, J¼8.5, ArH). C NMR
(75 MHz, CDCl ): 37 (N]CCH ), 53 (OCH ), 74 (CHOH), 93
CON), 126, 127, 128, 130, 132, 136 and 138 (C and C ), 156
). EIMS m/z¼346 [M] . Anal. Calcd for
NCl: C, 62.52; H, 4.63; N, 4.05. Found: C, 62.81; H, 4.94;
nmax 3503, 1741, 1599 cm .
1
3
d
ꢁ1
n
max 3482, 1740, 1601 cm
.
2
3
1
13
3
d
2
3
3
d
2
3
13
(
(
1
3
):
d
40
(CH
(CH
2
6
H
5
6 4
H
þ
2
3
2
2
C]NO), 170 (COOCH
3
6
H
5
6
H
4
2
3
18 16 4
C H O
þ
m/z¼312 [MþH] . Anal. Calcd for C18
H
17
O
4
N, 4.36.
Compound 7e: white solid. IR (KBr):
H NMR (300 MHz, CDCl ):
2.89 (d, 1H, J¼3.8, CHOH), 3.67 (s, 2H,
N]CCH ), 3.74 (s, 3H, OCH
), 5.20 (d, 1H, J¼3.8, CHOH), 7.33–7.38
(m, 5H, ArH), 7.47 (d, 2H, J¼8.5, ArH), 7.58 (d, 2H, J¼8.5, ArH).
NMR (75 MHz, CDCl ): 39 (N]CCH ), 53 (OCH ), 75 (CHOH), 91
CON), 126, 127, 128, 130, 132, 136 and 138 (C and C ), 156
). EIMS m/z¼346 [M] . Anal. Calcd for
NCl: C, 62.52; H, 4.63; N, 4.05. Found: C, 62.81; H, 4.94;
ꢁ
1
4
.50. Found: C, 69.74; H, 5.73; N, 4.84.
Compound 7b: white solid. IR (KBr):
H NMR (300 MHz, CDCl ):
2.82 (d, 1H, J¼6.3, CHOH), 3.57 (d, 1H,
), 3.64 (s, 3H, OCH ),
), 3.70 (d, 1H, J¼15.6, N]CCH
nmax 3503, 1741, 1599 cm .
ꢁ1
1
n
max 3482, 1740, 1601 cm
.
3
d
1
3
d
2
3
13
J¼15.6, N]CCH
2
3
2
C
5
.17 (d, 1H, J¼6.3, CHOH), 7.17–7.30 (m, 6H, ArH), 7.38–7.46 (m, 4H,
3
d
2
3
13
ArH). C NMR (75 MHz, CDCl
CHOH), 91 (CH CON), 126, 127, 128, 129, 130 and 137 (C
), 156 (N]CCH
Calcd for C18 N: C, 69.45; H, 5.47; N, 4.50. Found: C, 69.74; H,
3
):
d
42 (N]CCH
2
), 53 (OCH
3
), 74
and
(CH
(CH
2
6
H
5
6 4
H
þ
(
C
2
6
H
5
2
C]NO), 170 (COOCH
3
þ
H
6 4
2
), 170 (COOCH
3
). EIMS m/z¼312 [MþH] . Anal.
18 16 4
C H O
N, 4.36.
H
17
O
4
5
.73; N, 4.84.
4.5.6. 3-(3,4-(Methylenedioxy)phenyl)-5-(1-phenyl-
4.5.3. 3-(4-Methoxyphenyl)-5-(1-phenyl-hydroxymethyl)-5-
hydroxymethyl)-5-methoxycarbonyl isoxazoline
methoxycarbonyl isoxazoline
Compound 6f: pale yellow solid. IR (KBr): nmax 3242, 1738,
ꢁ
1
ꢁ1 1
Compound 6c: white solid. IR (KBr):
n
max 3418, 1726, 1606 cm
.
1633 cm . H NMR (300 MHz, CDCl
3
):
), 3.78 (s, 3H, OCH
O), 6.80 (d, 1H, J¼8.0, ArH), 7.03 (d, 1H, J¼8.0, ArH),
d
2.91 (d, 1H, J¼3.9, CHOH),
1
H NMR (300 MHz, CDCl
), 3.77 (s, 3H, COOCH
CHOH), 6.90 (d, 2H, J¼8.7, ArH), 7.33–7.36 (m, 5H, ArH), 7.56 (d, 2H,
3
):
d
3.19 (br s, 1H, CHOH), 3.70 (s, 2H,
), 3.82 (s, 3H, PhOCH ), 5.35 (s, 1H,
3.66 (s, 2H, N]CCH
5.99 (s, 2H, OCH
7.11 (s, 1H, ArH), 7.21–7.48 (m, 5H, ArH). C NMR (75 MHz, CDCl
38 (N]CCH ), 53 (OCH ), 74 (CHOH), 93 (CH CON), 101, 114, 115,
122, 126, 127, 128, 129, 136, 149 and 151 (C
(CH C]NO), 170 (COOCH
for C19
N, 4.11.
2
3
), 5.34 (d, 1H, J¼3.9, CHOH),
N]CCH
2
3
3
2
1
3
3
):
13
J¼8.7, ArH). C NMR (75 MHz, CDCl
COOCH ), 55 (PhOCH ), 74 (CHOH), 93 (CH
37 and 161 (C and C ), 156 (N]CCH
3
):
d
37 (N]CCH
CON),114,120,126,128,
), 170 (COOCH ). EIMS
N: C, 66.86; H, 5.57; N, 4.11.
2
), 53
d
2
3
2
(
1
3
3
2
6
H
5
and C
6
3
H ), 156
þ
6
H
5
6
H
4
2
3
2
3
). EIMS m/z¼356 [M] . Anal. Calcd
þ
m/z¼342 [M] . Anal. Calcd for C19
H
19
O
5
17 6
H O N: C, 64.23; H, 4.79; N, 3.94. Found: C, 64.55; H, 4.91;
Found: C, 66.98; H, 5.81; N, 4.36.
ꢁ1
Compound 7c: white solid. IR (KBr):
H NMR (300 MHz, CDCl ):
2.90 (d, 1H, J¼6.5, CHOH), 3.69 (d, 1H,
J¼17.3, N]CCH ), 3.72 (s, 3H, COOCH ), 3.82 (d, 1H, J¼17.3,
N]CCH ), 3.92 (s, 3H, PhOCH
), 5.23 (d, 1H, J¼6.5, CHOH), 6.85 (d,
n
max 3418, 1726, 1606 cm
.
Compound 7f: pale yellow solid. IR (KBr): nmax 3242, 1738,
1
ꢁ1 1
3
d
1633 cm . H NMR (300 MHz, CDCl
3
):
), 3.80 (s, 3H, OCH
O), 6.79 (d, 1H, J¼8.0, ArH), 7.05 (d, 1H, J¼8.0, ArH),
d
2.80 (d, 1H, J¼6.4, CHOH),
2
3
3.66 (s, 2H, N]CCH
5.99 (s, 2H, OCH
2
3
), 5.23 (d, 1H, J¼6.4, CHOH),
2
3
2

Y. Shang et al. / Tetrahedron 64 (2008) 5779–5783
5783
7
d
.10 (s, 1H, ArH), 7.23–7.50 (m, 5H, ArH). 13C NMR (75 MHz, CDCl
40 (N]CCH ), 53 (OCH ), 75 (CHOH), 92 (CH CON), 101, 114, 115,
22, 126, 127, 128, 129, 136, 149 and 151 (C and C ),
). EIMS m/z¼356 [M] . Anal. Calcd
N: C, 64.23; H, 4.79; N, 3.94. Found: C, 64.55; H, 4.91;
3
):
References and notes
2
3
2
1. (a) Lang, S. A., Jr.; Lin, Y.-I. Comprehensive Heterocyclic Chemistry; Potts, K. T., Ed.;
1
6
H
5
6 3
H
Pergamon: Oxford, 1984; (b) Padwa, A. Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 4; (c) Caramella, P.;
Grunanger, P. 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; John Wiley &
Sons: New York, NY, 1984; Vol. 1; (d) Gothelf, K. V.; Jorgensen, K. A. Chem. Rev.
þ
156 (CH
2
C]NO), 170 (COOCH
3
17 6
for C19H O
N, 4.11.
1998, 98, 863–909.
2
. (a) Curran, D. P. J. Am. Chem. Soc. 1983, 105, 5826–5833 and references cited
therein; (b) Jager, V.; Muller, V. Tetrahedron Lett. 1952, 23, 4777–4780; (c) Jager,
V.; Buss, V. Liebigs Ann. Chem. 1980, 101–120; (d) Jager, V.; Muller, V.; Paulus,
E. F. Tetrahedron Lett. 1985, 26, 2997–3000; (e) Bode, J. W.; Carreira, E. M.
J. Am. Chem. Soc. 2001, 123, 3611–3612; (f) Kim, H. C.; Woo, S. W.; Seo, M. J.;
Jeon, M. J.; Jeon, D. J.; No, Z.; Kim, H. R. Synlett 2002, 1691–1693; (g) Seo, M. J.;
Son, B. S.; Son, B. G.; Song, B. J.; Lee, S. D.; Kim, J. Y.; Kim, H. D.; No, Z.; Kim,
H. R. Bull. Korean Chem. Soc. 2005, 26, 1597–1599.
4
.5.7. 3-(2,4-Dichlorophenyl)-5-(1-phenyl-hydroxymethyl)-5-
methoxycarbonyl isoxazoline
ꢁ
1
Compound 6g: white solid. IR (KBr): nmax 3374, 1741, 1641 cm .
1
H NMR (300 MHz, CDCl
3
):
), 5.32 (s, 1H, CHOH), 7.22–7.44 (m, 8H,
ArH). 1 C NMR (75 MHz, CDCl
): 42 (N]CCH ), 53 (OCH ), 73
CHOH), 91 (CH CON),126,127,128,129,130,133,136 and 138 (C
and C ), 156 (CH
Anal. Calcd for C18
d 2.98 (br s, 1H, CHOH), 3.76 (s, 2H,
N]CCH
2
), 3.81 (s, 3H, OCH
3
3
3
d
2
3
3. (a) Huang, K. S.-L.; Lee, E. H.; Olmstead, M. M.; Kurth, M. J. J. Org. Chem. 2000,
(
2
6 5
H
65, 499–503; (b) Mishra, R. C.; Tewari, N.; Verma, S. S.; Tripathi, R. P.; Kumar,
þ
H
6 3
2
C]NO), 171 (COOCH
3
). EIMS m/z¼380 [M] .
M.; Shukla, P. K. J. Carbohydr. Chem. 2004, 23, 353–374; (c) Sengupta, J.;
Mukhopadhyay, R.; Bhattacharjya, A.; Bhadbhade, M. M.; Bhosekar, G. V. J. Org.
Chem. 2005, 70, 8579–8582; (d) Savage, G. P.; Wernert, G. T. Aust. J. Chem. 2005,
H
15
O
4
NCl : C, 56.84; H, 3.95; N, 3.68. Found: C,
2
5
6.98; H, 4.25; N, 3.97.
Compound 7g: white solid. IR (KBr):
H NMR (300 MHz, CDCl ):
2.84 (d, 1H, J¼5.4, CHOH), 3.74 (d, 1H,
), 3.81 (s, 3H, OCH ),
), 3.95 (d, 1H, J¼18.0, N]CCH
.27 (d,1H, J¼5.4, CHOH), 7.08–7.50 (m, 8H, ArH). C NMR (75 MHz,
CDCl ): 43 (N]CCH ), 53 (OCH ), 74 (CHOH), 90 (CH CON), 126,
27, 128, 129, 130, 133, 136 and 138 (C and C ), 156
). EIMS m/z¼380 [M] . Anal. Calcd for
: C, 56.84; H, 3.95; N, 3.68. Found: C, 56.98; H, 4.25; N,
58, 877–881.
ꢁ1
n
max 3374, 1741, 1641 cm
.
4. (a) Pal, A.; Bhattacharjee, A.; Bhattacharjya, A. Synthesis 1999, 9, 1569–1572; (b)
Nivlet, A.; Dechoux, L.; Martel, J.-P.; Proess, G.; Mannes, D.; Alcaraz, L.; Harnett,
J. J.; Le Gall, T.; Mioskowski, C. Eur. J. Org. Chem. 1999, 12, 3241–3249; (c) Aungst,
R. A., Jr.; Chan, C.; Funk, R. L. Org. Lett. 2001, 3, 2611–2613; (d) Kim, D.; Lee, J.;
Shim, P. J.; Lim, J. I.; Jo, H.; Kim, S. J. Org. Chem. 2002, 67, 764–771; (e) Moriya,
O.; Takenaka, H.; Iyoda, M.; Urata, Y.; Endo, T. J. Chem. Soc., Perkin Trans. 1 1994,
1
3
d
J¼18.0, N]CCH
2
3
2
13
5
3
d
2
3
2
413–417; (f) Fader, L. D.; Carreira, E. M. Org. Lett. 2004, 6, 2485–2488; (g) Ghorai,
1
6
H
5
6 3
H
S.; Mukhopadhyay, R.; Kundu, A. P.; Bhattacharjya, A. Tetrahedron 2005, 61,
2999–3012; (h) Kumar, V.; Kaushik, M. P. Tetrahedron Lett. 2006, 47, 1457–1460;
(
þ
(
CH
2
C]NO), 171 (COOCH
NCl
3
i) Zhao, Y.-H.; Zhao, G.; Cao, W.-G. Tetrahedron: Asymmetry 2007, 18, 2462–
467; (j) Deng, L.-S.; Huang, X.-P.; Zhao, G. J. Org. Chem. 2006, 71, 4625–4635.
. (a) Park, K. H.; Olmstead, M. M.; Kurth, M. J. J. Org. Chem. 1998, 63, 6579–6585;
b) Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi, F.; Raimondi, L. J. Org.
C
3
18
H
15
O
4
2
2
.97.
5
(
4
.5.8. 3-(3,4-Dimethoxyphenyl)-5-(1-phenyl-hydroxymethyl)-5-
Chem. 1995, 60, 4697–4706; (c) Fukuda, S.; Kamimura, A.; Kanemasa, S.; Hori, K.
Tetrahedron 2000, 56, 1637–1647; (d) Kanemasa, S.; Okuda, K.; Yamamoto, H.;
Kaga, S. Tetrahedron Lett. 1997, 38, 4095–4098; (e) Kanemasa, S.; Tsuruoka, T.;
Yamamoto, H. Tetrahedron Lett. 1995, 36, 5019–5022; (f) Kanemasa, S.; Nish-
iuchi, M.; Kamimura, A.; Hori, K. J. Am. Chem. Soc. 1994, 116, 2324–2339; (g) Luft,
J. A. R.; Meleson, K.; Houk, K. N. Org. Lett. 2007, 9, 555–558; (h) Kociolek, M. G.;
Hongfa, C. Tetrahedron Lett. 2003, 44, 1811–1813; (i) Houk, K. N.; Moses, S. R.;
Rondan, N. G.; Jager, V.; Schohe, R.; Fronczek, F. R. J. Am. Chem. Soc. 1984, 106,
3880–3882; (j) Houk, K. N.; Duh, H.-Y.; Wu, Y.-D.; Moses, S. R. J. Am. Chem. Soc.
methoxycarbonyl isoxazoline
ꢁ
1
Compound 6h: white solid. IR (KBr): nmax 3466, 1719, 1601 cm .
1
H NMR (300 MHz, CDCl
3
):
d
2.92 (d, 1H, J¼3.8, CHOH), 3.82 (s, 3H,
), 3.89 (s, 6H, PhOCH ), 5.31 (d, 1H,
OCH
3
), 3.86 (s, 2H, N]CCH
2
3
J¼3.8, CHOH), 6.84 (d, 1H, J¼8.2, ArH), 7.06 (d, 1H, J¼8.2, ArH), 7.27
1
3
(
(
1
1
C
3
s, 1H, ArH), 7.34–7.40 (m, 5H, ArH). C NMR (75 MHz, CDCl
N]CCH ), 53 (COOCH ), 56 (PhOCH ), 74 (CHOH), 93 (CH
12, 115, 120, 126, 127, 128, 129, 137, 150 and 152 (C and C
). EIMS m/z¼372 [M] . Anal. Calcd for
N: C, 64.69; H, 5.66; N, 3.77. Found: C, 64.85; H, 5.93; N,
.92.
Compound 7h: white solid. IR (KBr):
H NMR (300 MHz, CDCl ):
3.04 (d, 1H, J¼5.8, CHOH), 3.82 (s, 3H,
), 3.86 (s, 2H, N]CCH ), 3.89 (s, 6H, PhOCH ), 5.25 (d, 1H,
3
):
CON),
),
d
37
1986, 108, 2754–2755.
2
3
3
2
6
. (a) Sammelson, R. E.; Kurth, M. J. Chem. Rev. 2001, 101, 137–202 and references
cited therein; (b) Lidia, F.; Patricia, V.-L.; Fernando, A.; Mercedes, A. J. Comb.
Chem. 2007, 9, 521–565.
. (a) Gravert, D.; Janda, K. D. Chem. Rev. 1996, 97, 489–510; (b) Wentworth, P., Jr.;
Janda, K. D. Chem. Commun. 1999, 1917–1924; (c) Toy, P. H.; Janda, K. D. Acc.
Chem. Res. 2000, 33, 546–554.
8. (a) Chen, S.; Janda, K. D. J. Am. Chem. Soc. 1997, 119, 8724–8725; (b) Lopez-
Pelegrin, J. A.; Janda, K. D. Chem.dEur. J. 2000, 6, 1917–1922; (c) Ahn, J.-M.;
Wentworth, P., Jr.; Janda, K. D. Chem. Commun. 2003, 480–481; (d) Okudomi,
M.; Shimojo, M.; Nogawa, M. Tetrahedron Lett. 2007, 48, 8540–8543; (e) Kim,
C. B.; Cho, C. H.; Kim, C. K. J. Comb. Chem. 2007, 9, 1157–1163; (f) Li, H.-X.; Xie,
C.; Ding, M.-W. Synlett 2007, 2280–2282; (g) Albert, S.; Soret, A.; Blanco, L.
Tetrahedron 2007, 63, 2888–2900; (h) Li, Z.; Yang, J.-Y.; Wang, J.-K. Heteroat.
Chem. 2006, 17, 664–669; (i) Ribiere, P.; Declerck, V.; Nedellec, Y. Tetrahedron
6
H
5
6
H
3
þ
2 3
56 (CH C]NO),171 (COOCH
7
20 21 6
H O
ꢁ1
n
max 3466, 1719, 1601 cm
.
1
3
d
OCH
3
2
3
J¼5.8, CHOH), 6.84 (d, 1H, J¼8.2, ArH), 7.06 (d, 1H, J¼8.2, ArH), 7.27
1
3
(
(
1
1
C
3
s, 1H, ArH), 7.34–7.40 (m, 5H, ArH). C NMR (75 MHz, CDCl
N]CCH ), 53 (COOCH ), 56 (PhOCH ), 75 (CHOH), 92 (CH
12, 115, 120, 126, 127, 128, 129, 137, 150 and 152 (C and C
). EIMS m/z¼372 [M] . Anal. Calcd for
N: C, 64.69; H, 5.66; N, 3.77. Found: C, 64.85; H, 5.93; N,
3
):
CON),
),
d
39
2
3
3
2
6
H
5
6
H
3
2006, 62, 10456–10466.
þ
56 (CH
2
C]NO),171 (COOCH
3
9. (a) Shang, Y.-J.; Wang, Y.-G. Tetrahedron Lett. 2002, 43, 2247–2249; (b) Shang, Y. J.;
Shou, W. G.; Wang, Y. G. Synlett 2003, 1064–1067; (c) Shang, Y. J.; Wang, Y. G. Syn-
thesis 2002, 12, 1663–1668; (d) Shang, Y. J.; Wang, Y. G. Chin. J. Chem. 2003, 21, 7–8.
0. (a) Basavaiah, D.; Rao, A. J.; Satyanarayna, T. Chem.Rev. 2003, 103, 811–891 and
references cited therein; (b) Liu, X.-Y.; Chai, Z.; Zhao, G.; Zhu, S.-Z. J. Fluorine
Chem. 2005, 126, 1215–1221.
20 21 6
H O
.92.
1
1
1. Crystallographic data for 6a: space group P-1, a¼8.5400(3) Å, b¼10.5119(4) Å,
Acknowledgements
ꢀ
ꢀ
ꢀ
3
c¼20.8093(8) Å,
a
¼84.800(2) ,
b
¼88.209(2) ,
g
¼67.405(2) , V¼1717.59(11) Å ,
T¼293(2) K, Z¼4. Crystallographic data has been deposited with the Cambridge
Crystallographic Data Centre [CCDC 672089] for compound 6a. Copies of the
data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.
html or CCDC, 12 Union Road, Cambridge CB21EZ, UK (fax: þ44 1223 336 033;
e-mail: deposit@ccdc.cam.ac.uk).
This work was financially supported by the Key Sciencific Re-
search Foundation of Anhui Science and Technology Department
(
04022006) and the Natural Science Foundation of Education
Administration of Anhui Province (2006kj117B).
12. Li, Y.-W.; Liu, X.-Y.; Yang, Y.-Q.; Zhao, G. J. Org. Chem. 2007, 72, 288–291.