A highly efficient and stereoselective cycloaddition of nitrones to N-vinylpyrroles

Article abstract of DOI:10.1055/s-0033-1340479

1,3-Dipolar cycloadditions of a number of C-aryl, C-carbamoyl-, and C,C-bis(methoxycarbonyl)nitrones and substituted N-vinylpyrroles proceed with high efficiency and regioselectivity with the formation of only one isomeric substituted 5-(1H-pyrrol-1-yl)isoxazolidine cycloadduct. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1340479

PAPER
▌771
paper
A Highly Efficient and Stereoselective Cycloaddition of Nitrones to N-Vinyl-
pyrroles
Cycloaddition of Nitrones to N-Vinylpyrroles
Alexander P. Molchanov,*a Ruslan S. Savinkov,a Alexander V. Stepakov,a Galina L. Starova,a Rafael R. Kostikov,a
Victoriya S. Barnakova,b Andrey V. Ivanovb
a
Department of Chemistry, Saint Petersburg State University, Universitetsky pr. 26, 198504 Saint Petersburg, Russian Federation
Fax +7(812)4286939; E-mail: s.lab@pobox.spbu.ru
b
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences, 1 Favorsky Str., 664033 Irkutsk, Russian
Federation
Received: 02.10.2013; Accepted after revision: 29.11.2013
for 9–15 hours with high regio- and stereoselectivity to
Abstract: 1,3-Dipolar cycloadditions of a number of C-aryl, C-car-
give cis- and trans-5-(pyrrol-1-yl)isoxazolidines 6 and 7
bamoyl-, and C,C-bis(methoxycarbonyl)nitrones and substituted N-
only (Table 1 and Table 2).
vinylpyrroles proceed with high efficiency and regioselectivity with
the formation of only one isomeric substituted 5-(1H-pyrrol-1-
yl)isoxazolidine cycloadduct.
Stereoselectivity of the reaction of C,N-diarylnitrone 4a
with pyrrole 2 is lower and diastereomers 6i and 6i′ are
obtained in a ratio of 10:1.5. Reactions of N-methylni-
trone 4e with pyrroles 1–3 require prolonged heating (30–
Key words: pyrroles, nitrones, isoxazolidines, cycloaddition, stereo-
selectivity
100 h) and they afford modest yields of products, in these
cases the starting N-vinylpyrroles were recovered (30–
1,3-Dipolar cycloaddition is as one of the most powerful
tools to create five-membered N,O-heterocycles. In par-
ticular, dipolar cycloaddition of nitrones as 1,3-dipoles to
C=C bonds of different alkenes allows access to a variety
of isoxazolidines. These cycloadducts have attracted con-
siderable attention due to the potential biological activity
of isoxazolidines, and as promising precursors for the syn-
thesis of such natural products as β-lactam antibiotics and
alkaloids through reductive cleavage of the N–O bond.1
Earlier, it was shown that the regio- and stereoselectivity
of the reaction of nitrones with cyclopropenes and methy-
lenecyclopropanes substantially depends on substitution
on the double bond.2
40%); the ratio of diastereomers 6j–l and 6j′–l′ is close to
unity. Analysis of the reaction mixture of N-methylnitrone
4e and pyrrole 1 after 40, 100, and 140 hours of heating
shows that the ratio of diastereomers does not change. The
structure of products 6a–l and 6j′–l′ were established on
the basis of their spectral data. The cis orientation of sub-
stituents in adducts 6a–j was established on the basis of
the comparison of chemical shifts and coupling constants
between isoxazolidine protons and confirmed by X-ray
crystal structure analysis of compound 6d (Figure 1).7
Pyrroles and its derivatives are amongst the most impor-
tant fundamental structural units of biologically and phys-
iologically active molecules such as chlorophyll,
porphyrins, hemoglobin, vitamin B12 and others.3 The de-
velopment of synthetic strategies for the preparation of
pyrrolyl- or indolyl-triazoles, as well as pyrrolyl-imidaz-
ole ensembles, remains the subject of a steadily growing
number of investigations.4,5
Herein, we disclose an efficient method for the synthesis
of isoxazolidines, containing a pyrrolyl substituent at po-
sition 5. The method comprises the 1,3-dipolar cycloaddi-
tion of nitrones to the double bond of 2-phenyl-1-vinyl-
1H-pyrrole (1), 2-(thien-2-yl)-1-vinyl-1H-pyrrole (2), and
1-vinyl-4,5,6,7-tetrahydro-1H-indole (3), easily available
via the Trofimov reaction.6 It was found that C,N-diaryl-
nitrones 4a–d and N-aryl-C-carbamoylnitrones 5a–d re-
acted with vinylpyrroles 1–3 in toluene at reflux (110 °C)
Figure 1 X-ray crystal structure of 6d
The reactions of pyrroles 1–3 with C-carbamoylnitrones
5a–d require significantly shorter reaction times (6 h)
compared with nitrones 4a–e and usually give better
yields of cycloadducts (Table 2).
The reaction of nitrones 5a and 5d with 2-(thien-2-yl)pyr-
role 2 afford two diastereomers 7i,j and 7i′,j′ in a 10:1 ra-
tio. The structure of products 7a–j was established on the
basis of their spectral data and X-ray crystal structure data
for compound 7g (Figure 2).7 From the data obtained, the
main isomers of the products 7a–j have a cis relationship
SYNTHESIS 2014, 46, 0771–0780
Advanced online publication: 07.02.2014
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DOI: 10.1055/s-0033-1340479; Art ID: SS-2013-T0655-OP
© Georg Thieme Verlag Stuttgart · New York

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A. P. Molchanov et al.
PAPER
Table 1 Cycloaddition between Nitrones 4a–e and N-Vinylpyrroles 1–3
R2
R2
R1
R1
–
O
R2
R4
N
+
N
N
O
O
R4
R4
N
N
toluene
110 °C
R1
+
+
N
R3
R3
6a–l
R3
1–3
4a–e
6i'–l'
Pyrrole
Nitrone
R1
R2
R3
R4
Time (h)
Product
Yield (%)
Ratioa (cis/trans)
1
1
1
1
3
3
3
3
2
1
3
2
4a
4b
4c
4d
4a
4b
4c
4d
4a
4e
4e
4e
Ph
Ph
Ph
Ph
H
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
15
15
15
15
11
15
11
9
6a
81
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
10:1.5
10:7
Me
6b
90
OMe
Cl
6c
85
6d
80
(CH2)4
(CH2)4
(CH2)4
(CH2)4
2-thienyl
Ph
H
6e
95
Me
OMe
Cl
6f
78
6g
79
6h
59
H
H
H
9
6i/6i′
6j/6j′
6k/6k′
6l, 6l′
87 (57b)
30b
57b
28b
Cl
30
100
35
(CH2)4
2-thienyl
Cl
10:6
H
Cl
10:8
a From 1H NMR analysis of the crude reaction mixture.
b Isolated yield of pure cis isomer.
between the substituents in the 3- and 5-positions on the gives the same ratio of diastereomers. The increased steric
isoxazolidine ring.
hindrance of N,C,C-trisubstituted nitrones may cause in-
version of the regioselectivity of the 1,3-dipolar cycload-
dition reaction,8 but in our case the reaction of pyrroles 1–
3 with N-aryl-C,C-bis(methoxycarbonyl)nitrones 8a–c af-
fords only 5-(pyrrol-1-yl)isoxazolidines 9a–g in high
yields (Table 3).
Cleavage of the N–O bond is the most synthetically useful
reaction for the modification of the obtained cycload-
ducts, which can be done by a variety of methods, includ-
ing hydrogenation over Raney nickel, Pd/C, or Pd(OH)2,9–13
reaction with Zn/H+,9,10,14 Mo(CO)6/H2O,15 Zn/Cu(OAc)2/
AcOH,16 and SmI2.17 As an illustration, in our studies
(Scheme 1), adducts 6c and 7c were hydrogenated on
Pd/CaCO3 to give 1,3-amino alcohols 10a,b in good iso-
lated yields (~66–95%).
The basic treatment of isoxazolidines suitably activated at
the 3-position of the ring has been exploited for a synthet-
ic approach to 3-(alkylamino)furan-2(5H)-ones, versatile
synthons for β-lactams18,19 and (or) β-enaminones.20
Treatment of isoxazolidines 7c,d with sodium hydride or
tetrabutylammonium fluoride led to the formation of com-
Figure 2 X-ray crystal structure of 7g
The reaction of nitrones 5a–d with pyrroles 1–3 under mi-
crowave heating requires substantially shorter time and
Synthesis 2014, 46, 771–780
© Georg Thieme Verlag Stuttgart · New York

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Cycloaddition of Nitrones to N-Vinylpyrroles
773
Table 2 Cycloaddition between Nitrones 5a–d and N-Vinylpyrroles 1–3
R2
R2
R3
R3
R1
R1
R3
R2
O–
N
O
N+
N
O
N
N
+
O
R1
N
+
O
NH
R4
O
N
R4
N
H
H
R4
1–3
5a–d
7a–j
7i', j'
Pyrrole
Nitrone
R1
R2
R3
R4
Product
Yield (%)
Conventional heatinga MWb
Ratioc cis/trans
1
1
1
1
3
3
3
3
2
2
5a
5b
5c
5d
5a
5b
5c
5d
5a
5d
Ph
Ph
Ph
Ph
H
H
H
H
H
H
7a
82
89d
97d
93e
94d
97e
83e
93d
93e
–
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
10:1
H
Me
Cl
H
7b
84
H
7c
91
Me
H
7d
85
(CH2)4
H
7e
82
(CH2)4
H
Me
Cl
H
7f
80
(CH2)4
H
7g
85
(CH2)4
Me
H
7h
87
2-thienyl
2-thienyl
H
H
H
7i/7i′
7j/7j′
92 (55d)
84 (72d)
Me
H
–
10:1
a Toluene, 110 °C, 6 h.
b Microwave, toluene–chlorobenzene (3:1), 100 °C, 40 min.
c From 1H NMR analysis of the crude reaction mixture.
d Isolated yield of pure cis isomer.
e Spectroscopic (NMR) yield.
O
H
N
N
R4
H2, Pd/CaCO3
N
HO
R3
O
R3
Ph
EtOAc, r.t., 24 h
NH
N
N
OH
11a R1 = H, R2 = Cl
11b R1 = Me, R2 = H
N
O
R1
R1
10 R = 4-MeOC6H4
N
base, THF
R4
+
6c R = 4-MeOC6H4
7c R = 4-C(O)NH-4-ClC6H4
10b R = 4-C(O)NH-4-ClC6H4
O
N
H
Ph
Scheme 1 Hydrogenation of isoxazolidines 6c and 7c
N
H
7c R1 = Cl, R2 = H
7d R1 = Me, R2 = H
12
pounds 11a,b (55–75% yield) and 2-phenyl-1H-pyrrole
(12) (Scheme 2).21
Scheme 2 The treatment of isoxazolidines 7c,d with base
In summary, we have demonstrated that the reaction be-
tween C,N-diaryl-, N-aryl-C-carbamoyl-, and C,C-
bis(methoxycarbonyl)nitrones with 2-phenyl-1-vinyl-1H-
pyrrole, 2-(thien-2-yl)-1-vinyl-1H-pyrrole, and 1-vinyl-
4,5,6,7-tetrahydro-1H-indole proceeds as a normal 1,3-di-
polar cycloaddition with high regioselectivity to give only
5-(pyrrol-1-yl)isoxazolidines in good yields. The hydro-
genation of the obtained cycloadducts led to 1,3-amino al-
cohols and the treatment of the isoxazolidines by a base
afforded 3-(arylamino)-5-hydroxy-1,5-dihydro-2H-pyr-
rol-2-ones.
All reactions were performed in anhydrous solvents under an argon
atmosphere. Toluene was distilled from Na metal/benzophenone.
Reaction progress was monitoring using TLC on precoated Silufol
UV–254 plates. The IR spectra were measured on a Bruker Tensor
1
27 spectrophotometer. H and 13C NMR spectra were recorded in
CDCl3 using a Bruker DPX-300 spectrometer or Bruker Avance
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 771–780

774
A. P. Molchanov et al.
PAPER
Table 3 Cycloaddition between Nitrones 8a–c and N-Vinylpyrroles 1–3
R2
R3
R1
R2
O–
N+
N
O
+
R3
N
R1
N
MeO2C
8a–c
CO2Me
MeO2C
CO2Me
1–3
9a–g
Pyrrole
Nitrone
R1
R2
R3
Time (h)
Product
Yield (%)
Conventional heatinga MWb
1
1
1
3
3
3
2
8a
8b
8c
8a
8b
8c
8a
Ph
H
H
H
H
7
7
9a
9b
9c
9d
9e
9f
78
80
90
92
87
87
94
91c
88d
89c
91d
95c
95c
–
Ph
Me
Cl
H
Ph
7
(CH2)4
(CH2)4
(CH2)4
2-thienyl
15
7
Me
Cl
H
7
H
5
9g
a Toluene, 110 °C.
b Microwave, toluene–chlorobenzene (3:1), 100 °C, 40 min.
c Spectroscopic (NMR) yield.
d Isolated yield of pure cis isomer.
400. HRMS spectra were obtained with a Bruker-microTOF and
Bruker-maXis (QTOF). In microwave experiments used the Dis-
cover SP DC7299 apparatus. Nitrones were prepared using known
procedures.22
2-Phenyl-5-(2-phenyl-1H-pyrrol-1-yl)-3-(p-tolyl)isoxazolidine
(6b)
Prepared from nitrone 4b and pyrrole 1 as a white solid; yield: 342
mg (90%); mp 132–133 °C; Rf = 0.53 (9% EtOAc–hexane).
IR (KBr): 3138, 3097, 3050, 3024, 2968, 2951, 2921, 2876, 1597,
1489, 1464, 1405, 1294, 1237, 762, 702 cm–1.
Cycloaddition Reactions; General Procedure
A mixture of nitrone (1.0 mmol) and N-vinylpyrrole (1.3 mmol) in
toluene (5 mL) was heated at reflux until TLC showed complete
consumption of the nitrone (see Tables 1–3). The solvent was evap-
orated under reduced pressure, and the residue was subjected to col-
umn chromatography (silica gel, petroleum ether–EtOAc) followed
by crystallization (EtOH) to give the product. In some cases (MW
irradiation), the product was not isolated, and the yield was calcu-
lated on the basis of 1H NMR spectra of the reaction mixture using
1,1,2,2-tetrachloroethane as an internal standard.
1H NMR (300 MHz, CDCl3): δ = 2.42 (s, 3 H, CH3), 2.84 (ddd,
J = 13.0, 6.7, 6.3 Hz, 1 H), 3.20 (ddd, J = 13.0, 7.8, 7.4 Hz, 1 H),
4.76 (dd, J = 7.8, 6.7 Hz, 1 H), 6.18 (dd, J = 7.4, 6.3 Hz, 1 H), 6.22–
6.32 (m, 2 Hpyrrole), 6.90–7.05 (m, 4 Harom), 7.15–7.25 (m, 4 Harom),
7.35–7.55 (m, 7 Harom).
13C NMR (75 MHz, CDCl3): δ = 21.6 (CH3), 46.1 (CH2), 70.2 (CH),
83.9 (CH), 109.9 (CH), 110.1 (CH), 116.7 (2 CH), 119.6 (CH),
123.2 (CH), 127.0 (2 CH), 127.8 (CH), 128.9 (2 CH), 129.1 (2 CH),
129.9 (2 CH), 130.1 (2 CH), 133.2 (C), 135.8 (C), 137.9 (2 C), 150.7
(C).
2,3-Diphenyl-5-(2-phenyl-1H-pyrrol-1-yl)isoxazolidine (6a)
Prepared from nitrone 4a and pyrrole 1 as a white solid; yield: 296
mg (81%); mp 142–143 °C; Rf = 0.50 (9% EtOAc–hexane).
HRMS (ESI): m/z [M + K]+ calcd for C26H24KN2O: 419.1520;
found: 419.1503.
IR (KBr): 3140, 3104, 3060, 3032, 2989, 2951, 1597, 1486, 1464,
1442, 1411, 1296, 1241, 762, 698 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.85 (ddd, J = 13.0, 6.7, 6.3 Hz, 1
H), 3.23 (ddd, J = 13.0, 7.8, 7.4 Hz, 1 H), 4.83 (dd, J = 7.8, 6.7 Hz,
1 H), 6.20 (dd, J = 7.4, 6.3 Hz, 1 H), 6.23–6.30 (m, 2 Hpyrrole), 6.95–
7.04 (m, 4 Harom), 7.18–7.30 (m, 2 Harom), 7.35–7.68 (m, 10 Harom).
13C NMR (75 MHz, CDCl3): δ = 45.9 (CH2), 70.3 (CH), 84.0 (CH),
109.9 (CH), 110.2 (CH), 116.5 (2 CH), 119.5 (CH), 123.2 (CH),
127.0 (2 CH), 127.9 (CH), 128.2 (CH), 128.9 (2 CH), 129.2 (2 CH),
129.4 (2 CH), 129.9 (2 CH), 133.2 (C), 135.8 (C), 141.0 (C), 150.0
(C).
3-(4-Methoxyphenyl)-2-phenyl-5-(2-phenyl-1H-pyrrol-1-
yl)isoxazolidine (6c)
Prepared from nitrone 4c and pyrrole 1 as a white solid; yield: 336
mg (85%); mp 117–118 °C; Rf = 0.35 (9% EtOAc–hexane).
IR (KBr): 3095, 3073, 3022, 2976, 2939, 2874, 2843, 1598, 1510,
1491, 1465, 1294, 1244, 1172, 756, 702 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.84 (ddd, J = 13.0, 6.7, 6.3 Hz, 1
H), 3.19 (ddd, J = 13.0, 7.8, 7.4 Hz, 1 H), 3.88 (s, 3 H, OCH3), 4.74
(dd, J = 7.8, 6.7 Hz, 1 H), 6.19 (dd, J = 7.4, 6.3 Hz, 1 H), 6.25–6.32
(m, 2 Hpyrrole), 6.85–7.05 (m, 6 Harom), 7.20–7.30 (m, 2 Harom), 7.35–
7.55 (m, 7 Harom).
13C NMR (75 MHz, CDCl3): δ = 46.1 (CH2), 55.8 (OCH3), 70.1
(CH), 83.9 (CH), 109.9 (CH), 110.1 (CH), 114.8 (2 CH), 116.8 (2
CH), 119.6 (CH), 123.3 (CH), 127.8 (CH), 128.3 (2 CH), 128.9 (2
Anal. Calcd for C25H22N2O: C, 81.94; H, 6.05; N, 7.64. Found: C,
81.83; H, 6.10; N, 7.57.
Synthesis 2014, 46, 771–780
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Cycloaddition of Nitrones to N-Vinylpyrroles
775
CH), 129.1 (2 CH), 129.9 (2 CH), 132.8 (C), 133.3 (C), 135.8 (C),
150.6 (C), 159.6 (C).
1-[3-(4-Methoxyphenyl)-2-phenylisoxazolidin-5-yl]-4,5,6,7-tet-
rahydro-1H-indole (6g)
Prepared from nitrone 4c and pyrrole 3 as a yellowish solid; yield:
295 mg (79%); mp 114–117 °C; Rf = 0.22 (9% EtOAc–hexane).
Anal. Calcd for C26H24N2O2: C, 78.76; H, 6.10; N, 7.07. Found: C,
78.58; H, 6.14; N, 7.06.
IR (KBr): 3073, 3040, 2997, 2938, 2833, 1597, 1513, 1485, 1440,
1304, 1246, 1177, 1036, 798, 760 cm–1.
3-(4-Chlorophenyl)-2-phenyl-5-(2-phenyl-1H-pyrrol-1-yl)isox-
azolidine (6d)
Prepared from nitrone 4d and pyrrole 1 as a white solid; yield: 320
mg (80%); mp 152–153 °C; Rf = 0.48 (9% EtOAc–hexane).
1H NMR (300 MHz, CDCl3): δ = 1.72–1.88 (m, 2 H, CH2), 1.85–
1.99 (m, 2 H, CH2), 2.51–2.69 (m, 3 H), 2.73–2.86 (m, 2 H, CH2),
3.19 (ddd, J = 13.0, 7.8, 7.4 Hz, 1 H), 3.87 (s, 3 H, OCH3), 4.79–
4.88 (m, 1 H), 6.02 (d, J = 3.0 Hz, 1 Hpyrrole), 6.02–6.09 (m, 1 H),
6.72 (d, J = 3.0 Hz, 1 Hpyrrole), 6.98 (d, J = 8.5 Hz, 2 Harom), 6.98–
7.10 (m, 3 Harom), 7.24–7.32 (m, 2 Harom), 7.50 (d, J = 8.5 Hz, 2
IR (KBr): 3140, 3063, 3043, 2990, 2952, 1597, 1488, 1463, 1347,
1296, 1240, 762, 693 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.79 (ddd, J = 13.0, 6.7, 6.3 Hz, 1
H), 3.21 (ddd, J = 13.0, 7.8, 7.4 Hz, 1 H), 4.81 (dd, J = 7.8, 6.7 Hz,
1 H), 6.19 (dd, J = 7.4, 6.3 Hz, 1 H), 6.22–6.32 (m, 2 Hpyrrole), 6.90
(s, 1 Hpyrrole), 6.95–7.05 (m, 3 Harom), 7.20–7.30 (m, 2 Harom), 7.40–
7.55 (m, 9 Harom).
13C NMR (75 MHz, CDCl3): δ = 45.9 (CH2), 69.6 (CH), 84.1 (CH),
110.0 (CH), 110.3 (CH), 116.4 (2 CH), 119.4 (CH), 123.5 (CH),
127.9 (CH), 128.4 (2 CH), 129.0 (2 CH), 129.3 (2 CH), 129.6 (2
CH), 129.9 (2 CH), 133.1 (C), 134.0 (C), 135.9 (C), 139.7 (C),
150.4 (C).
Harom).
13C NMR (75 MHz, CDCl3): δ = 21.9 (CH2), 23.1 (CH2), 23.2
(CH2), 23.5 (CH2), 44.6 (CH2), 55.3 (CH3), 69.6 (CH), 82.9 (CH),
108.6 (CH), 114.3 (2 CH), 115.4 (2 CH), 116.2 (CH), 118.7 (C),
122.3 (CH), 127.7 (2 CH), 128.5 (C), 128.8 (2 CH), 133.1 (C),
150.9 (C), 159.1 (C).
HRMS (ESI): m/z [M + H]+ calcd for C24H27N2O2: 413.1626; found:
413.1618.
1-[3-(4-Chlorophenyl)-2-phenylisoxazolidin-5-yl]-4,5,6,7-tetra-
hydro-1H-indole (6h)
Prepared from nitrone 4d and pyrrole 3; grey solid; yield: 223 mg
(59%); mp 152–154 °C; Rf = 0.34 (9% EtOAc–hexane).
Anal. Calcd for C25H21ClN2O: C, 74.90; H, 5.28; N, 6.99. Found: C,
74.97; H, 5.35; N, 6.97.
1-(2,3-Diphenylisoxazolidin-5-yl)-4,5,6,7-tetrahydro-1H-indole
(6e)
Prepared from nitrone 4a and pyrrole 3 as a white solid; yield: 326
mg (95%); mp 98–99 °C; Rf = 0.39 (9% EtOAc–hexane).
IR (KBr): 3059, 2996, 2936, 2835, 1597, 1488, 1440, 1370, 1296,
1205, 796, 760 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.75–1.84 (m, 2 H, CH2), 1.84–
1.93 (m, 2 H, CH2), 2.50–2.69 (m, 3 H, CH2 + CHCH2CH), 2.71–
2.80 (m, 2 H, CH2), 3.22 (ddd, J = 13.4, 8.2, 7.4 Hz, 1 H,
CHCH2CH), 4.89 (t, J = 7.4 Hz, 1 H, CHCH2CH), 6.02 (d, J = 2.6
Hz, 1 Hpyrrole,), 6.02–6.09 (m, 1 H, CHCH2CH), 6.61 (d, J = 2.6 Hz,
1 Hpyrrole), 7.00–7.07 (m, 3 Harom), 7.26–7.32 (m, 2 Harom), 7.42 (d,
J = 8.5 Hz, 2 Harom), 7.53 (d, J = 8.5 Hz, 2 Harom).
13C NMR (75 MHz, CDCl3): δ = 21.8 (CH2), 23.0 (CH2), 23.2
(CH2), 23.5 (CH2), 44.1 (CH2), 69.2 (CH), 83.0 (CH), 108.9 (CH),
115.1 (2 CH), 116.1 (CH), 118.9 (C), 122.5 (CH), 127.9 (2 CH),
128.6 (C), 129.0 (2 CH), 129.1 (2 CH), 133.4 (C), 139.8 (C), 150.8
(C).
IR (KBr): 3127, 3089, 3059, 3028, 3001, 2923, 2844, 1598, 1483,
1446, 1372, 1294, 1019, 891, 739, 692 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.72–1.84 (m, 2 H, CH2), 1.85–
1.99 (m, 2 H, CH2), 2.48–2.69 (m, 3 H), 2.71–2.88 (m, 2 H, CH2),
3.18–3.29 (m, 1 H), 4.84–4.95 (m, 1 H), 5.94 (d, J = 3.0 Hz, 1
Hpyrrole), 6.02–6.09 (m, 1 H), 6.67 (d, J = 3.0 Hz, 1 Hpyrrole), 6.98–
7.11 (m, 3 Harom), 7.23–7.51 (m, 5 Harom), 7.60 (d, J = 7.0 Hz, 2
Harom).
13C NMR (75 MHz, CDCl3): δ = 21.9 (CH2), 23.1 (CH2), 23.2
(CH2), 23.5 (CH2), 44.4 (CH2), 69.9 (CH), 83.0 (CH), 108.7 (CH),
115.2 (2 CH), 116.2 (CH), 118.8 (C), 122.3 (CH), 126.5 (2 CH),
127.7 (CH), 128.5 (C), 128.9 (2 CH), 129.0 (2 CH), 141.3 (C),
151.0 (C).
HRMS (ESI): m/z [M + H]+ calcd for C23H24ClN2O: 379.1572;
found: 379.1575.
HRMS (ESI): m/z [M + H]+ calcd for C23H25N2O: 345.1961; found:
345.1956.
2,3-Diphenyl-5-[2-(thiophen-2-yl)-1H-pyrrol-1-yl]isoxazoli-
dine (6i/6i′)
Prepared from nitrone 4a and pyrrole 2; yield: 301 mg (87%). Crys-
tallization (EtOH) gave cis-isomer 6i as a grey solid; yield: 212 mg
(57%); mp 114–115 °C; Rf = 0.51 (20% EtOAc–hexane).
1-[2-Phenyl-3-(p-tolyl)isoxazolidin-5-yl]-4,5,6,7-tetrahydro-1H-
indole (6f)
Prepared from nitrone 4b and pyrrole 3 as a white solid; yield: 279
mg (78%); mp 96–97 °C; Rf = 0.54 (9% EtOAc–hexane).
IR (KBr): 3142, 3064, 3033, 2986, 2950, 1597, 1486, 1465, 1411,
1290, 764, 702 cm–1.
1H NMR (400 MHz, CDCl3): δ (major isomer) = 2.85 (ddd,
J = 13.3, 7.0, 5.5 Hz, 1 H), 3.29 (dt, J = 13.3, 8.1 Hz, 1 H), 4.75–
4.84 (m, 1 H), 6.26 (t, J = 3.3 Hz, 1 Harom), 6.31–6.36 (m, 2 H, H +
IR (KBr): 3122, 3096, 3070, 3035, 2999, 2928, 2849, 2832, 1597,
1485, 1437, 1293, 1206, 793, 759 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.71–1.83 (m, 2 H, CH2), 1.84–
1.97 (m, 2 H, CH2), 2.41 (s, 3 H, CH3), 2.49–2.59 (m, 2 H, CH2),
2.59–2.69 (m, 1 H), 2.70–2.87 (m, 2 H, CH2), 3.20 (ddd, J = 13.4,
7.8, 7.4 Hz, 1 H), 4.84 (t, J = 7.8 Hz, 1 H), 5.97–6.08 (m, 2 H, H +
Harom), 6.99–7.07 (m, 4 Harom), 7.12–7.20 (m, 2 Harom), 7.21–7.27
(m, 2 Harom), 7.35–7.41 (m, 2 Harom), 7.41–7.47 (m, 2 Harom), 7.56–
7.61 (m, 2 Harom).
Hpyrrole), 6.71 (d, J = 3.0 Hz, 1 Hpyrrole), 6.96–7.05 (m, 1 Harom), 7.06
1H NMR (400 MHz, CDCl3): δ (minor isomer) = 2.91 (dt, J = 13.6,
7.3 Hz, 1 H), 3.26–3.33 (m, 1 H), 4.99–5.08 (m, 1 H), 6.16 (t, J = 3.3
Hz, 1 Harom), 6.37 (dd, J = 3.5, 1.7 Hz, 1 Harom), 6.41 (dd, J = 7.3, 3.4
Hz, 1 H), 6.86–6.95 (m, 4 Harom), 7.12–7.20 (m, 2 Harom), 7.32–7.35
(m, 2 Harom), 7.35–7.41 (m, 2 Harom), 7.41–7.47 (m, 2 Harom), 7.51–
7.55 (m, 2 Harom).
13C NMR (75 MHz, CDCl3): δ (major isomer) = 45.6 (CH2), 69.7
(CH), 83.3 (CH), 109.6 (CH), 111.4 (CH), 116.3 (2 CH), 119.8
(CH), 122.9 (CH), 125.8 (CH), 126.6 (2 CH), 127.0 (CH), 127.1
(d, J = 7.8 Hz, 2 Harom), 7.20–7.31 (m, 4 Harom), 7.47 (d, J = 7.8 Hz,
2 Harom).
13C NMR (75 MHz, CDCl3): δ = 21.1 (CH3), 21.9 (CH2), 23.0
(CH2), 23.2 (CH2), 23.5 (CH2), 44.6 (CH2), 69.8 (CH), 82.9 (CH),
108.6 (CH), 115.2 (2 CH), 116.3 (CH), 118.7 (C), 122.2 (CH),
126.4 (2 CH), 128.5 (C), 128.8 (2 CH), 129.6 (2 CH), 137.3 (C),
138.2 (C), 151.0 (C).
Anal. Calcd for C24H26N2O: C, 80.41; H, 7.31; N, 7.81. Found: C,
80.20; H, 7.34; N, 7.66.
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(C), 127.4 (CH), 127.8 (CH), 128.7 (2 CH), 129.0 (2 CH), 133.8
(C), 140.4 (C), 150.1 (C).
HRMS (ESI): m/z [M + H]+ calcd for C23H21N2OS: 373.1369;
13C NMR (100 MHz, CDCl3): δ = 43.0 (CH3), 47.5 (CH2), 72.8
(CH), 82.2 (CH), 109.4 (CH), 110.9 (CH), 119.6 (CH), 125.6 (CH),
126.6 (CH), 126.7 (C), 127.4 (CH), 128.8 (2 CH), 129.1 (2 CH),
134.0 (C), 134.2 (C), 136.2 (C).
13C NMR (100 MHz, CDCl3): δ (minor isomer 6l′) = 43.1 (CH3),
72.8 (CH), 82.5 (CH), 109.9 (CH), 111.2 (CH), 118.6 (CH), 125.6
(CH), 126.6 (CH), 127.5 (CH), 129.0 (2 CH), 129.0 (2 CH), 133.6
(C), 134.0 (C), 136.4 (C). Some signals overlapped with signals of
major isomer 6l.
found: 373.1372.
3-(4-Chlorophenyl)-2-methyl-5-(2-phenyl-1H-pyrrol-1-yl)isox-
azolidine (6j)
Prepared from nitrone 4e and pyrrole 1 as a white solid; yield: 100
mg (30%); mp 102–103 °C; Rf = 0.47 (9% EtOAc–hexane).
IR (KBr): 3104, 3062, 2992, 2958, 2865, 2847, 1600, 1491, 1467,
1400, 1287, 1234, 700 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.65 (s, 3 H, CH3), 2.67–2.79 (m,
1 H), 3.16 (dt, J = 13.7, 8.0 Hz, 1 H), 3.63 (dd, J = 10.0, 8.0 Hz, 1
H), 6.07 (dd, J = 8.0, 4.8 Hz, 1 H), 6.22–6.30 (m, 1 Hpyrrole), 6.33–
6.39 (m, 1 Hpyrrole), 7.22–7.47 (m, 10 Harom).
13C NMR (75 MHz, CDCl3): δ = 43.4 (CH3), 48.0 (CH2), 73.3 (CH),
82.7 (CH), 109.5 (CH), 109.9 (CH), 119.5 (CH), 127.5 (CH), 128.9
(2 CH), 129.3 (2 CH), 129.6 (2 CH), 129.8 (2 CH), 133.4 (C), 134.4
(C), 135.3 (C), 136.6 (C).
HRMS (ESI): m/z [M + H]+ calcd for C18H18ClN2OS: 345.0823;
found: 345.0826.
N,2-Diphenyl-5-(2-phenyl-1H-pyrrol-1-yl)isoxazolidine-3-car-
boxamide (7a)
Prepared from nitrone 5a and pyrrole 1 as a white solid; yield: 350
mg (82%); mp 138–139 °C; Rf = 0.45 (20% EtOAc–hexane).
IR (KBr): 3341, 3135, 3059, 3032, 2963, 1685, 1599, 1524, 1490,
1442, 1307, 1243, 758 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.91 (ddd, J = 13.7, 9.0, 8.5 Hz, 1
H), 3.26 (ddd, J = 13.7, 5.2, 2.6 Hz, 1 H), 4.67 (dd, J = 9.0, 2.6 Hz,
1 H), 6.17 (dd, J = 8.5, 5.2 Hz, 1 H), 6.27 (m, 1 Hpyrrole), 6.30 (m, 1
HRMS (ESI): m/z [M + H]+ calcd for C20H20ClN2O: 339.1259;
found: 339.1261.
Hpyrrole), 7.05–7.12 (m, 4 Harom), 7.14–7.20 (m, 1 Harom), 7.30–7.60
(m, 9 Harom), 7.72 (d, J = 8.0 Hz, 2 Harom), 9.16 (s, 1 H, NH).
1-[3-(4-Chlorophenyl)-2-methylisoxazolidin-5-yl]-4,5,6,7-tetra-
hydro-1H-indole (6k, 6k′)
Prepared from nitrone 4e and pyrrole 3 as an oil, mixture of diaste-
reomers; yield: 180 mg (57%); Rf = 0.28 (17% EtOAc–hexane).
13C NMR (75 MHz, CDCl3): δ = 36.6 (CH2), 70.3 (CH), 85.3 (CH),
110.4 (CH), 111.1 (CH), 115.0 (CH), 119.0 (CH), 120.5 (2 CH),
124.1 (CH), 125.3 (CH), 128.2 (CH), 128.9 (2 CH), 129.2 (2 CH),
129.5 (2 CH), 129.9 (2 CH), 130.0 (CH), 132.9 (C), 136.2 (C),
137.5 (C), 149.4 (C), 169.1 (CO).
IR (KBr): 3093, 2991, 2927, 2865, 2847, 1492, 1458, 1367, 1293,
1090, 1014, 829 cm–1.
1H NMR (400 MHz, CDCl3): δ (mixture of isomers) = 1.70–1.82
(m, 3.2 H, major + minor), 1.82–1.95 (m, 3.2 H, major + minor),
2.48–2.57 (m, 3.2 H, major + minor), 2.57–2.76 (m, 4.8 H, major +
minor), 2.61 (s, 3 H, CH3, major), 2.64 (s, 1.8 H, CH3, minor), 2.86–
2.96 (m, 0.6 H, minor), 3.15 (dt, J = 13.6, 7.9 Hz, 1 H, major), 3.64
(dd, J = 9.6, 7.9 Hz, 1 H, major), 3.80–3.90 (m, 0.6 H, minor), 5.93
(dd, J = 7.9, 5.0 Hz, 1 H, major), 5.98 (dd, J = 8.3, 4.2 Hz, 0.6 H,
minor), 6.06 (d, J = 3.0 Hz 1 Hpyrrole, major), 6.08 (d, J = 2.9 Hz, 0.6
HRMS (ESI): m/z [M + H]+ calcd for C26H23N3O2: 410.1863; found:
410.1865.
2-Phenyl-5-(2-phenyl-1H-pyrrol-1-yl)-N-(p-tolyl)isoxazolidine-
3-carboxamide (7b)
Prepared from nitrone 5b and pyrrole 1 as a white solid; yield: 368
mg (84%); mp 81–82 °C; Rf = 0.46 (20% EtOAc–hexane).
IR (KBr): 3371, 3336, 3137, 3105, 3060, 3033, 2968, 2918, 2863,
1681, 1592, 1520, 1489, 1306, 1243, 764, 701 cm–1.
Hpyrrole, minor), 6.85 (д, J = 2.9 Hz, 0.6 Hpyrrole, minor), 7.04 (d,
J = 3.0 Hz, 1 Hpyrrole, major), 7.34–7.45 (m, 6.4 Harom).
1H NMR (300 MHz, CDCl3): δ = 2.37 (s, 3 H, CH3), 2.90 (ddd,
J = 13.7, 9.3, 8.5 Hz, 1 H), 3.26 (ddd, J = 13.7, 5.2, 2.5 Hz, 1 H),
4.65 (dd, J = 9.3, 2.5 Hz, 1 H), 6.16 (dd, J = 8.5, 5.2 Hz, 1 H), 6.20–
6.24 (m, 1 Hpyrrole), 6.25–6.32 (m, 1 Hpyrrole), 7.00–7.10 (m, 4 Harom),
7.12–7.15 (m, 2 Harom), 7.20–7.35 (m, 2 Harom), 7.40–7.62 (m, 7
13C NMR (75 MHz, CDCl3): δ (major isomer) = 21.9 (CH2), 23.1
(CH2), 23.2 (CH2), 23.5 (CH2), 43.0 (CH3), 46.3 (CH2), 72.8 (CH),
81.4 (CH), 108.2 (CH), 116.2 (CH), 118.3 (C), 128.0 (C), 128.8 (2
CH), 129.1 (2 CH), 133.9 (C), 136.5 (C).
H
arom), 9.20 (s, 1 H, NH).
13C NMR (100 MHz, CDCl3): δ (minor isomer) = 21.9 (CH2), 23.1
(CH2), 23.2 (CH2), 23.5 (CH2), 43.0 (CH3), 45.1 (CH2), 72.1 (CH),
82.0 (CH), 108.8 (CH), 115.5 (CH), 118.7 (C), 128.4 (C), 129.0 (2
CH), 129.0 (2 CH), 134.0 (C), 136.8 (C).
HRMS (ESI): m/z [M + H]+ calcd for C18H22ClN2O: 317.1415;
found: 317.1406.
13C NMR (75 MHz, CDCl3): δ = 21.3 (CH3), 36.6 (CH2), 70.2 (CH),
85.3 (CH), 110.4 (CH), 111.0 (CH), 115.0 (2 CH), 119.1 (CH),
120.5 (2 CH), 124.0 (CH), 128.1 (CH), 128.9 (2 CH), 129.8 (2 CH),
130.0 (2 CH), 130.4 (2 CH), 132.9 (C), 134.9, 135.0 (C), 136.2 (C),
149.5 (C), 168.9 (CO).
HRMS (ESI): m/z [M + Na]+ calcd for C27H25N3NaO2: 446.1839;
found: 446.1841.
3-(4-Chlorophenyl)-2-methyl-5-[2-(thiophen-2-yl)-1H-pyrrol-
1-yl]isoxazolidine (6l)
Prepared from nitrone 4e and pyrrole 2 as an oil; yield: 96 mg
(28%); Rf = 0.42 (9% EtOAc–hexane).
N-(4-Chlorophenyl)-2-phenyl-5-(2-phenyl-1H-pyrrol-1-yl)isox-
azolidine-3-carboxamide (7c)
Prepared from nitrone 5c and pyrrole 1 as a white solid; yield: 418
mg (91%); mp 113–114 °C; Rf = 0.55 (20% EtOAc–hexane).
IR (KBr): 3102, 2992, 2960, 2916, 2872, 2849, 1492, 1463, 1433,
1411, 1282, 1014, 701 cm–1.
IR (KBr): 3338, 3135, 3102, 3060, 3034, 2964, 1687, 1590, 1519,
1491, 1400, 1305, 1241, 762, 700 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.83–2.95 (m, 1 H), 3.20–3.32 (m,
1 H), 4.68 (d, J = 8.8 Hz, 1 H), 6.17 (dd, J = 8.2, 5.6 Hz, 1 H), 6.27–
6.30 (m, 1 Hpyrrole), 6.31–6.34 (m, 1 Hpyrrole), 6.97–7.00 (m, 1
1H NMR (400 MHz, CDCl3): δ = 2.65 (s, 3 H), 2.65–2.74 (m, 1 H),
3.18 (dt, J = 13.6, 7.9 Hz, 1 H), 3.64 (dd, J = 9.8, 7.9 Hz, 1 H), 6.19
(dd, J = 7.9, 4.7 Hz, 1 H), 6.30–6.34 (m, 2 Hpyrrole), 7.03–7.08 (m, 1
Harom), 7.08–7.13 (m, 1 Harom), 7.31–7.35 (m, 1 Harom), 7.38–7.47
(m, 5 Harom).
H
pyrrole), 7.02–7.15 (m, 3 Harom), 7.25–7.60 (m, 9 Harom), 7.64 (d,
1H NMR (400 MHz, CDCl3): δ (minor isomer 6l′) = 2.66 (s, 3 H),
2.68–2.81 (m, 1 H), 2.91 (ddd, J = 13.5, 7.2, 3.6 Hz, 1 H), 3.85–4.05
(s, 1 H), 6.23 (dd, J = 8.4, 3.6 Hz, 1 H), 6.34–6.37 (m, 2 Hpyrrole),
7.09–7.15 (m, 1 Harom), 7.16–7.21 (m, 2 Harom), 7.33–7.44 (m, 5
Harom).
J = 8.0 Hz, 2 Harom), 9.29 (s, 1 H, NH).
13C NMR (75 MHz, CDCl3): δ = 36.5 (CH2), 70.2 (CH), 85.3 (CH),
110.5 (CH), 111.1 (CH), 115.0 (2 CH), 118.8 (CH), 121.7 (2 CH),
124.2 (CH), 128.2 (CH), 128.9 (2 CH), 129.5 (2 CH), 129.9 (2 CH),
Synthesis 2014, 46, 771–780
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Cycloaddition of Nitrones to N-Vinylpyrroles
777
130.0 (2 CH), 130.3 (C), 132.8 (C), 136.1 (C), 136.3 (C), 149.2 (C),
169.2 (CO).
HRMS (ESI): m/z [M + H]+ calcd for C25H28N3O2: 402.2176; found:
402.2179.
HRMS (ESI): m/z [M + Na]+ calcd for C26H22ClN3NaO2: 466.1293;
found: 466.1293.
N-(4-Chlorophenyl)-2-phenyl-5-(4,5,6,7-tetrahydro-1H-indol-
1-yl)isoxazolidine-3-carboxamide (7g)
Prepared from 5c and 1 as a white solid; yield: 359 mg (85%); mp
183–184 °C; Rf = 0.48 (20% EtOAc–hexane).
N-Phenyl-5-(2-phenyl-1H-pyrrol-1-yl)-2-(p-tolyl)isoxazolidine-
3-carboxamide (7d)
Prepared from nitrone 5d and pyrrole 1 as a white solid; yield: 370
mg (85%); mp 161–162 °C; Rf = 0.49 (20% EtOAc–hexane).
IR (KBr): 3263, 3136, 3093, 3054, 3034, 2957, 2930, 2849, 1676,
1588, 1522, 1489, 1401, 1304, 763, 693 cm–1.
IR (KBr): 3335, 3140, 3051, 3011, 2985, 2921, 2860, 1687, 1599,
1520, 1505, 1442, 1413, 1307, 1290, 1245, 814, 762, 752, 695 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.33 (s, 3 H), 2.89 (ddd, J = 13.7,
9.3, 8.6 Hz, 1 H), 3.26 (ddd, J = 13.7, 5.2, 2.6 Hz, 1 H), 4.63 (dd,
J = 9.3, 2.6 Hz, 1 H), 6.17 (dd, J = 8.6, 5.2 Hz, 1 H), 6.27 (m, 1
1H NMR (300 MHz, CDCl3): δ = 1.69–1.82 (m, 2 H), 1.83–1.98 (m,
2 H), 2.45–2.53 (m, 2 H), 2.54–2.82 (m, 2 H), 2.92–3.08 (m, 1 H),
3.21 (ddd, J = 13.7, 5.6, 3.0 Hz, 1 H), 4.68 (dd, J = 9.6, 3.0 Hz, 1
H), 6.02 (d, J = 3.0 Hz, 1 Hpyrrole), 6.03–6.12 (m, 1 H), 6.71 (d,
J = 3.0 Hz, 1 Hpyrrole), 7.10–7.24 (m, 3 Harom), 7.34 (d, J = 8.9 Hz, 2
Harom), 7.38–7.46 (m, 2 Harom), 7.59 (d, J = 8.9 Hz, 2 Harom), 9.19 (s,
Hpyrrole), 6.29 (m, 1 Hpyrrole), 6.95–7.05 (m, 3 Harom), 7.10–7.20 (m, 3
1 H, NH).
Harom), 7.37–7.60 (m, 7 Harom), 7.70 (d, J = 8.0 Hz, 2 Harom), 9.30 (s,
1 H, NH).
13C NMR (75 MHz, CDCl3): δ = 21.7 (CH2), 23.0 (CH2), 23.1
(CH2), 23.4 (CH2), 35.8 (CH2), 69.4 (CH), 84.0 (CH), 109.8 (CH),
114.3 (2 CH), 115.9 (CH), 119.5 (C), 121.2 (2 CH), 123.6 (CH),
128.7 (C), 129.0 (2 CH), 129.6 (2 CH), 129.8 (C), 135.7 (C), 149.1
(C), 168.8 (CO).
13C NMR (75 MHz, CDCl3): δ = 21.0 (CH3), 36.5 (CH2), 70.3 (CH),
85.3 (CH), 110.3 (CH), 111.0 (CH), 115.1 (2 CH), 119.1 (CH),
120.4 (2 CH), 125.3 (CH), 128.1 (CH), 128.9 (2 CH), 129.5 (2 CH),
130.0 (2 CH), 130.4 (2 CH), 132.9 (C), 133.8 (C), 136.2 (C), 137.6
(C), 147.0 (C), 169.2 (CO).
HRMS (ESI): m/z [M + H]+ calcd for C24H25ClN3O2: 422.1630;
found: 422.1627.
Anal. Calcd for C27H25N3O2: C, 76.57; H, 5.95; N, 9.92. Found: C,
76.41; H, 6.03; N, 9.82.
N-Phenyl-5-(4,5,6,7-tetrahydro-1H-indol-1-yl)-2-(p-tolyl)isoxa-
zolidine-3-carboxamide (7h)
Prepared from nitrone 5d and pyrrole 3 as a white solid; yield: 349
mg (87%); mp 164–165 °C; Rf = 0.55 (20% EtOAc–hexane).
N,2-Diphenyl-5-(4,5,6,7-tetrahydro-1H-indol-1-yl)isoxazoli-
dine-3-carboxamide (7e)
Prepared from nitrone 5a and pyrrole 3 as a white solid; yield: 317
mg (82%); mp 109–110 °C; Rf = 0.49 (20% EtOAc–hexane).
IR (KBr): 3269, 3130, 3097, 3031, 3016, 2962, 2928, 2848, 1669,
1593, 1507, 1448, 1306, 712 cm–1.
IR (KBr): 3277, 3132, 3092, 3057, 2928, 2843, 1675, 1597, 1526,
1488, 1442, 1298, 757, 693 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.69–1.82 (m, 2 H), 1.83–1.98 (m,
2 H), 2.37 (s, 3 H), 2.45–2.54 (m, 2 H), 2.55–2.80 (m, 2 H), 2.92–
3.08 (m, 1 H), 3.20 (ddd, J = 13.7, 5.8, 3.0 Hz, 1 H), 4.65 (dd,
J = 9.5, 3.0 Hz, 1 H), 6.01 (d, J = 3.0 Hz, 1 Hpyrrole), 6.02–6.12 (m,
1 H), 6.74 (d, J = 3.0 Hz, 1 Hpyrrole), 7.08 (d, J = 8.5 Hz, 2 Harom),
7.15–7.24 (m, 1 Harom), 7.22 (d, J = 8.5 Hz, 2 Harom), 7.32–7.46 (m,
2 Harom), 7.63 (d, J = 7.8 Hz, 2 Harom), 9.20 (s, 1 H, NH).
13C NMR (75 MHz, CDCl3): δ = 20.6 (CH3), 21.7 (CH2), 23.0
(CH2), 23.1 (CH2), 23.4 (CH2), 35.8 (CH2), 69.4 (CH), 84.0 (CH),
109.7 (CH), 114.4 (2 CH), 116.0 (CH), 119.3 (C), 120.0 (2 CH),
124.7 (CH), 128.8 (C), 129.0 (2 CH), 130.0 (2 CH), 133.1 (C),
137.1 (C), 146.9 (C), 168.8 (CO).
1H NMR (300 MHz, CDCl3): δ = 1.70–1.80 (m, 2 H), 1.82–1.92 (m,
2 H), 2.45–2.52 (m, 2 H), 2.53–2.67 (m, 1 H), 2.68–2.80 (m, 1 H),
3.01 (ddd, J = 13.7, 9.3, 8.2 Hz, 1 H), 3.22 (ddd, J = 13.7, 6.1, 3.3
Hz, 1 H), 4.69 (dd, J = 9.3, 3.3 Hz, 1 H), 6.02 (d, J = 3.0 Hz, 1
Hpyrrole), 6.09 (dd, J = 8.2, 6.1 Hz, 1 H), 6.76 (d, J = 3.0 Hz, 1
Hpyrrole), 7.10–7.12 (m, 4 Harom), 7.32–7.60 (m, 4 Harom), 7.63 (d,
J = 7.8 Hz, 2 Harom), 9.28 (s, 1 H, NH).
13C NMR (75 MHz, CDCl3): δ = 22.2 (CH2), 23.4 (CH2), 23.6
(CH2), 23.8 (CH2), 36.4 (CH2), 69.9 (CH), 84.3 (CH), 110.2 (CH),
114.8 (2 CH), 116.5 (CH), 119.9 (CH), 120.5 (2 CH), 123.9 (CH),
125.2 (C), 129.1 (C), 129.5 (2 CH), 130.0 (2 CH), 137.5 (C), 150.0
(C), 169.2 (CO).
Anal. Calcd for C25H27N3O2: C, 74.79; H, 6.78; N, 10.47. Found: C,
74.62; H, 6.61; N, 10.32.
HRMS (ESI): m/z [M + K]+ calcd for C24H25KN3O2: 426.1578;
found: 426.1578.
N,2-Diphenyl-5-(2-(thiophen-2-yl)-1H-pyrrol-1-yl)isoxazoli-
dine-3-carboxamide (7i/7i′)
Prepared from nitrone 5a and pyrrole 2 to give a mixture of isomers;
yield: 382 mg (92%). Pure cis-isomer was separated by crystalliza-
tion from EtOH as a white solid; yield: 228 mg (55%); mp 160–162
°C; Rf = 0.32 (20% EtOAc–hexane).
2-Phenyl-5-(4,5,6,7-tetrahydro-1H-indol-1-yl)-N-(p-tolyl)isoxa-
zolidine-3-carboxamide (7f)
Prepared from nitrone 5b and pyrrole 3 as a white solid; yield: 320
mg (80%); mp 118–119 °C; Rf = 0.40 (20% EtOAc–hexane).
IR (KBr): 3269, 3138, 3092, 3033, 2927, 2843, 1673, 1593, 1524,
1486, 1298, 759, 693 cm–1.
IR (KBr): 3341, 3260, 3105, 3057, 3032, 2971, 1676, 1596, 1527,
1490, 1443, 1320, 1294, 760, 694 cm–1.
1H NMR (400 MHz, CDCl3): δ (major isomer) = 2.96 (ddd,
J = 14.0, 9.1, 9.0 Hz, 1 H), 3.28 (ddd, J = 14.0, 5.0, 2.5 Hz, 1 H),
4.67 (dd, J = 9.1, 2.5 Hz, 1 H, CHCH2CH), 6.27 (t, J = 3.2 Hz, 1
1H NMR (300 MHz, CDCl3): δ = 1.69–1.81 (m, 2 H), 1.82–1.98 (m,
2 H), 2.36 (s, 3 H), 2.45–2.53 (m, 2 H), 2.54–2.80 (m, 2 H), 2.93–
3.08 (m, 1 H), 3.22 (ddd, J = 13.7, 5.9, 3.3 Hz, 1 H), 4.67 (dd,
J = 9.3, 3.3 Hz, 1 H), 6.01 (d, J = 3.0 Hz, 1 Hpyrrole), 6.05–6.16 (m,
1 H), 6.75 (d, J = 3.0 Hz, 1 Hpyrrole), 7.18 (d, J = 8.2 Hz, 2 Harom),
7.09–7.21 (m, 3 Harom), 7.41 (t, J = 7.8 Hz, 2 Harom), 7.51 (d, J = 8.2
Hz, 2 Harom), 9.12 (s, 1 H, NH).
13C NMR (75 MHz, CDCl3): δ = 20.9 (CH3), 21.7 (CH2), 23.0
(CH2), 23.1 (CH2), 23.4 (CH2), 36.0 (CH2), 69.4 (CH), 84.0 (CH),
109.7 (CH), 114.3 (2 CH), 116.0 (CH), 119.4 (C), 120.1 (2 CH),
123.4 (CH), 128.7 (C), 129.5 (2 CH), 129.5 (2 CH), 134.4 (C),
134.5 (C), 149.4 (C), 168.5 (CO).
Hpyrrole), 6.29–6.36 (m, 2 H, H + Harom), 7.04–7.07 (m, 1 Harom),
7.08–7.27 (m, 6 Harom), 7.30–7.48 (m, 5 Harom), 7.60–7.71 (m, 2
Harom), 9.24 (s, 1 H, NH).
1H NMR (400 MHz, CDCl3): δ (minor isomer) = 3.22 (ddd,
J = 14.0, 7.2, 5.8 Hz, 1 H), 3.36 (ddd, J = 14.0, 9.1, 3.5 Hz, 1 H,
CHCH2CH), 4.84 (dd, J = 9.1, 5.8 Hz, 1 H), 5.92 (t, J = 3.2 Hz, 1
H
pyrrole), 6.38 (dd, J = 7.2, 3.5 Hz, 1 H), 6.49–6.53 (m, 1 Hpyrrole),
6.87 (d, J = 7.8 Hz, 2 Harom), 6.95–7.01 (m, 1 Harom), 7.08–7.27 (m,
6 Harom), 7.30–7.48 (m, 5 Harom), 9.08 (s, 1 H, NH).
© Georg Thieme Verlag Stuttgart · New York
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A. P. Molchanov et al.
PAPER
13C NMR (100 MHz, CDCl3): δ (major isomer) = 36.1 (CH2), 69.8
(CH), 84.6 (CH), 110.6 (CH), 112.1 (CH), 114.7 (2 CH), 119.3
(CH), 120.0 (2 CH), 123.7 (CH), 124.8 (CH), 126.3 (CH), 127.3
(CH), 127.5 (CH), 127.5 (C), 129.0 (2 CH), 129.4 (2 CH), 133.2
(C), 137.0 (C), 149.0 (C), 168.5 (CO).
Dimethyl 5-(2-Phenyl-1H-pyrrol-1-yl)-2-(p-tolyl)isoxazolidine-
3,3-dicarboxylate (9b)
Prepared from nitrone 8b and pyrrole 1 as a white solid; yield: 336
mg (80%); mp 140–141 °C; Rf = 0.43 (20% EtOAc–hexane).
IR (KBr): 3117, 3061, 3031, 3006, 2954, 2926, 2842, 1758, 1738,
1508, 1467, 1433, 1290, 1271, 1202, 1079, 800, 708 cm–1.
HRMS (ESI): m/z [M + H]+ calcd for C24H22N3O2S: 416.1427;
1H NMR (300 MHz, CDCl3): δ = 2.32 (s, 3 H, CH3), 3.31 (dd,
J = 13.8, 5.0 Hz, 1 H), 3.51 (dd, J = 13.8, 7.4 Hz, 1 H), 3.55 (s, 3 H),
3.71 (s, 3 H), 6.20–6.25 (m, 2 H), 6.31–6.35 (m, 1 Hpyrrole), 7.10 (d,
J = 8.1 Hz, 2 Harom), 7.28–7.33 (m, 2 Harom), 7.34–7.39 (m, 1 Harom),
7.41–7.48 (m, 5 Harom).
13C NMR (75 MHz, CDCl3): δ = 21.3 (CH3), 45.0 (CH2), 53.1
(CH3), 53.4 (CH3), 78.2 (C), 81.7 (CH), 110.3 (CH), 110.8 (CH),
120.1 (CH), 120.6 (2 CH), 127.7 (CH), 129.0 (2 CH), 129.3 (2 CH),
129.8 (2 CH), 133.0 (C), 135.5 (C), 135.8 (C), 143.7 (C), 167.9
(CO), 168.4 (CO).
found: 416.1431.
N-Phenyl-5-(2-(thiophen-2-yl)-1H-pyrrol-1-yl)-2-(p-tolyl)isoxa-
zolidine-3-carboxamide (7j/7j′)
Prepared from nitrone 5d and pyrrole 2 as a mixture of isomers;
yield: 360 mg (84%). Crystallization (EtOH) gave cis-isomer 7j as
a white solid; yield: 309 mg (72%); mp 159–160 °C; Rf = 0.43 (20%
EtOAc–hexane).
IR (KBr): 3256, 3137, 3012, 2952, 1668, 1593, 1528, 1505, 1449,
1419, 1320, 1282, 723, 696 cm–1.
Major Isomer 7j
Anal. Calcd for C24H24N2O5: C, 68.56; H, 5.75; N, 6.66. Found: C,
68.43; H, 5.84; N, 6.59.
1H NMR (400 MHz, CDCl3): δ = 2.35 (s, 3 H), 2.95 (dt, J = 14.0,
9.2 Hz, 1 H), 3.26 (ddd, J = 14.0, 5.0, 2.6 Hz, 1 H), 4.63 (dd, J = 9.2,
2.6 Hz, 1 H), 6.22–6.28 (m, 1 Hpyrrole), 6.29–6.40 (m, 2 H), 6.96–
7.07 (m, 3 Harom), 7.11–7.18 (m, 3 Harom), 7.18–7.23 (m, 2 Harom),
7.38–7.48 (m, 3 Harom), 7.66 (d, J = 7.6 Hz, 2 Harom), 9.27 (s, 1 H,
NH).
Dimethyl 2-(4-Chlorophenyl)-5-(2-phenyl-1H-pyrrol-1-yl)isox-
azolidine-3,3-dicarboxylate (9c)
Prepared from nitrone 8c and pyrrole 1 as a white solid; yield: 396
mg (90%); mp 132–133 °C; Rf = 0.45 (20% EtOAc–hexane).
13C NMR (100 MHz, CDCl3): δ = 20.5 (CH3), 36.0 (CH2), 69.8
(CH), 84.6 (CH), 110.6 (CH), 112.0 (CH), 114.8 (2 CH), 119.3
(CH), 120.0 (2 CH), 124.8 (CH), 126.3 (CH), 127.3 (CH), 127.4
(CH), 127.5 (C), 129.0 (2 CH), 129.9 (2 CH), 133.2 (C), 133.4 (C),
137.1 (C), 146.6 (C), 168.6 (CO).
IR (KBr): 3118, 3060, 3044, 3009, 2954, 2842, 1758, 1737, 1483,
1467, 1432, 1296, 1276, 1205, 1080, 836, 770, 722 cm–1.
1H NMR (300 MHz, CDCl3): δ = 3.33 (dd, J = 13.8, 5.0 Hz, 1 H),
3.48–3.55 (m, 1 H), 3.56 (s, 3 H), 3.78 (s, 3 H), 6.21–6.27 (m, 2 H),
6.32–6.36 (m, 1 Hpyrrole), 7.26 (d, J = 8.5 Hz, 2 Harom), 7.34 (d,
J = 8.5 Hz, 2 Harom), 7.39–7.42 (m, 1 Harom), 7.43–7.47 (m, 5 Harom).
HRMS (ESI): m/z [M + H]+ calcd for C25H24N3O2S: 430.1584;
13C NMR (75 MHz, CDCl3): δ = 45.9 (CH2), 53.3 (CH3), 53.6
(CH3), 78.1 (C), 81.8 (CH), 110.0 (CH), 110.5 (CH), 119.9 (CH),
121.5 (2 CH), 127.9 (CH), 128.7 (2 CH), 129.0 (2 CH), 129.8 (2
CH), 130.8 (C), 132.9 (C), 135.9 (C), 144.9 (C), 167.6 (CO), 168.2
(CO).
HRMS (ESI): m/z [M + H]+ calcd for C23H22ClN2O5: 441.1212;
found: 441.1211.
found: 430.1587.
Minor Isomer 7j′
1H NMR (400 MHz, CDCl3): δ = 2.29 (s, 3 H, CH3), 3.21 (ddd,
J = 13.9, 7.2, 5.5 Hz, 1 H), 3.32 (ddd, J = 13.8, 8.8, 4.0 Hz, 1 H),
4.79 (dd, J = 8.8, 5.5 Hz, 1 H), 5.99–6.06 (m, 1 Hpyrrole), 6.30–6.40
(m, 2 H), 6.51–6.56 (m, 1 Harom), 6.78 (d, J = 8.5 Hz, 2 Harom), 6.97–
7.07 (m, 2 Harom), 7.11–7.22 (m, 2 Harom), 7.29–7.33 (m, 1 Harom),
7.34–7.48 (m, 3 Harom), 7.64 (d, J = 7.6 Hz, 2 Harom), 9.12 (s, 1 H,
NH).
Dimethyl 2-Phenyl-5-(4,5,6,7-tetrahydro-1H-indol-1-yl)isoxa-
zolidine-3,3-dicarboxylate (9d)
Prepared from nitrone 8a and pyrrole 3 as a white solid; yield: 353
mg (92%); mp 96–98 °C; Rf = 0.43 (20% EtOAc–hexane).
13C NMR (100 MHz, CDCl3): δ = 20.5 (CH3), 37.8 (CH2), 69.0
(CH), 85.4 (CH), 109.6 (CH), 112.0 (CH), 114.0 (2 CH), 119.1
(CH), 119.8 (2 CH), 124.8 (CH), 125.8 (CH), 126.6 (CH), 127.6
(CH), 128.0 (C), 129.0 (2 CH), 129.5 (2 CH), 132.2 (C), 133.7 (C),
137.0 (C), 147.8 (C), 168.6 (CO).
IR (KBr): 2946, 2846, 1761, 1733, 1488, 1437, 1305, 1279, 1197,
1172, 1081, 959, 695 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.70–1.80 (m, 2 H), 1.80–1.91 (m,
2 H), 2.48–2.58 (m, 2 H), 2.58–2.73 (m, 2 H), 3.33 (dd, J = 13.7, 5.9
Hz, 1 H), 3.46 (dd, J = 13.7, 7.1 Hz, 1 H), 3.59 (s, 3 H), 3.71 (s, 3
H), 6.05 (d, J = 3.0 Hz, 1 Hpyrrole), 6.12 (t, J 6.5 Hz, 1 H), 7.05 (d,
J = 3.0 Hz, 1 Hpyrrole), 7.05–7.12 (m, 1 Harom), 7.21–7.30 (m, 2
Dimethyl 2-Phenyl-5-(2-phenyl-1H-pyrrol-1-yl)isoxazolidine-
3,3-dicarboxylate (9a)
Prepared from nitrone 8a and pyrrole 1 as a white solid; yield: 317
mg (78%); mp 83–85 °C; Rf = 0.39 (20% EtOAc–hexane).
IR (KBr): 3116, 3056, 3026, 2956, 1760, 1737, 1491, 1432, 1294,
1268, 1204, 1082, 767, 696 cm–1.
1H NMR (300 MHz, CDCl3): δ = 3.33 (dd, J = 13.7, 5.2 Hz, 1 H),
3.53 (s, 3 H), 3.54 (dd, J = 13.7, 7.4 Hz, 1 H), 3.75 (s, 3 H), 6.22–
6.25 (m, 1 Hpyrrole), 6.25 (dd, J = 7.4, 5.2 Hz, 1 H), 6.33–6.35 (m, 1
Harom), 7.35 (d, J = 7.8 Hz, 2 Harom).
13C NMR (75 MHz, CDCl3): δ = 21.8 (CH2), 23.0 (CH2), 23.1
(CH2), 23.4 (CH2), 44.6 (CH2), 52.8 (OCH3), 53.0 (OCH3), 77.8 (C),
80.8 (CH), 109.0 (CH), 116.6 (CH), 118.6 (C), 119.4 (2 CH), 124.9
(CH), 128.2 (2 CH), 128.4 (C), 146.1 (C), 167.8 (CO), 167.9 (CO).
H
pyrrole), 7.10–7.16 (m, 1 Harom), 7.26–7.32 (m, 2 Harom), 7.36–7.42
Anal. Calcd for C21H24N2O5: C, 65.61; H, 6.29; N, 7.29. Found: C,
65.41; H, 6.30; N, 7.15.
(m, 3 Harom), 7.43–7.46 (m, 5 Harom).
13C NMR (75 MHz, CDCl3): δ = 45.6 (CH2), 52.7 (CH3), 53.1
(CH3), 77.8 (C), 81.3 (CH), 109.5 (CH), 110.0 (CH), 119.6 (CH),
119.7 (2 CH), 125.2 (CH), 127.3 (CH), 128.3 (2 CH), 128.6 (2 CH),
129.4 (2 CH), 132.5 (C), 135.4 (C), 145.9 (C), 167.4 (CO), 168.0
(CO).
Dimethyl 5-(4,5,6,7-Tetrahydro-1H-indol-1-yl)-2-(p-tolyl)isoxa-
zolidine-3,3-dicarboxylate (9e)
Prepared from nitrone 8b and pyrrole 3 as a white solid; yield: 346
mg (87%); mp 86–89 °C; Rf = 0.48 (20% EtOAc–hexane).
IR (KBr): 2935, 2843, 1767, 1739, 1505, 1435, 1273, 1270, 1068,
832 cm–1.
HRMS (ESI): m/z [M + H]+ calcd for C23H23N2O5: 407.1601; found:
407.1601.
Synthesis 2014, 46, 771–780
© Georg Thieme Verlag Stuttgart · New York

PAPER
Cycloaddition of Nitrones to N-Vinylpyrroles
779
1H NMR (300 MHz, CDCl3): δ = 1.70–1.80 (m, 2 H), 1.80–1.90 (m,
2 H), 2.30 (s, 3 H), 2.48–2.55 (m, 2 H), 2.55–2.72 (m, 2 H), 3.31
(dd, J = 13.7, 5.9 Hz, 1 H), 3.43 (dd, J = 13.7, 7.4 Hz, 1 H), 3.61 (s,
3 H), 3.70 (s, 3 H), 6.05 (d, J = 3.0 Hz, 1 Hpyrrole), 6.09 (dd, J = 7.4,
5.9 Hz, 1 H), 7.02–7.08 (m, 1 Hpyrrole), 7.07 (d, J = 8.5 Hz, 2 Harom),
7.25 (d, J = 8.5 Hz, 2 Harom).
13C NMR (75 MHz, CDCl3): δ = 20.8 (CH3), 21.8 (CH2), 23.0
(CH2), 23.1 (CH2), 23.4 (CH2), 44.5 (CH2), 52.8 (OCH3), 52.9
(OCH3), 77.8 (C), 80.8 (CH), 108.9 (CH), 116.6 (CH), 118.6 (C),
119.9 (2 CH), 128.4 (C), 128.8 (2 CH), 134.8 (C), 143.5 (C), 167.8
(CO), 167.9 (CO).
(m, 2 H, NH, OH, exchange), 4.40 (dd, J = 7.6, 6.3 Hz, 1 H), 5.74
(dd, J = 8.0, 4.0 Hz, 1 H), 6.21 (s, 1 Hpyrrole), 6.34 (t, J = 2.9 Hz, 1
Hpyrrole), 6.53 (d, J = 7.9 Hz, 2 Harom), 6.67–6.74 (m, 1 Harom), 6.83
(d, J = 8.4 Hz, 2 Harom), 7.12 (d, J = 8.4 Hz, 2 Harom), 7.06–7.13 (m,
1 Harom), 7.14–7.23 (m, 4 Harom), 7.23–7.35 (m, 3 Harom).
13C NMR (100 MHz, CDCl3): δ = 45.5 (CH2), 55.2 (OCH3), 55.3
(CH), 77.7 (CH), 109.3 (CH), 109.7 (CH), 114.1 (2 CH), 114.2 (2
CH), 117.7 (CH), 118.0 (CH), 127.1 (CH), 127.2 (2 CH), 128.4 (2
CH), 129.0 (2 CH), 129.1 (2 CH), 132.6 (C), 134.1 (C), 134.6 (C),
146.7 (C), 158.8 (C).
HRMS (ESI): m/z [M + H]+ calcd for C26H27N2O2: 399.2067; found:
399.2068.
HRMS (ESI): m/z [M + H]+ calcd for C22H27N2O5: 399.1914; found:
399.1917.
N-(4-Chlorophenyl)-4-hydroxy-2-(phenylamino)-4-(2-phenyl-
1H-pyrrol-1-yl)butanamide (10b)
Prepared from isoxazolidine 7c as a white solid; yield: 147 mg
(66%); mp 140–145 °C; Rf = 0.24 (20% EtOAc–hexane).
Dimethyl 2-(4-Chlorophenyl)-5-(4,5,6,7-tetrahydro-1H-indol-
1-yl)isoxazolidine-3,3-dicarboxylate (9f)
Prepared from nitrone 8c and pyrrole 3 as a white solid; yield: 364
mg (87%); mp 90–92 °C; Rf = 0.50 (20% EtOAc–hexane).
IR (KBr): 3440, 3402, 3370, 3314, 3285, 3102, 2892, 1666, 1604,
1512, 1494, 1401, 1286, 1090, 1053, 757 cm–1.
IR (KBr): 2950, 2930, 2842, 1765, 1738, 1484, 1437, 1298, 1268,
1068, 842 cm–1.
1H NMR (400 MHz, CDCl3): δ = 2.48 (ddd, J = 14.5, 8.1, 8.0 Hz, 1
H), 2.58 (ddd, J = 14.5, 4.2, 3.9 Hz, 1 H), 3.55 (d, J = 3.8 Hz, 1 H,
NH), 3.78 (ddd, J = 8.0, 3.9, 3.8 Hz, 1 H), 4.53 (d, J = 3.2 Hz, 1 H,
OH), 5.90 (ddd, J = 8.1, 4.2, 3.2 Hz, 1 H), 6.22 (dd, J = 1.7, 3.3 Hz,
1 Hpyrrole), 6.35 (t, J = 3.3 Hz, 1 Hpyrrole), 6.55 (d, J = 7.8 Hz, 2 Harom),
6.80–6.90 (t, J = 7.4 Hz, 1 Harom), 7.08–7.12 (m, 1 Hpyrrole), 7.15–
7.25 (m, 2 Harom), 7.26–7.38 (m, 6 Harom), 7.40 (d, J = 8.8 Hz, 2
1H NMR (300 MHz, CDCl3): δ = 1.69–1.81 (m, 2 H), 1.81–1.91 (m,
2 H), 2.47–2.55 (m, 2 H), 2.55–2.72 (m, 2 H), 3.32 (dd, J = 13.7, 5.9
Hz, 1 H), 3.47 (dd, J = 13.7, 7.4 Hz, 1 H), 3.62 (s, 3 H), 3.74 (s, 3
H), 6.05 (d, J = 3.0 Hz, 1 Hpyrrole), 6.09 (dd, J = 7.4, 5.9 Hz, 1 H),
7.01 (d, J = 3.0 Hz, 1 Hpyrrole), 7.23 (d, J = 8.9 Hz, 2 Harom), 7.30 (d,
J = 8.9 Hz, 2 Harom).
H
arom), 8.73 (s, 1 H, C(O)NH).
13C NMR (75 MHz, CDCl3): δ = 21.8 (CH2), 23.0 (CH2), 23.1
(CH2), 23.4 (CH2), 44.5 (CH2), 52.9 (OCH3), 53.1 (OCH3), 77.7 (C),
80.8 (CH), 109.1 (CH), 116.5 (CH), 118.8 (C), 120.8 (2 CH), 128.2
(2 CH), 128.5 (C), 130.1 (C), 144.6 (C), 167.5 (CO), 167.6 (CO).
13C NMR (100 MHz, CDCl3): δ = 39.6 (CH2), 58.5 (CH), 78.2
(CH), 109.8 (CH), 110.0 (CH), 114.4 (2 CH), 117.9 (CH), 120.1
(CH), 121.2 (2 CH), 127.4 (CH), 128.7 (2 CH), 128.9 (2 CH), 129.0
(2 CH), 129.5 (2 CH), 129.7 (C), 132.4 (C), 133.8 (C), 135.5 (C),
146.0 (C), 171.2 (CO).
HRMS (ESI): m/z [M + H]+ calcd for C26H25ClN3O2: 446.1630;
found: 446.1634.
Anal. Calcd for C21H23N2O5Cl: C, 60.22; H, 5.53; N, 6.69. Found:
C, 60.03; H, 5.51; N, 6.48.
Dimethyl 2-Phenyl-5-[2-(thiophen-2-yl)-1H-pyrrol-1-yl]isoxa-
zolidine-3,3-dicarboxylate (9g)
Prepared from 8a and 2 as a pink solid; yield: 381 mg (93%); mp
105–106 °C; Rf = 0.35 (20% EtOAc–hexane).
1-(4-Chlorophenyl)-5-hydroxy-3-(phenylamino)-1,5-dihydro-
2H-pyrrol-2-one (11a)
To a solution of isoxazolidine 7c (0.66 mmol) in anhydrous THF (6
mL) was added TBAF·3H2O (1 mmol) and the mixture was stirred
for 4 h at r.t. The mixture was quenched with H2O (3 mL), and the
organic layer was separated. The aqueous layer was extracted with
CH2Cl2 (2 × 5 mL), and the combined organic extracts were dried
(Na2SO4) and concentrated. The product was purified by column
chromatography (silica gel, petroleum ether–EtOAc) followed by
crystallization (EtOH) to give a yellowish solid; yield: 138 mg
(75%); mp 170–175 °C (dec); Rf = 0.30 (17% EtOAc–hexane).
IR (KBr): 3139, 3099, 3085, 3015, 2953, 2842, 1758, 1740, 1595,
1488, 1434, 1293, 1286, 1247, 1211, 1078, 697 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.31 (dd, J = 14.0, 4.6 Hz, 1 H),
3.52 (s, 3 H), 3.59 (dd, J = 14.0, 7.8 Hz, 1 H), 3.78 (s, 3 H), 6.29–
6.32 (m, 1 Harom), 6.33 (dd, J = 3.5, 1.8 Hz, 1 Harom), 6.38 (dd,
J = 7.8, 4.6 Hz, 1 H), 7.07–7.16 (m, 3 Harom), 7.25–7.34 (m, 2 Harom),
7.35–7.42 (m, 3 Harom), 7.43–7.47 (m, 1 Harom).
13C NMR (100 MHz, CDCl3): δ = 45.5 (CH2), 52.7 (OCH3), 53.1
(OCH3), 77.7 (C), 81.2 (CH), 109.2 (CH), 111.2 (CH), 119.6 (2
CH), 120.2 (CH), 125.2 (CH), 125.8 (CH), 126.9 (CH), 127.2 (C),
127.5 (CH), 128.3 (2 CH), 133.6 (C), 145.8 (C), 167.3 (CO), 168.0
(CO).
IR (KBr): 3296, 3219, 3122, 3057, 1680, 1658, 1594, 1477, 1428,
1402, 1070 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 6.07 (dd, J = 10.1, 2.3 Hz, 1
H), 6.12 (d, J = 2.3 Hz, 1 H, OH), 6.32 (d, J = 10.1 Hz, 1 H), 6.92–
6.96 (m, 1 Harom), 7.25–7.38 (m, 4 Harom), 7.49 (d, J = 8.8 Hz, 2
HRMS (ESI): m/z [M + H]+ calcd for C21H21N2O5S: 413.1166;
found: 413.1169.
Harom), 7.80 (d, J = 8.8 Hz, 2 Harom), 8.16 (s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): δ = 81.7 (CH), 106.2 (CH), 117.6
(2 CH), 121.2 (CH), 122.6 (2 CH), 128.5 (C), 129.1 (2 CH), 129.5
(2 CH), 133.9 (C), 136.6 (C), 142.2 (C), 165.6 (CO).
HRMS (ESI): m/z [M + H]+ calcd for C16H14ClN2O2: 301.0738;
found: 301.0733.
3-(4-Methoxyphenyl)-3-(phenylamino)-1-(2-phenyl-1H-pyrrol-
1-yl)propan-1-ol (10a); Typical Procedure
To a solution of isoxazolidine 6c (0.5 mmol) in EtOAc (4 mL) was
added 5% Pd/CaCO3 (150 mg) and the mixture was stirred under an
atmosphere of H2 at r.t. for 24 h. The mixture was filtered and con-
centrated. The product was purified using column chromatography
(silica gel, petroleum ether–EtOAc) followed by crystallization
(CH2Cl2–hexane) to give 10a as a white solid; yield: 189 mg (95%);
mp 114–116 °C; Rf = 0.26 (20% EtOAc–hexane).
5-Hydroxy-1-phenyl-3-(p-tolylamino)-1,5-dihydro-2H-pyrrol-
2-one (11b)
To a solution of isoxazolidine 7d (281 mg, 0.66 mmol) in anhydrous
THF (6 mL) was added NaH (35 mg, 60%, 0.88 mmol) and the mix-
ture was stirred for 4 h at r.t. The mixture was quenched with H2O
(3 mL), and the organic layer was separated. The aqueous layer was
extracted with CH2Cl2 (2 × 5 mL), and the combined organic ex-
tracts were dried (Na2SO4) and concentrated. The product was puri-
IR (KBr): 3471, 3382, 2948, 2920, 2838, 1765, 1603, 1508, 1282,
1232, 750 cm–1.
1H NMR (400 MHz, CDCl3): δ = 2.29 (ddd, J = 14.1, 6.3, 4.0 Hz, 1
H), 2.57 (ddd, J = 14.1, 8.0, 7.6 Hz, 1 H), 3.80 (s, 3 H), 3.40–4.00
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 771–780

780
A. P. Molchanov et al.
PAPER
fied by column chromatography (silica gel, petroleum ether–
EtOAc) followed by crystallization (EtOH) to give a grey solid;
yield: 103 mg (55%); mp 155–157 °C; Rf = 0.44 (11% EtOAc–
hexane).
(5) Belyaeva, K. V.; Andriankova, L. V.; Nikitina, L. P.; Ivanov,
A. V.; Afonin, A. V.; Ushakov, I. A.; Malkina, A. G.;
Mikhaleva, A. I.; Trofimov, B. A. Synthesis 2011, 2843.
(6) (a) Tedeschi, R. J. Acetylene, In Encyclopedia of Physical
Science and Technology, Vol. 1, 3rd ed.; Meyers, R. A., Ed.;
Academic Press: San Diego, 2001, 55–89. (b) Wang, Z.
Comprehensive Organic Name Reactions and Reagents,
Part 3; Wiley: London, 2009, 2793–2796. (c) Name
Reactions in Heterocyclic Chemistry II; Li, J. J., Ed.; Wiley-
VCH: Hoboken, 2011, 72–82.
(7) Suitable crystals were obtained from abs EtOH.
Crystallographic data for the structures 6d and 7g have been
deposited with the Cambridge Crystallographic Data Centre
as supplementary publication numbers CCDC 973813 and
945026 respectively. Copies of these data can be obtained on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK (e-mail: deposit@ccdc.cam.ac.uk).
IR (KBr): 3289, 3131, 3063, 3030, 2915, 1680, 1659, 1503, 1435,
1404, 1061 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 2.25 (s, 3 H), 6.02 (d, J = 2.3
Hz, 1 H, OH), 6.06 (dd, J = 9.9, 2.3 Hz, 1 H), 6.24 (d, J = 9.9 Hz, 1
H), 7.11 (d, J = 8.4 Hz, 2 Harom), 7.15–7.21 (m, 1 Harom), 7.23 (d,
J = 8.4 Hz, 2 Harom), 7.39–7.49 (m, 2 Harom), 7.75 (d, J = 7.6 Hz, 2
Harom), 8.02 (s, 1 H, NH).
13C NMR (75 MHz, DMSO-d6): δ = 20.8 (CH3), 81.7 (CH), 105.2
(CH), 117.7 (2 CH), 121.3 (2 CH), 124.6 (CH), 129.1 (2 CH), 129.9
(2 CH), 130.0 (C), 134.2 (C), 137.7 (C), 139.8 (C), 165.6 (CO).
HRMS (ESI): m/z [M + H]+ calcd for C17H17N2O2: 281.1285; found:
281.1295.
(8) (a) Brandi, A.; Cicchi, S.; Cordero, F. M.; Goti, A. Chem.
Rev. 2003, 103, 1213. (b) Brandi, A.; Goti, A. Chem. Rev.
1998, 98, 589. (c) Goti, A.; Cordero, F. M.; Brandi, A. Top.
Curr. Chem. 1996, 178, 1. (d) Revuelta, J.; Cicchi, S.; de
Meijere, A.; Brandi, A. Eur. J. Org. Chem. 2008, 1085.
(e) Cardona, F.; Goti, A.; Brandi, A. Eur. J. Org. Chem.
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H.; de Meijere, A. Eur. J. Org. Chem. 2006, 5485.
(9) Huisgen, R.; Hauck, H.; Grashey, R.; Seidl, H. Chem. Ber.
1968, 101, 2568.
Acknowledgement
We gratefully acknowledge the financial support from the Russian
Foundation for Basic Research (Project No 12-03-01008-a). In this
research were used resources of the X-ray Diffraction Centre, the
Centre for Magnetic Resonance and the Centre for Chemical Ana-
lysis and Material of Saint Petersburg State University.
(10) Huisgen, R.; Hauck, H.; Grashey, R.; Seidl, H. Chem. Ber.
1969, 102, 736.
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© Georg Thieme Verlag Stuttgart · New York