Synthesis of 5-alkyl-5-aryl-1-pyrroline N-oxides from 1-aryl-substituted nitroalkanes and acrolein via Michael addition and nitro reductive cyclization

Article abstract of DOI:10.1016/j.tet.2014.07.046

A general method for accessing 5-alkyl-5-aryl-1-pyrroline N-oxides (AAPOs) has been established using readily available aryl bromides, nitroalkanes, and acrolein as the starting materials. The palladium-catalyzed arylation of nitroalkanes gave the 1-aryl-substituted nitroalkanes, which underwent the Et₃N-catalyzed Michael addition with acrolein at room temperature to afford the 4-aryl-4-nitroaldehydes. The latter were then subjected to the nitro reductive cyclization using Zn-HOAc in EtOH at 0 °C followed by warming the reaction mixture to room temperature for 24 h, furnishing the 5-alkyl-5-aryl-1-pyrroline N-oxides in good overall yields. Selected examples of 1,3-dipolar cycloaddition of the cyclic nitrones with methyl methacrylate were also described.

Full text of DOI:10.1016/j.tet.2014.07.046

Tetrahedron 70 (2014) 6384e6391
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Tetrahedron
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Synthesis of 5-alkyl-5-aryl-1-pyrroline N-oxides from 1-aryl-
substituted nitroalkanes and acrolein via Michael addition and
nitro reductive cyclization
,
a,
b
, ,
y
Jingjing Xu a, Xingyao Li a, Jinlong Wu a , Wei-Min Dai
*
*
a Laboratory of Asymmetric Catalysis and Synthesis, Department of Chemistry, Zhejiang University, Hangzhou 310027, China
b Laboratory of Advanced Catalysis and Synthesis, Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay,
Kowloon, Hong Kong SAR, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 June 2014
Received in revised form 7 July 2014
Accepted 14 July 2014
Available online 17 July 2014
A general method for accessing 5-alkyl-5-aryl-1-pyrroline N-oxides (AAPOs) has been established using
readily available aryl bromides, nitroalkanes, and acrolein as the starting materials. The palladium-
catalyzed arylation of nitroalkanes gave the 1-aryl-substituted nitroalkanes, which underwent the
Et3N-catalyzed Michael addition with acrolein at room temperature to afford the 4-aryl-4-
nitroaldehydes. The latter were then subjected to the nitro reductive cyclization using ZneHOAc in
EtOH at 0 ꢀC followed by warming the reaction mixture to room temperature for 24 h, furnishing the 5-
alkyl-5-aryl-1-pyrroline N-oxides in good overall yields. Selected examples of 1,3-dipolar cycloaddition
of the cyclic nitrones with methyl methacrylate were also described.
Keywords:
Arylation
Cyclization
Michael addition
Nitroalkanes
Nitrones
Ó 2014 Elsevier Ltd. All rights reserved.
Palladium
1. Introduction
The 1-pyrroline N-oxide (3,4-dihydro-2H-pyrrole 1-oxide) is the
core structure of a number of cyclic nitrone spin traps, such as
DMPO (1),1 MPPO (2),2 EMPO (3),3 AMPO (4),4 and DEPMPO (5)5
(Fig. 1). These cyclic nitrones and the well known acyclic conge-
ners represented by (Z)-a
-phenyl-N-tert-butylnitrone (PBN, 7)6 and
disodium (Z)-4-[(tert-butylimino)methyl]benzene-1,3-disulfonate
N-oxide (OKN-007, formerly referred to as NXY-059, 8)7 have
been extensively studied as therapeutics for oxidative stress-
related diseases, such as neurodegeneration, cardiovascular dis-
ease, and cancer.8 Among them, the nitrone 8 has reached to clin-
ical trials for treatment of acute stroke,7a and it delivers anticancer
activity in animal glioma models7bed and hepatocellular carcino-
ma.7c,e Over the years, acyclic nitrones represented by the general
structure I (Ar¼aryl or heteroaryl) have been synthesized for im-
proved spin trap properties9aec and for stroke treatment.9d,e Novel
benzoxazinic nitrones 9e1110 and other cyclic nitrones11 have also
been reported for studying their reactivity toward oxygen- and
Fig. 1. Structures of cyclic and linear nitrone spin traps 1e11.
carbon-centered radicals and as possible antioxidants in biological
systems. Moreover, conjugates of acyclic and cyclic nitrones with
* Corresponding authors. Tel./fax: þ86 571 87953128; e-mail addresses: wyz@
cholesterol,12a,e
b
-cyclodextrin,12b,c and fluorinated amphiphilic
zju.edu.cn (J. Wu), chdai@zju.edu.cn, chdai@ust.hk (W.-M. Dai).
carriers12d,f have been synthesized and evaluated for spin-trapping
y
Tel.: þ852 23587365; fax: þ852 23581594.
http://dx.doi.org/10.1016/j.tet.2014.07.046
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

J. Xu et al. / Tetrahedron 70 (2014) 6384e6391
6385
behavior12aed and antioxidant properties in biomimetic mem-
brances,12f and as antioxidants against light-induced retinal
degeneration.12e
(Fig. 2c).16deg This synthetic sequence is advantageous not only for
its generality but also for its tolerance of the functional groups, such
as carboxylic esters, which could not survive under the Grignard
addition conditions as employed in Janzen and Merino’s prepara-
tions, respectively (Fig. 2a and b). The functional group X on the
phenyl ring of 15 should enable formation of conjugates for
achieving enhanced spin-trapping properties as demonstrated in
the prior work mentioned above.12
Substituent effect on the spin-trapping behavior of 1-pyrroline
N-oxides has been examined. Replacement of one C5-methyl
group in DMPO (1) by a phenyl group as in MPPO (2) improved
its stability to have an excellent shelf life.2a Moreover, longer life-
times of the spin adducts of MPPO were observed while similar
spin-trapping rate constants as compared to those of DMPO were
achieved. The unique stereochemistry of the spin adducts of MPPO
rendered easy detection of the spin-adduct spectra. In some cases
one major trans (with respect to the phenyl group) and one minor
cis adducts were formed in addition reactions with the carbon-
centered radicals while the reverse selectivity was observed for
the superoxide/peroxyl radical adducts. For the hydroxyl radical
adduct of MPPO, only one EPR spectrum was detected. In contrast,
substitution of the C5-methyl group in DEPMPO (5) by a phenyl
group gave DEPPPO (6)13 with a significant decrease of the spin-
trapping properties, such as non-stereoselective addition of free
radicals on the nitronyl moiety due to less steric bias among the
two substituents on the C5 position. It seems interesting to in-
vestigate the spin-trapping properties of the general structure II
(Fig. 1) on the basis of MPPO (2).
2. Results and discussion
1-Aryl-substituted nitroalkanes 13aeg and 13n (entries 1e7 and
14, Table 1) were obtained by the Pd-catalyzed
a-arylation of
nitroalkanes under the optimized conditions in our previous
work.19 The compounds 13hem were newly synthesized by fol-
lowing the same procedure in good to excellent yields.
Table 1
Results of Pd-catalyzed arylation of nitroalkanesa
There are two general methods for synthesis of nitrones, i.e.,
condensation of hydroxylamines with carbonyl compounds14 and
oxidation of hydroxylamines or secondary amines.15 In the former
cases, the hydroxylamines could be formed from reduction of nitro
compounds, providing an efficient synthesis of cyclic nitrones from
reductive cyclization of nitro carbonyl precursors.16,17 Janzen and
co-workers2c synthesized MPPO (2) by a four-step sequence
(Fig. 2a), consisting of the Michael addition of nitromethane with
methyl vinyl ketone,16d,e the nitro reductive cyclization, the
Grignard addition with 2-methyl-1-pyrroline N-oxide, and finally
the oxidation of the cyclic hydroxylamine. Merino and co-
workers18 prepared a similar nitrone 12 designed for studying
neutral 2-aza-Cope rearrangement (Fig. 2b). Starting from the
parent 1-pyrroline N-oxide, two iterative Grignard addition and
hydroxylamine oxidation cycles were used and the overall yield of
12 was excellent. In our recent work, we established a general
Entry
1c
2
16: X
R
t (h)
13: Yieldb (%)
16a: 2-(1,3-Dioxolan-2-yl)
16b: 3-Me
16c: 4-Me
16d: 2-MeO
16e: 4-MeO
Me
Me
Me
Me
Me
Me
Me
Et
Et
Et
Et
Et
24
14
14
18
14
14
14
14
18
14
14
18
14
14
13a: 71d
13b: 90d
13c: 78d
13d: 91d
13e: 74d
13f: 84d
13g: 88d
13h: 75
13i: 72
3
4e
5
6
7
8
16f: 4-Cl
16g: 4-MeO2C
16h: 4-(1,3-Dioxolan-2-yl)
16i: 2-Me
16b: 3-Me
16c: 4-Me
16d: 2-MeO
16f: 4-Cl
16g: 4-MeO2C
9e
10
11
12e
13
14
13j: 89
13k: 88
13l: 91
Et
Et
13m: 80
synthesis of 5-alkyl-5-aryl-g-lactams from 1-aryl-substituted
13n: 87d
nitroalkanes.19,20 We envisioned that 5-alkyl-5-aryl-1-pyrroline N-
oxides (AAPOs) of the general structure II (Fig. 1) could be syn-
thesized from the readily available 1-aryl-substituted nitroalkanes
13 via the Michael addition with acrolein followed by the reductive
cyclization of the nitro aldehydes 14 to give the nitrones 15
a
Reaction conditions: 1 mol % Pd2(dba)3, 4 mol % 17, 2 equiv of RCH2NO2, and
1.3 equiv of K3PO4, DME, 50 ꢀC for 14 h.
b
Isolated yields.
c
Using 5 mol % Pd2(dba)3 and 20 mol % 17 in 1,4-dioxane at 110 ꢀC.
d
Data are taken from Ref. 19 for comparison.
Using 5 mol % Pd2(dba)3 and 10 mol % 17 at 50 ꢀC for 18 h.
e
a. Janzen et al.
1. MeNO2
(83%)
1. PhMgCl
(57%)
Ph
O
In general, the ortho-substituent in the aryl bromides 16 ren-
dered the arylation much more difficult to occur. For example,
much higher temperature and catalyst loading should be applied
for the arylation of 16a as compared to 16h (entry 1 vs entry 8, Table
1). Also, the reactions of 16d and 16i required higher catalyst
loading and longer reaction time (entries 4, 9, and 12, Table 1). On
the other hand, the R group in nitroalkanes, i.e., Me (entries 2e4, 6,
and 7, Table 1) versus Et (entries 10e14, Table 1) did not show
notable influence on the arylation results.
Me
N
O
N
O
Me
Me
2. Zn (61%)
2. [O] (28%)
2: MPPO
b. Merino et al.
Ph
1. PhMgBr
2. MnO2 74%
for 2 steps)
1. AllylMgBr
Ph
N
O
N
O
N
O
2. MnO2 (76%
for 2 steps)
In our previous work on the Michael addition of the 1-aryl-
substituted nitroalkanes 13 with methyl acrylate, it was found that
Et3N was not an efficient base to promote formation of the Michael
adducts. Instead, DBU (0.5e1.0 equiv) should be used to facilitate
the Michael addition in MeCN at room temperature for 2.5 h to
furnish the adducts in excellent yields.19 For the Michael addition of
13 with acrolein,16f,g we found that only 0.1 equiv of Et3N was
sufficient to catalyze the formation of the adducts 14 at room
temperature. For the substrates 13bed and 13f (R¼Me) possessing
12
c. current work:
CHO
X
CHO
[H]
X
X
R
N
O
R
NO2
NO2
13
R
14
15
Fig. 2. Synthetic approaches toward 5-alkyl-5-aryl-1-pyrroline N-oxides.

6386
J. Xu et al. / Tetrahedron 70 (2014) 6384e6391
Table 3
a methyl group at the a-carbon, their Michael adduct yields are
Results of formation of nitrones 15 via reductive cyclization of 14a
generally higher than the corresponding Et analogues 13jem (en-
tries 2e4 and 6 vs entries 10e13, Table 2). These results indicate
that a bulky R group renders the Michael addition difficult to take
place. When the acidity of the a-proton of the nitroalkanes 13g and
13n increases due to the presence of the para-carboxylic ester
moiety on the benzene ring, the same yields are obtained (entry 7
vs entry 14, Table 2) regardless the bulkiness of the R group. The
ortho-(1,3-dioxolan-2-yl) group in 13a and ortho-methyl group in
13i also affect the Michael addition to give diminished yields for
14a (entry 1, Table 2) and 14i (entry 9, Table 2), but the ortho-
methoxy group in 13d,l did not reduce the yields of the adducts 14d
(entry 4, Table 2) and 14l (entry 12, Table 2). Moreover, the yields of
some Michael adducts could be improved by extending the reaction
times to 48 h (entries 2, 3, 5, and 10, Table 2).
Entry
14: X
R
15: Yieldb (%)
1
2
3
4
5
6
7
8
14a: 2-(1,3-Dioxolan-2-yl)
14b: 3-Me
14c: 4-Me
14d: 2-MeO
14e: 4-MeO
Me
Me
Me
Me
Me
Me
Me
Et
15a: 70
15b: 83 (83)
15c: 63 (63)
15d: 80 (60)
15e: 77 (77)
15f: 73
15g: 79 (71)
15h: 78
15i: 71
14f: 4-Cl
14g: 4-MeO2C
14h: 4-(1,3-Dioxolan-2-yl)
14i: 2-Me
9
Et
10
11
12
13
14
14j: 3-Me
14k: 4-Me
14l: 2-MeO
14m: 4-Cl
Et
Et
Et
Et
15j: 86 (82)
15k: 73
15l: 72 (83)
15m: 77
Table 2
Results of Michael addition of 13 with acroleina
14n: 4-MeO2C
Et
15n: 74 (74)
a
Reaction conditions: 14 (1.0 mmol), zinc powder (3.0 mmol), and AcOH
(6.0 mmol) in EtOH (10 mL) at 0 ꢀC fro 30 min and then at room temperature for
72 h.
b
Isolated yields. The numbers given in the parentheses are the yields obtained
14: Yieldb (%)
after reaction for 24 h.
Entry
13: X
R
1
2
3
4
5
6
7
8
13a: 2-(1,3-Dioxolan-2-yl)
13b: 3-Me
13c: 4-Me
13d: 2-MeO
13e: 4-MeO
Me
Me
Me
Me
Me
Me
Me
Et
14a: 66
14b: 80 (93)
14c: 84 (96)
14d: 83 (83)
14e: 84 (93)
14f: 73
14g: 88 (88)
14h: 71
14i: 57
41.5 h furnished the adducts 18b and epi-186b in 96:4 di-
astereomeric ratio and in 73% isolated yield of 18b and epi-18b as an
inseparable mixture (entry 2, Table 4). The other possible
regioisomers were not detected by 1H NMR analysis of the crude
reaction mixture. The yield of the reaction of 15c with methyl
methacrylate could be improved to 78% by heating at 40 ꢀC for 24 h
with the same diastereoselectivity (entry 3, Table 4). Further in-
crease of the reaction temperature to 80 ꢀC in refluxing MeCN
significantly shortened the reaction time to 5 h, providing the ad-
ducts in 80% combined yield but with slightly diminished di-
astereomeric ratio of 90:10 (entry 4, Table 4). By keeping the
reaction temperature at 40 ꢀC, other cyclic nitrones 15b,d,e,j were
13f: 4-Cl
13g: 4-MeO2C
13h: 4-(1,3-Dioxolan-2-yl)
13i: 2-Me
9
Et
10
11
12
13
14
13j: 3-Me
13k: 4-Me
13l: 2-MeO
13m: 4-Cl
Et
Et
Et
Et
14j: 64 (94)
14k: 70
14l: 68 (69)
14m: 67
13n: 4-MeO2C
Et
14n: 87 (86)
a
Reaction conditions: 13 (1 mmol), acrolein (1.5 mmol), and Et3N (0.1 mmol) in
MeCN (4 mL) at room temperature for 24 h.
b
Isolated yields. The numbers given in the parentheses are the yields obtained
after reaction for 2 days.
Table 4
Results of 1,3-dipolar cycloaddition of 15 with methyl methacrylatea
The reductive cyclization of the nitro aldehydes 14 went
smoothly in the presence of zinc powder and AcOH in EtOH first at
0
ꢀC for 30 min followed by warming up to room temperature for
72 h.16 The yields of the 5-alkyl-5-aryl-1-pyrroline N-oxides 15aen
are listed in Table 3. In general, yields ranging from 70 to 80% were
obtained except for the nitrone 15c (entry 3, Table 3). Some of the
reductive cyclization experiments were repeated at room temper-
ature for 24 h instead of 72 h and the nitrone yields were similar,
suggesting that a longer reaction time might be not necessary.
However, the yield and reaction time relationship for the two ortho-
methoxy-substituted substrates is opposite and no explanation
could be offered (entry 4 vs entry 12, Table 3).
Entry
15: X
R
Yieldb (%)
dr (18/epi-18)c
Cyclic nitrones in chiral or achiral forms have been used in 1,3-
dipolar cycloadditions with a variety of olefins.21 Although DMPO
(1) and similar cyclic nitrones were reported to undergo 1,3-dipolar
cycloadditions,22 to the best of our knowledge, unsymmetrical 5,5-
disubstituted 1-pyrroline N-oxides 15 have not been investigated
for this reaction type. It might be interesting to examine the regio-
and stereoselectivity of 15 in 1,3-dipolar cycloaddition reactions.
After preliminary screening of olefin substrates, it was found that
cycloadditions of methyl acrylate and methyl crotonate with 15n,
for example, afforded good to excellent yields of the adducts but
with low regio- and stereoselectivity. Fortunately, the cycloaddition
of methyl methacrylate with 15c at room temperature in MeCN for
1
15b: 3-Me
15c: 4-Me
15c: 4-Me
15c: 4-Me
15d: 2-MeO
15e: 4-MeO
15j: 3-Me
Me
Me
Me
Me
Me
Me
Me
18a: 80
18b: 73
18b: 78
18b: 80
18c: 82
18d: 80
18e: 87
95:5
96:4
95:5
90:10
94:6
94:6
95:5
2d
3
4e
5
6
7
a
Reaction conditions: 15 (1.0 mmol), methyl methacrylate (2.0 mmol) in MeCN
(10 mL) in a closed process vial at 40 ꢀC for 24 h.
b
Isolated yields of both diastereomers 18 and epi-18.
c
Determined by 1H NMR spectroscopy analysis.
d
Carried out at room temperature for 41.5 h.
Carried out under refluxing for 5 h.
e

J. Xu et al. / Tetrahedron 70 (2014) 6384e6391
6387
used for the same 1,3-dipolar cycloaddition with methyl methac-
rylate to afford the adducts 18a and 18cee in 80e87% yields and
with 94:6 to 95:5 diastereoselectivity (entries 1 and 5e7, Table 4).
The structures of the major adducts 18 were assigned according to
the preferred endo approach23 assuming that the C5-aryl group in
15 (such as 2-methoxyphenyl in 15d) is sterically more demanding
than the C5-alkyl group (R¼Me).
J¼8.4 Hz, 2H), 7.48 (d, J¼8.0 Hz, 2H), 5.82 (s, 1H), 5.37 (dd, J¼8.8,
6.8 Hz, 1H), 4.14e4.07 (m, 2H), 4.07e4.00 (m, 2H), 2.55e2.44 (m,
1H), 2.15e2.06 (m, 1H), 0.97 (t, J¼7.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3)
d
139.9, 135.4, 127.9 (ꢃ2), 127.2 (ꢃ2), 103.1, 92.8, 65.5 (ꢃ2),
27.5, 10.7; HRMS (þEI) calcd for C12H15O2 191.1072 (MþꢂNO2),
found 191.1070.
4.2.2. 1-Methyl-2-(1-nitropropyl)benzene (13i). Prepared according
to the general procedure A in 72% yield as a colorless oil; Rf¼0.43
(9% EtOAc in hexane); IR (film): 2976, 2935, 2875, 1552, 1463,
3. Conclusion
In summary, we have established a general and efficient syn-
thesis of 5-alkyl-5-aryl-1-pyrroline N-oxides 15 by the Michael
addition of 1-aryl-substituted nitroalkanes 13 with acrolein fol-
lowed by the reductive cyclization of the nitro aldehydes 14. Since
1366 cmꢂ1 1H NMR (400 MHz, CDCl3)
; d 7.53e7.51 (m, 1H),
7.32e7.22 (m, 3H), 5.72 (dd, J¼8.8, 6.4 Hz, 1H), 2.62e2.50 (m, 1H),
2.48 (s, 3H), 2.17e2.06 (m, 1H), 1.03 (t, J¼7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 137.0, 133.2, 131.0, 129.6, 127.0, 126.4, 88.6, 27.2,
the palladium-catalyzed
a
-arylation of nitroalkanes tolerates a va-
19.6, 10.8; HRMS (þEI) calcd for C10H13 133.1017 (MþꢂNO2), found
riety of aryl bromides/chlorides, such as 16aei,19,20 the above de-
scribed synthetic protocol offers access to the diversely substituted
5-alkyl-5-aryl-1-pyrroline N-oxides 15 from the readily available
nitro compounds 13. The functional group, such as the carboxylic
ester in 15g,n, should provide a tethering point for formation of
conjugates useful for application of these cyclic nitrone spin traps
in biologically relevant systems. Moreover, these unique cyclic
nitrones possessing 5,5-disubstituents have been examined for 1,3-
dipolar cycloaddition with methyl methacrylate at 40 ꢀC to furnish
the adducts with only one regioisomer and in ꢁ94:6
diastereoselectivity.
133.1014.
4.2.3. 1-Methyl-3-(1-nitropropyl)benzene (13j). Prepared according
to the general procedure A in 89% yield as a colorless oil; Rf¼0.53
(9% EtOAc in hexane); IR (film): 2977, 2938, 2881, 1552, 1462,
1367 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d 7.31e7.26 (m, 3H), 7.22 (d,
J¼6.8 Hz,1H), 5.34 (dd, J¼8.8, 6.8 Hz,1H), 2.57e2.45 (m,1H), 2.38 (s,
3H), 2.17e2.06 (m, 1H), 0.99 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d 138.9, 134.6, 130.6, 129.0, 128.4, 124.8, 93.2, 27.4, 21.5, 10.8;
HRMS (þEI) calcd for C10H13 133.1017 (MþꢂNO2), found 133.1020.
4.2.4. 1-Methyl-4-(1-nitropropyl)benzene (13k). Prepared accord-
ing to the general procedure A in 88% yield as a colorless oil;
Rf¼0.54 (9% EtOAc in hexane); IR (film): 2977, 2938, 2881, 1550,
4. Experimental
4.1. General methods
1516, 1462, 1367 cmꢂ1 1H NMR (400 MHz, CDCl3)
; d 7.36 (d,
J¼8.0 Hz, 2H), 7.21 (d, J¼8.0 Hz, 2H), 5.35 (dd, J¼8.4, 6.4 Hz, 1H),
1H and 13C NMR spectra were recorded in CDCl3 or acetone-d6
(400 or 500 MHz for 1H and 100 or 125 MHz for 13C, respectively).
IR spectra were taken on an FT-IR spectrophotometer. Mass spectra
(MS) were measured by the ESI or EI method. Silica gel plates pre-
coated on glass were used for thin-layer chromatography using UV
light, or 7% ethanolic phosphomolybdic acid and heating as the
visualizing methods. Silica gel was used for flash column chroma-
tography. Yields refer to chromatographically and spectroscopically
(1H NMR) homogeneous materials. Reagents were obtained com-
mercially and used as received.
2.56e2.44 (m, 1H), 2.36 (s, 3H), 2.16e2.05 (m, 1H), 0.98 (t, J¼7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3)
d
139.9, 131.7, 129.7 (ꢃ2), 127.7
(ꢃ2), 92.9, 27.3, 21.3, 10.8; HRMS (þEI) calcd for C10H13 133.1017
(MþꢂNO2), found 133.1019.
4.2.5. 1-Methoxy-2-(1-nitropropyl)benzene (13l).20 Prepared accord-
ing to the general procedure A in 91% yield as a colorless oil; Rf¼0.45
(9% EtOAc in hexane); IR (film): 2974, 2941, 1549, 1494, 1464, 1368,
1250, 1027 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d
7.43 (d, J¼7.6 Hz, 1H),
7.36 (t, J¼8.0 Hz, 1H), 7.00 (t, J¼8.0 Hz, 1H), 6.92 (d, J¼8.4 Hz, 1H),
5.89 (dd, J¼8.4, 6.8 Hz,1H), 3.85 (s, 3H), 2.52e2.40 (m,1H), 2.15e2.04
4.2. General procedure A for the arylation of nitroalkanes
(m, 1H), 1.01 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 157.2,
130.8, 127.7, 123.3, 121.0, 111.0, 85.8, 55.8, 26.7, 10.9.
A dried 10-mL process vial was charged with appropriate
amounts of Pd2(dba)3 and 2-(di-tert-butylphosphinyl)-20-methyl-
biphenyl (17), and 1.3 equiv of K3PO4. The vial was sealed with as
cap containing a silicon septum. The loaded vial was evacuated and
backfilled with nitrogen for three times. Then, aryl bromide 16
(1.0 mmol), nitroalkane (2.0 mmol), and degassed DME (5.0 mL)
were added sequentially via a syringe. The resultant mixture was
stirred vigorously for 1 min at room temperature, and then at 50 ꢀC
for 14 h. After cooling to ambient temperature the reaction mixture
was diluted with EtOAc. The resulting solution was filtered off
through a plug of Celite with washing by EtOAc. The combined
filtrate was washed with water and brine, dried over anhydrous
Na2SO4, filtered, and condensed under reduced pressure. The res-
idue was purified by flash column chromatography over silica gel to
give the product 13. The results are found in Table 1. Character-
ization data for the compounds 13aeg,n are found in our previous
work.19
4.2.6. 1-Chloro-4-(1-nitropropyl)benzene (13m). Prepared accord-
ing to the general procedure A in 78% yield as a colorless oil;
Rf¼0.45 (9% EtOAc in hexane); IR (film): 2977, 2938, 1553, 1494,
1460, 1366, 1093, 1016 cmꢂ1 1H NMR (400 MHz, CDCl3)
; d 7.41 (d,
J¼9.2 Hz, 2H), 7.38 (d, J¼8.0 Hz, 2H), 5.34 (dd, J¼8.8, 6.8 Hz, 1H),
2.54e2.43 (m, 1H), 2.14e2.03 (m, 1H), 0.98 (t, J¼7.2 Hz, 3H); 13C
NMR (100 MHz, CDCl3)
d
136.1, 133.0, 129.4 (ꢃ2), 129.3 (ꢃ2), 92.4,
27.5, 10.7; HRMS (þEI) calcd for C9H1035Cl 153.0471 (MþꢂNO2),
found 153.0472.
4.3. General procedure B for the Michael addition of nitro-
alkanes 13 with acrolein
To a solution of 13 (1.0 mmol) and acrolein (1.5 mmol) in MeCN
(4.0 mL) at room temperature under a nitrogen atmosphere was
added Et3N (0.1 mmol). The resultant mixture was stirred at room
temperature for 24 h. The reaction mixture was condensed under
reduced pressure and the residue was purified by flash column
chromatography over silica gel to afford the nitro aldehyde 14. The
results are found in Table 2.
4.2.1. 2-[4-(1-Nitropropyl)phenyl][1,3]dioxolane
(13h). Prepared
according to the general procedure A in 75% yield as a colorless oil;
Rf¼0.41 (9% EtOAc in hexane); IR (film): 2976, 2938, 2884, 1704,
1552, 1368, 1085 cmꢂ1 1H NMR (400 MHz, CDCl3)
; d 7.52 (d,

6388
J. Xu et al. / Tetrahedron 70 (2014) 6384e6391
4.3.1. 4-[2-(1,3-Dioxolan-2-yl)phenyl]-4-nitropentanal
(14a). Prepared according to the general procedure B in 66% yield
as a pale yellow oil; Rf¼0.41 (25% EtOAc in hexane); IR (film): 2953,
2893, 2730, 1723, 1538, 1450, 1388, 1342, 1212, 1134, 1096,
Rf¼0.38 (25% EtOAc in hexane); IR (film): 2999, 2954, 2840, 2732,
1727, 1542, 1436, 1410, 1345, 1284, 1195, 1116 cmꢂ1 1H NMR
(400 MHz, CDCl3)
9.73 (s, 1H), 8.05 (d, J¼8.4 Hz, 2H), 7.41 (d,
;
d
J¼8.4 Hz, 2H), 3.92 (s, 3H), 2.80e2.72 (m, 1H), 2.67e2.59 (m, 1H),
1066 cmꢂ1; 1H NMR (500 MHz, CD3COCD3)
d
9.66 (s, 1H), 7.76e7.74
2.48 (t, J¼8.0 Hz, 2H),1.95 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 199.4,
(m, 1H), 7.54e7.52 (m, 1H), 7.49e7.47 (m, 2H), 5.65 (s, 1H),
4.15e4.10 (m, 2H), 3.98e3.93 (m, 2H), 2.79 (t, J¼9.0 Hz, 2H),
2.50e2.43 (m, 1H), 2.26e2.19 (m, 1H), 2.05 (s, 3H); 13C NMR
166.3, 143.7, 131.0, 130.3 (ꢃ2), 125.5 (ꢃ2), 92.6, 52.5, 39.3, 31.6, 24.4;
HRMS (þEI) calcd for C13H15O3 219.1021 (MþꢂNO2), found 219.1019.
(125 MHz, CD3COCD3)
d
200.7, 137.8, 137.6, 130.2, 129.8, 129.8, 127.7,
4.3.8. 4-[4-(1,3-Dioxolan-2-yl)phenyl]-4-nitrohexanal
(14h). Prepared according to the general procedure B in 71% yield
as a colorless oil; Rf¼0.38 (25% EtOAc in hexane); IR (film): 2978,
99.8, 93.7, 66.2, 66.1, 39.9, 33.0, 27.5; HRMS (þEI) calcd for C14H17O3
233.1178 (MþꢂNO2), found 233.1178.
2887, 2733, 1723, 1538, 1391, 1350, 1086, 1020 cmꢂ1 1H NMR
;
4.3.2. 4-Nitro-4-(3-tolyl)pentanal (14b). Prepared according to the
general procedure B (at room temperature for 2 days) in 93% yield
as a colorless oil; Rf¼0.35 (17% EtOAc in hexane); IR (film): 2988,
2946, 2873, 2834, 2730, 1724, 1539, 1456, 1386, 1343 cmꢂ1; 1H NMR
(500 MHz, CDCl3)
d
9.66 (s, 1H), 7.49 (d, J¼8.0 Hz, 2H), 7.29 (d,
J¼8.5 Hz, 2H), 5.79 (s, 1H), 4.13e4.06 (m, 2H), 4.06e3.98 (m, 4H),
2.72e2.61 (m, 2H), 2.50e2.43 (m, 1H), 2.40e2.25 (m, 3H), 0.84 (t,
J¼7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 199.7, 139.0, 138.9, 127.1
(400 MHz, CDCl3)
3H), 2.78e2.70 (m, 1H), 2.67e2.59 (m, 1H), 2.46 (t, J¼7.6 Hz, 2H),
2.36 (s, 3H); 13C NMR (100 MHz, CDCl3)
199.9, 139.0, 138.9, 129.9,
d
9.73 (s, 1H), 7.28 (t, J¼8.0 Hz, 1H), 7.19e7.13 (m,
(ꢃ2), 125.9 (ꢃ2), 103.0, 96.5, 65.4 (ꢃ2), 38.9, 29.6, 27.5, 8.4; HRMS
(þEI) calcd for C15H18O3 246.1256 (MþꢂHNO2), found 246.1258.
d
128.9, 125.9, 122.3, 92.7, 39.5, 31.7, 24.3, 21.7; HRMS (þEI) calcd for
4.3.9. 4-Nitro-4-(2-tolyl)hexanal (14i). Prepared according to the
general procedure B in 57% yield as a colorless oil; Rf¼0.34 (17%
EtOAc in hexane); IR (film): 2982, 2944, 2878, 2828, 2729, 1724,
C
12H15O 175.1123 (MþꢂNO2), found 175.1125.
4.3.3. 4-Nitro-4-(4-tolyl)pentanal (14c). Prepared according to the
general procedure B (at room temperature for 2 days) in 96% yield
as a colorless oil; Rf¼0.32 (17% EtOAc in hexane); IR (film): 2991,
2953, 2920, 2863, 2727, 1723, 1538, 1515, 1386, 1343 cmꢂ1; 1H NMR
1538, 1455, 1362 cmꢂ1 1H NMR (400 MHz, CDCl3)
; d 9.65 (s, 1H),
7.30e7.24 (m, 3H), 7.23e7.20 (m, 1H), 2.79e2.65 (m, 2H), 2.48e2.31
(m, 3H), 2.30e2.21 (m, 3H), 2.19 (s, 3H), 0.84 (t, J¼7.6 Hz, 3H); 13C
NMR (100 MHz, CDCl3) d 199.7,136.4,136.0,133.2,128.8,127.1,126.1,
(400 MHz, CDCl3)
d
9.73 (s, 1H), 7.25 (d, J¼8.0 Hz, 2H), 7.20 (d,
96.4, 39.3, 29.3, 26.9, 20.1, 8.7; HRMS (þEI) calcd for C13H16
O
J¼8.0 Hz, 2H), 2.77e2.69 (m, 1H), 2.69e2.61 (m, 1H), 2.46 (t,
188.1201 (MþꢂHNO2), found 188.1200.
J¼7.6 Hz, 2H), 2.35 (s, 3H), 1.93 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
199.9, 139.2, 136.0, 129.7 (ꢃ2), 125.3 (ꢃ2), 92.5, 39.5, 31.7, 24.2,
4.3.10. 4-Nitro-4-(3-tolyl)hexanal (14j). Prepared according to the
general procedure B (at room temperature for 2 days) in 94% yield
as a colorless oil; Rf¼0.41 (17% EtOAc in hexane); IR (film): 2978,
21.1; HRMS (þEI) calcd for C12H15O 175.1123 (MþꢂNO2), found
175.1123.
2947, 2923, 2881, 2724, 1725, 1538, 1455, 1350 cmꢂ1 1H NMR
;
4.3.4. 4-(2-Methoxyphenyl)-4-nitropentanal
according to the general procedure B in 83% yield as a colorless oil;
(14d). Prepared
(400 MHz, CDCl3)
d
9.69 (s, 1H), 7.28 (t, J¼7.6 Hz, 1H), 7.18 (d,
J¼7.2 Hz, 1H), 7.09 (d, J¼6.4 Hz, 1H), 7.06 (s, 1H), 2.75e2.63 (m, 2H),
Rf¼0.30 (17% EtOAc in hexane); IR (film): 2945, 2841, 2727, 1715,
2.54e2.43 (m, 1H), 2.41e2.27 (m, 3H), 2.36 (s, 3H), 0.87 (t, J¼7.6 Hz,
1544,1494,1462,1250,1025 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d
9.64
3H); 13C NMR (100 MHz, CDCl3)
d 199.9, 138.8, 138.2, 129.8, 128.8,
(s, 1H), 7.35 (t, J¼8.4 Hz, 1H), 7.25 (d, J¼8.4 Hz, 1H), 6.99 (t, J¼7.6 Hz,
1H), 6.90 (d, J¼8.4 Hz, 1H), 3.73 (s, 1H), 2.83e2.76 (m, 1H),
2.69e2.61 (m, 1H), 2.46e2.38 (m, 1H), 2.33e2.25 (m, 1H), 1.88 (s,
126.3, 122.8, 96.7, 39.0, 29.5, 27.5, 21.7, 8.4; HRMS (þEI) calcd for
C
13H17O 189.1279 (MþꢂNO2), found 189.1283.
3H); 13C NMR (100 MHz, CDCl3)
d
200.3, 156.8, 130.6, 127.5, 126.9,
4.3.11. 4-Nitro-4-(4-tolyl)hexanal (14k). Prepared according to the
general procedure B in 70% yield as a colorless oil; Rf¼0.35 (17%
EtOAc in hexane); IR (film): 2979, 2944, 2923, 2884, 1714, 1538,
120.8, 112.0, 90.7, 55.5, 39.6, 29.7, 24.9; HRMS (þEI) calcd for
C
12H14O2 190.0994 (MþꢂHNO2), found 190.0996.
1455, 1412, 1348 cmꢂ1 1H NMR (400 MHz, CDCl3)
; d 9.69 (s, 1H),
4.3.5. 4-(4-Methoxyphenyl)-4-nitropentanal
according to the general procedure B (at room temperature for 2
(14e). Prepared
7.21e7.16 (m, 4H), 2.72e2.62 (m, 2H), 2.53e2.44 (m, 1H), 2.42e2.26
(m, 3H), 2.35 (s, 3H), 0.87 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz,
days) in 93% yield as a colorless oil; Rf¼0.34 (17% EtOAc in hexane);
CDCl3)
d
200.0, 139.1, 135.3, 129.7 (ꢃ2), 125.7 (ꢃ2), 96.5, 39.1, 29.5,
IR (film): 2976, 2935, 2839, 1730, 1515, 1253, 1182, 1031 cmꢂ1
;
1H
27.5, 21.2, 8.5; HRMS (þEI) calcd for C13H17O 189.1279 (MþꢂNO2),
NMR (400 MHz, CDCl3)
J¼8.8 Hz, 2H), 3.80 (s, 3H), 2.76e2.62 (m, 2H), 2.44 (dd, J¼7.6,
6.8 Hz, 2H), 1.93 (s, 3H); 13C NMR (100 MHz, CDCl3)
199.8, 160.1,
d
9.73 (s, 1H), 7.31 (d, J¼8.8 Hz, 2H), 6.89 (d,
found 189.1275.
d
4.3.12. 4-(2-Methoxyphenyl)-4-nitrohexanal (14l). Prepared accord-
ing to the general procedure B in 68% yield as a colorless oil; Rf¼0.35
(17% EtOAc in hexane); IR (film): 2976, 2944, 2884, 2840, 2730, 1723,
130.71, 127.0 (ꢃ2), 114.3 (ꢃ2), 92.1, 55.5, 39.5, 31.6, 23.9; HRMS
(þEI) calcd for C12H14O2 190.0994 (MþꢂHNO2), found 190.0998.
1543, 1493, 1463, 1250, 1025 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d 9.61
4.3.6. 4-(4-Chlorophenyl)-4-nitropentanal (14f). Prepared accord-
ing to the general procedure B in 73% yield as a colorless oil;
Rf¼0.45 (25% EtOAc in hexane); IR (film): 2993, 2941, 2873, 2834,
(s, 1H), 7.35 (t, J¼7.6 Hz, 1H), 7.24 (d, J¼7.6 Hz, 1H), 6.99 (t, J¼7.6 Hz,
1H), 6.92 (d, J¼8.0 Hz,1H), 3.73 (s, 3H), 2.82e2.74 (m, 1H), 2.66e2.58
(m,1H), 2.40e2.16 (m, 4H), 0.82 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz,
2731, 1724, 1539, 1495, 1403, 1387, 1345, 1098 cmꢂ1
;
1H NMR
CDCl3) d 200.2, 156.8, 130.4, 127.5, 126.8, 120.6, 112.1, 94.3, 55.5, 39.3,
(400 MHz, CDCl3)
d
9.71 (s, 1H), 7.34 (d, J¼7.2 Hz, 2H), 7.29 (d,
28.3, 26.0, 8.5; HRMS (þEI) calcd for C13H17O2 205.1229 (MþꢂNO2),
J¼7.2 Hz, 2H), 2.74e2.67 (m, 1H), 2.62e2.56 (m, 1H), 2.44 (t,
found 205.1229.
J¼6.4 Hz, 2H), 1.90 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 199.5, 137.4,
135.2, 129.2 (ꢃ2), 126.9 (ꢃ2), 92.0, 39.2, 31.5, 23.9; HRMS (þEI)
4.3.13. 4-(4-Chlorophenyl)-4-nitrohexanal (14m). Prepared accord-
ing to the general procedure B in 67% yield as a colorless oil; Rf¼0.51
(25% EtOAc in hexane); IR (film): 2979, 2941, 2884, 2834, 2727,
1724, 1539, 1496, 1352, 1097, 1013 cmꢂ1; 1H NMR (400 MHz, CDCl3)
calcd for C11H12O35Cl 195.0577 (MþꢂNO2), found 195.0578.
4.3.7. Methyl 4-(2-nitro-5-oxopentan-2-yl)benzoate (14g). Prepared
according to the general procedure B in 88% yield as a colorless oil;
d
9.70 (s, 1H), 7.37 (d, J¼8.8 Hz, 2H), 7.23 (d, J¼8.8 Hz, 2H), 2.67 (t,

J. Xu et al. / Tetrahedron 70 (2014) 6384e6391
6389
J¼7.6 Hz, 2H), 2.50e2.41 (m, 1H), 2.41e2.24 (m, 3H), 0.85 (t,
2.74e2.67 (m, 1H), 2.60e2.44 (m, 2H), 2.23e2.15 (m, 1H), 1.84 (s,
3H); 13C NMR (100 MHz, CDCl3)
156.9, 135.8, 129.3, 128.8, 127.5,
120.8, 111.5, 79.1, 55.4, 34.6, 25.6, 24.5; HRMS (þEI) calcd for
12H15NO2 205.1103 (Mþ), found 205.1111.
J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d
199.5, 136.6, 135.2, 129.2
d
(ꢃ2), 127.4 (ꢃ2), 96.1, 38.8, 29.6, 27.3, 8.4; HRMS (þEI) calcd for
C
12H14O35Cl 209.0733 (MþꢂNO2), found 209.0731.
C
4.3.14. Methyl 4-(3-nitro-6-oxohexan-3-yl)benzoate (14n). Prepared
according to the general procedure B in 87% yield as a colorless oil;
Rf¼0.43 (25% EtOAc in hexane); IR (film): 2980, 2953, 2881, 2843,
4.4.5. 2-(4-Methoxyphenyl)-2-methyl-3,4-dihydro-2H-pyrrole 1-
oxide (15e). Prepared according to the general procedure C in 77%
yield as a brown oil; Rf¼0.35 (9% EtOH in EtOAc); IR (film): 2974,
2730, 1727, 1542, 1436, 1284, 1194, 1116 cmꢂ1
;
1H NMR (400 MHz,
2937, 2837, 1611, 1574, 1514, 1455, 1297, 1251, 1186, 1029 cmꢂ1 1H
;
CDCl3)
d
9.67 (s, 1H), 8.04 (d, J¼8.4 Hz, 2H), 7.34 (d, J¼8.4 Hz, 2H),
NMR (400 MHz, CDCl3)
J¼8.8 Hz, 2H), 3.79 (s, 3H), 2.63e2.57 (m, 2H), 2.55e2.48 (m, 1H),
2.39e2.31 (m, 1H), 1.83 (s, 3H); 13C NMR (100 MHz, CDCl3)
159.1,
133.8, 133.6, 126.7 (ꢃ2), 114.1 (ꢃ2), 79.0, 55.4, 37.0, 25.2,
25.0; HRMS (þEI) calcd for C12H15NO2 205.1103 (Mþ), found
205.1107.
d
7.30 (d, J¼8.8 Hz, 2H), 7.04 (s, 1H), 6.88 (d,
3.90 (s, 3H), 2.68 (t, J¼7.2 Hz, 2H), 2.51e2.26 (m, 4H), 0.85 (t,
J¼7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d
199.4, 166.2, 142.8, 130.8,
d
130.2 (ꢃ2), 126.0 (ꢃ2), 96.5, 52.4, 38.8, 29.8, 27.5, 8.3; HRMS (þEI)
calcd for C14H17O3 233.1178 (MþꢂNO2), found 233.1176.
4.4. General procedure C for the synthesis of nitrones 15
4.4.6. 2-(4-Chlorophenyl)-2-methyl-3,4-dihydro-2H-pyrrole 1-oxide
(15f). Prepared according to the general procedure C in 73% yield
as a brown oil; Rf¼0.37 (9% EtOH in EtOAc); IR (film): 2980, 2935,
1713, 1581, 1494, 1455, 1401, 1269, 1238, 1199, 1096, 1013 cmꢂ1; 1H
To a solution of the nitro aldehydes 14 (1.0 mmol) and zinc
powder (3.0 mmol) in EtOH (10 mL) cooled in an ice-water bath
(0 ꢀC) was added AcOH (6.0 mmol) slowly. The resultant mixture
was stirred at 0 ꢀC for 0.5 h followed by warming up to room
temperature and stirring at the same temperature for 72 h. The
reaction mixture was filtered off through a plug of Celite with
washing by EtOAc. The combined filtrate was condensed under
reduced pressure and the residue was purified by flash column
chromatography over silica gel to give the nitrone 15. The results
are found in Table 3.
NMR (400 MHz, CDCl3)
d 7.31 (s, 4H), 7.09 (s,1H), 2.64e2.52 (m,1H),
2.50e2.44 (m, 1H), 2.40e2.32 (m, 1H), 1.81 (s, 3H); 13C NMR
(100 MHz, CDCl3)
d
140.2, 134.9, 133.9, 129.0 (ꢃ2), 127.1 (ꢃ2), 79.2,
37.0, 25.2, 25.1; HRMS (þEI) calcd for C11H12ClNO 209.0607 (Mþ),
found 209.0609.
4.4.7. 2-[4-(Methoxycarbonyl)phenyl]-2-methyl-3,4-dihydro-2H-
pyrrole 1-oxide (15g). Prepared according to the general procedure
C in 79% yield as a brown oil; Rf¼0.31 (9% EtOH in EtOAc); IR (film):
2983, 2952, 2850, 1722, 1580, 1436, 1283, 1240, 1194, 1113,
4.4.1. 2-[2-(1,3-Dioxolan-2-yl)phenyl]-2-methyl-3,4-dihydro-2H-
pyrrole 1-oxide (15a). Prepared according to the general procedure
C in 70% yield as a brown oil; Rf¼0.24 (9% EtOH in EtOAc); IR (film):
2929, 2890, 1715, 1584, 1540, 1233, 1210, 1127, 1085, 1060 cmꢂ1; 1H
1019 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d
8.00 (d, J¼8.4 Hz, 2H), 7.43
(d, J¼8.0 Hz, 2H), 7.09 (s, 1H), 3.88 (s, 3H), 2.66e2.54 (m, 2H),
NMR (500 MHz, CDCl3)
d
7.70 (dd, J¼6.5, 2.5 Hz, 1H), 7.41 (dd, J¼7.0,
2.53e2.45 (m, 1H), 2.44e2.34 (m, 1H), 1.85 (s, 3H); 13C NMR
2.0 Hz, 1H), 7.35e7.29 (m, 2H), 7.18 (s, 1H), 6.07 (s, 1H), 4.22e4.18
(m, 2H), 4.05e4.01 (m, 2H), 2.83e2.78 (m, 1H), 2.59e2.53 (m, 1H),
2.51e2.43 (m, 1H), 2.43e2.37 (m, 1H), 1.95 (s, 3H); 13C NMR
(125 MHz, CDCl3)
d
166.7, 146.6, 134.5, 130.0 (ꢃ2), 129.6, 125.5 (ꢃ2),
79.5, 52.2, 37.0, 25.1, 24.9; HRMS (þEI) calcd for C13H15NO3
233.1052 (Mþ), found 233.1055.
(125 MHz, CDCl3)
100.5, 80.6, 65.65, 65.60, 37.8, 27.4, 25.1; HRMS (þEI) calcd for
14H17NO3 247.1208 (Mþ), found 247.1217.
d 149.9, 135.7, 134.4, 129.6, 128.5, 128.1, 126.1,
4.4.8. 2-[4-(1,3-Dioxolan-2-yl)phenyl]-2-ethyl-3,4-dihydro-2H-pyr-
role 1-oxide (15h). Prepared according to the general procedure C
in 78% yield as a brown oil; Rf¼0.29 (9% EtOH in EtOAc); IR (film):
2979, 2888, 1582, 1423, 1392, 1311, 1225, 1085, 1020 cmꢂ1; 1H NMR
C
4.4.2. 2-Methyl-2-(3-tolyl)-3,4-dihydro-2H-pyrrole 1-oxide
(15b). Prepared according to the general procedure C in 83% yield
as a brown oil; Rf¼0.43 (9% EtOH in EtOAc); IR (film): 2982, 2932,
400 MHz, CDCl3)
d 7.42 (s, 4H), 7.12 (s, 1H), 5.76 (s, 1H), 4.06e4.02
(m, 2H), 4.02e3.97 (m, 2H), 2.58e2.32 (m, 4H), 2.27e2.20 (m, 1H),
2857, 1682, 1580, 1489, 1454, 1240, 1210, 1191 cmꢂ1 1H NMR
;
2.13e2.07 (m, 1H), 0.95 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
(400 MHz, CDCl3)
J¼7.6 Hz, 1H), 2.63e2.58 (m, 2H), 2.55e2.49 (m, 1H), 2.41e2.32 (m,
1H), 2.35 (s, 3H), 1.85 (s, 3H); 13C NMR (100 MHz, CDCl3)
141.4,
d
7.25 (t, J¼7.6 Hz, 1H), 7.19e7.15 (m, 3H), 7.10 (d,
d
142.4, 137.4, 136.1, 126.7 (ꢃ2), 125.6 (ꢃ2), 103.2, 82.4, 65.3,
31.9, 30.0, 25.2, 8.2; MS (þEI) m/z 205 (Mþ, 14), 190 (MþꢂMe,
100); HRMS (þEI) calcd for C15H19NO3 261.1365 (Mþ), found
261.1362.
d
138.4, 134.9, 128.6, 128.5, 125.9, 122.4, 79.5, 37.2, 25.1, 25.0, 21.7;
HRMS (þEI) calcd for C12H15NO 189.1154 (Mþ), found 189.1158.
4.4.9. 2-Ethyl-2-(2-tolyl)-3,4-dihydro-2H-pyrrole 1-oxide
(15i). Prepared according to the general procedure C in 71% yield
as a brown oil; Rf¼0.41 (9% EtOH in EtOAc); IR (film): 2966, 2935,
2879, 1583, 1489, 1463, 1225, 1194 cmꢂ1; 1H NMR (400 MHz, CDCl3)
4.4.3. 2-Methyl-2-(4-tolyl)-3,4-dihydro-2H-pyrrole 1-oxide
(15c). Prepared according to the general procedure C in 63% yield
as a brown oil; Rf¼0.38 (9% EtOH in EtOAc); IR (film): 2978, 2936,
2859, 1707, 1574, 1515, 1454, 1274, 1239, 1195, 1081, 1021 cmꢂ1
;
1H
d 7.47e7.44 (m, 1H), 7.27 (s, 1H), 7.18e7.12 (m, 3H), 2.66e2.54 (m,
NMR (400 MHz, CDCl3)
2H), 7.06 (s, 1H), 2.61e2.56 (m, 2H), 2.53e2.47 (m, 1H), 2.39e2.30
(m, 1H), 2.31 (s, 3H), 1.83 (s, 3H); 13C NMR (100 MHz, CDCl3)
138.5,
d
7.25 (d, J¼7.6 Hz, 2H), 7.15 (d, J¼8.0 Hz,
2H), 2.52e2.41 (m, 3H), 2.40 (s, 3H), 2.22e2.13 (m, 1H), 1.02 (t,
J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 139.8, 137.3, 134.7, 132.7,
d
127.7, 126.6, 126.2, 84.0, 31.2, 29.3, 25.9, 21.4, 8.5; HRMS (þEI) calcd
137.5, 134.2, 129.4 (ꢃ2), 125.3 (ꢃ2), 79.2, 37.1, 25.1, 25.0, 21.0; HRMS
for C13H17NO 203.1310 (Mþ), found 203.1309.
(þEI) calcd for C12H15NO 189.1154 (Mþ), found 189.1158.
4.4.10. 2-Ethyl-2-(3-tolyl)-3,4-dihydro-2H-pyrrole 1-oxide
(15j). Prepared according to the general procedure C in 86% yield
as a brown oil; Rf¼0.46 (9% EtOH in EtOAc); IR (film): 2970, 2932,
2880, 1698, 1607, 1574, 1488, 1463, 1269, 1238, 1205, 1183 cmꢂ1; 1H
4.4.4. 2-(2-Methoxyphenyl)-2-methyl-3,4-dihydro-2H-pyrrole 1-
oxide (15d). Prepared according to the general procedure C in
80% yield as a brown oil; Rf¼0.38 (9% EtOH in EtOAc); IR (film):
2977, 2938, 2838, 1698, 1593, 1582, 1493, 1463, 1436, 1244, 1193,
NMR (400 MHz, CDCl3)
7.06 (t, J¼2.8 Hz,1H), 2.62e2.56 (m, 2H), 2.45 (dd, J¼7.6, 6.4 Hz, 2H),
2.35 (s, 3H), 2.34e2.26 (m, 1H), 2.19e2.09 (m, 1H), 1.01 (t, J¼7.2 Hz,
d
7.27e7.20 (m, 3H), 7.09 (d, J¼6.8 Hz, 1H),
1070, 1024 cmꢂ1; 1H NMR (400 MHz, CDCl3)
7.23 (d, J¼6.0 Hz, 1H), 7.10 (s, 1H), 6.92e6.85 (m, 2H), 3.81 (s, 3H),
d
7.32 (d, J¼6.8 Hz, 1H),

6390
J. Xu et al. / Tetrahedron 70 (2014) 6384e6391
3H); 13C NMR (100 MHz, CDCl3)
d
141.5, 138.2, 135.5, 128.5, 128.4,
J¼8.0 Hz, 1H), 7.02 (d, J¼7.6 Hz, 1H), 3.78 (s, 3H), 3.67e3.61 (m, 1H),
2.62 (dd, J¼12.8, 2.0 Hz, 1H), 2.48 (dd, J¼12.8, 7.6 Hz, 1H), 2.34 (s,
3H), 2.31e2.27 (m, 1H), 2.19 (dt, J¼12.8, 10.0 Hz, 1H), 1.83e1.73 (m,
1H), 1.61 (s, 3H), 1.57 (s, 3H), 1.56e1.45 (m, 1H); 13C NMR (100 MHz,
126.1, 122.6, 82.5, 32.1, 29.9, 25.3, 21.7, 8.2; HRMS (þEI) calcd for
C
13H17NO 203.1310 (Mþ), found 203.1316.
4.4.11. 2-Ethyl-2-(4-tolyl)-3,4-dihydro-2H-pyrrole 1-oxide
(15k). Prepared according to the general procedure C in 73% yield
as a brown oil; Rf¼0.43 (9% EtOH in EtOAc); IR (film): 2970, 2925,
2879, 2850, 1682, 1656, 1580, 1515, 1463, 1227, 1192 cmꢂ1; 1H NMR
CDCl3)
52.2, 47.0, 34.5, 31.0, 26.9, 25.3, 21.5; HRMS (þEI) calcd for
17H23NO3 289.1678 (Mþ), found 289.1668.
d 173.9, 145.8,137.5,127.9, 127.2, 126.4,122.6, 82.2, 74.5, 63.9,
C
(400 MHz, CDCl3)
d
7.33 (d, J¼8.4 Hz, 2H), 7.16 (d, J¼8.4 Hz, 2H), 7.10
4.5.2. (2R*,3aR*,6R*)-Methyl
2,6-dimethyl-6-(4-tolyl)hexahy-
(s, 1H), 2.61e2.54 (m, 2H), 2.47e2.41 (m, 2H), 2.36e2.23 (m, 1H),
dropyrrolo[1,2-b]isoxazole-2-carboxylate (18b). Prepared from 15c
according to the general procedure D in 78% combined yield as
a 95:5 inseparable mixture of 18b and epi-18b. A colorless oil;
Rf¼0.35 (9% EtOAc in PE); IR (film): 2985, 2952, 2872, 1755, 1738,
2.32 (s, 3H), 2.20e2.10 (m, 1H), 0.99 (t, J¼7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3)
d
138.6, 137.6, 135.1, 129.4 (ꢃ2), 125.7 (ꢃ2), 82.4,
32.1, 30.2, 25.4, 21.1, 8.4; HRMS (þEI) calcd for C13H17NO 203.1310
(Mþ), found 203.1308.
1511, 1455, 1369, 1302, 1212, 1164, 1123 cmꢂ1 1H NMR (400 MHz,
;
CDCl3)
d
7.41 (d, J¼8.4 Hz, 2H), 7.11 (d, J¼8.0 Hz, 2H), 3.78 (s, 3H),
4.4.12. 2-Ethyl-2-(2-methoxyphenyl)-3,4-dihydro-2H-pyrrole 1-
oxide (15l). Prepared according to the general procedure C (at
room temperature for 24 h) in 83% yield as a brown oil; Rf¼0.41 (9%
EtOH in EtOAc); IR (film): 2964, 2935, 2875, 2838, 1698, 1581, 1492,
3.65e3.56 (m, 1H), 2.61 (dd, J¼12.4, 2.4 Hz, 1H), 2.47 (dd, J¼12.8,
8.0 Hz, 1H), 2.32 (s, 3H), 2.32e2.27 (m, 1H), 2.19 (dt, J¼12.8,
10.0 Hz, 1H), 1.84e1.73 (m, 1H), 1.61 (s, 3H), 1.57 (s, 3H), 1.57e1.50
(m, 1H); 13C NMR (100 MHz, CDCl3)
d 173.9, 142.7, 136.2, 128.8
1463, 1436, 1243, 1190, 1025 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d
7.44
(ꢃ2), 125.7 (ꢃ2), 82.3, 74.6, 64.0, 52.3, 47.0, 34.4, 31.1, 27.0, 25.4,
20.9; HRMS (þEI) calcd for C17H23NO3 289.1678 (Mþ), found
289.1677.
(dd, J¼7.6, 1.2 Hz, 1H), 7.27e7.22 (m, 1H), 7.17 (s, 1H), 6.93e6.87 (m,
2H), 3.81 (s, 3H), 2.56e2.49 (m, 3H), 2.41e2.29 (m, 2H), 2.26e2.17
(m, 1H), 0.97 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d
156.8, 137.0, 129.8, 129.0, 127.4, 120.7, 111.5, 82.2, 55.4, 30.4, 27.9,
4.5.3. (2R*,3aR*,6R*)-Methyl 6-(2-methoxyphenyl)-2,6-
dimethylhexahydropyrrolo[1,2-b]isoxazole-2-carboxylate
(18c). Prepared from 15d according to the general procedure D in
82% combined yield as a 94:6 inseparable mixture of 18c and epi-
18c. A colorless oil; Rf¼0.24 (9% EtOAc in PE); IR (film): 2985, 2951,
2875, 1738, 1597, 1580, 1487, 1455, 1435, 1367, 1300, 1281, 1236,
26.0, 8.1; HRMS (þEI) calcd for C13H17NO2 219.1259 (Mþ), found
219.1264.
4.4.13. 2-(4-Chlorophenyl)-2-ethyl-3,4-dihydro-2H-pyrrole 1-oxide
(15m). Prepared according to the general procedure C in 77%
yield as a brown oil; Rf¼0.43 (9% EtOH in EtOAc); IR (film): 2972,
2937, 2880, 1688, 1581, 1494, 1464, 1401, 1223, 1095, 1013 cmꢂ1; 1H
1180, 1161, 1124, 1088, 1027 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d 7.69
(d, J¼8.0 Hz, 1H), 7.18 (t, J¼8.0 Hz, 1H), 6.90 (t, J¼7.6 Hz, 1H), 6.85 (d,
J¼8.4 Hz, 1H), 3.96e3.90 (m, 1H), 3.82 (s, 3H), 3.77 (s, 3H),
2.58e2.47 (m, 3H), 2.22 (dt, J¼12.8, 8.8 Hz, 1H), 1.78e1.68 (m, 1H),
1.63 (s, 3H), 1.62 (s, 3H), 1.60e1.54 (m, 1H); 13C NMR (100 MHz,
NMR (400 MHz, CDCl3)
d
7.40 (d, J¼8.4 Hz, 2H), 7.33 (d, J¼8.4 Hz,
2H), 7.06 (s, 1H), 2.61e2.57 (m, 2H), 2.51e2.40 (m, 2H), 2.32e2.22
(m, 1H), 2.17e2.07 (m, 1H), 0.99 (t, J¼7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3)
d
140.1, 135.6, 133.8, 128.8 (ꢃ2), 127.3 (ꢃ2), 82.2,
CDCl3)
55.0, 52.3, 46.9, 35.4, 30.5, 25.1, 22.4; HRMS (þEI) calcd for
17H23NO4 305.1627 (Mþ), found 305.1627.
d 173.7, 156.4, 134.2, 127.6, 127.5, 120.4, 111.2, 83.0, 72.9, 63.4,
31.9, 30.2, 25.3, 8.3; HRMS (þEI) calcd for C12H14ClNO 223.0764
(Mþ), found 223.0765.
C
4.4.14. 2-Ethyl-2-[4-(methoxycarbonyl)phenyl]-3,4-dihydro-2H-pyr-
role 1-oxide (15n). Prepared according to the general procedure C
in 74% yield as a brown oil; Rf¼0.33 (9% EtOH in EtOAc); IR (film):
2971, 2953, 2881, 2850, 1722, 1611, 1580, 1435, 1281, 1230, 1193,
4.5.4. (2R*,3aR*,6R*)-Methyl 6-(4-methoxyphenyl)-2,6-
dimethylhexahydropyrrolo[1,2-b]isoxazole-2-carboxylate
(18d). Prepared from 15e according to the general procedure D in
80% combined yield as a 94:6 inseparable mixture of 18d and epi-
18d. A colorless oil; Rf¼0.19 (9% EtOAc in PE); IR (film): 2985, 2952,
2836, 1747, 1731, 1608, 1581, 1505, 1455, 1369, 1297, 1247, 1212, 1124,
1113 cmꢂ1
;
1H NMR (400 MHz, CDCl3)
d
7.99 (d, J¼8.8 Hz, 2H),
7.50 (d, J¼9.2 Hz, 2H), 7.07 (t, J¼2.4 Hz, 1H), 3.88 (s, 3H),
2.60e2.54 (m, 2H), 2.52e2.38 (m, 2H), 2.34e2.24 (m, 1H),
2.17e2.08 (m, 1H), 0.99 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz,
1034 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d
7.44 (d, J¼8.8 Hz, 2H), 6.83
(d, J¼8.4 Hz, 2H), 3.79 (s, 3H), 3.78 (s, 3H), 3.63e3.57 (m, 1H), 2.61
(dd, J¼12.4, 2.0 Hz, 1H), 2.46 (dd, J¼12.8, 7.6 Hz, 1H), 2.34e2.25 (m,
1H), 2.18 (dt, J¼12.4,10.0 Hz,1H),1.84e1.74 (m,1H),1.60 (s, 3H),1.56
CDCl3)
d
166.7, 146.8, 135.0, 130.0 (ꢃ2), 129.6, 125.8 (ꢃ2), 82.6,
52.2, 32.0, 30.1, 25.2, 8.2; HRMS (þEI) calcd for C14H17NO3
247.1208 (Mþ), found 247.1210.
(s, 3H), 1.56e1.50 (m, 1H); 13C NMR (100 MHz, CDCl3)
d 173.9, 158.2,
137.7, 126.9 (ꢃ2), 113.4 (ꢃ2), 82.3, 74.3, 64.0, 55.1, 52.3, 46.9, 34.4,
31.1, 27.0, 25.4; HRMS (þEI) calcd for C17H23NO4 305.1627 (Mþ),
found 305.1623.
4.5. General procedure D for 1,3-dipolar cycloaddition of cy-
clic nitrones 15 with methyl methacrylate
A solution of the nitrone 15 (1.0 mmol) and methyl methacrylate
(2.0 mmol) in MeCN (10 mL) was stirred at 40 ꢀC for 24 h. The
solution was evaporated under reduced pressure and the residue
was purified by flash chromatography over silica gel to afford the
adducts 18 and epi-18. The results are found in Table 4.
4.5.5. (2R*,3aR*,6R*)-Methyl
6-ethyl-2-methyl-6-(3-tolyl)hexahy-
dropyrrolo[1,2-b]isoxazole-2-carboxylate (18e). Prepared from 15j
according to the general procedure D in 87% combined yield as
a 95:5 inseparable mixture of 18e and epi-18e. A colorless oil;
Rf¼0.38 (9% EtOAc in PE); IR (film): 2973, 2876, 1751, 1738, 1605,
1487, 1455, 1367, 1300, 1211, 1160, 1124 cmꢂ1 1H NMR (400 MHz,
;
4.5.1. (2R*,3aR*,6R*)-Methyl
2,6-dimethyl-6-(3-tolyl)hexahy-
CDCl3)
d
7.30 (s, 1H), 7.26 (d, J¼7.2 Hz, 1H), 7.17 (t, J¼8.0 Hz, 1H),
dropyrrolo[1,2-b]isoxazole-2-carboxylate (18a). Prepared from 15b
according to the general procedure D in 80% combined yield as
a 95:5 inseparable mixture of 18a and epi-18a. A colorless oil;
Rf¼0.35 (9% EtOAc in PE); IR (film): 2985, 2952, 2873, 1755, 1732,
7.02 (d, J¼7.2 Hz, 1H), 3.78 (s, 3H), 3.60e3.54 (m, 1H), 2.61 (d,
J¼12.8 Hz, 1H), 2.47 (dd, J¼12.8, 8.0 Hz, 1H), 2.34 (s, 3H),
2.32e2.28 (m, 1H), 2.16e2.06 (m, 2H), 1.97e1.88 (m, 1H),
1.79e1.69 (m, 1H), 1.61 (s, 3H), 1.44e1.52 (m, 1H), 0.68 (t, J¼7.6 Hz,
1605, 1486, 1455, 1369, 1301, 1212, 1163, 1120 cmꢂ1
;
1H NMR
3H); 13C NMR (100 MHz, CDCl3)
d 174.1, 143.2, 137.2, 127.6, 127.3,
(400 MHz, CDCl3)
d
7.35 (s, 1H), 7.30 (d, J¼8.0 Hz, 1H), 7.18 (t,
127.2, 123.7, 81.6, 78.8, 63.6, 52.2, 46.9, 33.3, 32.3, 30.9, 25.3, 21.6,

J. Xu et al. / Tetrahedron 70 (2014) 6384e6391
6391
9.3; HRMS (þEI) calcd for C18H25NO3 303.1834 (Mþ), found
ꢀ
ꢀ
Hadjipavlou-Litina, D.; Alcazar, A.; Ayuso, I.; Oset-Gasque, M. J.; Gonzalez, M. P.;
Monjas, L.; Rodríguez-Franco, M. I.; Marco-Contelles, J.; Samadi, A. J. Med. Chem.
2012, 55, 153e168.
303.1831.
10. For benzoxazinic nitrones, see: (a) Battistoni, P.; Bruni, P.; Fava, G. Tetrahedron
1979, 35, 1771e1775; (b) Astolfi, P.; Marini, M. G.; Stipa, P. J. Org. Chem. 2007, 72,
8677e8682; (c) Astolfi, P.; Carloni, P.; Marini, M. G.; Mobbili, G.; Pisani, M.;
Stipa, P. RSC Adv. 2013, 3, 22023e22030; (d) Stipa, P. Tetrahedron 2013, 69,
4591e4596.
Acknowledgements
The Laboratory of Asymmetric Catalysis and Synthesis is
established under the Cheung Kong Scholars Program of The Min-
istry of Education of China. This work is supported in part by the
Zhejiang Natural Science Foundation, Zhejiang, China (Grant No.
Y207295).
11. For other cyclic nitrones, see: (a) El Fangour, S.; Marini, M.; Good, J.; McQuaker,
S. J.; Shiels, P. G. Age 2009, 31, 269e276; (b) Golubev, V. A.; Sen’, V. D. Russ. J. Org.
Chem. 2010, 46, 1049e1052; (c) Golubev, V. A.; Sen’, V. D. Russ. Chem. Bull. Int.
ꢀ
ꢀ
ꢀ
Ed. 2010, 59, 2081e2085; (d) Soto-Otero, R.; Mendez-Alvarez, E.; Sanchez-Ig-
lesias, S.; Labandeira-García, J. L.; Rodríguez-Pallares, J.; Zubkov, F. I.; Zaytsev, V.
P.; Voskressensky, L. G.; Varlamov, A. V.; de Candia, M.; Fiorella, F.; Altomare, C.
Arch. Pharm. Chem. Life Sci. 2012, 345, 598e609; (e) Kim, S.-U.; Villamena, F. A. J.
Phys. Chem. A 2012, 116, 886e898.
Supplementary data
12. For conjugates of nitrones, see: (a) Hardy, M.; Ouari, O.; Charles, L.; Finet, J.-P.;
Iacazio, G.; Monnier, V.; Rockenbauer, A.; Tordo, P. J. Org. Chem. 2005, 70,
10426e10433; (b) Han, Y.; Tuccio, B.; Lauricella, R.; Villamena, F. A. J. Org. Chem.
2008, 73, 7108e7117; (c) Han, Y.; Liu, Y.; Rockenbauer, A.; Zweier, J. L.; Durand,
G.; Villamena, F. A. J. Org. Chem. 2009, 74, 5369e5380; (d) Durand, G.; Prosak,
R. A.; Han, Y.; Ortial, S.; Rockenbauer, A.; Pucci, B.; Villamena, F. A. Chem. Res.
Toxicol. 2009, 22, 1570e1581; (e) Choteau, F.; Durand, G.; Ranchon-Cole, I.;
Cercy, C.; Pucci, B. Bioorg. Med. Chem. Lett. 2010, 20, 7405e7409; (f) Ortial, S.;
Morandat, S.; Bortolato, M.; Roux, B.; Polidori, A.; Pucci, B.; Durand, G. Colloids
Surf., B 2014, 113, 384e393.
1H and 13C NMR spectra for compounds 13e15 and 18 are
available. Supplementary data related to this article can be found at
http://dx.doi.org/10.1016/j.tet.2014.07.046.
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