High diastereoselectivity induced by intermolecular hydrogen bonding in [3?+?2] cycloaddition reaction: experimental and computational mechanistic approaches

Article abstract of DOI:10.1002/poc.3629

A diastereoselective [3?+?2] cycloaddition of N-aryl substituted maleimides with N,α-diphenyl nitrone possessing 11-hydroxyundecyloxy as a flexible substituent was performed. Experimental and comprehensive mechanistic density functional theory studies reveals that intermolecular H-bonding and steric repulsive interaction predominate exo-Z and exo-E cycloaddition transition states, respectively. The reaction proceeded smoothly depending on the reactants and gave a good yield of (syn) cis-isoxazolidine or (anti) trans-isoxazolidine as a single diastereomer.

Full text of DOI:10.1002/poc.3629

Received: 19 April 2016
DOI 10.1002/poc.3629
Revised: 12 July 2016
Accepted: 26 July 2016
R E S E A R C H A R T I C L E
High diastereoselectivity induced by intermolecular hydrogen
bonding in [3 + 2] cycloaddition reaction: experimental and
computational mechanistic approaches
1* 2
Ayhan Yıldırım | Yunus Kaya
1
Department of Chemistry, Uludağ University,
Abstract
1
6059 Bursa, Turkey
2
A diastereoselective [3 + 2] cycloaddition of N‐aryl substituted maleimides with
N,α‐diphenyl nitrone possessing 11‐hydroxyundecyloxy as a flexible substituent
was performed. Experimental and comprehensive mechanistic density functional
theory studies reveals that intermolecular H‐bonding and steric repulsive interaction
predominate exo‐Z and exo‐E cycloaddition transition states, respectively. The reac-
tion proceeded smoothly depending on the reactants and gave a good yield of (syn)
cis‐isoxazolidine or (anti) trans‐isoxazolidine as a single diastereomer.
Department of Chemistry, Faculty of Natural
Sciences, Architecture and Engineering, Bursa
Technical University, Bursa, Turkey
Correspondence
Ayhan Yıldırım, Department of Chemistry, Uludağ
University, 16059 Bursa, Turkey.
Email: yildirim@uludag.edu.tr
KEYWORDS
DFT, diastereoselective synthesis, H‐bonding, maleimide, nitrone, transition states
[
19]
1
|
INTRODUCTION
furnishing some tetrahydroquinolinoisoxazoles.
On the
other hand, intramolecular reaction of nitrones derived from
optically active aldehyde allows diastereoselective synthesis
Cycloaddition reactions between acyclic/cyclic nitrones
azomethine‐N‐oxides) and N‐aryl substituted maleimides have
[
20]
(
of some fused isoxazolidines.
Banerji et al isolated diaste-
[1–14]
been studied extensively in the last 2 decades.
As is well
reomeric isoxazolidines from the intermolecular reaction
between methyl cinnamate and nitrone with stereocontrol pro-
known aldonitrones may have 2 configurations that may inter-
convert. One of them is the syn or E configuration and the other
is the anti or Z configuration. In some studies UV and nuclear
magnetic resonance (NMR) spectroscopic analysis pointed
[
21]
vided by different reaction conditions.
In addition, some
studies presented that triflates can be used as a catalyst to pro-
[
22–24]
vide diastereoselectivity in [3 + 2] cycloadditions.
[15]
[25]
[26]
out that the Z configuration is more preferred.
Merino et al
and Mekelleche and Benchouk
have
A typical reaction between nitrone and N‐substituted
maleimide results in formation of fused 5 membered
isoxazolidine cycloadduct. Generally, depending on the
structure of the starting compounds, 2 diastereoisomers can
reported studies that include computational investigation of
diastereoselectivity in intermolecular reactions between
nitrones‐1,2‐diaza‐1,3‐dienes and nitrone‐methacrolein,
respectively.
[3,7,10–12]
occur, each with 2 enantiomers.
There are some studies on H‐bonding–induced
[
27–30]
Cycloaddition reactions between diarylnitrones and elec-
diastereoselectivity in different reactions.
Kilic et al
tron‐deficient dipolarophiles may proceed via concerted or
reported that diastereoselectivity can be obtained through
[16,17]
[27]
(
alternatively) stepwise zwitterionic mechanism.
In the literature, there are various examples of
diastereoselective intramolecular and intermolecular [3 + 2]
H‐bonding in some aziridination reactions.
On the other
[
28]
[29]
hand, according to Jones et al
and Aviyente et al
diastereoselective [4 + 2] cycloadditions can also be
performed guided by H‐bonding. One study reported that
internally H‐bonded chiral methylene nitrones undergo
[18–24]
cycloaddition reactions.
O'Neil et al reported a highly
diastereoselective intramolecular cycloaddition of cyclic
[
30]
nitrone obtained via Cope elimination to give tricyclic
diastereoselective [3 + 2] cycloaddition.
In addition sev-
[
18]
isoxazolidines.
Bakthadoss and Devaraj also reported
eral examples exist in the literature for H‐bonding–induced
regioselective and diastereoselective [3 + 2] cycloadditions
diastereoselective intramolecular nitrone cycloaddition
J. Phys. Org. Chem. 2016; 1–12
wileyonlinelibrary.com/journal/poc
Copyright © 2016 John Wiley & Sons, Ltd.
1

2
YILDIRIM AND KAYA
of nitrile oxides with some dipolarophiles to afford fused or
spirocyclic isoxazolines.
(383.53): C 75.16, H 8.67, N 3.65. Found: C 75.18, H 8.65,
N 3.68.
[31–33]
In the present study N,α‐diphenyl nitrones were reacted
with N‐aryl maleimides in benzene to afford isoxazolidines.
Recrystallization from suitable solvents furnished pure cis‐
or trans‐stereoisomer in fairly good yields. However, cis/
trans diastereomer mixture with ratio (55/45) was obtained
in the case of both long‐chained reagents. Intermolecular
H‐bonding plays a crucial role in the case of cis‐
diastereoselectivity. Density functional theory (DFT) calcu-
lations reveal that [3 + 2] cycloadditions proceeds via one
step, but strongly asynchronous mechanism.
2.1.2
| 4‐(2,5‐Dioxo‐2,5‐dihydro‐1H‐pyrrol‐1‐yl)‐N‐
dodecylbenzamide (5d)
In a 50‐mL 2‐necked flask fitted with a reflux condenser
(protected by a CaCl guard tube), dodecylamine (0.98 g,
5.29 mmol/L) and NEt3 (0.74 mL, 5.31 mmol/L) were
dissolved in (15 mL) CHCl and cooled to 0°C. Acyl chloride
4 (1.25 g, 5.31 mmol/L) in (15 mL) CHCl3 was added
dropwise over 30 minutes. The resulting mixture was stirred
at room temperature for 4 hours. Thereafter, the reaction mix-
ture was washed successively with 2 × 15 mL of 0.1M HCl
2
3
and H O (25 mL). The organic phase was dried over anhy-
2
drous Na SO , and the solvent was removed on a rotary evap-
orator. The residue was crystallized from hexane/EtOAc to
afford white solid product. Yield 1.01 g, 49%. Mp: 169‐
2
4
2
2
|
EXPERIMENTAL
.1 | Materials
1
71°C; IR (ATR): νmax 3328, 3103, 3074, 2921, 2848,
All reagents and solvents were purchased from either Merck
or Sigma‐Aldrich (St. Louis, MO) and used without further
purification. Thin‐layer chromatography was performed
using silica gel (60 F254, Merck, Darmstadt, Germany) plates.
Melting points were recorded by BÜCHI melting point B‐
1776, 1702, 1629, 1609, 1580, 1535, 1505, 1464, 1396,
1324, 1303, 1256, 1210, 1156, 1108, 1058, 1037, 1020,
−
1
1
950, 870, 851, 834, 771, 711, 687, 631, 619 cm ; H
NMR (600 MHz, DMSO‐d ) δ 8.50 (t, J = 5.4 Hz, 1H,
6
−NH), 7.90 (d, J = 8.4 Hz, 2H, Ar), 7.41 (d, J = 8.4 Hz,
2H, Ar), 7.16 (s, 2H, −CH=CH–), 3.23 (q, J = 6.6 Hz, 2H,
540 apparatus (BUCHI Labortechnik AG in Flawil, Switzer-
land). The NMR spectra were measured using A600a Agilent
DD2 600 MHz NMR spectrometer (Santa Clara, California,
−CH
−CH
2
NH–), 1.49 (quin,
J
=
6.6 Hz, 2H,
–), 0.82
); C NMR (150 MHz, DMSO‐
) δ 170.10, 165.92, 135.21, 134.25, 134.13, 128.14,
126.55, 45.05, 31.72, 29.45, 29.43, 29.42, 29.19, 29.13,
26.89, 22.52, 14.37, 8.96; Anal calc for C23
CH CH NH–), 1.26‐1.15 (m, 18H, 9×–CH
2
2
2
2
1
3
USA) dimethyl sulfoxide (DMSO)‐d using tetramethylsilane
(t, J = 6.6 Hz, 3H, −CH
3
6
(TMS) as an internal standard. Chemical shifts (δ) are
d
6
reported in ppm and J values in Hertz. The starting com-
[
34]
[35]
[36] [37]
[38]
pounds 1,
2a,
3b,
4,
and 5a‐c
were prepared
H
32
N
O
2
3
according to reported procedures.
(384.52): C 71.84, H 8.39, N 7.29. Found: C 71.83, H 8.41,
N 7.27.
2
.1.1
|
(Z)‐1‐(4‐((11‐Hydroxyundecyl)oxy)phenyl)‐N‐
2.1.3 | Typical experimental procedure for the synthesis of
phenylmethanimine oxide (3a)
isoxazolidines (6a‐d, 7)
In a 100‐mL flask aldehyde 2a (4.31 g, 1.47 mmol/L) and β‐
phenylhydroxylamine (1.61 g, 1.48 mmol/L) were dissolved
in EtOH (15 mL). The flask was sealed and allowed to stand
for 48 hours in the dark. Thereafter, the obtained bright yel-
low crystals were filtered under vacuum to afford 3a. Yield
In a 100‐mL flask nitrone 3a (0.49 g, 1.28 mmol/L) and
maleimide 5b (0.24 g, 1.28 mmol/L) were dissolved in
(15 mL) of benzene. The flask was heated at 70°C for
3.5 hours, at which point thin layer chromatography (TLC)
(7:3, Hexane:EtOAc) indicated complete consumption of
the nitrone. Thereafter, the solvent was removed with rotary
evaporator and the residue was crystallized from MeOH/
EtOAc.
3
2
1
8
.91 g, 69%. Mp: 111‐112°C; IR (ATR): νmax 3369, 3060,
917, 2850, 1603, 1554, 1507, 1472, 1459, 1420, 1397,
307, 1256, 1184, 1112, 1064, 1022, 942, 914, 893, 843,
−
1
1
07, 757, 719, 684, 634 cm ; H NMR (600 MHz,
DMSO‐d ) δ 8.40 (d, J = 9.0 Hz, 2H, Ar), 8.20 (s, 1H,
2.1.4 | cis‐3‐(4‐((11‐Hydroxyundecyl)oxy)phenyl)‐2,5‐
diphenyltetrahydro‐4H‐pyrrolo[3,4‐d]isoxazole‐4,6(5H)‐dione (6a)
6
=
CH–), 7.81 (d, J = 7.8 Hz, 2H, Ar), 7.45‐7.39 (m, 3H,
Ar), 6.93 (d, J = 9.0 Hz, 2H, Ar), 4.16 (t, J = 4.8 Hz, 1H,
OH), 3.98 (t, J = 6.6 Hz, 2H, PhOCH CH –), 3.38 (q,
Yield 75%, white crystalline solid, mp: 173.5‐174.5°C; IR
(ATR): νmax 3549, 3066, 2919, 2850, 1799, 1713, 1611,
1598, 1511, 1489, 1455, 1392, 1312, 1292, 1246, 1181,
1099, 1051, 1028, 960, 930, 889, 851, 823, 758, 739, 722,
−
2
2
J = 6.6 Hz, 2H, −CH CH OH), 1.72 (quin, J = 6.6 Hz,
2
2
2
H, PhOCH CH CH –), 1.40 (quin, J = 6.6 Hz, 2 × 2H,
2
2
2
−
1
1
−
CH CH CH OH and PhOCH CH CH –), 1.31‐1.23 (m,
692, 630, 588 cm ; H NMR (600 MHz, DMSO‐d ) δ
2
2
2
2
2
2
6
1
3
1
1
1
2
2H, quin, 6×–CH –); C NMR (150 MHz, DMSO‐d ) δ
7.45 (t, J = 7.8 Hz, 2H, Ar), 7.39 (t, J = 7.8 Hz, 1H, Ar),
7.31 (d, J = 9.0 Hz, 2H, Ar), 7.24 (t, J = 7.8 Hz, 2H, Ar),
7.09‐7.04 (m, 5H, Ar), 6.88 (d, J = 8.4 Hz, 2H, Ar), 5.39
2
6
60.85, 148.78, 133.65, 131.31, 129.61, 129.13, 124.02,
21.57, 114.44, 68.05, 61.49, 32.97, 29.57, 29.47, 29.46,
9.45, 29.28, 29.09, 25.95, 25.94; Anal calc for C H NO
3
3
6a
(d, J = 7.8 Hz, 1H, H ), 4.94 (d, J = 7.8 Hz, 1H, H ),
2
4
33

YILDIRIM AND KAYA
3
3
a
4
3
2
.31 (t, J = 5.4 Hz, 1H, −OH), 4.12 (t, J = 7.8 Hz, 1H, H ),
25.94; Anal calc for C H N O (600.71): C 69.98, H
6.71, N 4.66. Found: C 69.99, H 6.69, N 4.68.
3
5 40 2 7
.90 (t, J = 6.6 Hz, 2H, PhOCH CH –), 3.36 (q, J = 6.6 Hz,
H, −CH CH OH), 1.66 (quin, J = 6.6 Hz, 2H,
2
2
2
2
PhOCH CH CH –), 1.40‐1.35 (m, 4H, 2×–CH –), 1.29‐
2.1.7 | N‐Dodecyl‐4‐(3‐(4‐((11‐hydroxyundecyl)oxy)phenyl)‐
4,6‐dioxo‐2‐phenylhexahydro‐5H‐pyrrolo[3,4‐d]isoxazol‐5‐yl)
benzamide (6d)
2
2
2
2
1
3
1
.24 (m, 12H, 6×–CH –); C NMR (150 MHz, DMSO‐d6)
2
δ 174.71, 172.45, 158.92, 148.01, 132.23, 129.40, 129.27,
1
7
2
29.13, 128.92, 127.32, 126.99, 125.00, 119.61, 114,85,
7.72, 70.61, 67.81, 61.19, 54.89, 33.01, 29.55, 29.47,
9.44, 29.42, 29.26, 29.16, 26.00, 25.97; Anal calc for
Yield 80%, beige solid, mp: 129‐130°C; IR (ATR): νmax
3348, 3275, 3069, 2921, 2852, 1785, 1716, 1634, 1611,
1583, 1549, 1508, 1490, 1467, 1390, 1305, 1293, 1246,
1179, 1111, 1085, 1033, 1019, 959, 923, 895, 827, 804,
C H N O (556.70): C 73.36, H 7.24, N 5.03. Found: C
7
3
4 40 2 5
−
1
1
3.35, H 7.26, N 5.01.
759, 721, 692, 623 ,591 cm ; H NMR (600 MHz,
DMSO‐d ) δ 8.49–8.45 (m, 1H, −NH), 7.89 (d, J = 8.4 Hz,
6
1
1
H, Ar), 7.81 (d, J = 8.4 Hz, 1H, Ar), 7.43 (d, J = 8.4 Hz,
H, Ar), 7.31 (d, J = 8.4 Hz, 1H, Ar), 7.25‐7.20 (m, 2H,
2
.1.5
| cis‐3‐(4‐((11‐Hydroxyundecyl)oxy)phenyl)‐2‐phenyl‐5‐
(p‐tolyl)tetrahydro‐4H‐pyrrolo[3,4‐d]isoxazole‐4,6(5H)‐dione (6b)
Ar), 7.17‐7.15 (m, 2H, Ar), 7.05 (t, J = 8.4 Hz, 2H, Ar),
6
6
Yield 89%, white solid, mp: 164.5‐165°C; IR (ATR): νmax
.91 (t, J = 8.4 Hz, 1H, Ar), 6.88 (d, J = 8.4 Hz, 1H, Ar),
3
1
1
6
547, 3065, 3034, 2921, 2851, 1797, 1717, 1610, 1599,
583, 1512, 1490, 1467, 1396, 1313, 1290, 1247, 1184,
111, 1095, 1047, 1022, 996, 967, 890, 853, 814, 756, 738,
3
.75 (d, J = 8.4 Hz, 1H, Ar), 5.75 (s, 1H, trans‐H ), 5.41
3
6a
(
t, J = 7.2 Hz, 1H, cis‐H ), 4.94 (d, J = 8.4 Hz, 1H, H ),
3a
4
3
−
.31–4.29 (m, 1H, −OH), 4.14 (t, J = 8.4 Hz, 1H, H ),
−
1 1
90, 652, 611, 572 cm ; H NMR (600 MHz, DMSO‐d )
6
.94‐3.89 (m, 2H, PhOCH CH –), 3.38‐3.34 (m, 2H,
2
2
δ 7.30 (d, J = 9.0 Hz, 2H, Ar), 7.24 (t, J = 7.8 Hz, 4H,
Ar), 7.05 (t, J = 8.4 Hz, 3H, Ar), 6.95 (d, J = 7.8 Hz, 2H,
Ar), 6.88 (d, J = 8.4 Hz, 2H, Ar), 5.38 (d, J = 7.8 Hz, 1H,
H ), 4.94 (d, J = 8.4 Hz, 1H, H ), 4.31 (t, J = 5.4 Hz, 1H,
−
CH CH OH), 3.25‐3.20 (m, 2H, −CH NH–), 1.70‐1.64
2
2
2
(
m, 2H, PhOCH CH CH –), 1.52‐1.45 (m, 2H,
2
2
2
−
CH CH CH NH–), 1.40‐1.35 (m, 4H, 2×–CH –), 1.30‐
3
6a
2
2
2
2
13
1
.23 (m, 24H, 12×–CH –); 0.84‐0.82 (m, 3H, −CH );
C
3
a
2
3
OH), 4.10 (t, J = 8.4 Hz, 1H, H ), 3.90 (t, J = 6.6 Hz,
H, PhOCH CH –), 3.36 (q, J = 6.6 Hz, 2H, −CH CH OH),
.30 (s, 3H, −CH ), 1.67 (quin, J = 6.6 Hz, 2H,
NMR (150 MHz, DMSO‐d ) δ 174.82, 174.52, 173.60,
6
2
2
2
2
2
2
1
1
1
1
7
4
2
2
72.25, 165.74, 165.64, 158.95, 158.69, 149.23, 147.99,
35.29, 135.15, 134.28, 134.02, 131.32, 129.40, 129.24,
29.12, 128.85, 128.25, 128.08, 127.29, 126.60, 126.53,
24.97, 122.61, 119.56, 114.87, 114.86, 114.77, 78.12,
7.77, 70.60, 68.67, 67.88, 67.82, 61.18, 57.04, 54.96,
6.05, 33.02, 31.76, 29.57, 29.56, 29.52, 29.48, 29.46,
9.44, 29.30, 29.26, 29.18, 29.14, 26.93, 26.01, 25.98,
2.56, 14.38; Anal calc for C H N O (768.05): C 73.50,
3
PhOCH CH CH –), 1.40–1.35 (m, 4H, 2×–CH –), 1.29–
1
δ 174.71, 172.47, 158.91, 148.08, 138.45, 132.23, 129.83,
1
1
2
2
2
2
2
1
3
.24 (m, 12H, 6×–CH –); C NMR (150 MHz, DMSO‐d6)
2
29.63, 129.27, 129.13, 127.37, 126.73, 124.92, 119.48,
14,82, 77.71, 70.59, 67.81, 61.19, 54.85, 33.02, 29.57,
9.49, 29.45, 29.43, 29.28, 29.16, 26.01, 25.97, 21.14; Anal
47 65 3 6
calc for C H N O (570.73): C 73.66, H 7.42, N 4.91.
Found: C 73.65, H 7.40, N 4.93.
35 42 2 5
H 8.53, N 5.47. Found: C 73.49, H 8.55, N 5.49.
2
.1.8 | trans‐4‐(4,6‐Dioxo‐2,3‐diphenylhexahydro‐5H‐pyrrolo
2
.1.6
|
cis‐3‐(4‐((11‐Hydroxyundecyl)oxy)phenyl)‐4,6‐dioxo‐2‐
[3,4‐d]isoxazol‐5‐yl)‐N‐dodecylbenzamide (7)
phenylhexahydro‐5H‐pyrrolo[3,4‐d]isoxazol‐5‐yl)benzoic acid (6c)
Yield 93%, white solid, mp: 156‐157°C; IR (ATR): νmax
3259, 3064, 3035, 2924, 2853, 1782, 1714, 1638, 1616,
1544, 1506, 1489, 1467, 1451, 1386, 1306, 1259, 1190,
1112, 1078, 1059, 1017, 950, 903, 857, 835, 763, 723, 695,
Yield 78%, white solid, mp: 172°C (dec.); IR (ATR): νmax
3
1
1
7
445, 3074, 2923, 2851, 1785, 1717, 1686, 1609, 1597,
514, 1491, 1469, 1430, 1377, 1321, 1299, 1247, 1178,
129, 1108, 1049, 1017, 959, 923, 892, 857, 819, 778, 757,
−1
1
627 cm ; H NMR (600 MHz, DMSO‐d ) δ 8.45 (t,
6
−
1
1
24, 691, 663, 611, 581 cm ; H NMR (600 MHz,
J = 5.4 Hz, 1H, −NH), 7.80 (d, J = 8.4 Hz, 2H, Ar), 7.55
(d, J = 7.2 Hz, 2H, Ar), 7.40 (t, J = 7.2 Hz, 2H, Ar), 7.32
(t, J = 7.2 Hz, 1H, Ar), 7.23 (t, J = 7.2 Hz, 2H, Ar), 7.19
(d, J = 7.8 Hz, 2H, Ar), 6.93 (t, J = 7.2 Hz, 1H, Ar), 6.71
DMSO‐d ) δ 8.03 (d, J = 8.4 Hz, 2H, Ar), 7.30 (d,
6
J = 9.0 Hz, 2H, Ar), 7.25‐7.22 (m, 4H, Ar), 7.06‐7.04 (m,
3
1
1
H, Ar), 6.88 (d, J = 9.0 Hz, 2H, Ar), 5.40 (d, J = 7.8 Hz,
3
6a
3
H, H ), 4.92 (d, J = 8.4 Hz, 1H, H ), 4.14 (t, J = 8.4 Hz,
(d, J = 8.4 Hz, 2H, Ar), 5.85 (s, 1H, H ), 5.41 (d,
3a
6a
3a
H, H ), 3.90‐3.87 (m, 2H, PhOCH CH –), 3.36 (q,
J = 7.8 Hz, 1H, H ), 4.13 (d, J = 7.8 Hz, 1H, H ), 3.23–
2
2
J = 6.6 Hz, 2H, −CH CH OH), 1.65 (quin, J = 7.2 Hz,
3.20 (m, 2H, −CH NH–), 1.48 (quin, J = 6.6 Hz, 2H,
2
2
2
2
H, PhOCH CH CH –), 1.38–1.36 (m, 4H, 2×–CH –),
−CH CH CH NH–), 1.26–1.23 (m, 18H, 9×–CH –), 0.84
2
2
2
2
2
2
2
2
1
3
13
1.28–1.22 (m, 12H, 6×–CH –); C NMR (150 MHz,
(t, J = 6.6 Hz, 3H, −CH3); C NMR (150 MHz, DMSO‐
d6) δ 174.76, 173.52, 165.64, 149.38, 139.55, 135.33,
133.98, 129.49, 129.02, 128.26, 128.07, 127.49, 126.53,
122.73, 114.72, 78.25, 69.05, 57.03, 31.75, 29.50, 29.47,
29.23, 29.16, 26.91, 22.55, 14.40; Anal calc for
2
DMSO‐d ) δ 174.59, 172.24, 167.02, 158.96, 147.84,
6
1
1
3
35.88, 131.11, 130.44, 129.22, 129.12, 127.13, 126.91,
25.15, 119.82, 114.91, 77.72, 70.68, 67.81, 61.21, 54.96,
2.95, 29.53, 29.45, 29.41, 29.40, 29.25, 29.13, 25.99,

4
YILDIRIM AND KAYA
C H N O (581.76): C 74.33, H 7.45, N 7.22. Found: C
tional shapes. Thus, it can be proposed that the flexible
hydrocarbon chain of the nitrone is capable of adopting suit-
able interaction conformation throughout exo‐Z transition
state (Figure 1). In the case of the exo‐Z transition state, the
DFT results confirm that the cycloaddition proceeded
through this state, wherein hydroxyl group at the end of the
hydrocarbon chain forms a hydrogen bond with the carbonyl
functional group of the maleimide making this state favor-
3
6 43 3 4
74.35, H 7.43, N 7.21.
3
| RESULTS AND DISCUSSION
[
34]
[35]
[36] [37]
The known starting materials, 1,
2a,
3b,
4,
and
[38]
5a‐c
were prepared according to the literature procedures.
[
39–42]
[39]
Nitrone 3a and long‐chained N‐substituted maleimide 5d
used in this study were prepared according to the general
routes shown in Schemes 1 and 2, respectively. The newly
synthesized compounds 3a and 5d were characterized by
Infrared (IR), NMR spectroscopic techniques, and elemental
analysis. For the general cycloaddition reaction, the corre-
sponding nitrones and maleimides was heated in benzene
for 3.5 hours at 70°C. Thereafter, the reaction mixture was
concentrated under vacuum and the obtained solid was
recrystallized from suitable solvent to give a single diastereo-
mer in fairly good yield (Table 1).
The cycloaddition reaction of N‐phenyl‐α‐(p‐(11‐
hydroxy)undecyloxyphenyl)nitrone with N‐arylmaleimides
gave only (syn) cis‐diastereomers as a product. On the
other hand, the reaction of N‐phenyl‐α‐phenylnitrone with
N‐(4‐dodecylcarbamoylphenyl)maleimide gave only (anti)
trans‐diastereomer as a product (Scheme 3). However,
cis/trans‐diastereomers mixture was obtained when the
cycloaddition reaction was performed between the N‐
phenyl‐α‐(p‐(11‐hydroxy)undecyloxyphenyl)nitrone and N‐(4‐
dodecylcarbamoylphenyl)maleimide.
able.
According to Praly et al,
chiral nitrones with
racemic 3‐substituted butenes give H‐bonding–induced
diastereoselective intermolecular [3 + 2] cycloadditions via
exo‐transition state predominantly. On the other hand,
[
40]
Sadownik and Philip
demonstrated that some nitrones
and maleimides can afford cis‐isoxazolidines via transition
states including intermolecular H‐bonding. Therefore,
these studies in the literature, supporting the high
diastereoselectivity in [3 + 2] cycloaddition reactions
performed in this study.
Endo‐E transition state is another possible transition state
on the reaction route to the cis‐diastereomer (Figure 1). The
secondary orbital interactions, noncovalent attractive inter-
actions between the N‐bonded aromatic rings belonging to
the E‐nitrone and the maleimide can cause the reaction to
[
4,13,43–45]
proceed via this transition state.
There are large
numbers of studies that support cycloaddition reactions via
[
46–51]
E‐nitrones.
However, their sandwich interaction is
largely unfavorable and computational calculations reveal
that exo‐Z is the more favorable transition state. On the other
hand, one may expect high repulsion between the voluminous
11‐hydroxyundecyloxy substituent and aryl group of
maleimide in the exo‐Z and endo‐E transition states. If the
steric factors were decisive in the reaction of the nitrone 3a
with maleimides 5a‐c, the exo‐E or endo‐Z must be the pre-
ferred transition states furnishing the trans‐isoxazolidine dia-
In these reactions, the cis‐ or trans‐diastereoselectivity
arises from the noncovalent interactions at the transition
states. The cis selectivity is substantially controlled by the
11‐hydroxyundecyloxy group on the phenyl ring of nitrone
3a. The molecule can adopt a number of different conforma-
SCHEME 1 Synthesis of nitrones 3a and 3b
SCHEME 2 Synthesis of maleimide 5d

YILDIRIM AND KAYA
5
TABLE 1 [3 + 2] Cycloaddition of azomethine‐N‐oxides with N‐aryl substituted maleimides
a
Entry
Nitrone
3a
Maleimide
R
1
R
2
Diastereomer
cis‐6a
Yield %
75
1
2
3
4
5
5a
5b
5c
5d
5d
O(CH
O(CH
O(CH
O(CH
H
2
2
2
2
)
)
)
)
11OH
11OH
11OH
11OH
H
3a
CH
3
cis‐6b
89
3a
COOH
cis‐6c
78
3a
CONH(CH
CONH(CH
2
2
)
11CH
3
3
cis/trans‐6d (55/45)
trans‐7
80
3b
)
11CH
93
a
Yields after recrystallization.
SCHEME 3 Synthesis of isoxazolidine 7
FIGURE 1 Trajectories of transitions states leading to cis‐isoxazolidines
stereomer. But the NMR result reveals the cis‐isoxazolidine
as a single product. As reported previously, only Z configura-
tion has been shown to actually exist for aldonitrones by UV,
In the case of trans selectivity the cycloaddition is con-
trolled possibly by 2 factors, one of which is the absence of
the steric repulsion effect between the long‐chained
dodecylcarbamoyl moiety of the maleimide and phenyl rings
of the E‐nitrone. This factor can cause the cycloaddition reac-
tion to proceed via the exo‐E transition state (Figure 2).
[52]
IR, and NMR spectroscopy.
Accordingly, only one signal
was observed at δ 8.20 ppm as a methine proton in the NMR
spectrum of the nitrone 3a.

6
YILDIRIM AND KAYA
FIGURE 2 Trajectories of transitions states leading to trans‐isoxazolidines
3
3a
6a
Another factor that may affect the transition state is the (sec-
ondary orbital interactions) noncovalent attractive interac-
tions between the N‐bonded aromatic ring of Z‐nitrone and
maleimide aromatic ring that can lead the reaction to proceed
via the endo‐Z transition state (Figure 2). However, it is not
the possible transition state because of sandwich repulsion.
A computational analysis reveals that the trans‐diastereoisomer
was obtained via the more preferred exo‐E transition state.
The stereochemistry of the cycloadduct was determined
from the peak splitting patterns and coupling constants
H proton and H , H protons are in the antiposition and
3
3a
the spin‐spin coupling between H proton and H could
not be seen. Additionally, H protons have chemical shift
6a
3a
at 5.41 ppm giving a doublet or triplet peak and H protons
have chemical shift between 4.13 and 4.14 ppm giving a
doublet peak (triplet for the compound 6d). The spectra also
clearly showed the spin‐spin coupling of H and H pro-
tons. The cis/trans ratio for the isoxazolidine 6d, was deter-
mined by integration of signals assigned to each
diastereomer in the H NMR spectra. A 55/45 cis/trans ratio
was obtained by integrating the cis and trans H protons at
5.41 and 5.75 ppm, respectively.
3a
6a
1
3
3a
3
related to isoxazolidine ring protons numbered as H , H ,
6a
and H (Figure 3).
The spin multiplicities of these protons are decisive for
1
the cis‐ and trans‐diastereomers. The evaluation of
H
3
3a
3.1 | Computational method
NMR spectra of the obtained cis‐stereoisomers (H , H
syn‐relationship) showed that H protons have chemical shift
3
In the present work, the Becke‐Lee‐Yang‐Parr functional
[
53]
between 5.38 and 5.40 ppm giving a doublet peak. The
(B3LYP) method
using 6‐31G and 6‐311G(d,p) basis sets
cycloadducts 6a‐c, showed J
range expected of a H , H syn‐relationship. The H protons
= 7.8 Hz, which is in the
‐3a
were adopted and all calculations were performed using the
3
3
3a
6a
[54]
GAUSSIAN 09 program package.
Harmonic frequencies
have chemical shift between 4.92 and 4.94 ppm giving a dou-
of the structures were calculated at the same method and
basis sets to find local minima (all positive force constants)
or transition states (one imaginary force constant only). The
intrinsic reaction coordinate calculation has been used to ver-
ify the true transition structure. For the calculations of solvent
3a
blet peak and H protons have chemical shift between 4.14
and 4.10 ppm giving a pseudo triplet instead of doublet of
doublet peak (Figure 4A).
1
The evaluation of H NMR spectra of the obtained
3
3a
trans‐stereoisomers (H , H trans‐relationship) showed that
effect on the reaction paths, the polarizable continuum
3
[55]
H protons have chemical shift at 5.75 or 5.85 ppm and
model,
in which the cavity is created via a series of
appears as a singlet peak (Figure 4B). This peak proves that
overlapping spheres, was used. As the DFT functional poorly
describe dispersion effects, dispersion correction for reaction
heat and free energy barrier were also estimated using the
wB97X‐D/6‐311G(d,p) method developed by Grimme and
[
56]
coworkers.
The global electrophilicity index, ω is given by the fol-
[
57]
2
lowing expression
(ω = μ /2η), in terms of the electronic
chemical potential μ and the chemical hardness η. Both quan-
tities may be approached in terms of the one‐electron ener-
gies of the frontier molecular orbitals (FMOs) highest
occupied molecular orbital (HOMO) and lowest unoccupied
molecular orbital (LUMO), ε and ε , as μ ≅ −(ε + ε )/2
H
L
H
L
and η ≅ (ε − ε )/2, respectively. Global softness, S, is
L
H
related to global hardness and is given by the inverse of
[
58]
FIGURE 3 Diagnostic hydrogen atoms of diastereomers
2η.

YILDIRIM AND KAYA
7
a
FIGURE 4 (A) 1H nuclear magnetic resonance
(
NMR) spectra of compound 6a. (B) 1H NMR
b
spectra of compound 7
[
57]
All calculations were performed at 298 K and pressure of
molecule.
The HOMO and LUMO energy and energy
1
atm. Absolute entropies of critical structures (S) were esti-
gap (ΔE) absolute electronegativity (χ), chemical hardness
(η), softness (S), and electrophilicity index (ω) of the nitrones
mated from complete vibrational analysis. Enthalpies (H)
were corrected to Gibbs free energies (G) using calculated
entropies.
[
59,60]
and the maleimides are listed in Table 2.
and LUMO energies of nitrone, which is 3a, are lowered by
.381 and 0.190 eV, respectively, compared with 3b. The
The HOMO
0
HOMO acts as an electron donor, while the LUMO is an
electron acceptor. The energy gap (ΔE) represents the chem-
ical reactivity of compounds. For a system lower value of ΔE
makes it more reactive or less stable. The HOMO/LUMO
energy gaps for the cycloaddition reactions of nitrones 3a
and 3b to maleimides 5a‐d have been listed in Table 3.
The energy differences indicate that HOMOnitrone‐
LUMOmaleimide interaction results in a lower gap than
HOMOmaleimide‐LUMOnitrone interaction; hence, the former
3
.2 | Frontier molecular orbitals
All of the molecules were optimized by DFT/B3LYP method
and 6‐31G basis set. The calculated optimized free energies
of nitrones 3a and 3b and maleimides 5a‐d has been provided
in Table 2.
The HOMOs and LUMOs are known as FMOs which
played an important role for evaluating molecular chemical
stability, chemical reactivity, and hardness‐softness of the

8
YILDIRIM AND KAYA
TABLE 2 Highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energies, the energy gap (ΔE), absolute electro-
negativity (χ), chemical hardness (η), softness (S), and electrophilicity index (ω) of nitrones 3a and 3b and maleimides 5a‐d using B3LYP/6‐31G level
Compound Global Reactivity Descriptors
3a
3b
5a
5b
5c
5d
E (HOMO, a.u.)
−0.189
−0.059
3.54
−0.195
−0.066
3.51
−0.261
−0.107
4.19
−0.250
−0.105
3.94
−0.254
−0.122
3.59
−0.253
−0.118
3.67
E (LUMO, a.u.)
ΔE, eV
χ
−3.373
1.768
0.28
−3.550
1.754
0.29
−5.005
2.094
0.24
−4.828
1.972
0.25
−5.114
1.795
0.28
−5.046
1.836
0.27
η
S
ω
3.22
3.59
5.99
5.92
7.30
6.93
TABLE 3 The density functional theory/B3LYP‐6‐31G calculated highest
occupied molecular orbital (HOMO)/lowest unoccupied molecular orbital
calculated at 2.767, 2.701, 4.077, 3.706, and 3.334, respec-
tively. These results indicate that the least polar character
for the cycloaddition reactions is 3a to 5b, while the highest
global electrophilicity difference (Δω) was observed in the
reaction of 3a with 5c.
(LUMO) energy gaps for the cycloaddition reactions of the nitrones and the
maleimides
LUMOmaleimide
HOMOnitrone, eV
‐
LUMOnitrone‐
Reaction
HOMOmaleimide, eV
The electron density in both FMOs, HOMO and LUMO
of 3a and 3b, was collected on nitrone group and phenyl ring,
while in the maleimides HOMO orbital this density is
delocalized on phenyl ring and LUMO orbital is delocalized
on maleimide group as shown in Figures S9 and S10.
6a (3a + 5a)
6b (3a + 5b)
6c (3a + 5c)
6d (3a + 5d)
7 (3b + 5d)
2.230
5.494
5.195
5.304
5.277
5.086
2.285
1.822
1.931
2.094
3
.3 | Molecular electrostatic potential map
is the predominant interaction involved in each case. This
reveals a normal electron demand character of the cycloaddi-
tion reactions. The HOMOnitrone‐LUMOmaleimide energy gap
is least along the serials for the cycloaddition reactions of
The chemical reactivity of the compounds are easily deter-
mined with the help of molecular electrostatic potential map
(MEP), which differentiates the electrophilic and nucleo-
[
62]
3a to 5a‐d and the largest for the reaction involving 3b.
philic sites in a molecule quite easily.
For this purpose
The energy gap, ΔE is directly involved with hardness/
the MEPs have been calculated for the nitrones and the
maleimides at the B3LYP/6‐31G level. In MEP plots as rep-
resented in Figure S11, the negative regions represented by
red color are preferable sites for electrophilic attack and the
positive regions represented by blue color are favored nucle-
ophilic attack. Here, the negative potentials are generated
over the electronegative nitrone O and N atoms, whereas
the H‐atoms of maleimide group in maleimides have the pos-
itive potential region in the structures. These negative and
positive sites help to predict the regions in a compound
softness of a chemical species. The higher value of ΔE repre-
sents more hardness or less softness of compounds, the sys-
tem having the maximum hardness being the most
[
61]
stable.
The global reactivity descriptor chemical potential
(
I), which is represented by HOMO energy, occurs from
charge distribution between 2 systems having different chem-
ical potential. Here, all compounds act as electrophiles, and
hence, their electronic potentials (I) are negative. Another
global reactivity descriptor electrophilicity index (ω)
describes the electron accepting ability of the systems quite
similar to η and I. High values of electrophilicity index
increases electron accepting abilities of the molecules.
As depicted in Table 2, the electronic chemical potentials
of the nitrones, 3a (−3.373 eV) and 3b (−3.550 eV) are
higher than that of the maleimides, 5a‐d (−4.828 to
[
63]
responsible for noncovalent interactions.
3
.4 | Diastereoselectivity of the performed
cycloaddition reactions
DFT is the more popular method in recent years in computa-
tional chemistry. It provides an appropriate level of theory
and costs for a number of problems supporting experimental
research. However, there is a limitation to describe dispersion
effect. Therefore, DFT/B3LYP hybrid functional is not satis-
factory to obtain reliable energies. Development has been
done to treat this nontrivial matter. Excellent reviews on dis-
−
5.114 eV). On the other hand, the global hardness of the
maleimides, 5a‐d (1.795 to 2.094 eV), is higher than that of
the nitrones, 3a and 3b (1.768 and 1.754 eV, respectively).
This predicts that the net charge transfer will take place from
the nitrones to the maleimides in each case along the cycload-
dition reactions. This is in complete agreement with the
HOMO/LUMO energy gap predictions. The global electro-
philicity indices of the maleimides are higher than those of
the nitrones. This is in agreement with FMO and electronic
chemical potential calculations. The global electrophilicity
differences (Δω) between 3a and 5a‐d and 3b and 5d are
[
64]
persion interactions in DFT are given by Johnson et al and
[
65]
Grimme,
including the widely accepted scheme by
[
66,67]
Grimme of dispersion‐corrected DFT that are DFT‐D
and DFT‐D3.
[
56]
Therefore, all the calculations were first
done on the B3LYP/6‐311G(d,p) level, and then, they were

YILDIRIM AND KAYA
9
TABLE 4 Kinetic and thermodynamic parameters for the cycloaddition reactions of nitrones (3a and 3b) with maleimides (5a‐d) according to DFT calcula-
tions (T = 298 K)
B3LYP/6‐311G(d,p)
ΔS, J/mol K
−88.7
W697X‐D/6‐311G(d,p)
ΔS, J/mol K
−76.4
Transition
ΔH, degrees (°)
82.4
ΔG, kJ/mol
108.8
196.1
−15.0
132.8
159.5
−30.7
100.2
174.7
−39.9
116.7
136.2
−49.3
115.6
176.6
−19.4
131.1
142.3
−30.8
110.6
167.2
−20.2
127.3
146.0
−26.6
122.9
187.4
−3.3
ΔH, degrees (°)
65.6
ΔG, kJ/mol
88.4
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
a + 5a → TSEXO−Z
a + 5a → TSENDO−E
a + 5a → 6acis
165.7
−64.6
107.6
130.5
−82.7
75.9
−102.1
−166.2
−84.5
144.1
−45.7
85.6
−88.4
170.5
−5.2
−136.0
−81.5
a + 5a → TSEXO−E
a + 5a → TSENDO−Z
a + 5a → 6atrans
109.9
141.9
−19.7
79.4
−97.4
116.3
−66.9
57.8
−85.9
−174.5
−81.4
−158.2
−72.4
a + 5b → TSEXO−Z
a + 5b → TSENDO−E
a + 5b → 6bcis
145.5
−87.9
92.9
−97.8
113.3
−55.9
75.1
−81.8
137.7
−18.4
96.5
−161.0
−79.7
−125.7
−71.9
a + 5b → TSEXO−E
a + 5b → TSENDO−Z
a + 5b → 6btrans
106.6
−99.2
94.2
−99.4
81.4
−88.3
107.7
−25.6
99.6
−167.2
−71.9
−69.3
81.1
−146.5
−62.0
a + 5c → TSEXO−Z
a + 5c → TSENDO−E
a + 5c → 6ccis
148.1
−67.2
105.0
114.7
−79.6
87.2
−95.7
130.4
−45.2
85.1
−81.4
154.7
−8.0
−160.1
−87.4
−124.8
−73.1
a + 5c → TSEXO−E
a + 5c → TSENDO−Z
a + 5c → 6ctrans
106.9
123.5
−23.3
89.5
−92.5
99.5
−80.4
−163.7
−78.4
−66.4
69.8
−144.7
−66.1
a + 5d → TSEXO−Z
a + 5d → TSENDO−E
a + 5d → 6dcis
141.0
−67.7
102.7
118.7
−76.7
101.3
160.7
−50.2
86.9
−87.9
118.9
−50.4
77.5
−74.9
141.2
−8.4
−159.4
−82.5
−141.0
−70.4
a + 5d → TSEXO−E
a + 5d → TSENDO−Z
a + 5d → 6dtrans
98.5
−91.4
93.7
−82.5
118.3
−11.0
105.7
170.0
1.8
−167.6
−72.4
−56.2
88.2
−151.5
−58.7
b + 5d → TSEXO−Z
b + 5d → TSENDO−E
b + 5d → 7cis
−89.5
147.0
−40.4
69.7
−77.2
−157.2
−86.2
−141.5
−80.4
b + 5d → TSEXO−E
b + 5d → TSENDO−Z
b + 5d → 7trans
112.6
152.5
−9.3
93.7
125.5
−56.2
−90.4
113.2
−49.9
−79.5
136.9
−6.8
−157.4
−144.7
additionally performed by wB97X‐D method using the 6‐
11G(d,p) basis set. Enthalpies (a.u.) of the reactants, transi-
which is lower than that of the other 3 pathways:
3b 5d TSEXO‐Z 3b 5d TSENDO‐E
3
+
→
,
+
→
,
tion states, and the products for the cycloaddition reactions of
nitrones (3a and 3b) with maleimides (5a‐d) calculated at
3b + 5d → TSENDO‐Z (calcd. 105.7, 170.0, and 136.9 kJ/
mol, respectively). This result shows that the molecule 7,
synthesized from 3b and 5d is the trans isomer. On the other
hand, other molecules, 6a‐d, are adopted cis isomers, because
298 K are given in Table S1, while the relative enthalpies,
entropies, and free energies of all the molecules are listed in
Table 4. The third and sixth column in Table 4 show the rel-
ative free energies calculated with B3LYP and wB97X‐D,
respectively, for all reactions, while the other columns present
the relative enthalpies and entropies. In general, the relative
free energies of all molecules calculated from wB97X‐D are
lower than those from the B3LYP level. All of the energy
discussions are based on the wB97X‐D method and 6‐311G
their Gibbs free energies of transition state, TS
, are
EXO‐Z
(
d,p) basis set because of the inclusion of the dispersion
effect.
The analysis of the Gibbs free energies of the transition
states for the performed cycloaddition reaction reveals that
the exo‐Z and exo‐E are less energetic than endo‐E and
endo‐Z (Table 4). The relative Gibbs free energy of the
reaction 3b + 5d → TSEXO‐E was calculated at 93.7 kJ/mol,
FIGURE 5 Reaction profiles for the cycloaddition reactions of nitrones (3a
and 3b) with maleimides (5a and 5d)

1
0
YILDIRIM AND KAYA
lower than those of the other 3 pathways. The calculated free
energies of TSEXO‐Z of 6a‐d molecules are 88.4, 79.4, 99.6,
and 89.5 kJ/mol, respectively. The energy profiles of the for-
mation reaction of the compounds 6a, 6d, and 7 are shown in
Figure 5.
TABLE 5 Essential molecular properties of the molecules of the cycload-
dition reactions of nitrones (3a and 3b) with maleimides (5a‐d) according to
DFT calculations
5
1
3
4
C –O
C –C
b
Molecule
CT (e)
r, Å
Ia
r, Å
Ia
Analysis of transition states geometries shows that the reac-
tion course is determined by attack of the nucleophilic oxygen
atom from the CNO moiety of nitrone onto the electrophilic
center of dipolarophile. Similar tendency has been observed
3a + 5a
TSa
2.783
2.060
1.465
2.614
2.087
1.466
2.704
2.105
1.464
2.711
2.247
1.465
2.843
2.291
1.463
TS
3.984
1.984
1.577
3.956
2.001
1.578
3.842
2.016
1.578
3.927
2.101
1.576
3.987
2.169
1.564
0.00
0.36
0.594
0.742
6a
3a + 5b
TSb
0.00
0.41
[45,68]
recently in other reactions involving diarylnitrones.
0.576
0.562
0.466
0.434
0.732
0.722
0.667
0.613
The intermolecular H‐bonding or repulsive interactions
between phenyl rings makes the exo approaches more
favorable (Figures 1 and 2). In endo‐E and endo‐Z transition
states steric repulsion is possible between the phenyl ring of
the maleimide and the N‐phenyl ring of the nitrone. The
optimized structures of the transition states exo‐Z and exo‐E
respectively of the compounds 6a and 7 are given in
6b
3a + 5c
TSc
0.00
0.37
6c
3a + 5d
TSd
0.00
0.38
6d
5
1
3
4
Figure 6. For 6a the lengths of the C –O and C –C
3b + 5d
TS7
0.00
0.38
forming bonds are 2.060 and 1.984 A°, respectively, and
the H‐bond length is 2.388 A° at the transition state exo‐Z.
7
5
1
3
4
On the other hand, for 7 the lengths of the C ‐O and C –C
a
3 + 5
X − Y = 1 − (rX − Y − rX − Y
TS
TS
I
/rX − Y ), where rX‐Y is the distance between
3
+ 5
forming bonds are 2.291 and 2.169 A°, respectively, at the
the reaction centers X and Y in the transition structure and rX‐Y
distance in the corresponding product.
is the same
transition state exo‐E. The asynchronicity according to
5
1
3
4
[69]
b
A A
CT = − Σq , where q is the net charge and the sum is taken over all the atoms of
the dipolarophile.
Δr = [d(C –O ) − d(C –C )]
at the transition states
during the formation of compound 6a is 0.076 at exo‐Z
and 0.313 at endo‐E, whereas the asynchronicity at the
transition states during the formation of compound 7 is 0.122
at exo‐E and 0.675 at endo‐Z. Therefore, the more favorable
transition states exo‐Z (0.076) and exo‐E (0.122) are more
synchronous than transition states endo‐E and endo‐Z.
FIGURE 6 Optimized structures of transition states of 6a (exo‐Z) and 7 (exo‐E)

YILDIRIM AND KAYA
11
According to another more realistic approach, global and
local reactivity indices as distance between reaction centers
of transition states and/or products also indicate a polar char-
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[
17]
acter of the cycloadditions (Table 5).
On the other hand,
5
1
3
4
C –O and C –C bonds have different nature and different
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3
4
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Thus, DFT calculations also reveal that cycloadditions
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4
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selected two N,α‐diphenyl nitrones. Depending on the reac-
tants either cis‐ or trans‐cycloadduct was obtained as a single
diastereomer confirmed by NMR. The optimized transition
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states. On the other hand, global and local reactivity indices
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