Efficient method for the synthesis of 1,2,3-triazole functionalized isoxazolidine derivatives by 1,3-dipolar cycloaddition of nitrones with terminal olefins

Article abstract of DOI:10.1080/00397911.2016.1271133

1-Phenyl-1,2,3-triazole-4-carbaldehyde 1 was treated with different N-alkyl hydroxylamine hydrochlorides 2 using NaHCO₃to obtain 1,2,3-triazole substituted N-alkyl nitrones 3a–c. The nitrones 3a–c were further reacted with different substituted

Full text of DOI:10.1080/00397911.2016.1271133

An efficient method for the synthesis of 1,2,3-triazole functionalized isoxazolidine
derivatives by 1,3-dipolar cycloaddition of nitrones with terminal olefins
P. Sambasiva Rao1, K. Chinna Ashalu1, G. Jitender Dev1, N. Ravi Kumar1, PVSS
Srinivas1, B. V. Thomas1, B. Narsaiah1
1Fluoroorganic Division, CSIR-Indian Institute of Chemical Technology, Tarnaka,
Hyderabad, India
Address correspondence to B. Narsaiah. E-mail: narsaiah@iict.res.in
Abstract
1-Phenyl-1,2,3-triazole-4-carbaldehyde 1 was treated with different N-alkyl
hydroxylamine hydrochlorides 2 using NaHCO3 to obtain 1,2,3-triazole substituted N-
alkyl nitrones 3a-c. The nitrones 3a-c were further reacted with different substituted
olefins and furnished 2-alkyl-3-(1-phenyl-1H-1,2,3-triazol-4-yl)-5-
(substituted)isoxazolidine derivatives 4a-p in high yields via 1,3-dipolar cycloaddition
reaction.
GRAPHICAL ABSTRACT
KEYWORDS: 1,2,3-Triazole, Nitrones, Olefins, 1,3-Dipolar cycloaddition,
Isoxazolidine
INTRODUCTION
1

There has been an ever increasing quest for natural products containing the isoxazolidine
moiety due to their vast applications as biologically active substances, e.g., plant growth
regulators,1,2 antiviral and anticancer compounds.3-5 The 1,3-dipolar cycloaddition
reaction of an alkene with a nitrone is one of the most reliable strategies for the
construction of highly substituted five membered isoxazolidine derivatives.6
Isoxazolidines can be used as potential precursors for the synthesis of exceptionally
useful natural products such as alkaloids, β-lactams, sugar derivatives, and amino acids.7-
12 Isoxazolidines are useful synthetic intermediates towards the synthesis of 1,3-amino
alcohols,13 as well as a variety of bicyclic heterocycles. Synthetic applications as well as
biological activities of isoxazolidines prompted us to synthesize the title compounds.
Based on our earlier work on synthesis of substituted triazoles, isoxazoles and their
anticancer activity,14-17 we have developed an efficient method for the synthesis of 1,2,3-
triazole functionalized isoxazolidine derivatives.
It is known that 1,3-dipoles are of two types such as allyl anion type and the
propargyl/allenyl anion type. Nitrones belongs to allyl anion type of 1,3-dipoles.18 The
most commonly used dipolarophiles are alkenes and alkynes. 19 The 1,3-dipolar
cycloaddition of alkenes with nitrones produce substituted isoxazolidines as racemic
mixtures20 or with stereo induction if chirality is present either in dipole or
dipolarophile.21 More recently, Romeo and co-workers5d-f reported the synthesis and
biological activity of 1,2,3-triazolyl functionalized isoxazolidines. Aouadi and co-
workers22 also reported a stereoselective synthesis of 1,2,3-triazolyl-functionalized
isoxazo lidines via two consecutive 1,3-dipolar cycloadditions. The 1,3-dipolar
2

cycloaddition reaction of menthone derived chiral nitrone as a dipole with allyl bromide
as a dipolarophile resulted as a single stereoisomer of substituted isoxazolidine. Cu(I)-
catalyzed azide alkyne cycloaddition (CuAAC) applied to an azidomethyl intermediate
afforded to a series of six heterocycles possessing a 4-substituted-(1,2,3-triazolyl) methyl
moiety linked to an isoxazolidine.22
We have choosen triazole functionalized nitrones as 1,3-dipoles and terminal olefins as
dipolarophiles for the synthesis of racemic isoxazolidines via 1,3-dipolar cycloaddition.
RESULTS AND DISCUSSION
The reaction of 1-phenyl-1,2,3-triazole-4-carbaldehyde 1 and N-benzylhydroxylamine
hydrochloride 2 was performed in the presence of sodium bicarbonate in ethanol at reflux
temperature to furnish nitrone 3a. Subsequent treatment of nitrone 3a with styrene in
toluene at reflux temperature afforded the triazole functionalized isoxazolidine. The
sequence of the reaction is mainly by condensation of 1-phenyl-1,2,3-triazole
carbaldehyde 1 with N-benzylhydroxyl amine hydrochloride 2 to form nitrone 3a which
underwent 1,3-dipolar cycloaddition with styrene to result in 1,2,3-triazole functionalized
isoxazolidine product 4a, the reaction is outlined in Scheme 1.
It is commonly accepted that, the 1,3-dipolar cycloaddition reaction of nitrones represent
a one-step concerted mechanism in which two new σ bonds are formed as shown in
Scheme 2.
3

The regiochemistry was determined based on 1H and 13C NMR for compounds 4a-p. The
stereochemistry of our synthesized compounds 4a-p has been determined based on 2D
NOESY spectrum of one of our synthesized compound 4h.
The reaction of nitrones (1,3-dipole) with monosubstituted alkenes (unsymmetrical
dipolarophiles) resulted 3,5-disubstituted isoxazolidine derivatives 4a-p and the reaction
is considered to be regioselective. More specifically, the 1,3-dipolar cycloaddition of
nitrone 3a with styrene furnished only one regioisomer 3,5-disubstituted isoxazolidine 4a
as shown in Scheme 1. NMR data supports the presence of only one proton on C-5
carbon in down field at δ 4.62 ppm. In general, the 1,3-dipolar cycloaddition reactions
with alkenes are cis stereoselective. In this case, 1,3-dipolar cycloaddition of nitrones
with mono substituted alkenes resulted 4a-p as 1:1 ratio of cis stereoisomers. It is also
confirmed by measuring the optical rotation as zero and found to be racemic. The
NOESY spectrum of representative compound 4h shows that there is NOE between C-3
and C-5 protons as shown in Figure 1 and enclosed in supporting information.
1-Phenyl-1,2,3-triazole-4-carbaldehyde 1 was reacted with different N-alkyl
hydroxylamine hydrochlorides 2a-c in presence of sodium bicarbonate as a base in
ethanol at reflux temperature and obtained 1,2,3-triazole substituted N-alkyl nitrone
derivatives 3a-c16 in a single step. These nitrone derivatives 3a-c were further underwent
1,3-dipolar cycloaddition with various terminal olefins and furnished 2-alkyl-3-(1-
phenyl-1H-1,2,3-triazol-4-yl)-5-(substituted)isoxazolidine derivatives 4a-p in high yields.
4

The products formed in each case, are described in Scheme 3 and the results are tabulated
in Table 1.
CONCLUSIONS
In conclusion, we have developed an efficient method for the synthesis of 1,2,3-triazole
functionalized isoxazolidine derivatives by 1,3 dipolar cycloaddition of nitrones with
various terminal olefins.
EXPERIMENTAL
General Procedure For The Synthesis Of (1,2,3)-Triazole Substituted-N-
Alkylnitrone Derivatives (3a-C)16
A mixture of the corresponding 1-substituted-1H-1,2,3-triazole-4-carbaldehyde (1 equiv),
N-alkylhydroxylamine hydrochloride (1.5 equiv) and sodium bicarbonate (1.5 equiv) in
absolute ethanol (6mL/mmol) as solvent was heated to reflux until the aldehyde
consumed (after 2-3 hours checked by TLC). The reaction mixture was brought to room
temperature and ethanol was removed under reduced pressure. The residue was diluted
with water and the product was extracted with ethyl acetate. The organic layers were
combined and the solvent was removed under reduced pressure. The crude product was
purified by column chromatography (SiO2, eluted in petroleum ether/EtOAc).
N-((1-Phenyl-1H-1,2,3-Triazol-4-Yl)Methylene)Cyclohexanamine Oxide (3c)
White solid, m.p.102-104 oC, Yield: 82%, I.R. (KBr, cm-1): 2992 (HC=C), 1606 (-C=N),
1
1459 (N-O); H NMR (CDCl3, 300 MHz): δ 1.30-1.48 (m, 6H, -(CH2)3), 1.99-2.18 (m,
5

4H, -(CH2)2), 3.95 (m, 1H, CHN), 7.46 (t, J=7.6 Hz, 1H, Ar-H), 7.54 (t, J=8.1 Hz 2H, Ar-
H), 7.80 (d, J=8.1 Hz, 2H, Ar-H), 7.92 (s, 1H, Triazole-H), 9.32 (s, 1H, HC=N); 13C
NMR (CDCl3, 75 MHz): δ 140.3, 136.6, 129.7, 128.8, 125.2, 123.2, 120.3, 74.1, 31.1,
24.8; MS (ESI, 70eV): m/z: 293 (M+Na); HRMS m/z calcd. for C15H18N4ONa
([M+Na]+): 293.1372. Found 293.1369.
General Procedure For The Synthesis Of 2-Alkyl-3-(1-Phenyl-1H-1,2,3-Triazol-4-
Yl)-5-(Substituted)Isoxazolidine (4a-P)
A mixture of (1,2,3)-triazole substituted-N-alkyl nitrone (1 equiv) and 1-substituted
ethylene (1.5 equiv) in toulene (5mL) as solvent was refluxed until the nitrone was
consumed (after 3-4 hours checked by TLC). The solvent was removed under reduced
pressure and the residue was purified by column chromatography (SiO2, eluted with
petroleum ether/EtOAc).
2-Benzyl-5-Phenyl-3-(1-Phenyl-1H-1,2,3-Triazol-4-Yl)Isoxazolidine (4a)
White solid, m.p. 124-126 oC, Yield: 81%, I.R. (KBr, cm-1): 2957 (HC=C), 1598 (-N=N),
1495(N-O), 1295(C-N), 1282(C-O); 1H NMR (CDCl3, 300 MHz): δ 2.65-2.75 (m, 1H, -
CH), 3.26-3.36 (m, 1H, -CH), 4.21 (s, 2H, CH2N), 4.62 (t, J=6.6 Hz, 1H, -CH), 5.40 (t,
J=7.9 Hz, 1H, -CH), 7.24-7.37 (m, 7H, Ar-H), 7.38-7.47 (m, 3H, Ar-H), 7.49-7.58 (m,
3H, Ar-H), 7.69 (d, J=7.6 Hz, 2H, Ar-H), 7.89 (s, 1H, Triazole-H); 13C NMR (CDCl3, 75
MHz): δ 148.3, 136.2, 135.7, 129.4, 129.0, 128.6, 128.0, 127.1, 126.2, 122.1, 119.1, 76.6,
61.2, 40.2, 28.4, 21.6; MS (ESI, 70eV): m/z: 383 (M+H); Anal. Calcd. for C24H22N4O: C,
75.37; H, 5.80; N, 14.65%. Found: C, 75.35; H, 5.81; N, 14.68 %.
6

2-(Tert-Butyl)-5-Phenyl-3-(1-Phenyl-1H-1,2,3-Triazol-4-Yl)Isoxazolidine (4g)
White solid, m.p. 142-144 oC, Yield: 84%, I.R. (KBr, cm-1): 2986 (HC=C), 1539 (-N=N),
1
1421(N-O), 1245(C-N), 1212(C-O); H NMR (CDCl3, 300 MHz): δ 1.22 (s, 9H, (CH3)3),
2.46-2.57 (m, 1H, -CH), 3.09-3.20 (m, 1H, -CH), 4.88 (t, J=7.9 Hz, 1H, -CH), 5.24 (t,
J=8.6 Hz, 1H, -CH), 7.28-7.36 (m, 3H, Ar-H), 7.39-7.46 (m, 3H, Ar-H), 7.50 (t, J=7.2
Hz, 2H, Ar-H), 7.68 (t, J=7.9 Hz, 2H, Ar-H), 7.89 (s, 1H, Triazole-H); 13C NMR (CDCl3,
75 MHz): δ 152.6, 139.9, 137.1, 128.2, 129.6, 126.3, 119.4, 120.2, 80.3, 60.4, 56.7, 47.8,
26.2; MS (ESI, 70eV): m/z: 349 (M+H); HRMS m/z calcd. for C21H25N4O ([M+H]+):
349.2022. Found 349.2016.
2-Cyclohexyl-5-Phenyl-3-(1-Phenyl-1H-1,2,3-Triazol-4-Yl)Isoxazolidine (4k)
White solid, m.p. 144-146 oC, Yield: 82%, I.R. (KBr, cm-1): 2988 (HC=C), 1556 (-N=N),
1
1387(N-O), 1245(C-N), 1198(C-O); H NMR (CDCl3, 300 MHz): δ 1.18-1.35 (m, 6H,
(CH2)3), 1.61-1.87 (m, 4H, (CH2)2), 2.22 (m, 1H, NCH), 2.49-2.62 (m, 1H, -CH), 3.18-
3.30 (m, 1H, -CH), 4.83 (t, J=6.1 Hz, 1H, -CH), 5.21 (t, J=7.5 Hz, 1H, -CH), 7.24-7.36
(m, 5H, Ar-H), 7.41 (t, J=8.3 Hz, 1H, Ar-H), 7.50 (t, J=7.5 Hz, 2H, Ar-H), 7.72 (d, J=8.3
Hz, 2H, Ar-H), 8.01 (s, 1H, Triazole-H); 13C NMR (CDCl3, 75 MHz): δ 139.3, 137.1,
129.6, 128.5, 127.8, 126.7, 120.2, 119.5, 78.8, 44.8, 31.2, 29.7, 25.8, 24.7, 24.5; MS
(ESI, 70eV): m/z: 375 (M+H); HRMS m/z calcd. for C23H27N4O ([M+H]+): 375.2179.
Found 375.2178.
SUPPORTING INFORMATION
7

1
Full experimental details, copies of H and 13C NMR spectra, can be found via the
“Supplementary Content” section of this article’s webpage.
ACKNOWLEDGEMENTS
B.N, KCA, PVSS, BVT are thankful to the Council of Scientific and Industrial Research
(CSIR), New Delhi, India for providing funding through XII five year plan project
DITSF code: CSC-0204. The other authors are also thankful to the CSIR, New Delhi,
India for providing financial assistance in the form of senior research fellowships.
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Table 1. Preparation of compounds 3c and 4a-p
S. No Compound No R1 R2
Yield (%)a
1
Cyclohexyl –
82
81
84
86
3c
4a
4b
4c
4d
4e
4f
2
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
t-Butyl
t-Butyl
t-Butyl
t-Butyl
C6H5
3
4-CH3C6H4
4-CH3OC6H4
4
5
Naphthalene-2-yl 82
6
CN
84
78
84
82
78
7
COOEt
C6H5
8
4g
4h
4i
9
4-CH3C6H4
4-CH3OC6H4
10
11
12
13
14
15
16
17
Naphthalene-2-yl 79
4j
Cyclohexyl C6H5
82
84
80
4k
4l
Cyclohexyl 4-CH3C6H4
Cyclohexyl 4-CH3OC6H4
4m
4n
4o
4p
Cyclohexyl Naphthalene-2-yl 78
Cyclohexyl CN
74
72
Cyclohexyl COOEt
aIsolated yields.
11

Scheme 1. Synthesis of 2-benzyl-5-Phenyl-3-(1-phenyl-1H-1,2,3-triazol-4-
yl)isoxazolidine 4a
12

Scheme 2. Plausible mechanism for conversion of 3a-c to 4a-p
13

Scheme 3. Synthesis of 2-alkyl-3-(1-phenyl-1H-1,2,3-triazol-4-yl)-5-
(substituted)isoxazolidine derivatives 4a-p
14

Figure 1. Characterestic NOE of compound 4h
15