α-N-Methyl/phenyl furan derivatives as dipolarophiles for synthesis of spiro isoxazolidine derivatives with α-chloro and simple nitrones

Article abstract of DOI:10.3184/030823410X12675422347141

1,3-Dipolar cycloaddition reactions of α-chloro and simple nitrones have been studied with novel α-N-methyl/phenyl furan derivatives as new dipolarophiles. The reactions are found to be highly regioselective to afford single 5-spiro isoxazolidines with high yield in a short reaction time.

Full text of DOI:10.3184/030823410X12675422347141

JOURNAL OF CHEMICAL RESEARCH 2010
RESEARCH PAPER 147
MARCH, 147–150
α-N-Methyl/phenyl furan derivatives as dipolarophiles for synthesis of
spiro isoxazolidine derivatives with α-chloro and simple nitrones
Bhaskar Chakraborty*, Prawin Kumar Sharma, Neelam Rai, Saurav Kafley and Manjit Chhetri
Organic Chemistry Laboratory, Sikkim Government College, Gangtok, Sikkim-737102, India
1,3-Dipolar cycloaddition reactions of α-chloro and simple nitrones have been studied with novel α-N-methyl/phenyl
furan derivatives as new dipolarophiles. The reactions are found to be highly regioselective to afford single 5-spiro
isoxazolidines with high yield in a short reaction time.
Keywords: α-N-methyl/phenyl furan derivatives, spiro cycloadducts, regioselectivity
In addition to the reported dipolarophiles for 1,3-dipolar cyclo-
addition reactions of nitrones,1 we now describe some further
novel and efficient dipolarophiles (α-N-methyl/phenyl furan
derivatives) for the cycloaddition reactions to afford solely
5-spiro isoxazolidines with high yield in a very short reaction
time (4–6 h) with different nitrones at RT (Scheme 1). A
detailed literature survey reveals that these type of cycloaddi-
tion reactions are generally diastereomeric in nature with the
predominance of one of the isomers.2 The synthetic potential
of α-chloro nitrones (1) has been proved not only in cycloaddi-
tion reactions but also in the synthesis of novel dipolarophiles
(2) when treated with alkyl halides.3 α-N-methyl/phenyl furan
derivatives (2) were isolated as side-products and in single E
isomeric forms (almost 20%) in the reported oxidation reac-
tion of alkyl halides to aldehydes and ketones using α-chloro
nitrones4–8 (Scheme 2). The novel 5-spiro isoxazolidines (3–8)
were predominantly obtained regioselectively in high yields
(78–88%) as single isomers in the reactions of α-chloro,
α-amino and simple nitrones. This could be due to the fact that
the nitrone (LUMO)–dipolarophile (HOMO) interactions are
strong enough to dominate the reaction9–11 and lead to the for-
mation solely of 5-spiro cycloadducts (3–8) via an exo approach
of the nitrone 1 (all the reported nitrones have a Z configura-
tion) to the furan derivatives 2 (transition state 1). At the outset
of this work it was unclear whether the side-products obtained
during aldehyde and ketone synthesis could be employed as
efficient dipolarophiles. For the present study, we have used
five different nitrones: N-methyl-α-chloro nitrone,6 N-phenyl-
α-chloro nitrone,8 N-methyl-α-amino nitrone,12 N-phenyl-α-
amino nitrone13–15 and N-methyl/phenyl nitrones16 respectively
in order to generalise regioselectivity in cycloaddition reac-
tions using novel dipolarophiles (2). The stereochemistry of
the isoxazolidine derivatives (3–8) were rationalised by con-
sidering the multiplicity of the proton signals at 3-H, 4-H,
CHCl (in the case of α-chloro nitrones only) asymmetric
centres along with their coupling constant values.17,18 In the 1H
NMR spectrum of cycloadducts 3–4, 3-H resonates around δH
2.50–3.50 ppm while 4-H around δH 3.00–5.85 ppm and the
coupling constant is J ~ 9.16 Hz implying a cis relationship
between H-3 and H-4.3T,4 he CHCl proton also resonates upfield
around δ 2.20–2.60 ppm. The 3-H and CHCl protons are also
syn as evHidenced from their coupling constant values (J3,CHCl
~
9.40 Hz).17,18 Almost similar coupling constant values are
obtained for H-3 and H-4 protons in the case of other reported
cycloadducts (5–8). Cycloaddition of Z nitrone via exo-
transition state geometry results in syn spiro isoxazolidine
derivatives. The 1H NMR spectra of 3–8 also show significant
long range coupling between H-4 with H-3’ and vice-versa in
most of the spiro cycloadducts. In the mass spectra, in addition
to molecular ion peaks, prominent base peak values are
obtained in all the cycloadducts and significant M+2 peaks of
characteristic relative heights are also obtained in 3–4 which is
due to the isotopic abundance of Cl37 atoms. Studies of HRMS
spectra show almost exact masses for the majority of the
compounds. The experimental procedure is very simple. α-
N-methyl/phenyl furan derivatives (2) are added to nitrone 1 in
diethyl ether at RT. Smooth reaction ends with the production
of the novel spiro cycloadducts with extremely good yield in a
very short reaction time. In general, the reactions are very
clean and high yielding compared to other cycloaddition reac-
tions of α-chloro and α-amino nitrones.1,3–8,13–15 The products
are characterised from their spectroscopic (IR, 1H NMR,
HRMS, 13C NMR) data. No catalyst or co-organic solvent is
required. All the novel isoxazolidine derivatives (3-8) were
also screened for antibacterial activity and found to be very
active.
A preferential conformation for the spiro cycloadducts (3–8)
is shown in Fig. 1.
A new mechanistic pathway for the synthesis of novel
dipolarophiles (α-N-methyl/phenyl furan derivatives) may be
represented in the following mechanism3 (Scheme 2).
Scheme 1
* Correspondent. E-mail: bhaskargtk@yahoo.com

148 JOURNAL OF CHEMICAL RESEARCH 2010
Fig. 1
Scheme 2
TLC’s were run on Fluka silica gel precoated TLC plates while column
chromatography was performed with silica gel (E.Merck India) 60–
200 mesh. All the alkyl halides, reagents and solvents were purified
after receiving from commercial suppliers. N-methylhydroxylamine
was purchased from Aldrich Chemical Company and was used as
received. N-Phenylhydroxylamine was prepared following standard
methods available in the literature and has been used already for
the reported synthesis of aldehydes and in cycloaddition reactions
involving α-amino, α-chloro nitrones in aqueous phase and in organic
solvents.3–8,12–15
Finally, we have reported the synthesis of novel spiro
cycloadducts using novel dipolarophiles with different nitrones
in 1,3-dipolar cycloaddition reaction. The formation of the
desired compounds was obtained in good yields within a short
reaction time. The notable advantages offered by this method
are one-pot synthesis, simple operation, easy workup, mild
and faster reaction conditions with high yield of products.
Experimental
1H NMR spectra were recorded with a Bruker Avance DPX 300 spec-
trometer (300 MHz, FT NMR) using TMS as internal standard. 13C
NMR spectra were recorded on the same instrument at 75 MHz. The
coupling constants (J) are given in Hz. IR spectra were obtained with
a Perkin-Elmer RX 1-881 as film or as KBr pellets for all the products.
MS spectra were recorded with a Jeol SX-102 (FAB) instrument. The
HRMS spectra were recorded on a Q–Tof micro instrument (YA–105).
General procedure for synthesis of aldehyde and furan derivatives 2
To a stirred solution of nitrone 1 (R=Me; 500mg, 3.0198 mmol) in dry
ether (25 ml) was added pyridine (1 equivalent) and stirred at RT with
a magnetic stirrer under N2 atmosphere for 1 h while the formation of
transient nitrone 1a (not isolated) was monitored by TLC (Rf = 0.38).
Benzyl chloride (292.mg, 1 equiv) was added at this stage and the
reaction mixture was stirred for another 3 h until the intermediate

JOURNAL OF CHEMICAL RESEARCH 2010 149
compound 1b (not isolated) was developed (monitored by TLC; R =
0.40). Solid Na CO3 (2g.) was added at this stage and the reactifon
mixture was stir2red for a further 1 h while the progress of the reaction
was again monitored by TLC (Rf = 0.43, 0.50). During this process the
N–O bond was cleaved in the basic medium.19 Basic workup, removal
of pyridine hydrochloride and silica gel column chromatographic
purification using ethyl acetate-hexane provided the desired benzalde-
hyde as a colourless liquid (702 mg, 82%) and α-N-phenyl furan
derivative (2) as a pale yellow gummy liquid (88mg, 17%). This pro-
cedure was followed for the synthesis of α-N-methyl furan derivative
with other alkyl halides.
2 [(E)-1-(dihydrofuran-2-(3H)-ylidene)-N-methyl methanamine)/(E)-
1-(dihydrofuran-2-(3H)-ylidene)-N-phenyl methanamine)] listed in
Table 1.
(R=Me; α-N-methyl furan derivative) [(E)-1-(dihydrofuran-2-(3H)-
ylidene)-N-methyl methanamine)] (2): IR (KBr): 3125–3054 (br),
1
2838 (m), 1652 (s), 1455 (m), 1210 (m) cm−1; H NMR (CDCl3):
δ 4.81 (br, 1H, N-H), 4.56 (s, 1H, C=CH), 3.30 (N-Me), 2.50–2.16
(m, 6H); 13C NMR (CDCl3): δ 103.00, 101.76 (double bonded
carbons), 26.22, 25.30, 23.65 (3 CH2 carbons); FAB–MS: m/z 113
(M+), 98, 97; HRMS-EI: Calcd for C6H11ON (M), 113.1000. Found:
M+, 112.9876.
(R=Ph; α-N-phenyl furan derivative) [(E)-1-(dihydrofuran-2-(3H)-
General procedure for cycloaddition (for regioselective spiro cycload-
ducts)
ylidene)-N-phenyl methanamine)] (2): IR (KBr): 3150-3060 (br),
1
2860 (m), 1640 (s), 1430 (m), 1140 (m), 778 (s) cm−1; H NMR
To a well stirred solution of nitrone 1 (R=Me; 1 mmole) in diethyl
ether (20 mL) taken in a 50 mL conical flask, was added the α-
N-methyl furan derivative [(E)-1-(dihydrofuran-2-(3H)-ylidene)-
N-methyl methanamine)] (1 equiv) which was stirred at RT with a
magnetic stirrer under N atmosphere for 4 h. The progress of the
reaction was monitored b2y TLC (Rf = 0.53). After completion of the
reaction and work-up, the crude spiro-cycloadduct was concentrated
in a rotary evaporator and finally purified by column chromatography
using ethyl acetate - hexane to afford pure spiro-cycloadduct 3 (entry
1, Table 1, Scheme 1). This procedure was followed for the reaction
of nitrone 1 (R= Me,Ph) with the α-N-methyl/phenyl furan derivatives
(CDCl3): δ 7.83 (m, 5H, C6H5), 6.29 (br, 1H, N-H), 2.17 (s, 1H,
C=CH), 1.79–1.18 (m, 6H); 13C NMR (CDCl3): δ 137.20, 135.65,
134.00, 132.15 (aromatic carbons), 106.24, 104.18 (double bonded
carbons), 28.46, 27.10, 24.84 (3 CH2 carbons). FAB–MS (m/z): 175
(M+), 98, 97, 77. HRMS-EI: Calcd for C11H13ON (M), 175.0993.
Found: M+, 175.0981.
(S)-4-Chloro-4-((3S,4S,5R)-2methyl-4-(methylamino)-1,6-dioxa-2-
azaspiro[4.4]nonan-3-yl)butan-1-ol (3): Pale yellow gummy liquid.
Yield 88%, Rf = 0.53; IR (KBr): 3460–3326 (br), 2948 (m), 2420 (m),
1485 (s), 1325 (m), 810 (m), 774 (s) cm−1; 1H NMR (CDCl3): δ 4.83
(br, 1H, CH2OH, exchanged in D2O), 4.60 (s, 1H, NHCH3), 3.37
Table 1 Cycloaddition reaction of nitrone 1 with novel dipolarophiles (2)
Entry Nitrone
Novel dipolarophilesa
Spiro cycloadductsb
Time /h Nature of
products
Yield /%c
88
(1)
(2)
(3–8)
1
2
3
4
5
6
R = Me
4
5
5
6
5
6
Pale yellow
R1 = CHCl(CH2)3OH
gummy liquid
3
4
5
6
7
R = Ph
Dark red viscous
liquid
86
84
81
78
78
R1 = CHCl(CH2)3OH
R = Me
Grey viscous
liquid
R1 = NH2
R = Ph
Dark grey viscous
liquid
R1 = NH2
R = Me
R1 = Ph
Colourless
gummy liquid
R = R1 = Ph
Colourless
gummy liquid
8
a Reaction conditions: nitrone (1 mmole), furan derivative (1 equiv),dry ether, N2atmosphere, RT.
b All the spiro cycloadducts were characterised by IR, 1H NMR, MS, 13C NMR spectral data.
c Isolated yield after purification.

150 JOURNAL OF CHEMICAL RESEARCH 2010
(s, 6H, 2 x N-CH3), 3.12 (dd, 1H, J = 9.20, 8.32 Hz, C3H), 2.70 (dt,
1H, J = 8.10, 7.88 Hz, C4H), 2.35 (dt~m, 1H, CHCl), 1.88–1.42 (m,
6H); 13C NMR (CDCl ): δ 93.00 (CHCl), 87.55 (C ), 76.20 (C3), 55.20
(C4), 41.97 (N-CH3),340.24 (NH-CH3), 33.37, 351.50, 28.68, 26.00,
25.12, 23.40 (6 CH2 carbons); MS (m/z): 280 (M++2), 278 (M+), 263,
248, 156 (B.P), 141, 107; HRMS-EI: Calcd for C12H23O3N2Cl (M),
278.6710. Found: M+, 278.6698.
(S)-4-Chloro-4-((3S,4S,5R)-2-phenyl-4-(phenylamino)-1,6-dioxa-
2-azaspiro[4.4]nonan-3-yl)butan-1-ol (4): Dark red viscous liquid.
Yield 86%, Rf = 0.48; IR (KBr): 3485–3290 (br), 2962 (m), 2425 (m),
1620 (s), 1490 (s), 1260 (m), 1040 (m), 780 (s) cm−1; 1H NMR
(CDCl3): δ 6.98 - 6.92 (m, 10H, 2 x C6H5), 5.84 (dd, 1H, J = 8.55, 8.20
Hz, C3H), 5.00 (br, 1H, CH2OH, exchanged in D O), 3.60 (dt, 1H, J =
9.34, 7.88 Hz, C H), 3.40 (s, 1H, N–H proton of2NHPh), 2.68 (dt~m,
1H, CHCl), 1.904(dt, 1H, J = 6.82, 6.64 Hz, C3’H), 1.50–1.12 (m, 4H);
13C NMR (CDCl ): δ 138.00, 136.50, 134.30, 133.80, 131.75, 130.42,
129.46, 128.64 (3aromatic carbons), 95.10 (CHCl), 86.40 (C ), 73.75
(C3), 53.30 (C4), 30.20, 28.55, 27.34, 26.22, 25.73, 24.375 (6 CH2
carbons); MS (m/z): 404 (M++2), 402 (M+), 325, 310, 309, 218 (B.P),
107, 91, 77. HRMS-EI: Calcd for C22H27O3N2Cl (M), 402.7130.
Found: M+, 402.7122.
(S)-3-Amino-(3S,4S,5S)-2-methyl-4-(methylamino)-1,6-dioxa-2-
azaspiroisoxazole (5): Grey viscous liquid. Yield 84%, Rf = 0.52; IR
(KBr): 3430–3380 (br ), 3033 (m), 2955 (m), 1773 (s), 1662 (s), 1480
(s), 1282 (m), 1178 (s), 806 (s) cm−1; 1H NMR (CDCl3): δ 4.90 (br,s,
2H, NH2, exchanged in D O), 4.60 (br, 1H, NHCH3), 3.36 (s, 6H, 2 x
N-CH3), 3.00 (d, 1H, J = 27.54 Hz, C3H), 2.70 (dt, 2H, J = 6.24, 6.28
Hz, C3’2H), 2.38 (dt, 1H, J = 7.12, 6.70 Hz, C4H), 1.70–1.48 (m, 4H);
13C NMR (CDCl3): δ 88.50 (C5/C2’), 77.12 (C3), 56.26 (C4), 40.94
(N-CH3), 38.13 (NH-CH3), 32.07, 31.22, 29.34 (3’,4’,5’CH2 carbons);
MS (m/z): 187 (M+), 172, 157, 156 (B.P), 141. HRMS-EI: Calcd for
C8H17O2N3 (M), 187.1633. Found: M+, 187.1613.
(S)-3-Amino-(3S,4S,5S)-2-phenyl-4-(phenylamino)-1,6-dioxa-2-
azaspiroisoxazole (6): Dark grey viscous liquid.Yield 81%, Rf = 0.48;
IR (KBr): 3436–3390 (br ), 3030 (m), 2952 (m), 1780 (s), 1674 (s),
1480 (m), 1276 (m), 815 (s) cm−1; 1H NMR (CDCl3): δ 7.02–6.90 (m,
10H, 2 x C6H5), 5.86 (d, 1H, J = 6.30 Hz, C3H), 5.00 (br,s, 2H, NH ,
exchanged in D2O), 3.50 (dt, 2H, J = 6.74, 6.06 Hz, C3’ 2H), 3.328
(br,s,1H, NHC6H5), 2.70 (dt, 1H, J = 7.20, 6.18 Hz,C4H), 1.52–1.28
(m, 4H); 13C NMR(CDCl3): δ 137.21, 135.44, 134.00, 133.10, 130.66,
129.40, 128.32, 127.84 (aromatic carbons), 86.94 (C5/C2’), 74.24 (C3),
55.70 (C4), 27.87, 25.63, 24.00 (3’,4’,5’ CH2 carbons); MS (m/z): 311
(M+), 295, 218, 203 (B.P), 202, 92, 77; HRMS-EI: Calcd for
C18H21O2N3 (M), 311.2054. Found: M+, 311.2037.
(S)-3-Phenyl-(3S,4S,5S)-2-phenyl-4-(phenylamino)-1,6-dioxa-2-
azaspiroisoxazole (8): Colourless gummy liquid. Yield 78%, Rf =
0.48; IR (KBr): 3024 (m), 2950 (m), 1772 (s), 1670 (s), 1468 (m),
1382 (m), 805 (m), 780 (s) cm−1; 1H NMR (CDCl ): δ 7.50–6.62 (m,
15H, 3 x C H ), 5.84 (s,1H, NHC H5), 4.63 (d, 1H,3J = 6.06 Hz, C3H),
4.02 (dt, 16H,5J = 6.18, 6.20 Hz,6 C4H), 2.64 (dt, 2H, J = 5.28, 4.10
Hz,C3’2H), 2.00–1.26 (m, 4H); 13C NMR (CDCl3): δ 136.76, 136.53,
136.24, 135.15, 134.90, 134.62, 134.30, 133.78, 132.44, 132.18,
130.92, 130.37 (aromatic carbons), 83.22 (C5/C2’), 71.52 (C3), 52.89
(C4), 23.61, 22.57, 21.14 (3’,4’,5’ CH2 carbons); MS (m/z): 372 (M+),
295, 280, 218, 203 (B.P), 92, 77; HRMS-EI: Calcd for C24H24O2N2
(M), 372.2286. Found: M+, 372.2270.
The authors thank Dr M.P Kharel, Principal, Sikkim Govern-
ment College, Gangtok for providing facilities and constant
encouragement. We are pleased to acknowledge the financial
support from UGC, New Delhi (Grant no:34-304/2008-SR)
and also to CDRI, Lucknow for providing spectral data.
Received 23 January 2010; accepted 27 February 2010
Paper 100976 doi: 10.3184/030823410X12675422347141
Published online: 22 March 2010
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