Studies on the intermolecular cycloaddition of diphenylacetonitrile oxide with substituted olefins

Article abstract of DOI:10.1080/00397910802138777

We present our findings on the regio- and stereo chemical outcome of the cycloadditions of sterically crowded diphenylacetonitrile oxide towards mono and disubstituted electron deficient and electron rich olefins. The resultant Δ2-isoxazolines are further

Full text of DOI:10.1080/00397910802138777

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Studies on the Intermolecular
Cycloaddition of
Diphenylacetonitrile Oxide
with Substituted Olefins
Karuna S. Wankhede a , Vipraja V. Vaidya a
,
Hariharan Suriyanarayanan b , Manikrao M. Salunkhe
a & Girish K. Trivedi a b
a Institute of Science, Mumbai, India
b Indian Institute of Technology, Mumbai, India
Published online: 11 Jul 2008.
To cite this article: Karuna S. Wankhede , Vipraja V. Vaidya , Hariharan
Suriyanarayanan , Manikrao M. Salunkhe & Girish K. Trivedi (2008) Studies on the
Intermolecular Cycloaddition of Diphenylacetonitrile Oxide with Substituted Olefins,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 38:14, 2404-2412, DOI: 10.1080/00397910802138777
To link to this article: http://dx.doi.org/10.1080/00397910802138777
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Synthetic Communications1, 38: 2404–2412, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802138777
Studies on the Intermolecular Cycloaddition
of Diphenylacetonitrile Oxide with
Substituted Olefins
Karuna S. Wankhede,1 Vipraja V. Vaidya,1
Hariharan Suriyanarayanan,2 Manikrao M. Salunkhe,1
and Girish K. Trivedi1,2
1Institute of Science, Mumbai, India
2Indian Institute of Technology, Mumbai, India
Abstract: We present our findings on the regio- and stereo chemical outcome of
the cycloadditions of sterically crowded diphenylacetonitrile oxide towards mono
and disubstituted electron deficient and electron rich olefins. The resultant D2-
isoxazolines are further transformed to their corresponding b-hydroxy carbonyl
compounds employing Curran’s protocol.
Keywords: b-Hydroxy ketones; 1,3-Dipolar cycloaddition; Diphenylacetonitrile
oxide; Isoxazolines; Regioselectivity
1,3-Dipolar cycloaddition reactions of nitrile oxides to olefins are of con-
siderable interest as the resulting isoxazolines are versatile intermediates
in the synthesis of a variety of natural products.[1] In the cycloaddition
reactions of nitrile oxides with dipolarophiles, the formation of furoxane
(i.e., nitrile oxide dimmer) is a serious impediment. It hampers the puri-
fication of the desired cycloadduct, and the yield of the cycloaddition
reaction is brought down. One of the methods to overcome this problem
is blocking the nitrile oxide dimerization with the use of sterically
crowded nitrile oxide. Utilization of sterically crowded nitrile oxide in
intermolecular cycloadditions are of growing importance because evi-
dence suggests that yields of cycloadditions are maximized with respect
to the competing furoxane formation. Another important aspect of the
Received March 17, 2007
Address correspondence to Manikrao M. Salunkhe, Institute of Science, 15
Madam Cama Road, Mumbai 400 032, India. E-mail: mmsalunkhe@hotmail.com
2404

Cycloaddition of Diphenylacetonitrile Oxide with Substituted Olefins
2405
congested nitrile oxides is the high regioselectivity observed in their
cycloaddition reaction with substituted olefins, with the selective
formation of 5-substituted regiomer over the 4-substituted regiomer.[2]
Even though many sterically crowded nitrile oxides are employed in inter-
molecular cycloaddition, surprisingly utilization of diphenylacetonitrile
oxide (DPANO) is limited. In an earlier reports Eckstein and coworkers[3]
studied the 1,3-dipolar cycloaddition of DPANO with enol forms of acet-
oanilides, ethyl acetoacetate, and acetyl acetone, leading to isoxazole
derivatives. In the recent past, Baskaran et al.[4] have reported regioselec-
tive cycloaddition of rac. 1-(4-methoxy phenyl)-1-phenyl acetohydroxa-
moyl chloride with enantiomerically pure propargyl ethers in the
presence of triethylamine and diethyl ether. In the present work, we have
studied 1,3-dipolar cycloaddition of a sterically hindered DPANO with
the different olefins. The details of the work are presented in this article.
The nitrile oxide (DPANO) was generated in situ from the corre-
sponding chloro-oxime (1) prepared from b-nitrostyrene following the
procedure developed by Hurd and coworkers.[5] The nitrile oxide so
obtained was made to react with several olefins in dry ether as shown
in Scheme 1.
The yields of the desired cycloadducts are quantitative with respect to
furoxane. As expected in all the cases, only a single regioisomer was
1
obtained, which was characterized by H NMR and 13C NMR as 5-
substituted isoxazolines (Table 1). However, in the case of dicyclopenta-
diene (DCP), an inseparable mixture of two regio-isomeric exo-adducts[6]
was obtained in the ratio of 1:1. A similar observation was made by
Namboothiri and his coworkers[7] during the cycloaddition of acetonitrile
oxide and benzonitrile oxide with DCP.
That the cycloadduct 2h is indeed a regiomeric mixture could be con-
firmed by hydrogenating it in the presence of 10% Pd=C to the corre-
sponding dihydro product 3 (Scheme 2).
To generate b-hydroxy ketones and also to reascertain the regiochem-
istry of the derived cycloadducts, the isoxazolines 2c, 2d, and 2g were
made to undergo a hydrogenolysis reaction, using Curran’s protocol,[8]
Scheme 1. Cycloaddition of diphenyl hydroxamoyl chloride with olefins.

2406
K. S. Wankhede et al.
Table 1. Cycloaddition of (1) with olefins
Entry
1
Olefin
Cycloadduct
Yield(%)
Furoxane (%)
75
10
2
3
65
80
20
–
4
80
–
5
6
75
85
–
–
7
8
70
90
–
–

Cycloaddition of Diphenylacetonitrile Oxide with Substituted Olefins
2407
Scheme 2. Hydrogenation of compound 2h.
which revalidated the assigned regiochemistry and is in keeping with the
observation that sterically crowded nitrile oxides add to substituted ole-
fins to form 5-substituted cycloadducts. The structures assigned to
b-hydroxy ketones were duly supported by IR, 1H NMR, and 13C NMR
data (Scheme 3).
In conclusion, we have studied the regio- and stereo- outcomes of the
diphenyl acetonitrile oxide with different olefins, which have not been
studied earlier. To generate the b-hydroxy carbonyl system and also to
confirm the regiochemistry, the isoxazolines were made to undergo a
hydrogenolysis reaction, which confirmed the regiochemistry of isoxazo-
lines derivatives and is in keeping with the observation that sterically
crowded nitrile oxides regioselectively add to substituted olefin to form
5-substituted cycloadduct. Isoxazolines were converted to b-hydroxy car-
bonyl compounds; thus, following Curran’s protocol, a simple method
has been developed for the conversion of nitro olefins (b-nitrostyrene)
into a more useful b-hydroxy carbonyl system via the intermediary role
of nitrile oxide and isoxazoline cycloadduct.
Scheme 3. Hydrogenolysis of isoxazolines under Curran’s protocol.

2408
K. S. Wankhede et al.
EXPERIMENTAL
The products were characterized by IR, 1H NMR, 13C NMR, and
1
mass spectroscopy (MS). H NMR was recorded on a Jeol (300-MHz)
instrument using CDCl3 as solvent. GC-MS was recorded on a Schi-
madzu QP 2010 spectrophotometer equipped with a dp5 column. All
other chemicals and reagents were of analytical grade and purchased
from Sd-Fine Chemicals and Sigma-Aldrich Chemicals.
General Procedure for the Preparation of Isoxazolines
To a stirred solution of diphenyl acetohydroxamoyl chloride (10 mmol)
and olefin (20 mmol) maintained at room temperature, triethylamine
(10 mmol) in ether (20mL) was added dropwise. The addition was com-
pleted in 2 h. The reaction mixture was allowed to stir for an additional
3 h and further refluxed for 1 h. Triethylamine hydrochloride residue was
removed by washing with water; the organic layer was then dried over
anhydrous sodium sulphate and concentrated. The desired product was
separated by column chromatography.
Hydrogenation of Compound 2h
To a solution of cycloadduct 2h (0.341 g, 1 mmol) in tetrahydrofuran
(THF) (10 ml), 10% Pd=C (10 mg) was added and stirred under a hydro-
gen atmosphere at room temperature for 3 h. The reaction mixture was
filtered through a pad of Celite1, and the solvent was evaporated under
reduced pressure. The residue was purified by column chromatography to
provide the product 3 in quantitative yield.
SPECTRAL DATA
Compound 2a
White crystalline solid, mp 91ꢀC. IR (CHCl3): n ¼ 3500, 3380, 3020,
1620, 1600, 1495, 1450, 1330 cmꢁ1 1H NMR (300 MHz, CDCl3):
.
d ¼ 2.30 (t, 1H, J ¼ 6 Hz), 2.81–2.99 (m, 2H), 3.48–3.56 (m, 1H), 3.69–
3.76 (m, 1H), 4.63–4.72 (m, 1H), 5.17 (s, 1H), 7.23–7.35 (m, 10H) ppm.
13C NMR (75 MHz, CDCl3): d ¼ 37.75, 50.29, 63.61, 80.54,
127.14, 127.20, 128.57, 128.63, 128.76, 139.35, 160.51 ppm. MS (EI):
m=z ¼ 267 [Mþ ].

Cycloaddition of Diphenylacetonitrile Oxide with Substituted Olefins
Compound 2b
2409
White crystalline soild, mp 139 ꢀC. IR (CHCl3): n ¼ 3380, 3240, 1640,
1
1600, 1580 cmꢁ1. H NMR (300 MHz, CDCl3): d ¼ 3.16 (bs, 1H), 3.40
(d, 1H, J ¼ 12Hz), 3.80–3.98 (m, 5H), 4.64 (d, 1H, J ¼ 9Hz), 5.10 (s,
1H), 7.25–7.37 (m, 10H) ppm. 13C NMR (75 MHz, CDCl3): d ¼ 50.00,
53.20, 57.41, 60.04, 63.97, 81.83, 127.01, 127.54, 128.74, 128.95, 129.04,
138.77, 162.10 ppm. MS (EI): m=z ¼ 297 [Mþ].
Compound 2c
White solid, mp 70 ꢀC. IR (Nujol): n ¼ 2923, 2723, 1595, 1457, 1376,
1
1314, 1262 cmꢁ1. H NMR (300 MHz, CDCl3): d ¼ 2.84–2.92 (dd, 1H),
3.26–3.36 (dd, 1H), 5.20 (s, 1H), 5.54–5.61 (t, 1H), 7.18–7.29 (m, 15H)
ppm. 13C NMR (75 MHz, CDCl3): d ¼ 44.41, 50.27, 81.90, 125.68,
127.15, 127.20, 127.98, 128.63, 128.74, 139.40, 140.86, 159.52 ppm. MS
(EI): m=z ¼ 313 [Mþ ].
Compound 2d
White solid, mp 60 ꢀC. IR (CDCl3): n ¼ 3000, 1610, 1500, 1455, 1380,
1
1330, 1273 cmꢁ1. H NMR (300 MHz, CDCl3): d ¼ 1.68 (s, 3H), 2.96–
3.11 (q, 2H), 5.16 (s, 1H), 7.08–7.41 (m, 10H), 7.38–7.41 (m, 15H)
ppm. 13C NMR (75 MHz, CDCl3): d ¼ 27.97, 49.68, 50.38, 87.59,
124.68, 127.03, 127.17, 127.22, 128.38, 128.55, 128.64, 128.77, 139.45,
145.42, 160.01 ppm. MS (EI): m=z ¼ 327 [Mþ ].
Compound 2e
White solid, mp 96 ꢀC. IR (Nujol): n ¼ 3000, 2260, 1605, 1500, 1460,
1
1390, 1340 cmꢁ1. H NMR (300 MHz, CDCl3): d ¼ 3.22–3.38 (m, 2H),
5.20 (dd, 1H,), 5.24 (s, 1H), 7.12–7.54 (m, 10H) ppm. 13C NMR
(75 MHz, CDCl3): d ¼ 42.41, 46.64, 48.88, 49.71, 66.13, 127.69, 127.79,
128.39, 128.42, 128.65, 128.68, 128.97, 129.04, 135.47, 138.25,
162.80 ppm. MS (EI): m=z ¼ 262 [Mþ].
Compound 2f
Off-white solid, mp 63 ꢀC. IR (Nujol): n ¼ 2883, 2723, 1597, 1454, 176,
1179, 1090, 1032 cmꢁ1
(t, 3H), 2.81 (d, 1H), 2.88–2.90 (dd, 1H), 3.55 (t, 1H), 3.87 (t, 1H), 5.23
.
1H NMR (300 MHz, CDCl3): d ¼ 1.18–1.23

2410
K. S. Wankhede et al.
(s, 1H), 5.51 (d, 1H), 7.24–7.32 (m, 10H) ppm. 13C NMR (75 MHz,
CDCl3): d ¼ 14.97, 42.90, 50.06, 63.39, 102.42, 127.05, 127.21, 128.58,
128.64, 128.93, 139.50, 139.69, 160.41 ppm. MS (EI): m=z ¼ 281 [Mþ ].
Compound 2g
Yellow oil. IR (CHCl3): n ¼ 3040, 1750, 1610, 1505, 1460, 1380, 1280,
1
1230 cmꢁ1. H NMR (300 MHz, CDCl3): d ¼ 1.24–1.29 (t, 3H), 3.15 –
4.24 (m, 2H), 4.17–4.24 (q, 2H), 4.93–4.99 (dd, 1H), 5.21 (s, 1H), 7.12–
7.29 (m, 10H) ppm. 13C NMR (75 MHz, CDCl3): d ¼ 14.06, 40.22,
49.75, 61.77, 127.24, 127.39, 128.41, 128.52, 128.64, 128.76, 128.81,
139.02, 139.18, 159.34, 170.24 ppm. MS (EI): m=z ¼ 309 [Mþ ].
Compound 2h
ꢀ
White solid, mp 146 C. IR (Nujol): n ¼ 2923, 2856, 1596, 1458, 1376,
1
1161 cmꢁ1. H NMR (300 MHz, CDCl3): d ¼ 1.31–1.34 (d, 1H), 1.54–
1.63 (m, 2H), 1.87–2.27 (m, 2H), 2.50–2.69 (m, 2H), 2.98–3.10 (dd,
2H), 4.36–4.48 (dd, 1H), 4.92–4.97 (d, 1H), 5.38 & 5.61 (m, 1H), 5.53
(m, 1H), 7.31 (m, 10H) ppm. 13C NMR (75 MHz, CDCl3): d ¼ 31.79,
32.65, 35.13 & 35.63, 39.87, 41.07, 42.25, 43.86, 46.00, 47.77, 50.37 &
50.46, 50.71, 52.02, 52.79, 56.17 & 56.21, 82.58, 85.04, 127.24 & 127.42,
128.69, 128.4, 128.97, 129.01, 129.20, 131.02 & 131.40, 132.25, 139.93
& 140.34, 161.03 ppm. MS (EI): m=z ¼ 341 [Mþ ].
Compound 3
ꢀ
White Solid, mp 138 C. IR (Nujol): n ¼ 2924, 2856, 2723, 1459, 1376,
1
1157 cm ꢁ 1. H NMR (300 MHz, CDCl3): d ¼ 1.34–1.61 (m, 8H), 2.08
(s, 1H), 2.40–2.49 (m, 3H), 3.24–3.27 (d, 1H), 4.62–4.65 (d, 1H), 4.94
(s, 1H), 7.27–7.34 (m, 10H) ppm. 13C NMR (75 MHz, CDCl3):
d ¼ 26.27, 26.87, 28.30, 36.73, 43.50, 43.60, 44.20, 48.17, 50.08, 54.17,
83.50, 126.97, 127.19, 128.42, 128.72, 128.94, 139.64, 160.19 ppm. MS
(EI): m=z ¼ 343 [Mþ ].
Compound 4a
Yellow oil, IR (neat): n ¼ 3480, 3000, 1720, 1608, 1590, 1500, 1455, 1368,
1325 cm ꢁ 1. 1H NMR (300 MHz, CDCl3): d ¼ 1.47 (s, 3H), 2.93 (d, 1H),
3.25 (d, 1H), 4.57 (s, 1H), 4.90 (s, 1H), 6.85 (s, 1H), 7.13–7.31 (m, 14H)
ppm. 13C NMR (75 MHz, CDCl3): d ¼ 30.59, 53.39, 65.51, 73.61, 124.47,

Cycloaddition of Diphenylacetonitrile Oxide with Substituted Olefins
2411
126.71, 127.29, 127.49, 128.23, 128.62, 128.80, 128.93, 129.10, 137.03,
146.74, 210.21 ppm. MS (EI): m=z ¼ 330 [Mþ ].
Compound 4b
Yellow oil, IR (neat): n ¼ 3480, 3000, 1720, 1608, 1590, 1500, 1455,
1
1368 cmꢁ1. H NMR (300 MHz, CDCl3): d ¼ 2.93–2.98 (m, 2H), 3.28
(s, 1H), 5.09 (s, 1H), 5.14 (m, 1H), 7.18–7.29 (m, 15H) ppm. 13C NMR
(75 MHz, CDCl3): d ¼ 51.00, 64.98, 70.36, 125.65, 126.96, 127.36,
127.45, 127.66, 128.48, 128.72, 128.85, 128.98, 129.02, 137.53, 17.73,
142.62, 209.02 ppm. MS (EI): m=z ¼ 316 [Mþ ].
Compound 4c
White solid, mp 80ꢀC. IR (Nujol): n ¼ 3500, 2920, 2840, 1725, 1710, 1600,
1
1490, 1450, 1375 cmꢁ1. H NMR (300 MHz, CDCl3): d ¼ 1.23 (t, 2H),
3.03 (d, 2H), 3.18 (s, 1H), 4.21 (q, 2H), 4.48 (t, 1H), 5.15 (s, 1H), 7.08–
7.46 (m, 10H) ppm. MS (EI): m=z ¼ 312 [Mþ ].
ACKNOWLEDGMENT
Authors gratefully thank the University Grants Commission, New Delhi,
for the financial support.
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