Intramolecular low-temperature 1,3-dipolar cycloadditions of nitrones: synthesis of chromano-heterocycles

Article abstract of DOI:10.1016/j.tet.2007.03.086

In contrast to the reported facile intramolecular 1,3-dipolar cycloadditions of in-situ generated nitrone on heterocyclic systems, reactions of 2-(N-allyl/crotyl/cinnamyl-anilino)-3-formylchromones with N-phenyl-/methylhydroxylamine under comparable condi

Full text of DOI:10.1016/j.tet.2007.03.086

Tetrahedron 63 (2007) 4773–4778
Intramolecular low-temperature 1,3-dipolar cycloadditions of
nitrones: synthesis of chromano-heterocycles
a
Gurpinder Singh, M. P. S. Ishar, Vivek Gupta, Gurmit Singh,
a,*
b
a
b
Mohit Kalyan and Surinderjit Singh Bhella
a
a
Bio-Organic and Photochemistry Laboratory, Department of Pharmaceutical Sciences, Guru Nanak Dev University,
Amritsar-143 005, Punjab, India
b
Department of Physics, University of Jammu, Jammu Tawi-180 006, India
Received 28 October 2006; revised 25 February 2007; accepted 15 March 2007
Available online 18 March 2007
Abstract—In contrast to the reported facile intramolecular 1,3-dipolar cycloadditions of in-situ generated nitrone on heterocyclic systems,
reactions of 2-(N-allyl/crotyl/cinnamyl-anilino)-3-formylchromones with N-phenyl-/methylhydroxylamine under comparable conditions,
afford fused isoxazolidines only in low to moderate yields; the corresponding amides derived from rearrangement of in situ generated nitrones
are formed as major products. However, when reactions were carried by stirring the reactants at an ice-cold temperature in dichloromethane,
highly stereoselective intramolecular 1,3-dipolar cycloadditions lead to novel fused isoxazolidines in high yields (80–90%).
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
intramolecular 1,3-diploar cycloadditions to obtain chro-
mone-fused isoxazolidines are investigated.
1,3-Dipolar cycloadditions to olefinic and acetylenic dipolar-
ophiles are the most straightforward approach to regio- and
1
stereo-selective synthesis of five-membered heterocycles;
these have also been extensively exploited for the synthesis
2. Results and discussion
2
of precursors/ scaffolds for a variety of molecular frame-
works. In particular, the intramolecular 1,3-dipolar cyclo-
additions have shown potential in the synthesis of carbo- and
1
,2
The starting compounds 4a–c were obtained by a route re-
ported earlier (Scheme 1). Initially, the reactions of 4a–c
7
1
1
–3
were carried with N-phenyl-/methylhydroxylamine (R ¼
heterocyclic frameworks.
The immediate product of
Ph, Me) by stirring their dichloromethane solutions at
ambient temperature, which led to the formation of fused
isoxazolidines 5a, c–f, and 6c in low to moderate yield (5–
nitrone–olefin cycloaddition i.e., isoxazolidines have now
been well established as heterocyclic analogues of the five-
membered sugar moiety of nucleosides and a variety of
isoxazolidine-based molecules are being investigated for
37%) and corresponding amides 7a–f were obtained as major
4
products (44–90%). Carrying out reactions under more dras-
tic conditions such as refluxing their dry benzene solutions
and heating their toluene solutions in sealed tubes led to in-
creased formation of amides and no cycloadducts were iso-
lated; the results are summarized in Scheme 1 and Table 1.
antiviral, and anticancer activities. Recently, intramolecular
nitrone–olefin cycloadditions on carbo- and heterocyclic
systems have been utilized to obtain fused isoxazolidines
of either biological significance or the obtained isoxazo-
lidines have been cleaved to obtain useful synthetic precur-
2,3,5
sors.
However, intramolecular cycloadditions have
However, when aldehydes, 4a–c, were mixed with N-
methylhydroxylamine in dichloromethane at an ice-cold
temperature and the stirred solution was slowly brought to
the room temperature, regio- and stereo-selective intramo-
lecular 1,3-dipolar cycloadditions of the in situ generated
nitrones led to chromano–piperidine-fused isoxazolidines
stereochemical constraints and under forcing conditions the
nitrone to amide rearrangement may also intervene.
A variety of biological activities have been attributed to
molecules possessing chromone moiety and presently
6
5
d–f in very high yields (80–90%, Scheme 2) and the corre-
Keywords: Chromone; Nitrone; Isoxazolidine; 1,3-Dipolarcycloadditions;
Stereoselectivity; p-Facial selectivity.
sponding amides 7d–f were isolated as minor products; no
such improvement of yields was observed under similar con-
ditions with N-phenylhydroxylamine.
*
Corresponding author. Tel.: +91 183 2258802 09x3321; fax: +91 183
258820; e-mail: mpsishar@yahoo.com
2
0
040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.03.086

4774
G. Singh et al. / Tetrahedron 63 (2007) 4773–4778
O
O
O
O
O
O
O
Ph
O
O
O
O
N
H
benzene
H
PhNHOH
Br
R
H
+
H , Δ
NH
Ph
K2CO3
dry benzene
O
(2)
dry acetone
N
Ph
R
(1)
(3)
(4)
1
R NHOH
4a, R = H
4b, R = CH3
R1
H
R1
2
1
1
2
O
N
O
O
N O Hb 4c, R = Ph
O
NHR1
O
H
5
8
10
7
3
10
7
H
3
1
1a
3a
11a
3a
R
6
7
4
9
8
11
11b
Ph
9
8
11
3
11b
1
'
3'
+
+
H
5
N
H
4
5
N
4
2
O
N
Ph
R
O
O
2'
Hc
1
6
(6)
6
R = H, Me, Ph
1
Hd
Ph
Ph
(7)
(5)
R = Ph, Me
Scheme 1.
Table 1. Reaction time, reaction conditions, and % yield of various reaction products
1
R
Entry
R
Solvent
Reaction conditions
reaction time, h)
Product (% yield)
(
5
6
7
1
2
3
4
5
6
7
8
9
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
CH
CH
CH
Benzene
Benzene
Benzene
Toluene
Toluene
Toluene
2
2
2
Cl
Cl
Cl
2
2
2
Stir, rt (72)
Stir, rt (72)
Stir, rt (72)
Reflux (24)
Reflux (24)
Reflux (24)
Sealed tube, 140 C (5)
Sealed tube, 140 C (5)
Sealed tube, 140 C (5)
Stir, rt (48)
Stir, rt (48)
Stir, rt (48)
Reflux (24)
Reflux (24)
Reflux (24)
Sealed tube, 140 C (5)
Sealed tube, 140 C (5)
Sealed tube, 140 C (5)
5a (37)
5b (Nil)
5c (8)
6a (Nil)
6b (Nil)
6c (5)
7a (44)
7b (90)
7c (80)
7a (70)
7b (95)
7c (80)
7a (90)
7b (80)
7c (80)
7d (60)
7e (80)
7f (80)
7d (80)
7e (85)
7f (85)
7d (90)
7e (85)
7f (85)
CH
Ph
H
CH
Ph
H
CH
Ph
H
CH
Ph
H
CH
Ph
H
CH
Ph
3
3
3
3
3
3
5a (5)
6a (Nil)
6b (Nil)
6c (Nil)
6a (Nil)
6b (Nil)
6c (Nil)
6d (Nil)
6e (Nil)
6f (Nil)
6d (Nil)
6e (Nil)
6f (Nil)
6d (Nil)
6e (Nil)
6f (Nil)
5b (Nil)
5c (10)
5a (5)
ꢀ
ꢀ
ꢀ
5b (Nil)
5c (10)
5d (30)
5e (10)
5f (20)
5d (10)
5e (15)
5f (15)
5d (<5)
5e (Nil)
5f (10)
Ph
10
11
12
13
14
15
16
17
18
CH
CH
CH
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
3
3
3
CH
CH
CH
2
2
2
Cl
2
Cl
2
Cl
2
Benzene
Benzene
Benzene
Toluene
Toluene
Toluene
ꢀ
ꢀ
ꢀ
O
O
H
O
O
CH3
N
dry CH2Cl2
O
H
H
+
3
CH NHOH
NaHCO3
O
N
R
N
R
Ph
Ph
(4 a-c)
ice cold, stirred and
brought to ambient temp.
(
2 h)
H3C
2
O
N1
O
O
O
H
1
7
0
3
H
R
5
1
1a
3a
4
3
2
CH3
H
9
8
11
6
7
N
H
1
1b
5
N
H
+
4
3'
N 1'
Ph
R
O
8
O
2'
1
6
5
d, R = H (80%)
Ph
5
e, R = Me (85%)
f, R = Ph (90%)
7d, R = H (15%)
7e, R = Me (10%)
f, R = Ph (<5%)
5
7
Scheme 2.
The products were isolated by column chromatography and
have been characterized by detailed spectroscopic analysis,
including a comparison of the spectroscopic data with that
olefinic protons of the allylic moiety or aldehydic-H and
indicated the presence of an isoxazolidine moiety. The
assigned stereochemistry around the isoxazolidine moiety
5
a,8
5
a,8
of related compounds.
That the compound 5a is derived
is based on the value of J3a,11b¼8.4 Hz, indicating a cis rela-
5
a,8
1
1
13
from intramolecular 1,3-dipolar cycloaddition of an in situ
formed nitrone was established from its mass spectrum,
which revealed a M ion peak at m/z 396. Its H NMR spec-
tionship between these hydrogens.
Overall H and
C
13
NMR spectral assignments, aided by H– C hetero-COSY
experiments, corroborated the assigned structure. The
assigned C3a–C11b cis geometry in the case of obtained
+
1
trum indicated the absence of resonances attributable to

G. Singh et al. / Tetrahedron 63 (2007) 4773–4778
4775
cycloadducts 5a and c–f has been further established by an
X-ray crystallographic analysis of 5d (Fig. 1).
R
O
9
N
H
O
H
R
H
In the case of isomeric cycloadduct 6c the C1–H was ob-
servedasadoubletatd5.8(J¼4.3 Hz)andC11b–Hasabroad
singlet at d 4.23; lack of observable coupling between C11b–
H and C3a–H was indicative of a trans relationship. The
changes in the chemical shift values of C11b–H, C3a–H,
O
N
Ph
H H
(8)
5
a,10
Mechanistically, the regio- and stereo-chemical outcomes of
intramolecular cycloadditions of nitrones are dependent on
an interplay of various factors; the major contributing factors
being the conformational constraints and steric influences of
The formation of the obtained products
in the present investigations can be rationalized in term of
various approaches outlined in Figure 2.
and C3–H on going from 5c to 6c are as anticipated.
may be mentioned here that an alternative structure 8 for
It
the obtained products was rigorously ruled out on the basis
1
1
1
of obtained H NMR spectral data, including H– H connec-
tivities, though formation of such products has been reported
in intramolecular cycloadditions of nitrones in related sys-
8
e,11
the substituents.
8
e
tems. The structural assignments of 7a–f are also based
on spectroscopic analysis.
Approaches A and B differ in the conformation around the
0
N–C1 bond and consequently lead to different p-facial se-
lectivities, with approach A leading to the cis arrangement
between C11b–H and C3a–H (5a, c–f) and approach B lead-
ing to the trans relationship (6c). Approach A is favored both
at higher and lower temperatures and corresponds to an
endo-orientation of the substitutient R and exo-orientation
of the relatively bulky substituient on the dipolarophile in
the transition state. For steric reasons the endo-orientation
of the bulky substitutient (R¼Me, Ph) raises the barrier to
cycloaddition and alternative pathway of isomerization of
0
nitrone to amide becomes the predominant mode; for R ¼Ph
and R¼Me, and Ph cycloaddition is completely prohibited.
Carrying out the reactions of 4a–c with N-methylhrdoxyl-
amine at a low temperature and slowly bringing the reaction
mixture to the room temperature suppresses the competitive
formation of amide and leads to the formation of cyclo-
adducts in high yields. Mechanistically, the rearrangement
leading to the formation of amides from nitrones is known
1
2
to involve oxaziridines as intermediates.
3
. Conclusions
The investigations have provided easy access to chromone-
fused isoxazolidines by carrying out reactions at low
Figure 1. ORTEP diagram of 5d.
O
O
R'
R1
H
N
O
O
N O
O
H
R
R
H
H
H
N
Ph
H
N
Ph
H
5
A
O
R1
R'
N
H
O
O
N O
O
O
R1
H
H
R
O
H
R
N
1
H
R NHOH
O
H
H
4
O
N
N
Ph
N
R
H
6
Ph
Ph
B
R1
N
R1
O
O
O
H
N
R
H
O
H
H
N
H
H
O
R
H
O
N
Ph
H
H
H
8
Ph
C
Figure 2.

4776
G. Singh et al. / Tetrahedron 63 (2007) 4773–4778
temperature, which helps to circumvent the isomerization of
nitrones to the corresponding amides.
the residue was resolved by column chromatography over
silica gel (60–1200 mesh, packed in hexane) using hexane/
ethyl acetate gradient as an eluent to obtain adduct 5a–c
along with amide 7a–c.
4. Experimental
Adduct (% yield) 5a (5); 5b (nil); 5c (10); 5d (<5); 5e (nil);
5f (10); Amide 7a (90); 7b (80); 7c (80); 7d (90); 7e (85); 7f
4
.1. General information
(85).
Starting materials and reagents were purchased from com-
mercial suppliers and used after further purification (crystal-
lization/distillation). Bruker AC-200 FT (200 MHz) and
JEOL (300 MHz) NMR spectrometers were used to record
the H NMR and C NMR (50 and 75 MHz) spectra. Chem-
ical shifts are reported in parts per million, tetramethylsilane
is used as the internal standard and J values in hertz. IR spec-
tra were recorded on Shimadzu 8400 S FT-IR spectropho-
tometer as KBr pellets. Mass spectra, EI and ESI-methods,
were recorded on Shimadzu GCMS-QP-2000A and Bruker
Daltonics Esquire 300 mass spectrometers, respectively.
Elemental analyses were carried out on a Perkin–Elmer
4.1.3.1. Adduct (5a). Colorless crystalline solid (37%);
mp 112–113 C (CHCl /hexane, 1:2); [Found: C, 75.82; H,
ꢀ
3
4.96; N, 6.98; C H N O requires C, 75.74; H, 5.08; N,
2
5 20 2 3
1
13
7.07]; nmax (KBr) 1646, 1628, 1596, 1592, 1516, 1504,
1487, 1443, 1382 cm ; dH (CDCl , 200 MHz) 8.19 (dd,
ꢁ
1
3
1H, J 7.7 & 1.4 Hz, C10–H), 7.49–7.41 (m, 4H, Ar–Hs),
7.32–7.26 (m, 6H, Ar–Hs), 7.07 (d, 2H, J 8.3 Hz, Ar–H),
6.97 (t, 1H, J 7.2 Hz, Ar–Hs), 5.39 (d, 1H, J 8.4 Hz, C11b–
H), 4.43 (t, 1H, J 8.1 Hz, C3–H), 4.07–3.99 (m, 2H, C3–H
& C4–H), 3.75 (dd, 1H, J 12.4 & 2.2 Hz, C4–H), 3.21–3.17
(m, 1H, C3a–H); d (CDCl , 75 MHz) 175.2(C11), 159.1
C
3
2
40C elemental analyzer and are reported in percent atomic
(C5a), 152.9 (C6a), 150.7 (q), 141.6 (q), 132.0 (CH), 129.0
(CH), 128.5 (CH), 125.8 (CH), 125.1 (CH), 124.4 (CH),
124.1 (CH), 123.1 (C10a), 121.7 (CH), 116.3 (C7), 114.8
abundance. All melting points are uncorrected and measured
in an open glass-capillaries using Veego Precision Digital
Melting Point Apparatus.
(CH), 98.7 (C11a), 68.9 (C3), 62.3 (C11b), 50.8 (C4), 40.5
(C3a); m/z (EI) 396 (M , 21), 381 (21), 380 (24), 355 (19),
169 (100).
+
4
.1.1. Reaction of 2-(N-allyl/crotyl/cinnamyl-anilino)-3-
formylchromone (4a–c) with N-phenyl/methyl-hydroxyl-
amine at room temperature. To a solution of 2-(N-allyl/
crotyl/cinnamyl-anilino)-3-formylchromone (300 mg) in
dry CH Cl (50 mL) was added N-phenyl/methyl-hydroxyl-
4.1.3.2. Adduct (5c). A cream colored semi-solid (8%);
mp 102–104 C (CHCl /hexane, 1:3); [Found: C, 78.95; H,
ꢀ
5.27; N, 5.76; C H N O requires C, 78.79; H, 5.12; N,
3
2
2
31 24 2 3
amine (1 M equiv) and the solution was stirred at room tem-
perature. After the completion of reaction (TLC), solvent
was removed under vacuum and the residue was resolved
by column chromatography over silica gel (60–1200 mesh,
packed in hexane) using hexane/ethyl acetate gradient as
an eluent to obtain adduct 5a and 5c–f along with amide
5.93]; d (CDCl , 200 MHz) 8.10 (dd, 1H, J 7.6 & 1.4 Hz,
H 3
C10–H), 7.71 (d, 1H, J 7.12 Hz, Ar–H), 7.62–7.21 (m, 9H,
Ar–Hs), 7.19–7.00 (m, 8H, Ar–Hs), 5.31 (d, 1H, J 6.8 Hz,
C3–H), 5.23 (d, 1H, J 7.4 Hz, C11b–H), 4.12 (dd, 1H, J
12.3 & 3.9 Hz, C4–H), 3.78 (dd, 1H, J 12.3 & 5.4 Hz, C4–
+
H), 3.04–2.98 (m, 1H, C13–H); m/z (ESI) 474.4 (M +2,
32), 473.3 (M +1, 100).
+
7
a–c.
4
.1.2. Reaction of 2-(N-allyl/crotyl/cinnamyl-anilino)-3-
4.1.3.3. Adduct (6c). A cream colored solid (5%); mp
147–148 C (CHCl /hexane, 1:2); [Found: C, 78.61; H,
ꢀ
5.03; N, 5.75; C H N O requires C, 78.79; H, 5.12; N,
formylchromone (4a–c) with N-phenyl/methyl-hydroxyl-
amine in dry benzene. To a solution of 2-(N-allyl/crotyl/
cinnamyl-anilino)-3-formylchromone (300 mg) in dry benz-
ene (50 mL) was added N-phenyl/methyl-hydroxylamine
3
3
1 24 2 3
5.93]; dH (CDCl , 200 MHz) 8.31(br d, 1H, J 6.4 Hz,
3
C10–H), 7.71(d, 1H, J 7.1 Hz, ArH), 7.21–7.62(m, 9H,
Ar–Hs), 7.19–7.00 (m, 8H, Ar–Hs), 5.80 (d, 1H, J 4.3 Hz,
C3–H), 4.23(br d, 1H, C11b–H), 3.97–3.90 (m, 2H, C4–
(
1 M equiv) and the solution was stirred with refluxing under
anhydrous conditions, After the completion of reaction
TLC), solvent was removed under vacuum and the residue
was resolved by column chromatography over silica gel (60–
200 mesh, packed in hexane) using hexane/ethyl acetate
gradient as an eluent to obtain adduct 5a–c along with amide
a–c.
(
Hs), 2.79–2.74 (m, 1H, C3a–H); dC (CDCl , 75 MHz)
3
176.0 (C11), 159.0 (C5a), 153.0 (C7), 150.4 (q), 141.6 (q),
141.2 (q), 132.3 (CH), 129.3 (CH), 129.0 (CH), 128.3
(CH), 127.8 (CH), 127.0 (CH), 126.4 (CH), 126.0 (CH),
125.4 (CH), 124.9 (C10a), 121.1 (CH), 116.3 (C9), 114.6
1
7
(CH), 95.0 (C11a), 73.0 (C3), 68.6 (C11b), 50.9 (C4), 47.9
(C3a); m/z (ESI) 495 (M +Na), 472 (M ).
+
+
Adduct (% yield) 5a (5); 5b (nil); 5c (10); 5d (10); 5e (15); 5f
(15); Amide 7a (70); 7b (75); 7c (80); 7d (80); 7e (85); 7f
(85).
4.1.3.4. Amide (7a). A cream colored solid (44%); mp
ꢀ
9
5–96 C (CHCl /hexane, 1:3); [Found: C, 75.34; H, 4.82;
3
4
.1.3. Reaction of 2-(N-allyl/crotyl/cinnamyl-anilino)-3-
N, 6.95; C H N O requires C, 75.74; H, 5.08; N, 7.07];
25 20 2 3
formylchromone (4a–c) with N-phenyl/methyl-hydroxyl-
amine in dry toluene (sealed tube). To a solution of 2-(N-
allyl/crotyl/cinnamyl-anilino)-3-formylchromone (300 mg)
in dry toluene (50 mL) was added N-phenyl/methyl-hydr-
oxylamine (1 M equiv) and the solution was heated in Pyrex
nmax (KBr) 3350, 1635, 1605, 1583, 1502, 1466, 1441,
1395 cm ; dH (CDCl , 200 MHz) 9.94 (s, 1H, D O ex-
ꢁ
1
3
2
changeable, amidic-H), 7.83 (br d, 1H, J 7.5 Hz, C5–H),
6.83–7.47 (m, 13H, Ar–Hs), 5.93–6.06 (m, 1H, C2 –H),
0
5.37 (d, 1H, J 17.2 Hz, C3 –H), 5.17 (d, 1H, J 10.1 Hz,
0
C3 –H), 4.53 (d, 2H, C1 –Hs); d (CDCl , 75 MHz) 171.4
ꢀ
0
0
glass sealed tube at 140 C for 5 h. After the completion of
reaction (TLC), solvent was removed under vacuum and
C
3
(C4), 167.5 (CONH ), 160.8 (C2), 152.1 (C8a), 142.9 (q),
2

G. Singh et al. / Tetrahedron 63 (2007) 4773–4778
4777
+
1
1
36.2 (q), 132.4 (CH), 129.1 (CH), 128.8 (CH), 128.2 (CH),
27.5 (CH), 126.5 (CH), 125.0 (CH), 125.7 (CH), 125.1
44.9 (N–CH ), 38.2 (C3a); m/z (ESI) 356.97 (M +Na), 334
3
(M ).
+
(
9
CH), 123.1 (C4a), 122.1 (CH), 117.3 (CH ), 116.2 (CH),
2
6.9 (C3), 53.2 (C1 ); m/z (EI) 305 (M ꢁ91, 23), 132 (100).
0
+
4.1.4.2. Adduct (5e). A cream colored solid (85%); mp
ꢀ
9
2–93 C (CHCl /hexane, 1:3); [Found: C, 72.63; H, 5.82;
3
4.1.3.5. Amide (7b). A cream colored solid (90%); mp
9–100 C (CHCl /hexane, 1:3); [Found: C, 76.49; H,
N, 7.87 C H N O requires C, 72.40; H, 5.79; N, 8.04];
21 20 2 3
ꢀ
.63; N, 6.56 C H N O requires C, 76.08; H, 5.40; N,
9
5
6
1
nmax (KBr) 1612, 1591, 1548, 1494, 1465, 1429, 1407,
3
ꢁ
1311, 1274, 1217, 1174 cm ; d (CDCl , 200 MHz) 8.14
H 3
1
2
6
22
2
3
.82]; nmax (KBr) 3310, 1639, 1609, 1591, 1512, 1491,
482, 1462, 1425 cm ; d (CDCl , 200 MHz) 9.92 (s, 1H,
(dd, 1H, J 7.7 & 1.4 Hz, C10-H), 7.49–7.38 (m, 4H, Ar–
H), 7.34–7.32 (m, 3H, Ar–Hs), 7.01 (d, 1H, J 8.1 Hz, Ar–
H), 4.16 (d, 1H, J 5.6 Hz, C3H), 4.06 (d, 1H, J 11.4,
C11b–H), 3.95–3.89 (m, 1H, C4H), 3.70–3.61 (m, 1H,
C4H), 3.37–3.29 (m, 1H, C3aH), 2.93 (s, 3H, N–CH3),
1.38 (d, 3H, J 6.1 Hz, CH ); d (CDCl , 75 MHz) 175.3
ꢁ
1
H
3
D O exchangeable, amidic-H), 7.83 (br d, 1H, J 7.5 Hz,
2
C5–H), 7.47–7.06 (m, 13H, Ar–Hs), 5.73–5.57 (m, 2H,
0
0
0
C2 –H & C3 –H), 4.46 (br d, 2H, C1 –Hs), 1.64 (d, 3H, J
.8 Hz, –CH ); d (CDCl , 75 MHz) 171.4 (C4), 167.3
4
3
C
3
3
C
3
(
1
(
1
(
3
CONH ), 160.5 (C2), 152.2 (C8a), 142.8 (q), 136.3 (q),
2
(C]O), 159.1 (C5a), 152.7 (C6a), 141.3 (q), 132.1 (CH),
129.2 (CH), 127.1 (CH), 125.7 (CH), 125.5 (CH), 124.7
(CH), 122.6 (C10a), 116.2 (C7), 92.3 (C11a), 76.2 (C3),
32.36 (CH), 129.1 (CH), 128.7 (CH), 128.2 (CH), 127.5
CH), 126.8 (CH), 126.5 (CH), 125.8 (CH), 125.7 (CH),
25.0 (CH), 123.1 (C4a), 122.0 (CH), 116.2 (CH), 97.2
60.2 (C11b), 51.3 (C4), 44.9 (N–CH ), 14.0 (CH3); m/z
3
0
+
+
+
C3), 52.6 (C1 ), 17.6 (CH ); m/z (EI) 318 (M ꢁ92, 19),
(ESI) 370.99 (M +Na), 348 (M ).
3
+
17 (M ꢁ93, 17), 169 (100).
4.1.4.3. Adduct (5f). A cream colored solid (90%); mp
148–49 C (CHCl /hexane, 1:3); [Found: C, 76.19; H,
ꢀ
5.46; N, 6.69 C H N O requires C, 76.08; H, 5.40; N,
6.82]; nmax (KBr) 1627, 1614, 1593, 1552, 1483, 1465,
4.1.3.6. Amide (7c). A cream colored solid (80%); mp
04–105 C (CHCl /hexane, 1:3); [Found: C, 78.93; H,
3
ꢀ
.27; N, 5.39 C H N O requires C, 78.79; H, 5.12; N,
1
5
5
1
3
26 22 2 3
3
1 24 2 3
ꢁ
1
.93]; nmax (KBr) 3320, 1640, 1615, 1582, 1520, 1478,
455, 1418 cm ; dH (CDCl , 200 MHz) 10.20 (s, 1H,
1434, 1309, 1299, 1271, 1255, 1222 cm ; dH (CDCl3,
200 MHz) 8.16 (dd, 1H, J 7.7 & 1.6 Hz, C10–H), 7.50–
7.43 (m, 7H, Ar–Hs), 7.39–7.28 (m, 5H, Ar–Hs), 7.0 (d,
1H, J 7.8 Hz, Ar–H), 4.74 (d, 1H, J 2.7 Hz, C3H), 4.36 (d,
1H, J 5.5 Hz, C11b–H), 4.22 (d, 1H, J 11.3 Hz, C4H),
ꢁ
1
3
D O exchangeable, amidic-H), 8.20 (br d, 1H, J 7.80 Hz,
2
C5–H), 7.42–7.27 (m, 18H, Ar–Hs), 6.58 (d, 1H, J
0 0
5.9 Hz, C3 –H), 6.37–6.26 (dt, 1H, J 15.9 & 5.9 Hz, C2 –
1
0
+
H), 4.75 (d, 2H, J 5.9 Hz, C1 –Hs); m/z (EI) 381 (M ꢁ91,
3.85–3.76 (m, 1H, C4H), 3.07 (s, 3H, NCH ), 2.65–2.58
3
+
3
0), 380 (M ꢁ92, 45), 116 (100).
(m, 1H, C3aH); d (CDCl , 75 MHz) 174.9 (C]O), 158.8
C
3
(C5a), 152.6 (C6a), 141.4 (q), 140.3 (q), 131.9 (CH), 129.1
4
.1.4. Reaction of 2-(N-allyl/crotyl/cinnamyl-anilino)-3-
(CH), 128.3 (CH), 127.9 (CH), 127.0 (CH), 126.2 (CH),
126.4 (CH), 125.6 (CH), 124.5 (CH), 122.6 (C10a), 116.1
(C7), 95.9 (C11a), 82.1 (C3), 60.5 (C11b), 51.3 (C4), 46.1
formylchromone (4a–c) with N-methyl-hydroxylamine-
hydrochloride at low temperature. To an ice-cold solution
of 2-(N-allyl/crotyl/cinnamyl-anilino)-3-formylchromone
+
+
(NCH ), 44.5 (C3a); m/z (ESI) 433.1 (M +Na), 410 (M ).
3
(
300 mg) in dry CH Cl (50 mL) were added N-methyl-
2 2
hydroxylamine-hydrochloride (1 M equiv) and NaHCO3
excess), suspension was stirred for an hour, the stirred sus-
4.1.4.4. Amide (7d). A cream colored solid; mp 99–
ꢀ
(
100 C (CHCl /hexane, 1:3); [Found: C, 71.92; H, 5.51; N,
3
pension was brought to ambient temperature in 30 min and
was stirred in excess for another 30 min at room tempera-
ture. After the completion of reaction (TLC), the suspension
was filtered and NaHCO3 was washed with CH Cl
8.13 C H N O requires C, 71.84; H, 5.43; N, 8.38]; n
max
2
0
18
2
3
ꢁ
1
(KBr) 3305, 1615, 1604, 1556, 1529, 1487, 1429 cm ; dH
(CDCl , 200 MHz) 7.78 (dd, 1H, J 7.1 & 1.4 Hz, C5–H),
3
7.41–7.36 (m, 3H, Ar–Hs), 7.33–7.18 (m, 5H, Ar–Hs),
6.10–5.87 (m, 1H, C2 –H), 5.30 (dd, 1H, J 17.1 & 1.3 Hz,
2
2
0
C3 –H), 5.13 (dd, 1H, J 10.2 & 1.2 Hz, C3 –H), 4.47 (d,
(
2ꢂ20 mL), combined extracts were evaporated under re-
0
2H, J 5.4 Hz, C1 –Hs), 3.88 (s, 3H, NCH ); d (CDCl3,
0
duced pressure and the residue was resolved by column
chromatography over silica gel (60–120 mesh, packed in
hexane) using hexane/ethyl acetate gradient as an eluent to
obtain adduct 5d–f along with amide 7d–f.
0
75 MHz) 171.0 (C]O), 167.5 (CONH), 160.5 (C2), 149.5
(C8a), 142.4 (q), 136.0 (q), 131.8 (CH), 129.3 (CH), 128.4
3
C
(CH), 128.1 (CH), 126.4 (CH), 126.2 (CH), 126.0 (CH),
124.8 (CH), 115.9 (CH), 52.6 (C1 ); m/z (ESI) 357
(M +Na), 334 (M ).
0
4.1.4.1. Adduct (5d). A cream colored solid (80%); mp
82–184 C (CHCl /hexane, 1:3); [Found: C, 71.93; H,
ꢀ
.52; N, 8.13 C H N O requires C, 71.84; H, 5.43; N,
+
+
1
5
8
1
3
2
0 18 2 3
.38]; nmax (KBr) 1614, 1589, 1548, 1479, 1467, 1433,
423, 1361, 1298, 1267 cm ; d (CDCl , 200 MHz) 8.13
4.1.4.5. Amide (7e). A cream colored solid; mp 110–
112 C (CHCl /hexane, 1:3); [Found: C, 72.52; H, 5.84; N,
ꢁ
1
ꢀ
7.91 C H N O requires C, 72.40; H, 5.79; N, 8.04];
H
3
3
(
dd, 1H, J 7.7 & 1.5 Hz, C10H), 7.84–7.48 (m, 4H, Ar–
2
1 20 2 3
Hs), 7.36–7.26 (m, 3H, Ar–Hs), 7.01 (d, 1H, J 7.6 Hz, Ar–
H), 4.31 (t, 1H, J 7.2 Hz, C3H), 4.11 (d, 1H, J 4.2 Hz,
C4H), 4.04 (d, 1H, J 11.5 Hz, C11b-H), 3.68–3.63 (m, 2H,
nmax (KBr) 3305, 1614, 1593, 1550, 1497, 1463, 1434,
1406, 1218, 1107 cm ; dH (CDCl , 300 MHz) 7.79 (d,
ꢁ
1
3
1H, J 6.3 Hz, Ar–H), 7.45–7.43 (m, 2H, Ar–Hs), 7.42–
7.31 (m, 2H, Ar–Hs), 7.26–7.16 (m, 4H, Ar–Hs), 5.64–
C3-H & C4-H), 2.96 (s, 3H, N–CH ), 2.80–2.78 (m, 1H,
3
0
C1 Hs), 3.14 (d, 3H, J 5.2 Hz, NH–CH ), 1.65 (d, 3H, J
0
C3a-H); d (CDCl , 75 MHz) 175.1 (C]O), 158.7 (C5a),
C
5.53 (m, 2H, C2 H & C3 H), 4.40 (d, 2H, J 4.8 Hz,
3
0
4.8 Hz, C3 H); d (CDCl , 50 MHz) 171.0 (C]O), 167.5
1
(
1
52.8 (C6a), 141.6 (q), 131.9 (CH), 129.3 (CH), 127.1
CH), 125.8 (CH), 125.7 (CH), 124.7 (CH), 122.8 (C10a),
16.3 (C7), 93.2 (C11a), 68.5 (C3), 61.1 (11b), 51.5 (C4),
3
0
(CONH), 160.5 (C2), 149.5 (C8a), 142.4 (quat.), 136.0
C
3

4778
G. Singh et al. / Tetrahedron 63 (2007) 4773–4778
(
1
(
(
quat.), 131.8 (CH), 129.3 (CH), 128.4 (CH), 128.1 (CH),
26.4 (CH), 126.2 (CH), 126.0 (CH), 124.8 (CH), 115.9
P.; Anoro, S.; Franco, F. L.; Merchan, T. T.; Tunon, V. J. Org.
Chem. 2000, 65, 1590; (j) Dagoneau, C.; Tomassini, A.;
Denis, J.-N.; Vallee, Y. Synthesis 2001, 150; (k) Mernyak, E.;
Benedek, G.; Schneider, G.; Wolfling, J. Synlett 2005, 637;
0
CH), 97.3 (C3), 52.6 (C1 ), 27.7 (NH–CH ), 17.7
3
0
+
+
C3 CH ); m/z (ESI) 370.98 (M +Na), 348.98 (M ).
3
(
2002, 43, 657.
l) Kanemasa, S.; Ueno, N.; Shirahase, M. Tetrahedron Lett.
ꢀ
CHCl /hexane, 1:3); [Found: C, 76.12; H, 5.54; N, 6.73
4
.1.4.6. Amide (7f). A cream colored solid; mp 90–91 C
(
3. (a) Frank, E.; Wolfing, J.; Aukszi, B.; Koning, V.; Schneider,
T. R.; Schneider, G. Tetrahedron 2002, 58, 6843; (b) Aurich,
H. G.; Geiger, M.; Gentes, C.; Harmas, K.; Coster, H.
Tetrahedron 1998, 54, 3281; (c) Narayanan, I. N.; Hassner,
A.; Gottlieb, H. E. J. Org. Chem. 1997, 62, 485; (d) Zaho,
Q.; Han, F.; Romero, D. L. J. Org. Chem. 2000, 67, 3317; (e)
Gu, Y. G.; Zhang, X.; Clark, R. F.; Djuric, S. W.; Ma, Z.
Tetrahedron Lett. 2004, 45, 3051.
4. (a) Chiacchio, U.; Balestrieri, E.; Macchi, B.; Iannazzo, D.;
Piperno, A.; Rescifina, A.; Romeo, R.; Saglimbeni, M.;
Sciortino, T.; Vincenza, V.; Mastino, A.; Romeo, G. J. Med.
Chem. 2005, 48, 1389 and references cited therein; (b)
Chiacchio, U.; Corsaro, A.; Iannazzo, D.; Piperno, A.;
Pistara, V.; Rescifina, A.; Romeo, R.; Sindona, G.; Romeo,
G. Tetrahedron: Asymmetry 2003, 14, 2717.
5. (a) Gotoh, M.; Mizui, T.; Sun, B.; Hiryama, K.; Noguchi, M. J.
Chem. Soc., Perkin Trans. 1 1995, 1857; (b) Gotoh, M.; Sun, B.;
Hiryama, K.; Noguchi, M. Tetrahedron 1996, 52, 887; (c)
Noguchi, M.; Yamada, K. Synthesis 1993, 145; (d) Mora de
la, M. A.; Cuevas, E.; Muchowski, J. M.; Cruz Almanza, R.
Tetrahedron Lett. 2001, 42, 5351; (e) Noguchi, M.; Okada,
H.; Nishimura, S.; Yamagata, Y.; Takamura, S.; Tanaka, M.;
Kakehi, A.; Yamamoto, H. J. Chem. Soc., Perkin Trans. 1
1999, 185.
6. (a) Morris, J.; Wishka, D. G.; Lin, A. H.; Humphery, W. R.;
Wiltse, A. L.; Gammill, R. B.; Judge, T. M.; Bisaha, S. N.;
Olds, N. L.; Jacob, C. S.; Bergh, C. L.; Cudahy, M. M.;
Williams, D. J.; Nishijawa, E. E.; Thomas, E. W.; Gorman,
R. R.; Benjamin, C. W.; Shebuski, R. J. J. Med. Chem. 1993,
3
C H N O requires C, 76.08; H, 5.40; N, 6.82]; n
max
2
6
22
2
3
(
KBr) 3305, 1627, 1552, 1487, 1427, 1402, 1255, 1217,
ꢁ
157, 1112, 1074, 1026 cm ; d (CDCl , 300 MHz) 13.7
H 3
1
1
(
br, 1H, NH), 7.81 (d, 1H, J 7.8 Hz, Ar–H), 7.75 (unresolved
dd, 1H, Jw4.7 Hz, Ar–H), 7.54–7.35 (m, 3H, Ar–Hs), 7.39–
.23 (m, 4H, Ar–Hs), 7.21–7.14 (m, 2H, Ar–Hs), 7.08–7.03
7
0
m, 2H, Ar–Hs), 6.55 (d, 1H, J 15.9 Hz, C3 H), 6.30 (td, 1H,
J 15.9 & 6.0 Hz, C2 H), 4.62 (d, 2H, J 6.0 Hz, C1 Hs), 2.72
(
0
0
(
(
(
s, 3H, N–CH ); d (CDCl , 50 MHz) 171.0 (C]O), 164.6
3 C 3
CONH), 158.1 (C2), 152.3 (C8a), 143.9 (quat.), 136.8
quat.), 133.2 (quat.), 132.0 (CH), 129.1 (CH), 128.3 (CH),
1
28.2 (CH), 127.4 (CH), 126.5 (CH), 126.4 (CH), 126.3
(
CH), 125.9 (CH), 124.8 (CH), 123.1 (CH), 115.9 (CH),
0
9.1 (C3), 52.9 (C1 ), 27.7 (NH–CH ); m/z (ESI) 433.08
3
M +Na), 410 (M ).
9
(
+
+
Acknowledgements
The work was supported by research grant [E-7-14/2003
FD-III)] from University Grants Commission (UGC),
(
Govt. of India. Gurpinder Singh also thanks UGC for Project
Fellowship. NMR, 300 MHz, facility funded by Department
of Science and Technology, Govt. of India, at Guru Nanak
Dev University, Amritsar, is gratefully acknowledged.
References and notes
3
6, 2026; (b) Gross, A.; Borcherding, D. R.; Friedrich, D.;
1
. (a) Carruthers, W. R. Cycloadditions in Organic Synthesis;
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Oppolozer, W.; Weber, H. P. Tetrahedron Lett. 1970, 1121; (c)
Gree, R.; Carric, R. Tetrahedron Lett. 1972, 2987; (d) Gree, R.;
Tonnard, F.; Carric, R. Tetrahedron 1976, 57, 8323; (e)
Broggini, G.; Rosa, C. L.; Tenanco, A.; Zechi, G.
Tetrahedron 1976, 57, 8323.
1991; Vol. 5, Chapter 3; (e) Frederickson, M. Tetrahedron
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Rev. 1998, 98, 863; (g) Padwa, A.; Schoffstall, A. M.
Advances in Cycloaddition; Curran, D., Ed.; JAI: Greenwich,
CT, 1990; p 2.
9. Crystallographic data for compound 5d is deposited (CCDC
No. 604656).
2
. (a) Simonsen, K. B.; Bayon, P.; Hazell, R. G.; Goethelf, K. V.;
Jorgensen, K. A. J. Am. Chem. Soc. 1999, 121, 3845; (b)
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R.; Kikuchi, M.; Miyawaki, T.; Mita, N.; Yamashita, M.;
Ishibashi, H.; Sakamoto, M. J. Org. Chem. 2000, 65, 8544;
10. (a) Huisgen, R.; Grashey, R.; Hauck, H.; Seidl, H. S. Chem. Ber.
1968, 101, 2548; (b) Huisgen, R.; Hauck, H.; Seidl, H. S.;
Berger, M. Chem. Ber. 1969, 102, 1117; (c) Kamaanitzky,
A. V.; Levina, I. S.; Mortikora, E. I.; Shitkin, V. M.;
Edyanov, B. S. Tetrahedron 1977, 33, 2135; (d) Girdhar,
N. K.; Ishar, M. P. S. Tetrahedron Lett. 2000, 41, 7551 and
references cited therein.
11. (a) Werner, K. M.; de los Santos, J. M.; Weinreb, S. M.
J. Org. Chem. 1999, 64, 4865; (b) Hems, W. P.; Tan, C. H.;
Stork, T.; Feeder, N.; Holmes, A. B. Tetrahedron Lett.
1999, 40, 1393.
(
c) Aurich, H. G.; Geiger, M.; Gentes, C.; Harms, K.; Koster,
H. Tetrahedron 1998, 54, 3181; (d) Goethelf, K. V.; Hazell,
R. G.; Jorgensen, K. A. J. Org. Chem. 1998, 63, 5483; (e)
Chiacchio, U.; Corsaro, A.; Iannazzo, D.; Piperno, A.;
Procopio, A.; Rescifena, A.; Romeo, G.; Romeo, R. J. Org.
Chem. 2002, 67, 4380; (f) Knobloch, K.; Eberbach, W. Org.
Lett. 2000, 2, 1117; (g) Long, A.; Baldwin, S. W.
Tetrahedron Lett. 2001, 42, 5343; (h) Voinov, M. A.;
Grigor’ev, I. A. Tetrahedron Lett. 2002, 43, 2445; (i) Merino,
12. (a) Krimm, H. Chem. Ber. 1958, 91, 1057; (b) Hamer, J.;
Macaluso, A. Chem. Rev. 1964, 64, 473 and references cited
therein.