A new route to the synthesis of isoxazoline derivatives from dihydropyran via cycloaddition reaction in ionic liquid

Article abstract of DOI:10.1016/j.tetlet.2013.07.159

A new approach to the synthesis and 1,3-dipolar cycloadditions of nitrones has been described from 2,3-dihydro-4H-pyran and various hydroxylamines, with electron-deficient alkynes for the synthesis of isoxazoline derivatives. Significant rate acceleration and improved yields of exclusively exo isoxazolines in 1-butyl-3-methylimidazolium based ionic liquids have been observed. Novel isoxazolines may be used as a precursor for the synthesis of variety of peptides.

Full text of DOI:10.1016/j.tetlet.2013.07.159

Tetrahedron Letters 54 (2013) 5532–5536
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A new route to the synthesis of isoxazoline derivatives
from dihydropyran via cycloaddition reaction in ionic liquid
⇑
Bhaskar Chakraborty , Chiran Devi Sharma
Organic Chemistry Laboratory, Sikkim Government College, Gangtok, Sikkim 737102, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A new approach to the synthesis and 1,3-dipolar cycloadditions of nitrones has been described from
2,3-dihydro-4H-pyran and various hydroxylamines, with electron-deficient alkynes for the synthesis of
isoxazoline derivatives. Significant rate acceleration and improved yields of exclusively exo isoxazolines
in 1-butyl-3-methylimidazolium based ionic liquids have been observed. Novel isoxazolines may be used
as a precursor for the synthesis of variety of peptides.
Received 12 June 2013
Revised 27 July 2013
Accepted 31 July 2013
Available online 8 August 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Dihydropyran derived nitrones
Cycloaddition reaction
Novel isoxazolines
Ionic liquid
Peptides
Nitrones are effective 1,3-dipoles and can undergo readily
cycloaddition reaction with various alkynes to produce substituted
isoxazolines.1 Moreover, nitrones can be used as potential oxidiz-
ing reagents in the conversion of various alkyl halides into alde-
hydes and ketones with atom-efficiency.2,3 They are also versatile
intermediates for the synthesis of natural products and many bio-
logically interesting molecules.4 Owing to the labile nature of the
N–O bond under mild reducing conditions, isoxazolines provide
easy access to a variety of fascinating 1,3-difunctional amino alco-
hols.5 Despite their potential utility, many of these procedures re-
quire high temperatures and prolonged reaction times (drastic
experimental conditions) and also suffer from poor regioselectivi-
ty, and lack of simplicity. In a few cases, the yields and selectivities
reported are far from satisfactory due to the occurrence of several
side reactions.6
Since ionic liquids are entirely composed of non-coordinating
ions, they can provide an ideal reaction medium for reactions that
involve reactive ionic intermediates. Due to the stabilization of
charged intermediates by ionic liquids, they can promote unprece-
dented selectivities and enhance reaction rates. As a result of their
green credentials and potential to enhance reaction rates and
selectivities, ionic liquids are finding increasing applications in or-
ganic synthesis10 with an ever-increasing quest for exploration of
newer reactions in ionic liquids.11 There are many reports concern-
ing the applications of ionic liquids as solvents and catalysts in 1,3-
dipolar cycloadditions.12,13 Several butylmethylimidazolium based
ILs, [bmim]X, with varying anions ðX ¼ PFꢀ6 ; Brꢀ; BF4ꢀÞ were
screened for this reaction. After a detailed study, [bmim]BF4 was
found to be superior in terms of yield (91%) and reaction time
(35 min) as compared with [bmim]PF6 (87%; 40 min; entry
1).14,15 These reagents are safe, easy to handle, environmentally be-
nign, and present fewer disposal problems. Therefore, we thought
[bmim]BF4 could be an excellent solvent for the employment of
our proposed reactions (Fig. 1).
The use of ionic liquids (ILs)7 as support for organic synthesis, in
particular in cycloaddition reactions, has been described in some
recent publications.8 In recent years ionic liquids have received a
good deal of attention, since classical organic reactions can be per-
formed in these media with great advantages (yield and selectiv-
ity) as compared with conventional conditions. Taking into
account the advantages offered by ILs, we have combined our past
experience in the field of cycloadditions with the versatile proper-
ties of ILs9 with the aim to find new routes for efficient isoxazoline
synthesis.
In continuation of our effort to establish green methodologies in
nitrone cycloaddition reactions,16,17 herein, we wish to report a
new route to the synthesis and 1,3-dipolar cycloaddition reactions
of dihydropyran derived nitrones (having vast synthetic potentials)
N
N
-
BF4
⇑
Corresponding author. Tel.: +91 9434318330; fax: +91 3592231917.
E-mail address: bhaskargtk@yahoo.com (B. Chakraborty).
Figure 1. The chemical structure of the ionic liquid used in this study.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.159

B. Chakraborty, C. D. Sharma / Tetrahedron Letters 54 (2013) 5532–5536
5533
Compared to conventional conditions, the cycloaddition reac-
tions performed in ionic liquids are much faster and selective. As
an example, the reaction between nitrone 1 and alkynes, afforded
cycloaddition derivative 2 at room temperature after 21 h in 62%
yield in CH2Cl2 and after 35 min 91% yield in [bmim]BF4 (entry
1) respectively. In a typical procedure 1 mmol of nitrone was
mixed with 1 equiv of alkynes in [bmim]BF4 (2 mL) under stirring,
at 40 °C for the synthesis of novel isoxazoline derivatives (2). After
the completion of reaction, the rest of the viscous ionic liquid was
further washed with diethyl ether and dried at 80 °C under re-
duced pressure to retain its activity in subsequent runs and was re-
used up to five times without loss of activity or selectivity after five
cycles. We have intentionally stopped the recycle at the fifth cycle,
however we are convinced that this process may be carried on
many more times. For optimizing the conditions, we used the sub-
strates in different ratios. It was found that best results were ob-
tained using 1:1 reactant ratio. The reaction in [bmim]BF4 was
also conducted at elevated temperatures (60–80 °C) for optimizing
the conditions but no significant improvements were observed in
yields and reaction times. For example, reaction of nitrone 1
(R = C6H5; CH2C6H5) with methyl phenyl propiolate and dimethyl
RNHOH
O-
O
OH
O
N+
[bmim]BF4
N
R
OH
O
1
R
R
R
R3
R1
R2
N
N
O-
2
O
R3
1
3
H
N+
R
OH
[bmim]BF4
5
4
R2
R1
1
R1
2
R2
2a
R = CH3/C6H5/C6H11/ C6H5CH2/4-HOC6H4/2-HOC6H4
R1 = Ph ; R2 = COOCH3
R1 = R2 = COOCH3
R1 = R2 = COOH
R3 = -(CH2)4OH
Scheme 1.
with electron-deficient alkynes to produce novel isoxazoline deriv-
atives (2) in an one pot operation (Scheme 1). Diastereoselective
synthesis of novel isoxazolidine derivatives using nitrone 1 has
been recently successfully tested with various maleimides.18
Table 1
1,3-Dipolar cycloaddition reaction of dihydropyran derived nitrones with alkynes in ionic liquid
Entry
Nitronea
Alkyne
Productb (2)
Timec (min)
Yield (%)
C6H5
O-
Ph
C6H5
COOCH3
H
C
N+
R3
N
2
R3
O
3
1
1
35 (1260) 35 (70 °C)
91 (62) 90 (70 °C)
H3
5
4
Ph
COOCH3
C6H5
O-
HOOC
H3COOC
Ph
COOH
C6H5
H
C
N+
N+
N+
N+
N+
R3
N
2
3
R3
O
1
2
3
4
5
6
36 (1200)
36 (1200)
35 (1230)
35 (1230)
36 (1200)
87 (60)
85 (60)
83 (59)
81 (60)
H3
5
4
HOOC
COOH
C6H5
C6H5
O-
COOCH3
H
C
R3
N
2
R3
O
3
1
5
H3
4
H3COOC
CH3
COOCH3
CH3
O-
COOCH3
H
C
R3
H3
N
2
R3
O
3
1
5
4
Ph
COOCH3
CH3
CH3
O-
H3COOC
HOOC
COOCH3
H
R3
H3
C
N
2
3
4
R3
O
1
5
H3COOC
COOCH3
CH2C6H5
O-
COOH
CH2C6H5
H
R3
H3
C
N
2
3
R3
O
1
81 (58)
5
4
HOOC
COOH
(continued on next page)

5534
B. Chakraborty, C. D. Sharma / Tetrahedron Letters 54 (2013) 5532–5536
Table 1 (continued)
Entry
Nitronea
Alkyne
Productb (2)
Timec (min)
Yield (%)
CH2C6H5
O-
CH2C6H5
Ph
COOCH3
H
C
C
C
C
N+
N+
N+
N+
R3
H3
N
2
R3
O
3
1
7
32 (1230)
80 (56)
5
4
Ph
COOCH3
CH2C6H5
CH2C6H5
O-
COOCH3
H3COOC
HOOC
Ph
H
R3
N
2
3
4
R3
O
1
5
8
9
30 (1200) 30 (65 °C)
80 (52) 81 (65 °C)
H3
H3COOC
COOCH3
C6H11
O-
COOH
C6H11
N
H
R3
H3
2
3
R3
O
1
5
34 (1200)
78 (56)
4
HOOC
COOH
C6H11
O-
C6H11
COOCH3
H
R3
H3
N
2
R3
O
1
3
10
11
36 (1380)
32 (1230)
76 (57)
84 (55)
5
4
Ph
COOCH 3
O
OH
OH
H3COOC
COOCH3
H3COOC
1
5
N
2
OH
H
4
3
C
N+
H3COOC
HOOC
O-
R3
H3
R3
HOOC
Ph
COOH
COOCH3
COOH
O
1
5
N
2
OH
H
4
12
13
14
30 (1200)
32 (1230)
32 (1200)
80 (53)
82 (52)
80 (58)
3
C
N+
HOOC
C6H5
H3
O-
O-
R3
R3
H
HO
HO
O
1
5
4
N
2
C
N+
3
H3COOC
HOOC
R3
H
H3
R3
HO
HOOC
HOOC
HO
O
1
5
4
N
2
C
N+
3
R3
H
O-
HOOC
H3
R3
CH3
O-
COOH
CH3
R3
C
N+
N
2
R3
O
1
5
3
15
33 (1260)
78 (54)
H3
4
HOOC
COOH
a
b
c
Reaction conditions: nitrone (1 mmol), alkynes (1 equiv), [bmim]BF4 (2 ml), N2 atmosphere.
All products were characterized by IR, 1H NMR, 13C NMR, and MS spectral data.
Isolated yield after purification. Figures in parentheses indicate reactions performed in conventional methods.
acetylene dicarboxylate was studied at 70 °C and 65 °C respectively
but no such improvement was observed as far as the yield of the
reactions is concerned (Table 1, entry 1 and 8). We examined the
reactions under neat condition also, without using IL, to
demonstrate catalytic ability of [bmim]BF4. This result clearly indi-
cates that [bmim]BF4 has a significant catalytic role in these
reactions (Table 1). The reaction of nitrone 1 with various alkynes
follows the general mechanistic pattern of 1,3-dipolar
cycloaddition reactions as found in the literature.4,19 The addition
of nitrone 1 to alkynes can be rationalized by an exo approach of
the nitrone which has the Z configuration (transition state I).20
All the cycloadducts are found to be moderately stable and have
prominent molecular ion peak and base peaks in the mass spec-
trum as expected. But while keeping for a longer period, the isox-
azoline derivatives (2) undergo ‘Baldwin rearrangement’ to furnish
corresponding aziridine derivatives (2a). Therefore, like other isox-
azoline derivatives reported in the literature,4,21,22 we have also
obtained expected fragmentation peaks due to the development

B. Chakraborty, C. D. Sharma / Tetrahedron Letters 54 (2013) 5532–5536
5535
C6H5
C6H5
activity and thereby showing their importance in peptide chemistry
as well (Scheme 2). All the novel peptides (3; Table 2, entries 1–4)
have been found to be very effective against gram positive and gram
negative organisms which gives an opportunity to develop new
broad spectrum antimicrobial agents. Screening studies (SEM and
TEM) on these novel peptides are going on at present. Initial studies
on the synthesis of peptides have been successfully conducted with
glycine and alanine using isoxazoline derivatives 2 (entry 1) in DMF.
Studies in detail are in progress.
O
O
NH2CHR4COOH
DCC, DMF
N
R
O
C
N
R
H
HN
C
O
HOOC
R3
C
HO
H
H
R3
R4
2
3
R4 = H; CH3
Scheme 2.
To explore the potential of this procedure we have extended the
protocol, to N-substituted nitrones (with hydroxy derivatives in
phenyl ring also) for the synthesis of exclusively exo isoxazoline
derivatives (Table 1).
In addition, these molten salts could be easily recovered on
work-up. Since the products are fairly soluble in ionic media, they
could be easily extracted with ether. Enhanced reaction rates,
excellent yields, and high selectivity are the features observed in
these ionic solvents. All the products were characterized by 1H
NMR, 13C NMR, IR, and MS spectroscopic data.23
In conclusion, we have reported a new methodology for the
synthesis of nitrones and isoxazolines from dihydropyran (an
unusual source for the synthesis of nitrone, because nitrones
are usually synthesized from either aldehydes or ketones or their
derivatives) via 1,3-dipolar cycloaddition reactions and also
shown that these cycloadditions may be conveniently carried
out in RTIL’s with the obtainment of corresponding novel isoxaz-
olines in good conversions and yields24,25 with high synthetic
potentials and selectivities. We have also introduced a new ap-
proach to the synthesis of peptides from isoxazolines. The ionic
liquid may be recycled several times without loss of activity or
selectivity.
of different aziridine derivatives. Base peaks are obtained due to
loss of PhCO for phenyl methyl propiolate, COOCH3 for dimethyl
acetylene dicarboxylate, and COOH for acetylene dicarboxylic acid
cycloadducts respectively. Hence it is confirmed that during mass
fragmentation, the cycloadducts underwent rearrangement to azi-
ridine derivatives.
H
R3
C
R
N
O
R2
R1
I
TS
Furthermore, the novel isoxazoline derivatives (2) are found to have
vast synthetic potential as they could be used as precursor for the
synthesis of variety of novel peptides (3) with potential biological
Table 2
Synthesis of Peptides from isoxazoline derivatives in DMF
Entry
Isoxazolinea (2)
Amino acid
Glycine
Peptideb (3)
Timec (min)
Yield (%)
C6H5
O
C6H5
O
O
N
C6H5
O
H
N
C6H5
HN
C
1
180
71
HOOC
C
O
R3
R3
C
H
H
H
HO
HO
H
H
C6H5
C6H5
O
N
CH3
CH3
O
C
N
H
C
HN
HOOC
2
3
4
Glycine
Alanine
Alanine
180
200
200
70
66
61
C
O
R3
R3
H
C6H5
C6H5
O
O
O
O
N
C6H5
N
C6H5
O
C
H
HN
HN
HOOC
C
O
R3
R3
C
H
H
HO
HO
H
H
CH3
C6H5
C6H5
N
CH3
CH3
O
C
N
H
HOOC
C
O
R3
R3
C
CH3
a
b
c
Reaction conditions: isoxazoline (1 mmol), amino acid (1 equiv), DMF (10 ml).
All products were characterized by IR, 1H NMR, 13C NMR, and MS spectral data.
Isolated yield after purification.

5536
B. Chakraborty, C. D. Sharma / Tetrahedron Letters 54 (2013) 5532–5536
20. Coskun, N.; Ozturk, A. Tetrahedron 2007, 63, 1402–1408.
Acknowledgements
21. Padwa, A.; Pearson, W. H. Synthetic Application of 1,3-dipolar Cycloaddition
Chemistry Toward Heterocycles and Natural Products; Wiley: New Jersy, 2003.
22. Gayon, E.; Debleds, O.; Nicauleau, M.; Lamaty, F.; Lee, A. D.; Vrancken, E.;
Campagne, J. M. J. Org. Chem. 2010, 75, 6050–6053.
23. Deshong, P.; Li, W.; Kennington, J. W.; Ammon, H. L. J. Org. Chem. 1991, 56,
1364–1369.
We are pleased to acknowledge the financial support from the
Department of Science and Technology, Government of India,
New Delhi (grant no: SR/S1/OC-34/2011). We are also grateful to
CDRI, Lucknow for providing spectral data.
24. Representative experimental procedure for nitrone and isoxazoline synthesis
(Table
1,
entry
1):
2,3-dihydro
4H-pyran
(1 mmol)
and
N-
phenylhydroxylamine (1 equiv) were added to [bmim]BF4 (2 ml) in a 10 ml
conical flask, mixed thoroughly, and stirred at 40 °C for 60 min. The formation
of nitrone was monitored by TLC (Rf = 0.36). Methyl phenyl propiolate
(1 mmol) was added at the time of development of nitrone and the reaction
mixture was further stirred at 40 °C for an appropriate time (Table 1). After
completion of reaction, as indicated by TLC (Rf = 0.52), the reaction mixture
was washed with diethyl ether (3 ꢁ 10 ml). The combined ether extracts were
concentrated in vacuo and the resulting product was directly charged on silica
gel column and eluted with a mixture of ethyl acetate:n-hexane (1:8) to afford
pure isoxazoline 2 (Table 1, entry 1, 91%) as dark red gelatinous mass. The rest
of the viscous ionic liquid was further washed with ether and dried at 80 °C
under reduced pressure to retain its activity in subsequent runs. Spectroscopic
data for nitrone 1 (R = C6H5): UV kmax 235 nm. IR (KBr): mmax 3520 (br), 3015
Supplementary data
Supplementary data associated with this article can be found, in
the
online
version,
at
http://dx.doi.org/10.1016/
j.tetlet.2013.07.159.
References and notes
1. Gothelf, K. V.; Jørgensen, K. A. Chem. Rev. 1998, 98, 863–910.
2. Chakraborty, B.; Sharma, P. K. Synth. Commun. 2012, 42, 1804–1812.
3. Chakraborty, B.; Sharma, P. K.; Rai, N.; Kafley, S.; Chhetri, M. S. J. Chem. Res.
2010, 34, 147–150.
4. Kobayashi, S.; Jørgensen, K. A. Cycloaddition Reactions in Organic Synthesis;
Wiley-VCH: Weimheim, 2002.
5. (a) Boggelen van, P. M.; Dommelen van, B. F. G. A.; Jiang, S.; Singh, G.
Tetrahedron Lett. 1995, 36, 1899–1902; (b) Jung, H. S.; Lee, E. J.; Koh, Y. H. Bull.
Korean Chem. Soc. 1998, 19, 33–35.
6. Confalone, P. N.; Huie, E. M. Org. React. 1988, 36, Chapter 1, 1–173.
7. Welton, T. Coord. Chem. Rev. 2004, 248, 2459–2477.
8. (a) Hornyak, M.; Kovacs, L.; Forgo, P.; Howarth, N. M. Nucleosides, Nucleotides
Nucleic Acids 2006, 25, 867–870; (b) Padar, P.; Bokros, A.; Paragi, G.; Forgo, P.;
Kele, Z.; Howarth, N. M.; Kovacs, L. J. Org. Chem. 2006, 71, 8669–8672; (c)
Silvero, G.; Arevalo, M. J.; Bravo, J. L.; A valos, M.; Jimenez, J. L.; Lopez, I.
Tetrahedron 2005, 61, 7105–7111; (d) Rodriquez, M.; Sega, A.; Taddei, M. Org.
Lett. 2003, 5, 4029–4031; (e) Fraga-Dubreuil, J.; Bazureau, J. P. Tetrahedron Lett.
2000, 41, 7351–7355; (g) Aggarwal, A.; Lancaster, N. L.; Sethi, A. R.; Welton, T.
Green Chem. 2002, 4, 517–520.
9. Bortolini, O.; De Nino, A.; Maiuolo, L.; Tocci, A.; Fantin, G.; Fogagnolo, M. Chem.
Lett. 2007, 472–473.
10. Gordon, C. M. Appl. Catal., A: Gen. 2001, 222, 101–105.
11. (a) Yadav, J. S.; Reddy, B. V. S.; Baishya, G. J. Org. Chem. 2003, 68, 7098–7104; (b)
Yadav, J. S.; Reddy, B. V. S.; Reddy, J. S. S.; Srinivas Rao, R. Tetrahedron 2003, 59,
1599–1603.
(m), 1614 (s), 1430 (m), 1205 (m), 788 (s) cmꢀ1 1H NMR (300 MHz, CDCl3): d
.
7.73–7.28 (m, 5H, C6H5), 6.45 (t, 1H, J = 5.00 Hz, –CH@N+), 5.12 (br s, 1H, –OH,
exchangeable in D2O), 3.46 (dtꢂm, 2H, CH2 protons of –CH2–(CH2)3OH), 2.04
(m, 6H, CH2 protons). 13CNMR (75 MHz, CDCl3): d 143.22 (CH@N+), 131.56,
131.43, 131.22, 131.06 (aromatic carbons), 30.25, 30.17, 30.08, 29.96 (CH2
carbons). Spectroscopic data for isoxazoline 2 (Table 1, entry 1): IR (KBr): mmax
3545 (br), 3012 (m), 2250 (m), 1820 (s), 1770 (s), 1685 (m), 1610 (s), 1485 (s),
1320 (s), 1230 (m), 1125 (s), 985 (m), 784 (s) cmꢀ1 1H NMR (CDCl3): d 7.86–
.
7.20 (m, 2 ꢁ 5H, C6H5), 4.79 (br s, 1H, –OH, exchangeable in D2O), 3.79 (t, 1H,
J = 4.06 Hz, C3H), 3.38 (s, 3H, –COOCH3), 3.20 (dtꢂm, 2H, CH2 protons of –CH2–
(CH2)3OH), 1.73–1.30 (m, 6H, CH2 protons). 13C NMR (CDCl3): d 171.70 (–
COOCH3), 133.65, 133.60, 133.53, 133.46, 130.24, 130.18, 130.14, 130.08
(aromatic carbons), 85.60 (C5), 76.92 (C3), 64.28 (–CH2OH), 59.32 (C4), 44.10 (–
COOCH3), 32.16, 32.04, 31.93 (CH2 carbons). FAB-MS (m/z): 353 (M+), 294, 276,
203 (BP), 77, 73. Anal. Calcd for C21H23O4N: C, 71.35; H, 6.55; N, 3.96%. Found:
C, 71.12; H, 6.38; N, 3.64%.
25. Representative experimental procedure for peptide synthesis (Table 2, entry 1): A
mixture of hydrolyzed isoxazoline (1 mmol), glycine (1 equiv), and DCC (1
equiv) were added to DMF (10 ml). The mixture was heated with constant
stirring at 80 °C for 180 min. After the completion of reaction as monitored by
TLC (Rf = 0.46), the precipitated dicyclohexylurea was collected off and the
filtrate was poured into ice-cold water. The solid that separated out was
collected to afford 3 (Table 2, entry 1) as white crystals (yield 71%, mp 86 °C).
Spectroscopic data for peptide 3 (Table 2, entry 1): IR (KBr): mmax 3420–3405
(br), 3328 (m), 3150 (br), 2990 (br), 1722 (s), 1665 (s), 1423 (m), 1345 (s), 1180
12. Dubreuil, J. F.; Bazureau, J. P. Tetrahedron Lett. 2000, 41, 7351–7355.
13. Conti, D.; Rodriquez, M.; Sega, A.; Taddei, M. Tetrahedron Lett. 2003, 44, 5327–
5331.
14. Safaei-Ghomi, J.; Taheri, M.; Ghasemzadeh, M. A. Org. Prep. Proced. Int. 2010, 42,
485–493.
15. Safaei-Ghomi, J.; Hajipour, A. R. Org. Prep. Proced. Int. 2011, 43, 372–379.
16. Chakraborty, B.; Sharma, P. K.; Chhetri, M. S. J. Heterocycl. Chem. 2012, 49,
1260–1265.
17. Chakraborty, B.; Sharma, P. K.; Kafley, S. Green Chem. Lett. Rev. 2013, 6, 141–
147.
(s), 851 (m), 786 (s), 680 (s) cmꢀ1 1H NMR (300 MHz, CDCl3): d 10.12 (s, 1H,
.
COOH), 9.80 (s, 1H, –NH, D2O exchangeable), 7.54–7.32 (m, 2 ꢁ 5H, C6H5
protons), 5.38 (br s, 1H, –OH, D2O exchangeable), 4.33 (t, 1H, J = 2.74 Hz, C3H),
4.22 (s, 2H, –CH2), 3.24 (dtꢂm, 2H, CH2 protons of –CH2–(CH2)3OH), 1.80–1.43
(m, 6H, CH2 protons). 13C NMR (75 MHz, CDCl3): d 176.55 (–COOH), 167.14 (–
CONH), 137.80, 137.74, 136.95, 136.88, 132.32, 132.28, 132.23, 132.18
(aromatic carbons), 85.06 (C5), 76.13 (C3), 64.24 (CH2OH), 55.24 (C4), 26.12,
25.86, 25.70, 25.66 (CH2 carbons). LC–MS (m/z): 396.2 [M+H]+. Anal. Calcd for
18. Chakraborty, B.; Sharma, P. K.; Rai, N.; Sharma, C. D. J. Chem. Sci. 2012, 124,
679–685.
C22H24O5N2: C, 66.63; H, 6.09; N, 7.07. Found: C, 66.54; H, 6.10; N, 6.96.
19. Frederickson, M. Tetrahedron 1997, 53, 403–425.