Reduction of chromano–piperidine-fused isoxazolidines: Tandem intramolecular rearrangements leading to 2-(methylamino)-4-oxo-N-phenyl-N-propyl-4H-chromene-3-carboxamide

Article abstract of DOI:10.1016/j.tetlet.2017.05.032

Reductive ring opening of isoxazolidine moiety of chromano–piperidine-fused isoxazolidines (3a–c) with HCOONH₄ and 10% Pd/C in a mixture of solvents (THF/MeOH) at ambient temperature, affords novel 2-(methylamino)-4-oxo-N-phenyl-N-propyl-4H-chromene-3-carboxamide (4), which is apparently derived from reductive N[sbnd]O bond cleavage followed by tandem intramolecular rearrangements. Plausible mechanistic rationale for the formation of compound 4 is proffered.

Full text of DOI:10.1016/j.tetlet.2017.05.032

Accepted Manuscript
Reduction of chromano–piperidine-fused isoxazolidines: Tandem intramolec-
ular rearrangements leading to 2-(methylamino)-4-oxo-N-phenyl-N-prop-
yl-4H-chromene-3-carboxamide
Gagandeep Singh, Naman Gupta, Vivek Gupta, Mohan Paul Singh Ishar
PII:
S0040-4039(17)30612-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.05.032
TETL 48925
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
7 March 2017
3 May 2017
11 May 2017
Please cite this article as: Singh, G., Gupta, N., Gupta, V., Ishar, M.P.S., Reduction of chromano–piperidine-fused
isoxazolidines: Tandem intramolecular rearrangements leading to 2-(methylamino)-4-oxo-N-phenyl-N-propyl-4H-
chromene-3-carboxamide, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.05.032
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Graphical Abstract
Reduction of chromano–piperidine-fused
isoxazolidines: Tandem intramolecular
rearrangements leading to 2-(methylamino)-4-oxo-N-phenyl-N-propyl-4H-chromene-3-
Leave this area blank for abstract info.
carboxamide
Gagandeep Singh,a Naman Gupta,a Vivek Gupta,b Mohan Paul Singh Ishar a,c
*
H3C
O
N
O
O
H2
C
CH3
R
N
O
O
C
H2
10%Pd/C,
HCOONH4
O
N
MeOH:THF (3:1)
RT
NH
CH3
R; a = H,
b = Cl,
c = F
4
3a-c
ORTEP view of compound 4

1
Tetrahedron Letters
journal homepage: www.els evier.com
Reduction of chromano–piperidine-fused isoxazolidines: Tandem intramolecular
rearrangements leading to 2-(methylamino)-4-oxo-N-phenyl-N-propyl-4H-chromene-
3-carboxamide
Gagandeep Singh,a Naman Gupta,a Vivek Gupta,b Mohan Paul Singh Ishar a,c
*
aBio-Organic and Photochemistry Laboratory, Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar-143 005, Punjab, India,
bPost-Graduate Department of Physics & Electronics, University of Jammu, Jammu Tawi-180 006, India
cVice Chancellor, Maharaja Ranjit Singh Punjab Technical University, Badal Road, Bathinda.
Corresponding author: Tel.; 0164-2280197 (O), 2283197 (R) Fax: 0164-2282197 (O) E-mail address: mpsishar@yahoo.com
ARTICLE INFO
ABSTRACT
Article history:
Received
Reductive ring opening of isoxazolidine moiety of chromano–piperidine-fused isoxazolidines
(3a-c) with HCOONH4 and 10% Pd/C in a mixture of solvents (THF/MeOH) at ambient
temperature, affords novel 2-(methylamino)-4-oxo-N-phenyl-N-propyl-4H-chromene-3-
carboxamide (4), which is apparently, derived from reductive N-O bond cleavage followed by
tandem intramolecular rearrangements. Plausible mechanistic rationale for the formation of
compound 4 is proffered.
Received in revised form
Accepted
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
1,3-dipolar cycloaddition;
Chromano–piperidine-fused isoxazolidine;
N-O bond cleavage;
Tandem reorganization;
Chromone-3-(N-phenyl)carboxamide
Chromones and flavones are ubiquitous structures that occur
in a variety of natural products and synthetic compounds
exhibiting various important pharmacological activities such as
anti-inflammatory/analgesic,1a antitumoral,1b P-glycoprotein
binding (to overcome multidrug resistance),1c neuroprotective,1d
HIV-inhibitory,1e antioxidant, 1f antifungal and antimicrobial.1g
Inhibition of enzymes such as oxidoreductases,2a kinases,2b
tyrosinases,2c and cyclooxygenases2d have also been reported for
chromone based molecules. Additionally, 3-formylchromone
possessing three electrophilic centers,2d is a highly reactive and
versatile synthon for constructing various heterocycles;
consequently, chromone chemistry continues to draw
Inspired by this development6 and in continuation of our work
to develop new synthetic pathways for constructing heterocyclic
scaffolds possessing chromone moiety,7 it was decided to attempt
the reductive cleavage of N-O bond of chromano–piperidine-
fused isoxazolidine moiety, which was anticipated to provide
novel chromone based peptidomimetic precursor, however, the
reaction followed a more complex pattern with tandem
rearrangements providing substituted chromone-3-(N-
phenyl)carboxamide (4).
Initially, chromano–piperidine-fused isoxazolidines (3a-c)
were prepared as reported earlier,7h by mixing respective
aldehydes (2a–c), with N-methylhydroxylamine in
considerable interest of synthetic organic and medicinal
chemists. On the other hand, it is well established that highly
regio- and stereoselective 1,3-dipolar cycloaddition reactions of
nitrones with olefins is a very useful methodology for the
formation of isoxazolidines,3 which are present in different
bioactive compounds and have been reported as precursors for
the asymmetric synthesis of natural products;4 isoxazolidines are
also important precursors to β-amino acids, β-lactams, 1,3-amino
alcohols, pyrrolidinones, and can be further transformed to obtain
variety of heterocycles such as modified nucleosides,
dichloromethane at an ice-cold temperature (0oC-4oC) with
continuous stirring and the stirred solution was slowly brought to
the room temperature; regio- and stereo-selective intramolecular
1,3-dipolar cycloadditions of the in situ generated nitrones [A]
led to chromano–piperidine-fused isoxazolidines 3a–c in very
good yields and the results are summarized in Scheme-1 and
Table-1. Column chromatographic resolution (silica gel 60–120
mesh, eluant hexane/ethylacetate; as gradient mixture) of the
crude product afforded the cycloadducts 3a–c, which were
characterized by rigorous spectroscopic analysis (1H NMR, 13
C
carbohydrate mimics, and diverse range of alkaloids.5
NMR and HRMS), including a comparison of the spectroscopic
data with that of related compounds.8
We have recently reported the synthesis of peptidomimetic
constrained β2,3,3–amino alcohols,6a indole based natural product
analogs and peptidomimetic precursors6b,6c via reductive cleavage
of N-O bond of substituted isoxazolidine moiety.

2
Tetrahedron Letters
O
O
O
O
O
O
N
O
O
CH3
O
CH3NHOH
dry CH2Cl2
R
R
R
N
H
H
Br
K2CO3
dry Acetone
H
NaHCO3
ice cold cond.n
NH
N
H
1a-c
2a-c
[A]
R; a = H,
b = Cl,
c = F
ice cold , stirred and
brought to ambient temperature
H3C
O
N
O
H
H
H
R
H
O
N
3a-c
R; a = H,
b = Cl,
c = F
Scheme-1: Synthesis of chromano-piperidine fused isoxazolidine (3a-c)
Table 1: Reaction time and Yields (%) of products 3a-c
Serial No.
R
Reaction time (h)
Yield (%) of various products
1
2
3
3a; R = -H
3b; R = -Cl
3c; R = -F
4
4
4
80%
78%
75%
The 1H NMR spectrum of compound 4 showed signals at δ 3.12
ppm (d, 3H, J = 5.0 Hz) and δ 7.84 ppm (m, 1H, exchangeable
with D2O) ascribed to NH-CH3 and NH protons, respectively,
which confirms the presence of NH-CH3 moiety. Resonances at δ
3.83 (m, 2H, CH2), δ 1.62 (q, 2H, J = 7.5Hz, CH2), and δ 0.92 (t,
3H, J = 7.5 Hz, CH3) were indicative of the presence of propyl
chain, and the structure was also corroborated by 13C NMR
spectral assignments. Overall 1H and 13C NMR spectral
assignments, aided by 1H-13C hetero-COSY experiments,
corroborated the assigned structure. Finally, the structure of
compound 4 was established by X-ray crystallography (Figure-
1).9
In the next step, reductive ring opening of obtained fused-
isoxazolidines (3a-c) via cleavage of N-O bond was attempted
under mild reductive conditions as employed earlier.6a Thus,
compounds 3a-c were subjected to reduction with HCOONH4
and 10% Pd/C (10 equiv.) in a mixture of solvents (THF/MeOH)
at room temperature, till the completion of reaction as monitored
by Tlc. The reaction was very neat and clean as monitored by
Tlc, affording a single product 46d in good yield (Scheme 2 and
Table 2). The final products were purified by column
chromatography and characterized spectroscopically (1H NMR,
13C NMR, 2D-NMR and HRMS).
H3C
O
N
O
O
H2
C
CH3
R
N
O
O
C
H2
10%Pd/C,
HCOONH4
O
N
MeOH:THF (3:1)
RT
NH
CH3
R; a = H,
b = Cl,
c = F
4
3a-c
Scheme 2: Transformation of fused-isoxazolidines (3a-c)
Table 2: Reaction times and Yields (%) of product 4
(a)
(b)
Entry Reducing agent
Reaction
times (h)
2
Yield (%)* of
Figure-1: (a) ORTEP view of compound 4; (b) Packing
arrangement of molecules (4) viewed down the a-axis
various products
3a
3b
3c
10% Pd/C-HCOONH4
4 (80%)
(10 equiv.)
Thus, it was found that contrary to anticipated amino alcohol
product, the attempted reductive ring opening reaction of 3a-c,
afforded 2-(methylamino)-4-oxo-N-phenyl-N-propyl-4H-
chromene-3-carboxamide (4, Scheme-2), derived from reductive
cleavage of N-O bond of isoxazolidine moiety, followed by
subsequent tandem ring opening-recyclization rearrangements
(Scheme-3) with concomitant reductive loss of halogens6a in the
case of 3b,c.
10% Pd/C-HCOONH4
(10 equiv.)
3
3
4 (72%)
4 (65%)
10% Pd/C-HCOONH4
(10 equiv.)
* Based on isolated pure products.

3
CH3
NH
H3C
H
CH3
NH
CH3
Ph
O
O
O
N
O
H
H
O
O
HN
OH
H
H
..
N
O
N
HO
N
O
N
O
C
O
O
Ph
3a
B
B
Ph
CH3
Ph
Ph
N
Ph
N
O
N
O
O
O
HN
O
O
O
1,5-H shift
N
O
O
H
O
O
NH
NH
NH
CH3
CH3
CH3
D
E
4
D
Scheme-3: Plausible mechanistic transformation of 3a
Mechanistically, the formation of compound 4 can be
References
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single bond in D followed by recyclization to yield E and the
latter after a 1,5-H shift leads to formation of compound 4. Such
opening of the chromone ring via nucleophilic attack at C2-
position of pyrone moiety and subsequent recyclization has
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of N-O bond of obtained chromano–piperidine-fused
isoxazolidines (3a-c) with ammonium formate in the presence of
10% Pd/C followed a novel pathway of reductive N-O bond
cleavage–intramolecular tandem rearrangements providing a
concise access to chromone-3-(N-phenyl)carboxamide analog
(4). As it is well established that substituted chromones bearing
the carboxamide moiety at position 3 of the pyrone nucleus are
selective MAO-B inhibitors with IC50 values in the micro or
nanomolar range, and the nature and position of the substituents
of the aromatic ring at the carboxamide nitrogen modulates
affinity and selectivity for the hMAO-B,12 therefore, the
inhibition potential and mechanism of compound 4 at molecular
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Acknowledgments
University Grants Commission, New Delhi is acknowledged for
grant to Guru Nanak Dev University, Amritsar under University
for Potential for Excellence programme. We are also thankful to
Prof. A. S. Brar (Vice Chancellor), G. N. D. U., Amritsar for his
continuous support and encouragement.
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Singh, P.; Ishar, M. P. S. Eur. J. Med. Chem. 2017, 127, 210-
222; b) Singh, G.; Sharma, S.; Gupta, V.; Raj, T.; Singh, P.;
Ishar, M. P. S. Tetrahedron 2016, 72, 900-911; c) Singh, G.;
Raj, T.; Gupta, V.; Ishar, M. P. S. Tetrahedron Lett. 2016, 57,
4688-4692; d) A solution of (3a-c, 1.5 mmol) in Ammonium
formate (10 equiv.), methanol (15 ml) and THF (5 ml) was
stirred at ambient temperature (25-28 oC). Activated 10%
palladium on charcoal (10 equiv.) was added to the above
Conflict of interest
The authors declare they have no conflict of interests.

4
Tetrahedron Letters
solution and stirred the mixture for 2-3 hours (monitored by
Uriarte, E.; Remiao, F.; Alcaro, S.; Ortuso, F.; Borges, F. J. Med.
Chem., DOI: 10.1021/acs.jmedchem.6b00527; e) Ibrahim, M. A.
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Tlc). The reaction mixture was filtered and the filtrate extracted
with ether (30 ml). The aqueous phase was basified with aqueous
sodium hydroxide (10%) and extracted with dichloromethane (3x
50 ml). The combined organic layer was dried over Na2SO4 and
concentrated under reduced pressure and vacuum. Purification by
column chromatography (70% ethyl acetate in hexane) afforded
compound 4; Rf 0.30 (CHCl3/EtOAc 7:3) as colourless solid,
yield (65-80%), 1H NMR (CDCl3, 500 MHz): δ 7.85-7.82 (m,
2H, Ar-H and NH), 7.47-7.44 (m, 1H, Ar-H), 7.24-7.18 (m, 6H,
Ar-Hs), 7.10-7.07 (m, 1H, Ar-H), 3.83(m, 2H, CH2), 3.12 (d, 3H,
J = 5.0 Hz, NH-CH3), 1.62 (q, 2H, J = 7.5Hz, CH2), 0.92 (t, 3H,
J = 7.5Hz, CH3); 13C NMR (CDCl3, 125 MHz): δ 170.42,
168.13, 164.40, 152.36, 142.96, 131.85, 128.17, 126.85, 126.29,
125.94, 124.78, 123.17, 115.93, 95.59, 52.09, 27.77, 21.27,
11.35; HRMS (ESI, m/z): calculated for C20H20N2O3 [M]+,
336.1474, found 336.1469.
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5
Highlights
ꢀ Reductive cleavage of N-O bond of
isoxazolidines (3a-c) has been attempted.
ꢀ Reductive N-O bond cleavage followed by
intra-molecular tandem rearrangements.
ꢀ
Providing chromene-3-carboxamide
(4) having potential medicinal significance.
Plausible mechanistic rationale for
ꢀ
the formation of compound 4 is proffered.