Synthesis and stereodynamics of N-Formyl-1,2,3-selenadiazolopyridines

Article abstract of DOI:10.1080/10426507.2011.627899

The 4,6-diaryl-6,7-dihydro-[1,2,3]selenadiazolo[5,4-c]pyridine-5(4H)- carbalde hydes were synthesized from 2,6-diarylpiperidin-4-ones and characterized using infrared, ¹H, ¹³C Nuclear Magnetic Resonance (NMR), and mass spectroscopic techniques. On the NMR time scale, the compounds exist in syn and anti isomeric forms. Separate signals were obtained for isomers in the NMR spectra. The compounds stereodynamic nature was studied based on the intensity and position of NMR signals. Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.

Full text of DOI:10.1080/10426507.2011.627899

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Synthesis and Stereodynamics of N-
Formyl-1,2,3- Selenadiazolopyridines
M. Ingarsal a , P. Amutha a , M. Gopalakrishnan a & S. Nagarajan a
a Department of Chemistry , Annamalai University ,
Annamalainagar , India
Published online: 31 Jan 2012.
To cite this article: M. Ingarsal , P. Amutha , M. Gopalakrishnan & S. Nagarajan (2012) Synthesis and
Stereodynamics of N-Formyl-1,2,3- Selenadiazolopyridines, Phosphorus, Sulfur, and Silicon and the
Related Elements, 187:4, 515-522, DOI: 10.1080/10426507.2011.627899
To link to this article: http://dx.doi.org/10.1080/10426507.2011.627899
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Phosphorus, Sulfur, and Silicon, 187:515–522, 2012
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2011.627899
SYNTHESIS AND STEREODYNAMICS OF
N-FORMYL-1,2,3- SELENADIAZOLOPYRIDINES
M. Ingarsal, P. Amutha, M. Gopalakrishnan, and S. Nagarajan
Department of Chemistry, Annamalai University, Annamalainagar, India
GRAPHICAL ABSTRACT
Ph
N
Ph
N
N
N
N
Ph
N
O
Ph
Se
Se
syn
anti
O
Abstract The 4,6-diaryl-6,7-dihydro-[1,2,3]selenadiazolo[5,4-c]pyridine-5(4H)-carbalde
hydes were synthesized from 2,6-diarylpiperidin-4-ones and characterized using infrared,
1H, 13C Nuclear Magnetic Resonance (NMR), and mass spectroscopic techniques. On the
NMR time scale, the compounds exist in syn and anti isomeric forms. Separate signals were
obtained for isomers in the NMR spectra. The compounds’ stereodynamic nature was studied
based on the intensity and position of NMR signals.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.
Keywords 1,2,3-Selenadiazoles; piperidone; N-formyl compounds; stereodynamics
INTRODUCTION
In the past decade, a lot of effort has been directed towards the development of
stable organoselenium compounds. Selenium is an essential biological trace element and
the organoselenium compounds are used as antioxidants, enzyme inhibitors, antitumor
agents, anti-infective agents, cytokine inducers, and anti-immuno modulators.1,2 In addi-
tion, organoselenium compounds are widely used in enzymology, bioorganic chemistry, and
material science.3–8 Similarly, formamides have been widely used in the synthesis of phar-
maceutically important compounds such as fluoroquinones,9 substituted aryl imidazoles,10
Received 18 July 2011; accepted 25 September 2011.
Authors are thankful to the NMR Research Centre, Indian Institute of Science, Bangalore for NMR spectral
measurements.
Address correspondence to S. Nagarajan, Department of Chemistry, Annamalai University, Annamalainagar
608 002, India. E-mail: nagarajan.au@gmail.com
515

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M. INGARSAL ET AL.
1,2-dihydroquinolines,11 and nitrogen bridged heterocycles.12 The organoselenium com-
pound with N-formyl group can increase its synthetic as well as pharmaceutical utility.13
In this article synthesis and stereodynamics of new series of N-formyl-1,2,3-selenadiazoles
are reported.
RESULTS AND DISCUSSION
The r-2,c-6-diarylpiperidin-4-ones 1a–e were prepared by condensing appropriate
benzaldehyde, ammonium acetate, and appropriate aliphatic ketones.14 On treatment with
formic acid and acetic anhydride, the piperidin-4-ones gave N-formyl derivatives. The
N-formylpiperidones react with semicarbazide hydrochloride and sodium acetate, gave
corresponding N-formylpiperidone semicarbazones. The semicarbazones on reaction with
selenium dioxide gave N-formylselenodiazoles as shown in Scheme 1. The Fourier trans-
form infrared (FT-IR) spectra of the compounds exhibit characteristic bands for aromatic
C H stretching around 3100–3000 cm−1, CHO stretching around 1680 cm−1, and C C
skeletal stretching around 1650 cm−1. The bands for CH in-plane and out-of-plane bending
were appeared at around 1000 cm−1 and 675 cm−1, respectively. The molecular ion peaks
were observed in the mass spectra of the compounds.
O
O
4
4
R
R
5
6
5
6
3
3
2
2
N
1
HCOOH
N
1
(CH3CO)2O
CHO
H
X
X
X
X
2a--e
1a--e
NH2CONHNH2.HCl
CH3COONa/
EtOH,
∆
N
N
NNHCONH2
4
R
Se
R
5
6
3
2
N
1
SeO2/CH3COOH
N
∆
CHO
CHO
X
X
X
X
3a--e
4a--e
R
H
CH3
CH3
C2H5
X
H
H
a
b
c
d
e
4-OCH3
H
H
CH(CH3)2
Scheme 1

SYNTHESIS AND STEREODYNAMICS OF N-FORMYL-1,2,3- SELENADIAZOLOPYRIDINES 517
Figure 1 Syn and anti conformations of 1,2,3-Selenadiazolopyridine.
The preferred conformation of the piperidine ring (1a–e) has been shown to be the
chair, with a slight flattening or distortion of the ring depending upon the position and size
of the substituents.15 In N-formylselenadiazoles the formyl group is co-planar to the ring.
Due to the co-planar orientation of CHO group the lone pair of electrons on the nitrogen
atom gets delocalized and N C O bond acquires partial double bond character.8,13 The
partial double bond character hindered the rotation about N C bond in N CHO group
(Figure 1). Due to the restricted rotation of N C O bond, the formyl derivatives are
being unsymmetrical and hence two sets of Nuclear Magnetic Resonance (NMR) signals
1
are observed for the protons and carbons.16 The H and 13C NMR spectral data for the
4,6-diaryl-6,7-dihydro-[1,2,3]selenadiazolo[5,4-c]pyridine-5(4H)-carbaldehydes 4a–e are
summarized in Tables 1 and 2.
From the syn and anti isomer signals, the signals of the respective isomeric forms
were separated with the help of peak position and intensities. The syn side protons (C6)
experience steric interference with the formyl group but this is not possible between the anti
side proton and formyl group and hence the syn and anti conformers of these compounds
have different energies, thus leading to the unequal populations. The more populated isomer
(anti isomer) exhibits the spectral lines of higher intensities than the less populated isomer
(syn isomer).
The 1H NMR spectrum of 4,6-diphenyl-6,7-dihydro-[1,2,3]selenadiazolo[5,4-
c]pyridine-5(4H)-carbaldehydes 4a shows the methylene protons signals for C-3 as two
doublet of doublets at 3.57 and 3.66 ppm and two broad doublets at 4.24 and 4.36 ppm.
The two doublet of doublets are due to the ring methylene proton from syn to anti isomers.
The other ring methylene protons gave two broad doublets from syn and anti isomers. The
benzylic proton H-4 shows one triplet at 6.86 ppm and three doublets at 6.38, 6.55, and
6.69 ppm from the anti and syn isomers, respectively. The appearance of more than one
signal for each isomer may be due to the existence of other conformations of the respective
isomers. The H-6 proton gives one doublet at 5.35 ppm and a singlet at 6.19 ppm for anti
and syn isomers, respectively. The formyl proton signal is appeared as two singlets in the
downfield region at 8.72 and 8.58 ppm for syn and anti isomers, respectively. The NMR
chemical shift values are given in Table 1.
The 13C NMR spectrum of compound 4a shows two sets of signals, the methylene
carbon resonates in the upfield region at 27.0 and 28.3 ppm for the syn and anti isomers,

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519

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M. INGARSAL ET AL.
respectively. Two different benzylic carbon signals were observed for C4 and C6 carbons,
this non-equivalence arises due to syn and anti orientations of formyl group. The C-6 carbon
resonates at 47.5 ppm for syn and 54.2 ppm for the anti forms. The other benzylic carbon,
C-4 signal appeared at 54.4 ppm for the anti isomer and 59.8 ppm for syn isomer. The C-1
carbon resonates at 154.3 ppm. The C-2 carbon gave two signals corresponding to syn and
anti isomers at 156.1 and 155.1 ppm, respectively. The formyl carbon signals appeared in
the downfield region at 162.7 and 162.5 ppm. Representative 1H and 13C NMR spectra for
4a and 4c are found in the Supplemental Materials (Figures S1–S 4).
In 7-methyl-4,6-diphenyl-6,7-dihydro-[1,2,3]selenadiazolo[5,4-c]pyridine-5(4H)-car-
baldehyde 4b, the methyl and methine protons gave single signals from each protons. The
doublet at 1.57 ppm was due to methyl protons. The methylene protons signal appeared as
a multiplet in the region 4.56–4.65 ppm. The H-6 benzylic proton shows three singlets, one
singlet at 4.91 ppm with high interaction and other two singlets at 6.12 and 6.17 ppm with
low integrations. The H-4 benzylic proton shows two doublets with different intensities
at 6.54 and 6.70 ppm. The doublet at 6.54 ppm was due to H-4 benzylic proton of syn
isomer, whereas the other doublet at 6.70 ppm with high integral was assigned to H-4 of
anti isomer. The formyl proton signals appeared similar to that of compound 4a. In 4c, the
methoxy protons appeared as singlets, H-4 benzylic proton gave one doublet at 6.41 ppm
with integration value corresponding to two protons. The H-6 benzylic proton gave three
singlets at 4.84 ppm from anti isomer and the other singlets at 6.02–6.10 ppm with low
integration values are assigned to syn isomer. The other signal assignments were similar to
4b.
In 4d, the methylene protons ( CH2) gave two multiplets and a broad peak at
room temperature. At 40 ◦C, −30 ◦C, and −50 ◦C, the hump disappeared. The double of
multiplets is due to the diastereotopicity of the methylene protons. The methine protons
H-3 signal appeared as a multiplet at 4.30–4.38 ppm. At low temperature the splitting due
to methylene and methane protons decreases. The benzylic proton H-6 gave three singlets
at 5.09, 6.12, and 6.31 ppm. Among three singlets, two singlets at 6.12 and 6.31 ppm from
the syn isomer, the signal intensities varied on changing◦temperature. The other signal at
5.09 ppm from anti isomer remains unchanged. At 40 C, the singlet at 6.31 ppm was
with higher intensity than the singlet at 6.12 ppm. The singlet corresponding to 6.31 ppm
conformation predominates over other conformations at that temperature. The benzylic
proton H-4 gives two doublets at 6.52 and 6.66 ppm. The temperature change has no effect
on the H-4 benzylic proton signal except slight change in the chemical shift value. The
formyl proton appeared as two singlets in the most downfield region at 8.59 ppm from anti
isomer and 8.81 ppm from syn isomer. On lowering the temperature from 40 ◦C to −50 ◦C,
the formyl proton signal was slightly shifted to downfield region.
In 4e, the methyl protons from isopropyl group gave three doublets and a singlet in
the downfield region. The CH proton from isopropyl group gave an unresolved peak at
1.79 ppm and a multiplet (1.98–2.08 ppm). The ring methylene proton gave two doublets
with different intensities at 4.13 ppm (J = 7.97 Hz) and 4.16 ppm (J = 8.05 Hz). The
H-6 benzylic proton gave three singlets, H-5 proton shows two doublets from each isomer.
The reference compound 3-isopropyl-N-formyl-2,6-diphenylpiperidin-4-one also gave two
separate doublets for the ring methine proton. The 13C NMR spectra of 4b–4e show signals
for each carbon due to the syn and anti isomers and the values are given in Table 2. The
large and small coupling constant values of H-3 axial and H-3 equatorial protons of syn
and anti isomers 4a suggested trans coupling and the phenyl group at C-4 is in equatorial

SYNTHESIS AND STEREODYNAMICS OF N-FORMYL-1,2,3- SELENADIAZOLOPYRIDINES 521
orientation. The C-6 phenyl is also at equatorial orientation due to the steric effect of
selenadiazole ring at the “c-face” of the pyridine ring.
The chair or boat, or other conformations of the compounds were not deduced from the
coupling constant values due to the presence of the selenadiazole ring. Single crystal studies
are needed to confirm the stable conformation. This paper deals only the stereodynamics
of the set of compounds studied.
CONCLUSION
We have described in this article the synthesis of new N-formyl-1,2,3-selenadiazoles
starting from r-2,c-6-diphenylpiperidin-4-ones. The N-formyl compounds gave average
signals in NMR at room temperature. The benzylic protons for all the compounds gave two
sets of signals correspond to syn and anti isomers. The signals due to syn and anti forms for
other protons and carbons were absent in some cases. The assignment of syn and anti isomer
proton and carbons were based on their intensities, chemical shifts, and coupling constant
values. This work demonstrates the stereodynamics of 1,2,3-selenadizolopyridines.
EXPERIMENTAL
Instruments
All melting points were taken on an electrically heated block with a calibrated
thermometer. The IR spectra were recorded on a NICOLET AVATAR 360 FT-IR instrument
by using KBr pellets. The 1H (400 MHz) and 13C NMR (100 MHz) spectra were recorded
on a 400-MHz Bruker instrument in CDCl3 with TMS as an internal standard. Mass
spectrometry was performed on a GC Perkin-Elmer Autosystem and a Perkin-Elmer Turbo
mass spectrometer.
Preparation of Compounds
The r-2,c-6-diarylpiperidin-4-ones and N-formyl-2,6-diarylpiperidin-4-ones were
prepared as per the reported literature methods.14
General Procedure for Preparation of N-formyl-2,6-diarylpiperidin-
4-one Semicarbazones (3a–3e)
A mixture of respective N-formyl-2,6-diphenylpiperidin-4-one (5 mmol), semicar-
bazide hydrochloride (6 mmol), and sodium acetate (20 mmol) in distilled ethanol (75 mL)
was refluxed for 3 h on a steam bath and then cooled. The reaction mixture was poured into
crushed ice. The separated solid was filtered and washed with distilled water. The dried
compounds were recrystallized from ethanol.
General Procedure for Preparation of N-formyl-1,2,3,-selenadiazoles
(4a–4e)
The appropriate N-formyl-2,6-diarylpiperidin-4-one semicarbazone (3 mmol) was
treated with selenium dioxide (3 mmol) in acetic acid (50 mL) and the mixture was gently

522
M. INGARSAL ET AL.
◦
◦
heated at 50 C–60 C for about 4 h with stirring. The reaction mixture was cooled,
filtered, and then poured into crushed ice. The product obtained was subjected to column
chromatography. The column was packed with silica gel (100–200 mesh) in petroleum ether
and toluene-ethyl acetate (95:5%) mixture was used as eluent. The purity of the compounds
was checked by using the Co-TLC method.
Analytical Data
4a: 4,6-Diphenyl-6,7-dihydro-[1,2,3]selenadiazolo[5,4-c]pyridine-5(4H)-carbaldeh
yde: C18H15N3OSe: Anal. Calc.% C 58.02 (58.70); H 3.90 (4.11); N 12.00 (11.41); m/z
368.3 [M]+; Yield: 60%; m.p. 94 ◦C–96 ◦C.
4b: 7-Methyl-4,6-diphenyl-6,7-dihydro-[1,2,3]selenadiazolo[5,4-c]pyridine-5(4H)-
carbaldehyde: C19H17N3Ose:: Anal. Calc.% C 60.01 (59.69); H 4.86 (4.48); N 11.09
(10.99); m/z 368.3 [M]+; Yield: 58%; m.p. 124 ◦C–126 ◦C.
4c: 4,6-Bis(4-methoxyphenyl)-7-methyl-6,7-dihydro-[1,2,3]selenadiazolo[5,4-c] pyr
idine-5(4H)-carbaldehyde: C21H21N3O3Se: Anal. Calc.% C 58.03 (57.02); H 5.03 instead
of (4.78); N 9.42 (9.49); m/z 442.4 [M]+; Yield: 56%; m.p. 86 ◦C–87 ◦C.
4d:7-Ethyl-4,6-diphenyl-6,7-dihydro-[1,2,3]selenadiazolo[5,4-c]pyridine-5(4H)-car
baldehyde: C20H19N3OSe: Anal. Calc.% C 60.60 (60.60); H 4.78 (4.83); N 10.55 (10.60);
m/z 396.3 [M]+; Yield: 55%; m.p. 119 ◦C–122 ◦C.
4e:7-Isopropyl-4,6-diphenyl-6,7-dihydro-[1,2,3]selenadiazolo[5,4-c]pyridine-5(4H)-
carbaldehyde: C21H21N3OSe: Anal. Calc.% C 61.89 (61.46); H 5.48 (5.16); N 10.49 (10.23);
m/z 410.4 [M]+; Yield: 50%; m.p. 104 ◦C–106 ◦C.
REFERENCES
1. Schrauzer, G. N. In: A. S. Prasad (Ed.), Selenium in Nutritional Cancer Prophylaxis: An Update.
Vitamins, Nutrition and Cancer; Karger: Basel, 1984; pp. 240-250.
2. Klayman, D. L.; Gunther, W. H. H. Organic Selenium Compounds Their Chemistry and Biology;
Wiley-Interscience: New York, 1972; 731 pp.
3. Lalezari, I.; Shafiee, A.; Yazdany, S. J. Pharm. Sci. 1974, 63, 628-629.
4. Lalezari, I.; Shafiee, A. Tetrahedron Lett. 1969, 58, 5105-5106.
5. Al-Smadi, M.; Ratrout, S. Molecules 2004, 9, 957-967.
6. Saravanan, S.; Athimoolam, S.; Muthusubramanian, S. ARKIVOC. 2007, (i), 22-33.
7. Plano, D.; Moreno, E.; Font, M.; Enc´ıo, I.; Palop, J. A.; Sanmart´ın, C. Arch. Pharm. 2010, 343,
680-691.
8. Khanna, P. K. Phosphorus, Sulfur, Silicon Relat. Elem. 2005, 180, 951-955.
9. Jackson, A.; Meth-Cohn, O. J. Chem. Soc. Chem. Commun. 1995, 1319-1319.
10. Chen, B. C.; Bednarz, M. S.; Zhao, R.; Sundeep, J. E.; Chen, P.; Shen, Z.; Skoumbourdis, A. P.;
Barrish, J. C. Tetrahedron Lett. 2000, 41, 5453-5456.
11. Kobayashi, K.; Nagato, S.; Kawakita, M.; Morikawa, O.; Konishi, H. Chem. Lett. 1995, 575-576.
12. Kakahi, A.; Ito, S.; Hayashi, S.; Fujii, T. Bull. Chem. Soc. Jpn. 1995, 68, 3573-3580.
13. Hannigan, M.; Zhan, L.; Li, Z.; Ai, Y.; Wu, D.; Huang, C. K. Proc. Natl. Acad. Sci. USA 2002,
99, 3603-3608.
14. Balasankar, T.; Gopalakrishnan, M.; Nagarajan, S. J. Enzyme Inhib. Med. Chem. 2007, 22,
171-175.
15. Amutha, P.; Nagarajan, S. Helv. Chim. Acta 2010, 93, 430-434.
16. Hemalatha, T.; Nagarajan, S. J. Mol. Struct. 2010, 963, 111-114.