Hypervalent iodine in synthesis. 76. An efficient oxidation of 1,4-dihydropyridines to pyridines using iodobenzene diacetate

Article abstract of DOI:10.1081/SCC-120002521

Iodobenzene diacetate was used as an effective oxidizing agent for the oxidation of 1,4-dihydropyridines to the corresponding pyridine derivatives at room temperature with high yields.

Full text of DOI:10.1081/SCC-120002521

SYNTHETIC COMMUNICATIONS, 32(5), 793–798 (2002)
HYPERVALENT IODINE IN SYNTHESIS.
76. AN EFFICIENT OXIDATION OF
1,4-DIHYDROPYRIDINES TO PYRIDINES
USING IODOBENZENE DIACETATE
*
Dong-Ping Cheng and Zhen-Chu Chen
Department of Chemistry, Zhejiang University
(Xi-Xi Campus), Hangzhou, 310028, P.R. China
ABSTRACT
Iodobenzene diacetate was used as an effective oxidizing
agent for the oxidation of 1,4-dihydropyridines to the corres-
ponding pyridine derivatives at room temperature with high
yields.
The oxidation of Hantzsch 1,4-dihydropyridines (Hantzsch 1,4-DHP)
and analogs to the corresponding pyridines is of interest because of its
relevance to the biological NADH redox processes1–3 as well as to the
metabolic studies pertaining to 1,4-DHP based cardiovascular drugs such
as Nifedipine and Niguldipine.3–5 Furthermore, the oxidation of readily
accessible Hantzsch 1,4-DHP constitutes by for the easiest method to
obtain pyridine derivatives. A number of methods and reagents have been
reported recently in the literature for this purpose.6–21 However, some
of these methods suffer from disadvantages such as long reaction times,
*Corresponding author.
793
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

ORDER
REPRINTS
794
CHENG AND CHEN
the lower yields of the products, the requirement of severe conditions and the
use of strong or toxic oxidants. Therefore, development and introduction of
convenient, milder and efficient method for the oxidation of 1,4-dihydro-
pyridines to the corresponding pyridines is of practical importance and is
still in demand.6–7
The versatile synthetic utility of hypervalent iodine reagents is of
current interest. It has been demonstrated that the iodobenzene diacetate
(IBD) is a general, universal oxidizing reagent.22–24 In the course of our
studies on the applications of hypervalent iodine reagent in synthesis. We
planned to study the oxidation of 1,4-DHP to the corresponding pyridines
employing IBD. Herein, we would like to report a milder, facile and efficient
method for the oxidation of different types of 4-substituted 1,4-DHP to their
corresponding pyridines with IBD (Scheme 1).
Scheme 1.
In fact, simple stirring the mixture of 1,4-DHP and IBD in methylene
chloride at room temperature gave after work up and isolation, the
desired pyridine derivative in good yield. The reaction is clean and
efficient. The results are summarized in Table 1. The products were
characterized by 1H NMR, IR and m.p., which were consistent with
literature data.
According to the experiment, we observed that oxidation of 1,4-
dihydropyridine with alkyl group at the 4-position only gave the dealkylated
pyridine derivative (3) (Table 1, Entry 2). This is agreement with the
observation made by other.6–7 But 4-aryl-1,4-dihydropyridines were
oxidized with retention of substituent at 4-position, to afford the corre-
sponding pyridine derivatives (Entries 3–10). We also observed that in
comparison with methylene chloride, the reaction times were longer and
the yields of the products were rather lower when the solvent was
acetonitrile or THF.
The latest member of the family of hypervalent iodine oxidants, the
hydroxy(tosyloxy)iodobenzene (HTIB) is also widely used, generally more
reactive than IBD.24 We found that HTIB is a superior reagent for the

ORDER
REPRINTS
HYPERVALENT IODINE IN SYNTHESIS. 76
795
Table 1. Oxidation of 1,4-DHP by IBD or HTIB or PIBD
Substrate
(R)
Time
(t, min)
Yield
(%)a
Entry
Product
1
2
3
4
5
6
7
8
1a, H
1b, n-C4H7
1c, C6H5
1d, m-NO2C6H4
1e, p-NO2C6H4
1f, p-CH3OC6H4
1g, p-ClC6H4
1h, m-BrC6H4
1i, p-CH3C6H4
2C6H3
1d, m-NO2C6H4
1f, p-CH3OC6H4
1c, C6H5
1d, m-NO2C6H4
1e, p-NO2C6H4
1g, p-ClC6H4
1g, p-ClC6H4
3
3
2090
35
85
2c
2d
2e
2f
2g
2h
2i
6087
7088
6089
3092
6091
5086
5087
7089
5
9
101j, 2,4-Cl
2j
11
12
13
14
15
16
17
2d
2f
2c
2d
2e
2g
2g
90
93
5
12085
18086
18084
12090
12086
b
aIsolated yields based on 1,4-DHP.
bUse the regenerated PIBD.
oxidation of 1,4-DHP to corresponding pyridines. The reaction is very quick
(Entries 11 and 12).
The advantages of polymer-supported reactive species are now widely
recognized by organic chemistry and the exploitation of these systems is
developing both in academic and industrial laboratories. Recently, we
have already investigated the preparation and reactivity of Polystyrene-
supported iodobenzene diacetate (PIBD) and found its property is similar
to the property of the IBD.25 So we have also tried to use the PIBD to
oxidize the 1,4-dihydropyridines. The yield is also satisfying (Entries 13–17).
Utilization of the solid-supported inorganic reagents to oxidize the 1,4-dihy-
dropyridines has been reported,26–30 but up to our knowledge the polymer-
supported organic reagent was first applied to this reaction.
In summary, we have found IBD or HTIB or PIBD to be a
valuable addition to the existing methods available for the oxidation of
Hantzsch 1,4-DHP with added advantages of ease of manipulation,
mild reaction conditions and high yields. Furthermore, the range of useful
applications of iodobenzene diacetate in organic synthesis has been
extended.

ORDER
REPRINTS
796
CHENG AND CHEN
EXPERIMENTAL
1
Melting points are uncorrected. H NMR spectra were recorded on
a Brucker 400 MHz instrument as CDCl3 solutions using TMS as internal
standard. IR spectra were determined on a Vector-22 spectrometer.
Elemental analyses were performed on a EA-1110instrument. 1,4-Dihydro-
pyridines were prepared according to described procedures.31
General Procedure for the Oxidation of 1,4-Dihydropyridines
In a 50ml round-bottomed flask, dichloromethane (10ml) was added
to the mixture of 1,4-dihydropyridine (1 mmol) and IBD or HTIB or PIBD
(1.1 mmol). The mixture was stirred for the time indicated in Table 1. The
progress of the reaction was monitored by TLC. After completion of the
reaction, the mixture was washed with water (3 ꢀ 10ml) and dried over
Mg2SO4. The solvent was distilled off and the residue obtained was purified
on a silica-gel plate using cyclohexane–acetate (3 : 1) as developer. The pure
product was obtained. If the oxidative reagent is PIBD, the mixture was
washed with water (3 ꢀ 10ml) and ether (20ml) was added to the mixture,
then filtered. After removal the solvent, the product obtained was recrystal-
lized with ethanol. The characterization and spectral data of the products
are given as following:
3: m.p. 70–71ꢁC (lit32 72ꢁC). H NMR (CDCl3): d 1.39–1.44 (t, 6H,
1
J ¼ 7.12 Hz), 4.37–4.43 (q, 4H, J ¼ 7.12 Hz), 2.87 (s, 6H), 8.70(s, 1H); IR:
2977, 1719, 1591, 1556, 1297, 1222, 1123, 771 cmꢂ1
.
2c: m.p. 62–63ꢁC (lit32 64ꢁC). H NMR (CDCl3): d 0.88–0.92 (t, 6H,
J ¼ 7.12 Hz), 3.98–4.03 (q, 4H, J ¼ 7.12 Hz), 2.65 (s, 6H), 7.24–7.38 (m, 5H);
1
IR: 2986, 1723, 1591, 1498, 1302, 1250, 1170, 791, 760 cmꢂ1
.
2d: m.p. 61.5–62.5ꢁC (lit32 63ꢁC). 1H NMR (CDCl3): d 0.98–1.02
(t, 6H, J ¼ 7.08 Hz), 4.04–4.09 (q, 4H, J ¼ 7.08 Hz), 2.70 (s, 6H), 7.60–8.29
(m, 4H); IR: 2980, 1712, 1590, 1520, 1280, 1183, 785 cmꢂ1
.
2e: m.p. 115–116ꢁC (lit32 117ꢁC). 1H NMR (CDCl3): d 0.96–1.00 (t, 6H,
J ¼ 7.04 Hz), 4.01–4.07 (q, 4H, J ¼ 7.04 Hz), 2.69 (s, 6H), 7.45–8.28 (m, 4H);
IR: 2977, 1723, 1557, 1518, 1349, 1106, 865, 841, 748 cmꢂ1
.
1
2f: m.p. 49.5–50.5ꢁC (lit32 51–53ꢁC). H NMR (CDCl3): d 0.97–1.01
(t, 6H, J ¼ 7.12 Hz), 4.03–4.09 (q, 4H, J ¼ 7.12 Hz), 2.66 (s, 6H), 3.82 (s, 3H),
6.89–7.20(m, 4H); IR: 2973, 1729, 1614, 1557, 1291, 1170, 857, 835,
779 cmꢂ1
.
2g: m.p. 66–68ꢁC (lit32 68ꢁC). H NMR (CDCl3): d 0.97–1.00 (t, 6H,
J ¼ 7.12 Hz), 4.03–4.08 (q, 4H, J ¼ 7.12 Hz), 2.69 (s, 6H), 7.19–7.39 (m, 4H);
1
IR: 2984, 1725, 1580, 1233, 1104, 864 cmꢂ1
.

ORDER
REPRINTS
HYPERVALENT IODINE IN SYNTHESIS. 76
797
2h: m.p. 70–72ꢁC. 1H NMR (CDCl3): d 0.97–1.01 (t, 6H, J ¼ 7.08 Hz),
4.04–4.10 (q, 4H, J ¼ 7.08 Hz), 2.66 (s, 6H), 7.20–7.44 (m, 4H); IR: 2976,
1729, 1561, 1291, 1230, 1108, 1044, 861, 780, 697 cmꢂ1: Anal. Calcd for
C19H20BrNO4: C 56.17, H 4.96, N 3.45; Found: C 56.22, H 5.05, N 3.17.
2i: m.p. 71–72ꢁC (lit32 72–73ꢁC). 1H NMR (CDCl3): d 0.93–0.07 (t, 6H,
J ¼ 7.12 Hz), 4.01–4.06 (q, 4H, J ¼ 7.12 Hz), 2.64 (s, 6H), 2.37 (s, 3H),
7.13–7.19 (m, 4H); IR: 2980, 1726, 1557, 1446, 1239, 1033, 821, 856,
775 cmꢂ1
.
2j: m.p. 77.5–79.5ꢁC. 1H NMR (CDCl3): d 0.98–1.02 (t, 6H,
J ¼ 7.12 Hz), 4.02–4.09 (q, 4H, J ¼ 7.12 Hz), 2.67 (s, 6H), 7.11–7.45
(m, 3H); IR: 2986, 1736, 1560, 1480, 1283, 1231, 1108, 856, 775 cmꢂ1: Anal.
Calcd for C19H19Cl2NO4: C 57.58, H 4.83, N 3.53; Found: C 57.29, H 4.84,
N 3.32.
REFERENCES
1. Stout, D.M.; Meyers, A.I. Chem. Rev. 1982, 82, 223.
2. Kill, R.J.; Widdowson, D.A. In Bioorganic Chemistry, Van Tamelon,
E.E., Ed.; Academic Press: NY, 1978; Vol. 4, p. 239.
3. Sabir, H.; Mashraqui; Madhari A. Karnik. Tetrahedron Lett. 1998,
39, 4895.
4. Wei, X.Y.; Rutledge, D.J. J. Mol. Pharmacol. 1989, 35, 541.
5. Gordeev, M.F.; Patel, D.V.; Gordon, E.M. J. Org. Chem. 1996, 61, 924
and references cited threin.
6. Mohammadpoor-Baltork, I.; Sadeghi, M.M.; Memarian, H.R.;
Pairow, R. J. Chem. Research 2000, 40 .
7. Zolfigol, M.A.; Maryam, K.B.; Sadeghi, M.M.; Mohammadpoor-
Baltork, I.; Memarian, H.R. Synth. Commun. 2000, 30, 3919.
8. Hantzsch, A. Ann. 1882, 215, 1.
9. Huntress, E.H.; Shaw, E.N. J. Org. Chem. 1948, 13, 674.
10. Kamal, A.; Ahmad, M.; Mohd, N.; Hamid, A.M. Bull. Chem. Soc.
Jpn. 1964, 37, 610.
11. Itoh, T.; Nagata, K.; Okada, M.; Ohsawa, A. Tetrahedron Lett. 1995,
36, 2269.
12. Pfister, J.R. Synthesis 1990, 689.
13. Eisner, U.; Sadeghi, M.M.; Hambright, W.P. Tetrahedron Lett. 1978,
19, 303.
14. Mashraqui, S.H.; Karnik, M.A. Synthesis 1998, 713.
15. Vanden Eynde, J.J.; Delfosse, F.; Mayence, A.; Van Haverbeke, Y.
Tetrahedron 1995, 51, 6511.

ORDER
REPRINTS
798
CHENG AND CHEN
16. Vanden Eynde, J.J.; D’Orazio, R.; Van Haverbeke, Y. Tetrahedron
1994, 50, 2479.
17. Vanden Eynde, J.J.; Mayence, A.; Maquestiau, A. Tetrahedron 1992,
48, 463.
18. Sabir H. Mashraqui; Madhari A. Karnik. Tetrahedron Lett. 1998, 39,
4895.
19. Chavan, S.P.; Dantale, S.W.; Kalkote, U.R.; Jyothirmai, V.S.; Kharul,
R.K. Synth. Commun. 1998, 28, 2789.
20. Itoh, T.; Nagata, K.; Matsuya, Y.; Miyazaki, M.; Ohsawa, A. J. Org.
Chem. 1997, 62, 3582.
21. Bocker, R.H.; Guengerich, F.P. J. Med. Chem. 1986, 29, 1596.
22. Moriarty, R.M.; Prakash, O. Adv. In Het. Chem. 1998, 69, 1.
23. Varvoglis, A. The Organic Chemistry of Polyvalent Iodine, VCH:
New York, 1992.
24. Stang, P.G.; Zhdankin, V.V. Chem. Rev. 1996, 96, 1123.
25. Wang, G.P.; Zhen, Z.C. Synth. Commun. 1999, 29, 2859.
26. Khadilkar, B.; Borkar, S. Synth. Commun. 1998, 28, 207.
27. Delgado, F.; Alvarez, C.; Garcia, O.; Penieres, G.; Marquez, C. Synth.
Commun. 1991, 21, 2137.
28. Balogh, M.; Hermecz, I.; Meszaros, Z.; Laszla, P. Helv. Chem. Acta
1984, 67, 2270.
29. Garcia, O.; Deigado, F. Tetrahedon Lett. 1993, 34, 623.
30. Maquestiau, A.; Mayence, A.; Vanden Eynde, J.J. Tetrahedon Lett.
1991, 32, 3839.
31. Norcross, B.E.; Clement, G.; Weinstein, M. J. Chem. Education 1969,
46, 694.
32. (a) According to the handbook Beilstein: compound 3: 22, I 536.; 2c,
2c, 2h: 22, II 127.; 2d: 22, II 128.; 2g: 22, II 206.; 2j: 22, IV 1721; (b)
compound 2i: Love, B.; Snader, K.M. J. Org. Chem. 1965, 30, 1914.
Received in Japan December 15, 2000

Request Permission or Order Reprints Instantly!
Interested in copying and sharing this article? In most cases, U.S. Copyright
Law requires that you get permission from the article’s rightsholder before
using copyrighted content.
All information and materials found in this article, including but not limited
to text, trademarks, patents, logos, graphics and images (the "Materials"), are
the copyrighted works and other forms of intellectual property of Marcel
Dekker, Inc., or its licensors. All rights not expressly granted are reserved.
Get permission to lawfully reproduce and distribute the Materials or order
reprints quickly and painlessly. Simply click on the "Request
Permission/Reprints Here" link below and follow the instructions. Visit the
U.S. Copyright Office for information on Fair Use limitations of U.S.
copyright law. Please refer to The Association of American Publishers’
(AAP) website for guidelines on Fair Use in the Classroom.
The Materials are for your personal use only and cannot be reformatted,
reposted, resold or distributed by electronic means or otherwise without
permission from Marcel Dekker, Inc. Marcel Dekker, Inc. grants you the
limited right to display the Materials only on your personal computer or
personal wireless device, and to copy and download single copies of such
Materials provided that any copyright, trademark or other notice appearing
on such Materials is also retained by, displayed, copied or downloaded as
part of the Materials and is not removed or obscured, and provided you do
not edit, modify, alter or enhance the Materials. Please refer to our Website
User Agreement for more details.
Order now!
Reprints of this article can also be ordered at
http://www.dekker.com/servlet/product/DOI/101081SCC120002521