New strategy for the oxidation of Hantzsch 1,4-dihydropyridines and dihydropyrido[2,3-d]pyrimidines catalyzed by DMSO under aerobic conditions

Article abstract of DOI:10.1080/00397910701410442

A novel metal-salt-oxidant-free, efficient, and economical method for the oxidation of Hantzsch 1,4-dihydropyridines that uses aerial oxygen and solvent-grade dimethylsulfoxide is described. Also, the synthesis of pyrido[2,3-d]pyrimidines is achieved from in situ oxidation of dihydropyrido[2,3-d]pyrimidines that arise from the reaction of 6-aminouracils and cyano olefins in dimethylsulfoxide. Copyright Taylor & Francis Group, LLC.

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New Strategy for the Oxidation of
Hantzsch 1,4‐Dihydropyridines and
Dihydropyrido[2,3‐d]pyrimidines Catalyzed
by DMSO under Aerobic Conditions
Anil Saini a , Sanjay Kumar a & Jagir S. Sandhu a
a Department of Chemistry , Punjabi University , Patiala, Punjab, India
Published online: 11 Jul 2007.
To cite this article: Anil Saini , Sanjay Kumar & Jagir S. Sandhu (2007) New Strategy for the Oxidation
of Hantzsch 1,4‐Dihydropyridines and Dihydropyrido[2,3‐d]pyrimidines Catalyzed by DMSO under Aerobic
Conditions, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 37:14, 2317-2324, DOI: 10.1080/00397910701410442
To link to this article: http://dx.doi.org/10.1080/00397910701410442
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Synthetic Communicationsw, 37: 2317–2324, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701410442
New Strategy for the Oxidation of Hantzsch
1,4-Dihydropyridines and
Dihydropyrido[2,3-d]pyrimidines Catalyzed
by DMSO under Aerobic Conditions
Anil Saini, Sanjay Kumar, and Jagir S. Sandhu
Department of Chemistry, Punjabi University, Patiala, Punjab, India
Abstract: A novel metal-salt-oxidant-free, efficient, and economical method for the
oxidation of Hantzsch 1,4-dihydropyridines that uses aerial oxygen and solvent-
grade dimethylsulfoxide is described. Also, the synthesis of pyrido[2,3-d]pyrimidines
is achieved from in situ oxidation of dihydropyrido[2,3-d]pyrimidines that arise from
the reaction of 6-aminouracils and cyano olefins in dimethylsulfoxide.
Keywords: aerial oxidation, dimethylsulfoxide, Hantzsch pyridines, pyrido[2,3-d]
pyrimidines
The Hantzsch reaction,[1] discovered in 1881 for the production of 1,4-dihy-
dropyridine-3,5-dicarboxylates (DHPs), continues to be of considerable
interest. This appears to be because the DHP scaffold is present in a variety
of bioactive molecules of pharmacological significance, which act as vasodi-
lator,[2] bronchodilator,[3] antitumor, antiatherosclerotic, hepatoprotective,
geroprotective, and antidiabetic agents. Some DHPs are clinically used for
the treatment of hypertension and angina pectoris,[4] including a few of
those that are on the market: niguldipine 1, felodipine 2, and nifedipine 3
(see Fig. 1).[5] The very fact that several molecules with dihydropyridine
scaffold are commercially available in the marketplace makes it amply clear
Received in India September 20, 2006
Address correspondence to Jagir S. Sandhu, Department of Chemistry, Punjabi
University, Patiala, 147 002 Punjab, India. E-mail: j_sandhu2002@yahoo.com
2317

2318
A. Saini, S. Kumar, and J. S. Sandhu
Figure 1. 1,4-Dihydropyrine derivatives with chemotherapeutic properties.
that these are stable to normal aerial uncatalyzed oxidation. These drugs
metabolize in the human body by the liver enzyme Cytochrome P-450,[6]
and themselves are oxidized to fully aromatic substituted pyridines, which
in turn are inactive. The 1,4-DHP scaffold is also present in nicotinamide
adenine dinucleotide (NADH and NADPH) coenzyme and several other
similar structures, which are responsible for several reductive biotransform-
ations in biological systems.[6] To understand and model or mimic these bio-
logical functions and also to find a facile and efficient method for the
production of a variety of substituted pyridines, various oxidative methods
have been devised for aromatization of these 1,4-DHPs. These include tert-
butyl hydroperoxide,[7a] Co(II)-catalyzed auto oxidation,[7b] 2,3-dichloro-
5,6-dicyano-1,4-benzoquinone (DDQ),[7c] FeCl3 6H2O,[7d] pyridinium chlor-
.
ochromate (PCC),[7e] CrO3,[7f] nitrous acid,[7g] KBrO3/SnCl4 5H2O,[7h] and
.
HNO3.[7i] Several of these methods involve harsh reaction conditions, long
reaction times, or oxidative de-alkylation or de-arylation of 4-substituted
DHP substrate, leaving considerable scope for the development of a clean,
facile, and efficient process for this transformation.
In this article, we report a novel, efficient, and economical method for this
oxidation, which does not employ any other well-known traditional oxidant or
inorganic metal salts but rather uses aerial oxygen and solvent-grade
dimethylsulfoxide. Initially, we started our investigation for this transform-
ation with I2/DMSO, a well-known oxidizing system. The reaction
proceeds well with even a small amount of iodine, viz. 5 mol%. With this
success, we were tempted to use DMSO (dimethylsulfoxide) only for this
oxidation process in the presence of aerial oxygen. However, we failed to
obtain any oxidized pyridine when the reaction was carried at room tempera-
ture. Then the temperature of the reaction mixture was raised, and 708C was
found to be the optimum temperature for this oxidative aromatization. For
critical evaluation and other solvents, see Table 1.
In search of a better solvent system for this transformation, we tried DMF,
THF, and 1,4-dioxane in the presence of aerial oxygen; though the reaction
proceeds, later solvent systems did not prove as efficient as DMSO. Also, it
is worth mentioning here that air or DMSO solvent do not perform this
oxidation when tried individually.

DMSO-Catalyzed Aerobic Oxidation
2319
Table 1. Oxidation of diethyl 1,4-dihydro-2,6-dimethylpyridine-
3,5-dicaboxylatea
Entry
Solvent
Temp (8C)
Time (h)
Yield (%)b
1
2
3
4
5
1,4-Dioxane
THF
DMF
70
70
70
r.t.
70
6
8
62
36
30
nrc
88
8
DMSO
DMSO
12
4
aReaction condition: passed dry air through a solution of DHP
(1 mmol) in solvent (25 mL).
bIsolated yield after recrystallization.
cNo or negligible reaction.
Several 1,4-dihydropyridines are oxidized to corresponding pyridines in
high yield by simply passing dry air through a solution of 1,4-DHPs in
DMSO at 708C. In general, reactions are very clean, high-yielding and
completed within 4–5 h. The method is mild and tolerates substituents such
as alkyl and aryl at the 4-position of DHPs; no de-alkylated or de-arylated
pyridines were obtained in the present method (Table 2), a serious drawback
of earlier reported procedures. Also, there was no evidence for the overoxida-
tion of pyridines to pyridine-N-oxides.[8] When the oxidation of DHP was
carried out in nitrobenzene, a well-known oxidant under similar conditions,
oxidation did not proceed past 20% and could not be improved further by
varying any of the variables such as temperature or time (Scheme 1).
Table 2. Synthesis of pyridines by oxidative aromatization of 1,4-DHP
derivatives
Entry
Producta
R
R1
Time (h)
Yield (%)b
1
2
5a
5b
5c
5d
5e
5f
H
Me
Et
Et
4.0
4.0
4.5
4.0
4.5
5.0
4.0
4.0
4.5
4.0
4.5
90
91
91
94
90
89
92
88
95
91
91
3
Et
Ph
Et
Et
4
5
4-Cl-C6H4
4-NO2C6H4
4-MeOC6H4
H
Et
Et
6
7
5g
5h
5i
Et
8
Me
Me
Me
Me
9
Ph
4-OCH3-C6H4
4-Cl-C6H4
10
11
5j
5k
1
aAll products were characterized by comparison of their IR and H
NMR data with authentic samples.
bIsolated yields after recrystallization.

2320
A. Saini, S. Kumar, and J. S. Sandhu
Scheme 1.
Encouraged by these results, we extended our investigation to the
synthesis of pyrido[2,3-d]pyrimidines from the reaction of 6-aminouracils 6
and cyano olefins 7–9 (Table 3). Air was bubbled through a solution of an
equimolar amount of 6-aminouracil and cyano olefin in dimethylsulfoxide
at 708C to get pyrido[2,3-d]pyrimidines in excellent yield via in situ
oxidation of dihydropyrido[2,3-d]pyrimidine I (Scheme 2). This is in
contrast to a previous report[9a] in which an excess of cyano olefin is used
both as reactant and as an oxidant. The dihydropyrido[2,3-d]pyrimidine inter-
mediate I, initially formed by the Michael addition of 6 to 7 subsequently
underwent oxidation to fully aromatized pyrido[2,3-d]pyrimidine in the
presence of excess of 7 and 7 was reduced to the corresponding benzylmalo-
nitrile (Scheme 3). This method circumvents the reduction of one of the
reactants (i.e., 7) and thus is superior to earlier reported procedures.[9]
Also, there is no evidence of formation of any side product. The aerobic
oxidation using DMSO for various transformations has been reported.[10] The
specific role of DMSO in this oxidation and mechanism is not clear at the
moment.
In conclusion, we have described the first ever metal-salt-free, novel,
efficient, and economical method of oxidation of dihydropyridines and
efficient synthesis of pyrido[2,3-d]pyrimidines, which does not employ any
Table 3. Synthesis of pyrido[2,3-d]pyrimidines from 6-aminouracil
and cyano olefins
Entry
Producta
R
R1
Time (h)
Yield (%)b
1
2
3
4
5
6
10a
10b
11a
11b
12a
12b
Me
H
CN
CN
3.5
3.5
4.0
4.0
4.5
4.5
90
90
88
90
87
88
Me
H
CO2Et
CO2Et
CONH2
CONH2
Me
H
aMelting-point, IR, and 1H NMR data were in accordance with those
of authentic samples.
bIsolated yields after recrystallization.

DMSO-Catalyzed Aerobic Oxidation
2321
Scheme 2.
other well-known traditional oxidant but rather uses aerial oxygen and
solvent-grade dimethylsulfoxide. Further merits of this method are its general-
ity, selectivity,[9] short reaction times, lack of harsh reaction conditions and
simple workup. Certainly, the merits of the present protocol are a major
advancement in this reaction.
EXPERIMENTAL
Melting points were determined on a Buchi melting-point apparatus and are
uncorrected. Reagent-grade chemicals were purchased from a commercial
source and used without further purification. IR spectra were recorded in KBr
Scheme 3.

2322
A. Saini, S. Kumar, and J. S. Sandhu
1
discs on a Perkin-Elmer 24OC analyzer. H NMR spectra were recorded on
Varian Gemini 300 (300-MHz) spectrometer using TMS as internal standard.
Elemental analyses were performed with TMS as an internal standard on a
Hitachi 026 CHN analyzer,. Air was dried by passing it through an anhydrous
calcium chloride column. The progress of reaction was monitored by thin-
layer chromatography (TLC) using silica gel G (Merck).
Typical Procedure for the Oxidation of Hantzsch
1,4-Dihydorpyridines
Over a solution of diethyl 1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxy-
late (2 mmol) in dimethylsulfoxide (25 mL), dry air (dried over anhydrous
calcium chloride) was passed at 708C for 4 h. After completion of the
reaction (monitored via TLC), the solvent was evaporated at reduced
pressure; the solid thus obtained was purified by recrystallization from
aqueous ethanol to give pyridine 5a in 90% yield as a colorless solid.
Typical Procedure for the Synthesis of Pyrido[2,3-d]pyrimidines
Dry air was bubbled through the solution of 1,3-dimethyl-6-aminouracil
(2 mmol) and benzylidenemalononitrile (2 mmol) in dimethylsulfoxide at
608C for 3.5 h. After completion of reaction (via TLC), the solvent was evap-
orated under reduced pressure. The solid thus obtained was purified by recrys-
tallization from ethanol to obtain pyrido[2,3-d]pyrimidine 10a in 90% yield as
a light brown solid.
Representative Spectral Data
Compound 5a: colorless solid; mp 70–718C (lit.[7c] Mp 70–718C); IR (KBr):
3041, 1723, 1590, 1557, 1290, 1250, 1224, 1110, 1045, 775 cm21; 1H NMR
(300 MHz, CDCl3) d ¼ 8.58 (s, 1H), 4.36 (q, J ¼ 7.0 Hz, 4H), 2.75 (s, 6H),
1.43 (t, J ¼ 7.0 Hz, 6H). Anal. calcd. for C13H17NO4: C, 62.14; H, 6.82; N,
5.57. Found: C, 62.30; H, 6.75; N, 5.52.
Compound 5b: Colorless oil.[7g] IR (KBr): 3059, 1726, 1588, 1439, 1219,
1106, 1034, 994 cm21; 1H NMR (300 MHz, CDCl3) d ¼ 4.29 (q, J ¼ 6.9 Hz,
4H), 2.40 (s, 6H), 2.24 (s, 3H), 1.23 (t, J ¼ 6.9 Hz, 6H). Anal. calcd. for
C14H19NO4: C, 63.41; H, 7.16; N, 5.26. Found: C, 63.49; H, 7.09; N, 5.21.
Compound 5d: Pale yellow solid, mp 63–648C (lit.[7c] mp 63–648C); IR
(KBr): 3042, 1736, 1574, 1445, 1378, 1230, 1105, 855 cm21 1H NMR
;
(300 MHz, CDCl3) d ¼ 7.27–7.32 (m, 5H), 4.10 (q, J ¼ 7.0 Hz, 4H), 2.52
(s, 6H), 1.23 (t, J ¼ 7.0 Hz, 6H). Anal. calcd. for C19H21NO4: C, 69.74; H,
6.41; N, 4.27. Found: C, 69.72; H, 6.43; N, 4.20.

DMSO-Catalyzed Aerobic Oxidation
2323
Compound 5f: Pale yellow solid; mp 114–1168C (lit.[7c] mp 114–1168C); IR
(KBr): 3029, 1730, 1599, 1539, 1351, 1235, 1105, 1044, 843 cm21; 1H NMR
(300 MHz, CDCl3) d ¼ 8.03 (d, J ¼ 8.9, 2H), 7.29 (d, J ¼ 8.9, 2H), 4.09
(q, J ¼ 7.2 Hz, 4H), 2.45 (s, 6H), 1.02 (t, J ¼ 7.2 Hz, 6H). Anal. calcd. for
C19H20N2O6: C, 63.31; H, 5.37; N, 7.52. Found: C, 63.42; H, 5.30; N, 7.42.
Compound 5h: Colorless solid; mp 100–1018C (lit.[5] mp 50–528C); IR
(KBr): 3040, 1725, 1408, 1391, 1221, 1113, 745 cm21
;
1H NMR
(300 MHz, CDCl3) d ¼ 8.67 (s, 1H), 3.80 (s, 6H), 2.73 (s, 6H). Anal. calcd.
for C11H13NO4: C, 59.19; H, 5.87; N, 6.27. Found: C, 59.30; H, 5.73; N, 6.18.
Compound 5i: Colorless solid, mp 134–1368C (lit.[5] Mp 134–1368C); IR
(KBr): 3038, 1732, 1559, 1290, 1120, 1040, 830 cm21
;
1H NMR
(300 MHz, CDCl3) d ¼ 7.30 (m, 3H), 7.20 (m, 2H), 3.75 (s, 6H), 2.34
(s, 6H). Anal. calcd. for C19H16NO4: C, 68.21; H, 5.72; N, 4.68. Found: C,
68.45; H, 5.65; N, 4.60.
Compound 5j: Pale yellow solid; mp 114–1158C (lit[5] mp 114–1158C); IR
(KBr): 3040, 1732, 1559, 1510, 1289, 1235, 1120, 1020, 832 cm21; 1H NMR
(300 MHz, CDCl3) d ¼ 7.12 (d, J ¼ 9.1, 2H), 6.90 (d, J ¼ 9.2, 2H), 3.70
(s, 3H), 3.46 (s, 6H), 2.56 (s, 6H). Anal. calcd. for C18H19NO5: C, 65.67; H,
5.77; N, 4.25. Found: C, 65.60; H, 5.71; N, 4.19.
Compound 10a: Light brown solid; mp 309–3128C (lit.[9] mp 308–3128C);
IR (KBr): 3435, 3300, 2200, 1712 cm21 1H NMR (300 MHz, CDCl3)
;
d ¼ 2.91 (s, 3H), 3.35 (s, 3H), 6.80–7.30 (m, 5H). Anal. calcd. for
C16H13N5O2: C, 62.53; H, 4.26; N, 22.79. Found: C, 62.42; H, 4.20; N, 22.71.
Compound 11a: Pale yellow solid; mp 148–1508C; (lit.[9] mp 149–1518C);
IR (KBr): 3440, 3345, 1732, 1669 cm21 1H NMR (300 MHz, CDCl3)
;
d ¼ 1.29 (t, J ¼ 7.1 Hz, 3H), 3.25 (s, 3H), 3.29 (s, 3H), 4.30 (q, J ¼ 7.1 Hz,
2H), 6.85–7.75 (m, 5H). Anal. calcd. for C18H18N4O4: C, 61.00; H, 5.12;
N, 15.81. Found: C, 60.85; H, 5.20; N, 15.72.
Compound 12a: Pale yellow solid; mp 212–2148C (lit.[9] mp 212–2148C);
IR (KBr): 3440, 3348, 3105, 1700 cm21 1H NMR (300 MHz, TFA)
;
d ¼ 3.20 (s, 3H), 3.37 (s, 3H), 6.95–7.15 (m, 5H). Anal. calcd. for
C16H15N5O3: C, 59.07; H, 4.65; N, 21.53. Found: C, 59.23; H, 4.55; N, 21.47.
ACKNOWLEDGMENT
Authors thank the Council of Scientific and Industrial Research, New Delhi,
India, for financial support of this research project.

2324
A. Saini, S. Kumar, and J. S. Sandhu
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