An exceedingly mild and efficient synthesis of 1,2,4-Triazolo[4,3-α][1,8]naphthyridines using iodobenzene diacetate in the solid state

Article abstract of DOI:10.1081/SCC-120006009

An efficient and mild method for the synthesis of 1,2,4-triazolo[4,3-α][1,8]naphthyridines using iodobenzene diacetate (IBD) in the solid state at room temperature has been described. The reaction proceeds efficiently at room temperature in good yields and in a solid of high purity.

Full text of DOI:10.1081/SCC-120006009

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AN EXCEEDINGLY MILD AND EFFICIENT SYNTHESIS OF
1,2,4-TRIAZOLO[4,3-a][1,8]NAPHTHYRIDINES USING
IODOBENZENE DIACETATE IN THE SOLID STATE
K. Mogilaiah a , H. Ramesh Babu a & N. Vasudeva Reddy a
a Department of Chemistry , Kakatiya University , Warangal, 506 009, India
Published online: 16 Aug 2006.
To cite this article: K. Mogilaiah , H. Ramesh Babu & N. Vasudeva Reddy (2002) AN EXCEEDINGLY MILD AND EFFICIENT
SYNTHESIS OF 1,2,4-TRIAZOLO[4,3-a][1,8]NAPHTHYRIDINES USING IODOBENZENE DIACETATE IN THE SOLID STATE, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 32:15, 2377-2384, DOI:
10.1081/SCC-120006009
To link to this article: http://dx.doi.org/10.1081/SCC-120006009
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SYNTHETIC COMMUNICATIONS
Vol. 32, No. 15, pp. 2377–2384, 2002
AN EXCEEDINGLY MILD AND
EFFICIENT SYNTHESIS OF 1,2,4-
TRIAZOLO[4,3-a][1,8]NAPHTHYRIDINES
USING IODOBENZENE DIACETATE
IN THE SOLID STATE
*
K.Mogilaiah, H.Ramesh Babu,
and N.Vasudeva Reddy
Department of Chemistry,
Kakatiya University, Warangal-506 009, India
ABSTRACT
An efficient and mild method for the synthesis of 1,2,4-tria-
zolo[4,3-a][1,8]naphthyridines using iodobenzene diacetate
(IBD) in the solid state at room temperature has been
described. The reaction proceeds efficiently at room tempera-
ture in good yields and in a solid of high purity.
Development of organic solid state reactions has emerged as a frontier
area of research in synthetic organic chemistry.[1–5] Hypervalent iodine
chemistry has been much studied lately and increased the utility in organic
synthesis.[6–9] Certain fused heterocyclic 1,2,4-triazoles continue to attract
much attention as these molecules are of potential biological interest.[10,11]
Synthetic methods for fused 1,2,4-triazoles are many.[12–15] However, these
*Corresponding author. E-mail: mogiaiah_k@yahoo.com
2377
DOI: 10.1081/SCC-120006009
Copyright & 2002 by Marcel Dekker, Inc.
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2378
MOGILAIAH, RAMESH BABU, AND VASUDEVA REDDY
methods are not very satisfactory due to drawbacks such as low yields,
toxic reagents, longer reaction time at higher reaction temperature and
tedious work-up procedures. Therefore, a good and useful method for the
preparation of fused 1,2,4-triazoles is highly desirable. In view of this
and in continuation of our interest on solid state organic reactions on
1,8-naphthyridine derivatives,[16,17] we report herein an easy, practical and
efficient procedure for the synthesis of 1,2,4-triazolo[4,3-a][1,8]naphthyri-
dines in the solid state at room temperature.
2-Aminonicotinaldehyde 1 on condensation with p-methoxyphenyl-
acetonitrile 2 in the presence of piperidine without any solvent at room
temperature resulted in the formation of 2-amino-3-( p-methoxyphenyl)-
1,8-naphthyridine 3, which is converted into 1,2-dihydro-3-( p-methoxyphe-
nyl)-1,8naphthyridin-2-one 4 by the reaction with HNO2. Treatment of 4
with POCl3 yielded 2-chloro-3-( p-methoxyphenyl)-1,8-naphthyridine 5,
which on hydrazinolysis with refluxing hydrazine hydrate furnished
2-hydrazino-3-( p-methoxyphenyl)-1,8-naphthyridine 6.
Condensation of 6 with a variety of aromatic aldehydes in the presence
of p-toluenesulphonic acid (PTSA) in the absence of solvent at room tem-
perature afforded the corresponding aryl aldehyde 3-( p-methoxyphenyl)-
1,8-naphthyridin-2-ylhydrazones 7 in very good yields.
The hydrazones 7 on oxidative cyclization with iodobenzene diacetate
(IBD) in the solid state at room temperature resulted in the formation
of 1-aryl-4-( p-methoxyphenyl)-1,2,4-triazolo[4,3-a][1,8]-naphthyridines 8 in
good yields. For example, when an equimolar mixture of hydrazone 7b and
IBD was ground by pestle and mortar at room temperature for 5 min, the
mixture turned to a white solid. The solid was combined with water and
filtered to give 4-( p-methoxyphenyl)-1-( p-methylphenyl)-1,2,4-triazolo[4,3-
a][1,8]naphthyridine 8b in 82% yield. When the reaction was carried out in
dichloromethane with stirring for the same reaction time as above (5 min) at
room temperature, the product was obtained only in 15% yield.
The reaction is fairly general, facile and efficient and is devoid of any
side products. The process is environmentally benign. The experimental
procedure is very simple and avoids sophistication.
Incidentally, this is the first observation of IBD mediated synthesis of
fused 1,8-naphthyridines in the solid state.
In conclusion, we have developed an efficient, environmentally
friendly, economically viable and cleaner methodology for the preparation
of 1,2,4-triazolo[4,3-a][1,8]naphthyridines under solid state conditions at
room temperature. Due to simplicity of the conditions, high yields and
purity of the products, the above methodology should find utility in organic
synthesis. In addition this method is safer because it minimizes the use of
toxic or hazardous reagents. Further, we found that the solid state oxidation

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1,2,4-TRIAZOLO[4,3-a][1,8]NAPHTHYRIDINES
2379
Scheme 1.
proceeds much faster and more efficiently than the solution reaction, prob-
ably because the solid state reaction is a very high concentration reaction.
EXPERIMENTAL SECTION
Melting points were determined in open capillary tubes using Cintex
apparatus and were uncorrected. The IR spectra in KBr were determined on
1
a Perkin Elmer spectrum BX series FT-IR spectrophotometer. H NMR
spectra were recorded in CDCl3 or DMSO-d6 on a Varian Gemini

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2380
MOGILAIAH, RAMESH BABU, AND VASUDEVA REDDY
200 MHz spectrometer using TMS as an internal standard (ꢀ units) and mass
spectra (EI) on a Jeol JMS D-300 spectrometer. Analytical TLC was per-
formed on Merk 60F-254 silica gel plates.
2-Amino-3-( p-methoxyphenyl)-1,8-naphthyridine 3
Amixture of 2-aminonicotinaldehyde 1 (1.22 g, 0.01 mol), p-methoxy-
phenylacetonitrile 2 (1.47 g, 0.01 mol) and piperdine (5 drops) was ground
by pestle and mortar at room temperature for 8 min and treated with water.
The resultant product was filtered, washed with water and recrystallized
from methanol to give 3 (2.46 g, 98%) as a pale yellow compound, mp
264ꢀC. IR (KBr) 3483, 3096, 1634, 1607 cmꢁ1 1H NMR (DMSO-d6) ꢀ
.
3.83 (s, 3H, OCH3); 6.41 (s, 2H, NH2); 7.06–7.49 (m, 5H, C6-H, 4 Ar-H);
7.84 (m, 1H, C4-H), 8.13 (m, 1H, C5-H), 8.75 (m, 1H, C7-H). EIMS m/z Mþ
251 (100%). Anal. calcd for C15H13N3O: C, 71.71; H, 5.18; N, 16.73. Found:
C, 71.93; H, 5.23; N, 16.82.
1,2-Dihydro-3-( p-methoxyphenyl)-1,8-naphthyridin-2-one 4
To a cold solution of 3 (2.51 g, 0.01 mol) in 2 N HCl (25 mL) was
added NaNO2 solution (0.01 mol in 25 mL water) and the reaction mixture
was stirred at room temperature for 0.5 h. It was then treated with chilled
water. The solid that precipitated was filtered, washed with water and
recrystallized from methanol to afford 4 (1.89 g, 75%) as pale yellow
crystals, mp 295ꢀC. IR (KBr) 3350, 1657, 1609 cmꢁ1. H NMR (DMSO-
1
d6) ꢀ 3.99 (s, 3H, OCH3); 7.04–7.57 (m, 4H, Ar-H); 8.17 (m, 1H, C4-H);
8.41 (m, 1H, C5-H); 7.76 (m, 1H, C6-H); 8.49 (m, 1H, C7-H); 12.32 (s, 1H,
NH). EIMS m/z Mþ 252 (100%). Anal. calcd for C15H12N2O2: C, 71.43; H,
4.76; N, 11.11. Found: C, 71.60; H, 4.82, N, 11.21.
2-Chloro-3-( p-methoxyphenyl)-1,8-naphthyridine 5
Asolution of 4 (2.52 g, 0.01 mol) in POCl3 (20 mL) was refluxed for 2 h
and cooled. The reaction mixture was then added to crushed ice and
NaHCO3. The precipitated product was filtered, washed with water and
recrystallized from methanol to furnish 5 (2.30 g, 85%) as white crystals,
mp 150ꢀC. IR (KBr) 1608, 760 cmꢁ1. H NMR (DMSO-d6) ꢀ 3.92 (s, 3H,
1
OCH3); 7.15–7.63 (m, 4H, Ar-H); 8.70 (m, 1H, C54-H); 8.79 (m, 1H, C5-H);
7.91 (m, 1H, C6-H); 9.25 (m, 1H, C7-H). EIMS m/z Mþ 270 (100%). Anal.

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1,2,4-TRIAZOLO[4,3-a][1,8]NAPHTHYRIDINES
2381
calcd for C15H11N2OCl: C, 66.54; H, 4.07; N, 10.35. Found: C, 66.72; H,
4.02; N, 10.44.
2-Hydrazino-3-( p-methoxyphenyl)-1,8-naphthyridine 6
Amixture of 5 (2.70 g, 0.01 mol) and hydrazine hydrate (0.015 mol) in
ethanol (30 mL) was refluxed for 3 h. The reaction mixture was concentrated
to one third its original volume and allowed to cool. The resulting solid
which deposited was filtered off and recrystallized from ethanol to afford 6
(2.34 g, 88%) as brown crystals, mp 105ꢀC. IR (KBr) 3335, 1612 cmꢁ1
.
1H NMR (DMSO-d6) ꢀ 3.96 (s, 3H, OCH3); 6.35 (s, 2H, NH2); 6.98–7.39
(m, 6H, C6-H, NH, 4Ar-H); 7.64 (m, 1H, C4-H); 7.98 (m, 1H, C5-H); 8.84
(m, 1H, C7-H). EIMS m/z Mþ 266 (100%). Anal. calcd for C15H14N4O: C,
67.67; H, 5.26; N, 21.05. Found: C, 67.82; H, 5.21; N, 21.18.
p-Methylbenzaldehyde-3-( p-methoxyphenyl)-
1,8-naphthyridin-2-ylhydrazone 7b
Amixture of 6 (2.66 g, 0.01 mol), p-methylbenzaldehyde (1.20 g,
0.01 mol) and PTSA(1.72 g, 0.01 mol) was ground by pestle and mortar at
room temperature for 3 min. The solid thus obtained was treated with water,
filtered and recrystallized from methanol to give 7b (3.50 g, 95%) as yellow
crystals, mp 160ꢀC. IR (KBr) 3350, 1623 cmꢁ1. 1H NMR (CDCl3) ꢀ 2.42 (s,
3H, CH3); 3.88 (s, 3H, OCH3); 6.97–7.28 (m, 8H, Ar-H); 7.75 (m, 3H, C4-H,
C5-H, C6-H); 8.34 (m, 1H, C7-H); 8.49 (s, 1H, N¼CH); 10.29 (s, 1H, NH).
EIMS m/z Mþ 368 (40.1%). Anal. calcd for C23H20N4O: C, 75.00; H, 5.43;
N, 15.22. Found: C, 75.22; H, 5.49; N, 15.35. Other compounds in the series
7 were similarly prepared (see Table 1).
4-( p-Methoxyphenyl)-1-( p-methyphenyl)-
1,2,4-triazolo[4,3-a][1,8]naphthyridine 8b
Amixture of 7b (3.68 g, 0.01 mol) and IBD (2.65 g, 0.01 mol) was
ground by pestle and mortar at room temperature for 5 min and treated
with water. The resultant solid was filtered and recrystallized from ethanol
to give 8b (3.00 g, 82%) as white crystals, mp 240ꢀC. IR (KBr) 1607 cmꢁ1
.
1H NMR (DMSO-d6) ꢀ 2.47 (s, 3H, CH3); 3.86 (s, 3H, OCH3); 6.95–7.85 (m,
9H, C7-H, 8 Ar-H); 8.25 (m, 1H, C5-H); 8.46 (m, 1H, C6-H); 8.62 (m, 1H,
C8-H). EIMS m/z Mþ 366 (65.7%). Anal. calcd for C23H18N4O: C, 75.41; H,

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2382
MOGILAIAH, RAMESH BABU, AND VASUDEVA REDDY

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1,2,4-TRIAZOLO[4,3-a][1,8]NAPHTHYRIDINES
2383

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2384
MOGILAIAH, RAMESH BABU, AND VASUDEVA REDDY
4.92; N, 15.30. Found: C, 75.59; H, 4.98; N, 15.41. Other compounds in the
series 8 were prepared similarly (see Table 1).
ACKNOWLEDGMENT
We wish to thank CSIR, New Delhi for the award of Senior Research
Fellowship to NVR.
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Received in Japan May 8, 2001