Sulfamic acid: An efficient, cost-effective, and reusable solid acid catalyst for the synthesis of 1,8-naphthyridines under solvent-free heating and microwave irradiation

Article abstract of DOI:10.1080/00397910802109281

An efficient and convenient method is described for the synthesis of 1,8-naphthyridines in excellent yields by condensation of 2-aminonicotinaldehyde with various active methylene compounds in the presence of sulfamic acid as the catalyst in a solvent-free media using both conventional heating and microwave irradiation. Copyright Taylor & Francis Group, LLC.

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Sulfamic Acid: An Efficient,
Cost-Effective, and Reusable
Solid Acid Catalyst for
the Synthesis of 1,8-
Naphthyridines Under Solvent-
Free Heating and Microwave
Irradiation
Y. Thirupathi Reddy a , P. Raghotham Reddy a , M.
Nikhil Reddy b , B. Rajitha b & Peter A. Crooks b
a Department of Pharmaceutical Sciences, College
of Pharmacy, University of Kentucky, Lexington,
Kentucky, USA
b Department of Chemistry, National Institute of
Technology, Warangal, India
Published online: 09 Sep 2008.
To cite this article: Y. Thirupathi Reddy , P. Raghotham Reddy , M. Nikhil Reddy , B.
Rajitha & Peter A. Crooks (2008): Sulfamic Acid: An Efficient, Cost-Effective, and
Reusable Solid Acid Catalyst for the Synthesis of 1,8-Naphthyridines Under Solvent-
Free Heating and Microwave Irradiation, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 38:18, 3201-3207
To link to this article: http://dx.doi.org/10.1080/00397910802109281

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Synthetic Communications1, 38: 3201–3207, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802109281
Sulfamic Acid: An Efficient, Cost-Effective, and
Reusable Solid Acid Catalyst for the Synthesis of
1,8-Naphthyridines Under Solvent-Free Heating
and Microwave Irradiation
Y. Thirupathi Reddy,1 P. Raghotham Reddy,1 M. Nikhil Reddy,2
B. Rajitha,2 and Peter A. Crooks2
1Department of Pharmaceutical Sciences, College of Pharmacy,
University of Kentucky, Lexington, Kentucky, USA
2Department of Chemistry, National Institute of Technology, Warangal, India
Abstract: An efficient and convenient method is described for the synthesis of
1,8-naphthyridines in excellent yields by condensation of 2-aminonicotinaldehyde
with various active methylene compounds in the presence of sulfamic acid as the
catalyst in a solvent-free media using both conventional heating and microwave
irradiation.
Keywords: Microwave irradiation, 1,8-naphthyridines, solvent-free, sulfamic acid
INTRODUCTION
1,8-Naphthyridines and their derivatives are pharmacologically impor-
tant because their wide range of biological and therapeutic properties,
and there are numerous reports that highlight their chemistry and thera-
peutic use.[1] Thus, 1,8-naphthyridines and their derivatives have emerged
as powerful tools in organic synthesis. 1,8-Naphthyridines are prepared
by using either the Friedlander condensation[2] or the Knoevenagel reac-
tion.[3] Even though various procedures are reported, disadvantages,
including low yields, prolonged reactions times, use of an excess of
Received February 3, 2008.
Address correspondence to Peter A. Crooks, Department of Pharmaceutical
Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536,
USA. E-mail: pcrooks@email.uky.edu
3201

3202
Y. T. Reddy et al.
Scheme 1. Sulfamic acid (SA)-catalyzed synthesis of 1,8-naphthyridines.
reagents=catalysts, and use of toxic organic solvents necessitate the devel-
opment of an alternative route for the synthesis of 1,8-naphthyridines.
Recently, sulfamic acid has emerged as a promising solid acid catalyst
for acid-catalyzed reactions such as functional group protection and
deprotection,[4] and synthesis of isoamyl acetate,[5] polymeric ether,[6]
and xanthanes.[7] In addition, some important organic transformations,
such as the Beckmann rearrangement,[8] Pechmann,[9] and Biginelli con-
densation[10] reactions have been performed successfully in the presence
of a catalytic amount of sulfamic acid. In recent years, organic reactions
in solvent-free conditions (solid state) have been increasingly attractive
to synthetic organic chemists because of their simplicity and synthetic
value.[11–13] Moreover, solvent-free reactions have many advantages,
including ecofriendliness, commercial viability, and simplicity in proces-
sing, handling, and workup. In continuation of our work[7,14–16] on the
development of new synthetic methodologies using acid catalysts and
microwave irradiation, we have observed that sulfamic acid (SA) is an
efficient catalyst for the synthesis of 1,8-naphthyridines from 2-aminoni-
cotinaldehyde and active methylene compounds in solvent-free media uti-
lizing both conventional heating and microwave irradiation (Scheme 1).
RESULTS AND DISCUSSION
In the microwave irradiation procedure for the synthesis of 1,8-naphthyr-
idines, the reaction mass containing 2-aminonicotinaldehyde and
active methylene compound was irradiated in a domestic microwave
oven at 300 w over 30-s intervals in an open vessel for 2–5 min. The

Sulfamic Acid Catalyst for 1,8-Naphthyridines
3203
Table 1. Effect of five acid catalysts on the reaction of 2-aminonicotinaldehyde
with N-phenyl acetoacetamide under conventional and microwave heating
Method A
Method B
Catalyst
Time (min)
Yield (%)
Time (h)
Yield (%)
Sulfamic acid
Silica sulfuric acid
p-TsOH
3
3
3
3
93
68
62
42
1
1
1
1
82
56
48
35
H2SO4
1,8-naphthyridines were also conventionally prepared at 50ꢀC over 1–2 h.
The structures of all newly synthesized 1,8-naphthyridines were con-
1
firmed by H NMR, 13C NMR, and mass spectral data.
To study the efficiency of a number of acidic catalysts compared
to sulfamic acid in the synthesis of the 1,8-naphthyridines, we conduc-
ted a model reaction between 2-aminonicotinaldehyde and N-phenyl
acetoacetamide in the presence of either sulfamic acid, silica sulfuric
acid, p-toluenesulfonic acid, or sulfuric acid (all at 10 mol%) under
both microwave irradiation (Method A) and conventional heating
(Method B) conditions (Table 1). In this study, it was found that,
compared to the other acid catalysts utilized, sulfamic acid was a more
effective catalyst with respect to reaction time and yield of the resulting
1,8-naphthyridines (Table 1).
A variety of 2,3-disubstituted 1,8-naphthyridines were also synthe-
sized via the conventional heating and microwave procedures all of which
were obtained in good yields (Table 2), illustrating the versatility of
methods A and B.
Analytical Data of Novel Compounds
3-(3,4-Dimethoxyphenyl)-[1,8]-naphthyridin-2-yl-amine (Table 2, entry
3c): Pale yellow solid: mp 253 ꢀC. 1H NMR (300 MHz, CDCl3):
d ¼ 3.92 (s, 3H), 3.95 (s, 3H), 5.5 (bs, 2H), 7.00–7.06 (m, 4H), 7.73 (s,
1H), 7.95 (dd, 1H), 8.87 (dd, 1H); 13C NMR (75 MHz, CDCl3): d
56.33, 56.36, 111.88, 112.02, 118.38, 118.88, 121.42, 126.08, 129.41,
136.26, 137.19, 149.40, 149.56, 152.69, 159.18, 158.22; HRMS (EIþ ):
m=z found 281.1166; calcd. C16H15N3O2 (EIþ ): 281.1164.
3-(2,3,4-Trimethoxyphenyl)-[1,8]-naphthyridin-2-yl-amine (Table 2,
ꢀ
1
entry 3d): Pale yellow solid: mp 266 C. H NMR (300 MHz, CDCl3):

3204
Y. T. Reddy et al.
Table 2. Sulfamic acid (SA)–catalyzed synthesis of 1,8-naphthyridines via Scheme 1
Method A
Method B
Entry
3a
Product
Time (min) Yield (%) Time (hrs) Yield (%) Mp (ꢀC)
3.0
4.0
3.0
92
90
95
1.5
2.0
1.2
78
75
85
222[17]
220[17]
257
3b
3c
3d
3.0
92
1.5
80
242
3e
3f
4.0
3.0
2.0
1.5
90
93
90
78
2.0
1.0
1.2
5.0
75
82
80
93
143[2b]
215[2b]
150[2b]
160[2b]
3g
3h
3i
3j
1.0
1.5
76
74
4.0
3.0
91
93
280[2b]
218[2b]
aYields refer to pure products and all products were characterized by compari-
1
son of their physical data and H NMR, 13C NMR, and mass spectral data with
those of authentic samples.

Sulfamic Acid Catalyst for 1,8-Naphthyridines
3205
d ¼ 3.94 (s, 6H), 3.96 (s, 3H), 5.6 (bs, 2H), 6.98–7.02 (m, 3H), 7.71 (s,
1H), 7.98 (dd, 1H), 8.88 (dd, 1H); 13C NMR (75 MHz, CDCl3): d
56.33, 56.36, 111.88, 112.02, 118.38, 118.88, 121.42, 126.08, 129.41,
136.26, 137.19, 149.40, 149.56, 152.69, 159.18, 158.22; HRMS (EIþ ):
m=z found 311.1273; calcd. C17H17N3O3 (EIþ ): 311.1270.
EXPERIMENTAL
General Procedure: Microwave Irradiation Method (Method A)
Sulfamic acid (0.1 mmol) was added to a mixture of 2-aminonicotinalde-
hyde 1 (1 mmol) and active methylene compound 2 (1 mmol), and the
mixture was inserted in a microwave oven (BPL, 800 T model) and irra-
diated at 300 W for the appropriate time (Table 2). Completion of the
reaction was indicated by thin-layer chromatography (TLC). After com-
pletion, the reaction mass was cooled to room temperature, water was
added, and the mixture was stirred for 5 min. The resultant solid was fil-
tered, washed with water, and recrystallized from an appropriate solvent
to afford pure crystalline 1,8-naphthyridine derivative 3.
Conventional Heating Method (Method B)
A mixture of 2-aminonicotinaldehyde 1 (1 mmol), active methylene com-
ꢀ
pound 2 (1 mmol), and sulfamic acid (0.1 mmol) was stirred at 50 C for
the appropriate time (Table 2). Completion of the reaction was indicated
by TLC analysis. The reaction was cooled to room temperature and
treated with water. The resultant solid was filtered, washed with water
and recrystallized from an appropriate solvent to afford pure crystalline
1,8-naphthyridine derivative 3.
CONCLUSION
We have demonstrated an efficient and very simple procedure for the syn-
thesis of 1,8-naphthyridines via the condensation of 2-aminonicotinalde-
hyde with various active methylene compounds in solvent-free media
under conventional heating and microwave irradiation using sulfamic
acid, which is inexpensive, nontoxic, and a readily available solid acid
catalyst. Prominent among the advantages of this new procedure are easy
workup, good yields, short reaction times, and operational simplicity.

3206
Y. T. Reddy et al.
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