Sulfamic acid: An efficient, cost-effective and recyclable solid acid catalyst for the Friedlander quinoline synthesis

Article abstract of DOI:10.1016/j.tetlet.2005.08.042

o-Aminoaryl ketones undergo smooth condensation with α-methylene ketones in the presence of sulfamic acid (NH₂SO₃H) (SA) under mild reaction conditions to afford the corresponding polysubstituted quinolines in excellent yields. The c

Full text of DOI:10.1016/j.tetlet.2005.08.042

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7249–7253
Sulfamic acid: an efficient, cost-effective and recyclable solid
acid catalyst for the Friedlander quinoline synthesis
J. S. Yadav,* P. Purushothama Rao, D. Sreenu, R. Srinivasa Rao, V. Naveen Kumar,
K. Nagaiah and A. R. Prasad
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500007, India
Received 30 May 2005; revised 3 August 2005; accepted 10 August 2005
Available online 6 September 2005
Abstract—o-Aminoaryl ketones undergo smooth condensation with a-methylene ketones in the presence of sulfamic acid
(NH2SO3H) (SA) under mild reaction conditions to afford the corresponding polysubstituted quinolines in excellent yields. The
catalyst can be recovered by simple filtration and can be recycled in subsequent reactions. The method is simple, cost-effective
and environmentally benign.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Quinolines are very important compounds due to their
wide spectrum of biological activities behaving as anti-
malarial, anti-bacterial, anti-asthmatic, anti-hyperten-
sive, anti-inflammatory, anti-platelet activity and tyro-
kinase PDGF-RTK inhibiting agents.1–3 In addition to
medicinal applications, quinoline derivatives are found
to undergo hierarchical self-assembly into a variety of
nano-structures and meso-structures with enhanced
electronic and photonic functions.4 In addition quino-
lines have been employed in the study of bioorganic
and bioorgano-metallic processes.5 Considering the
significant applications in the fields of medicinal, bio-
organic, industrial and synthetic organic chemistry,
there has been tremendous interest in developing effi-
cient methods for the synthesis of quinolines. Conse-
quently, various procedures such as the Skraup,
Doebner-Von Miller, Friedlander and Combes methods
have been developed for the synthesis of quinoline deriv-
atives.6,7 Among them, the Friedlander annulation7b
is still one of the most simple and straightforward
approaches for the synthesis of polysubstituted quino-
lines. The Friedlander quinoline synthesis consists of
the reaction between an aromatic ortho-amino aldehyde
and an aldehyde or ketone and an alpha-methylene
functionality. Friedlander reactions are generally carried
out either by refluxing an aqueous or alcoholic solution
of reactants in the presence of a base or by heating a
mixture of the reactants at high temperatures ranging
from 150 to 220 ꢁC in the absence of a catalyst.8 Under
thermal or basic catalysis conditions, o-aminobenzophe-
none fails to react with simple ketones such as cyclohex-
anone, deoxybenzoin and b-keto esters.8e Subsequent
work showed that acid catalysts are more effective than
base catalysts for the Friedlander annulation.8e Acid
catalysts such as hydrochloric acid, sulfuric acid, p-tolu-
enesulfonic acid and polyphosphoric acids have been
widely employed for this conversion.8a,9 In addition,
modified methods employing phosphoric acid, diphos-
gene, AuCl3, NaF, ZnCl2, microwaves and ionic liquids
have been reported for the synthesis of quinolines.9,10
More recently, Y(OTf)3 has been employed for this
conversion.10f However, most of the synthetic protocols
reported so far suffer from high temperatures, prolonged
reaction times, harsh reaction conditions, low yields of
the products and the use of hazardous and often expen-
sive acid and base catalysts. Moreover, this reaction is
usually carried out in polar solvents such as acetonitrile,
THF, DMF and DMSO leading to tedious work-up
procedures. The main disadvantage of most of the exist-
ing methods is that the catalysts are destroyed in the
work-up procedure and cannot be recovered or re-used.
Therefore, the development of simple, convenient and
environmentally benign approaches for the synthesis of
quinolines is still desirable.
Keywords: Sulfamic acid (SA); o-Aminoaryl ketones; a-Methylene
ketones; Quinolines.
*
In recent years, the use of solid acids as heterogeneous
catalysts has received tremendous interest in different
Corresponding author. Tel.: +91 40 27160123; fax: +91 40
27160512; e-mail: yadavpub@iict.res.in
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.08.042

7250
J. S. Yadav et al. / Tetrahedron Letters 46 (2005) 7249–7253
areas of organic synthesis.11 Heterogeneous solid acids
are advantageous over conventional homogeneous acid
catalysts as they can be easily recovered from the reac-
tion mixture by simple filtration and can be re-used after
activation or without activation, thereby making the
process economically more viable. During the last few
years, sulfamic acid (NH2SO3H) (SA) has emerged as
a substitute for conventional acidic catalysts. Sulfamic
acid is a common inorganic acid with mild acidity, is
non-volatile and non-corrosive, and is insoluble in com-
mon organic solvents. It is a white crystalline solid12a
with outstanding physical and chemical properties and
is a commercially available cheap chemical. It has
already been determined by both X-ray and neutron dif-
fraction techniques12b,c that SA is comprised ꢀnot of an
amino sulfonic acid, but rather of H3N+SO3 zwitter-
ionic units. In recent years, SA has been used as an effi-
cient heterogeneous catalyst for acid catalyzed reactions,
viz. acetalization,13a esterification,13b,c acetylation of
alcohols and phenols,13d nitrile formation,13e tetra-
hydropyranylation of alcohols13f and transesterification
of b-ketoesters.13g Moreover, some important organic
transformations, including the Biginelli condensation,13h
the Beckmann rearrangement,13i inter- and intramole-
cular imino Diels–Alder reactions13j and very recently
Pechmann condensations,13k have been carried out in
the presence of SA. The distinctive catalytic features
and intrinsic zwitterionic property of SA are very differ-
ent from conventional acidic catalysts. This has encour-
aged us to investigate further the applications of SA as
an acidic catalysts in other carbon–carbon and car-
bon–heteroatom bond-forming reactions. However,
there are no reports on the use of SA for the synthesis
of quinolines via Friedlander annulation. The use of
SA as a recyclable catalyst makes the process conve-
nient, economic and environmentally benign.
O
Ph
N
O
(5 mol%)
NH2SO3H
Ph
NH2
+
n
70 oC, Solvent-free
n
Scheme 2.
estingly, cyclic ketones such as cyclopentanone and
cyclohexanone also underwent smooth condensation
with 2-aminoaryl ketones to afford the respective tricy-
clic quinolines (Scheme 2). In most cases, the products
were isolated by simple filtration. The crude products
were purified either by recrystallization from a mixture
of diethyl ether/n-hexane or by silica gel column
chromatography.
In addition, this method is equally effective for both
cyclic and acyclic ketones (Table 1). Various substituted
2-aminoaryl ketones such as 2-aminoacetophenone,
2-aminobenzophenone, 2-amino-5-chlorobenzophenone
and 2-amino-5-20-dichlorobenzophenone reacted smoo-
thly with a-methylene ketones to produce a range of
quinoline derivatives. In order to optimize the reaction
conditions, we conducted this reaction in different sol-
vents. The results showed that the efficiency and the
yield of the reaction in solution were much less than
those obtained under solvent-free conditions (Table 2).
The use of 5 mol % of the catalyst was sufficient to pro-
mote the reaction. Higher amounts of the catalyst did
not improve the yields. The best result was obtained
with 5 mol % of SA under solvent-free conditions at
70 ꢁC. However, in the absence of SA, the reaction did
not proceed even after long reaction times (12–24 h).
The insolubility of the catalyst SA in different organic
solvents provided an easy method for its separation
from the product. The catalyst was separated by filtra-
tion and reused after activation with only a gradual
decrease in its activity. For example, the reaction of
2-aminobenzophenone and ethyl acetoacetate afforded
the corresponding quinoline 3a in 92%, 89%, 85% and
80% yields over four runs. Furthermore, this method
is clean and free from side-reactions. Unlike previous
methods, the present protocol does not require either
strong acids such as concd HCl, concd H2SO4, p-TSA
and H3PO4 or high temperatures (190–250 ꢁC) to afford
quinoline derivatives. Thus, this method provides an
easy access to the preparation of substituted quinolines
with a wide range of substitution patterns. This method
offers several advantages such as higher yields, shorter
reaction times, cleaner reaction profiles and simple
experimental and work up procedures. All the products
were characterized by 1H NMR, 13C NMR, IR and
mass spectroscopy and also by comparison with authen-
tic samples.8a The scope and generality of this process is
illustrated with respect to various 2-aminoaryl ketones
and a-methylene ketones and the results are summarized
in Table 1.
In continuation of our efforts to develop new methods
in the synthesis of quinolines,14 herein, we wish to
report a mild and efficient approach for the synthesis
of polysubstituted quinolines via Friedlander annula-
tion using a catalytic amount of SA under solvent-free
conditions. Accordingly, treatment of 2-aminobenz-
ophenone (1) with 3-cyclopropyl-3-oxopropionic acid
methyl ester (2) in the presence of 5 mol % of SA
resulted in the formation of quinoline 3a in 95% yield15
(Scheme 1).
To study the generality of this process, several examples
were studied. Various 1,3-diketones such as 1,3-cyclo-
hexanedione, 5,5-dimethylcyclohexandione (dimedone)
and acyclic ketones including 2-butanone and 2-hexa-
none reacted efficiently with 2-aminobenzophenone to
produce the corresponding substituted quinolines. Inter-
O
Ph
O
O
O
(5 mol%)
NH2SO3H
Ph
OMe
In summary, we have described a mild and efficient
protocol for the synthesis of quinolines and polycyclic
quinolines via Friedlander condensation of 2-amino-
arylketones with a-methylene ketones using sulfamic
acid as a recyclable heterogeneous catalyst. The simple
+
OMe
70 oC, Solvent-free
NH2
N
1
2
3
Scheme 1.

J. S. Yadav et al. / Tetrahedron Letters 46 (2005) 7249–7253
Table 1. Sulfamic acid catalyzed synthesis of Friedlander quionlinesa
7251
Entry
2-Aminoketone
Ketone
Quinolineb
Time (min)
30
Yield (%)c
Ph
Ph
O
O
O
O
O
a
92
O
OEt
OEt
NH2
N
Ph
O
Ph
O
O
b
c
45
50
60
89
87
90
NH2
Ph
N
Ph
O
NH2
Ph
N
Ph
O
O
O
d
NH2
N
Ph
O
Ph
O
O
e
f
75
90
45
50
92
94
89
87
NH2
O
O
N
Ph
O
O
Ph
NH2
O
N
Ph
Ph
O
O
O
Cl
Cl
O
g
h
OEt
OEt
NH2
Ph
N
Ph
Cl
Cl
Cl
O
NH2
N
N
O
Cl
O
O
O
Cl
Cl
i
60
95
OMe
OMe
OEt
NH2
O
Cl
Cl
O
O
O
O
O
O
O
Cl
Cl
Cl
Cl
j
75
80
91
87
OEt
NH2
O
N
N
Cl
Cl
k
NH2
O
Cl
Cl
Cl
Cl
l
75
90
NH2
N
(continued on next page)

7252
J. S. Yadav et al. / Tetrahedron Letters 46 (2005) 7249–7253
Table 1 (continued)
Entry
2-Aminoketone
Ketone
Quinolineb
Time (min)
45
Yield (%)c
89
O
O
Cl
Cl
Cl
m
Cl
Cl
O
O
NH2
N
N
O
O
O
Cl
Cl
Cl
n
o
p
60
90
75
87
90
85
NH2
O
NO2
O
O
O
O2N
O2N
O2N
OEt
OEt
NH2
N
N
O
NO2
NO2
O
O2N
O2N
O2N
O2N
O
O
NH2
O
O2N
O2N
q
60
90
82
89
NH2
N
O
CH3
O
O
O
O2N
CH3
NH2
r
OEt
OEt
N
a Reaction conditions: 2-aminobenzophenone (1 mmol), ketone (1.5 mmol), sulfamic acid (5 mol %); 70 ꢁC, solvent-free.
b All products were characterized by 1H and 13C NMR, IR and mass spectroscopy.
c Isolated and unoptimized yields.
Table 2. Friedlander quinoline 3i synthesis catalyzed by SA in various
solventsa
benign for the synthesis of highly functionalized
quinolines.
Entry
Solvent
Temperature
(ꢁC)
Time
(h)
Yield
(%)b
Acknowledgements
1
2
3
4
5
6
7
8
9
CH2Cl2
CHCl3
CH3CN
1,2-Dichloroethane
MeOH
EtOH
Benzene
Toluene
Solvent-free
Solvent-free
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
rt
24
24
24
24
24
24
24
24
24
1.0
47
49
65
73
74
76
77
79
43
95
P.P.R., D.S. and R.S.R. thank CSIR New Delhi for the
award of fellowships.
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1H NMR (400 MHz, CDCl3), d: 0.95 (t, J = 6.9 Hz, 3H),
2.78 (s, 3H), 4.00–4.05 (q, J = 6.9 Hz, 2H), 7.38–7.48 (m,
6H), 7.55 (d, J = 8.1 Hz, 1H), 7.70 (t, J = 8.0 Hz, 1H), 8.05
(d, J = 8.1 Hz, 1H). 13C NMR (CDCl3) d: 13.3, 23.5, 60.8,
96.0, 125.2, 126.0, 126.2, 127.8, 128.2, 129.0, 129.3, 129.7,
135.7, 145.7, 147.7, 154.2, 167.7. EI-MS: m/z (%): 291 (M+,
80), 246 (100), 218 (46), 177 (10), 176 (20), 75 (27), 43 (25).
Compound 3i: Pale yellow solid, mp 162 ꢁC. IR (KBr):
3006, 2921, 2850, 1732, 1576, 1501, 1471, 1435, 1310, 1224,
1
1042, 755 cmꢀ1. H NMR (200 MHz, CDCl3) d: 1.05 (m,
1H), 1.25 (m, 1H), 1.38–1.48 (m, 2H), 2.20 (m, 1H), 3.55 (s,
3H), 7.15–7.25 (m, 2H), 7.35–7.50 (m, 3H), 7.55–7.60 (m,
1H), 7.90 (d, J = 8.0 Hz, 1H). FAB-MS: m/z (%): 373
(M+1, 15), 340 (6), 312 (3), 281 (4), 207 (6), 147 (29), 109
(18), 95 (37), 55 (100). Compound 3n: Pale yellow solid, mp
142 ꢁC. IR (KBr): 3059, 2960, 1607, 1475, 1385, 1210, 955,
1
756 cmꢀ1. H NMR (200 MHz, CDCl3) d: 2.10–2.30 (m,
2H), 2.70–2.80 (m, 1H), 2.85–2.95 (m, 1H), 3.20–3.30
(m, 2H), 7.20–7.28 (m, 2H), 7.38–7.48 (m, 2H), 7.55–7.60
(m, 2H), 7.98 (d, J = 8.2 Hz, 1H). 13C NMR (CDCl3) d:
23.2, 29.9, 34.8, 124.0, 126.7, 127.0, 129.2, 129.8, 130.0,
130.4, 131.4, 133.0, 134.8, 135.5, 139.1, 146.2, 167.8. FAB-
MS: m/z (%): 315 (M+1, 100), 278 (14), 251 (5), 241 (7), 207
(8), 191 (6), 147 (21), 133 (17), 115 (8), 105 (8).