Friedlaender synthesis of polysubstituted quinolines and naphthyridines promoted by propylphosphonic anhydride (T3P) under mild conditions

Article abstract of DOI:10.1039/c2nj21043f

A new convenient, efficient and environmentally eco-friendly protocol for Friedlaender synthesis of polysubstituted quinolines and naphthyridines is described. A wide variety of new products were readily prepared in the presence of propylphosphonic anhydride (T3P) in short reaction times and excellent yields under mild conditions. The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2012.

Full text of DOI:10.1039/c2nj21043f

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LETTER
¨
Friedlander synthesis of polysubstituted quinolines and naphthyridines
promoted by propylphosphonic anhydride (T3Ps) under mild conditionsw
Mouhamad Jida*ab and Benoit Deprezab
Received (in Montpellier, France) 16th December 2011, Accepted 13th February 2012
DOI: 10.1039/c2nj21043f
recent years.7 In addition, T3Ps is highly reactive and commonly
A new convenient, efficient and environmentally eco-friendly
¨
protocol for Friedlander synthesis of polysubstituted quinolines
used as a coupling agent and offers several advantages over
traditional reagents, such as low toxicity, commercial scale avail-
ability, low price, low epimerization tendency, high selectivity
yields, excellent purity, broad functional group, easy work up
procedures due to water-soluble byproducts.8 Further, a large
number of new applications for the non-toxic nature of T3Ps
have recently been developed in the literature.9
and naphthyridines is described. A wide variety of new products
were readily prepared in the presence of propylphosphonic
anhydride (T3Ps) in short reaction times and excellent yields
under mild conditions.
The construction of quinoline moieties has received great
attention in the field of medicinal chemistry due to their
biological activity.1 A large variety of quinoline derivatives
have been identified among privileged ones in drug discovery2
and used as antiasthmatic, anti-inflammatory, antibiotic, anti-
microbial, antibacterial, antiplatelet, antimalarial, insecticidal
agents and tyrosine kinase inhibiting agents.3 The quinoline
scaffold is also found in many natural compounds, particularly
in alkaloids.4 In addition, quinolines have been employed in
the study of bioorganic and bioorganometallic chemistry.5
Consequently, a variety of elegant methods leading to these
heterocyclic nuclei have been developed in the literature.6
Among these methods, the Friedlander reaction6f,g is a straight-
forward method for preparing the polysubstituted quinolines
and related azaheterocycles (Scheme 1).
The Friedlander reaction is usually carried out either by
heating an aqueous or alcoholic solution at reflux or by
heating the abovementioned reagents at high temperature in
the absence of catalysts.10 However, originally strong bases
were needed.11 Under thermal or base catalysis conditions,
2-aminobenzophenone failed to react with simple ketones such
as cyclohexanone and b-keto-esters.12 In addition, changed
methods employing iodine, Lewis acid, inorganic salts and a
combination of acidic catalysts were most frequently used but
the reaction has also been described with BrØnsted acidic
catalysts, in a microwave oven, or in ionic liquids, all methods
were widely used for the Friedlander annulation.13 Unfortunately
many of the reported methods suffered from harsh reaction
conditions, the use of high reaction temperatures (up to 250 1C)
and prolonged reaction times leads to several side products,
harmful organic solvents, low product yields, tedious work-up
procedure, no compliance with the green chemistry protocols, low
selectivity, required chromatographic isolation technique, the use
of stoichiometric and relatively expensive reagents and some of
these catalysts present limitations due to the use of toxic and
corrosive reagents. Moreover, the reaction has been performed in
the presence of solvent such as DMSO or DMF leading to
complex isolation and recovery procedures.
The propylphosphonic anhydride (T3Ps) catalyst represents
an important and powerful tool for the promotion of one-pot
synthesis of fused heterocycles from readily available starting
materials, the use of which in the organic chemistry as a mild
water scavenger in organic synthesis has increased rapidly in
In this communication, we report a rapid, convenient and
efficient one-pot synthesis of new polysubstituted quinolines
and naphthyridines via Friedlander reaction performed without
added solvent, using T3Ps as a promoter, an environmentally
benign and neutral catalyst under mild conditions.
Scheme 1 Friedlander annulation.
a Biostructures and Drug Discovery, INSERM U761,
´
Faculte de Pharmacie, Universite Lille Nord de France,
3 rue du Pr Laguesse, Lille F-59006, France.
´
In order to find the best reaction conditions for the synthesis
of quinoline derivatives, 2-amino-5-chlorobenzophenone and
cyclohexanone were chosen as model substrates to optimize
the reaction conditions (Table 1). However, under solvent-free
conditions, the reaction did not proceed when the mixture was
heated at 50 1C in an oil-bath for 1 hour in the absence of
E-mail: mhmd_jida@yahoo.com; Tel: +33 640607000
b
´
PRIM Poˆle de Recherche Interdisciplinaire sur le Medicament,
3 rue du Pr Laguesse, Lille F-59006, France.
Web: www.drugdiscoverylille.org
w Electronic supplementary information (ESI) available: Compounds
full characterization and NMR spectra. See DOI: 10.1039/c2nj21043f
c
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Table 1 Optimization of the reaction conditions
Firstly, we turned our attention to examining the scope of
the reaction between the cyclic mono-functionalized ketones
and 2-aminoarylketones. Excellent yields of tricyclic quinolines
were obtained in short reaction times (Table 2, entries 1–3).
To our delight, a variety of aromatic, heteroaromatic, bicyclic
and heterobicyclic ketones such as a-tetralone, chromanone,
dihydrobenzofuranone, and dihydrobenzothiophenone derivatives
also underwent smooth condensation with 2-aminoaryl
ketones to afford the respective quadricyclic quinolines in
excellent yields (Table 2, entries 14–17 and 24–26). In addition,
other functionalized ketones, such as ethyl pyruvate, diethyl
1,3-acetonedicarboxylate, tert-butyl and ethyl acetylacetate
derivatives, were also investigated in the presence of T3Ps
full conversion and satisfactory results were obtained (Table 2,
entries 8–12 and 21–23).
Entry
t/h
T/1C
T3Ps (equiv.)
Conversiona (%)
1
2
3
4
5
6
7
8
1
1
1
1
1
1
0.5
0.5
0.5
4
50
50
50
50
50
50
50
60
25
25
25
100
100
0
Traces
17
32
63
95
0.1
0.2
0.5
0.8
1
1
1
1
1
100
96
100b
77
However, compounds bearing acid sensitive functional
groups such as the ethyl ester and N-boc also gave excellent
yields with no sign of hydrolysis or deprotection, indicating
the mild nature of the conditions (Table 2, entries 4 and 5).
The quinoline resulting from cyclization through the terminal
CH3 of the methylketone was obtained in excellent yields
(Table 2, entry 18) showing the powerful effect of T3Ps in
the synthesis of quinolines. Furthermore, the Friedlander
reaction with unsymmetrical ketones afforded regiospecifically
only one regioisomer in satisfactory yields in contrast to
results obtained under acidic or basic conditions (Table 2,
entries 8–11).15 Theoretically, the Friedlander reaction with
unsymmetrical 1,3-diones (containing 4 a-positions of a
ketone) can have four possible routes for cyclisation, giving
rise to four regioisomers. Surprisingly, the reaction afforded
only one regioisomer in excellent yields (Table 2, entry 13).
The observed regioselectivity of the cyclization could be
explained by steric effects. This can be rationalized by the
preferred imine/enamine formation of the carbonyl group next
to the methyl group rather than the carbonyl group next to the
phenyl group. Interestingly, in the case of a-bromoketone
(Table 2, entries 19 and 20), 3-bromo-2,4-diarylquinoline is
formed in excellent yields showing the high reactivity of T3Ps
used as the reaction promoter.16 Thus, 3-bromoquinoline
can be further diversified by using known organopalladium
reaction, such as Heck reaction, Suzuki cross-couplings and
Sonogashira.17 We next examined the reaction of the sensitive
chloroketone, which also gave the corresponding quinoline in
excellent yields (Table 2, entries 10 and 23), and no significant
substituent effect was observed. Furthermore, the expected
product can generate a diverse array of polysubstituted quino-
line scaffolds.18 Finally, in order to generalize the process, we
used as the substrate 2-aminopyridine carboxaldehyde that
was condensed with ketone, the overall yield is quite reason-
able (Table 2, entries 29 and 30).19 It is noteworthy that
the reported procedure is an attractive methodology for
the Friedlander synthesis of 1,8 naphthyridines with great
efficiency.20 However, R, R3 and R4 can be alkyl or aryl
groups, and electron-donating or electron-withdrawing functional-
ities at different positions on the substrate were well tolerated and
had no influence on the yield. As expected, the reaction was
compatible with a wide scope of functional groups, and
substituents, such as halo and methoxy, to provide the corres-
ponding quinolines in excellent yields. Various substituted
9
10
11
12
13
89
8
1
1
0.5
100
100
100d
5 minc
5 minc
a
b
Determined by HPLC and LC-MS analysis. Isolated in 95% yield.
d
The reaction was performed under microwave irradiation. Quanti-
c
tative yield was obtained.
T3Ps (Table 1, entry 1). In order to establish the effectiveness
of the catalyst under the same conditions, weak conversion,
above 17% detected by LC/MS, was obtained with 0.1 equiv.
of T3Ps (50% solution in EtOAc) (Table 1, entry 2). Then,
upon increasing the amount of T3Ps the conversion slightly
increased to become total with 1 equiv. of T3Ps (Table 1,
entries 2–6). Further optimization showed that change of the
reaction conditions (time, temperature) was appropriate for
the cyclodehydration in good to excellent conversion (Table 1,
entries 7–11). A full conversion was obtained at 60 1C for
30 minutes with a 95% isolated yield of quinoline (Table 1,
entry 8). Nevertheless, performing the reaction in the presence
of catalytic amounts of T3Ps under microwave conditions at
100 1C for a power of 100 watts affords a total conversion after
only 5 minutes (Table 1, entries 12 and 13). However, the
conditions chosen to explore the scope of this protocol were
60 1C, 30–60 minutes and 1 equiv. of T3Ps (entry 8) because
this process is easy to scale up and widely accessible to all
chemists.
More recently, the synthesis of various polysubstituted quino-
line compounds prepared by the same reaction type in the
presence of T3Ps and DMF as the solvents under heating or
microwave irradiation conditions was reported by Augustine
and co-workers.14 However, in this manuscript, we reported
29 interesting new compounds prepared under solvent-free
conditions at 60 1C with short reaction times compared to the
conventional heating method or under microwave irradiation.14
In addition, this procedure is interesting as it shows that micro-
wave heating is not always necessary to reach high conversions
and excellent yields. After establishing the optimal reaction
conditions, the substrate scope is explored. The generality of this
reaction is illustrated with respect to various 2-aminoaryl ketones
and a wide array of a-methylene ketones and the detailed results
for these reactions are collected in Table 2.
c
870 New J. Chem., 2012, 36, 869–873
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Table 2 Friedlander synthesis of poly-substituted quinoline deriva-
tives in the presence of T3Ps
Table 2 (continued )
Yielda
(%)
Entry R R1 R2
X
Ketone
Quinoline
15
16
17
Ph H
Ph H
Ph H
Cl
Cl
Cl
CH
95
Yielda
(%)
Entry R R1 R2
X
Ketone
Quinoline
CH
CH
94
93
1
2
3
Ph H
Ph H
Ph H
Cl
Cl
Cl
CH
95
CH
CH
90
90
18
Ph H
Cl
CH
93
19
20
Ph H
Ph H
Cl
Cl
CH
CH
96
95
4
5
6
Ph H
Ph H
Ph H
Cl
Cl
Cl
CH
CH
CH
93
95
94
21
22
23
24
Me H
Me H
Me H
Me H
H
H
H
H
CH
CH
CH
CH
95
89
95
94
7
Ph H
Cl
CH
95
8
Ph H
Ph H
Ph H
Ph H
Cl
Cl
Cl
Cl
CH
CH
CH
CH
93
92
90
91
9
25
Me H
Me H
H
H
CH
CH
86
10
11
26
27
28
29
92
96
92
Me MeO MeO CH
Me MeO MeO CH
12
13
14
Ph H
Ph H
Ph H
Cl
Cl
Cl
CH
CH
CH
91
94
96
H
H
H
H
H
H
N
N
87
85
30
a
Yields refer to isolated pure products.
c
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2-aminoaryl ketones such as 2-amino-5-chloro-benzophenone
and 2-aminonicotinaldehyde reacted smoothly with an appro-
priately substituted carbonyl derivative containing a reactive
a-methylene group to produce a wide range of polysubstituted
quinoline derivatives (Table 2, entries 6, 7, 14, 15, 19, 20, 29
and 30). In all cases, the results showed the excellent reactivity
of T3Ps under these conditions. The expected products were
obtained with excellent purity and yields (85–96%) by recrys-
tallization or precipitation and proved to be much better
than those obtained using the classical methods reported in
the literature. In general, the reaction is very clean, rapid and
efficient.
Notes and references
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In conclusion, we have introduced a highly efficient and
robust method for the Friedlander annulation with T3Ps
under mild conditions. This method displayed high functional
group tolerance and offers a simple and very efficient route for
the synthesis of a wide range of polysubstituted, polycyclic
quinolines and naphthyridines. This method avoids the use
of hazardous acidic or basic reagents and harsh reaction
conditions. The advantages of this protocol include short
reaction times, excellent yields, simple work-up procedure,
cost-effectiveness, environmentally eco-friendly benign and
simple experimental operations. These advantages make this
methodology attractive for large scale synthesis.21 The access
to other heterocycles by using T3Ps is currently under
investigation in our laboratory.
7 (a) H. Wissmann and H.-J. Kleiner, Angew. Chem., Int. Ed. Engl.,
1980, 19, 133; (b) R. Escher and P. Bunning, Angew. Chem., Int.
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The authors are grateful to the institutions that supported
their laboratory (Inserm, Universite de Lille2, Institut Pasteur
de Lille, USTL).
8 Coupling Agent T3Ps—The Water Scavenger www.archimica.
com/PDF/ARCHIMICA_T3P_Brochure.pdf.
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Experimental
¨
General procedure for Friedlander reaction promoted by
propylphosphonic anhydride (T3Ps)
To a mixture of 2-aminoaryl ketone (0.5 mmol) and ketone
(0.5 mmol) was added T3Ps (50% in EtOAc) (0.5 mmol) in
drops. The mixture was heated to 60 1C without added solvent
for 0.5–1 h under air. After completion of the reaction
(monitored by LC-MS), water (3 ml) was added to the reaction
mixture and was shaken to dissolve the T3Ps. The crude
product was easily purified and isolated by recrystallization
from hot methanol (2 ml) for more purification to give the
pure polysubstituted quinolines. In all cases, the resulting
products were isolated in total purity, as determined by
LC-MS, and afforded analytically pure products in excellent
to good yields in 85–96% as a solid.
10 S. Glaldiali, G. Chelucci, M. S. Mudadu, M. A. Gastaut and
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76, 5774.
5,6-Dihydro-7-methylbenzo[c]acridine (24). Yield (115 mg,
1
94%); grey solid; mp = 92–94 1C; purity: 100%; H NMR
(300 MHz, CDCl3): d 8.68 (d, J = 7.5 Hz, 1H), 8.22 (d, J =
8.4 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.68 (dd, J = 9.6, 6.9
Hz, 1H), 7.53–7.38 (m, 3H), 7.28 (d, J = 7.5 Hz, 1H),
3.11–2.95 (m, 4H), 2.59 (s, 3H); 13C NMR (75 MHz, CDCl3):
d 152.62 (Cq), 146.88 (Cq), 139.77 (Cq), 139.11 (Cq), 135.28
(Cq), 130.25, 129.49, 128.40 (Cq), 128.26, 127.76 (Cq), 127.61,
127.25, 126.48, 125.83, 123.68, 28.17, 25.35, 13.91; rt (LCMS)
= 3.33 min (5 min, pH = 3.8); HRMS-ESI (m/z): [M + H]+
calcd for C18H16N 246.1283; found 246.1295.
c
872 New J. Chem., 2012, 36, 869–873
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21 The reaction was successfully performed by condensation of
2-amino-5-chlorobenzophenone with cyclohexanone and quantita-
tive yield was obtained when the reaction was conducted on a
10 mmol scale.
c
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New J. Chem., 2012, 36, 869–873 873