Friedl?nder reaction in the synthesis of 2-(phosphoryl)alkyl-substituted 1,6-naphthyridines

Article abstract of DOI:10.1016/j.mencom.2009.11.002

First 2-(phosphoryl)alkyl-substituted 1,6-naphthyridines have been synthesized by the Friedl?nder reaction between 4-amino-3-formylpyridine and phosphorus-containing ketones; their structures have been confirmed by 1H, 13C and 31P NMR spectroscopy and X-r

Full text of DOI:10.1016/j.mencom.2009.11.002

Mendeleev
Communications
Mendeleev Commun., 2009, 19, 303–305
Friedländer reaction in the synthesis of
2-(phosphoryl)alkyl-substituted 1,6-naphthyridines
Pavel S. Lemport,* Georgy V. Bodrin, Andrey I. Belyakov,
Pavel V. Petrovskii, Anna V. Vologzhanina and Edward E. Nifant’ev
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119991 Moscow,
Russian Federation. Fax: +7 495 135 6549; e-mail: pav-lemport@yandex.ru
DOI: 10.1016/j.mencom.2009.11.002
First 2-(phosphoryl)alkyl-substituted 1,6-naphthyridines have been synthesized by the Friedländer reaction between 4-amino-
3-formylpyridine and phosphorus-containing ketones; their structures have been confirmed by 1H, 13C and 31P NMR spectroscopy
and X-ray diffraction analysis.
Naphthyridines, aromatic systems with two endocyclic nitrogen
O
O
P
atoms, are of interest1 because they display various kinds of
biological activity.2 Nonetheless, phosphorus-containing naph-
thyridines are poorly studied.
CHO
NH2
N
Ph
Ph
+
Me
R1 R2
The Friedländer annulation is an important method for
preparing naphthyridines. The mechanism of this reaction is not
well understood in spite of the fact that the reaction has been
discovered more than 125 years ago. We have shown recently
that the above reaction can be used in the molecular design of
1,8-naphthyridine ligand systems.3,4 In a continuation of our
study on the design of new interesting organophosphorus mole-
cules, we have attempted to apply this method to the synthesis
of previously unknown 2-(phosphoryl)alkyl-substituted 1,6-naph-
thyridines.
3
4 R1 = H, R2 = Me
5 R1 = R2 = Me
O
N
NaOH
EtOH
P
Ph
Ph
N
R1 R2
6 R1 = H, R2 = Me
7 R1 = R2 = Me
It is well known that the Friedländer annulation of amino-
nicotinic aldehydes with unsymmetrical functionalized 2-alkanones
can result in a mixture of 2-monosubstituted and 2,3-disubsti-
tuted products in different ratios depending on the structures of
the ketone and the catalyst.5 We found3 that 2-amino-3-formyl-
pyridine 1 reacts with the simplest β-ketophosphine oxide,
namely, diphenylphosphorylacetone 2 (DPA), to give two phos-
phorus-containing products irrespective of the type of catalyst
used (Scheme 1).
Scheme 2
whereas 4-aminonicotinic aldehyde requires heating when it reacts
with compounds 4 and 5.
Along with the methylated derivatives of diphenylphosphoryl-
acetone, other ketones 8–10 containing reactive α-methyl groups
were also involved into condensation with aldehyde 3. Note
that these ketones also contain α-methylene groups capable of
participating in the Friedländer reaction. Nevertheless, these
groups are less reactive in comparison with those in DPA. We
found4 that ketones 8 and 10 readily react with 2-aminonicotinic
aldehyde. The target 2-substituted 1,8-naphthyridines can be
obtained in good yields using pyrrolidine as a catalyst that provides
high regioselectivity of condensation process in some cases.4,6
We attempted to apply this method to the synthesis of corre-
sponding 2-substituted 1,6-naphthyridines. The reaction proceeds
with high regioselectivity only for ketones 8 and 9 to give
phosphorus-containing naphthyridines 11 and 12 (Scheme 3).
In its turn, ketone 10 reacts with aldehyde 3 to yield a mixture
of isomeric 2-monosubstituted and 2,3-disubstituted 1,6-naphthy-
ridines 13 and 14 at an approximate ratio of 3:7 (Scheme 4).
O
O
P
CHO
NH2
catalyst
EtOH
Ph
Ph
+
Me
N
1
2
O
P
Ph
Ph
Me
O
P
+
Ph
Ph
Scheme 1
N
N
N
N
Taking into consideration those experiments, we carried out
the reaction of 4-amino-3-formylpyridine 3 with DPA deriva-
tives 4 and 5 containing a sole active in this reaction terminal
α-methyl group. The reaction readily proceeds in the presence of
catalytic amounts of NaOH to afford naphthyridines 6 and 7 in
good yields (Scheme 2).
4-Amino-3-formylpyridine 3 proved to be slightly less reactive
in comparison with 2-amino-3-formylpyridine 1. The reaction of
ketone 5 with aldehyde 1 proceeds at ambient temperature,3
NH
R2
R1
O
R1 R2
N
Ph
Ph
Ph
Ph
+
3
EtOH
Me
P
N
P
O
O
8 R1 = R2 = Me
9 R1 = H, R2 = (CH2)4Me
11 R1 = R2 = Me
12 R1 = H, R2 = (CH2)4Me
Scheme 3
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© 2009 Mendeleev Communications. All rights reserved.

Mendeleev Commun., 2009, 19, 303–305
O
Ph
Ph
C(18)
C(19)
NH
EtOH
+
C(17)
C(16)
C(15)
C(12)
3
Me
P
C(24)
C(25)
O
Ph
10
C(23)
C(22)
C(14)
N
P
Ph
N
Ph
+
O
C(20)
N
Me
N
P
Ph
P
N(1)
C(21)
C(8)
C(9)
O
O
13
14
C(11)
C(7)
C(2)
Scheme 4
C(13)
N(6)
C(10)
C(3)
Naphthyridines 6, 7, 11 and 12 are slightly coloured solids
readily soluble in DMSO, CHCl3, and EtOH but poorly soluble
in hexane and diethyl ether. The synthesized phosphorus-con-
taining compounds have been characterized by melting points,
elemental analysis data, and 1H, 13C and 31P NMR spectra.† The
structure of compound 7 was confirmed by X-ray diffraction
data, the ORTEP view of 7 is given in Figure 1.‡
C(5)
C(4)
Figure 1 General view of 7 in representation of atoms by thermal
ellipsoids at the 50% probability level. Selected bond lengths (Å): P–O
1.4908(19), P–C(14) 1.815(3), P–C(20) 1.823(3), P–C(11) 1.857(3), C(11)–
C(12) 1.529(3), C(11)–C(13) 1.540(3), C(11)–C(2) 1.532(3), N(1)–C(2)
1.329(3), C(2)–C(3) 1.423(3), C(3)–C(4) 1.362(4), C(4)–C(10) 1.420(3),
C(10)–C(5) 1.418(3), C(5)–N(6) 1.321(3), N(6)–C(7) 1.358(4), C(7)–C(8)
1.368(4), C(8)–C(9) 1.418(3), C(9)–C(10) 1.405(3), C(9)–N(1) 1.373(3).
†
The NMR spectra were recorded on a Bruker Avance-400 spectrometer
X-ray diffraction study shows that all P–C distances in the
molecule are consistent with single bond lengths, whereas the
P–O distance corresponds to a double bond. The bond lengths
in the heteroaromatic fragment of 1,6-naphthyridine (Napy) are
operating at 400.1 (1H), 100.6 (13C) and 162.0 MHz (31P) in CDCl3
solutions using the proton signal of the CHCl3 in CDCl3 as an internal
reference (1H) and 85% H3PO4 (31P) as external reference.
All reactions were conducted in an inert gas atmosphere.
4-Amino-3-formylpyridine 3 was obtained as described elsewhere.7
Compound 5 was synthesized as reported previously.3 Ketones 8 and 10
were obtained by the previously described procedure.4
4-(Diphenylphosphoryl)nonan-2-one 9. The compound was obtained
similarly to compound 8 according to the previously described procedure
starting from trans-non-3-en-2-one (2.37 g, 0.0168 mol). Yield 5.30 g
(92%), mp 104–105 °C. 31P NMR (CDCl3) d: 36.6. Found (%): C, 73.65;
H, 8.04; P, 9.08. Calc. for C21H27O2P (%): C, 73.66; H, 7.95; P, 9.05.
Naphthyridines 11 and 12 (general procedure). A solution of aldehyde
3 (5 mmol) and corresponding ketone 8 or 9 (5 mmol) in ethanol (10 ml)
was added to a catalyst prepared from 0.45 ml of pyrrolidine and one
drop of H2SO4. The mixture was allowed to stand for a day at ambient
temperature. The solvent was distilled off, the residue was dissolved in
CHCl3, the solution was washed twice with water and dried with K2CO3.
Chloroform was removed, the residue was triturated with diethyl ether
and recrystallized from ethyl acetate–hexane mixture (1:1).
2-[(2-Diphenylphosphoryl-2-methyl)propyl]-1,6-naphthyridine 11. A white
powder. Yield 76%, mp 167–168 °C. 31P NMR (CDCl3) d: 37.6. 1H NMR
(CDCl3) d: 9.18 (s, 1H, Napy-H5), 8.68 (d, 1H, Napy-H7, J 5.9 Hz), 8.10
(d, 1H, Napy-H4, J 8.4 Hz), 7.98–8.04 (m, 4H, m-Ph), 7.78 (d, 1H, Napy-H8,
J 5.9 Hz), 7.45–7.49 (m, 6H, o-Ph, p-Ph), 7.38 (d, 1H, Napy-H3, J 8.4 Hz),
3.30 (d, 2H, CH2, J 8.1 Hz), 1.28 [d, 6H, (CH2)3, J 15.8 Hz].
2-(Diphenylphosphoryl)butan-3-one 4. Sodium hydride (0.50 g of 60%
suspension in mineral oil) was added in small portions to a magnetically
stirred solution of 2.58 g (0.01 mol) of diphenylphosphorylacetone 2 in
20 ml of THF. After completion of the reaction detected with a bubbler,
0.8 ml of CH3I was added and the reaction mixture was left to stand for
6 h at ambient temperature. The solvent was removed under reduced
pressure, the residue was dissolved in CHCl3, and the solution was
washed twice with water, dried with K2CO3, and evaporated to afford a
yellow solid. The residue was recrystallized from hexane to give 1.90 g
(70%) of compound 4 as a white powder; mp 133–134 °C. 31P NMR
(CDCl3) d: 30.0. 1H NMR (CDCl3) d: 7.80–7.73 (m, 4H, m-Ph), 7.55–7.25
(m, 6H, o-Ph, p-Ph), 3.65–3.60 (m, 1H, CH–P), 2.21 (s, 3H, MeCO),
1.39 (dd, 3H, MeCH, JH,H 7.2 Hz, JH,P 16.2 Hz).
Naphthyridines 6 and 7 (general procedure). A solution of aldehyde 3
(2.5 mmol) and corresponding ketone 4 or 5 (2.5 mmol) in EtOH (8 ml)
was added with stirring to a suspension of 0.02 g of NaOH in 2 ml of
EtOH at ambient temperature. The reaction mixture was refluxed for 30 min
and concentrated in a vacuum. The residue was dissolved in CHCl3, and
the solution was washed twice with water and dried with K2CO3. The
solvent was removed and the residue was triturated with diethyl ether to
give the target product as a powder.
2-[1-(Diphenylphosphoryl)ethyl]-1,6-naphthyridine 6. A white powder.
Yield 70%, mp 159–160 °C. 31P NMR (CDCl3) d: 32.9. 1H-{31P} NMR
(CDCl3) d: 9.16 (s, 1H, Napy-H5), 8.66 (d, 1H, Napy-H7, J 5.9 Hz), 8.16
(d, 1H, Napy-H4, J 8.6 Hz), 7.90 (d, 3H, 2o-Ph + Napy-H3, J 8.2 Hz), 7.68
(d, 1H, Napy-H8, J 5.9 Hz), 7.64 (d, 2H, o-Ph, J 7.1 Hz), 7.55–7.48 (m, 3H,
2m-Ph, p-Ph), 4.21 (q, 1H, CH–P, J 7.4 Hz), 1.68 (d, 3H, CHMe, J 7.4 Hz).
13C NMR (CDCl3) d: 164.2 (d, 1C, Napy-C2, J 3.7 Hz), 152.37 (s, 1C,
Napy-C5), 149.6 (s, 1C, Napy-C9), 146.78 (s, 1C, Napy-C7), 135.8 (s, 1C,
Napy-C4), 131.7 (d, 2C, p-Ph, J 7.9 Hz), 131.4 (d, 2C, p-Ph, J 7.9 Hz),
131.2 (d, 2C, P–CPh, J 100.1 Hz), 130.9 (d, 4C, m-Ph, J 15.7 Hz), 128.6
(d, 2C, o-Ph, J 31.4 Hz), 128.0 (d, 2C, o-Ph, J 29.4 Hz), 122.8 (s, 1C,
Napy-C8), 122.4 (s, 1C, Napy-C10), 121.3 (s, 1C, Napy-C3), 44.5 (d, 1C,
P–CHMe, J 63.8 Hz), 14.22 (d, 2C, P–CHMe, J 3.0 Hz).
2-[(1-Diphenylphosphoryl-1-methyl)ethyl]-1,6-naphthyridine 7. A pale
yellow powder. Yield 74%, mp 136–137 °C. 31P NMR (CDCl3) d: 37.4.
1H-{31P} NMR (CDCl3) d: 9.18 (s, 1H, Napy-H5), 8.70 (d, 1H, Napy-H7,
J 5.9 Hz), 8.08 (d, 1H, Napy-H4, J 8.8 Hz), 7.80 (d, 1H, Napy-H3, J 8.8 Hz),
7.74 (d, 1H, Napy-H8, J 5.8 Hz), 7.68 (d, 4H, o-Ph, J 7.4 Hz), 7.43 (t, 2H,
p-Ph, J 7.4 Hz), 7.33 (t, 4H, m-Ph, J 7.4 Hz), 1.81 (s, 6H, 2Me). 13C NMR
(CDCl3) d: 166.9 (s, 1C, Napy-C2), 152.2 (s, 1C, Napy-C5), 149.0 (s, 1C,
Napy-C9), 146.7 (s, 1C, Napy-C7), 134.8 (s, 1C, Napy-C4), 132.2 (d, 4C,
2-[(2-Diphenylphosphory)heptyl]-1,6-naphthyridine 12. A white powder.
1
Yield 83%, mp 121–122 °C. 31P NMR (CDCl3) d: 36.1. H-{31P} NMR
(CDCl3) d: 9.13 (s, 1H, Napy-H5), 8.71 (d, 1H, Napy-H7, J 5.9 Hz), 7.97
(d, 1H, Napy-H4, J 8.4 Hz), 7.86 (d, 2H, o-Ph, J 7.0 Hz), 7.81 (d, 1H,
Napy-H8, J 5.9 Hz), 7.76 (d, 2H, o-Ph, J 7.0 Hz), 7.43–7.45 (m, 3H, p-Ph,
Napy-H3), 7.18–7.25 (m, 4H, m-Ph), 3.44–3.47 (m, 1H, CH–P), 3.39–3.43
(m, 1H, Napy-CH2), 3.18–3.23 (m, 1H, Napy-CH2), 1.55–1.75 (m, 2H,
CHP–CH2CH2), 1.01–1.30 [m, 6H, (CH2)3], 0.66–0.68 (m, 3H, Me).
‡
Crystallographic data. Crystals of 7 (C23H21N2OP, M = 372.39) are
–
triclinic, space group P1, at 100 K: a = 6.642(3), b = 10.301(5) and c =
=
14.741(5) Å, a = 76.706(9), b = 79.961(10), g = 71.955(9)°, V
= 927.4(7) Å3,
Z = 2, dcalc = 1.333 g cm–3, m = 0.164 cm–1, F(000) = 392. Intensities of
10385 reflections were measured with a Bruker SMART APEX2 CCD
diffractometer [l(MoKα) = 0.71072 Å, w-scans, 2q < 56°] and 4456
independent reflections (Rint = 0.0372) were used in the further refine-
ment. The structure was solved by direct methods and refined by the
full-matrix least-squares technique against F2 in the anisotropic approxi-
mation for non-hydrogen atoms. The positions of hydrogen atoms were
calculated, all hydrogen atoms were refined isotropically in riding model
with Uiso = 1.5Ueq(Ci) for methyl groups and 1.2Ueq(Cii) for other atoms,
where Ueq(C) are the equivalent thermal parameters of atoms to which
corresponding H atoms are bound. The refinement converged to wR2 =
= 0.0693 and GOF = 1.007 for all independent reflections and to R1 = 0.0323
for 2749 observed reflections with I > 2s(I). All calculations were performed
using SHELXTL PLUS 5.0.8
m-Ph, J 22.5 Hz), 131.4 (d, 2C, p-Ph, J 5.9 Hz), 130.6 (d, 2C, P–CPh
,
CCDC 731895 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
For details, see ‘Notice to Authors’, Mendeleev Commun., Issue 1, 2009.
J 95.4 Hz), 127.8 (d, 4C, o-Ph, J 30.1 Hz), 122.9 (s, 1C, Napy-C8), 121.9
(s, 1C, Napy-C10), 121.7 (s, 1C, Napy-C3), 46.4 (d, 1C, P–CHMe2, J 62.5 Hz),
23.6 (s, 2C, P–CMe2).
– 304 –

Mendeleev Commun., 2009, 19, 303–305
intermediate between those for single and double C–C and C–N
logically active compounds and bidentate heterodifunctional
ligands. We intend to compare their coordination properties
with those of corresponding phosphorus-containing 1,8-naph-
thyridines.
bonds. This fact together with the planarity of the fragment
structure [average deviation of atoms from the least-square plane
is 0.01(1) Å] confirms the delocalization of electron density within
naphthyridine core. The C(11) atom has an sp3 hybridization
and forms single bonds with all neighbours. The sp3 hybridiza-
tion of the C(11) atom allows the mutual rotation of the naph-
thyridine and phosphorus-containing fragments around C–C and
C–P bonds to occur. As a whole, the geometry of the molecule
suggests the mutual repulsion of its fragments. Indeed, the torsion
angles Napy–C(11)–C(12) (13°) and Napy–C(11)–C(13) (47°),
the position of methyl hydrogens (none of them is directed to
the Napy) and the staggered conformation of the molecule
along the C–P bond confirm this assumption.
References
1 V. P. Litvinov, Khimiya naftiridinov (The Chemistry of Naphthyridines),
Ekonomika, Moscow, 2008 (in Russian).
2 V. P. Litvinov, Adv. Heterocycl. Chem., 2006, 91, 189.
3 G. V. Bodrin, P. S. Lemport, S. V. Matveev, P. V. Petrovskii and E. E.
Nifant’ev, Mendeleev Commun., 2007, 17, 25.
4 P. S. Lemport, G. V. Bodrin, M. P. Passechnik, A. G. Matveeva, P. V.
Petrovskii, A. V. Vologzhanina and E. E. Nifant’ev, Izv. Akad. Nauk, Ser.
Khim., 2007, 1846 (Russ. Chem. Bull., Int. Ed., 2007, 56, 1911).
5 C. C. Cheng and S. J. Yan, Org. React., 1983, 28, 37.
Moreover, only weak stacking intermolecular contacts were
found in the crystal structure of compound 7: between two phenyl
rings of different molecules (the shortest distance between the
mean-plane of one molecule and the C atom of another mole-
cule is 3.56 Å) and between phenyl and Napy fragments (the
shortest distance is 3.37 Å).
6 P. G. Dormer, K. K. Eng, R. N. Farr, G. R. Humphrey, J. C. McWilliams,
P. J. Reider, J. W. Sager and R. P. Volante, J. Org. Chem., 2003, 68, 467.
7 J. A. Turner, J. Org. Chem., 1983, 48, 3401.
8 G. M. Sheldrick, SHELXTL v. 5.10, Structure Determination Software
Suite, Bruker AXS, Madison, Wisconsin, USA.
In summary, the Friedländer synthesis provides an efficient
and easy access to 2-(phosphoryl)alkyl-substituted 1,6-naphthy-
ridines. The synthesized naphthyridines are of interest as bio-
Received: 27th May 2009; Com. 09/3341
– 305 –