Efficient syntheses of 3-phosphorylquinolin-4-ones and 3-phosphoryl-1,8- naphthyridin-4-ones

Article abstract of DOI:10.1016/j.tetlet.2011.09.144

A series of 3-diethoxyphosphorylquinolin-4-ones and 3-diethoxyphosphoryl-1, 8-naphthyridin-4-ones containing various substituents at N-1 and C-7 was synthesized in a four-step reaction sequence starting from readily available ethyl 2-chlorobenzoates or et

Full text of DOI:10.1016/j.tetlet.2011.09.144

Tetrahedron Letters 52 (2011) 6623–6626
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Efficient syntheses of 3-phosphorylquinolin-4-ones
and 3-phosphoryl-1,8-naphthyridin-4-ones
⇑
Jacek Ke˛dzia, Jakub Modranka, Tomasz Janecki
_
´
´
Institute of Organic Chemistry, Technical University of Łódz, 90-924 Łódz, Zeromskiego 116, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 3-diethoxyphosphorylquinolin-4-ones and 3-diethoxyphosphoryl-1,8-naphthyridin-4-ones
containing various substituents at N-1 and C-7 was synthesized in a four-step reaction sequence starting
from readily available ethyl 2-chlorobenzoates or ethyl 2-chloronicotinates and diethyl methylphospho-
nate. Selected quinolinone and naphthyridinone products were transformed into free mono and diacids.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 1 August 2011
Revised 15 September 2011
Accepted 30 September 2011
Available online 6 October 2011
Keywords:
Quinolinones
Naphthyridinones
3-Diethoxyphosphorylquinolin-4-one
3-Diethoxyphosphoryl-1,8-naphthyridin-4-
one
Nitrogen-containing heterocycles are a very important class of
organic compounds which are widely used in medicinal and/or
synthetic chemistry.1 Particularly interesting from a biological
point of view are 3-carboxyquinolin-4-ones and 3-carboxy-1,8-
naphthyridin-4-ones which are well known antibacterial agents.2
Nalidixic acid (1) and ciprofloxacin (2) are good examples. Also,
quinolin-4-ones substituted at position 3 by electron-withdrawing
functionalities such as amide or sulfinyl groups possess desirable
biological activities; quinolin-4-one 3 was found to have strong
antiviral activity3 and flosequinan (4) has been used as a drug for
the treatment of congestive heart failure.4
In continuation of our research on phosphorylated oxa- and aza-
heterocycles,5 we became interested in developing a general and
efficient approach to phosphorus analogs of 3-carboxyquinolin-4-
ones and 3-carboxy-1,8-naphthyridin-4-ones of general structure
5 and 6, wherein the carboxyl group is replaced by a phosphoryl
group. These compounds are important for two reasons. Firstly, it
is well known that the phosphoryl group can mimic the tetrahedral
intermediates formed in enzymatic reactions involved in carboxyl
group metabolism.6 Therefore, the replacement of a carboxyl group
with a phosphoryl moiety can produce biologically active analogs
which might inhibit key enzymes or interact with receptors which
normally bind the corresponding original compounds.7 Secondly,
phosphorylated quinolinones 5 and naphthyridinones 6 are poten-
tially useful synthetic intermediates. For example, they can act as
Michael acceptors. Consequently, the addition of nucleophiles to
these compounds and subsequent Horner–Wadsworth–Emmons
olefination might give access to 3-alkylidenequinolin-4-ones and
O
N
O
O
N
O
O
N
O
F
NH2
OH
N
OH
N
N
HN
3-alkylidenenaphthyridin-4-ones containing an
a-alkylidenecar-
F
3
1
2
bonyl moiety. Many natural and synthetic heterocycles possessing
this structural motif display cytotoxic, anti-inflammatory, antimi-
crobial, and other biological activities.5a–c,e,8
O
O
O
O
O
P(OR)2
SOMe
R
P(OR)2
R
N
N
R
F
N
N
R
Several procedures for the synthesis of 3-phosphorylquinolinon-
4-ones have been described so far. 2-Amino-3-diethoxyphosphoryl-
quinolin-4-ones were prepared by condensation of isatoic
anhydrides9 or 2,4-benzoxazin-1-ones10 with phosphonoacetonitri-
le. 3-Dialkoxyphosphoryl-1-methylquinolin-4-ones were synthe-
sized in a four-step reaction sequence starting from the Arbuzov
reaction of 2-nitrophenacyl bromide and trialkyl phosphites.11 In
turn, preparation of 6-substituted-4-hydroxy-2-trifluoromethyl-
6
4
5
⇑
Corresponding author. Tel.: +48 42 6313220; fax: +48 42 6365533.
E-mail address: tjanecki@p.lodz.pl (T. Janecki).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.144

6624
J. Ke˛dzia et al. / Tetrahedron Letters 52 (2011) 6623–6626
quinolines was accomplished by the reaction of trifluoroacetimidoyl
chlorides with phosphonoacetates in the presence of NaH, followed
by intramolecular cyclization.12 Finally, condensation of ethyl
2-aminobenzoate with b-ketophosphonates or b-ketophosphine
oxides followed by intramolecular cyclization was employed in the
preparation of 2-substituted-3-phosphorylquinolin-4-ones.13 The
synthesis of 3-phosphoryl-1,8-naphthyridin-4-ones 6 has not been
reported so far.
Inspection of the 1H NMR spectra of 11a–d revealed that the
N,N-dimethyl groups appeared as two broad singlets. However,
when a sample of 11a in CDCl3 was heated gradually to 60 °C,
one sharp singlet (3.19 ppm) for both methyl groups was formed.
The coalescence temperature for the N,N-dimethyl groups was
reached at ca. 28 °C. We also tried to determine the rotational bar-
rier around the enamine double bond. However, after heating the
sample in DMSO-d6 to 120 °C and cooling to room temperature,
no additional signals were evident. Likewise, cooling a sample of
11a to À60 °C resulted in sharp singlets for the N,N-dimethyl group
(3.39 ppm and 2.98 ppm) but no additional signals in both the 1H
and 31P NMR spectra were found. These results support the conclu-
sion that the E isomer is more stable than the Z isomer. A likely
explanation is the strong steric interaction between the diethoxy-
phosphoryl and dimethylamino groups which destabilize the Z iso-
mer. Similar results were obtained in variable temperature NMR
experiments performed on diethyl 1-dimethylamino-3-oxobut-1-
en-2-ylphosphonate.19 For this compound the coalescence temper-
ature for N,N-dimethyl groups was À6 °C. However, it was possible
to determine the E/Z isomer ratio (E/Z = 93/7) because separate sig-
nals due to the vinyl protons of the E- and Z-isomers appeared in
the 1H NMR spectrum when the sample was cooled to À33 °C.
The synthesis of a wide range of alkyl- or arylaminovinylphosph-
onates 12a–j was accomplished by stirring dimethylaminovinyl-
phosphonates 11a–d with the appropriate primary amine at room
temperature (Table 2). Usually 1.0–1.5 equiv of the amine was
added. However, when the reaction was performed with highly vol-
atile methyl or ethyl amine addition of 10 equiv of these reagents
was necessary to obtain satisfactory yields. Substitution of the
dimethylamino group in 11a–d proceeded smoothly under these
conditions, providing vinylphosphonates 12a–j in excellent yields
as mixtures of E and Z isomers in the ratios given in Table 2.20 It is
noteworthy that the products 12a–j were formed as E/Z mixtures,
whereas substrates 11a–d appeared as single E isomers. A likely
explanation is the greater steric interaction between the diethoxy-
phosphoryl group and tertiary dimethylamine group in 11a–d in
comparison to the secondary amine group present in products
12a–j.
Aminovinylphosphonates 12a–j were next subjected to an
intramolecular nucleophilic aromatic substitution by heating in
boiling toluene in the presence of NaH. Standard work-up and
purification by column chromatography gave the expected 3-
diethoxyphosphorylquinolin-4-ones 13a–f or 3-diethoxyphospho-
ryl-1,8-naphthyridin-4-ones 13g–j in excellent yields (Table 2).21
The structures of the final products and the intermediates were
confirmed by IR, 1H, 13C, and 31P NMR spectroscopy and elemental
analysis.
Finally, we demonstrated that quinolinones and naphthyridi-
nones 13 could be easily transformed into the corresponding mono
and diacids using classic techniques (Scheme 1). Thus, treatment of
13c or 13h with trimethylbromosilane followed by solvolysis in
ethanol furnished diacids 14c or 14h in 96% and 95% yields, respec-
tively.22 Also, transformation of 13c or 13h into monoacids 15c or
15h was performed in boiling 2-butanone in the presence of LiBr.
Standard work-up and purification by crystallization from
CH2Cl2/hexane gave the expected monoacids in excellent 98%
and 96% yields, respectively.23
Herein we present a convenient and general approach to 3-dieth-
oxyphosphorylquinolin-4-ones 13a–f and 3-diethoxyphosphoryl-1,
8-naphthyridin-4-ones 13g–j. Treatment of ethyl 2-chlorobenzo-
ates 7a,b14a or ethyl 2-chloronicotinates 7c,d14b with diethyl meth-
ylphosphonate (8)15 in the presence of LDA gave, after standard
work-up and purification by column chromatography, 2-oxo-2-(2-
chlorophenyl)ethylphosphonates 9a,b or 2-oxo-2-(2-chloro-3-pyri-
dyl)ethylphosphonates 9c,d, respectively, in good to excellent yields
(Table 1). In the next step the enamine functionality was introduced
to phosphonates 9 using dimethylformamide–dimethyl acetal
(DMFDMA) (10).16 Heating of 2-oxo-2-phenylethylphosphonates
9a,b with DMFDMA (10) in toluene at 110 °C for 4.5 h, followed by
purification by column chromatography furnished diethyl 1-
dimethylaminomethylidene-2-oxo-2-phenylphosphonates 11a,b
in excellent yields (Table 1).17 Disappointingly, applying the same
procedure on 2-oxo-2-pyridylethylphosphonate (9c) provided
diethyl 1-dimethylaminomethylidene-2-oxo-2-pyridylphospho-
nate (11c) in a low 43% yield. However, we were pleased to observe
that heating both substrates at 80 °C for 2 h without solvent gave the
expected pyridylphosphonate 11c in almost quantitative yield. The
same procedure worked well for the synthesis of pyridylphospho-
nate 11d. However, our efforts to purify compounds 11c,d were
unsuccessful. During column chromatography, in the presence of
traces of water, these compounds decomposed. Analysis of the 31
P
and 1H NMR spectra of the eluted material revealed the presence
of starting phosphonates 9c or 9d along with other compounds,
which were difficult to identify. For this reason compounds 11c,d
were used as such in the next step. Phosphonates 11a–d were
3
obtained as single E isomers. The JHP coupling constants, deter-
mined from the 1H NMR spectra, and which fell into the range
14.8–15.3 Hz proved diagnostic being typical for the cis-relationship
between the phosphoryl group and vinyl hydrogen.18
Table 1
Synthesis of 2-oxoethylphosphonates 9a–d and 1-dimethylaminomethylidene-2-
oxophosphonates 11a–d
O
8
Me P(OEt)2
LDA, THF
O
O
O
P(OEt)2
OEt
Cl
7a-d
-78 oC, then rt,
16 h
R1
X
R1
X
Cl
9a-d
O
O
Cl
(MeO)2CHNMe2 10
P(OEt)2
X
R1
Δ
N
, toluene
or neat
11a-d
In conclusion, this new protocol facilitates considerably the syn-
thesis of diversified 3-diethoxyphosphorylquinolin-4-ones 13a–f
and 3-diethoxyphosphoryl-1,8-naphthyridin-4-ones 13g–j. The
synthetic pathway starts from readily available 2-chlorobenzoates
or 2-chloronicotinates and enables efficient introduction of various
alkyl or aryl substituents on the N-1 nitrogen atom. Formation of
the intermediate vinylphosphonates 11a–d as E isomers was ratio-
nalized on the basis of the steric effect between the diethoxyphos-
phoryl and dimethylamine groups. Effective transformation of the
Compound
X
R1
Yielda of 9 (%)
Yield of 11 (%)
a
b
c
CH
CH
N
Cl
F
H
79
77
80
85
89a
95a
ꢀ95b
d
N
Me
ꢀ95b
a
Yield of pure isolated product.
Yield of crude product estimated by 31P NMR spectroscopy.
b

J. Ke˛dzia et al. / Tetrahedron Letters 52 (2011) 6623–6626
6625
Table 2
Synthesis of aminovinylphosphonates 12a–j, 3-diethoxyphosphorylquinolin-4-ones 13a–f and 3-diethoxyphosphoryl-1,8-naphthyridin-4-ones 13g–j
O
O
R2NH2
P(OEt)2
11a-d
EtOH, Et2O
rt, 1 h
R1
X
Cl NHR2
12a-j
O
O
N
P(OEt)2
NaH
toluene
110 oC, 18 h
R1
X
R2
13a-j
Compound
X
R1
R2
Equiv of R2NH2
12
13 Yieldb (%)
E/Za
Yieldb (%)
a
b
c
d
e
f
g
h
i
CH
CH
CH
CH
CH
CH
N
N
N
N
Cl
Cl
Cl
Cl
Cl
F
H
H
H
Me
c-Hex
Ph
Me
(R)-Ph(Me)CH
(S)-Ph(Me)CH
Me
Me
c-Hex
Ph
1.0
1.5
10.0
1.0
65:35
45:55
55:45
60:40
60:40
55:45
75:25
65:35
60:40
70:30
80
94
97
92
97
98
81
86
74
82
93
85
80
84
86
83
76
89
88
92
1.0
10.0
10.0
1.0
1.2
10.0
j
Et
a
Determined from integration of the 31P NMR spectra.
Yield of pure isolated product.
b
_
5. (a) Janecki, T.; Błaszczyk, E.; Studzian, K.; Janecka, A.; Krajewska, U.; Rózalski,
_
M. J. Med. Chem. 2005, 48, 3516–3521; (b) Janecki, T.; Wa˛sek, T.; Rózalski, M.;
O
O
Krajewska, U.; Studzian, K.; Janecka, A. Bioorg. Med. Chem. Lett. 2006, 16, 1430–
1433; (c) Albrecht, A.; Koszuk, J. F.; Modranka, J.; Rózalski, M.; Krajewska, U.;
1) Me3SiBr,
rt, CH2Cl2
P(OH)2
_
Janecka, A.; Studzian, K.; Janecki, T. Bioorg. Med. Chem. 2008, 16, 4872–4882; (d)
Albrecht, A.; Koszuk, J.; Kobucin´ ski, M.; Janecki, T. Org. Biomol. Chem. 2008, 6,
1197–1200; (e) Modranka, J.; Albrecht, A.; Janecki, T. Synlett 2010, 2867–2870.
6. Kafarski, P.; Lejczak, B. Phosphorus, Sulfur 1991, 63, 193–215.
7. (a) Song, Y.; Niederer, D.; Lane-Bell, P. M.; Lam, L. K. P.; Crowley, S.; Palcic, M.
M.; Pickard, M. A.; Pruess, D. L.; Vederas, J. C. J. Org. Chem. 1994, 59, 5784–5793;
(b) Durette, P. L.; Chabin, R. M.; Fletcher, D. S.; Green, B. G.; Hanlon, W. A.;
Humes, J. L.; Knight, W. B.; Lanza, T. J.; Mumford, R. A.; Pacholok, S.; MacCoss,
M. Bioorg. Med. Chem. Lett. 1995, 5, 271–274.
R1
X
X
N
R2
2) EtOH
rt
14c,h
13c,h
1) LiBr,
O
O
Δ, 10 h
OEt
P
2-butanone
OH
R1
N
R2
2) H3O+
8. Janecki, T. In Targets in Heterocyclic Systems; Attanasi, O. A., Spinelli, D., Eds.;
Italian Society of Chemistry: Rome, 2000; Vol. 10, pp 301–320; (b) Zhang, S.;
Won, Y.-K.; Ong, C.-N.; Shen, H.-M. Curr. Med. Chem. Anti-Cancer Agents 2005, 5,
239–249; (c) Kitson, R. R. A.; Millemaggi, A.; Taylor, R. J. K. Angew. Chem., Int. Ed.
2009, 48, 9426–9452; (d) Elford, T. G.; Hall, D. G. Synthesis 2010, 893–907; (e)
Albrecht, A.; Albrecht, Ł.; Janecki, T. Eur. J. Org. Chem. 2011, 2747–2766.
9. (a) Coppola, G. M.; Hardtmann, G. E.; Pfister, O. R. J. Org. Chem. 1976, 41, 825–
831; (b) Coppola, G. M.; Hardtmann, G. E. J. Heterocycl. Chem. 1979, 16, 1605–
1610.
10. Kamel, A. A. Phosphorus, Sulfur Silicon Relat. Elem. 2007, 182, 765–777.
11. Yanagisawa, H.; Nakao, H.; Ando, A. Chem. Pharm. Bull. 1973, 21, 1080–1089.
12. Yuan, C.; Xiao, J.; Zhang, X. Heteroat. Chem. 2000, 11, 240–243.
13. Jelaiel, N.; Said, N.; Touil, S.; Efrit, M. L. Phosphorus, Sulfur Silicon Relat. Elem.
2010, 185, 2382–2392.
15c,h
Scheme 1. Synthesis of diacids 14c,h and monoacids 15c,h.
final phosphonates 13 into phosphonic diacids 14 or monoacids 15
was also demonstrated. Further investigations to elaborate the
scope of this methodology and to show the synthetic utility of the
products obtained are currently in progress in our laboratory.
Acknowledgment
14. Ethyl 2-chlorobenzoates 7a,b were prepared according to the literature
procedure: (a) Hosangadi, B. D.; Dave, R. H. Tetrahedron Lett. 1996, 37, 6375–
6378; Ethyl 2-chloronicotinates 7c,d were prepared according to the literature
procedure: (b) Olepu, S.; Suryadevara, P. K.; Rivas, K.; Yokoyama, K.; Verlinde,
C. L. M. J.; Chakrabarti, D.; Van Voorhisb, V. C.; Gelb, M. H. Bioorg. Med. Chem.
Lett. 2008, 18, 494–497.
15. Diethyl methylphosphonate was prepared according to the literature
procedure: Teulade, M.-P.; Savignac, P.; Aboujaoude, E. E.; Collignon, N. J.
Organomet. Chem. 1986, 312, 283–295.
This work was financed by the Ministry of Science and Higher
Education (Project No. N N204 005736).
References and notes
1. (a) Van der Jeught, S.; Stevens, C. V. Chem. Rev. 2009, 109, 2672–2702; (b)
Moonen, K.; Laureyn, I.; Stevens, C. V. Chem. Rev. 2004, 104, 6177–6215; (c)
Patent, SmithKline Beecham GB 91/24577, 1991; Chem. Abstr. 1993, 119,
180664.; (d) Petrolite Corporation, US 3673196, 1972; Chem. Abstr. 1972, 77,
88635.
2. (a) Milata, V.; Claramunt, R. M.; Elguero, J.; Zalupsky, P. In Targets in Heterocyclic
Systems; Attanasi, O. A., Spinelli, D., Eds.; Italian Society of Chemistry: Rome,
2000; Vol. 4, pp 167–203; (b) Da Silva, A. D.; De Almeida, M. V.; De Souza, M. V.
N.; Couri, M. R. C. Curr. Med. Chem. 2003, 10, 21–39.
3. Wentland, M. P.; Perni, R. B.; Dorff, P. H.; Brundage, R. P.; Castaldi, M. J.; Bailey,
T. R.; Carabateas, P. M.; Bacon, E. R.; Young, D. C.; Woods, M. G.; Rosi, D.; Drozd,
M. L.; Kullnig, R. K.; Dutko, F. J. J. Med. Chem. 1993, 36, 1580–1596.
4. Birch, A. M.; Davies, R. V.; Maclean, L.; Robinson, K. J. Chem. Soc., Perkin Trans. 1
1994, 387–392.
16. (a) Aboujaoude, E. E.; Collignon, N.; Savignac, P. Tetrahedron 1985, 41, 427; (b)
Janecki, T.; Albrecht, A.; Koszuk, J. F.; Modranka, J.; Słowak, D. Tetrahedron Lett.
2010, 51, 2274–2276.
17. Typical procedure for the preparation of phosphonates 11a,b: A solution of 9a
(3.25 g, 10.0 mmol) and DMFDMA (1.43 g, 12.0 mmol) in dry toluene (40 mL)
was heated at 110 °C for 4.5 h. The crude mixture was diluted with toluene
(20 mL) and the solvent removed. The residue was purified by column
chromatography on silica gel (CHCl3/MeOH, 100:1), to give pure 12a (3.38 g,
89%), as a yellow solid; mp = 78–80 °C. 31P NMR (63 MHz, CDCl3) d 22.76. 1H
NMR (250 MHz, CDCl3) d 1.18 (t, 6H,3JH–H = 7.1 Hz, 2 Â CH3CH2O); 3.03 (br s,
3H, CH3N); 3.27 (br s, 3H, CH3N); 3.80–4.00 (m, 4H, 2 Â CH2O); 7.22 (dd, 1H,
4
3
3JH–H = 8.2 Hz, JH–H = 2.0 Hz, CH); 7.34 (d, 1H, JH–H = 8.2 Hz, CH); 7.37 (d, 1H,
4JH–H = 2.0 Hz, CH); 7.73 (d, 1H, JH–P = 15.3 Hz, CHCP). 13C NMR (101 MHz,
3

6626
J. Ke˛dzia et al. / Tetrahedron Letters 52 (2011) 6623–6626
3
CDCl3) d 14.24 (d, JC–P = 7.1 Hz, 2 Â CH3CH2O); 41.29 (br s, CH3N); 46.08 (br s,
under reduced pressure. The residue was purified by column chromatography
on silica gel (CHCl3/MeOH, 100:1), to give 13a (2.23 g, 93%), as a yellow solid;
mp = 116–118 °C. 31P NMR (63 MHz, CDCl3) d 17.29. 1H NMR (250 MHz, CDCl3)
d 1.21–2.20 (m, 10H, 5 Â CH2); 1.36 (t, 6H, 3JH–H = 7.1 Hz, 2 Â CH3CH2O); 4.11–
2
1
CH3N); 59.71 (d, JC–P = 5.7 Hz, 2 Â CH2O); 91.89 (d, JC–P = 193.7 Hz, CP);
124.26 (s, CHAr); 127.48 (s, CHAr); 129.07 (s, CHAr); 130.54 (s, CC(O)); 133.57 (s,
2
2
CCl); 137.67 (s, CCl); 159.92 (d, JC–P = 16.9 Hz, CHCP); 186.46 (d, JC–P
=
12.2 Hz, C(O)). IR: 1056, 1244, 1636, 3070 cmÀ1. Anal. calcd for C15H20Cl2NO4P:
C, 47.39; H, 5.30; N, 3.68. Found: C, 47.63; H, 5.21; N, 4.01.
4.35 (m, 5H, 2 Â CH2O, CH); 7.39 (dd, 1H, JH–H = 8.6 Hz, JH–H = 1.7 Hz, CHAr);
3
4
4
7.53 (d, 1H, JH–H = 1.7 Hz, CHAr); 8.42 (d, 1H, 3JH–H = 8.6 Hz, CHAr); 8.45 (d, 1H,
3
18. Bentrude, W. G. W.N. Setzer. In Methods in Stereochemical Analysis, Vol. 8:
Phosphorus-31 NMR Spectroscopy in Stereochemical Analysis; Verkade, J. G., Quin,
L. D., Eds.; VCH Publishers Inc.: Deerfield Beach, Florida, 1987; pp 365–385.
19. Melnikov, N. N.; Kozlov, V. A.; Churusova, S. G.; Buvashkina, N. I.; Ivanchenko,
V. I.; Negrebetskii, W. W.; Grapov, A. F. Zh. Obsch. Khim. 1983, 53, 1689–1693.
Chem. Abstr. 1984, 100, 34616..
3JH–P = 13.8 Hz, CHCP). 13C NMR (101 MHz, CDCl3) d 14.59 (d, JC–P = 6.6 Hz,
2 Â CH3CH2O); 23.32 (s, CH2); 24.00 (s, 2 Â CH2); 30.71 (s, 2 Â CH2); 57.86 (s,
2
1
CH); 60.82 (d, JC–P = 5.8 Hz, 2xCH2O); 106.64 (d, JC–P = 193.6 Hz, CP); 113.19
3
(s, CHAr); 123.51 (s, CHAr); 124.52 (d, JC–P = 10.7 Hz, CC(O)); 127.57 (s, CHAr);
137.57 (s, CCl); 138.97 (s, CN); 144.90 (d, 2JC–P = 18.3 Hz, CHCP); 173.38 (d, 2JC–
P = 3.8 Hz, C(O)). IR: 1031, 1256, 1636, 3072 cmÀ1
.
Anal. calcd for
20. Typical procedure for the preparation of vinylphosphonates 12a–j: A solution of
11a (3.04 g, 8.0 mmol) and cyclohexylamine (0.79 g, 8.0 mmol) in a mixture of
EtOH and Et2O (2/1, 45 mL) was stirred at rt for 1 h. The solvent was removed
under reduced pressure. The residue was purified by column chromatography
on silica gel (EtOAc/hexane, 2:1), to give pure 12a (2.78 g, 80%), as a yellow
solid; mp = 124–126 °C. 31P NMR (63 MHz, CDCl3) d 22.02 (Z), 22.52 (E). 1H
NMR (300 MHz, CDCl3) d 1.16 (t, 6H,3JH–H = 7.0 Hz, 2 Â CH3CH2O, E); 1.33 (t,
6H,3JH–H = 7.0 Hz, 2 Â CH3CH2O, Z); 1.21–2.04 (m, 10H, 5 Â CH2, E, Z); 3.00–3.14
(m, 1H, CHNH, Z); 3.22–3.40 (m, 1H, CHNH, E); 3.79–4.00 (m, 4H, 2 Â CH2O, E);
4.04–4.20 (m, 4H, 2 Â CH2O, Z); 7.20–7.31 (m, 3H, CHAr, E, Z); 7.40–7.70 (m, 1H,
C19H25ClNO4P: C, 57.36; H, 6.33; N, 3.52. Found: C, 57.15; H, 6.56; N, 3.78.
22. Phosphonic diacids 20 were prepared according to the literature procedure:
McKenna, C. S.; Schidhauser, J. J. Chem. Soc., Chem. Commun. 1979, 739. For
example: product 14c was isolated as a brown solid, mp = 207–209 °C. 31P
NMR (63 MHz, CDCl3 + CF3COOH)
d
11.62. 1H NMR (250 MHz,
3
CDCl3 + CF3COOH) d 4.41 (s, 3H, CH3N); 7.88 (d, 1H, JH–H = 8.9 Hz, CHAr); 8.03
3
3
(s, 1H, CHAr); 8.55 (d, 1H, JH–H = 8.9 Hz, CHAr); 9.27 (d, 1H, JH–P = 10.8 Hz,
CHCP). 13C NMR (101 MHz, CDCl3 + CF3COOH) d 44.30 (s, CH3N); 106.29 (d, 1JC–
P = 190.3 Hz, CP); 117.55 (s, CHAr); 119.26 (d, 3JC–P = 10.8 Hz, CC(O)); 127.59 (s,
CHAr); 130.82 (s, CHAr); 141.02 (s, CCl); 145.18 (s, CN); 152.73 (d, 2JC–P = 15.5 Hz
3
3
2
CHCP, E); 7.95 (d, 1H, JH–H = 14.0 Hz, JH–P = 11.5 Hz, CHCP, Z); 9.42–9,55 (m,
1H, NH, Z); 11.00–11.15 (m, 1H, NH, E). 13C NMR (101 MHz, CDCl3) d 15.89 (d,
CHCP); 171.55 (d, JC–P = 4.6 Hz, C(O)). IR: 1040, 1127, 1612 cmÀ1. Anal. calcd
for C10H9ClNO4P: C, 43.90; H, 3.32; N, 5.12. Found: C, 43.74; H, 3.51; N, 4.89.
23. Phosphonic monoacids 15 were prepared according to the literature procedure:
Krawczyk, H. Synth. Commun. 1997, 27, 3151–3161. For example: product 15c
was isolated as a white solid, mp = 199-202 °C. 31P NMR (63 MHz, CDCl3) d
14.01. 1H NMR (250 MHz, CDCl3) d 1.28 (t, 3H, 3JH–H = 7.1 Hz, CH3CH2O); 4.00 (s,
3
3JC–P = 7.1 Hz, 2 Â CH3CH2O, E); 16.15 (d, JC–P = 6.7 Hz, 2 Â CH3CH2O, Z); 24.11
(s, CH2, Z); 24.28 (s, CH2, E); 24.87 (s, CH2, E, Z); 33.36 (s, CH2, Z); 33.46 (s, CH2,
E); 57.91 (s, CHNH, Z); 58.80 (s, CHNH, E); 61.30 (d, 2JC–P = 5.4 Hz, 2 Â CH2O, E);
2
1
62.28 (d, JC–P = 5.1 Hz, 2xCH2O, Z); 92.66 (d, JC–P = 206.8 Hz, CP, E); 92.97 (d,
1JC–P = 183.6 Hz, CP, Z); 125.66–139.21 (6 Â CAr, E, Z); 161.15 (d, JC–P = 19,0 Hz
3H, CH3N); 4.10 (dq, 2H, JH–H = 7.1; JH–P = 7.1, CH2O); 7.45 (dd, 1H, JH–
4 4
2
3
3
3
2
2
CHCP, E); 161.99 (d, JC–P = 10.0 Hz CHCP, Z); 189.49 (d, JC–P = 8.7 Hz, C(O), Z);
191.84 (d, 2JC–P = 15.8 Hz, C(O), E). IR: 1056, 1232, 1624, 3070 cmÀ1. Anal. calcd
for C19H26Cl2NO4P: C, 52.55; H, 6.03; N, 3.23. Found: C, 52.26; H, 6.29; N, 3.11.
21. Typical procedure for the preparation of 3-diethoxyphosphorylquinolin-4-ones
13a–f or 3-diethoxyphosphoryl-1,8-naphthyridin-4-ones 13g–j: NaH (0.22 g,
9.0 mmol) was added to a solution of 12a (2.60 g, 6.0 mmol) in dry toluene
(30 mL) at rt. The mixture was heated for 18 h at 110 °C. Next, H2O (10 mL) was
added and the aqueous layer was extracted with toluene (2 Â 10 mL). The
combined organic phases were dried over MgSO4 and the solvent removed
H = 8.7 Hz, JH–H = 1.6 Hz, CHAr); 7.53 (d, 1H, JH–H = 1.6 Hz, CHAr); 8.28 (d, 1H,
3JH–H = 8.7 Hz, CHAr); 8.63 (d, 1H, JH–P = 12.2 Hz, CHCP). 13C NMR (101 MHz,
3
3
2
CDCl3) d 16.33 (d, JC–P = 6.9 Hz, CH3CH2O); 41.74 (s, CH3N); 62.09 (d, JC–
1
P = 5.7 Hz, CH2O); 109.19 (d, JC–P = 181.0 Hz, CP); 116.10 (s, CHAr); 123.47 (d,
3JC–P = 10.7 Hz, CC(O)); 126.42 (s, CHAr); 128.25 (s, CHAr); 140.00 (s, CCl); 140.94
2
2
(s, CN); 150.90 (d, JC–P = 16.1 Hz CHCP); 176.22 (d, JC–P = 5.1 Hz, C(O)). IR:
1043, 1590, 1621 cmÀ1. Anal. calcd for C12H13ClNO4P: C, 47.78; H, 4.34; N, 4.64.
Found: C, 47.52; H, 4.29; N, 4.43.