Reaction of benzolactams with triethyl phosphite prompted by phosphoryl chloride affords benzoannulated monophosphonates instead of expected bisphoshonates

Article abstract of DOI:10.1016/j.jorganchem.2015.03.005

Abstract In contrast to aliphatic lactams, which gave cyclic aminomethylene-gem-bisphosphonates in reaction with triethyl phosphite and phosphoryl chloride, the corresponding benzoannulated lactams usually provide monophosphonates of variable structures, which depend on size of the substrate aliphatic ring. Most likely they are obtained by dephosphonylation of bisphosphonates, which form as initial products of this reaction. These phosphonate esters appeared to be unstable upon acid hydrolysis and upon storage. Mechanism of acid catalyzed degradation of these compounds has been proposed.

Full text of DOI:10.1016/j.jorganchem.2015.03.005

Journal of Organometallic Chemistry 785 (2015) 84e91
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Journal of Organometallic Chemistry
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Reaction of benzolactams with triethyl phosphite prompted by
phosphoryl chloride affords benzoannulated monophosphonates
instead of expected bisphoshonates
Ewa Chmielewska*, Patrycja Miszczyk, Joanna Kozłowska, Monika Prokopowicz,
Piotr Młynarz, Paweł Kafarski
_
ꢀ
Department of Bioorganic Chemistry, Faculty of Chemistry, Wrocław University of Technology, Wybrzeze Wyspianskiego 27, 50-370 Wrocław, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
In contrast to aliphatic lactams, which gave cyclic aminomethylene-gem-bisphosphonates in reaction
with triethyl phosphite and phosphoryl chloride, the corresponding benzoannulated lactams usually
provide monophosphonates of variable structures, which depend on size of the substrate aliphatic ring.
Most likely they are obtained by dephosphonylation of bisphosphonates, which form as initial products
of this reaction. These phosphonate esters appeared to be unstable upon acid hydrolysis and upon
storage. Mechanism of acid catalyzed degradation of these compounds has been proposed.
© 2015 Elsevier B.V. All rights reserved.
Received 25 November 2014
Received in revised form
3 March 2015
Accepted 4 March 2015
Available online 13 March 2015
Keywords:
Bisphosphonates
Aminophosphonates
Synthesis of CeP bond
Introduction
structurally variable benzolactams with trialkyl phosphite and
phosphoryl chloride (Scheme 1).
Geminal aminobisphosphonates represent interesting and still
not fully developed class of biologically active substances. The best
documented is their activity as drugs influencing bone resorption
being useful in combating osteoporosis, with alendronate being
one of the bestselling drugs [1e5]. Also their inhibitory effect to-
wards some enzymes cause that they might be considered as
promising anticancer, antiinflamatory, antiparasitic, antiviral and
antimicrobial agents [6e13].
There is a limited number of papers devoted to the synthesis of
cyclic aminomethylene-gem-bisphosphonates [14]. First they have
been synthesized in order to obtain derivatives of pyrrole oxides as
a new class of spin traps. The best results have been achieved by
Olive who developed a reaction between pyrrolidin-2-one with a
mixture of trialkyl phosphite and phosphoryl chloride [14]. We
have decided to enlarge the scope of this reaction by studying
reactivity of aromatic lactams, homologues of oxoindoles.
Reaction of oxoindoles failed to yield the desired bisphospho-
nates and gave diethyl 1-indol-2-ylphosphonates 1 as the major
products with diethyl phosphate being a side-product (Scheme 2).
These esters have been obtained in the literature by different ap-
proaches, compound 1a as a pure one [15,16], whereas 1b as the
unseparable mixture with isomeric diethyl 1-methylindol-3-
ylphosphonate (15:1 molar ratio) [16]. Hydrolysis of compounds
1 in concentrated hydrochloric caused decomposition of the ob-
tained esters with accompanied formation of phosphorous acid
(H3PO3).
No mechanism was reported to date for the reaction of lactams
with mixture of trialkylphosphite and phosphoryl chloride. How-
ever, a proposed mechanism of the reaction given in Scheme 3
indicates that this result is not surprising if taking into account
that the formed product is an aromatic one and thus aromatization
is a driving force for production of this molecule hindering addition
of phosphite to newly formed double bond.
When reacting six-membered lactam e 3,4-dihydroquinolin-
2(1H)-one, two products were obtained in 1:3 molar ratio. They
were correspondingly: the desired bisphoshonate 2 and diethyl
quinolin-2-ylphosphonate 3 (Scheme 4). The formation of the
quinolin-2-ylphosphonate is somewhat surprising. The observed
hydrogen transfer seems to be similar to the one described by
Results
Basing on the results described by Olive [14] we had expected
the formation of desired bisphosphonates in
a reaction of
* Corresponding author. Tel.: þ48 713202977; fax: þ48 713284064.
E-mail address: ewa.chmielewska@pwr.edu.pl (E. Chmielewska).
http://dx.doi.org/10.1016/j.jorganchem.2015.03.005
0022-328X/© 2015 Elsevier B.V. All rights reserved.

E. Chmielewska et al. / Journal of Organometallic Chemistry 785 (2015) 84e91
85
Scheme 1. Proposed reaction for obtaining desired bisphosphonates.
Scheme 2. Reaction of oxoindoles with triethyl phosphite and phosphoryl chloride.
Shindoh et al. [17,18] where air oxygen was acting as hydrogen
acceptor, similar to the ones described in other cases of oxidative
aromatization of dihydroquinolines [19,20]. Upon hydrolysis with
concentrated hydrochloric acid both compounds gave quinolin-2-
ylphosphonic acid 4. This finding and the fact that phosphorous
acid is the second product of hydrolysis of compound 2 seems to
indicate that it is most likely an intermediate in the synthesis of
compound 3.
If 6-hydroxy-3,4-dihydroquinolin-2(1H)-one served as a sub-
strate, bisphosphonate 2b appeared to be the sole product of re-
action. Its hydrolysis, however, once more led to several products
resulting from the destruction of the molecule.
provided the desired aminomethylene-gem-bisphosphonates 5 and
6 in moderate yields (Schemes 5 and 6) accompanied with side
products 7 and 8. Both bisphosphonate 5 and unsaturaded mono-
phosphonate 7 have been obtained earlier from six-membered
oximes via Beckman rearrangement [21,22]. We were unable to
purify compound 7 and therefore its structure was established
tentatively on the basis of 1H NMR and HMRS data and their
comparison with the data reported for this compound in the
literature [21]. The formation of compound 8 in the case of eight-
membered lactam (Scheme 6) was unexpected, however could be
explained in the view of proposed mechanism as non-classical
addition of diethyl phosphate (this compound is always formed
as the product of the reaction, see Scheme 2) to double azomethine
bond of monophosphonate.
Seven and eight-membered lactams - 2,3,4,5-tetrahydro-benzo
[b]azepin-2-one and 3,4,5,6-tetrahydrobenzo[b]-azocin-1(2H)-one
Scheme 3. Proposed mechanism of the studied reaction.

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E. Chmielewska et al. / Journal of Organometallic Chemistry 785 (2015) 84e91
Scheme 4. Reaction of six-membered lactams with triethyl phosphite and phosphoryl chloride.
Scheme 5. Reaction of seven-membered lactams with triethyl phosphite and phosphoryl chloride.
Scheme 6. Reaction of eight-membered lactams with triethyl phosphite and phosphoryl chloride.

E. Chmielewska et al. / Journal of Organometallic Chemistry 785 (2015) 84e91
87
Scheme 7. Products of the reaction of aliphatic lactams with triethyl phospite and phosphoryl chloride.
Acid hydrolysis of all the formed esters once more resulted in
their degradation and gave acids 9 and 10 alongside with phos-
phorous acid (H3PO3) as isolated products. According to our expe-
rience aminomethylenebisphosphonates are exceptionally stable
compounds and thus the explanation of the mechanism of this
unusual reaction requires additional studies.
On the contrary, five-, six- and seven-membered aliphatic lac-
tams provided easily the desired bisphosphonates, which is in
accordance with the literature [14,22e24]. Hydrolysis of these
bisphosphonates gave bisphosphonic acids also in good yields
(Scheme 7). This may indicate that strongly basic aliphatic amino-
moiety hampers the protonation of phosphonate oxygen and
therefore causes that aliphatic cyclic bisphosphonates 12 are
considerably stable.
PerkineElmer spectrometer. 1H and 31P NMR experiments were
performed on a Bruker Advance TM DRX operating at 300.13 MHz
(1H), 121.51 MHz (31P) and on Bruker Advance II Ultrashied Plus
600,58 MHz (1H), 243,12 MHz (31P) while 13C NMR studies on
Bruker Advance II Ultrashied Plus 600.58 MHz (1H) spectrometer
operating 151.016 MHz (13C). Measurements were made in CDCl3
(99.8 at % D), D2O (99.9 at % D), CD3OD (99.8 at % D) and DMSOd6
(99,8 at %D) solutions at temperature 300 K, all solvents were
supplied by ARMAR AG (Dottingen, Switzerland). Chemical shifts
are reported in parts per million relative to TMS or 85% H3PO4 used
as external standards, while coupling constants are reported in
Hertz. Melting points were determined on an Electrothermal 9200
apparatus and are reported uncorrected. Elemental analyses were
performed at Chemistry Department of University of Wroclaw on
Perkin Elmer 2400 CHN. Electrospray mass spectra were recorded
at Faculty of Chemistry, Wroclaw University of Technology using
Waters LCT Premier XE mass spectrometer (methods of ionization
ESI).
Discussion
The presence of aniline-like amino group in benzoannulated
aminobisphosphonates seems to promote cleavage of carbon-to-
phosphorus bonds and degradation of phosphonate molecules
obtained by reacting of lactams with triethyl phosphite and phos-
phoryl chloride upon acidic hydrolysis.
Procedure and Characterization data
Synthesis of lactams (Schmidt reaction)
Starting lactams were prepared by a modified procedure [29].
Thus, a mixture of cyclic ketone (30 mmol), polyphosphoric acid
(100 g) and phosphoric acid (20 mL) was warmed to 55 ꢀC followed
by addition of sodium azide (66 mmol) for 2 h, stirring vigorously.
Next, the mixture was heated until gas stopped to bubble (12 h) and
the warm mixture was poured into ice-cold ammonia solution
(800 mL) and stirred until the resulting oil solidified. The crude
lactam was filtered and recrystallized from mixture of acetyl ace-
tate: hexane (2:1).
Application of mild conditions, for removal of ester groups,
namely the use of trimethylbromosilane followed by methanolysis
gave similar results. Such a phenomenon is observed quite rarely
and is usually promoted by the ability of aromatic fragment of the
molecule to accept electrons from phosphorus atom [25e28]. It is
also worth to note that compounds 1, 2, 7 and 8 are also unstable
and decompose upon storage, even in the refrigerator. The two
steps of removal of phosphonate groups from bisphosphonate
molecule being most probably SN1- like reactions with elimination
of the second phosphonate resulting in degradation of aliphatic
ring. Both steps require the protonation of phosphonate oxygens
(Scheme 8). Anilinic amino group is a weak base and therefore its
protonation is probably concurring with the presumed protonation
of phosphonate.
3,4-dihydro-quinolin-2(1H)-one. Yield 63% (2.78 g) as a creamy
solid; m.p. 168e170 ꢀC (lit m.p. [30,31] 163-164 ꢀC); physico-
chemical data and NMR data in a good agreement with literature
[30,31].
To test additionally the assumption that anilinic structure pro-
motes decomposition of these phosphonates, the preparation of
tetraethyl (5-phenylazazepan-2,2-diyl)bisphosphonate (13) was
successfully undertaken. Compound 13 was quite readily hydro-
lyzed to the corresponding acid 14 (Scheme 9), however, the ob-
tained acid was practically insoluble even in acidic and basic
aqueous solutions and in DMSO, which significantly hampered
analysis of its structure.
2,3,4,5-Tetrahydro-benzo[b]azepin-2-one. Yield 84% (4.06 g) as a
brownish solid; m.p. 138-140 ꢀC (lit m.p. [32] 140.5-141 ꢀC);
physicochemical data and NMR data in a good agreement with
literature [32,33].
3,4,5,6-Tetrahydrobenzo[b]azocin-2-one. Yield 48% (2.54 g) as
a
creamy solid; m.p. 148-150 ꢀC (lit m.p. [34] 154-155 ꢀC); physico-
chemical data and NMR data in a good agreement with literature
[34,35].
Experimental
Materials and methods
5-Phenylazepan-2-one. Yield 65% (3,70 g) as a creamy solid; m.p.
138e139 ꢀC; 1HNMR (300.13 MHz, CDCl3, ppm):
d
¼ 1.61-1.81 (2H,
All solvents and reagents were purchased from commercial
suppliers, were of analytical grade and used without further puri-
fication. Unless otherwise specified solvents were removed with a
rotary evaporator. Infrared spectra were measured on a 1600 FT-IR
m), 1.93-2.04 (2H, m), 2.48-2.66 (2H, m), 2.74-2.80 (m, 1H), 3.23-
3.41 (2H, m), 6.61(1H, s, NH), 7.13-7.17 (2H, m), 7.18-7.24 (1H, m),
7.24-7.32 (2H, m); 13CNMR (151.02 MHz, CDCl3, ppm):
35.36, 37.31, 41.07, 48.21, 126.25, 126.69, 128.51, 147.08, 178.46;
d
¼ 30.57,

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E. Chmielewska et al. / Journal of Organometallic Chemistry 785 (2015) 84e91
Scheme 8. Presumable mechanism of degradation of CeP bonds in compound 5.
HRMS (ESI þ TOF) m/z: [MþH]þ Calcd for C12H15NO 190.1232,
Drying agent was removed by filtration and the solvent removed
under reduced pressure. Crude esters were separated and purified
by column chromatography (silica/ethyl acetate/methanol).
Found 190.1211.
General procedure for reacting of lactams
Diethyl (1H-indol-2-yl)phosphonate (1a). Yield 35% (lit. [16] 44%,
melting point not given) (0.86 g) as a white solid; m.p. 66e67 ꢀC
(lit. m.p. [15] 86 ꢀC); physicochemical data in a good agreement
with literature [16].
Appropriate lactam (10 mmol) and triethyl phosphite (3.43 mL,
20 mmol) were mixed in ice bath and phosphoryl chloride (1.83 mL,
20 mmol) was added dropwise for 20 min under argon atmosphere.
The solution was left overnight and the mixture was poured to cold
solution of ammonia (final pH 7). The product was extracted with
chloroform (3 x 50 mL). The organic layer was concentrated to
obtain a yellow oil. This oil was dissolved in chloroform (100 mL)
and extracted with hydrochloric acid (pH 1). The aqueous layer was
separated and washed with chloroform (3 x 50 mL). Sodium hy-
droxide was added to the aqueous layer until pH reached 10. This
layer was then extracted with chloroform (3 x 50 mL). The chlo-
roform layers were combined and dried over sodium sulfate.
Diethyl (1-methylindol-2-yl)phosphonate (1b). Yield 83% (2.21 g) as
a orange oil (lit. [16] yellow oil as a unseparable mixture of 1b with
diethyl 1-methylindol-3-ylphosphonate); 31PNMR (121.51 MHz,
CDCl3, ppm):
d
¼ 10.68; 1HNMR (300.13 MHz, CDCl3, ppm):
d
¼ 1.30e1.36 (6H, m, POCH2CH3), 3.32 (3H, s, NCH3), 4.05-4.18 (4H,
m, POCH2CH3), 6.81 (1H, d, J ¼ 8.7 Hz CH]CP), 7.03 (1H, t,
J ¼ 6.0 Hz, Ar), 7.11-7.38 (3H, m, Ar); 13CNMR (600.58 MHz, CDCl3,
Scheme 9. Synthesis of (5-phenylazazepan-2,2-diyl)bisphosphonic acid 14.

E. Chmielewska et al. / Journal of Organometallic Chemistry 785 (2015) 84e91
89
ppm):
d
¼ 13.77 (d, J ¼ 6,25 Hz POCH2CH3), 33.61, 61.43 (d,
Tetraethyl [1,2,3,4,5,6-hexahydro-benzo[b]azocin-2,2-diyl]-bisphospho-
J ¼ 5.58 Hz, POCH2), 106.69, 112.50 (d, J ¼ 17.76 Hz), 118.67; 120.85,
122.45 (d, J ¼ 3.18 Hz), 123.12, 126.09 (d, J ¼ 1.47 Hz), 127.9 (d,
J ¼ 190.87 Hz, CP); HRMS (ESI þ TOF) m/z: [MþH]þ Calcd for
nate (6). Yield 28% (1.21 g) as an yellow oil; 31PNMR (121.51 MHz,
CDCl3, ppm):
d
¼ 22.03; 1HNMR (300.13 MHz, CDCl3, ppm):
¼ 1.26
d
(6H, t, J ¼ 7.2 Hz, POCH2CH3), 1.28 (6H, t, J ¼ 7.4 Hz, POCH2CH3), 1.66-
1.90 (2H, m, CH2), 1.77-1.82 (2H, m, CH2), 1.82-2.00 (2H, m, CH2),
2.69-2.73 (2H, m, CH2), 4.04-4.22 (8H, m POCH2), 6.38-7.18 (m, 4H);
C
13H18NO3P 268.1103; Found 268.1111.
13CNMR (151.02 MHz, CDCl3, ppm):
d
¼ 16.28 (d, J¼2.7 Hz,
Tetraethyl (3,4-dihydroquinolin-2,2-diyl)diphosphonate (2a). yield 17%
(0.70 g) as an yellow oil; 31PNMR (121.51 MHz, CDCl3, ppm):
POCH2CH3), 16.30 (d, J ¼ 2.7 Hz, POCH2CH3), 16.47 (d, J ¼ 2.5 Hz,
POCH2CH3), 16.49 (d, J ¼ 2.6 Hz, POCH2CH3), 23.20 (t, J ¼ 9.8 Hz),
27.32, 30.98, 31.72, 62.65 (d, J ¼ 3.6 Hz, POCH2), 62.67 (d, J ¼ 3.6 Hz,
POCH2), 63.62 (d, J ¼ 2.8 Hz, POCH2), 63.64 (d, J ¼ 2.8 Hz, POCH2),
66.41 (t, J ¼ 140.5 Hz, CP), 124.93, 125.82, 127.31, 129.82, 139.82,
142.14 (t, J ¼ 7.7 Hz); HRMS (ESI þ TOF) m/z: [MþH]þ Calcd for
d
¼ 20.73; 1HNMR (300.13 MHz, CDCl3, ppm):
d
¼ 1.20 (6H, t,
J ¼ 7.0 Hz, POCH2CH3), 1.30 (6H, t, J ¼ 7.2 Hz, POCH2CH3), 2.33-2.48
(2H, m, CH2CH2CP), 2.86 (2H, t, J ¼ 6.4 Hz, CH2CH2CP), 4.03-4.29 (8H,
m, POCH2), 6.77 (1H, t, J ¼ 7.5 Hz, Ar), 6.54-6.62 (1H, m, Ar), 6.66 (1H,
t, J ¼ 7.4 Hz, Ar), 6.93-7.02 (1H, m, Ar); 13CNMR (151.02 MHz, CDCl3,
C19H33NO6P2 434.1861, Found 434.1859.
ppm):
d
¼ 16.16 (d, J ¼ 22.6 Hz, POCH2CH3), 23.28 (t, J ¼ 12.1 Hz,
PCCH2), 29.73, 55.94 (t, J ¼ 295.2 Hz, PeCeP), 63.75, 65.15, 115.54,
118.02, 120.25, 127.34, 128.51, 141.50; HRMS (ESI þ TOF) m/z:
[MþNa]þ Calcd for C17H29NO6P2Na 428,1368, Found 428,1359.
Diethyl [2-(diethoxy-phosphoryloxy)-1,2,3,4,5,6-hexahydro-benzo[b]
azocin-2-yl]-phosphonate (8). Yield 11% (0.50 g) as an yellow oil;
31PNMR (121.51 MHz, CDCl3, ppm):
d
¼ 1.07 (d, J ¼ 21.9 Hz), 22.13
(d, J ¼ 21.9 Hz); 1HNMR (300.13 MHz, CDCl3,ppm):
¼ 1.33-1.35 (m,
d
Diethyl (quinolin-2-yl)phosphonate (3a). Yield about 30% (0.81 g) as
an yellow oil; this compound is described in the literature [36] with
basically the same 1H NMR spectrum, however, coupling constant
for POCH2CH3 is mistakenly given in the literature as 3.9 Hz. Our
spectrum contains signals from diethyl phosphate, MeOH-d4 and
traces of ethanol. This compound was obtained after column
12H, POCH2CH3), 1.69-2.00 (m, 6H, CH2CH2CH2), 2.64-2.75 (m, 2H,
CH2Ph), 4.15 (m, JPH ¼ J ¼ 7.0 Hz, 2H, POCH2), 4.0-4.25 (m, 6H,
POCH2), 7.09-7.36 (m, 4H) 13CNMR (151,02 MHz, CDCl3, ppm):
d
¼ 16.05 (d, J ¼ 7.0 Hz, POCC), 16.09 (d, J ¼ 6.8 Hz, POCC), 16.44 (d,
J ¼ 5.8 Hz, POCC), 16.49 (d, J ¼ 5.7 Hz, POCC), 25.15 (d, J ¼ 10.7 Hz),
29.49, 30.84 (d, J ¼ 2.1 Hz), 31.33 (d, J ¼ 19.8 Hz), 62.85 (d, J ¼ 6.2 Hz,
POC), 62.89 (d, J ¼ 6.8 Hz, POC), 64.09 (d, J ¼ 6.0 Hz, POC), 72.89 (dd,
J ¼ 7.2 Hz, J ¼ 170.2 Hz, CP), 126.74, 126.95, 127.75, 128.52 (d,
J ¼ 4.3 Hz), 129.98, 130.44; HRMS (ESI þ TOF) gives a product of
rearrangement of 8 under measurement conditions, of the struc-
ture shown in Supporting Information File 2, page 21 m/z: [M-O-M
- Et2O3P-O-PO3Et2þH]þ Calcd for C30H46N2O7P2 609.2858, Found
609.2836.
chromatography. 31PNMR (121.51 MHz, MeOH-d4, ppm):
d
¼ 11.05;
1HNMR (300.13 MHz, MeOH-d4, ppm):
d
¼ 1.40 (6H, t, J ¼ 7.2 Hz,
POCH2CH3) 4.34 (4H, mz, POCH2), 7.75 (1H, dt, J ¼ 9.2 Hz, J ¼ 3.5 Hz,
Ar), 7.89 (1H, dt, J ¼ 9.2 Hz, J ¼ 3.5 Hz, Ar), 7.98 (1H, dd, J ¼ 6.5 Hz,
J ¼ 3.0 Hz, Ar), 8.03 (1H, d, J ¼ 9.2 Hz, Ar), 8.22 (1H, d, J ¼ 9.2 Hz, Ar),
8.51 (1H, dd, J ¼ 6.5 Hz, J ¼ 9.2 Hz, Ar); 13CNMR (151.02 MHz,
MeOH-d4, ppm):
d
¼ 15.07 (d, J ¼ 10.6 Hz, POCH2CH3), 63.90 (d,
J ¼ 6.4 Hz, POC), 122.77 (d, J ¼ 27.2 Hz, PeC]C), 127.90 (d,
J ¼ 1.51 Hz), 128.62, 128.81 (d, J ¼ 3.02 Hz), 129.24 (d, J ¼ 1.51 Hz),
130.61, 136.92 (d, J ¼ 12.1 Hz), 147.96 (d, J ¼ 25.6 Hz), 151.79 (d,
Tetraethyl (pyrrolidine-2,2-diyl) bisphosphonate (11a). Yield 27%
J ¼ 226.5 Hz, CP); IR (
n
cmꢁ1): 3214 (NH), 1239 & 1213 (P]O), 1017
(3.26 g) (lit. 47% [14]) as a yellowish oil; 31PNMR (121.51 MHz,
(POC); HRMS (ESI þ TOF) m/z: [MþH]þ Calcd for C13H16NO3P
CDCl3, ppm):
agreement with literature [14,37].
d
¼ 24.26; - other physicochemical data in a good
266.0946, Found 266.0962.
Tetraethyl (6-hydroxy-3,4-dihydroquinolin-2,2-diyl)bisphosphonate
Tetraethyl (piperidine-2,2-diyl)bisphosphonate (11b). Yield 65%
(2b). Yield 27% (1.14 g) as an yellow solid, mp. 66e67 ꢀC; 31PNMR
(7.02 g) (lit.70% [23]) as a yellowish oil; 31PNMR (121.51 MHz, CDCl3,
(121.51 MHz, CDCl3, ppm):
ppm):
CH2CH2CP), 2.70-2.86 (2H, m, CH2CH2CP), 3.96-4.29 (8H, m,
POCH2), 4.81 (1H, bs, NH), 6.21-6.52 (1H, m, Ar), 6.65-6.78 (1H, m,
Ar), 6.86-7.02 (1H, m, Ar); 13CNMR (151.02 MHz, CDCl3, ppm):
d
¼ 20.38; 1HNMR (300.13 MHz, CDCl3,
ppm):
with literature [22,23].
d
¼ 23.61; other physicochemical data in a good agreement
d
¼ 1.10-1.37 (12H, m, POCH2CH3), 2.32-2.67 (2H, m,
Tetraethyl (azepan-2,2-diyl)bisphosphonate (11c). Yield 38% (3.79 g)
as a yellowish oil; 31PNMR (121.51 MHz, CDCl3, ppm):
other physicochemical data in a good agreement with literature
[22,23].
d
¼ 23.72;
d
¼ 16.28 (d, J ¼ 6.31 Hz, POCH2CH3), 16.43 (d, J ¼ 6.31 Hz,
POCH2CH3), 16.61 (bt, J ¼ 2.78 Hz, POCH2CH3), 24.50, 31.36, 61.70 (t,
J ¼ 220.78 Hz, PCP), 63.59 (d, J ¼ 5.78 Hz, POCH2), 102.86, 109.33,
114.16,128.67,139.42,157.00; HRMS (ESI þ TOF) m/z: [MþH]þ Calcd
for C17H29NO7P2 422.1497 Found 422.1496.
Tetraethyl (5-phenylazazepan-2,2-diyl)bisphosphonate (13). Yield 28%
(1.25 g); as an yellow oil; 31PNMR (121,51 MHz, CDCl3, ppm):
d
¼ 23.01 & 25.35 (AB system; JAB- ¼ 48.6 Hz); 1HNMR (300,13 MHz,
Tetraethyl [2,3,4,5-tetrahydro-1H-benzo[b]azepin-2,2-diyl]-bisphosph-
CDCl3, ppm):
d
¼ 1.22 (6H, t, J ¼ 7.0 Hz, POCH2CH3) 1.26 (6H, t,
onate (5). Yield 30% (1.26 g) as an yellow oil; 31PNMR (121,51 MHz,
J ¼ 7.0 Hz, POCH2CH3), 1.62-1,71 (2H, m, CH2), 1.76-1.86 (2H, m,
CH2),1.90-2.04 (2H, m, CH2), 2.69-2.73 (2H, m, CH2), 4.0-4.3 (8H, m,
POCH2), 6.94-7.05 (4H, m, Ar), 7.10-7.15 (1H, m); 13CNMR
CDCl3, ppm):
agreement with literature [22].
d
¼ 21.81; other physicochemical data in a good
(151.02 MHz, CDCl3, ppm):
d
¼ 16.04 (d, J ¼ 6.7 Hz, POCH2CH3), 16.41
Diethyl (4,5-dihydro-1H-benzo[b]azepin-2-yl)-phosphonate (7).
(d, J ¼ 5.8 Hz, POCH2CH3), 16.53 (d, J ¼ 5.5 Hz, POCH2CH3), 16.56 (d,
J ¼ 5.7 Hz, POCH2CH3), 28.96 (d, J ¼ 5.7 Hz), 31.0 (d, J ¼ 13.3 Hz),
41.64 (d, J ¼ 4.5 Hz), 42.99 (d, J ¼ 13.86 Hz), 49.16, 61.49 (dd,
J ¼ 155.5 Hz, J ¼ 23.2 Hz, CP), 62.66 (d, J ¼ 7.5 Hz, POCH2), 62.85 (d,
J ¼ 7.6 Hz, POCH2) 63.10 (d, J ¼ 7.8 Hz, POCH2), 63.95 (d, J ¼ 7.3 Hz,
POCH2), 125.85, 126.55, 126.67, 128.29, 128.52, 147.62; HRMS
(ESI þ TOF) m/z: [MþH]þ Calcd for C20H35NO6P2 448.2018, Found
448.2020.
Yield 28% (0.80 g) (lit. 20% [22]) as yellow oil; 31PNMR (121.51 MHz,
CDCl3, ppm):
d
¼ 16.78; 1HNMR (300.13 MHz, CDCl3, ppm):
¼ 1.36
d
(6H, t, J ¼ 7.0 Hz, POCH2CH3), 2.58-2.62 (2H, m, C]CCH2), 2.98 (2H,
t, J ¼ 7.2 Hz, PhCH2), 4.06-4.20 (4H, m, POCH2), 5.56 (1H, dt,
JPH ¼ 19.3 Hz, J¼ 5.3 Hz, PC]CH), 5.89 (1H, bd, JPH ¼ 8.5 Hz, NH),
6.74-7.24 (4H, m); HRMS (ESI þ TOF) m/z: [MþH]þ Calcd for
C
14H20NO3P 282.1259, Found 282.1258.

90
E. Chmielewska et al. / Journal of Organometallic Chemistry 785 (2015) 84e91
Hydrolyses e general procedure
Appendix A. Supplementary data
The obtained ester (0.030 mol) was refluxed for 12 h in 20 mL
6 M aqueous hydrochloric acid solution. Then the volatile compo-
nents were evaporated and the resulting crude product was
recrystallized from water, anhydrous ethanol or water-ethanol
mixture.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.jorganchem.2015.03.005.
References
Quinolin-2-ylphosphonic acid (4). Yield from monophosphonate -
45% (1.20 g) as a creamy solid; from bisphosphonate - 24% (0.97 g)
as an orange solid; mp. 283e284 ꢀC; 31PNMR (121.51 MHz, D2O,
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d
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(1H, d, J ¼ 8.7 Hz, Ar), 8.20 (dd, 1H, J ¼ 8.7 Hz, J ¼ 3.95 Hz, PC]CH)
13CNMR (151.02 MHz, D2O, ppm):
d
¼ 123.13 (d, J ¼ 21.2 Hz), 126.85,
127.48 (d, J ¼ 3.2 Hz), 127.96 (d, J ¼ 6.0 Hz), 129.86, 136.20 (d,
J ¼ 9.1 Hz), 146.67, 146.80, 164.46 (d, J ¼ 181.4 Hz PC); IR (
cmꢁ1):
cmꢁ1): 1239 & 1213 (P]
n
3200-2500, 1146 (P]O), 1077 (POC); IR (
n
O), 1016 (POC); HRMS (ESI-TOF) m/z: [MꢁH]- Calcd for C9H8NPO3
208.0164 Found 208.0164. Anal. Calcd for C9H8NO3P ꢂ 1/2H2O: C,
49.55; H, 4.16; N, 6.42. Found: C, 49.82; H, 3.77; N, 6.27.
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4-(2-Aminophenyl)butanoic acid hydrochloride (9). Yield from
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bisphosphonate e 21% (0.88 g) as a white solid; both melting at
163e164 ꢀC, (lit. mp. [37] 196.5e200 ꢀC); other physicochemical
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5-(2-Aminophenyl)pentanoic acid hydrochloride (10). Yield 42%
(1.82 g) as
a
creamy solid; m.p. 180e182 ꢀC. (lit. mp. [38]
183e184 ꢀC); other physicochemical data in a good agreement
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(Pyrrolidine-2,2-diyl) bisphosphonic acid (12a). Yield 71% (0.98 g) as
a white solid; m.p. 265e266 ꢀC (lit mp. [23] 277 ꢀC); 31PNMR
(300.13 MHz, D2O, ppm):
good agreement with literature [14,39].
d
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(Piperidine-2,2-diyl)bisphosphonic acid (12b). Yield 69% (3.02 g) as a
white solid; m.p. 248e249 ꢀC (lit mp [23] 249 ꢀC); 31PNMR
(121.51 MHz, D2O, ppm):
ppm):
d
¼ 13.53; 1HNMR (300.13 MHz, D2O,
d
¼ 1.55-1.63 (2H, m, CH2), 1.67-1.77 (2H, m, CH2), 1.93-2.10
(2H, m, JPH¼19.4 Hz, J ¼ 5.7 Hz), 3.28 (2H, t, J ¼ 5.7 Hz, CH2N);
13CNMR (151.02 MHz, D2O, ppm):
d
¼ 18.87 (t, J ¼ 4.6 Hz, CH2CP),
23.05, 26.89, 41.71, 59.61 (t, J ¼ 122.4 Hz, PCP); HRMS (ESI-TOF) m/
z: [MꢁH]- Calcd for C5H13NO6P2 244.0140, Found 244.0133.
(Azepan-2,2-diyl)bisphosphonic acid (12c). Yield 10% (1.74 g) as a
white solid; m.p. 249e251 ꢀC (lit mp. [23] 257 ꢀC); 31PNMR
(121.51 MHz, D2O, ppm):
good agreement with literature [40,41].
d
¼ 14.60; other physicochemical data in a
(5-Phenylazazepan-2,2-diyl)bisphosphonic acid (14). Yield 51%
(0.51 g) as a creamy solid; m.p. 205e207 ꢀC; very badly soluble,
31PNMR (121.51 MHz, D2O, ppm):
d
¼
15.94 Hz; 1HNMR
¼ 3.44-4.03 (9H, m),
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Acknowledgements
Support from the National Science Centre, Poland (Grant 2011/
01/B/ST5/00843), is gratefully acknowledged.

E. Chmielewska et al. / Journal of Organometallic Chemistry 785 (2015) 84e91
91
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