Efficient synthesis of substituted cyclic α-aminophosphonates

Article abstract of DOI:10.1055/s-0028-1083349

The addition of diethyl phosphite to cyclic imines bearing alkyl, aryl, or heteroaryl substituents at the α-position in diethyl ether at room temperature presents an efficient route to substituted cyclic α-aminophosphonates. The application of boron trifl

Full text of DOI:10.1055/s-0028-1083349

PAPER
577
Efficient Synthesis of Substituted Cyclic a-Aminophosphonates
S
ubstitut
r
ed Cycli
i
c
a
-
Am
n
inophosphon
a
ates L. Odinets,*a Oleg. I. Artyushin,a Nikolay Shevchenko,b Pavel V. Petrovskii,a Valentin G. Nenajdenko,b
Gerd-Volker Röschenthalerc
a
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28 Vavilova Street, 119991 Moscow,
Russian Federation
Fax +7(499)1355085; E-mail: odinets@ineos.ac.ru
Moscow State University, Leninskie Gory, 119992 Moscow, Russian Federation
Institute of Inorganic and Physical Chemistry, University of Bremen, Leobener Str., 28334 Bremen, Germany
b
c
Received 28 July 2008; revised 8 October 2008
cation in the synthesis of biologically and synthetically at-
tractive molecules, such as derivatives of indole, pyrazole,
isoxazole, amino acids, and seminatural peptides.15
Abstract: The addition of diethyl phosphite to cyclic imines bear-
ing alkyl, aryl, or heteroaryl substituents at the a-position in diethyl
ether at room temperature presents an efficient route to substituted
cyclic a-aminophosphonates. The application of boron trifluoride–
diethyl ether complex as a catalyst significantly accelerates the re-
action.
Taking into account that the most convenient approach to
build phosphonate P–C–N systems generally comprises
the addition of dialkyl phosphites16–20 or alkali metal
phosphides21 to the carbon–nitrogen double bond of
Schiff bases, we believe that the phosphorylation of sub-
stituted cyclic imines may be an advantageous strategy to
obtain a-substituted cyclic a-aminophosphonates.
Key words: diethyl phosphonate, cyclic imines, addition reactions,
a-aminophosphonates
a-Aminophosphonates have attracted constant attention
over several decades because of the high and diverse bio-
logical activity determining their practical applications,
and there have been ongoing searches for and investiga-
tions of novel structures of this type.1 Being analogous to
amino acids, they have been found to be useful for a num-
ber of applications, e.g. as antibiotics,2 enzyme inhibi-
tors,3 anticancer agents,4 and herbicides.5 These a-
aminophosphonate compounds are also of undoubted in-
terest as ligands in homogeneous6 or organic7 catalysis.
In this paper, we report the effective synthesis of cyclic a-
aminophosphonates with different ring sizes on the basis
of the above-mentioned methodology.
Depending on the structure and electrophilicity of a Schiff
base, dialkyl phosphites are known to add to its carbon–
nitrogen double bond under thermal,16a,b ultrasonic,16c or
microwave18 initiation and in the presence of strong
bases17 or Lewis acids.18,20 We found, however, that the
addition of diethyl phosphite to substituted five-, six-, and
seven-membered cyclic imines 1a–e, 2a and 2b, and 3
proceeded smoothly in diethyl ether at room temperature
without any catalyst to afford the corresponding a-amino-
phosphonates 4a–e, 5a and 5b, and 6, respectively
(Scheme 1). The reaction rate was much higher in the case
of alkyl-substituted derivatives. For such substrates, the
reaction was complete in approximately 30 hours at ambi-
ent conditions. In the case of aryl- or heteroaryl-substitut-
ed imines 1c–e, 2b, and 3, the reaction was complete
within 3–5 days. After workup, the crude phosphonates
were isolated in good yields with purity higher than 95%
according to their corresponding 1H and 31P NMR spectra.
Cyclic or heterocyclic rings introduced into the molecular
skeleton increase the rigidity and modify the electronic ef-
fects of these compounds. Thus, many cyclic a-amino-
phosphonic acids bearing an exocyclic amino group have
been prepared, mostly in racemic series.8 However,
among the a-aminophosphonates synthesized, those con-
taining nitrogen as a ring heteroatom are scarce. The syn-
thetic routes to such products are limited mostly to the
addition of hydrophosphoryl compounds to triazine deriv-
atives,9 lactam alkylation using dialkyl phosphite sodium
salts10 or multistep asymmetric synthesis11 for unsubsti-
tuted five- and six-membered compounds, and some pro-
cedures developed for aziridinylphosphonates.12 The
synthesis of diethyl 2-methyl- and 2-phenylpyrrolidin-2-
ylphosphonates, used as precursors for phosphorylated ni-
trones, has also been reported.13
Our attempts to accelerate the reaction using microwave
or thermal initiation resulted in the formation of a com-
plex product mixture. When room-temperature ionic
liquids 1-butyl-3-methylimidazolium tetrafluoroborate
and hexafluorophosphate ([bmim]BF4 and [bmim]PF6, re-
spectively) were used as activating reaction media, in a
similar manner to the synthesis of a-aminophosphonates
via the Kabachnik–Fields reaction,22 the increase in the
conversion rate was negligible (ca. 5–9% for the same pe-
riod of time). No significant influence of the anionic na-
ture of the reaction medium using ionic liquids was
observed.
Cyclic imines with various aliphatic or aromatic substitu-
ents at the a-position can be easily prepared according to
literature procedures14 from cheap, commercially avail-
able starting materials, and these imines open up broad
synthetic possibilities. We have demonstrated their appli-
SYNTHESIS 2009, No. 4, pp 0577–0582
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x
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x
x
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Advanced online publication: 02.02.2009
DOI: 10.1055/s-0028-1083349; Art ID: T12308SS
© Georg Thieme Verlag Stuttgart · New York

578
I. L. Odinets et al.
PAPER
acting as a proton donor for a-aminophosphonates has
P(O)(OEt)2
been previously reported.23
R
4a–e
N
H
68–95% (>95% purity)
46–58% (isolated yield)
The reaction is very sensitive to the steric conditions of
both the starting cyclic imine and dialkyl phosphite. For
example, when the substituent at the 2-position of the sub-
strate was a tert-butyl group, the yield of product (2-tert-
butylpyrrolidin-2-yl)phosphonate 4f did not exceed about
10% according to the 31P NMR spectroscopic data of the
reaction mixture. The result was the same even after a pro-
longed reaction time and using a catalyst. 6-tert-Butyl-
2,3,4,5-tetrahydropyridine (2c) did not undergo phospho-
rylation either using the above conditions or at elevated
temperatures. The introduction of an ortho-methyl group
on the phenyl substituent of the six-membered cyclic imi-
ne substrate 2d inhibited the reaction as well. Moreover,
we failed to perform the reaction of 1b using chiral dimen-
thyl phosphonate (Scheme 2).
(EtO)2P(O)H
P(O)(OEt)2
n
5a,b
N
R
R
N
H
92–96% (>95% purity)
58–63% (isolated yield)
1a–e; 2a,b; 3
n = 1: 1a–e
n = 2: 2a,b
n = 3: 3
P(O)(OEt)2
N
H
6
Me
85% (>95% purity)
59% (isolated yield)
R = Me (2a, 5a), i-Pr (1a, 4a), n-Bu (1b, 4b), Ph (1c, 2b, 4c, 5b),
(1e, 4e), 4-MeC6H4 (3)
(1d, 4d),
N
S
P(O)(OEt)2
(EtO)2P(O)H
4f
t-Bu
N
Scheme 1 Reaction conditions: Et2O or THF as solvent, r.t.; without
catalyst, 30 h to 5 d; with BF3·OEt2 (20 mol%) as catalyst, 12–24 h.
H
~ 10% estimated yield
cat. BF3⋅OEt2
(20 mol%)
n
(EtO)2P(O)H
P(O)(OEt)2
Et2O or THF
r.t., 18–48 h
R
N
The catalyst of choice for the synthesis was boron trifluo-
ride–diethyl ether complex (BF3·OEt2) (20 mol%), and
using this catalyst the reaction was complete over 12–24
hours depending on the substituent R and ring size of the
starting imine in either diethyl ether or tetrahydrofuran. A
comparison of the reaction rates using the different cata-
lytic systems in the synthesis of cyclic a-aminophospho-
nate 4b are shown in Table 1.
no reaction
R
N
H
1b,f, 2c,d
(MntO)2P(O)H
P(O)(OMnt)2
n-Bu
N
H
n = 1, R = n-Bu (1b), t-Bu (1f);
n = 2, R = t-Bu (2c), 2,5-(Me)2C6H3 (2d)
no reaction
MntO =
O
Table 1 Influence of a Catalyst on the Reaction Rate
P(O)(OEt)2
Bu
(EtO)2P(O)H
r.t.
Scheme 2
Bu
N
H
N
4b
1b
The a-aminophosphonates obtained can be easily con-
verted into their corresponding a-aminophosphonic acids
via reaction with trimethylsilyl bromide in chloroform,
followed by treatment with aqueous methanol
(Scheme 3). Because the cyclic aminophosphonic acids
easily undergo quaternization with hydrogen bromide
formed as a result of the hydrolysis of trimethylsilyl bro-
mide, they are isolated as the corresponding hydrobro-
mides 7. Further treatment with propylene oxide affords
the free amino acids 8, as illustrated using (2-pyridin-4-
ylpyrrolidin-2-yl)- and (2-phenylpiperidin-2-yl)phospho-
nic acid hydrobromide (7c) and (7d), respectively
(Scheme 3). Naturally, the isolation of the intermediate
hydrobromides is an optional step. The high melting
points of acids 8a and 8b and the presence of an absorp-
tion band at around 1628 cm–1 in their IR spectra are
Entry Reaction conditions
Time (h)
Yield (%) of 4ba
1
2
3
4
Et2O, without catalyst
6
24
35
66
[bmim]BF4
6
24
32
75
[bmim]PF6
6
24
33
71
Et2O, 20 mol% BF3·OEt2
6
12
54
95
a Yield according to 31P NMR spectroscopic data.
Excluding solid (2-pyridin-4-ylpyrrolidin-2-yl)phospho-
nate 4d, a-aminophosphonates 4–6 are all yellowish oils
and water soluble. It should be noted that these com-
pounds are inclined to form stable hydrates and solvate
with chloroform; in the case of compound 6 such a CHCl3
solvate, for example, could be destroyed only after pro-
longed drying in vacuo (1 mmHg, 4–5 h) at approximately
100 °C. The formation of strong solvates with chloroform
+
characteristic24 of ammonium species >NH2 , which al-
lows one to suggest that these compounds exist as their
corresponding zwitterions.
To conclude, we have developed a simple and convenient
approach to synthesize a-alkyl-, a-aryl-, and a-heteroaryl-
substituted cyclic a-aminophosphonates via diethyl phos-
Synthesis 2009, No. 4, 577–582 © Thieme Stuttgart · New York

PAPER
Substituted Cyclic a-Aminophosphonates
579
1) TMSBr,
CHCl3
n
n
P(O)(OH)2
P(O)(OH)2
n
O
P(O)(OEt)2
N
N
R
H
N
H
R
Br–
R
2) MeOH (aq)
+
H
H
85–94%
82–84%
8a,b
7a–e
4b–d, 5b, 6
n = 1, R = Bu (7a), Ph (7b), 4-Py (7c, 8a)
n = 2, R = Ph (7d, 8b)
n = 3, R = 4-MeC6H4 (7e)
Scheme 3
13C NMR (75 MHz, CDCl3): d = 16.23 and 16.31 (both d, 3JP,C = 6.6
phite addition to readily available cyclic imines and have
elucidated the benefits and limitations of this reaction.
3
Hz, CH3CH2O), 17.56 [d, JP,C = 7.5 Hz, (CH3)2CH], 18.23 [d,
3
3JP,C = 4.4 Hz, (CH3)2CH], 26.06 (d, JP,C = 3.1 Hz, C-4), 29.40
(2JP,C = 2.1 Hz, CH), 34.31 (d, 3JP,C = 9.8 Hz, C-3), 47.17 (d, 3JP,C
=
The NMR spectra were recorded with Bruker Avance 300 (1H,
300.13; 31P, 121.49; and 13C, 75.47 MHz) and Avance 400 (1H,
400.13; 31P, 161.97; and 13C, 100.61 MHz) spectrometers using re-
sidual proton signals of the deuterated solvent as an internal stan-
5.2 Hz, C-5), 61.25 (d, 2JP,C = 7.7 Hz, OCH2), 62.15 (d, 2JP,C = 7.7
Hz, OCH2), 66.29 (d, 1JP,C = 158.3 Hz, C-2).
31P NMR (121 MHz, CDCl3): d = 30.6.
dard (1H and 13C) and H3PO4 as an external standard (31P). The 13
C
Anal. Calcd for C11H24NO3P·H2O: C, 49.43; H, 9.80; N, 5.24; P,
11.34. Found: C, 49.49; H, 9.86; N, 5.24; P, 11.10.
NMR spectra were registered using the JMODECHO mode; the sig-
nals for the C atom bearing odd and even numbers of protons have
opposite polarities. The IR spectra were recorded in a thin layer on
a Fourier transform spectrometer Magna-IR750 (Nicolet) (resolu-
tion 2 cm–1, 128 scans). Mass spectrometry was performed on a tan-
dem Finnigan LCQ Advantage instrument using positive mode.
Analytical TLC was performed with Merck silica gel 60 F254 plates.
Visualization was accomplished using UV light or by spraying with
Ce(SO4)2 soln in 5% H2SO4. Flash chromatography was carried out
using Merck silica gel 60 (230–400 mesh ASTM). Melting points
were determined with an Electrothermal IA9100 Digital Melting
Point Apparatus and are uncorrected. The starting cyclic imines
1a–f, 2a–d, and 3 were obtained according to known procedures.14
Other reactants were purchased from Aldrich and used without fur-
ther purification.
Diethyl (2-Butylpyrrolidin-2-yl)phosphonate (4b)
Obtained in Et2O as reaction solvent. Yield: 1.25 g (95%, crude),
1.13 g (86%, after TLC purification), 0.71 g (54%, after column
chromatography); viscous oil.
IR (KBr): 957, 1029 and 1057 (P–O–C), 1235 (P=O), 2934, 2958
(NH), 3318 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.90 (t, 3JH,H = 7.0 Hz, 3 H, CH3),
3
1.33 (t, JH,H = 7.0 Hz, 6 H, 2 CH3CH2O), overlapped with 1.28–
1.48 [m, 4 H, CH3(CH2)2], 1.62–2.00 (m, 5 H), 2.11–2.26 (m, 1 H,
cyclic CH2), 3.09–3.23 (m, 2 H, NCH2), 4.10–4.21 (m, 4 H, 2
OCH2).
13C NMR (75 MHz, CDCl3): d = 14.09 (CH3), 16.66 (d, 3JP,C = 4.2
3
Hz, CH3CH2O), 23.35 (CH3CH2), 25.60 (d, JP,C = 2.8 Hz,
Diethyl Pyrrolidin-2-ylphosphonates, Piperidin-2-ylphospho-
nates, and Hexahydro-1H-azepin-2-ylphosphonates 4–6;
General Procedure
CH3CH2CH2), 26.27 (d, 3JP,C = 5.6 Hz, C-4), 32.34 (C-3), 36.30 (d,
3
2JP,C = 5.6 Hz, PCCH2), 47.53 (d, JP,C = 5.6 Hz, C-5), 62.89 (d,
2
2JP,C = 8.4 Hz, OCH2), 63.18 (d, JP,C = 7.0 Hz, OCH2), 64.04 (d,
To a solution of the appropriate cyclic imine 1–3 (5 mmol) and
diethyl phosphite (0.83 g, 6 mmol) in anhyd Et2O or THF (ca. 2 mL)
was slowly added BF3·OEt2 (0.14 g, 1 mmol) via syringe. The mix-
ture was stirred at r.t. over 12–24 h while monitoring the course of
the reaction using 31P NMR spectroscopy or TLC. Then, CH2Cl2 (10
mL) was added and the mixture was extracted with dil HCl (10 mL).
The organic layer was discarded, the aqueous layer was adjusted to
pH 10 with 20% NaOH, and this mixture was extracted with CH2Cl2
(3 × 25 mL). The combined organic phases were dried (Na2SO4),
and CH2Cl2 was removed by evaporation in vacuo to give the crude
target phosphonates 4–6 in 68–96% yield with >95% purity accord-
ing to NMR spectroscopic data. Analytically pure samples were ob-
tained using silica gel column chromatography (CHCl3–EtOH,
100:6). It should be noted that the column chromatography resulted
in a large loss of the compounds because of their high affinity to sil-
ica gel; TLC purification gave better results. However, for the syn-
thesis of the corresponding phosphonic acids, crude compounds 4–
6 can be successfully used without further purification.
1JP,C = 160.0 Hz, C-2).
31P NMR (121 MHz, CDCl3): d = 28.9.
ESI-MS: m/z (%) = 263 (18) (M+), 126 (100) [M – P(O)(OEt)2]+.
Anal. Calcd for C12H26NO3P: C, 54.74; H, 9.95; N, 5.32; P, 11.76.
Found: C, 54.73; H, 9.80; N, 5.17; P, 11.72.
Diethyl (2-Phenylpyrrolidin-2-yl)phosphonate (4c)13b
Obtained in THF as reaction solvent. Yield: 1.22 g (86%, crude),
0.76 g (54%, after column chromatography), 1.02 g (72%, after
TLC purification); viscous yellowish oil.
IR (KBr): 961, 1026 and 1053 (P–O–C), 1241 (P=O), 1600 (Ar),
2978 (NH) cm–1.
1H NMR (300 MHz, CDCl3): d = 1.14 and 1.22 (both t, 3JH,H = 7.1
Hz, 3 H + 3 H, 2 CH3CH2O), 1.60–1.72 (m, 1 H, cyclic CH2), 1.86–
1.95 (m, 1 H, cyclic CH2), 2.18–2.32 (m, 2 H, NH + cyclic CH2),
2.48–2.61 (m, 1 H, cyclic CH2), 2.91–2.98 (m, 1 H, NCH2), 3.16–
3.23 (m, 1 H, NCH2), 3.72–3.82 (m, 1 H, OCH2), 3.84–3.93 (m, 1
H, OCH2), 3.94–4.03 (m, 2 H, OCH2), 7.20–7.26 (m, 1 H, CHAr),
7.28–7.34 (m, 2 H, 2 CHAr), 7.55–7.59 (m, 2 H, 2 CHAr).
Diethyl (2-Isopropylpyrrolidin-2-yl)phosphonate (4a)
Obtained in Et2O as reaction solvent. Yield: 0.9 g (72%, crude),
0.61 g (49%, after column chromatography), 0.79 g (63%, after
TLC purification); oil.
3
13C NMR (75 MHz, CDCl3): d = 16.48 (d, JP,C = 4.2 Hz,
3
CH3CH2O), 25.30 (d, JP,C = 7.1 Hz, C-4), 32.34 (C-3), 46.66 (d,
IR (KBr): 961, 1028 and 1055 (P–O–C), 1097, 1228 (P=O), 1391,
1444, 1471, 2974, 2908, 2977 (NH), 3360, 3442 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.95 and 1.00 [both d, 3JH,H = 6.8
Hz, 3 H + 3 H, (CH3)2CH], 1.27 (t, 3JH,H = 7.0 Hz, 6 H, 2 CH3CH2O),
1.62–2.18 (m, 6 H, CH + NH + 2 cyclic CH2), 2.92–3.03 (m, 2 H,
NCH2), 4.04–4.17 (m, 4 H, 2 OCH2).
2
3JP,C = 8.4 Hz, C-5), 62.61 (d, JP,C = 7.0 Hz, OCH2), 62.98 (d,
2JP,C = 7.1 Hz, OCH2), 67.08 (d, 1JP,C = 150.3 Hz, C-2), 127.12 (d,
3
5JP,C = 2.8 Hz, C-4 in Ph), 127.58 (d, JP,C = 4.3 Hz, C-2 in Ph),
127.96 (d, 4JP,C = 2.8 Hz, C-3 in Ph), 141.19 (ipso-C in Ph).
31P NMR (121 MHz, CDCl3): d = 27.58.
Synthesis 2009, No. 4, 577–582 © Thieme Stuttgart · New York

580
I. L. Odinets et al.
PAPER
ESI-MS: m/z (%) = 146 (100) [M – P(O)(OEt)2]+.
31P NMR (121 MHz, CDCl3): d = 30.6.
Anal. Calcd for C14H22NO3P: C, 59.35; H, 7.83; N, 4.94; P, 10.93.
Found: C, 59.52; H, 7.85; N, 4.90; P, 11.06.
Anal. Calcd for C10H22NO3P·0.5H2O: C, 49.17; H, 9.49; P, 12.68.
Found: C, 49.07; H, 8.77; P, 12.38.
Diethyl (2-Pyridin-4-ylpyrrolidin-2-yl)phosphonate (4d)
Obtained in THF as reaction solvent. Yield: 0.97 g (68%, crude),
0.65 g (46%, after column chromatography); white solid; mp 64–65
°C.
Diethyl (2-Phenylpiperidin-2-yl)phosphonate (5b)
Obtained in THF as reaction solvent. Yield: 1.43 g (96%, crude),
0.94 g (63%, after column chromatography); yellowish oil.
IR (KBr): 964, 1025 (P–O–C), 1062, 1236 (P=O), 2864, 2934,
2980, 3322 (br), 3456 (br) cm–1.
IR (KBr): 967, 1021 and 1055 (P–O–C), 1231 (P=O), 1593 (Ar),
2927 and 2981 (NH), 3328 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.16 and 1.20 (both t, 3JH,H = 7.0
Hz, 3 H + 3 H, 2 CH3CH2O), 1.23–1.40 (m, 1 H, cyclic CH2), 1.40–
1.54 (m, 2 H, cyclic CH2), 1.60–1.67 (m, 1 H, cyclic CH2), 2.09–
2.22 (m overlapped with br s, 2 H, cyclic CH2 + NH), 2.51–2.56 (m,
1 H, cyclic CH2), 2.59–2.68 (m, 1 H, NCH2), 2.82–2.86 (m, 1 H,
NCH2), 3.71–3.83 and 3.84–4.02 (both m, 1 H + 3 H, 2 OCH2),
1H NMR (300 MHz, CDCl3): d = 1.20 and 1.24 (both t, 3JH,H = 7.1
Hz, 3 H + 3 H, 2 CH3CH2O), 1.52–1.73 (m, 1 H, cyclic CH2), 1.80–
2.00 (m, 1 H, cyclic CH2), 2.12–2.28 (m, 1 H, cyclic CH2), 2.40 (br,
1 H, NH), 2.40–2.65 (m, 1 H, cyclic CH2), 2.83–2.97 (m, 1 H,
NCH2), 3.14–3.25 (m, 1 H, NCH2), 3.80–4.18 (m, 4 H, 2 OCH2),
7.54 (br, 2 H, py), 8.55 (br, 2 H, py).
3
7.23–7.28 (m, 1 H, CHAr), 7.37 (t, JH,H = 7.8 Hz, 2 H, 2 CHAr),
7.53–7.57 (m, 2 H, 2 CHAr).
3
13C NMR (75 MHz, CDCl3): d = 16.59 (d, JP,C = 5.6 Hz,
3
3
CH3CH2O), 25.47 (d, JP,C = 7.0 Hz, C-4), 36.41 (C-3), 46.91 (d,
13C NMR (101 MHz, CDCl3): d = 16.33 (d, JP,C = 4.8 Hz,
3JP,C = 8.4 Hz, C-5), 63.12 (d, JP,C = 7.0 Hz, OCH2), 63.40 (d,
CH3CH2O), 19.66 (d, 3JP,C = 11.8 Hz, C-4), 26.42 (C-3), 29.74 (C-
5), 40.61 (d, 3JP,C = 13.1 Hz, C-6), 60.39 (d, 1JP,C = 154.3 Hz, C-2),
2
2JP,C = 7.1 Hz, OCH2), 66.70 (d, 1JP,C = 149.1 Hz, C-2), 122.83 (CH
2
2
in py), 149.58 (CHN in py), 151.38 (d, 2JP,C = 2.8 Hz, ipso-C in py).
62.75 (d, JP,C = 7.6 Hz, OCH2), 63.08 (d, JP,C = 7.6 Hz, OCH2),
126.87 (5JP,C = 3.4 Hz, C-4 in Ph), 128.25, 128.78 (d, 3JP,C = 4.8 Hz,
C-2 in Ph), 136.48 (2JP,C = 7.6 Hz, ipso-C in Ph).
31P NMR (121 MHz, CDCl3): d = 27.1.
ESI-MS: m/z = 146 (100) [M – P(O)(OEt)2]+.
31P NMR (121 MHz, CDCl3): d = 25.23.
Anal. Calcd for C13H21N2O3P: C, 54.92; H, 7.45; N, 9.85; P, 10.90.
Found: C, 54.97; H, 7.58; N, 10.02; P, 10.21.
Anal. Calcd for C15H24NO3P: C, 60.59; H, 8.14; N, 4.71; P, 10.42.
Found: C, 60.49; H, 8.14; N, 4.69; P, 10.05.
Diethyl [2-(2-Thienyl)pyrrolidin-2-yl]phosphonate (4e)
Obtained in Et2O as reaction solvent. Yield: 1.04 g (72%, crude),
0.84 g (58%, after column chromatography); yellowish oil.
Diethyl [2-(4-Tolyl)hexahydro-1H-azepin-2-yl]phosphonate (6)
Obtained in Et2O as reaction solvent. Yield: 1.38 g (85%, crude),
0.96 g (59%, after column chromatography); yellow oil.
IR (KBr): 965, 1023 and 1053 (P–O–C), 1237 (P=O), 1433, 1611,
2861, 2976, 3071, 3457 and 3466 (br) cm–1.
IR (KBr): 961, 1026 and 1055 (P–O–C), 1236 (P=O), 2854, 2925,
2979, 3373 (br) cm–1.
1H NMR (400 MHz, CDCl3): d = 1.20 and 1.26 (both t, 3JH,H = 7.1
Hz, 3 H + 3 H, 2 CH3CH2O), 1.72–1.83 (m, 1 H, cyclic CH2), 1.83–
1.94 (m, 1 H, cyclic CH2), 2.22–2.39 (br m, 2 H, NH + cyclic CH2),
2.42–2.54 (m, 1 H, cyclic CH2), 3.03–3.16 (m, 2 H, NCH2), 3.83–
1H NMR (400 MHz, CDCl3): d = 1.21 and 1.24 (both t, 3JH,H = 7.0
Hz, 3 H + 3 H, 2 CH3CH2O), 1.29–1.37 (m, 1 H, cyclic CH2), 1.47–
1.64 (m, 3 H, cyclic CH2), 1.73–1.82 (m, 1 H, cyclic CH2), 2.07 (br,
1 H, NH), 2.14–2.24 (m, 2 H, cyclic CH2), 2.31 (d, J = 1.9 Hz, 3 H,
CH3), 2.57–2.73 (m, 1 H + 1 H, cyclic CH2 + NCH2), 3.05–3.12 (m,
1 H, NCH2), 3.62–3.73, 3.79–3.88, and 3.93–4.04 (all m, 1 H + 1 H
3.94 and 3.95–4.16 (both m, 1 H + 3 H, 2 OCH2), 6.97 (dd, 3JH,H
=
4JP,H = 4.88 Hz, 1 H, =CH), 7.07 (apparent dt, J = 4.88, 1.21 Hz, 1
H, =CH), 7.17 (br d, 3JH,H = 4.88 Hz, 1 H, =CH).
+ 2 H, 2 OCH2), 7.13 (d, 3JH,H = 8.4 Hz, 2 CHAr), 7.46 (dd, 3JH,H
=
3
13C NMR (75 MHz, CDCl3): d = 16.38 (d, JP,C = 5.5 Hz,
8.4 Hz, 4JP,H = 2.5 Hz, 2 CHAr).
3
CH3CH2O), 25.38 (d, JP,C = 8.3 Hz, C-4), 37.70 (C-3), 47.03 (d,
3
13C NMR (75 MHz, CDCl3): d = 16.38 (d, JP,C = 4.8 Hz,
CH3CH2O), 20.93 (CH3), 23.18 (d, 3JP,C = 23.8 Hz, C-4), 29.99 (C-
5), 32.88 (C-6), 36.05 (C-3), 43.57 (d, 3JP,C = 11.8 Hz, C-7), 62.44
(d, 2JP,C = 7.6 Hz, OCH2), 62.96 (d, 2JP,C = 7.6 Hz, OCH2), 63.03 (d,
1JP,C = 148.8 Hz, C-2), 126.50 (ipso-C in Ph), 127.84 (d, 3JP,C = 4.8
Hz, C-2 in Ph), 128.59, 138.37 (CArCH3).
2
3JP,C = 9.0 Hz, C-5), 63.27 (d, JP,C = 7.1 Hz, OCH2), 63.78 (d,
1
2JP,C = 7.0 Hz, OCH2), 66.70 (d, JP,C = 158.5 Hz, C-2), 124.59,
124.79 (d, 2JP,C = 5.5 Hz), 127.37, 128.93 (d, 3JP,C = 9.0 Hz).
31P NMR (121 MHz, CDCl3): d = 25.4.
Anal. Calcd for C12H20NO3PS: C, 49.81; H, 6.97; P, 10.71. Found:
49.84; H, 6.59; P, 10.41.
31P NMR (121 MHz, CDCl3): d = 27.66.
Anal. Calcd for C17H28NO3P·0.25CHCl3: C, 58.32; H, 8.02; N, 3.94;
P, 8.72. Found: C, 58.72; H, 7.97; N, 3.90; P, 8.88.
Diethyl (2-Methylpiperidin-2-yl)phosphonate (5a)
Obtained in Et2O as reaction solvent. Yield: 1.08 g (92%, crude),
0.68 g (58%, after column chromatography), 0.92 g (78%, after
TLC purification); yellowish oil.
Pyrrolidin-2-yl-, Piperidin-2-yl-, and Hexahydro-1H-azepin-2-
ylphosphonic Acid Hydrobromides 7 and the Corresponding
Free Acids 8; General Procedure
IR (KBr): 957, 1029 and 1058 (P–O–C), 1096, 1238 (P=O), 1367,
1391, 1443, 2867, 2933 (NH), 2978, 3300, 3478 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.27–1.32 (m, 9 H, CH3), 1.42–
1.58 (m, 4 H, 2 cyclic CH2), 1.70 (br, 1 H, NH), 1.80–1.89 (m, 2 H,
cyclic CH2), 2.75–2.83 (m, 1 H, NCH2), 2.91–2.97 (m, 1 H, NCH2),
4.10–4.18 (m, 4 H, 2 OCH2).
A solution of TMSBr (0.72 g, 5 mmol) in CHCl3 (2 mL) was added
dropwise to a solution of the appropriate aminophosphonate (2
mmol) in CHCl3 (2 mL). The mixture was allowed to stir at r.t. over-
night, then the solvent was removed under reduced pressure (rotor
evaporator) and the residue was dissolved in MeOH (5 mL). Hydro-
bromides 7b–e were precipitated from MeOH as light-yellow sol-
ids, collected by filtration, and dried in vacuo. Because
hydrobromide 7a represented a very hydroscopic material, it was
additionally converted into the corresponding tert-butylammonium
13C NMR (101 MHz, CDCl3): d = 16.00 and 16.05 (both d, 3JP,C
=
3
2.3 Hz, CH3CH2O), 19.14 (d, JP,C = 8.8 Hz, C-4), 20.02 (CH3),
3
25.34 (C-3), 30.56 (C-5), 40.33 (d, JP,C = 9.9 Hz, C-6), 52.38 (d,
2
1JP,C = 154.0 Hz, C-2), 61.55 (d, JP,C = 7.3 Hz, OCH2), 61.61 (d,
2JP,C = 7.1 Hz, OCH2).
Synthesis 2009, No. 4, 577–582 © Thieme Stuttgart · New York

PAPER
Substituted Cyclic a-Aminophosphonates
581
salt by treatment with an excess of t-BuNH2 (0.3 g, 4 mmol), fol-
lowed by recrystallization (MeCN).
H, cyclic CH2), 3.95–3.98 (m, 2 H, NCH2), 7.47 (d, 3JH,H = 8.4 Hz,
2 CHAr), 7.75 (d, 3JH,H = 6.0 Hz, 2 CHAr).
To obtain free acids 8, propylene oxide (0.5 mL) was added to a so-
lution of isolated hydrobromide 7c or crude product 7d (2 mmol) in
EtOH (5 mL) at r.t., and the mixture was stirred overnight. The sol-
vent was then evaporated to half of the initial volume of the mixture,
Et2O was added (2 mL), and the precipitated acid was collected by
filtration and dried in vacuo.
31P NMR (121 MHz, D2O): d = 3.00.
Anal. Calcd for C13H20NO3P·0.25HBr: C, 53.93; H, 7.05; N, 4.84.
Found: C, 53.81; H, 6.68; N, 4.70.
(2-Pyridin-4-ylpyrrolidin-2-yl)phosphonic Acid (8a)
Yield: 0.47 g (82%); yellowish solid; mp 243–244 °C.
IR (KBr): 564, 895, 920, 1011, 1069, 1100, 1204 (P=O), 1425,
(2-Butylpyrrolidin-2-yl)phosphonic Acid tert-Butylammonium
Salt Hydrobromide (7a)
1606, 1628 (>NH2 ), 2396, 2444, 2773, 2937, 2979 cm–1.
+
1H NMR (400 MHz, D2O): d = 1.92–2.10 (m, 1 H, cyclic CH2),
2.25–2.43 (m, 1 H, cyclic CH2), 2.44–2.61 (m, 1 H, cyclic CH2),
2.80–2.95 (m, 1 H, cyclic CH2), 3.40–3.51 (m, 1 H, NCH2), 3.61–
3.76 (m, 1 H, NCH2), 7.73 (s, 2 H, py), 8.60 (s, 2 H, py).
13C NMR (101 MHz, D2O): d = 22.47 (C-4), 33.00 (C-3), 46.10 (C-
5), 71.34 (d, 1JP,C = 124.0 Hz, C-2), 123.38 (CH in py), 141.5 (CHN
in py), 153.25 (d, 2JP,C = 12.3 Hz, ipso-C in py).
Yield: 0.61g (85%); light-yellow crystalline solid; mp 145–146 °C.
1H NMR (300 MHz, D2O): d = 0.75 (t, 3JH,H = 7.1 Hz, 3 H, CH3),
1.22 (s, 9 H, CH3 in t-Bu), overlapped with 1.15–1.39 [m, 4 H,
CH3(CH2)2], 1.62–1.76 [m, 2 H, CH3(CH2)2CH2], 1.86–2.02 (m, 3
H, cyclic CH2), 2.04–2.19 (m, 1 H, cyclic CH2), 3.22 (t, 3JH,H = 6.3
Hz, 2 H, NCH2).
13C NMR (75 MHz, D2O): d = 13.59 (CH3CH2), 22.90 (CH3CH2),
24.39 (d, 3JP,C = 5.6 Hz, CH3CH2CH2), 26.43 (d, 3JP,C = 4.2 Hz, C-
4), 27.10 [C(CH3)3], 31.83 (C-3), 34.92 [CH3(CH2)2CH2], 46.80 (C-
5), 52.27 [C(CH3)3], 68.04 (d, 1JP,C = 142.0 Hz, C-2).
31P NMR (162 MHz, D2O): d = 9.65.
Anal. Calcd for C9H13N2O3P·0.5H2O: C, 45.57; H, 5.95; N, 11.81.
Found: C, 45.16; H, 5.42; N, 11.74.
31P NMR (121 MHz, D2O): d = 16.6.
(2-Phenylpiperidin-2-yl)phosphonic Acid (8b)
Yield: 0.40 g (84%); white solid; mp 253–254 °C.
Anal. Calcd for C12H29N2O3P·HBr: C, 39.90; H, 8.37; N, 7.75.
Found: C, 39.99; H, 8.24; N, 7.82.
IR (KBr): 575, 943, 1044, 1066, 1088, 1172, 1222 (P=O), 1446,
+
1462, 1629 (>NH2 ), 2321, 2455, 2574, 2687, 2737, 2939 cm–1.
(2-Phenylpyrrolidin-2-yl)phosphonic Acid Hydrobromide (7b)
Yield: 0.57 g (92%); light-brown solid; mp 116 °C.
1H NMR (300 MHz, D2O): d = 1.73–1.98 (m, 1 H, cyclic CH2),
1.99–2.26 (m, 1 H, cyclic CH2), 2.28–2.74 (m, 2 H, cyclic CH2),
3.12–3.31 (m, 1 H, NCH2), 3.32–3.53 (m, 1 H, NCH2), 7.26 (br m,
5 H, C6H5).
1H NMR (300 MHz, D2O): d = 1.41–1.58 (m, 1 H, cyclic CH2),
1.60–1.88 (m, 3 H, cyclic CH2), 2.16–2.27 (m, 1 H, cyclic CH2),
2.66–2.75 (m, 1 H, cyclic CH2), 2.93–3.14 (m, 1 H, NCH2), 3.18–
3.28 (m, 1 H, NCH2), 7.34–7.52 (m, 5 H, 5 CHAr).
13C NMR (75 MHz, HCl–DMSO-d6): d (HCl salt) = 17.30 (d, C-4,
3JP,C = 7.7 Hz), 21.38 (C-3), 26.91 (C-5), 41.16 (d, 3JP,C = 13.1 Hz,
C-6), 60.39 (d, C-2, 1JP,C = 146.5 Hz), 127.91 (CHAr), 128.42 (p-C
in Ph), 129.06 (CHAr), 131.33 (ipso-C in Ph).
13C NMR (75 MHz, D2O): d = 22.50 (d, 3JP,C = 4.2 Hz, C-4), 32.96
1
(C-3), 46.01 (C-5), 70.75 (d, JP,C = 140.1 Hz, C-2), 127.02 (d,
5
3JP,C = 4.2 Hz, C-2 in Ph), 128.83 (d, JP,C = 2.8 Hz, C-4 in Ph),
129.10 (C-3 in Ph), 136.16 (d, 2JP,C = 2.8 Hz, ipso-C in Ph).
31P NMR (121 MHz, D2O): d = 14.3.
31P NMR (121 MHz, D2O): d = 12.4.
Anal. Calcd for C11H16NO3P·0.5H2O: C, 52.80; H, 6.85; N, 5.60.
Found: C, 52.51; H, 6.61; N, 5.26.
Anal. Calcd for C10H14NO3P·HBr: C, 38.98; H, 4.91; N, 4.55.
Found: C, 39.21; H, 5.01; N, 4.39.
(2-Pyridin-4-ylpyrrolidin-2-yl)phosphonic Acid Hydrobromide
(7c)
Acknowledgment
The authors thank the Deutsche Forschungsgemeinschaft (grant
nos. 436 RUS 113/812/0-1 and 436 RUS 113/905/0-1) and the
Russian Foundation of Basic Research (grant 06-03-04003).
Yield: 0.58 g (94%); light-brown solid; mp 214–215 °C (MeCN–
EtOH, 8:2).
1H NMR (400 MHz, D2O): d = 2.05–2.18 (m, 1 H, cyclic CH2),
2.35–2.46 (m, 1 H, cyclic CH2), 2.53–2.67 (m, 1 H, cyclic CH2),
2.90–3.01 (m, 1 H, cyclic CH2), 3.50–3.57 (m, 1 H, NCH2), 3.68–
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3
3.75 (m, 1 H, NCH2), 8.07 (d, JH,H = 7.0 Hz, 2 H, py), 8.83 (d,
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Synthesis 2009, No. 4, 577–582 © Thieme Stuttgart · New York