A Straightforward Synthesis of Six-Membered-Ring Heterocyclic α-Aminophosphonic Acids from N-Acyliminium Ions

Article abstract of DOI:10.1002/jhet.3593

A convenient synthesis of phosphonic analogues of pipecolic acid and its heterocyclic analogues is reported. The major step of the elaborated procedure is the introduction of the phosphonate group into the skeleton of the appropriate cyclic amide through N-acyliminium ions. The former ones were obtained by preparation of the hemiaminals or their methyl ethers from the N-protected cyclic amides. Finally, the reaction with trimethyl phosphite in the presence of BF₃·OEt₂ afforded the desired phosphonates, which were converted into phosphonic acids by the hydrolysis of phosphonate moiety with simultaneous cleavage of the nitrogen protecting groups.

Full text of DOI:10.1002/jhet.3593

Month 2019
A Straightforward Synthesis of Six-Membered-Ring Heterocyclic α-
Aminophosphonic Acids from N-Acyliminium Ions
Rubén Oswaldo Argüello-Velasco,a
Grecia Katherine Sánchez-Muñoz,a
José Luis Viveros-Ceballos,a
a
b
*
*
Mario Ordóñez,
and Pawel Kafarski
aCentro de Investigaciones Químicas-IICBA, Universidad Autónoma del Estado de Morelos, Avenue Universidad 1001,
62209, Cuernavaca, Morelos, Mexico
bDepartment of Bioorganic Chemistry, Wroclaw University of Science and Technology, Wybrzeże Wyspiańskiego 27, 50-
370, Wrocław, Poland
*E-mail: palacios@uaem.mx; pawel.kafarski@pwr.wroc.pl
Received December 10, 2018
DOI 10.1002/jhet.3593
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
A convenient synthesis of phosphonic analogues of pipecolic acid and its heterocyclic analogues is re-
ported. The major step of the elaborated procedure is the introduction of the phosphonate group into the skel-
eton of the appropriate cyclic amide through N-acyliminium ions. The former ones were obtained by
preparation of the hemiaminals or their methyl ethers from the N-protected cyclic amides. Finally, the reac-
tion with trimethyl phosphite in the presence of BF3·OEt2 afforded the desired phosphonates, which were
converted into phosphonic acids by the hydrolysis of phosphonate moiety with simultaneous cleavage of
the nitrogen protecting groups.
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
as precursors for the preparation of more complex
scaffolds exhibiting pharmacological activities [20–24]
or acting as organocatalysts [25–27]. The preparation of
their phosphonic analogues 5–8 has not been explored
sufficiently with scarce reports being published so far
[28–34], despite the acknowledgement of the importance
of α-aminophosphonic acids and their derivatives in
organic and medicinal chemistry [35–38]. Hence, there is
still strong need to develop new procedures for the
preparation of this class of compounds [39–41].
The development of new peptidomimetics is now
receiving substantial interest because these compounds
might be considered as mimics of therapeutic peptides in
their preferable conformations. The introduction of such
scaffolds usually results in their greater bioavailability
and stability and limits undesirable physiologic effects.
In this regard, the synthesis of conformationally restricted
amino acids, where the nitrogen is introduced into
aliphatic ring, has been the focus of extensive search as
they may induce secondary structural and functional
alterations in peptidomimetics, becoming synthetic tools
for drug discovery [1–3]. It is well known that the
presence of proline in peptide chain is crucial for
protein structural and dynamic properties; thence, cyclic
amino acids attract increasing attention in medicinal
chemistry, and thus, structurally variable six-membered-
ring heterocyclic amino acids have been introduced
as building blocks for the preparation of bioactive
compounds [4–7]. Thus, intensive research efforts
have been dedicated to their preparation, particularly
pipecolic acid 1 [8–11], piperazine-2-carboxylic acid
2 [12–14], morpholine-3-carboxylic acid 3 [15,16],
Considering the possible importance of these non-
proteinogenic amino acids analogues, which is in line
with our current research interest in the synthesis of
conformationally restricted α-aminophosphonic acids
[42–45], we now report a straightforward synthesis of
phosphopipecolic acid 5, piperazine-2-phosphonic acid 6,
morpholine-3-phosphonic acid 7, and thiomorpholine-3-
phosphonic acid 8. N-Acyliminium ions were chosen as
key substrates here.
and thiomorpholine-3-carboxylic acid
Additionally, these cyclic amino acids have also been used
4
[17–19].
© 2019 Wiley Periodicals, Inc.

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R. O. Argüello-Velasco, G. K. Sánchez-Muñoz, J. L. Viveros-Ceballos, M. Ordóñez, and P. Kafarski
Scheme 2. Synthesis of N-Boc protected cyclic amides 13–16.
RESULTS AND DISCUSSION
Retrosynthetic analysis of possible procedures leading to
acids 5–8 indicated the N-acyliminium ions as appropriate
precursors. Preparation of N-acyliminium ions might be
achieved on a synthetic pathway composed of (i)
reduction of the carbonyl group of imides obtained
from the corresponding cyclic amides leading to
hemiaminals (Y = OH) and (ii) their conversion into
appropriate methyl ethers (Y = OMe), (iii) followed by
their transformation into N-acyliminium ions by means
of elimination reaction. Action of phosphite allows the
incorporation of the phosphonate functionality into the
α position to a nitrogen atom [34]. The excellent results
in our previous work [42–45] stimulated our interest in
the use of N-acyliminium ions for the synthesis of the
target compounds (Scheme 1).
In order to protect reactive nitrogen atom from substrate
lactams tert-butoxycarbonyl (Boc) group was selected
because its subsequent deprotection to generate the amino
function can be accomplished under mild conditions. In
order to avoid interference of the amino group at N-4
position in the piperazine derivative (X = NH), we
decided to use the N-Cbz-2-ketopiperazine 10 as starting
material, considering that orthogonal deprotection could
be valuable in further potential applications of this
compound for the preparation of peptidomimetics. In
this context, and following the protocol described in
the literature [46], the cyclic amides 9–12 were reacted
with (Boc)2O, Et3N, and 4-(dimethylamino)pyridine
(DMAP) in CH2Cl2 at room temperature, yielding N-Boc
protected derivatives 13–16 in moderate to excellent
yields (Scheme 2).
without isolation of the intermediates. Thus, we carried out
the reduction of carbonyl function of the N-Boc protected
cyclic amides 13–16 with sodium borohydride in a
MeOH:CH2Cl2 mixture at À15°C, obtaining the
hemiaminals [47]. As hemiaminal derivatization to its
methyl ether was used previously as N-acyliminium
reagent in the synthesis of cyclic amino acids [34,48], we
had treated unisolated hemiaminals with methanol in
the presence of catalytic amounts of pyridinium p-
toluenesulfonate to obtain the corresponding hemiaminal
methyl ethers. These ethers were reacted with trimethyl
phosphite in the presence of boron trifluoride etherate
(BF3·OEt2) in dichloromethane at À78°C and afforded
the cyclic N-Boc α-aminophosphonates 17–20 in 23 to
86% yield (Scheme 3).
In order to reduce the number of synthetic steps of the
procedure and taking into consideration reports that
describe that Lewis acids can mediate the direct addition
of nucleophiles to hemiaminals [49–51], we carried out
the reduction of the carbonyl function in the N-Boc
protected cyclic amides 13–16 with sodium borohydride
in a MeOH:CH2Cl2 mixture at À15°C, which resulted in
the corresponding hemiaminals [47], which without
Once the N-Boc protected cyclic amides 13–16 were
obtained, the incorporation of phosphonate group was
carried out in the next step. Thus, the amide functionality
in 13–16 was transformed into the desired cyclic α-
aminophosphonates 17–20 by three consecutive steps
Scheme 3. Synthesis of cyclic N-Boc α-aminophosphonates 17–20.
Scheme 1. Retrosynthetic analysis of phosphonic acids 5–8. [Color figure
can be viewed at wileyonlinelibrary.com]
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α-Aminophosphonic Acids and N-acyliminium Chemistry
Scheme 4. Short synthesis of N-Boc protected α-aminophosphonates 17–
20.
based on the reduction of N-Boc protected cyclic amides
13–16 and later use of hemiaminals or their corresponding
methyl ethers as substrates for in situ generation of
N-acyliminium ions. Direct reaction of these ions with
trimethyl phosphite gave desired phosphonic analogues of
heterocyclic amino acids. The use of hemiaminals as
substrates resulted in a shorter route of reaction, however,
on the cost of lower chemical yield. The total cleavage of
the protecting groups (from both phosphonate and amino
moieties) was accomplished by acidolysis by hydrogen
bromide in glacial acetic acid. The obtained results
show the utility of the N-acyliminium ions as valuable
intermediates for the synthesis of novel scaffolds, which
are of interest for medicinal and organic chemistry.
EXPERIMENTAL
Scheme 5. Preparation of the target compounds 5–8.
All commercial materials were used as received unless
otherwise noted. Flash chromatography was performed
with 230–400 mesh Silica Flash 60. Thin-layer
chromatography was performed with pre-coated TLC
sheets of silica gel (60 F254, Merck, Kenilworth, NJ), and
the plates were visualized with UV light and ninhydrin.
Melting points were determined with a Fisher–Johns
apparatus and are uncorrected. NMR spectra were
recorded on a Varian instrument (400 MHz for 1H;
Varian, Inc., Palo Alto, CA) or a Mercury instrument
purification were reacted with trimethyl phosphite using
boron trifluoride diethyl ether (BF3·OEt2) as catalyst.
Reaction carried out in dichloromethane at À78°C
yielded cyclic N-Boc α-aminophosphonates 17–20 in 21
to 87% yield. The synthesis of compounds similar to 17
and 18 through radical fragmentation-phosphorylation
reaction from heterocyclic α-amino acids [33] has already
been described in the literature. The new procedure
described in this article provides a proof of concept of a
general alternative, which might be especially useful
when the parent α-amino acids are unavailable (Scheme 4).
Total removal of the protecting groups in 17–20
(hydrolysis of phosphonic ester moiety and removal of
Boc from nitrogen) was accomplished through acidolysis
with a 33% solution of hydrogen bromide in glacial
acetic acid. Treatment of ethanolic solutions of obtained
hydrobromides with propylene oxide resulted in obtaining
corresponding heterocyclic α-aminophosphonic acids 5–8
in good yields (Scheme 5).
1
(200 MHz for H) and calibrated using tetramethylsilane,
P(O)Ph3, and the residual solvent signal as internal
standards; chemical shifts (δ) are expressed in parts per
million (ppm) and coupling constants (J) in Hertz, and an
asterisk (*) indicates a duplicate signal corresponding to
the minor rotamer. High-resolution FAB+ and CI+ mass
spectra [high-resolution mass spectrometry (HRMS)]
1
were obtained on a JEOL MStation MS-700. H and 13C
NMR data for the compounds 13–15 [46,52,53] and 5
[54] were identical to those described in the literature.
tert-Butyl 3-oxothiomorpholine-4-carboxylate (16). To a
solution of 12 (0.3 g, 2.6 mmol), Et3N (0.26 g, 0.4 mL,
2.6 mmol), and DMAP (0.31 g, 2.6 mmol) in CH2Cl2
(13 mL) was slowly added di-tert-butyl dicarbonate
(0.84 g, 3.8 mmol). The reaction mixture was stirred at
room temperature for 16 h, then diluted with CH2Cl2, and
washed with a saturated solution of NaHCO3. The
organic layer was washed with water and brine, dried
over anhydrous Na2SO4, filtered, and evaporated under
reduced pressure. The crude product was purified by flash
chromatography to give 0.523 g (94%) of 16 as a white
solid; m.p. 52–54°C. 1H NMR (500 MHz, CDCl3):
δ = 1.54 (s, 9H, C (CH3)3), 2.96–2.99 (m, 2H, H-6), 3.34
(s, 2H, H-2), 4.03–4.09 (m, 2H, H-5). 13C NMR
(126 MHz, CDCl3): δ = 26.4 (C-6), 28.2 ((CH3)3C), 31.6
(C-2), 44.2 (C-5), 84.1 (C (CH3)3), 151.9 (C═O), 168.0
CONCLUSIONS
A new general, practical, and efficient procedure for the
synthesis of phosphopipecolic acid 5, piperazine-2-
phosphonic acid 6, morpholine-3-phosphonic acid 7, and
thiomorpholine-3-phosphonic acid 8 was elaborated. It is
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R. O. Argüello-Velasco, G. K. Sánchez-Muñoz, J. L. Viveros-Ceballos, M. Ordóñez, and P. Kafarski
(C═O). HRMS (FAB+): calcd. for C9H16NO3S [M + H]+,
m/z 218.0851; found for [M + H]+, m/z 218.0867.
3), 3.08–3.25 (m, 1H, H-5), 3.35 (bs, 1H, H-6), 3.66 (d,
J = 10.9 Hz, 6H, (CH3O)2P), 3.90 (bs, 1H, H-6), 4.08–
4.16 (m, 1H, H-3), 4.45–4.56 (m, 2H, H-2, H-5), 5.14 (d,
J = 12.5 Hz, 1H, CH2Ph), 5.18 (d, J = 12.5 Hz, 1H,
CH2Ph), 7.25–7.41 (m, 5H, Harom). 13C NMR (100 MHz,
CDCl3): δ = 28.4 ((CH3)3C), 41.1 (C-6), 42.6 (C-5), 43.3
(C-3), 46.8 (d, J = 158.2 Hz, C-2), 52.8 (d, J = 7.2 Hz,
(CH3O)2P), 53.0 (d, J = 7.1 Hz, (CH3O)2P), 67.6
(CH2Ph), 81.3 (C (CH3)3), 128.2, 128.6, 136.6, 155.1
(C═O). 31P NMR (81 MHz, CDCl3): δ = 21.9, 22.8*.
HRMS (FAB+): calcd. for C19H30N2O7P [M + H]+, m/z
429.1791; found for [M + H]+, m/z 429.1799.
General procedure for the preparation of cyclic N-Boc α-
aminophosphonates 17–20. To a stirred solution of the
appropriate N-Boc protected cyclic amide (0.2 g, 1 eq) in
MeOH:CH2Cl2 (3:1, 8 mL) at 0°C was slowly added
NaBH4 (3 eq). The reaction mixture was stirred at 0°C
for 1.0 h and then quenched by the successive addition
of a saturated aqueous NaHCO3 (5 mL) and brine
(5 mL). The aqueous layer was extracted with CH2Cl2
(3 × 20 mL). The combined organic extracts were
washed with brine (10 mL), dried over anhydrous
Na2SO4, filtered, and evaporated under reduced pressure
to obtain the corresponding hemiaminal as a colorless oil.
It was dissolved in MeOH (7 mL), and catalytic amounts
of pyridinium p-toluenesulfonate (0.1 eq) were added.
The mixture was allowed to reach at room temperature
and stirred for an additional 2 h. The reaction was
quenched with Et3N (0.1 eq), and the solvent was
evaporated under reduced pressure, to give the
hemiaminal methyl ether as a colorless oil, which was
dissolved in anhydrous CH2Cl2 (5 mL) and kept under
nitrogen. Trimethyl phosphite (2 eq) was added, and the
resulting solution was cooled at À78°C. Boron trifluoride
diethyl ether (2 eq) was added dropwise, and the reaction
mixture was stirred for 1.0 h at À78°C, 1.0 h at 0°C, and
1 h at room temperature. The reaction was then quenched
with water and extracted with CH2Cl2 (2 × 20 mL). The
combined organic layers were washed with brine, dried
over anhydrous Na2SO4, filtered, and evaporated under
reduced pressure. Finally, the crude product was purified
by flash column chromatography.
Dimethyl 4-(tert-butoxycarbonyl)morpholine-3-phosphonate
1
(19). Colorless oil (0.254 g, 86%). H NMR (500 MHz,
CDCl3): δ = 1.30 (s, 9H, C (CH3)3), 3.28–3.59 (m, 2H,
H-5, H-6), 3.63* (dd, J = 12.16 Hz, 1H, H-2), 3.70 (dd,
J = 12.18 Hz, 1H, H-2), 3.79 (d, J = 10.7 Hz, 6H,
(CH3O)2P), 3.82* (d, J = 10.7 Hz, 6H, (CH3O)2P), 3.85–
3.98 (m, 1H, H-5), 4.21–4.36 (m, 1H, H-2), 4.37–4.54
(m, 1H, H-3). 13C NMR (125 MHz, CDCl3): δ = 28.5
((CH3)3C), 40.2* (C-6), 41.7 (C-6), 47.8 (d,
J = 148.8 Hz, C-3), 49.9* (d, J = 140.1 Hz, C-3), 53.0
((CH3O)2P), 53.1 ((CH3O)2P), 65.7 (C-2), 66.8 (C-6),
81.1 (C (CH3)3), 154.4 (C═O). 31P NMR (202 MHz,
CDCl3) δ = 30.5. HRMS (FAB+): calcd. for C11H23NO6P
[M + H]+, m/z 296.1263; found for [M + H]+, m/z
296.1277.
Dimethyl
4-(tert-butoxycarbonyl)thiomorpholine-3-
1
phosphonate (20). Yellow oil (0.071 g, 23%). H NMR
(500 MHz, CDCl3): δ = 1.40 (s, 9H, C (CH3)3), 2.43* (s,
1H, H-6), 2.46 (s, 1H, H-6), 2.59–2.63 (m, 1H, H-6),
2.64–2.71* (m, 1H, H-6), 2.81–2.90* (m, 2H, H-2),
2.90–2.95 (m, 2H, H-2), 3.21–3.44* (m, 1H, H-5), 3.44–
3.64 (m, 1H, H-5), 3.72 (d, J = 10.7 Hz, 6H, (CH3O)2P),
3.77* (d, J = 10.6 Hz, 6H, (CH3O)2P), 4–06-4.25 (m,
1H, H-5), 4.25–4.50* (m, 1H, H-5), 4.66–4.87* (m, 1H,
H-3), 4.87–5.19 (m, 1H, H-3). 13C NMR (126 MHz,
CDCl3): δ = 26.3 (C-2), 27.2 (C-6), 28.4 ((CH3)3C),
40.7* (C-5), 42.1 (C-5),47.8 (d, J = 154.6 Hz, C-3),
49.9* (d, J = 156.3 Hz, C-3), 52.9 ((CH3O)2P), 53.2
((CH3O)2P), 81.2 (C (CH3)3), 154.7 (C═O). 31P NMR
(202 MHz, CDCl3) δ = 25.7. HRMS (FAB+): calcd. for
C11H23NO5PS [M + H]+, m/z 312.1035; found for
[M + H]+, m/z 312.1035.
Dimethyl 1-(tert-butoxycarbonyl)piperidine-2-phosphonate
1
(17).
White solid (0.243 g, 83%); m.p. 50–52°C. H
NMR (500 MHz, CDCl3): δ = 1.24–1.30* (m, 1H, H-4),
1.41 (s, 9H, C (CH3)3), 1.55–1.59* (m, 2H, H-3, H-4),
1.78–1.83 (m, 1H, H-5), 1.83–1.89 (m, 1H, H-5)* 1.93–
2.03 (m, 1H, H-6), 2.03–2.13* (m, 1H, H-6), 2.90–3.09*
(m, 1H, H-3), 3.10–3.22 (m, 1H, H-3), 3.71 (d,
J = 10.6 Hz, 6H, (CH3O)2P), 3.86–4.00 (m, 1H, H-6),
4.00–4.12* (m, 1H, H-6), 4.43–4.60* (m, 1H, H-2),
4.60–4.78 (m, 1H, H-2). 13C NMR (126 MHz, CDCl3):
δ = 20.4 (C-5), 24.7 (C-6), 25.4 (C-4), 28.5 ((CH3)3C),
40.7* (C-3), 42.0 (C-3), 46.9 (d, J = 148.5 Hz, C-2),
48.8* (d, J = 149.4 Hz, C-2), 52.7 (d, J = 6.1 Hz,
(CH3O)2P), 53.0 (d, J = 6.9 Hz, (CH3O)2P), 80.4 (C
(CH3)3), 155.0 (C═O). 31P NMR (202 MHz, CDCl3)
δ = 28.0. HRMS (FAB+): calcd. for C12H25NO5P
[M + H]+, m/z 294.1470; found for [M + H]+, m/z
294.1437.
General procedure for the preparation of heterocyclic α-
aminophosphonic acids 5–8.
The appropriate cyclic α-
aminophosphonate (0.2 g, 1 eq) was treated with a 33%
solution of hydrogen bromide in acetic acid (10 mL). The
reaction mixture was stirred at room temperature for 4 h,
and the volatiles were evaporated under reduced pressure.
The crude product was dissolved in the minimal amount
of ethanol, and the resulting solution was treated with
propylene oxide and stirred at room temperature for 12 h.
The precipitate formed was filtered; washed successively
Dimethyl
4-(benzyloxycarbonyl)-1-(tert-butoxycarbonyl)
piperazine-2-phosphonate (18).
White solid (0.64 g,
85%); m.p. 88–90°C. 1H NMR (400 MHz, CDCl3,
50°C): δ = 1.47 (s, 9H, C (CH3)3), 2.79–2.92 (m, 1H, H-
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α-Aminophosphonic Acids and N-acyliminium Chemistry
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with CH2Cl2, AcOEt, and MeOH; and dried under reduced
pressure.
Piperazine-2-phosphonic acid (6). White solid (0.163 g,
99%); m.p. 270–272°C. 1H NMR (400 MHz, D2O):
δ = 3.05–3.23 (m, 4H, H-2, H-5, H-6), 3.31–3.44 (m, 2H,
H-3, H-6), 3.45–3.55 (m, 1H, H-3). 13C NMR (100 MHz,
D2O): δ = 40.5 (C-6), 41.1 (C-5), 43.0 (C-3), 51.0 (d,
J = 127.9 Hz, C-2). 31P NMR (81 MHz, D2O): δ = 5.7.
HRMS (FAB+): calcd. for C4H12N2O3P [M + H]+, m/z
167.0586; found for [M + H]+, m/z 167.0827.
Morpholine-3-phosphonic acid (7). White solid (0.152 g,
95%); m.p. 261–265°C. 1H NMR (500 MHz, D2O):
δ = 3.25–3.33 (m, 1H, H-3), 3.34–3.40 (m, 1H, H-5),
3.48–3.55 (m, 1H, H-5), 3.79–3.87 (m, 2H, H-6), 4.06–
4.12 (m, 1H, H-2), 4.20–4.26 (m, 1H, H-2). 13C NMR
(126 MHz, D2O): δ = 44.1 (C-5), 53.2 (d, J = 133.7 Hz,
C-3), 63.4 (C-6), 65.2 (C-2). 31P NMR (202 MHz, D2O):
δ = 6.8. HRMS (FAB+): calcd. for C4H10NO4PNa
[M + Na]+, m/z 190.0245; found for [M + Na]+, m/z
190.0241.
Thiomorpholine-3-phosphonic acid (8).
White solid
1
(0.150 g, 76%); m.p. 255–258°C. H NMR (500 MHz,
D2O): δ = 2.11–2.18 (m, 1H, H5), 2.32–2.40 (m, 1H,
H5), 2.52–2.57 (m, 4H, H2, H3, H6), 2.96–3.03 (m,
1H, H2). 13C NMR (125 MHz, D2O): δ = 26.46 (C5),
28.27 (C6), 47.76 (d, J = 11.7 Hz, C2), 58.04 (d,
J = 137.1 Hz, C3). 31P NMR (202 MHz, D2O):
δ = 15.20. HRMS (FAB+): calcd. for C4H10NO3PSNa
[M + Na]+, m/z 206.0017; found for [M + Na]+, m/z
206.0010.
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Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet