A novel synthesis of 1-aminoalkanephosphonic acid derivatives from 1-(N-acylamino)-alkyltriphenylphosphonium salts

Article abstract of DOI:10.1080/10426500903436735

Efficient and convenient procedures for the -amidoalkylation of trialkylphosphites with 1-(N-acylamino)alkyltriphenylphosphonium salts followed by a Michaelis-Arbuzov-type reaction to afford 1-(N-acylamino)alkanephosphonic acid esters have been developed.

Full text of DOI:10.1080/10426500903436735

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Phosphorus, Sulfur, and Silicon and the
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A Novel Synthesis of 1-
Aminoalkanephosphonic Acid
Derivatives from 1-(N-Acylamino)-
alkyltriphenylphosphonium Salts
Roman Mazurkiewicz a , Agnieszka Październiok-Holewa a & Alicja
Kononienko a
a Department of Organic Chemistry, Biochemistry and
Biotechnology , Silesian University of Technology , Gliwice, Poland
Published online: 25 Aug 2010.
To cite this article: Roman Mazurkiewicz , Agnieszka Październiok-Holewa & Alicja Kononienko
(2010) A Novel Synthesis of 1-Aminoalkanephosphonic Acid Derivatives from 1-(N-Acylamino)-
alkyltriphenylphosphonium Salts, Phosphorus, Sulfur, and Silicon and the Related Elements, 185:9,
1986-1992, DOI: 10.1080/10426500903436735
To link to this article: http://dx.doi.org/10.1080/10426500903436735
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Phosphorus, Sulfur, and Silicon, 185:1986–1992, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500903436735
A NOVEL SYNTHESIS OF 1-AMINOALKANEPHOSPHONIC
ACID DERIVATIVES FROM 1-(N-ACYLAMINO)-
ALKYLTRIPHENYLPHOSPHONIUM SALTS
Roman Mazurkiewicz, Agnieszka Paz´dzierniok-Holewa,
and Alicja Kononienko
Department of Organic Chemistry, Biochemistry and Biotechnology,
Silesian University of Technology, Gliwice, Poland
Efficient and convenient procedures for the α-amidoalkylation of trialkylphosphites with
1-(N-acylamino)alkyltriphenylphosphonium salts followed by a Michaelis–Arbuzov-type re-
action to afford 1-(N-acylamino)alkanephosphonic acid esters have been developed. High
yields and simple isolation and purification protocols are the main advantages of this method.
Keywords 1-(N-Acylamino)alkanephosphonic acid esters; 1-(N-acylamino)alkyltriphenyl-
phosphonium salts; α-amidoalkylation; Michaelis–Arbuzov rearrangement; phosphorus
mimetics of α-amino acids
INTRODUCTION
1-Aminoalkanephosphonic acids, as structural analogues and mimetics of α-amino
acids, display a broad spectrum of biological activity, and therefore are currently of
significant interest to the chemical and biological communities.1–3 Various methods
for their synthesis have been reported. One of the most important approaches to 1-
aminoalkanephosphonic acids consists in the Michaelis–Arbuzov reaction of trialkyl phos-
phites with amidoalkylating agents.1,4–9
Recently, we described simple and effective syntheses of 1-(N-acylamino)alkyltriphe-
nylphosphonium salts 310,11 from easily accessible 4-phosphoranylidene-5(4H)-oxazolones
112 or their alkylation products 213 (Scheme 1). The obtained phosphonium salts are stable,
crystalline compounds and can be prepared on kilogram scale using these procedures.
We have also demonstrated that 1-(N-acylamino)alkyltriphenylphosphonium salts can be
considered as N-acylimine precursors, and therefore, strong α-amidoalkylating agents that
are able to react with a wide variety of nucleophiles.14
Received 14 September 2009; accepted 23 October 2009.
The financial help of the Ministry of Science and Higher Education of Poland (Grant No. N N204 238334)
is gratefully acknowledged.
Address correspondence to Agnieszka Paz´dzierniok-Holewa, Department of Organic Chemistry, Biochem-
istry and Biotechnology, Silesian University of Technology, Krzywoustego 4, PL 44-100, Gliwice, Poland. E-mail:
agnieszka.pazdzierniok@polsl.pl
1986

1-AMINOALKANEPHOSPHONIC ACID DERIVATIVES
1987
O
Ph3P
O
N
R1
HBF4
1
O
PPh3 X
H2O
R2Y
R1
N
H
R2
3
R2
O
Ph3P
1
O
Y
t
R = -Bu, Ph, Me
N
R2 = H, Me, CH2OMe, CH2CN, CH2C CH
R1
Y = I or Br; X = BF4, I or Br
2
Scheme 1
In this article, we describe the application of 1-(N-acylamino)alkyltriphenyl
phosphonium salts 3a–f to the amidoalkylation of trialkylphosphites followed by a
Michaelis–Arbuzov-type dealkylation that yields 1-(N-acylamino)alkanephosphonic acid
esters 4a–f (Scheme 2).
O
P(OR3)2
R2
O
P(OR3)3
R2
I
O
PPh3 X
R2 -Ph3P
O
i
R1
N
H
N
H
R1
N
H
4a-f
R1
-R3I
3a-f
R3I
+
Ph3P
R3PPh3 I
3
i
i
: Procedure A: P(OR )3, ( -Pr)2EtN, MePPh3 I
3
i
Procedure B: P(OR )3, ( -Pr)2EtN
Scheme 2
RESULTS AND DISCUSSION
N-Acylaminomethyltriphenylphosphonium tetrafluoroborates 3a–c (R2 = H, X =
BF4) react smoothly with trialkylphosphites in dichloromethane in the presence of triphe-
nylmethylphosphonium iodide (0.25 mol/mol of 3a–c) and catalytic amounts of Hu¨nig’s
base [(i-Pr)2EtN] at 50–60◦C to give N-acylaminometanephosphonic acid esters 4a–c in
good to excellent yields (Table I, procedure A). The use of a catalytic base is crucial for ob-
taining high yields and accelerating the reaction. A substoichiometric amount of triphenyl-
methylphosphonium iodide, which was found to be the optimum iodide anion source, is nec-
essary in order to transform the intermediate trialkoxyphosphonium salt into the phosphonic
acid esters via a Michaelis–Arbusov-type dealkylation (Scheme 2). Obviously, no additional

1988

1989

1990
R. MAZURKIEWICZ ET AL.
iodide anion source was needed in the case of 1-(N-acylamino)alkyltriphenylphosphonium
iodides 3d–f (R2 = H, X = I) (Table I, procedure B).
The 1-aminoalkanephosphonic acid esters were isolated from the reaction mixture and
purified by evaporation of CH2Cl2, extraction of the crude product from the resulting residue
with toluene, evaporation of toluene, and finally recrystallization of the product. Only
in the case of diethyl 1-(N-benzoylamino)ethanephosphonate 4e was additional column
chromatography required.
In addition, we have also demonstrated the applicability of procedure B for the
synthesis of the α-aminoethenephosphonic acid derivative 6 (Scheme 3); however, in this
case the yield of the reaction was poor.
O
O
O
Procedure B
P(OMe)3
O
PPh
3 I
O
P(OMe)2
H2O
Ph3P
I
O
t-Bu
N
H
N
t
N
H
-Bu
- MeOH
Lit.11
- MePPh3 I
t-Bu
2f
5
6
48%
Scheme 3
The structures of all reported 1-(N-acylamino)alkanephosphonic acid esters were
confirmed by their spectroscopic properties (IR, 1H, and 13C NMR). Satisfactory elemental
analysis results were also obtained for all new compounds (Tables I and II).
CONCLUSION
In conclusion, procedures for α-amidoalkylation of trialkylphosphites with 1-
(N-acylamino)alkyltriphenylphosphonium salts followed by a Michaelis–Arbuzov-type
dealkylation have been developed. This protocol offers a convenient and effective entry
into the synthesis of 1-(N-acylamino)alkanephosphonic acid esters. A simple procedure
for the isolation and purification of the products is of particular value.
EXPERIMENTAL
Melting points are determined in capillary tubes in a Stuart Scientific SMP3 melting
point apparatus, and are uncorrected. IR spectra were recorded on a Zeiss Specord M 80
spectrophotometer. 1H and 13C NMR spectra were recorded in CDCl3 on a Varian UNITY
INOVA-300 spectrometer at operating frequencies of 300 and 75.5 MHz or on a Varian 600
spectrometer at operating frequencies of 600 and 150.8 MHz, respectively, in the FT mode
using TMS as an internal standard.
Starting Materials
Commercial grade CH2Cl2 was distilled and dried over molecular sieves (4A).
The following reagents trimethylphosphite and triethylphosphite were of commercial

1-AMINOALKANEPHOSPHONIC ACID DERIVATIVES
1991
quality (Aldrich). The 1-(N-acylamino)alkyltriphenylphosphonium salts 3 and the 1-(N-
pivaloylamino)vinyltriphenylphosphonium iodide 5 were synthesized as described in the
literature.11,12
Synthesis of N-Acylaminoalkanephosphonic Acid Esters 4a–c:
(Procedure A)
Reactions were carried out in a glass vial sealed with a screw-cap. Triphenyl-
methylphosphonium iodide (0.2 g, 0.5 mmol), (i-Pr)2EtN (0.03 mL, 0.2 mmol), and
trialkylphosphite (3 mmol) were added to a solution of N-acylaminomethyltriphenyl
phosphonium tetrafluoroborate 3a–c (2 mmol) in CH2Cl2 (3.6 mL). The mixture was
kept at 60◦C (3a–c) or heated at 50◦C in a microwave reactor at a power of 8–10 W (3c,
CEM Matthews) for the times shown in Table I. The progress of the reaction was monitored
1
by H NMR. Upon completion, the solvent was evaporated under reduced pressure, the
residue was extracted with toluene, and the toluene was subsequently evaporated. The crude
product was recrystallized from a mixture of toluene and hexane (4a and 4c) or purified by
dissolving in ethyl acetate and precipitation by addition of diethyl ether (4b).
Synthesis of N-Acylaminoalkanephosphonic Acid Esters 4d–f
and α-Aminoethenephosphonic Acid Derivative 6 (Procedure B)
Reactions were carried out in a glass vial sealed with a screw-cap. (i-Pr)2EtN
(0.03 mL, 0.2 mmol) and trialkylphosphite (3 mmol) were added to a solution of
(N-acylamino)alkyltriphenylphosphonium iodide 3d–f or 1-(N-pivaloylamino)vinyltriphe
nylphosphonium iodide 5 (2 mmol) in CH2Cl2 (3.6 mL). The mixture was heated at 60◦C
for the time shown in Table I. In the case of compound 5, the reaction time was 2 h. The
1
progress of the reaction was monitored by H NMR. The solvent was evaporated under
reduced pressure, the residue was extracted with toluene, and the toluene was subsequently
evaporated. The crude products 4d and 4f were recrystallized from a mixture of toluene
and hexane. In the case of compounds 4e and 6, the crude product was purified by column
chromatography (silica gel, toluene/AcOEt, 1:5 v/v for 4e and toluene/MeOH, 20:1 v/v for
6). Finally, the product 4e was recrystallized from a mixture of toluene and hexane.
Spectral and analytical data for compound 6: oil, IR (CH2Cl2, cm−1) 3448m, 1688vs,
1
1512vs, 1505vs, 1272s. H NMR (600 MHz, CDCl3) δ = 7.45 (br s, 1H, NH), 6.70 (d,
JPH = 42.3 Hz, 1H, C CH), 5.50 (dd, JPH = 19.4 Hz, JHH = 1.0 Hz, 1H, C CH), 3.78 (d,
JPH = 11.4 Hz, 6H, P(OMe)2), 1.26 (s, 9H, t-Bu). 13C NMR (150.8 MHz, CDCl3, δ /
JPC (Hz)) = 177.8/9.2 (C O), 130.0/198.3 (C CH2), 113.2/9.2 (C CH2), 53.2/5.5
(P(O)(OMe)2), 39.7/1.9 (CMe3), 27.2 (CMe3). HR-EI-MS m/z for C9H18NO4P [M+]: calcd
235.0973; found 235.0964.
REFERENCES
1. V. P. Kukhar and H. R. Hudson, Aminophosphonic and Aminophosphinic Acids: Chemistry and
Biological Activity (Wiley, New York, 2000).
2. P. Kafarski and B. Lejczak, Curr. Med. Chem.—Anti-Cancer Agents, 1, 301 (2001).
3. V. P. Kukhar, V. A. Soloshonok, and V. A. Solodenko, Phosphorus, Sulfur, and Silicon, 92, 239
(1994).
4. B. J. Ivanov, S. Krochina, and J. A. Cernova, Izv. Akad. Nauk SSRR, Ser. Chim., 606 (1968).

1992
R. MAZURKIEWICZ ET AL.
5. D. J. Scharf, J. Org. Chem., 41, 28 (1976).
6. B. J. Ivanov and S. S. Krochina, Izv. Akad. Nauk SSRR, Ser. Chim., 2627 (1970).
7. T. Shono, Y. Matsumura, and K. Tsubata, Tetrahedron Lett., 22, 3249 (1981).
8. B. J. Ivanov, S. S. Krochina, and M. S. Skorobogatova, Izv. Akad. Nauk SSRR, Ser. Chim., 2768
(1972).
9. B. J. Ivanov and S. S. Krochina, Izv. Akad. Nauk SSRR, Ser. Chim., 2493 (1971).
10. R. Mazurkiewicz, A. Paz´dzierniok-Holewa, and M. Grymel, Tetrahedron Lett., 49, 1801 (2008).
11. R. Mazurkiewicz, A. Paz´dzierniok-Holewa, and M. Grymel, Phosphorus, Sulfur, and Silicon,
184, 1017 (2009).
12. R. Mazurkiewicz and A. Pierwocha, Monatsh. Chem., 127, 219 (1996).
13. R. Mazurkiewicz and A. Pierwocha, Monatsh. Chem., 128, 893 (1997).
14. R. Mazurkiewicz, A. Paz´dzierniok-Holewa, B, Orlin´ska, and S. Stecko, Tetrahedron Lett., 50,
4606 (2009).
15. M. J. Pulwer and T. M. Baltthazor, Synth. Commun., 16, 733 (1989).