Amidoalkylation of phosphorus trichloride with acetamide and alkyl oxocycloalkanecarboxylates

Article abstract of DOI:10.1080/10426500902737356

The course of the reaction between phosphorus trichloride, acetamide, and ethyl oxoalkanecarboxylates was studied in terms of the production of side-products. When alkyl 2-oxocycloalkanecarboxylates were used as substrates, together with the expected prod

Full text of DOI:10.1080/10426500902737356

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Amidoalkylation of
Phosphorus Trichloride
with Acetamide and Alkyl
Oxocycloalkanecarboxylates
Zyta Ziora a & Paweł Kafarski a
a Department of Bioorganic Chemistry, Faculty
of Chemistry , Technical University of Wrocław ,
Wrocław, Poland
Published online: 26 Mar 2009.
To cite this article: Zyta Ziora & Paweł Kafarski (2009) Amidoalkylation of
Phosphorus Trichloride with Acetamide and Alkyl Oxocycloalkanecarboxylates,
Phosphorus, Sulfur, and Silicon and the Related Elements, 184:4, 1047-1053, DOI:
10.1080/10426500902737356
To link to this article: http://dx.doi.org/10.1080/10426500902737356
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Phosphorus, Sulfur, and Silicon, 184:1047–1053, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500902737356
Amidoalkylation of Phosphorus Trichloride with
Acetamide and Alkyl Oxocycloalkanecarboxylates
Zyta Ziora and Pawelꢀ Kafarski
Department of Bioorganic Chemistry, Faculty of Chemistry,
Technical University of Wroclꢀaw, Wroclꢀaw, Poland
The course of the reaction between phosphorus trichloride, acetamide, and
ethyl oxoalkanecarboxylates was studied in terms of the production of side-
products. When alkyl 2-oxocycloalkanecarboxylates were used as substrates, to-
gether with the expected products—2-amino-2-phosphonocycloalkanecarboxylic
acids—three side-products, namely 1-aminocycloalkanephosphonic acids (decar-
boxylation products of the latter compounds), 1-aminoethane-1,1-diphosphonic
acids, and 1-hydroxyethane-1,1-diphosphonic acids were identified. Ethyl 1-
oxocycloalkanecarboxylate afforded 4-amino-4-phosphonocyclohexane carboxylic
acid in good yield.
Keywords Aminophosphonates; analogs of aspartic and glutamic acids; Oleksyszyn–
Soroka reaction
INTRODUCTION
Aminoalkanephosphonic acids are generally defined as analogs of
amino acids, in which the carboxylic group is replaced by a phosphonic
acid function or a related moiety. Today they attract considerable in-
terest because of their diverse and useful biological activities,1–3 and
consequently a wide variety of synthetic methods for their preparation
has been elaborated.1 The three-component amidoalkylation of triva-
lent phosphorus compounds is perhaps one of the simplest and most
commonly used methods for the preparation of structurally diverse
aminophosphonates. The final procedure of amidoalkylation, success-
fully introduced by Oleksyszyn et al.4–6 and further modified by Soroka
Received 8 January 2008; accepted 4 February 2008.
Dedicated to Professor Marian Mikolꢀajczyk from the CBMiM PAN in Lꢀ o´dz´, Poland,
on the occasion of his 70th birthday.
This work was supported by Polish Ministry of Science and Higher Education.
Address correspondence to Pawelꢀ Kafarski, Department of Biorganic Chemistry, Fac-
ulty of Chemistry, Technical University of Wroclꢀaw, Wybrzez˙e Wyspian´skiego 27, 50-370
Wroclꢀaw, Poland. E-mail: pawel.kafarski@pwr.wroc.pl
1047

1048
Z. Ziora and P. Kafarski
et al.,7,8 has been found as the method of choice. The mechanism of this
useful reaction is still not fully understood, and the formation of side
products has not been reported in the literature.
In this article, we report the results of our studies on the reaction be-
tween phosphorus trichloride, acetamide, and ethyl oxoalkanecarboxy-
lates, which upon application of the procedure introduced by Soroka,7
yielded unexpected side products, thus showing the limitation of this
reaction.
RESULTS AND DISCUSSION
Reaction of 2-oxocyclopentane carboxylate (1a) or ethyl 1-oxocyc-
lohexane carboxylate (1b) with acetamide and phosphorus trichloride,
followed by acid hydrolysis, afforded a set of four products. The expected
diastereomers of the 2-amino-2-phosphonocycloalkane carboxylic acids
(2) were accompanied by the products of their decarboxylation, namely
the 1-aminocycloalkane phosphonic acids (3) together with substan-
tial quantities of 1-aminoethane-1,1-diphosphonic acids 4 and small
amounts of 1-hydroxyethane-1,1-diphosphonic acids 5 (Scheme 1). The
presence of compounds 4 and 5 is not surprising, because they are
usually prepared by reacting acetamide or acetic acid with phosphorus
trichloride and phosphorous acid.9 The formation of compounds 2, 3,
and 4 was undoubtedly proven by comparing the 31P NMR spectra of
the mixture of reaction products with those of the pure compounds ob-
tained by independent synthesis. The molar ratios of the components of
the reaction mixtures calculated on the basis of their 31P NMR spectra
SCHEME 1

Amidoalkylation of PCl
1049
3
TABLE I Compounds Present in the Reaction Mixtures Obtained by
Amidolkylation of Phosphorus Trichloride with Acetamide and
Alkyl Oxocycloalkane Carboxylates
2 stereoisomer ratio
3
4
5
1a
1b
1c
64%
3:1
52%
9:1
90%
4:3
3%
29%
4%
23%
—
21%
10%
4%
—
are given in Table I. Unfortunately we were only successful in isolation
and characterization of some of the products (see the Experimental
section).
For comparison, the reaction of ethyl 4-oxocyclohexane carboxylate
(1c) was also studied. Interestingly, in this case the decarboxylation
product and compound 4 did not form, and the desired product was
isolated as a mixture of the trans and cis isomer in high (82%) yield.
This indicates that steric hindrance present in the proximity of the
reacting keto-group is governing the course of the reaction.
4-Amino-4-phosphonocyclohexane carboxylic acid (2c) was then con-
verted into its various ethyl esters by standard procedures.10,11 Direct
reaction of 2c with ethyl orthoformate did not yield the desired product
7, and C-esterification was required prior to this reaction. Thus, the C-
ethyl ester (6) was readily obtained by reacting 2c with ethanol in the
presence of HCl. Refluxing of compound 6 with ethyl orthoformate af-
forded crude triethyl 4-(N-formylamino)-4-phosphonocyclohexane car-
boxylate (7), which was not isolated but immediately converted into tri-
ethyl 4-amino-4-phosphonocyclohexane carboxylate hydrochloride (8)
by the action of hydrogen chloride in ethanol. Interestingly this com-
pound was accompanied by the diethyl ester 9. In this manner all the
possible esters of compound 2c were obtained (Scheme 2). These esters
might be further used in phosphonopeptide synthesis.1
EXPERIMENTAL
All reagents were obtained from commercial suppliers (Sigma-Aldrich,
Merck, POCh) and used without further purification. Melting points
were determined with a Boetius apparatus and are uncorrected. NMR
spectra were recorded with a Bruker Avance DRX 300 or a Bruker AV
instrument, operating at 300.13 MHz and 200.13 MHz (1H), 121.499

1050
Z. Ziora and P. Kafarski
SCHEME 2
MHz and 81.0 MHz (31P), and 75.46 MHz and 50.32 MHz (13C), respec-
tively. Measurements were made in D2O and CDCl3. The relation of
1
13C peaks to certain protons in H NMR spectra was done on the ba-
sis of 2D 13C-1H HETCOR spectra. Microanalyses were performed by
the Instrumental Analysis Unit of the Faculty of Chemistry, Wroclꢀaw
University of Technology.
Amidoalkylation: General Procedure
The reaction was carried out introducing a small modification (opti-
mized for a variety of substrates) in the procedure given by Soroka
et al.8 Acetamide (0.2 mol) was dissolved in acetic acid (40 mL) and
cooled in an ice-bath. Then acetyl chloride (0.1 mol) was added with
cooling, and the formation of a crystalline by-product was observed.
After 15 min, compound 1 was added, and the mixture was kept for
30 min in the ice-bath and then left for 1 day at room temperature.
Then the mixture was cooled again in an ice-bath, and phosphorus
trichloride (0,1 mol) was added. The resulting mixture was kept in
the bath for 30 min, then allowed to warm to room temperature, and
finally heated for 1 h to 70–75◦C. Evaporation of the volatile compo-
nents of the reaction mixture resulted in an oily product, which was
refluxed for 8 h in concentrated hydrochloric acid (100 mL). Then the
acid was evaporated in vacuo, and the resulting product was dissolved
in ethanol (50 mL) and left to complete the precipitation of ammonium
chloride, which was filtered off, and the ethanol was evaporated under
reduced pressure. The obtained oily residue was dissolved in ethanol
(50 mL) and the aminophosphonate was precipitated by addition of
pyridine.

Amidoalkylation of PCl
1051
3
Reaction of Methyl 2-Oxocyclopentane Carboxylate
After addition of pyridine fractional crystallization afforded the follow-
ing:
Ammonium 1-aminoethane-1,1-dipohosphonate (ammonium salt of
4): yield 20%; decomposition at 120–150◦C. 31P NMR (D2O): δ = 14.1.
1H NMR (D2O): δ = 1.50 (t, 3JPH = 16.5 Hz, CH3). Elemental analysis:
Calcd. for C2H12N2O6P2(222,07): C, 10.75; H, 6.20; N, 10.85; Found: C,
27.59; H, 10.55; N, 10.66%.
1-Hydroxyethane-1,1-diphosphonic acid (5): yield 4%. 31P NMR
3
(D2O): δ = 20.5. 1H NMR (D2O): δ = 1.50 (t, JPH = 16.5 Hz, CH3).
31P NMR titration excluded the presence of an amino group.
Although their presence in the reaction mixture was evident, we
were unable to obtain the other two components 2a and 3a in pure
form either by crystallization or by ion-exchange chromatography.
Reaction of Ethyl 2-Oxocyclohexane Carboxylate
Fractional crystallization afforded the following:
1-Aminocyclohexane phosphonic acid: yield 18%; mp 258–264◦C with
decomposition (ref. 4: mp 264–2655◦C). IR (KBr pellet): ν = 3130 (NH),
1202 (P=O), 1057, 1022 (PO3H−) cm−1. The NMR are data identical
with those reported in the literature.
2-Amino-2-phosphonocyclohexane carboxylic acid: yield 30%; mp
239–240◦C with decomposition. IR (KBr pellet): ν 3236 (NH), 1670
(C=O), 1219 (P=O), 1109 (CO) cm−1
.
31P NMR (D2O): δ = 16.4, which
1
indicates that one diastereoisomer was isolated. H NMR (D2O): δ =
1.27–1.49 (m, J = 3.5, 10.2 Hz, 2H, 6-CH2), 1.59–1.72 (m, J = 3.0,
12.3 Hz, 1H, CHCH2), 1.76–1.88 (m, 3H, CHCH2 and CH2CH2), 1.96
3
(ddd, J = 3.0, 11.9, 15.3 Hz, 2H, CCH2), 2.85 (ddt, JHH = 4.4, 11.9
Hz, 3JPH = 12.7 Hz, 1H, CCH).
Reaction of Ethyl 4-Oxocyclohexane Carboxylate
Upon addition of pyridine only 4-amino-4-phosphonocyclohexane car-
boxylic acid (2c) was isolated as a mixture of cis/trans isomers: yield
52%; mp 221–226◦C. IR (KBr pellet): ν 3531 (NH), 1685 (C=O), 1240
1
(P=O), 1095 (PO3H−). 31P NMR (D2O): δ = 17.1, 16.5 (7 : 6). H NMR
(D2O): δ = 1.55–1.70 (m, J = 4.0, 13.7, 9.5, 18.6 Hz, 2H, CHCH2), 1.73–
1.83 (m, J = 4.0, 7.7, 10.9, 15.4 Hz, 2H, CCH2), 1.82–2.03 (m, J =
3
4.0, 13.3, 9.0, 17.8 Hz, 2H CHCH2), 2.14 (dt, JHH = 4.1, 7.6 Hz, 2H,
CHCH2), 2.45 (d of quint, 3JHH = 4.5 Hz, 3JPH = 4.5 Hz, 1H, CH).

1052
Z. Ziora and P. Kafarski
Synthesis of Ethyl 4-Amino-4-phosphonocyclohexane
Carboxylate (6)
Ethanol (100 mL) was cooled in an ice-bath and reacted
with thionyl chloride (10 mL, added dropwise). Then 4-amino-4-
phosphonocyclohexane carboxylic acid (0.1 mol) was added with stir-
ring, and the mixture was left for 24 h. The volatile components of the
reaction mixture were evaporated off, and the residue was dissolved
in ethanol (100 mL). The product was precipitated by addition of pyri-
dine (3 mL, to pH 5-6). Pure ester 6 was obtained in 82% yield. Mp
217–220◦C. IR (KBr pellet): ν 1743 (C=O), 1235 (P=O), 1194, 1041, 938
(PO3H−). 31P NMR (D2O): δ = 16.5. 1H NMR (D2O): δ = 1.15 (t, 3JHH
=
7.1 Hz, 3H, CH3), 1.55–1.65 (m, J = 4.6, 7.3, 14.0 Hz, 2H, CHCH2),
3
1.70–1.80 and 1.85–1.95 (m, J = 5.7, 11.6, 19.5 Hz, JPH = 7.7 Hz,
CCH2), 2.06–2.19 (m, J = 4.6, 7.3, 14.0 Hz, 2H, CHCH2), 2.48 (d of
3
3
3
quint, JHH = 6.8 Hz, JPH = 4.5 Hz, 1H, CH), 4.07 (q, JHH = 7.1 Hz,
2H, OCH2).
Synthesis of Triethyl 4-Amino-4-phosphonocyclohexane
Carboxylate Hydrochloride (8) and Diethyl
4-Amino-4-phosphonocyclohexane Carboxylic Acid (9)
Compound 6 (10 mmol) was dissolved in ethyl orthoformate (100 mL),
and the mixture was heated for 3 h in a distillation apparatus to
remove the produced ethanol. Solid impurities were filtered off, and
the solvents were removed in vacuo. The N-formyl derivative 7 (31P
NMR (CDCl3): δ = 23.2, 23.8) was dissolved in a solution of hydrogen
chloride in ethanol (15 mL, prepared as described above) and left for
24 h at room temperature. Evaporation of the ethanol yielded a residue,
which was dissolved in chloroform (30 mL) and extracted with water
(30 mL). The chloroform layer containing product 7 of satisfactory pu-
rity was dried over anhydrous magnesium sulfate, and the product was
recovered upon evaporation of the chloroform with a total yield of 70%.
31P NMR (CDCl3): δ = 27.4. 1H NMR (D2O): δ = 1.23 (t, 3JHH = 7.1 Hz,
3
3H, COCH2CH3), 1.31 and 1.35 (t, JHH = 7.1 Hz, 3H, POCH2CH3),
1.73–1.83 and 2.46–2.58 (m, 2H, CHCH2), 1.94–2.06 and 2.23–2.27 (m,
3
3
2H, CCH2), 2.48 (d of quint, JHH = 6.8 Hz, JPH = 4.5 Hz, 1H, CHP),
3
3
3
4.04 (q, JHH = 7.1 Hz, 2H, COCH2CH3), 4.16 (dq, JHH = JPH = 7.1
Hz, 4H, POCH2).
The water extract was evaporated to dryness and dissolved in
ethanol (20 mL), and the product was precipitated by addition of pyri-
dine. After recrystallization from a water-ethanol mixture, pure com-
pound 9 was obtained in 15% yield. The yield of this product increases

Amidoalkylation of PCl
1053
3
upon prolonging the time of evaporation of the ethanol from the crude
reaction mixture. 31P NMR (CDCl3): δ = 23.2. 1H NMR (D2O): δ = 1.28
(dd, 3JHH = 7.1 Hz, 6 Hz, CH3); 1.57–1.72 (m, J = 4.6, 7.3, 14.0 Hz, 2H,
3
CHCH2), 1.66–1.77 and 1.70–1.76 (m, J = 5.7, 11.6, 19.5 Hz, JPH
=
7.7 Hz, 2H, CCH2), 2.47 (d of quint, 3JHH = 6.8 Hz, 3JPH = 4.5 Hz, 1H,
3
CHP), 4.23 (qq, 3JHH = JPH = 7.1 Hz, 4H, POCH2).
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