Amidoalkylation of phosphorus trichloride with acetamide and functionalized cyclic ketones-evidence of dominating role of side-reactions

Article abstract of DOI:10.1080/10426507.2014.905573

The course of the reaction between phosphorus trichloride, acetamide and ethyl oxoalkanecarboxylates was studied in terms of the production of side-products. When ethyl 2-oxocycloalkane-and 4-oxocyclohexanecarboxylates were used as substrates, not only mi

Full text of DOI:10.1080/10426507.2014.905573

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Phosphorus, Sulfur, and Silicon and the
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Amidoalkylation of Phosphorus
Trichloride with Acetamide and
Functionalized Cyclic Ketones-Evidence
of Dominating Role of Side-Reactions
Zofia A. Dziuganowskaa, Iga Andrasiaka, Katarzyna Ślepokurab &
Paweł Kafarskia
a Department of Biorganic Chemistry, Faculty of Chemistry,
Technical University of Wrocław, Wybrzeże Wyspiańskiego 27,
50-370 Wrocław, Poland
b Faculty of Chemistry, Wrocław University, ul. F. Joliot-Curie 14,
50-383 Wrocław, Poland
Accepted author version posted online: 14 May 2014.Published
online: 04 Aug 2014.
To cite this article: Zofia A. Dziuganowska, Iga Andrasiak, Katarzyna Ślepokura & Paweł Kafarski
(2014) Amidoalkylation of Phosphorus Trichloride with Acetamide and Functionalized Cyclic Ketones-
Evidence of Dominating Role of Side-Reactions, Phosphorus, Sulfur, and Silicon and the Related
Elements, 189:7-8, 1068-1075, DOI: 10.1080/10426507.2014.905573
To link to this article: http://dx.doi.org/10.1080/10426507.2014.905573
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Phosphorus, Sulfur, and Silicon, 189:1068–1075, 2014
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2014.905573
AMIDOALKYLATION OF PHOSPHORUS TRICHLORIDE
WITH ACETAMIDE AND FUNCTIONALIZED CYCLIC
KETONES-EVIDENCE OF DOMINATING ROLE
OF SIDE-REACTIONS
Zofia A. Dziuganowska,1 Iga Andrasiak,1
2
1
´
Katarzyna Slepokura, and Paweł Kafarski
1Department of Biorganic Chemistry, Faculty of Chemistry, Technical University of
Wrocław, Wybrzez˙e Wyspian´skiego 27, 50-370 Wrocław, Poland
2Faculty of Chemistry, Wrocław University, ul. F. Joliot-Curie 14, 50-383
Wrocław, Poland
GRAPHICAL ABSTRACT
Abstract The course of the reaction between phosphorus trichloride, acetamide and ethyl
oxoalkanecarboxylates was studied in terms of the production of side-products. When ethyl 2-
oxocycloalkane- and 4-oxocyclohexanecarboxylates were used as substrates, not only mixtures
of the expected products—aminophosphonocycloalkanecarboxylic acids and their ethyl esters
but also the formation of three side-products, namely 1-aminocycloalkanephosphonic
acids (products of decarboxylation of the latter ones) and 1-aminoethane-1,1-
diphosphonic and 1-hydroxyethane-1,1diphosphonic acids (products of the reaction of
Received 30 January 2014; accepted 18 February 2014.
This work is dedicated to Prof. Louis D. Quin on the occasion of his 86th birthday.
Address correspondence to Zofia A. Dziuganowska, Department of Biorganic Chemistry, Faculty of
Chemistry, Technical University of Wrocław, Wybrzez˙e Wyspian´skiego 27, 50-370 Wrocław, Poland. E-mail:
zofia.a.dziuganowska@gmail.com; zofia.a.dziuganowska@pwr.wroc.pl
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/gpss.
1068

AMIDOALKYLATION OF PHOSPHORUS TRICHLORIDE WITH ACETAMIDE
1069
substrate and solvent with phosphonylating agent) were observed. Ethyl 2-oxo-
cyclooctanecarboxylate afforded the expected 2-amino-2-pohosphonocyclooctanecarboxylic
acid in minute amounts. For comparison reactions of 1-butyloxocarbonyloxopiperidines
afforded the desired aminopiperidinephosphonic acids in good yields and without formation
of side-products.
Keywords Phosphonic analogues aspartic and glutamic acids; aminophosphonates;
Oleksyszyn-Soroka reaction; side products
INTRODUCTION
Aminoalkanephosphonic acids are broadly defined as analogues of amino acids,
which carboxylic group is replaced by phosphonic acid or related moiety. Today they at-
tract considerable interest because of their diverse and useful biological activities1–3 and
consequently, a wide variety of synthetic methods for their preparations have been elabo-
rated.1 Three-component reaction of amidoalkylation of trivalent phosphorus compounds
is perhaps one of the simplest and thus the most commonly used for the preparation of
structurally diverse aminophosphonates. Final procedure of amidoalkylation successfully
introduced by Oleksyszyn4–6 and further modified by Soroka7,8 has been found as a method
of choice. The mechanism of this useful reaction is still no fully understood. Previously,
we have shown that the reaction between phosphorus trichloride, acetamide, and cyclic
oxocarboxylates, upon application of procedure introduced by Soroka7 yielded side pro-
ducts which derive from the reaction of acetic acid (solvent) and acetamide (substrate) with
phosphonylating agent.8
RESULTS AND DISCUSSION
Reexamination of the reaction between ethyl 2-oxocyclohexanecarboxylate
(compound 1) and 4-oxocyclohexanecarboxylate (compound 2) with acetamide and phos-
phorus trichloride, followed by acid hydrolysis, surprisingly gave quite different results
than those described earlier.8 Small change in procedure of recovery of crude product
enabled better determination of the composition of these products. Thus, the examination
of 31P NMR spectra of crude reaction mixtures clearly showed the presence of four
products (Scheme 1): desired aminophosphonocycloalkanecarboxylic acids (compounds
3 and 4), their C-ethyl esters (compounds 5 and 6), 1-aminocyclohexanephosphonic
acid formed by decarboxylation of compounds 3 and 4 (compound 7), and a product of
reaction of phosphorus trichloride with acetic acid, namely 1-hydroxy-1,1-diphosphonic
acid (compound 8). The product of reaction of phosphonylating agent with acetamide—
1-aminoethane-1,1-diphosphonate (compound 9)-crystallized together with ammonium
chloride. The presence of these compounds was also confirmed by mass spectrometry (see
Experimental).
Fractional crystallization enabled us to obtain pure compounds 3, 4 (84:16 ratio of
isomers), 5 (82:18 ratio of isomers), 6 (pure cis-isomer), and 9. Structure of compound of
cis configuration was determined by X-ray crystallography (Figure 1).
As seen from Figure 1, this compound exists as zwitterion and crystallizes with one
molecule of water. The ratio of cis:trans isomers in the crude product was determined as
64:36 basing on 1H NMR studies.
Reaction of ethyl 2-oxocyclooctanecarboxylate (compound 10, Scheme 2)
provided 50% of crude product composed of compound 9 (8% of yield), hydroxyl

1070
Z. A. DZIUGANOWSKA ET AL.
Scheme 1
Figure 1 Asymmetric unit of 6·H2O crystal, showing the atom-numbering scheme and the symmetry-independent
O
level.
H···O hydrogen bond (thin dashed line; see Table 1.). Displacement ellipsoids are drawn at the 50% probability
derivative 8 (42% of yield) and minute amounts (0.2% of yield) of ethyl 2-amino-2-
phosphonocyclooctanecarboxylate (compound 11).
Scheme 2
Reactions of 2-indanone (compound 12) and diethyl 2,5-dioxo-1,4-dicarboxylate
(compound 13) did not provide desired aminophosphonates (Scheme 2). In the case of

AMIDOALKYLATION OF PHOSPHORUS TRICHLORIDE WITH ACETAMIDE
1071
compound 12 hydroxyphosphonate 8 was formed in 100% yield, whereas in the case of
compound 13 the mixture of 8 and 9 in a ratio of 15:85 was obtained in 89% of total yield.
For comparison, the same procedure had been applied using 1-butyloxocarbonyl-4-
oxopiperidine (compound 14) and 1-butyloxocarbonyl-3-oxopiperidine (compound 15) as
substrates. In this case, the expected products (compounds 16 and 17) have been obtained
(Scheme 3) with good yields and we had not observed formation of side-products 8 and 9.
Scheme 3
One of these compounds (16) crystallized as hydrochloride and its structure was
additionally supported by crystallography (Figure 2). Also in this case the compound
crystallizes as a monohydrate.
EXPERIMENTAL
All solvents and reagents were purchased from commercial suppliers (Aldrich, Sigma,
Merck, POCh), were of analytical grade and were used without further purification. Unless
otherwise specified solvents were removed with a rotary evaporator. Infrared spectra were
measured on a 1600 FT-IR Perkin-Elmer spectrometer. NMR experiments were performed
Figure 2 Asymmetric unit of [16+Cl−]·H2O crystal, showing the atom-numbering scheme and the symmetry-
independent N-H···O and N-H···Cl hydrogen bonds (thin dashed lines; see Table 1). Displacement ellipsoids are
drawn at the 50% probability level.

1072
Z. A. DZIUGANOWSKA ET AL.
Table 1 Hydrogen-bond geometry for 6·H2O and [16+Cl−]·H2O (Å, ◦)
D-H···A
D-H
H···A
D···A
D-H···A
6·H2O
O3-H3···O1W
0.82(4)
0.92(3)
1.01(3)
0.93(3)
0.99
1.69(4)
1.93(3)
1.75(4)
1.97(3)
2.60
2.510(3)
2.806(4)
2.729(4)
2.864(4)
3.191(4)
2.731(3)
2.707(3)
174(4)
160(3)
165(3)
161(3)
118
N1-H3NA···O1i
N1-H2NB···O2ii
N1-H1NC···O3iii
C3-H3A···O1Wi
O1W-H1W···O1iv
O1W-H2W···O2v
[16+Cl−]·H2O
O3-H3···O2vi
0.84
0.84
1.90
1.88
172
169
0.92(7)
0.99
0.99
0.98(5)
0.97(4)
0.93(6)
0.99
0.99
0.99
0.99
0.84
1.64(7)
2.18
1.95
1.79(5)
1.80(4)
2.23(6)
2.83
2.55
2.84
2.84
2.43
2.549(3)
3.107(3)
2.787(4)
2.736(4)
2.742(4)
3.153(3)
3.718(4)
3.332(4)
3.731(4)
3.646(4)
3.260(3)
2.912(4)
170(6)
156
140
161(4)
162(4)
170(5)
150
136
150
139
170
N1-H1NA···Cl1
N1-H1NB···O1W
N2-H2NA···O1vii
N2-H2NB···O2viii
N2-H2NC···Cl1ix
C2-H2B···Cl1ix
C3-H3A···O3x
C6-H6A···Cl1ix
C6-H6B···Cl1xi
O1W-H1W···Cl1xi
O1W-H2W···O1xii
0.84
2.11
159
Symmetry codes: (i) x, −y+1/2, z+1/2; (ii) −x+1, y−1/2, −z+1/2; (iii) −x+1, y+1/2, −z+1/2; (iv) x, y−1, z;
(v) −x+1,−y, −z; (vi) −x+1, −y+1, −z+1; (vii) −x+1, y−1/2, −z+3/2; (viii) −x+1, y+1/2, −z+3/2;
(ix) x, −y+3/2, z+1/2; (x) −x+1, −y+2, −z+1; (xi) −x+2, −y+1, −z+1; (xii) x+1, y, z.
on a Bruker DRX AVANCETM 300 MHz and Bruker AVANCETM 600 MHz spectrometers.
Measurements were made in CDCl3 (99.5 at. % D) or D2O (99.8 at. % D) solutions at
temperature 300 K, all solvents were supplied by Dr Glaser AG (Basel, Switzerland).
Chemical shifts are reported in parts per million relative to TMS or 85% H3PO4 used
as external standards, and coupling constants are reported in Hertz. Melting points were
determined on an Electrothermal 9200 apparatus and are reported uncorrected. Electrospray
mass spectra were recorded at Chemistry Department of University of Wroclaw using
Finnigan Mat TSQ 700 Electrospray mass spectrometer.
Crystal Structure Determination
The crystallographic measurements were performed at 80(2) or 100(2) K on a κ-
geometry Xcalibur R (ω scan) or Xcalibur PX (ω scan) automated four-circle diffractometer
with graphite-monochromatized MoKα or CuKα radiation (Table 2). Data were corrected
for Lorentz and polarization effects. Data collection, cell refinement, and data reduction and
analyses were carried out with CrysAlis CCD and CrysAlis RED, respectively.9 Empirical
(multi-scan) absorption correction was applied to the data with the use of CrysAlis RED.
The structures were solved by direct methods using the SHELXS-97 program10 and refined
on F2 by a full-matrix least-squares technique using SHELXL-201310 with anisotropic
thermal parameters for non-H atoms. All H atoms in 6·H2O and [16+Cl−]·H2O were
found in difference Fourier maps, and in the final refinement cycles, the C-bonded H
atoms and those form NH2 group in 16 were repositioned in their calculated positions
and refined using a riding model, with C H = 0.98–1.00 Å, N H = 0.99 Å, and with

AMIDOALKYLATION OF PHOSPHORUS TRICHLORIDE WITH ACETAMIDE
1073
Table 2 Crystallographic data for 6·H2O and [16+Cl−]·H2O
6·H2O
[16+Cl−]·H2O
Empirical formula
C9H20NO6P
269.23
C5H16ClN2O4P
Formula weight (g mol-1)
234.62
monoclinic
P21/c (No. 14)
10.734(3)
6.653(2)
14.154(4)
90.39(3)
1010.8(5)
4
Crystal system
Space group
a (Å)
monoclinic
P21/c (No. 14)
14.777(4)
6.292(2)
13.113(4)
94.75(3)
1215.0(6)
4
b (Å)
c (Å)
β (◦)
V (Å3)
Z
T (K)
Dcalcd (g cm–3
μ (mm-1)
80(2)
1.472
0.24
100(2)
1.542
4.80
)
Crystal size (mm)
Radiation type, λ (Å)
θ range (◦)
0.22 × 0.04 × 0.01
MoKα, 0.71073
2.8–28.5
−10 ≤ h ≤ 19
−8 ≤ k ≤ 4
−16 ≤ l ≤ 17
0.918/1.000
5602
0.42 × 0.22 × 0.10
CuKα, 1.5418
4.1–78.0
−13 ≤ h ≤ 12
−7 ≤ k ≤ 8
−17 ≤ l ≤ 16
0.327/1.000
4387
Index ranges
Tmin/Tmax
Reflections collected
Independent reflections
Observed reflections [I > 2σ(I)]
Rint
2925
1779
0.071
2083
2006
0.053
Data/restraints/parameters
R1 [Fo2 > 2σ(Fo2)]
wR2 (all data)
2925/2/173
0.070 a)
0.117 a)
2083/2/137
0.066 a)
0.184 a)
GOF = S
1.00
0.43/–0.52
1.12
0.64/−0.67
ρmax
/
ρmin (e Å−3
)
ꢁ
ꢀ
ꢀ
ꢀ
ꢀ
a)R1 = ||Fo| − |Fc|| / |Fo|; wR2 =
[w(Fo2 − Fc2)2]/ [w(Fo2)2]. Detailed values of the weighting
scheme (w) in each system are given in the crystallographic information files (CIF) provided as Supporting
Information.
Uiso(H) = 1.2Ueq(C) for CH, CH2, NH2, or 1.5Ueq(C) for CH3. H atoms from NH3 group in
6 were refined freely. Water H atoms in 6·H2O and [16+Cl−]·H2O were refined isotropically
with the O H distances restrained to 0.840(2) Å, and then were constrained to ride on their
parent atoms (AFIX 3 instruction in SHELXL-2013). The structure plots were prepared
with DIAMOND.11
CCDC 983797 and 983798 for 6·H2O and [16+Cl−]·H2O, respectively contain the
supplementary crystallographic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/retrieving.html (or from the Cambridge Crystallographic
Data Centre, 12, Union Road, Cambridge, B2 1EZ, UK; fax +44 1223 336033; or
deposit@ccdc.cam.ac.uk).
1. Amidoalkylation-General Procedure
Reaction was carried out by a small modification of the procedure described by
Soroka.12 Thus, acetamide (0.2 mole) was dissolved in acetic acid (40 mL) and cooled in

1074
Z. A. DZIUGANOWSKA ET AL.
ice-bath. Then, acetyl chloride (0.1 mole) was added with cooling and the formation of
crystalline by-product was observed. After 15 min ketone was added and the mixture kept
for 30 min in ice-bath and then left for a day at room temperature. Then, the mixture was
cooled once more in ice-bath and phosphorus trichloride (0.1 mole) 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 at 70–75◦C. Evaporation of volatile components of the reaction mixture
resulted in oily product, which was refluxed for 8 h in concentrated hydrochloric acid
(100 mL). Then, acid was evaporated in vacuo and the resulting product dissolved in ethanol
(50 mL), left for completeness of precipitation of ammonium chloride accompanying by
1-aminoethane-1,1-dipohosphonate ammonium salt, which was filtered off and ethanol
was evaporated under reduced pressure. The obtained oily residue was dissolved in ethanol
(50 mL) and aminophosphonate precipitated by addition of one droplet of pyridine. Then,
31P NMR spectra of crude products were recorded and the fractional crystallization of the
resulting mixture was carried out. Yields of single products one were estimated on the basis
of 31P NMR and total weight of crude product.
1.1. Reaction of ethyl 2-oxocyclohexanecarboxylate as Substrate. Yields
of single products in crude product were: 16% of compound 5 (δ = 13.43 ppm), 32% of
compound 3 (δ = 15.29 ppm); 4% of compound 8 (δ = 19.01 ppm) and 3% of compound
7 (δ = 22.24 ppm). Fractional crystallization afforded:
1-aminocyclohexanephosphonic acid (7) and 2-amino-2-phosphonocyclohexane
carboxylic acid (3) of physicochemical data identical as reported in the literature.4,8 HRMS
for compound 3 (H2O, TOF MS ESI+): found 224.0688 [MH+], C7H15NO5P requires
224.1723.
Ethyl 2-amino-2-phosphonocyclohexanecarboxylate (5): yield 30%; mp. 224◦C with
decomposition; 31P NMR (D2O): δ = 15.29 and 15.23 ppm (82:18 molar ratio); 1H NMR
(D2O): δ = 1.23 (t, J = 7.1 Hz, POCH3, minor isomer), 1.32 (t, J = 7.1 Hz, POCH3, major
isomer), 1.40–1.58 (m, 4H, CH2 ), 1.60–1.83 (m, 4H, CH2), 1.80–1.95 (m, 2H, CH2), 2.62
(m, J = 7.0 Hz, 1H, CH), 2.96 (m, OCH2, major), 3.58 (q, J = 7.1 Hz, OCH2, minor) ppm;
HRMS (H2O, TOF MS ESI+): found 252.1122 [MH+], C9H19NO5P requires 252.2256.
1.2. Reaction of ethyl 4-oxocyclohexanecarboxylate as Substrate. Yields
of single products in crude solid were: 24% of compound 6 (δ = 13.43 ppm), 18%
of compound 4 (δ = 15.29 and 15.30 ppm, (84:16 molar ratio)); 8% of compound 8
(δ = 19.01 ppm) and 10% of compound 7 (δ = 22.24 ppm). Fractional crystallization af-
forded 1-aminocyclohexanephosphonic acid (7) and 4-amino-4-phosphonocyclohexanene-
carboxylic acid (4), which physicochemical data are in accordance with the literature.4,8
HRMS for compound 4 (H2O, TOF MS ESI+): found 224.0743 [MH+], C7H15NO5P re-
quires 224.1723, (TOF MS ESI−) found 222.0535 [M−], C7H13NO5P requires 222.1564.
Ethyl cis-4-amino-4-phosphonocyclohexanenecarboxylate (6): mp. 225◦C with de-
1
composition 31P NMR (D2O): δ = 16.56 ppm; H NMR (D2O): δ = 1.13 and 1.14 (t,
J = 7.1 Hz, 3H, OCH2CH3), 1.65–1.77 (m, 2H, CH2), 1.91–2.01(m, 4H, CH2), 2.20-2.29
(m, 2H each, CH2), 2.53–2.60 (m, 1H, CH), 3.60 and 3.61 (q, J= 7.1 Hz, 2H, OCH2) ppm.
HRMS (H2O, TOF MS ESI+): found 252.1010 [MH+], C9H19NO5P requires 252.2256,
(TOF MS ESI−) found 250.0842 [M−], C9H17NO5P requires 250.2098.
1.3. Reaction of ethyl 4-oxocyclooctanecarboxylate as Substrate. Yields
of single products in crude solid were: 0.2% of compound 11 (mixture of two isomers), 8%
of compound 9 (δ = 12.89 ppm); 42% of compound 8 (δ = 19.33 ppm).
Ethyl 2-amino-2-phosphonocyclooctanecarboxylate (11): mp. 227◦C with decompo-
sition; 31P NMR (D2O): δ = 24.72 and 24.97 (83:17 molar ratio); 1H NMR (D2O): δ = 1.04

AMIDOALKYLATION OF PHOSPHORUS TRICHLORIDE WITH ACETAMIDE
1075
(t, J = 7.1 Hz, 3H, POCH3), 1.18–1.38 (m, 2H, CH2), 1.54–1.75 (m, 8H, CH2), 2.16–2.20
(m, 2H, CH2), 2.50–2.54 (m, 1H, CH), 3.50 (q, J = 7.1 Hz, OCH2, major), 3.505 (q,
J = 7.1 Hz, OCH2, minor).
1.4. 4-Aminopiperidine-4-phosphonic acid (16). 89% of yield; mp. 200◦C
with decomposition; 31P NMR (D2O): δ = 13.25 ppm; 1H NMR (D2O): δ = 1.90–2.01 (m,
2H, CH2), 2.27–2.30 (m, 2H, CH2), 3.19–3.24 (m, 2H, CH2), 3.40–3.46 (m, 2H, CH2); 13
C
NMR (D2O): δ = 27.08, 39.64, 39.70, 51.15 (d, J = 141.1 Hz, CP). HRMS (H2O, TOF
MS ESI+): found 181.0738 [MH+], C5H14N2O3P requires 181.1507.
1.5. 3-Aminopiperidine-3-phosphonic acid (17). 100% of yield; mp. 250◦C
1
with decomposition; 31P NMR (D2O): δ = 8.80 and 8.00 ppm (35:65); H NMR (D2O):
δ = 1.52–2.19 (m, 4H, CH2), 2.85-3.14 (m, 1.35 H, CH2), 3.30–3.49 (m, 2H, CH2),
3.79–3.86 (m, 0.65H, CH2); 13C NMR (D2O): δ = 16.57, 20.16, 24.54 (d, J = 6.8 Hz,
major), 24.88 (d, J = 9.1 Hz, minor), 43.75 (d, J = 4.5 Hz, major), 44.54 (d, J = 6.0 Hz,
minor), 45.52 (d, J = 3.8 Hz, major), 46.64 (d, J = 3.0 Hz, minor), 54.36 (d, J = 129.0 Hz,
CP, major), 53.92 (d, J = 129.8 Hz, CP, minor). HRMS (H2O, TOF MS ESI+): found
181.0742 [MH+], C5H14N2O3P requires 181.1507.
FUNDING
This work was supported by Polish Ministry of Science and Higher Education.
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