α-(Ferrocenyl)-aminomethanephosphonous acids. First synthesis and preparation of their esters with cholesterol and adenosine

Article abstract of DOI:10.1016/j.jorganchem.2004.02.025

The series of aminophosphonous acids bearing the ferrocenyl moiety was obtained by the addition of hypophosphorous acid to Schiff bases of ferrocenecarboxaldehyde. They were subsequently condensed with cholesterol and adenosine to form their cholesteryl a

Full text of DOI:10.1016/j.jorganchem.2004.02.025

Journal of Organometallic Chemistry 689 (2004) 1684–1690
www.elsevier.com/locate/jorganchem
a-(Ferrocenyl)-aminomethanephosphonous acids. First synthesis
and preparation of their esters with cholesterol and adenosine
*
ꢀ
Jarosław Lewkowski , Monika Rzezniczak, Romuald Skowronski
ꢀ
Department of Organic Chemistry, University of Łꢀodꢀz, Narutowicza 68, 90-136 Łoꢀdꢀz, Poland
Received 10 October 2003; accepted 17 February 2004
Abstract
The series of aminophosphonous acids bearing the ferrocenyl moiety was obtained by the addition of hypophosphorous acid to
Schiff bases of ferrocenecarboxaldehyde. They were subsequently condensed with cholesterol and adenosine to form their cholesteryl
and adenosinyl esters. The concurrence reaction of DCC with amine nitrogen atom was observed.
Ó 2004 Elsevier B.V. All rights reserved.
Keywords: Ferrocenecarboxaldehyde; Hypophosphorous acid; Aminophosphonous acids; Adenosine; Cholesterol; Concurrence reaction
1. Introduction
oligonucleotides or carbohydrate phosphates [17]. The
compounds of phosphorous or aminophosphonic acids
with cholesterol or adenosine were not largely described.
Kashman [18] presented the synthesis of O-cholesteryl,
O-methyl phosphite by the reaction of dimethyl phos-
phite with cholesterol. Riess and co-workers [19] reported
the preparation of mono- or dicholesteryl phosphites by
the reaction of triethyl phosphite with cholesterol. Gibbs
and Larsen [20] and Knerr et al. [17] proposed the
preparation of monophosphites of cholesterol and uri-
dine and thymidine. Stec and co-workers [21] synthesized
adenosinyl and uridinyl esters of 1-aminoethanephos-
phonic acid.
The important biological function of aminophos-
phonic and aminophosphonous acids is well recognized
[1,2]. The importance of ferrocene-derived compounds is
well known too, as they have been widely employed in
the molecular recognition due to their ability to make
metal-centred redox systems to generate oxidized or
reduced form of different properties, as described by
Constable [3]. For the formation of such molecular
switches containing ferrocene moiety, it was proposed to
use dihydrocholesteryl ether of ferrocenedimethanol [3],
derivatives of di(ferrocenylmethyl)malonate [4] and fer-
rocene-containing thioethers [5] as well as some deriva-
tives of ferrocenylmethylamines [6] and ferrocenyl
ligands containing the tetrathiafulvalene molecules [7].
There were also attempts to mark peptides by binding
them to ferrocene-bearing amino acids. That is why,
studies on the synthesis of ferrocenylalanine [8–13] and
ferrocenoylalanine [14] have been performed. We con-
tributed to this topic too, publishing the synthesis of
variously substituted ferrocene-bearing aminomethane-
phosphonates [15,16].
Regarding all above, we wanted to combine proper-
ties of mentioned groups of compounds and that is why
we synthesized four new (ferrocenyl)aminomethane-
phosphonous acids and their cholesteryl and adenosinyl
esters.
2. Results and discussion
Acids 3a–d have been synthesized by the addition of
hypophosphorous acid to the azomethine bond of Schiff
bases derived from ferrocenecarboxaldehyde (2a–d).
Schiff bases 2a–d have been already described in our
previous paper [15], and they were identical to samples
described there, so we do not quote their data.
Biological substances often bear in their structure a
phosphorylated alcohol group. These are: phospholipids,
* Corresponding author. Tel.: +48-426784731; fax: +48-426786583.
E-mail address: jlewkow@uni.lodz.pl (J. Lewkowski).
0022-328X/$ - see front matter Ó 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2004.02.025

J. Lewkowski et al. / Journal of Organometallic Chemistry 689 (2004) 1684–1690
1685
The addition of hypophosphorous acid was per-
formed in dry 1,4-dioxane at the reflux temperature.
After 3 days, we observed the precipitation of acids 3a–
d, which were isolated by filtration in 56–65% yield.
They were purified by washing with cold water followed
by cold methanol. The identity of compounds was
chromatography on cellulose powder and their purifi-
cation was carried out in the same conditions.
Similar results were obtained in the course of con-
densation of acids 3a–d with O,O0-iso-propylideneade-
nosine, which was carried out in identical conditions i.e.
in dichloromethane, in the presence of dicyclohexylcar-
bodiimide (DCC) as a dehydrating agent (Scheme 1).
Adenosinyl esters 5a–d were obtained and, in a case of
N-diphenylmethyl and N-a-methylbenzyl derivatives,
corresponding esters (5c) and (5d) were exclusive prod-
ucts. Reactions with acids 3a and 3b led to desired esters
5a and 5b but also to side products 6a and 6b in a 3:1
and 1:6 (6–4) ratio, respectively. Adenosinyl derivatives
1
confirmed by the H and 31P NMR spectroscopy, the
mass spectrometry and the elemental analysis. Acids 3a–
c were obtained as racemates. In case of chiral Schiff
base 2d, the addition of hypophosphorous acid was not
highly stereoselective, which was surprising in front of
Hamilton, Walker and Walker’s discovery [22]. Diaste-
reoisomers formed in the 2:1 ratio, which astonishing
fact was preliminarily discussed in the communication
by Lewkowski [23] (Scheme 1).
Their cholesteryl esters 4a–d and were synthesized by
the condensation of acids 3a–d with cholesterol in the
presence of dicyclohexylcarbodiimide (DCC) as a de-
hydrating agent in dichloromethane. After 7 days of
refluxing, esters 4a–d have been obtained in fair yields as
low-melting solids (Scheme 1). They were purified by the
column chromatography on cellulose powder; our tests
demonstrated that obtained esters 4a–d decomposed on
silica gel as well as on neutral aluminium oxide. More-
over, too long contact of esters 4a–d with cellulose
powder resulted in decomposition, so that esters had to
be flash-chromatographed. A concurrence reaction oc-
curred in these conditions in case of N-benzyl and
N-furfuryl acids 3a and 3b. In case of the N-benzyl de-
rivative 3a, the side product 6a and the ester 4a formed
in a 3:1 ratio and in case of the N-furfuryl acid 3b, the
side product 6b and the ester 4b formed in a this ratio
was 1:5. We isolated the esters 4a–b by the column
1
5c and 5d were characterised by the H and 31P NMR
spectroscopy, the mass spectrometry and the elemental
analysis. N-benzyl ester 5a as well as N-furfuryl ester 5b
were isolated by the column chromatography on cellu-
lose powder and they were purified in the same way. The
identity of esters 4a–d and 5a–d was confirmed by the
1H, 13C and 31P NMR spectroscopy, the mass spec-
trometry and the elemental analysis.
The reaction between acids 3a–d and DCC in the
absence of any alcohol led to the unique formation of
aminophosphonous acids derivatives 6a–b. The most
probably they are formed by the attack of DCC on the
nitrogen atom. Normally, the mechanism of condensa-
tion of acids with alcohols passes through the interme-
diate 7a–d, which forms as a result of the DCC attack on
the oxygen atom. But when the nitrogen nucleophilic
centre is rather accessible, the attack on it is probable.
Acids 3c–d did not react with DCC in this way probably
due to the sterical hindrance of large diphenylmethyl
(3c) or a-methylbenzyl (3d) groups (Scheme 2).
PO2H2
CHO
H3PO2
RNH2
NR
Fe
Fe
NHR
Fe
2a-d
1
3a-d
cholesterol
a: R = CH2Ph
b: R = CH2Fur
c: R = CHPh2
adenosine
DCC
DCC
d: R = CH(CH3)Ph
NH2
N
N
N
Fe
NHR
Fe
NHR
HP
N
O
HP
O
O
O
O
4a-d
O
O
5a-d
Scheme 1.

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J. Lewkowski et al. / Journal of Organometallic Chemistry 689 (2004) 1684–1690
PO2H2
NHR
Fe
a = CH2Ph
b = CH2Fur
3a-b
Fe
RHN
HP
N
Fe
RN
HP
N
N
H
O
O
O
OH
N
H
7a-c
R'OH
6a-b
Fe
RHN
R'O PH
4a-d or 5a-d
O
Scheme 2.
Acid derivatives 6a–b were determined by the 1H, 13
C
ocenyl)methane phosphonous acid (3d), as its reaction
with cholesterol as well as isopropylidene adenosine in
the presence of DCC resulted in exclusively two diaste-
reoisomers in a 1:2 ratio in both cases. This demon-
strated that for each of the diastereoisomeric form of the
acid 3d, newly formed chiral centre on a phosphorus
atom occurs in the 100% stereoselectivity. The chiral
assistance of cholesterol or adenosine should be com-
bined with the assistance of the (R)-a-methylbenzyl
substituent on nitrogen. For now, the reason of such a
stereoselectivity remains unclear, there are too many
factors involved. This problem will be the subject of the
separate theoretical study.
and 31P NMR spectroscopy as well as the mass spec-
trometry and a high resolution mass spectrometry
(HRMS). They were not properly purified due to their
fragility, so their combustion analysis could not be
performed.
Each of esters 4a–c and 5a–c occurred as the mixture
of four diastereoisomers, which were clearly visible on
31P NMR spectra of cholesteryl esters 4a–c, as four well-
separated signals occurred. In a case of adenosinyl esters
5a–c, they gave generally four well-shaped 31P NMR
signals except the N-benzyl derivative 5a, which gave
three signals, but one of them, this in the middle, con-
sisted of two overlapping signals. The evidence of dia-
The separation of four diastereoisomers of esters
failed due to their fragility towards silica gel or alumina;
cellulose powder was not an adsorbent suitable enough
to provide a good resolution of diastereoisomers.
1
stereoisomers has been also confirmed by the H NMR
spectroscopy by the presence of two or four signals of
the P–H protons. In some cases two enlarged doublets
instead of four ones occurred, which was due to over-
lapping. The same phenomenon is observed on the 13C
NMR spectra. All is quoted in Section 3.
3. Experimental
Ratio of diastereoisomers of cholesteryl esters varied
from 2:2:3:3 in case of N-diphenylmethyl derivative 4c
to even 1:1:6:6 in case of 4b. Ratio of diastereoisomers
of adenosinyl esters differed much less, as it varied from
1:1:1:1 for the N-benzyl derivative 5a up to 1:1:3:3 in a
case of the N-diphenylmethyl one 5c. This might be
caused by the chiral assistance of a cholesterol or
adenosine molecule.
All solvents and furfural (POCh-Poland) were rou-
tinely distilled and dried prior to use. Hypophosphorous
acid 50% (Aldrich) were dehydrated following the pub-
lished procedure [2]. Amines, (Aldrich) as well as cho-
lesterol (Organika S.A. Poland) were used as received.
NMR spectra were recorded on a Varian Gemini 200
BB apparatus operating at 200 MHz (1H NMR) and 81
MHz (31P NMR). Schiff bases 2a–d were prepared
following the previously published procedure [19].
Much more interesting was the stereochemistry of the
ester formation from N-(R)-a-methylbenzylamino(ferr-

J. Lewkowski et al. / Journal of Organometallic Chemistry 689 (2004) 1684–1690
1687
Elemental analyses were made in the Centre for Mo-
lecular and Macromolecular Science of the Polish
ꢀ ꢀ
Academy of Science in Łodz.
Elemental analysis: Anal. Found: C, 64.52; H, 5.30;
N, 3.32%. Calc. for (C24H24FeNO2P): C, 64.74; H, 5.43;
N, 3.15%.
3.1. General procedure for the preparation of N-alkyla-
mino(ferrocenyl)methane phosphonous acid
3.1.4. N-(R)-a-methylbenzylamino(ferrocenyl)methane
phosphonous acid (3d)
m.p. ¼ 215–217 °C.
The Schiff base (5 mmol) was dissolved in acetonitrile
(30 ml) and hypophosphorous acid (5 mmol) was added
and the solution was refluxed for 1 h and then stirred for
3 days at room temperature. After this time, the pre-
cipitate was collected by filtration and washed several
times with cold water to remove impurities to obtain the
desired product.
1H NMR (NaOD/D2O, 200 MHz): d 7.23 (m, CHfur
,
1H); 6.47 (m, CHfur, 2H); 6.67 (dd, 1JPH ¼ 521:6 Hz and
3JHH ¼ 1:6 Hz, HP, 1H); 6.58 (dd, 1JPH ¼ 514:9 Hz and
3JHH ¼ 1:6 Hz, HP, 1H); 4.19 and 4.13 (2quart, J ¼ 6:7
Hz); 4.00 and 3.92 (m, CHfer, 4H); 3.78 (s, CHfer, 5H);
2
3
3.23 and 3.13 (dd, JPH ¼ 9:8 Hz and JHH ¼ 1:6 Hz,
1H, CHP); 1.32 and 1.16 (2d, J ¼ 6:7 Hz, 3H, CH3).
31P NMR (NaOD/D2O, 81 MHz): d 28.52 and 26.04
(2:1).
3.1.1. N-benzylamino(ferrocenyl)methane phosphonous
acid (3a)
EI-MS: m=z ¼ 383[Mþ]; 317[Mþ–P(OH)2]; 213[Fc–
CH@Nþ]; 121[CpFeþ]; 91[þCH2Ph]; 65[Cpþ].
Elemental analysis: Anal. Found:C, 59.17; H, 5.86;
N, 3.59%. Calc. for (C19H22FeNO2P): C, 59.55; H, 5.79;
N, 3.66.
Y ¼ (27%); m.p.: 206–208 °C.
1H NMR (NaOD/D2O, 200 MHz): d 7.44(m, ArH,
5H); 6.68 (dd, 1JPH ¼ 516:2 Hz and 3JHH ¼ 2:8 Hz, HP,
1H); 4.30 and 4.26 (m, CHfer, 2H); 4.21 (s, CHfer, 5H);
2
4.13 (s, CH2, 2H); 3.38 (dd, JPH ¼ 10:8 Hz and
3JHH ¼ 2:8 Hz, 1H).
3.2. Cholesteryl and isopropylidene adenosinyl
amino(ferrocenyl)methane phosphonite. Typical proce-
dure
31P NMR (NaOD/D2O, 81 MHz): d 31.28.
EI-MS: m=z ¼ 369[Mþ]; 303[Mþ–P(OH)2]; 213[Fc–
CH@Nþ]; 121[CpFeþ]; 91[þCH2Ph]; 65[Cpþ].
Elemental analysis: Anal. Found: C, 58.51; H, 5.29;
N, 3.77%. Calc. for (C18H20FeNO2P): C, 58.56; H, 5.46;
N, 3.79.
To a suspension of aminophosphonous acid 3a–d
(0.005 mol) in dichloromethane (30 ml), 0.005 mol of an
appropriete alcohol (cholesterol or isopropylidene
adenosine) and 0.005 mol (1.03 g) of DCC were added.
The mixture was then refluxed for 10 h with vigorous
stirring, then stirred overnight at room temperature and
the procedure repeated during next 7 days. After, the
mixture was filtered, the solid residue washed with di-
chloromethane and then discarded. The filtrate was
evaporated, the residue was re-dissolved in chloroform,
shaken with charcoal, filtered then chromatographed on
cellulose powder and evaporated to obtain the pure
product 3a–d and 4a–d.
3.1.2. N-furfurylamino(ferrocenyl)methane phosphonous
acid (3b)
Y ¼ (24%); m.p.: 194–196 °C.
1H NMR (NaOD/D2O, 200 MHz): d 7.56 (m, CHfur
,
1H); 6.47 (m, CHfur, 2H); 6.61 (dd, 1JPH ¼ 516:2 Hz and
3JHH ¼ 2:8 Hz, HP, 1H); 4.30 and 4.26 (m, CHfer, 4H);
4.21 (s, CHfer, 5H); 4.13 (s, CH2, 2H); 3.38 (dd,
3
2JPH ¼ 10:8 Hz and JHH ¼ 2:8 Hz, 1H).
31P NMR (NaOD/D2O, 81 MHz): d 30.34.
EI-MS: m=z ¼ 359[Mþ]; 293[Mþ–P(OH)2]; 213[Fc–
CH@Nþ]; 121[CpFeþ]; 81[þCH2Fur]; 65[Cpþ].
Elemental analysis: Anal. Found: C, 53.20; H, 5.03;
N, 3.94%. Calc. for (C16H18NO3PFe): C, 53.51; H, 5.05;
N, 3.90.
3.2.1. Cholesteryl N-benzylamino(ferrocenyl)methane
phosphonite (4a)
Y ¼ 1.07 g (29%); oily liquid.
1H NMR (CDCl3, 200 MHz): d 7.32 (m, PhH, 5H);
1
6.94 and 6.86 (2d, JPH ¼ 546:3 Hz, HP, 1H); 5.34 (m,
3.1.3. N-diphenylmethylamino(ferrocenyl)methane phos-
phonous acid (3c)
CH–Ocholest, 1H); 4.26 and 4.17 (m, CHfer, 4H); 4.10 (s,
CHfer, 5H); 3.53 (m, CH@Ccholest, 1H); 2.26 (m, CH2,
2H); 2.03–1.06 (m, CHcholest, 24H); 0.99 (s, CH3, 3H);
0.91 (d, J ¼ 9:4 Hz, CH3, 3H); 0.85 (d, J ¼ 6:6 Hz, CH3,
3H); 0.66 (s, CH3, 3H). 13C NMR (CDCl3, 50 MHz): d
149.0 (Ccholest); 141.5 (Cipso); 129.6 (Cortho); 130.4 and
Y ¼ (26%); m.p.: 191–194 °C.
1H NMR (NaOD/D2O, 200 MHz): d 7.35(m, ArH,
1
3
10H); 7.31 (dd, JPH ¼ 523:9 Hz and JHH ¼ 2:8 Hz,
HP, 1H); 5.62 (s, CH, 1H); 4.30 and 4.26 (m, CHfer, 2H);
2
1
4.21 (s, CHfer, 5H); 3.38 (dd, JPH ¼ 10:8 Hz and
129.6 (2d, JCP ¼ 105:6 Hz, C–P); 129.2 (Cmeta); 129.0
3JHH ¼ 2:8 Hz, 1H).
(Cpara); 122.8 (CHcholest); 70.9 (Cfer); 69.3 (Cp); 69.0
(Cfer); 68.7 (Cfer); 67.1 (CHcholest); 49.1 (CH2); 48.2, 46.4,
42.8, 40.5, 39.5 (Ccholest); 39.9, 39.7, 32.9, 32.7, 31.8,
30.2, 25.3, 21.6, 20.9 (CHc2holest); 48.2, 46.4, 42.8, 29.6,
EI-MS: m=z ¼ 445[Mþ]; 379[Mþ–P(OH)2]; 213[Fc–
CH@Nþ]; 121[CpFeþ]; 167[þCHPh2]; 65[Cpþ].
31P NMR (NaOD/D2O, 81 MHz): d 28.52.

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J. Lewkowski et al. / Journal of Organometallic Chemistry 689 (2004) 1684–1690
29.4, 28.5 (CHcholest); 22.3, 20.3, 18.5 (CHc3holest). 31P
NMR (CDCl3, 81 MHz): d 35.26, 35.14, 34.90, 34.86
(4:4:1:1).
Elemental analysis: Anal. Found: C, 75.21; H, 8.42;
N, 1.93%. Calc. for (C51H68FeNO2P): C, 75.26; H, 8.42;
N, 1.72.
FAB-MS: m=z ¼ 737[Mþ]; 304[Mþ–HP(O)OC27H45];
213[Fc–CH@NH]; 107 [þCH2Ph].
Elemental analysis: Anal. Found: C, 72.94; H, 9.02;
N, 2.11%. Calc. for (C45H64NO2PFe): C, 73.25; H, 8.74;
N, 1.90.
3.2.4. Cholesteryl N-(R)-a-methylbenzylamino(ferroce-
nyl)methane phosphonite (4d)
Y ¼ 2.37 g (63%); m.p.: 100–102 °C.
1H NMR (CDCl3, 200 MHz): d 7.43-7.33 (m, ArH,
1
5H); 7.05 and 7.01 (2d, JPH ¼ 537:1 Hz, HP, 1H); 5.40
3.2.2. Cholesteryl N-furfurylamino(ferrocenyl)methane
phosphonite (4b)
and 5.37 (m, CH–Ocholest, 1H); 4.27 and 4.19 (m, CHfer,
4H); 4.14 (s, CHfer, 5H); 3.60 (2m, CH–N, 1H); 3.67 (d,
1JPH ¼ 13:7 Hz, 1H); 3.52 (m, C@CHcholest, 1H); 2.28
(m, CH2C–Ocholest, 2H); 2.03–1.11 (m, CHcholest and
CH3 33H); 1.00 (s, CH3, 3H); 0.90 (d, J ¼ 9:2 Hz, CH3,
3H); 0.87 (d, J ¼ 6:6 Hz, 2xCH3, 6H); 0.67 (s, CH3, 3H).
13C NMR (CDCl3, 50 MHz): d 149.0 (Ccholest); 141.53
Y ¼ 2.05 g (56%); oily liquid.
5
1H NMR (CDCl3, 200 MHz): d 7.43 (m, Hfur, 1H);
1
6.83 and 6.75 (2d, JPH ¼ 543:9 Hz, HP, 1H); 6.37 (m,
4
3Hfur, 1H); 6.32 (m, Hfur, 1H); 5.37 (m, CH–Ocholest
,
1H); 4.26 and 4.18 (m, CHfer, 4H); 4.10 (s, CHfer, 5H);
3.53 (m, CH@Ccholest, 1H); 2.28 (m, CH2, 2H); 2.08-1.06
(m, CHcholest, 24H); 1.01 (s, CH3, 3H); 0.91 (d, J ¼ 9:4
Hz, CH3, 3H); 0.87 (d, J ¼ 6:8 Hz, CH3, 3H); 0.68 (s,
CH3, 3H). 13C NMR (CDCl3, 50 MHz): d 149.5 (C2fur);
149.0 (Ccholest); 143.1 (C5fur); 129.8 and 129.0 (2d,
1JCP ¼ 104:6 Hz, C–P); 111.2 (C3fur); 111.0 (C4fur); 122.8
(CHcholest); 70.9 (Cfer); 69.3 (Cp); 69.0 (Cfer); 68.7 (Cfer);
67.1 (CHcholest); 47.19 (CH2); 48.2, 46.4, 42.8, 40.5, 39.5
(Ccholest); 39.9, 39.7, 32.9, 32.7, 31.8, 30.2, 25.3, 21.6,
20.9 (CHc2holest); 48.2, 46.4, 42.8, 29.6, 29.4, 28.5
(CHcholest); 22.3, 20.3, 18.5 (CHc3holest). 31P NMR
(CDCl3, 81 MHz): d 36.23, 36.05, 35.98, 35.85. (6:6:1:1).
FAB-MS: m=z ¼ 727[Mþ]; 294[Mþ–HP(O)OC27H45];
213[Fc–CH@NH]; 81 [þCH2Fur]; 65.1[Cpþ].
1
(Cipso); 129.6 (Cortho); 125.4 and 124.8 (2d, JCP ¼ 105:6
Hz, C–P); 129.2 (Cmeta); 129.0 (Cpara); 122.8 (CHcholest);
70.9 (Cfer); 69.3 (Cp); 69.0 (Cfer); 68.7 (Cfer); 67.1
(CHcholest); 49.4 (CH); 48.2, 46.4, 42.8, 40.5, 39.5
(Ccholest); 39.9, 39.7, 32.9, 32.7, 31.8, 30.2, 25.3, 21.6,
20.9 (CHc2holest); 48.2, 46.4, 42.8, 29.6, 29.4, 28.5
(CHcholest); 24.6 (CH3); 22.3, 20.3, 18.5 (CHc3holest). 31P
NMR (CDCl3, 81 MHz): d 35.72, 35.37 (1:2).
FAB-MS: m=z ¼ 751[Mþ]; 318[Mþ–HP(O)OC27H45];
213[Fc–CH@NH]; 105 [þCH(CH3)Ph]; 65.1[Cpþ].
Elemental analysis: Anal. Found: C, 73.40; H, 8.56;
N, 1.93%. Calc. for (C46H66FeNO2P): C, 73.49; H, 8.85;
N, 1.86.
Elemental analysis: Anal. Found: C, 70.66; H, 8.40;
N, 1.75%. Calc. for (C43H62NO3PFe): C, 70.96; H, 8.59;
N, 1.92.
3.2.5. O,O0-iso-propylideneadenosinyl N-benzylamino-
(ferrocenyl)methane phosphonite (5a)
Y ¼ 0.82 g (25%); m.p.: 66–69 °C.
1H NMR (CDCl3, 200 MHz): d 8.34 (s, AdenH2, 1H);
8.15 (s, AdenH8, 1H); 7.35 (m, PhH, NH2, 7H); 7.13 and
6.98 (2d, 1JPH ¼ 550:3 Hz, HP, 1H); 6.12 (m, H1ryb, 1H);
5.33 (m, H3ryb, 1H); 4.97 (m, Hr2yb, 1H); 4.26 and 4.17 (m,
H1ryb, CHfer, 5H); 4.12 (s, CHfer, 5H); 3.56 (m, CHr2yb;, 2H);
1.54 and 1.32 (2s, CH3, 2x3H). 13C NMR (CDCl3, 50
MHz): d 154.9 (Cade); 152.0 (CHade); 147.9 (CHade); 144.8
(Cade); 141.5 (Cipso); 129.6 (Cortho); 130.4 and 129.3 (2d,
1JCP ¼ 105:6 Hz, C–P); 129.2 (Cmeta); 129.0 (Cpara); 128.4
(CHade); 85.0, 75.7, 72.8, 70.5 (CHryb); 70.9 (Cfer); 69.3
3.2.3.
nyl)methane phosphonite (4c)
Cholesteryl
N-diphenylmethylamino(ferroce-
Y ¼ 2.89 g (71%); m.p.: 65–67 °C.
1H NMR (CDCl3, 200 MHz): d 7.51-07.22 (m, ArH,
10H); 7.20 and 7.00 (2d, 1JPH ¼ 548:4 Hz, HP, 1H); 5.34
(s, CH, 1H); 4.30 and 4.26 (m, CHfer, 2H); 4.21 (s, CHfer,
5H); 4.13 (s, CH, 1H); 3.63 (m, CH@Ccholest, 1H); 2.44
(m, CH2, 2H); 2.04–1.02 (m, CHcholest, 24H); 0.99 (s,
CH3, 3H); 0.91 (d, J ¼ 9:4 Hz, CH3, 3H); 0.87 (d,
J ¼ 6:8 Hz, CH3, 3H); 0.68 (s, CH3, 3H). 13C NMR
(CDCl3, 50 MHz): d 149.0 (Ccholest); 143.5 (Cipso); 129.0
(Cp); 69.0 (Cfer); 68.7 (Cfer); 60.5 (CHr2yb); 49.1 (CH2). 31
P
NMR (CDCl3, 81 MHz): d 37.95, 37.68, 37.41 (1:2:1).
1
(Cmeta); 129.0 and 128.2 (2d, JCP ¼ 105:6 Hz, C–P);
FAB-MS: m=z ¼ 658[Mþ]; 304[Mþ–HP(O)OAden];
213[Fc–CH@NH]; 135[C5H5Nþ5 ] 91[þCH2Ph].
Elemental analysis: Anal. Found: C, 56.84; H, 5.31;
N, 12.73%. Calc. for (C31H35FeN6O5P): C, 56.55; H,
5.36; N, 12.76.
128.4 (Cortho); 127.0 (Cpara); 122.8 (CHcholest); 70.9 (Cfer);
69.3 (Cp); 69.0 (Cfer); 68.7 (Cfer); 67.1 (CHcholest); 56.4
(CH); 48.2, 46.4, 42.8, 40.5, 39.5 (Ccholest); 39.9, 39.7,
32.9, 32.7, 31.8, 30.2, 25.3, 21.6, 20.9 (CHc2holest); 48.2,
46.4, 42.8, 29.6, 29.4, 28.5 (CHcholest); 22.3, 20.3, 18.5
(CHc3holest). 31P NMR (CDCl3, 81 MHz): d 33.65, 33.58,
32.81, 32.74 (2:2:3:3).
3.2.6. O,O0-iso-propylideneadenosinyl N-furfurylamino
(ferrocenyl)methane phosphonite (5b)
FAB-MS: m=z ¼ 813[Mþ]; 380[Mþ–HP(O)OC27H45];
213[Fc–CH@NH]; 167 [þCHPh2]; 121 [CpFeþ]; 65.1
[Cpþ].
Y ¼ 2.01 g (62%); m.p.: 86–89 °C.
1H NMR (CDCl3, 200 MHz): d 8.35 (s, AdenH2, 1H);
8.17 (s, AdenH8, 1H); 7.61 (m, 5Hfur, 1H); 7.38 (s, NH2,

J. Lewkowski et al. / Journal of Organometallic Chemistry 689 (2004) 1684–1690
1689
1
2H); 7.21 and 7.09 (2d, JPH ¼ 554:6 Hz, HP, 1H); 6.41
(Cpara); 128.4 (CHade); 85.0, 75.7, 72.8, 70.5 (CHryb); 70.9
(Cfer); 69.3 (Cp); 68.9 (Cfer); 68.7 (Cfer); 60.5 (CHr2yb);
49.4 (CH); 24.6 (CH3). 31P NMR (CDCl3, 81 MHz): d
38.12, 37.83 (1:2).
(m, Hfur, 1H); 6.31 (m, Hfur, 1H); 6.12 (m, H1ryb, 1H);
3
4
5.34 (m, H3ryb, 1H); 4.97 (m, H2ryb, 1H); 4.24 (m, H1ryb
1H); 4.10 (s, CHfer, 5H); 4.00 and 3.94 (m, CHfer, 4H);
3.56 (m, CHr2yb;, 2H); 1.54 and 1.32 (2s, CH3, 2x3H). 13
,
C
FAB-MS: m=z ¼ 672[Mþ]; 318[Mþ–HP(O)OAden];
NMR (CDCl3, 50 MHz): d 154.9 (Cade); 152.0 (CHade);
213[Fc–CH@NH]; 107 [þCH(CH3)Ph].
Elemental analysis: Anal. Found: C, 57.24; H, 5.34;
N, 12.73%. Calc. for (C32H37FeNO2P): C, 57.15; H,
5.55; N, 12.50.
149.53 (C2fur); 147.9 (CHade); 144.8 (Cade); 143.09 (Cf5ur);
1
129.8 and 128.7 (2d, JCP ¼ 104:6 Hz, C–P); 128.4
(CHade); 111.2 (Cf3ur); 111.0 (Cf4ur); 85.0, 75.7, 72.8, 70.5
(CHryb); 70.9 (Cfer); 69.3 (Cp); 69.0 (Cfer); 68.7 (Cfer);
60.5 (CHr2yb); 47.2 (CH2). 31P NMR (CDCl3, 81 MHz): d
43.03, 42.87, 42.69, 42.53 (2:2:1:1).
3.3. N0,N00-dicyclohexyl-N-guanidyno)(ferrocenyl)meth-
ane phosphonous acid. Typical procedure
FAB-MS: m=z ¼ 648[Mþ]; 294[Mþ–HP(O)OAden];
213[Fc–CH@NH]; 81 [þCH2Fur]; 65.1[Cpþ].
Elemental analysis: Anal. Found: C, 53.94; H, 5.31;
N, 12.73%. Calc. for (C29H33FeN6O6P): C, 53.72; H,
5.13; N, 12.96.
To a suspension of aminophosphonous acid 3a–d
(0.005 mol) in dichloromethane (30 ml), 0.005 mol
(1.03 g) of DCC were added. The mixture was then
refluxed for 10 hours with vigorous stirring, then stirred
overnight at room temperature and the procedure re-
peated during next 7 days. After, the mixture was fil-
tered through the cellulose powder pad and evaporated
to obtain the product 6a–b.
3.2.7. O,O0-iso-propylideneadenosinyl N-diphenylmeth-
ylamino(ferrocenyl)methane phosphonite (5c)
Y ¼ 2.39 g (65%); m.p.: 104–107 °C.
1H NMR (CDCl3, 200 MHz): d 8.34 (s, AdenH2, 1H);
8.15 (s, AdenH8, 1H); 7.45–7.35 (m, ArH, 10H); 6.78,
3.3.1. N0,N00-dicyclohexyl-N-benzyl-guanidyno)(ferroce-
nyl)methane phosphonous acid (6a)
1
6.66, 6.61 and 6.58 (4d, JPH ¼ 570:4, 579.3, 585.6 and
592.0 Hz, HP, 1H); 6.21 (m, H1ryb, 1H); 5.43 (m, Hr3yb
,
1H NMR (CDCl3, 200 MHz): d 7.43 (m, PhH, 10H);
1H); 5.07 (m, Hr2yb, 1H); 4.30 (m, Hr1yb, 1H); 4.18 and
4.12 (m, CHfer, 4H); 4.06 and 4.04 (2s, CHfer, 5H); 3.56
(m, CH2ryb;, 2H); 1.54 and 1.32 (2s, CH3, 2x3H). 13C
NMR (CDCl3, 50 MHz): d 154.9 (Cade); 152.0 (CHade);
147.9 (CHade); 144.8 (Cade); 143.53 (Cipso); 129.0 (Cmeta);
1
6.83 (d, JPH ¼ 543:9 Hz, HP, 1H); 4.28 (m, CH2, 2H);
4.26 and 4.18 (m, CHfer, 4H); 4.10 (s, CHfer, 5H); 1.40
and 1.35 (2m, Hcyclohex, 2 ꢀ 11H).
13C NMR (CDCl3, 50 MHz): d 156.73 (Cguanidine);
1
141.53 (Cipso); 129.63 (Cortho); 130.38 (d, JCP ¼ 105:6
1
129.0 and 128.4 (2d, JCP ¼ 105:6 Hz, C–P); 128.4
Hz, C–P); 129.16 (Cmeta); 128.99 (Cpara); 70.92 (Cfer);
69.27 (Cp); 68.96 (Cfer); 68.69 (Cfer); 49.07 (CH2); 34.94,
34.00 (Ccyclohex); 25.68, 25.48, 25.02, 24.91, 24.72
(Ccyclohex).
(Cortho); 126.99 (Cpara); 128.4 (CHade); 85.0, 75.7, 72.8,
70.5 (CHryb); 70.9 (Cfer); 69.3 (Cp); 69.0 (Cfer); 68.7
(Cfer); 60.5 (CH2ryb); 56.4 (CH). 31P NMR (CDCl3, 81
MHz): d 37.80, 37.53, 37.23, 37.14 (1:1:3:3).
FAB-MS: m=z ¼ 734[Mþ]; 380[Mþ–HP(O)OAden];
213[Fc–CH@NH]; 167 [þCHPh2].
31P NMR (CDCl3, 81 MHz): d 16.36 (large signal).
FAB-MS:
m=z ¼ 576[Mþ];
511[Mþ–P(OH)2];
495[Mþ–CH2Ph]; 420[Mþ–CH2Ph-P(OH)2]; 294 [þFc–
CH–NH-CH2Ph]; 213 [294 [Fc–CH–NHþ].
HRMS: Found: 575.51998; Calc. for (C31H42FeN3
O2P): 575.52009.
Elemental analysis: Anal. Found: C, 60.24; H, 5.51;
N, 11.73%. Calc. for (C51H68FeNO2P): C, 60.50; H,
5.35; N, 11.44.
3.2.8. O,O0-iso-propylideneadenosinyl N-(R)-a-methyl-
benzylamino(ferrocenyl)methane phosphonite (5d)
Y ¼ 2.32 g (69%); m.p.: 111–114 °C.
3.3.2.
N0,N00-dicyclohexyl-N-furfuryl-guanidyno)(ferr-
ocenyl)methane phosphonous acid (6b)
1H NMR (CDCl3, 200 MHz): d 7.51 and 7.36 (m,
1
1H NMR (CDCl3, 200 MHz): d 8.35 (s, AdenH2, 1H);
8.16 (s, AdenH8, 1H); 7.45–7.35 (m, ArH, 10H); 6.76
5Hfur, 2H); 6.83 (d, JPH ¼ 534:2 Hz, HP, 2H); 6.49 (m,
3Hfur, Hfur, 2H); 6.31 (m, Hfur, 1H); 6.28 (m, Hfur
1H); 4.61 (m, CH2, 2H); 4.17 and 4.15 (m, CHfer, 24H);
,
4
3
4
1
and 6.65 (4d, JPH ¼ 569:1, 571.3, 567.6 and 572.0 Hz,
HP, 1H); 6.21 (m, Hr1yb, 1H); 5.43 (m, Hr3yb, 1H); 5.07 (m,
H2ryb, 1H); 4.30 (m, Hr1yb, 1H); 4.18 and 4.12 (m, CHfer,
4H); 4.06 and 4.04 (2s, CHfer, 5H); 3.60 (2m, CH–N,
1H); 3.56 (m, CH2ryb;, 2H); 1.54 and 1.32 (2s, CH3,
2x3H); 1.12 (d, J ¼ 9:2 Hz, CH3, 3H). 13C NMR
(CDCl3, 50 MHz): d 154.9 (Cade); 152.0 (CHade); 147.9
(CHade); 144.8 (Cade); 141.5 (Cipso); 129.6 (Cortho); 125.4
and 124.2 (d, 1JCP ¼ 105:6 Hz, C–P); 129.2 (Cmeta); 129.0
4.09 (s, CHfer, 5H); 1.40 and 1.35 (2m, Hcyclohex,
2 ꢀ 11H).
13C NMR (CDCl3, 50 MHz): d 156.84 (Cguanidine);
149.53 (C2fur); 143.09 (Cf5ur); 129.80 (d, JCP ¼ 104:6 Hz,
1
C–P); 111.16 (Cf3ur); 110.99 (C4fur); 70.92 (Cfer); 69.27
(Cp); 68.96 (Cfer); 68.69 (Cfer); 49.07 (CH2); 34.94, 34.00
(Ccyclohex); 25.68, 25.48, 25.02, 24.91, 24.72 (Ccyclohex).
31P NMR (CDCl3, 81 MHz): d 13.91.

1690
J. Lewkowski et al. / Journal of Organometallic Chemistry 689 (2004) 1684–1690
FAB-MS: m=z ¼ 566[Mþ]; 501[Mþ–P(OH)2]; 485
[7] A.J. Moore, P.J. Skabara, M.R. Bryce, A.S. Batsanov, J.A.K.
Howard, S.T.A.K. Daley, J. Chem. Soc., Chem. Commun. (1993)
417–419.
[Mþ–CH2Fur]; 420[Mþ–CH2Fur-P(OH)2]; 294 [þFc–
CH–NH-CH2Fur]; 213 [Fc–CH–NHþ].
HRMS: Found: 565.48145; Calc. for (C29H40FeN3-
O3P): 565.48125.
€
[8] K. Schlogl, Monatsh. Chem. 88 (1957) 601–621.
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Acknowledgements
€
[13] H. Brunner;, W. Konig, B. Nuber, Tetrahedron: Asym. 4 (1993)
699–707.
The financial support of the Polish State Committee
for Scientific Research (KBN) is kindly acknowledged.
[14] H.-B. Kraatz, J. Lusztyk, G.D. Enright, Inorg. Chem. 36 (1997)
2400–2405.
€
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[15] J. Lewkowski, M. RzeYniczak, R. Skowronski, J. Zakrzewski,
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