Aminophosphinic acids in a pyridine series, Part 2: Synthesis of 2-, 3-, and 4-pyridyl derivatives of 1-(Benzylamino)-methyl-H-phosphinic Acids

Article abstract of DOI:10.1080/10426500902947666

New 2-pyridyl, 3-pyridyl, and 4-pyridyl derivatives of 1-[N-(benzyl)amino]- methyl-H-phosphinic acid were prepared by the addition of bis(trimethylsilyl) phosphonite to the corresponding imines and subsequent methanolysis of the addition products. Treatment of the 2-pyridyl- and 1-(4-pyridyl)-1-(benzylamino) -methyl-H-phosphinic acids with aqueous mineral acids leads to cleavage and formation of the corresponding secondary amines and phosphorous acid (H3PO3).

Full text of DOI:10.1080/10426500902947666

This article was downloaded by: [RMIT University]
On: 27 September 2013, At: 04:13
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH,
UK
Phosphorus, Sulfur, and Silicon
and the Related Elements
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/gpss20
Aminophosphinic Acids in
a Pyridine Series, Part 2:
Synthesis of 2-, 3-, and 4-
Pyridyl Derivatives of 1-
(Benzylamino)-methyl-H-
phosphinic Acids
Waldemar Goldeman a & Bogdan Boduszek a
a Department of Organic Chemistry, Faculty of
Chemistry, Wrocław University of Technology,
Wrocław, Poland
Published online: 06 Jun 2009.
To cite this article: Waldemar Goldeman & Bogdan Boduszek (2009) Aminophosphinic
Acids in a Pyridine Series, Part 2: Synthesis of 2-, 3-, and 4-Pyridyl Derivatives of 1-
(Benzylamino)-methyl-H-phosphinic Acids, Phosphorus, Sulfur, and Silicon and the
Related Elements, 184:6, 1413-1425, DOI: 10.1080/10426500902947666
To link to this article: http://dx.doi.org/10.1080/10426500902947666
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the
information (the “Content”) contained in the publications on our platform.
However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness,
or suitability for any purpose of the Content. Any opinions and views
expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the
Content should not be relied upon and should be independently verified with

primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages,
and other liabilities whatsoever or howsoever caused arising directly or
indirectly in connection with, in relation to or arising out of the use of the
Content.
This article may be used for research, teaching, and private study purposes.
Any substantial or systematic reproduction, redistribution, reselling, loan,
sub-licensing, systematic supply, or distribution in any form to anyone is
expressly forbidden. Terms & Conditions of access and use can be found at
http://www.tandfonline.com/page/terms-and-conditions

Phosphorus, Sulfur, and Silicon, 184:1413–1425, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500902947666
Aminophosphinic Acids in a Pyridine Series, Part 2:
Synthesis of 2-, 3-, and 4-Pyridyl Derivatives of
1-(Benzylamino)-methyl-H-phosphinic Acids
Waldemar Goldeman and Bogdan Boduszek
Department of Organic Chemistry, Faculty of Chemistry, Wroclꢀaw
University of Technology, Wroclꢀaw, Poland
New 2-pyridyl, 3-pyridyl, and 4-pyridyl derivatives of 1-[N-(benzyl)amino]-methyl-
H-phosphinic acid were prepared by the addition of bis(trimethylsilyl)phosphonite
to the corresponding imines and subsequent methanolysis of the addition prod-
ucts. Treatment of the 2-pyridyl- and 1-(4-pyridyl)-1-(benzylamino)-methyl-H-
phosphinic acids with aqueous mineral acids leads to cleavage and formation of
the corresponding secondary amines and phosphorous acid (H PO ).
3
3
Keywords Aldimines; aminophoshinic acids; bis(trimethylsilyl)phosphonite (BTSP);
phosphinic acids; pyridines
INTRODUCTION
1-Aminoalkyl-H-phosphinic acids are isoelectronic and isosteric
analogs of 1-aminoalkylcarboxylic acids and have interesting biolog-
ical activity. For example, they are inhibitors of several enzymes, such
as an angiotensin-converting enzyme (Phosinopril),2 HIV protease,3
glutamine synthetase,4 and CN-ligase.5 Although the C P bond in the
aminophosphonates or in aminophosphonic acids is generally believed
to be stable in the basic or acidic medium, there are reports that some
aminophosphonic and aminophosphinic acids are susceptible to cleav-
age under such conditions.
A few years ago, we described and analyzed the acidic cleavage
of 2- and 4-pyridine derivatives of aminomethylphosphonic acid6 and
Received 30 November 2007; accepted 22 February 2008.
Dedicated to Professor Marian Mikolꢀajczyk, CBMiM PAN in Lꢀ o´dz´, Poland, on the
occasion of his 70th birthday.
The authors are thankful to the Faculty of Chemistry, Wroclꢀaw University of Tech-
nology, Wroclꢀaw, Poland for financial support.
Address correspondence to Bogdan Boduszek, Department of Organic Chemistry, Fac-
ulty of Chemistry, Wroclꢀaw University of Technology, Wybrzez˙e Wyspian´skiego 27, 50-370
Wroclꢀaw, Poland. E-mail: bogdan.boduszek@pwr.wroc.pl
1413

1414
W. Goldeman and B. Boduszek
their esters,6a aminomethyl(phenyl)-phosphinic acids,1,7 aminophos-
phine oxides,8 and some heterocyclic aminophosphonic derivatives of
2-pyrone, 2-chromone, and 4-coumarin.9
Pyridine derivatives of aminophosphonic and aminophosphinic
acids are currently known, in contrast to pyridine derivatives of
aminomethyl-H-phosphinic acids, having a P-H bond in the molecule.
They are also named the phosphonous acids. Among them, only the
1-amino-1-(3-pirydyl)-methyl-H-phosphinic acid was described in the
literature.10 Therefore, we decided to prepare some new 2-, 3-, and 4-
pyridyl derivatives of 1-(benzylamino)-methyl-H-phosphinic acids and
examine their stability under acidic solutions.
RESULTS AND DISCUSSION
Synthesis of Pyridine 1-Benzylamino-methyl-H-phosphinic
Acids
Synthesis of N-substituted 1-aminoalkyl-H-phosphinic acids by ad-
dition of anhydrous hypophosphorous acid (H3PO2) to imines, like-
wise as the reaction of amine salts of hypophosphorous acid with
carbonyl compounds, were described in 1948 by Schmidt.11 Baylis
et al.12 applied various aldimines prepared from benzhydrylamine to
receive the corresponding 1-aminoalkyl-H-phosphinic acids in a simi-
lar reaction. Addition of anhydrous hypophosphorous acid to imines,
or in situ derived imines, are the most common ways to prepare 1-
aminoalkyl-H-phosphinic acids.11–14 Other methods, for example, an
addition of hypophosphorous acid to bisamides15; Kabachnik–Fields-
like reaction with use of amines, carbonyl compounds, and hypophos-
phorous acid16; and recently, an addition of ethyl diethoxymethylphos-
phinate to imines,17 were also applied.
A very specific hydrophosphinylating agent is the bis(trimethylsilyl)-
phosphonite (BTSP),24 which allows the reaction to be carried out
in mild conditions. The first report on the BTSP addition to benzyli-
dene aniline and/or benzylidenemethyl imine was written in 1984 by
Romanov et al.18 However, the first useful application of BTSP for the
synthesis of amino-H-phosphinic acids was described by Grobelny.19
This method, with applying the N-(diphenylmethyl)-imines, was
further modified by the use of other imines, including N-(trityl)-
imines,10a,20 some heterocyclic imines,21 and resin bounded imines.10b
In our investigations on the synthesis of 1-(N-alkylamino)methyl(n-
pyridine)-phosphinic acids, we focused on modifications of the hy-
drophosphinylation of imines 3 by means of hypophosphorous acid (4A)
and its derivatives, including methyl phosphinate (4B) and BTPS (4C).

Aminophosphinic Acids in a Pyridine Series
1415
SCHEME 1
Thus, NMR monitoring of the reaction mixture of 2-pyridylmethyl-
benzylimine (3a) with anhydrous hypophosphorous acid (4A), af-
ter 2 h of reflux in absolute ethanol, revealed mainly the prod-
ucts of redox reaction, including phosphorous acid (8A) and N-(2-
pyridylmethyl)-benzylamine (7a), and also some other unidentified
compounds (Scheme 1). The obtained results suggested that an ap-
parent reduction of the starting imine (3a) by H3PO2 (4A) occurred as
a basic reaction under the conditions applied.
In turn, we examined the reaction of pyridine-2-carboxyaldehyde
(1a), benzylamine hydrochloride (2A), and hypophosphorous acid (4A)
in aqueous ethanol according to the procedure in the literature,12 except
that the reaction was run at room temperature (to prevent possible de-
compositions at higher temperature). After 3 days, the reaction mixture
contained ca. 40% of 1-benzylamino-1-(2-pyridyl)-methyl-H-phosphinic
acid (6a) and an unspecified amount of phosphorous acid (8A). By anal-
ogy with the data in the literature data,22 we have assumed that the use
of amine hydrochloride should prevent a possible reduction of the imine
3 by hypophosphorous acid. So, in this case, the presence of the H3PO3
clearly suggested a cleavage of the initially formed aminophosphinate
6, according to the pattern previously described by one of us.6a
For this reason, we have decided to use BTSP as the hydrophos-
phinylating agent. Thus, the reaction of BTSP with n-pyridylmethyl-
enebenzylamines 3a–c in dichloromethane solution occurred smoothly
and afforded the appropriate silyl esters 5, easily convertible to the final
amino-H-phosphinic acids 6a–c, by methanolysis (Scheme 2). Crystal-
lizations of 6a–c were performed in acetone or acetone-diethyl ether
mixtures affording the pure amino acids with average to good yields
(Table I).
In continuation, we applied this procedure to prepare the pure
optically active diastereomers of corresponding 1-(α-methylbenzyl-
amino)-1-(n-pyridyl)methyl-H-phosphinic acids 6d–f, by using

1416
W. Goldeman and B. Boduszek
SCHEME 2
(S)-α-methylbenzylamine for preparation of imines 3d–f. The crude
reaction mixtures of 6d–f were found to contain the diastereomeric
pairs [(S, S)-6 and (S, R)-6, respectively] existing in a following molar
ratio (determined by 31P NMR spectra): for 6d (2-Py) 58:42, for 6e
(3-Py) 60:40, and for 6f (4-Py) 61:39, respectively.
The major diastereomers of 6d–f were isolated by crystallization
from acetone or acetone-diethyl ether. Yields of all of the obtained 6d–f
are collected in the Table I.
Major diastereomers of 6d–f, were found to possess an opposite (R)
1
configuration on the tertiary α-carbon atom, according to the H and
31P NMR spectra and also in line with the data in the literature of
parent aminophosphine oxides.8
TABLE I 1-(N-Benzylamino)-n-pyridinemethyl-H-phosphinic Acids
6a–f
Yields [%]
n-Py
R
31P NMR yields
Isolation yields
6a
6b
6c
6d
6e
6f
2-Py
3-Py
4-Py
2-Py
3-Py
4-Py
PhCH2
PhCH2
PhCH2
(S)-Ph(CH3)CH
(S)-Ph(CH3)CH
(S)-Ph(CH3)CH
not determined
not determined
not determined
40
79
46
65
60
69
19a
28a
8a
aYield given for pure diastereomer.

Aminophosphinic Acids in a Pyridine Series
1417
SCHEME 3
Since the diastereomerically pure pyridine aminophosphinic acids
6d–f were obtained in low yields (Table I), we looked for alternative
methods of synthesis of these compounds. However, the additions either
hypophosphorous acid (4A) or methyl phosphonite (4B)23 to 3f were
found to afford mainly the products of the redox reaction. Thus, in
the latter case, methyl phosphonate (8B) and secondary 4-pyridyl-α-
methylbenzylamine (7f) (separated with 69% yield as 7f × C2O4H2)
were found as major constituents of the reaction mixture (Scheme 3).
Structures of the obtained products 6a–f were determined by spec-
1
troscopy methods H, 13C, 31P NMR, and IR) and by comparison with
1
data in the literature10,12 of similar compounds. In H NMR spectra
of the products 6a–f, there are observed the characteristic doublets at
∼
ca. 6.6–7.0 ppm with JP−H 550 Hz constants, responsible for the P-H
=
coupling.
Our results show that the title 2-, 3-, and 4-pyridyl derivatives of 1-
(benzylamino)-methyl-H-phosphinic acids 6 can be prepared by using
the BTSP in fair yields. Alternative application of other hydrophos-
phinylating reagents, such as hypophosphorous acid (4A) or methyl
phosphonate (4B), in reaction with imines 3, caused the redox-type re-
actions, suggesting the domination role of the reduction of imines 3 by
4A and/or 4B.
Acidic Cleavage of Pyridine 1-Benzylamino-methyl-H-
phosphinic Acids
Preliminary tests performed in the NMR tubes show that 1-
benzylamino-2-pyridylmethyl-H-phosphinic 6a,d and 1-benzylamino-
4-pyridylmethyl-H-phosphinic acids 6c,f are exceptionally easily
cleaved in 1M H2SO4/H2O (1M D2SO4/D2O) solutions at room tempera-
ture. In fact, after dissolving of amino acids 6a,d,e,f in 1M H2SO4/H2O

1418
W. Goldeman and B. Boduszek
SCHEME 4
(1M D2SO4/D2O) solutions, these compounds 6, according to 31P and
1H NMR data, practically disappeared in a few minutes of exposition.
The 31P NMR spectra of these solutions showed new peaks attributed
to phosphorous acid (8A), and 1H NMR spectra signals attributed
to the formed corresponding N-(n-pyridylmethyl)-benzylamines 7. A
presence of the formed products 7 and 8A indicates that the exam-
ined aminomethyl-H-phosphinic acids 6 are exceptionally susceptible
to breaking the C P bond under acidic conditions applied (Scheme 4).
In contrary, the corresponding 3-pyridyl derivatives 6b,e were
also cleaved, but more slowly and/or at considerably higher tem-
perature (ca ∼95◦C). It was estimated that rates of the cleavage of
1-(3-pyridyl)-1-(benzylamino)-methyl-H-phosphinic acids 6b,e were
several hundred times smaller at 95◦C than these of corresponding
2- or 4-pyridyl derivatives, easily cleaved at room temperature.
Since corresponding aminophosphonic analogs are stable at acidic
conditions, even at elevated temperatures,6a,b the susceptibility of
SCHEME 5

Aminophosphinic Acids in a Pyridine Series
1419
SCHEME 6
1-(3-pyridyl)-1-(benzylamino)-methyl-H-phosphinic acids 6b,e to
cleave was observed for the first time in our case.
These findings on the cleavage of all amino acids 6 examined
are in accordance with the data in the literature ontheacidic cleav-
age mechanisms of pyridine aminophosphonic acids,6 aminophos-
phinic acids,7 aminophosphine oxides,8 and also for 1-(hydroxyimino)-
methylphosphonates.25
By analogy with the data on the literature,6–8,25 two mechanisms of
cleavage of amino-H-phosphinic acids 6a–f, shown in Schemes 5 and 6,
respectively, are proposed.
Thus, the first mechanism drawn for the 6c,f (Scheme 5) is a
dissociative-type [SN1(P)], which assumes that after protonation of
the nitrogen atom, a cleavage of the C P bond occurs and the
metaphosphate-like moiety is departed, which then reacts with a nu-
cleophilic solvent to form the products.
The second one (Scheme 6) is an associative-type mechanism
[SN2(P)], which assumes first a nucleophilic attack of water (solvent)
molecule on the phosphorous atom, that consequently leads to breaking
of a C P bond.
Detailed kinetic and mechanistic studies on the cleavage of a series
of 2-, 3-, and 4-pyridine derivatives of aminomethyl-H-phosphinic acids
6 will be the subject of a separate article.
CONCLUSIONS
A series of new pyridine 1-N-(benzyl)amino-methyl-H-phosphinic acids
was synthesized by using bis(trimethylsilyl)-phosphonite (BTSP) in re-
action with pyridine imines in moderate yields. It was found that the
BTSP is a reagent of choice for the synthesis of these acids.

1420
W. Goldeman and B. Boduszek
The pyridine 1-N-(benzyl)amino-methyl-H-phosphinic acids were ex-
tremely unstable in acidic conditions. The sulfuric acid solutions of the
acids 6a–f decomposed quickly to form secondary pyridyl-benzylamines
and phosphorous acid. On the basis of the data in the literature, two
alternative mechanisms of the cleavage were proposed.
EXPERIMENTAL
1H, 31P and 13C NMR spectra were measured on a Bruker Avance
300 MHz spectrometer using TMS as an internal standard. IR spec-
tra were recorded on a Perkin Elmer 1600 FTIR spectrophotometer.
Melting points were determined using an Electrothermal 9200 ap-
paratus and a Boetius hot-stage apparatus and were uncorrected.
Elemental analyses were done in Department of Chemistry, Univer-
sity of Wroclaw, Wroclꢀaw, Poland. Reagents used were obtained from
´
the Sigma–Aldrich Company (Poznan, Poland). Solvents were of com-
mercial quality and purchased from a local supplier (POCh Gliwice,
Poland).
Synthesis of 1-(Alkylamino)-pyridylphosphinic Acids 6a–f:
General Procedure
To a solution of benzyl- or (S)-α-methylbenzylamine (30 mmol) in
dichloromethane (25 mL), the appropriate pyridine aldehyde (30 mmol)
was added at 0◦C and the mixture was stirred overnight at room tem-
perature over the anhydrous sodium sulfate. The mixture was filtered
and washed with dichloromethane (3 × 5 mL), and the solution of crude
imine was cooled to 0◦C. Bis(trimethylsilyl) phosphonite (30 mmol) in
dry dichloromethane (25 mL) was added dropwise, and the mixture was
stirred at room temperature for 2 h and left overnight. Then the sol-
vent was evaporated, and the residue was treated with cold methanol
(30 mL). Addition of methanol caused separation of a precipitate, which
after 10 min dissolved. The solution was again evaporated under re-
duced pressure, giving a crude product as thick oil. The crude product
was crystallized from the appropriate solvent (the 3-pyridyl derivatives
crystallized from cold acetone, in contrary to the 2- and 4-derivatives,
which were crystallized from mixture of acetone and diethyl ether or
methanol/diethyl ether at –20◦C).
NOTE: All 2- and 4-pyridyl derivatives should be stored in a refrig-
erator under inert gas due to decomposition under prolonged influence
of moisture.

Aminophosphinic Acids in a Pyridine Series
1421
1-Benzylamino-1-(2-pyridyl)-methyl-H-phosphinic Acid (6a)
It was obtained as colorless crystals: yield 40%; mp 155–156 C.
1
31P{ H} NMR (D2O): δ = 17.6 (s). 1H NMR (D2O): δ = 8.52 (d, J =
4.5 Hz, 1H, 6-PyH); 7.80 (t, J = 7.7 Hz, 1H, 4-PyH); 7.27-7.37 (m,7H,
PhCH2, PyH); 7.00 (d, J = 557.0 Hz, 1H, P-H); 4.33 (d, J = 13.5 Hz,
1H, CHP); 4.17 (s, 2H, PhCH2). 13C NMR (D2O+NaOD): δ = 50.8 (d,
3JPC = 5.6 Hz, PhC); 61.8 (d, JPC = 80.2 Hz, PyC); 124.1; 124.7 (d, J =
3.0 Hz); 129.0; 129.6; 130.0; 138.3; 148.6 (d, JPC = 4.6 Hz); 149.3; 149.9.
FTIR, νmax (KBr [cm−1]): 3410, 3039, 2950, 2737, 2551, 2403, 2307 (H-
P), 1602, 1587, 1476, 1436, 1200 (P O), 1169, 1070 (P-OH), 1022 (H-P),
975, 911, 889, 854, 793, 749, 693, 643, 600, 559, 534, 509, 481. Elemen-
tal anal. for 6a, Calcd.: C, 59.53; H, 5.77; N, 10.68. Found: C, 59.45; H,
5.98; N, 10.59%.
1-Benzylamino-1-(3-pyridyl)-methyl-H-phosphinic Acid (6b)
It was obtained as colorless crystals: yield 79%; mp 214–216◦C.
1
31P{ H} NMR (D2O): δ = 18.0 (s). 1H NMR (D2O): δ = 8.52 (d, J =
5.0 Hz, 1H, 4-Py); 8.43 (s, 1H, 2-Py); 7.93 (d, J = 8.0 Hz, 1H, 6-Py,); 7.54
(dd, J = 5.0 Hz, J = 8.0 Hz, 1H, 5-Py,); 7.35 (m, 3H, PhCH2); 7.24–7.27
(m, 2H, PhCH2); 7.03 (d, J = 550.3 Hz, 1H, P-H); 4.28 (d, J = 12.9 Hz,
1H, CHP); 4.14 (s, 2H, PhCH2). 13C NMR (D2O+NaOD): δ = 50.6 (d,
3JPC = 14.2 Hz, PhC); 59.9 (d, JPC = 96.2 Hz, PyC); 124.2; 127.4; 128.6
(d, J = 5.0 Hz); 132.1; 132.2; 137.1 (d, JPC = 5.1 Hz); 138.0; 147.7; 147.7.
FTIR, νmax (KBr [cm−1]): 3445, 3409, 3034, 2979, 2742, 2596, 2326 (H-
P), 1616, 1575, 1479, 1456, 1425, 1361, 1182, 1162 (P O), 1080 (P-OH),
1056 (H-P), 1024, 988, 959, 913, 852, 813, 787, 752, 711, 698, 645, 615,
593, 550, 479. Elemental anal. for 6b, Calcd.: C, 59.53; H, 5.77; N, 10.68.
Found: C, 59.65; H, 6.03; N, 10.41%.
1-Benzylamino-1-(4-pyridyl)-methyl-H-phosphinic Acid (6c)
It was obtained as colorless crystals: yield 46%; mp 105–106◦C.
1
31P{ H} NMR (D2O): δ = 19.4 (s). 1H NMR (D2O): δ = 8.52 (d,
J = 4.7 Hz, 2H, 2-,6-Py); 7.53 (d, J = 4.7 Hz, 2H, 3-,5-Py); 7.27–
7.32 (m, 3H, PhCH2); 7.20–7.26 (m, 2H, PhCH2); 6.92 (d, J = 551.8
Hz, 1H, P-H); 4.20 (d, J = 14.5 Hz, 1H, CHP); 4.00 (s, 2H, PhCH2).
3
13C NMR (D2O+NaOD): δ = 50.8 (d, JPC = 14.2 Hz, PhC); 62.7 (d,
JPC = 92.3 Hz, PyC); 124.0 (d, JPC = 4.6 Hz); 124.4 (d, JPC = 4.2 Hz);
127.5; 128.6; 128.7; 138.0; 148.7. FTIR, νmax (KBr [cm−1]): 3425, 3032,
3008, 2974, 2746, 2585, 2343 (H-P), 2296, 1641, 1607, 1562, 1497, 1480,
1456, 1428, 1417, 1382, 1349, 1227 (P O), 1164 (P-OH), 1075 (H-P),
1044, 1006, 975, 913, 870, 855, 822, 798, 752, 698, 630, 599, 549, 504,
492, 477, 464, 428. Elemental anal. for 6c, Calcd.: C, 59.53; H, 5.77; N,
10.68. Found: C, 59.37; H, 6.08; N, 10.39%.

1422
W. Goldeman and B. Boduszek
1-[(S)-α-(Methylbenzylamino)]-1-(R)-(2-pyridyl)-methyl-H
-phosphinic Acid (6d)
It was obtained as colorless crystals. The isolated yield of pure di-
astereoisomer: 19%; mp 166–168◦C (31P NMR yield of crude 6d: 65%).
1
1
31P{ H} NMR (D2O): δ = 18.0 (s). H NMR (D2O): δ = 8.40 (d, J = 4.0
Hz, 1H, 6-PyH); 7.66 (t, J = 7.5 Hz, 1H, 4-PyH); 7.22 (m,6H, Ph, 5-
PyH); 7.12 (d, J = 7.6 Hz, 1H, 3-PyH); 6.95 (d, J = 557.4 Hz, 1H, P-H);
4.41 (q, J = 6.6 Hz, 1H, CHCH3); 4.26 (d, 1H, J = 13.7 Hz, CHP); 1.56
(d, J = 6.6 Hz, 3H, CH3). 13C NMR (D2O+NaOD): δ = 21.0 (CH3); 57.0
3
(d, JPC = 12.1 Hz, CH3C); 60.1 (d, JPC = 93.1 Hz, PyC); 122.6; 123.6
(d, JPC = 3.8 Hz); 126.8; 127.1; 128.3; 137.4; 143.9; 148.2; 156.1. FTIR,
νmax (KBr [cm−1]): 3425, 3052, 3011, 2973, 2933, 2640, 2437, 2311 (H-
P), 2193, 1964, 1606, 1591, 1572, 1515, 1499, 1481, 1471, 1433, 1376,
1355, 1318, 1267, 1228, 1207 (P O), 1171 (P-OH), 1154, 1094, 1084,
1060 (H-P), 1016, 1005, 984, 940, 921, 895, 846, 790, 763, 745, 698,
649, 617, 596, 546, 510, 481, 452. Elemental anal. for 6d, Calcd.: C,
60.86; H, 6.20; N, 10.14. Found: C, 60.37; H, 6.18; N, 10.20%.
1-[(S)-α-(Methylbenzylamino)]-1-(R)-(3-pyridyl)-methyl-
H -phosphinic Acid (6e)
It was obtained as colorless crystals. The isolated yield of pure di-
astereoisomer: 28%; mp 242–243◦C (31P NMR yield of crude 6e: 60%).
1
31P{ H} NMR (D2O): δ = 18.6 (s). 1H NMR (D2O): δ = 8.39 (d, J =
5.2 Hz, 1H, 4-Py); 8.22 (s, 1H, 2-Py); 7.79 (d, J = 7.8 Hz, 1H, 6-Py);
7.42 (dd, J = 7.8 Hz, J = 5.2 Hz, 1H, 5-Py); 7.25 (s, 5H, Ph); 7.03 (d,
J = 549.5 Hz, 1H, P-H); 4.41 (q, J = 6.8 Hz, 1H, CHCH3); 4.17 (d,
J = 13.6 Hz, 1H, CHP); 1.54 (d, J = 6.8 Hz, 3H, CH3). 13C NMR
3
(D2O+NaOD): δ = 21.0 (CH3); 56.9 (d, JPC = 11.7 Hz, CH3C); 59.9
(d, JPC = 94.4 Hz, PyC); 123.9; 126.9; 127.2; 128.4; 132.9 (d, JPC = 3.2
Hz); 136.9 (d, JPC = 5.1 Hz); 143.8; 147.2; 148.5 (d, JPC = 6.0 Hz). FTIR,
νmax (KBr [cm−1]): 3431, 3059, 3046, 3009, 2938, 2939, 2794, 2759,
2641, 2439, 2363, 2317 (H-P), 2195, 1968, 1898, 1726, 1607, 1583, 1574,
1511, 1500, 1481, 1456, 1426, 1379, 1359, 1340, 1318, 1303, 1275, 1215
(P O), 1192 (P-OH), 1168, 1123, 1102, 1086, 1061 (H-P), 1036, 1025,
1016, 1004, 964, 957, 945, 922, 839, 810, 766, 703, 657, 649, 614, 567,
548, 511, 480, 452. Elemental anal. for 6e, Calcd.: C, 60.86; H, 6.20; N,
10.14. Found: C, 60.57; H, 6.22; N, 9.89%.
1-[(S)-α-(Methylbenzylamino)]-1-(R)-(4-pyridyl)-methyl-
H-phosphinic Acid (6f)
It was obtained as colorless crystals: The isolated yield of pure di-
astereoisomer: 8%; mp 139–141◦C (31P NMR yield of crude 6f: 69%).

Aminophosphinic Acids in a Pyridine Series
1423
1
1
31P{ H} NMR (D2O): δ = 18.7 (s). H NMR (D2O): δ = 8.26 (d, J = 6.2
Hz, 2H, 2-,6-Py); 7.30 (d, J = 6.2 Hz, 2H, 3-,5-Py); 7.09 (5H, Ph); 6.84
(d, J = 549.6 Hz, 1H, P-H); 4.08 (q, J = 6.7 Hz, 1H, CHCH3); 4.04 (d,
J = 15.3 Hz, 1H, CHP); 1.39 (d, J = 6.7 Hz, 3H, CH3). 13C NMR
3
(D2O+NaOD): δ = 21.2 (CH3); 57.2 (d, JPC = 11.4 Hz, CH3C); 60.4
(d, JPC = 94.3 Hz, PyC); 123.9; 127.3; 128.5; 130,2; 137.0 (d, JPC = 4.9
Hz); 143.8; 148.6 (d, JPC = 6.0 Hz). FTIR, νmax (KBr [cm−1]): 3411, 3057,
3029, 2979, 2934, 2791, 2756, 2635, 2448, 2319 (H-P), 2190, 1599, 1560,
1500, 1478, 1455, 1433, 1418, 1378, 1350, 1320, 1273, 1231, 1206 (P O),
1169 (P-OH), 1124, 1086, 1059 (H-P), 1017, 992, 981, 916, 847, 830, 822,
768, 750, 701, 665, 628, 616, 588, 548, 524, 479, 454. Elemental anal. for
6f, Calcd.: C, 60.86; H, 6.20; N, 10.14. Found: C, 60.55; H, 6.28; N, 9.98%.
Cleavage in Sulfuric Acid Solution
A sample of pyridine aminophosphinic acid 6a,c,d,f (1.5 mmol) was
dissolved in 1M H2SO4/H2O solution (8 mL) and kept at room temper-
ature for 15–20 min. In the case of 3-pyridyl derivatives 6b,e (8 mL,
1.5 mmol), the solution was heated at 95◦C (water bath) for 3 h. Then
the mixture was alkalized with an excess of 5% aqueous sodium bicar-
bonate solution and extracted with methylene chloride (1 × 10 mL and
3 × 5 mL). Organic layers were collected, dried (anhydr. Na2SO4), and
evaporated to dryness to give the free amines. The amine was dissolved
in acetone (5 mL), oxalic acid [(COOH)2· 2 H2O; 0,19 g, 1.5 mmol] in
acetone (5 mL) was added, and the mixture was refrigerated overnight.
Separated precipitate was filtered off, washed with acetone (5 × 2 mL),
and dried on air.
N-(2-Pyridylmethyl)-benzylamine Oxalate (7a × C2O4H2)
Colorless solid: yield 84%; mp 208–210◦C (lit. 182–194 ◦C6a).
Free amine 7a: 1H NMR spectroscopic data consistent with that
reported.6a 13C NMR (D2O): δ = 50.1 (PyC); 51.0 (PhC); 124.6; 124.9;
129.4; 129.9; 130.0; 130.5 (1-Ph); 139.4 (5-Py); 149.0 (3-Py); 149.7 (1-
Py); 165.7 [(COOH)2].
N-(3-Pyridylmethyl)-benzylamine Oxalate (7b × C2O4H2)
1
Colorless solid: yield 89%; mp 233–235◦C. H NMR (D2O): δ = 8.70
(s, 1H, 2-PyH); 8,67 (d, J = 5.6 Hz, 1H, 4-PyH); 8.35 (d, J = 7.8 Hz, 1H,
6-PyH); 7.84 (dd, J = 5.6 Hz, J = 7.8 Hz, 1H, 5-PyH); 7.40 (s, 5H, Ph);
4.40 (s, 2H, PyCH2); 4.28 (s, 2H, PhCH2). 13C NMR (D2O): δ = 47.0
(PyC); 51.3 (PhC); 126.9; 129.3; 129.8; 129.9; 130.0 (1-Ph); 144.5; 144.6;
145.4 (1-Py); 145.5; 165.6 [(COOH)2].

1424
W. Goldeman and B. Boduszek
N-(4-Pyridylmethyl)-benzylamine Oxalate (7c × C2O4H2)
Colorless solid: yield 97%; mp 227–228◦C. (lit. 214–216◦C6a).
Free amine 7c: 1H NMR spectroscopic data are consistent with that
reported.6a 13C NMR (D2O): 48.8 (PyC); 51.8 (PhC); 127.3 (2-,6-Py);
129.5 (2-,6-Ph); 130.0 (1-Ph); 130.1 (4-Ph); 130.2 (3-,5-Ph); 142.3 (3-,5-
Py); 151.3 (1-Py); 165.6 [(COOH)2].
N-(2-Pyridylmethyl)-(S)-α-methylbenzylamine Oxalate
(7d × C2O4H2)
Colorless solid: yield 77%; mp 128–131◦C. (lit. 135–137◦C8). 1H NMR
spectroscopic data are consistent with that reported.8 13C NMR (D2O):
18.3 (CH3); 48.1 (PyC); 58.8 (PhC); 125.1; 125.3; 127.7; 129.4; 129.8;
135.1 (1-Ph); 140.9 (5-Py); 147.5 (3-Py); 148.7 (1-Py); 165.7 [(COOH)2].
N-(3-Pyridylmethyl)-(S)-α-methylbenzylamine Oxalate
(7e × C2O4H2)
1
Colorless solid: yield 93%; mp 184–186◦C. H NMR (D2O): 8.62 (d,
J = 5.5 Hz, 1H, 4-PyH); 8.54 (s, 1H, 2-PyH); 8.27 (d, J = 8.1 Hz,
1H, 6-PyH), 7.80 (dd, J = 8.1 Hz, J = 5.5 Hz, 1H, 5-PyH); 7.38 (s,
5H, Ph); 4.44 (q, J = 7.0 Hz, 1H, CHCH3); 4.30 (d, J = 14.1 Hz,
1H, PhCH2); 4.10 (d, J = 14.1 Hz, 1H, PhCH2); 1.61 (d, J = 7.0 Hz,
3H, CH3). 13C NMR (D2O): 18.5 (CH3); 45.7 (PyC); 59.2 (PhC); 127.0;
127.8; 129.6; 130.0; 130.6 (1-Ph); 135.1 (1-Py); 143.9; 143.9; 145.8; 166.3
[(COOH)2].
N-(4-Pyridylmethyl)-(S)-α-methylbenzylamine Oxalate
(7f × C2O4H2)
Colorless solid: solid: yield 93%; mp 189–192◦C (lit. 178–181◦C8). 1H
NMR spectroscopic data are consistent with that reported.8 13C NMR
(D2O): δ = 18.2 (CH3); 47.5 (PyC); 59.7 (PhC); 127.0 (2-,6-Py); 127.9
(2-,6-Ph); 129.5 (4-Ph); 130.1 (3-,5-Ph); 134.8 (1-Ph); 142.3 (3-,5-Py);
151.0 (1-Py); 165.7 [(COOH)2].
REFERENCES
[1] Part 1: B. Boduszek, T. Olszewski, W. Goldeman, and M. Konieczna, Phosphorus,
Sulfur, and Silicon, 181, 787 (2006).
[2] M. J. Wyvratt and A. A. Patchett, Med. Res. Rev., 5, 483 (1985).
[3] (a) A. Peyman, K.-H. Budt, J. Spanig, B. Stowasser, and D. Ruppert, Tetrahedron
Lett., 33, 4549 (1992); (b) A. Peyman, W. Stahl, K. Wagner, D. Ruppert, and K.-H.
Budt, Bioorg. Med. Chem. Lett., 4, 2601 (1994).
[4] (a) E. Bayer, K. H. Gugel, G. Ha¨gele, H. Hagenmaier, S. Jessipow, W. A. Ko¨nig, and
A. Za¨hner, Helv. Chim. Acta, 55, 224 (1972); (b) G. K. Farrington, A. Kumar, and
F. C. Wedler, J. Med. Chem., 30, 2062 (1987).

Aminophosphinic Acids in a Pyridine Series
1425
[5] W. H. Parson, A. A. Patchett, H. G. Bull, W. R. Schoen, D. Taub, J. Davidson, P. L.
Combs, J. P. Springer, H. Gadebush, B. Weissberger, M. E. Valiant, T. N. Mellin, and
R. D. Bush, J. Med. Chem., 31, 1772 (1988).
[6] (a) B. Boduszek, Tetrahedron, 52, 12483 (1996); (b) B. Boduszek, R. Latajka, and W.
Leniak, Phosphorus, Sulfur, and Silicon, 165, 53 (2000).
[7] B. Boduszek, Synth. Commun., 33, 4087 (2003).
[8] W. Goldeman, T. K. Olszewski, B. Poduszek, and W. Sawka-Dobrowolska, Tetrahe-
dron, 62, 4506 (2006).
[9] B. Boduszek, R. Latarka, and U. Walkowiak, Polish J. Chem., 75, 63 (2001).
[10] (a) X.-Y. Jiao, C. Verbruggen, M. Borloo, W. Bollaret, A. De Groot, R. Dommisse, and
A. Haemers, Synthesis, 23 (1994); (b) E. A. Boyd, W. C. Chan, and V. M. Loh Jr.,
Tetrahedron Lett., 37, 1647 (1996).
[11] H. Schmidt, Chem. Ber., 81, 477 (1948).
[12] E. K. Baylis, C. D. Campbell, and J. G. Dingwall, J. Chem. Soc., Perkin Trans., 1,
2845 (1984).
[13] (a) N. Kreutzkamp, C. Schimpfky, and K. Storck, Archiv der Pharmazie, 300, 868
(1967); (b) W. M. Linfield, E. Jungermann, and E. Guttmann, J. Org. Chem., 26,
4088 (1961).
[14] (a) R. Hamilton, B. Walker, and B. J. Wlaker, Tetrahedron Lett., 36, 4451 (1995); (b)
B. Kaboudin and N. As-Habeu, Tetrahedron Lett., 44, 4243 (2003).
[15] R. Tyka and G. Ha¨gele, Phosphorus, Sulfur, and Silicon, 44, 103 (1989).
[16] S. A. Beers, C. F. Schwender, D. A. Loughney, E. Malloy, K. Demarest, and J. Jordan,
Biorg. Med. Chem., 4, 1693 (1996).
[17] (a) J. G. Dingwall, J. Ehrenfreund, R. G. Hall, and J. Jack, Phosphorus, Sulfur, and
Silicon, 30, 571 (1987); (b) L. Maier and P. Diel, Phosphorus, Sulfur, and Silicon,
57, 57 (1991).
[18] G. V. Romanov, R. Ya. Natzmutdinov, T. Ya. Ryzhikova, T. V. Gryaznova, and A. N.
Pudovik, Zh. Obshch. Khim., 54, 1749 (1884).
[19] D. Grobelny, Synthesis, 942 (1987).
[20] E. A. Boyd, S. P. H. Alexander, D. A. Kendall, and V. M. Loh Jr., Bioorg. Med. Chem.
Lett., 6, 2137 (1996).
[21] M. Hatam and J. Martens, Synth. Comm., 25, 2553 (1995).
[22] D. Redmore, J. Org. Chem., 43, 992 (1978).
[23] H.-J. Cristau, A. Coulombeau, A. Genevois-Borella, F. Sanchez, and J.-L. Pirat, J.
Organomet. Chem., 643–644, 381 (2002).
[24] E. A. Boyd and A. C. Regan, Tetrahedron Lett., 33, 813 (1992).
[25] J. Katzhendler, R. Karaman, D. Gibson, and E. Breuer, J. Chem. Soc. Perkin Trans.,
2, 589 (1989).