Addition of Di-(trimethylsilyl)phosphite to N, N′-dialkyl terephthalic schiff bases: Synthesis of 1, 4-Phenylene-bis- (aminomethyl)- phosphonic acids

Article abstract of DOI:10.1002/hc.20569

The addition of di-(trimethylsilyl)- phosphite to N,N′- terephthalylidene-alkyl-(or aryl-)- amines resulted in 1, 4-phenylene-bis-(N- alkylamino- methyl)-phosphonic acids in moderate yields. The stereochemical behavior of such reactions was studied, and N

Full text of DOI:10.1002/hc.20569

Heteroatom Chemistry
Volume 20, Number 7, 2009
Addition of Di-(trimethylsilyl)phosphite to
ꢀ
N,N -Dialkyl Terephthalic Schiff Bases:
Synthesis of 1,4-Phenylene-bis-
(aminomethyl)-Phosphonic Acids
Jarosꢀlaw Lewkowski and Marek Dzie˛gielewski
Department of Organic Chemistry, University of Lꢀ o´dz´, Tamka 12, 91-403 Lꢀ o´dz´, Poland
Received 5 October 2009; revised 7 December 2009
ture of a substituent to an aromatic ring [2]. Similar
ABSTRACT: The addition of di-(trimethylsilyl)-
phosphite to N,Nꢀ-terephthalylidene-alkyl-(or aryl-)-
amines resulted in 1,4-phenylene-bis-(N-alkylamino-
methyl)-phosphonic acids in moderate yields. The
stereochemical behavior of such reactions was stud-
ied, and NMR studies demonstrated that, for several
examples, this reaction led to the exclusive forma-
tion of only one diastereomeric form. The investiga-
tion of the chiral salt of the acid identified the pair of
results have been reported for the addition of dialkyl
phosphites to achiral N-alkyl and N-aryl terephthalic
Schiff bases [1,3–7].
These 1,4-phenylene-bis-(N-alkylaminomethyl)-
phosphonic derivatives have been found to have co-
ordination abilities toward Cu(II) ions [8] or di-
aminophosphonate peptide receptor for lysine and
arginine [9]. So, investigations of these compounds
and their synthesis deal with not only their mecha-
nism but also their applications.
That is why, we have adopted a methodology
for the preparation of nonprotected aminophos-
phonic acids [10] and applied it with case to 1,
4-phenylene-bis-(N-alkylaminomethyl)-phosphonic
derivatives. To our knowledge, it is the first
example of the preparation of 1,4-phenylene-
bis-(N-alkylaminomethyl)-phosphonic acids via
the addition of di(trimethylsilyl)phosphite to the
azomethine bond of terephthalic Schiff bases.
ꢁ
C
enantiomers.
2010 Wiley Periodicals, Inc. Het-
eroatom Chem 20:431–435, 2009; Published online in
Wiley InterScience (www.interscience.wiley.com). DOI
10.1002/hc.20569
INTRODUCTION
The addition of hypophosphorous acid to tereph-
thalic Schiff bases was stereoselective in a major-
ity of cases. The addition of hypophosphorous acid
to achiral N-alkyl terephthalic imines has been re-
ported [1,2] to be diastereoselective to 100% and lead
to a meso-form, whereas the reaction performed on
N-aryl imines has been noted to depend on the na-
RESULTS AND DISCUSSION
We have chosen several model amines 1a–g and pre-
pared their imines 2a–g with terephthalic aldehyde.
Imines 2a–g were prepared following the modifica-
tion of commonly known procedure by the conden-
sation of corresponding amines 1a–g with tereph-
thalic aldehyde in methanol at room temperature.
Schiff bases 2a–g were obtained in almost quantita-
tive yields [2,6,7] (Scheme 1).
Correspondence to: Jaroslꢀaw Lewkowski; e-mail: jlewkow@
uni.lodz.pl.
Contract grant sponsor: University of Lꢀ o´dz´.
Contract grant number: 505/0683.
c
ꢀ
2010 Wiley Periodicals, Inc.
431

432 Lewkowski and Dzie¸gielewski
O
(EtO)2P(O)H
Me3SiBr
OH
OH
NR
RHN
P
P
CHO
(Me3SiO)2P(O)H
CH2Cl2
(1a–g)
RNH2
MeOH
CHO
OH
OH
NR
RHN
O
2a–g
3a–g
a: R = CH2Ph; b: R = CH2Fur; c: R = C(CH3)3; d: R = p-CH3C6H4; e: R = p-CH3OC6H4;
f: R = m-CH3C6H4; g: R = m-CH3OC6H4
SCHEME 1
1,4-Phenylene-bis-(N-alkylaminomethyl)-phos-
surprising that the crude product has a very sharp
melting point, but results of their elemental analysis
were not within the accepted range.
phonic acids 3a–g were prepared using the method
of Boduszek [10]. Diethyl phosphite was reacted
with bromotrimethylsilane in dry dichloromethane.
In situ formed di(trimethylsilyl) phosphite then
was reacted with terephthalic Schiff bases 2a–g
in dry dichloromethane, and in the end the re-
action was stopped by methanolysis (Scheme 1).
Acids 3a–g were obtained as powder solids with
moderate yields approximately 65%, which was
expected, as Barycki and coworkers [1] suggested
much lower conversion rate for addition to two
azomethine groups. Acids 3a–g were purified by
dissolution in 10% aqueous NaOH followed by
precipitation by acidification with 1 M HCl and gave
appropriate results of spectroscopic and elemental
analysis. Nevertheless, 1,4-phenylene-bis-(N-(m-
methoxyphenyl)aminomethylphosphonic acid) (3g)
decomposed in the above-described conditions.
Therefore, its purification was very troublesome
and its identity was confirmed only by the NMR
spectroscopy and mass spectrometry measurements
of the crude product without purification. It may be
The 1H and 31P NMR spectroscopy demonstrated
that all investigated N-alkyl substituted acids 3a–c
occurred exclusively as one of two possible di-
astereoisomeric forms. The same situation has been
noticed in a case of N-aryl substituted acids 3d
and 3e, which also exclusively occurred as one di-
astereoisomeric form. The N-aryl-substituted acids
3f–g occurred as the mixture of two diastereomeric
forms, in a 10:1 ratio for 3f and 3:2 for 3g.
The following experiment was performed to
establish that which diastereomeric form of acids
3a–e occurred as a sole product (Scheme 2). 1,4-
Phenylene-bis-(N-(p-methoxyphenyl)-aminomethy-
lphosphonic acid) (3e) was dissolved in deuter-
ated DMSO, and the stoichiometric amount of
(R)-α-methylbenzylamine was added to form the
ammonium salt of the phosphonic acid (4e). Al-
1
though the appearance of two sets of H and 13C
NMR signals and two 31P NMR signals of the formed
salt is expected theoretically in both cases of the
O
Ph
Ph
O
OH
OH
H
N
O
O
H
N
P
P
Ph
H3N
H3N
Me
Me
2
2
H2N
Me
H3CO
H3CO
H3CO
H3CO
DMSO-D6
OH
OH
O
O
N
H
P
N
H
P
O
O
3e
4e
and the (S,S) enantiomer
and the (S,S,R) isomer
SCHEME 2
Heteroatom Chemistry DOI 10.1002/hc

Addition of Di-(trimethylsilyl)phosphite to N,Nꢀ-Dialkyl Terephthalic Schiff Bases 433
meso form and the pair of enantiomers, we expected
The addition of either dialkyl phosphites [1–6] or
hypophosphorous acid [1,2] or described above ad-
dition of di(trimethylsilyl) phosphite led to the sim-
ilar diastereoselectivity but the other diastereoiso-
meric form occurred. We feel that the addition
of any phosphorus nucleophile to N-alkyl (or N-
alkylaryl) terephthalic Schiff bases leads to the ex-
clusive formation of one diastereomeric form and
in some cases it is a meso-form and in others a
pair of enantiomers, but it is diastereoselective to
100% [1–7]. Contrary to this, the addition of a phos-
phorus nucleophile to N-aryl terephthalic Schiff
bases is not so well stereochemically defined—its
stereochemistry depends greatly on a phosphorus
nucleophile and the nature of N-aryl substituent.
Generally, more electron-donating character N-aryl
groups have higher diastereoselectivity, as the pos-
sibility of the formation of the intermediate 6 in-
creases [7]. This problem, however, will be investi-
gated in various aromatic dialdehydes.
the occurrence of one set of 1H and 13C NMR signals
and one 31P NMR signal of the formed salt in the
case of the meso form as it has been demonstrated
previously in [2,6,7].
The formed salt 4e gave two 31P NMR signals
and two sets of 1H and 13C NMR key signals, i.e. the
P C H doublet as well as the C P bond doublet. The
optical rotation of the formed salt 4e after the crys-
tallization from acetone (+6.07◦, c = 0.016) differed
significantly from the optical rotation of the purified
salt 4e before crystallization (+10.89◦, c = 0.016). Si-
multaneously, we observed the decrease in the peak
height of the signal at 12.68. The ratio became from
1:1 to 3:2. This allowed us to suggest that the exclu-
sive diastereoisomeric form occurring in the case of
acids 3a–e is most probably a pair of enantiomers.
So, contrary to previously published cases of ad-
dition to achiral terephthalic Schiff bases (i.e., addi-
tions of dialkyl phosphites, hypophosphorous acid)
[2,6,7], the addition of di(trimethylsilyl)phosphite
led to the formation of the enantiomeric pair.
Our explanation of this effect is the following
and is concordant with analogous explanations of
similar cases, which we have published previously
[2,67]. Barycki et al. [1] suggested a two-step mech-
anism of this type reaction, the addition of a nu-
cleophile to the first azomethine bond to form the
imino-aminophosphonate derivative 5 and then to
the other. Considering it, it is possible that two
imino-aminophosphonate molecules 5 form an in-
termediate dimer 6, inside which the coordina-
tion of di(trimethylsilyl) phosphite molecules oc-
curs, which attacks from the defined sides leading
to two enantiomers of a di(aminophosphonic) acid
3 (Scheme 3). In this scheme, formation of the S,S
enantiomer is depicted.
EXPERIMENTAL
All solvents (POCh, Poland) were routinely distilled
and dried prior to use. Amines, diethyl phosphite
,and terephthalic aldehyde (Aldrich) were used as
received. NMR spectra were recorded on a Varian
Gemini 200 BB apparatus operating at 200 MHz (1H
NMR), 50 MHz (13C NMR), and 81 MHz (31P NMR).
Elemental analyses were carried out at the Centre
for Molecular and Macromolecular Science of the
Polish Academy of Science in Lꢀ o´dz´, Poland.
1,4-Phenylene-bis-(aminomethylphosphonic
Acids) (3a–g)
General
Procedure. Diethyl
phosphite
The results discussed above are surprisingly
contrary to previously reported observations [1–7].
(10 mmol) was dissolved in dry dichloromethane,
and to this solution bromotrimethylsilane (42 mmol,
HO
OH
RN
OH
HO
P
O
RHN
RHN
P
O
H
P
O
RN
H
O
NR
H
OTMS
OTMS
TMSO
TMSO
RHN
P
H
O
P
RN
NHR
O
OH
HO
O
P
P
OH
HO
OH
HO
5
6
3
SCHEME 3
Heteroatom Chemistry DOI 10.1002/hc

434 Lewkowski and Dzie¸gielewski
5.6 mL) was added dropwise for 15 min. The mix-
ture was stirred for 1 h at room temperature. Then,
a solution of an appropriate Schiff base (5 mmol)
in dry dichloromethane was added, and the mix-
ture was refluxed for 4 h. Then, the solution was
evaporated in vacuo, and the residue was dissolved
in dry methanol. It was stirred for 30–45 min until
precipitation of a solid, which was filtered off and
collected. In the case, if the solid did not precipi-
tated, 10–20 mL of propylene oxide was added and
the mixture was refrigerated for 3–7 days. Then
the solid was filtered off and collected. Products
were purified by dissolution in 10% aqueous NaOH
followed by precipitation by acidification with 1 M
HCl.
53.44; H, 5.71; N, 5.67;. Found: C, 53.83; H, 5.85; N,
5.48.
1,4-Phenylene-bis-(N-(p-methoxyphenyl)amino-
methylphosphonic Acid) 3e. Yield = 95% (2.40 g);
mp: 186–188◦C. 1H NMR (NaOD/D2O, 200 MHz):
δ 7.18 (s, C6H4, 4H); 6.56 (d, J = 9.1 Hz, Part of
AAꢀXXꢀ system, 4H); 6.48 (d, J = 9.1 Hz, Part of
2
AAꢀXXꢀ system, 4H); 4.22 (d, JPH = 20.3 Hz, PCH,
2H); 3.48 (s, OCH3, 6H). 31P NMR (NaOD/D2O,
81 MHz): δ 14.76. Elemental analysis: Calcd for
.
C22H26N2O8P2·2H2O: C, 48.54; H, 5.55; N, 5.14.
Found: C, 48.95; H, 5.45; N, 5.04.
1,4-Phenylene-bis-(N-(m-methylphenyl)aminome-
thylphosphonic Acid) 3f. Y = 32% (0.77 g); mp:
1
160–162◦C. H NMR (DMSO-D6, 200 MHz): δ 7.35
1,4-Phenylene-bis-(N-benzylaminomethylphosph-
onic Acid) 3a. Yield = 92% (2.2 g); mp 242–244◦C.
1H NMR (NaOD/D2O, 200 MHz): δ 7.27 (s, C6H4,
(s, C6H4, 4H); 6.84 (dd, J = 7.9 and 7.2 Hz, m-C6H4,
2H); 6.48 (s, m-C6H4, 2H); 6.41 (d, J = 7.9 Hz,
m-C6H4, 2H); 6.29 (d, J = 7.2 Hz, m-C6H4, 2H); 4.57
2
4H); 7.21 (m, PhH, 10 H); 3.61 (d, JPH = 16.5 Hz,
2
(d, JPH = 23.2 Hz, PCH, 2H); 2.09 (s, CH3, 6H). 31P
2H); 3.57 (d, J = 12.4 Hz, CHAHB, 2H); 3.43 (d,
J = 12.4 Hz, CHAHB, 2H). 31P NMR (NaOD/D2O,
NMR (DMSO-D6, 81 MHz): δ 17.20; 17.10 (10:1).
.
3
Elemental analysis: Calcd for C22H26N2O6P2 · /2H2O:
81 MHz): δ 15.13. Elemental analysis: Calcd for
.
C, 52.49; H, 5.81; N, 5.56. Found: C, 52.65; H, 6.10;
N, 5.22.
C22H26N2O6P2·2H2O: C, 51.57; H, 5.90; N, 5.47.
Found: C, 51.89; H, 5.12; N, 5.51.
1,4-Phenylene-bis-(N-(m-methoxyphenyl)amino-
methylphosphonic Acid) 3g. Yield = 46% (1.17 g);
mp: 236–238◦C. 1H NMR (NaOD/D2O, 200 MHz):
δ 7.18 (s, C6H4, 4H); 6.84 (dd, J = 8.0 and 8.2 Hz,
m-C6H4, 2H); 6.15 (m, m-C6H4, 2×2H); 6.05 (m,
m-C6H4, 2H); 4.25 (d, 2 JPH = 20.2 Hz, PCH, 2H); 3.42
1,4-Phenylene-bis-(N-furfurylaminomethylphos-
phonic Acid) 3b. Yield = 79% (1.80 g); mp: 190–
1
193◦C. H NMR (NaOD/D2O, 200 MHz): δ 7.25 (m,
CH5fur, 2H); 7.14 (s, C6H4, 4H); 6.17 (dd, J = 1.8 and
3.2 Hz, H4fur, 2H); 6.00 (d, J = 3.2, Hf3ur, 2H); 3.49
(d, J = 13.9 Hz, CHAHB, 2H); 3.42 (d, J = 13.9 Hz,
(s, OCH3, 6H). 31P NMR (NaOD/D O, 81 MHz): δ
.
2
2
CHAHB, 2H); 3.61 (d, JPH = 24.1 Hz, 2H). 31P NMR
14.45; 14.39 (3:2). EI-MS: m/z = 508 [M+]; 346 [M+
(NaOD/D O, 81 MHz): δ 15.09. Elemental analysis:
.
2
− (PO3H2)2].
1
Calcd for C18H22N2O8P2 /2H2O: C, 46.46; H, 4.98; N,
6.02. Found: C, 46.19; H, 5.01; N, 5.91.
1,4-Phenylene-bis-(N-(p-Methoxyphenyl)amino-
methylphosphonic Acid) di-(R)-α-Methyl-benzyl-
ammonium Salt (4e)
1,4-Phenylene-bis-(N-t-butylaminomethylphos-
phonic Acid) 3c. Yield = 80% (1.63 g); mp: 214–
216◦C. 1H NMR (NaOD/D2O, 200 MHz): δ 7.27
1,4-Phenylene-bis-(N-(p-methoxyphenyl)aminome-
thylphosphonic acid) (3e) (0.95 g, 5 mmol) was
dissolved in acetone, and (R)-α-methylbenzylamine
(2.42 g, 20 mmol) was added during vigorous stir-
ring. The mixture was stirred at room temperature
for 24 h; the precipitated solid was filtered off, dried,
and carried out NMR study. Before crystallization
[α]20 = +10.89◦ (c = 0.016) after [αχ]20 = +6.07◦
(c= 0.016).
2
(s, C6H4, 4H); 3.62 (d, JPH = 19.7, PCH, 2H);
0.64 (s, C(CH3)3, 18H). 31P NMR (NaOD/D2O,
81 MHz): δ 16.64. Elemental analysis: Calcd for
.
C16H30N2O6P2·3H2O: C, 41.56; H, 7.85; N, 6.06.
Found: C, 41.92; H, 7.94; N, 5.52.
1,4-Phenylene-bis-(N-(p-methylphenyl)aminome-
thylphosphonic Acid) 3d. Yield = 93% (2.23 g); mp:
183–185◦C. H NMR (NaOD/D2O, 200 MHz): δ 7.11
1H NMR (DMSO-D6, 200 MHz): δ 7.44 (m, ArH,
4H); 7.31 (m, ArH, 6H); 7.12 (s, C6H4, 4H); 6.56 (d,
J = 8.9 Hz, part of AAꢀXXꢀ system, 4H); 6.48 (d,
J = 8.9 Hz, part of AAꢀXXꢀ system, 4H); 4.15 and
1
(s, C6H4, 4H); 6.72 (d, J = 7.7 Hz, Part of AAꢀXXꢀ
system, 4H); 6.37 (d, J = 7.7 Hz, Part of AAꢀXXꢀ sys-
tem, 4H); 4.19 (d, 2 JPH = 20.4 Hz, PCH, 2H); 1.93 (s,
2
CH3, 6H). 31P NMR (NaOD/D O, 81 MHz): δ 14.76.
4.11 (2d, JPH = 21.6 Hz, PCH, 2H); 4.04 (q, J =
.
2
Elemental analysis: Calcd for C22H26N2O6P2·H2O: C,
5.1 Hz, CHCH3, 2H); 3.58 (s, OCH3, 6H); 1.39 (d,
Heteroatom Chemistry DOI 10.1002/hc

Addition of Di-(trimethylsilyl)phosphite to N,Nꢀ-Dialkyl Terephthalic Schiff Bases 435
J = 5.1 Hz, CHCH3, 6H). 31P NMR (DMSO-D6, 81
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.
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(Cipso), 139.18 (Cipso), 128.85 (Cmeta), 128.31 (Cmeta),
128.64 (Cpara), 127.26 (Cortho), 127.04 (Cortho), 122.84
(Cortho+meta), 58.89 and 58.81 (d, 1 JPH = 132.0 Hz, CP),
55.47 (OCH3), 50.18 (CHCH3), 21.26 (CHCH3).
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[8] Galꢀe¸zowska, J.; Szyrwiel, Lꢀ .; Mlꢀynarz, P.; Sliwin´ska,
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Heteroatom Chemistry DOI 10.1002/hc