Stereochemical aspects of the hypophosphorous acid addition to terephthalic schiff bases. Synthesis of new 1,4-phenylene-bis-aminomethane-bis-phosphonous acids

Article abstract of DOI:10.1002/hc.20422

Terephthalic Schiff bases react with hypophosphorous acid to form 1,4-phenylene-bis-N-alkyl-aminomethanephosphonous acids in moderate yields. NMR studies demonstrated that - for several examples-this reaction led to the exclusive formation of only one dia

Full text of DOI:10.1002/hc.20422

Heteroatom Chemistry
Volume 19, Number 3, 2008
Stereochemical Aspects of the
Hypophosphorous Acid Addition to
Terephthalic Schiff Bases. Synthesis
of New 1,4-Phenylene-bis-aminomethane-
bis-phosphonous Acids
Jaroslꢀ aw Lewkowski and Malꢀ gorzata Rybarczyk
Department of Organic Chemistry, University of Lꢀ o´dz´, Narutowicza 68, 90-136 Lꢀ o´dz´, Poland
Received 13 June 2007; revised 22 August 2007
of terephthalic Schiff. The first report was pub-
ABSTRACT: Terephthalic Schiff bases react with
lished by Pudovik et al. [1], presenting the synthe-
hypophosphorous acid to form 1,4-phenylene-bis-N-
sis of a variety of 1,4-phenylene-bis-amino-methane-
alkyl-aminomethanephosphonous acids in moderate
bis-phosphonates, and hence it has historical im-
yields. NMR studies demonstrated that—for several
portance. Later papers authored by Finocchiaro
examples—this reaction led to the exclusive forma-
et al. [2–4] and Gancarz et al. [5] presented the
tion of only one diastereomeric form. NMR investiga-
discussion on the stereochemical aspect of these
tion of a chiral salt identified the meso form. In con-
reactions. Our group has also contributed to this
trast hereto, a corresponding addition of hypophos-
topic reporting about the stereochemistry of ad-
phorous acid to a chiral Schiff base proved to be
dition reactions to various N-substituted tereph-
not stereoselective; all three possible diastereoisomers
thalic imines [6–9]. A comprehensive and detailed
ꢀ
C
were formed in a 4:1:1 ratio. 2008 Wiley Periodicals,
report on NMR spectroscopic and molecular model-
Inc. Heteroatom Chem 19:283–287, 2008; Published on-
ing studies of 1,4-phenylene-bis-aminomethane-bis-
line in Wiley InterScience (www.interscience.wiley.com).
phosphonates and related structures is given in [10].
DOI 10.1002/hc.20422
In
contrast
to
the
1,4-phenylene-bis-
aminomethane-bis-phosphonates, the correspond-
ing formation of aminophosphonous analogs was
scarcely studied and described. Only Gancarz’s
paper [5] described the synthesis of 1,4-phenylene-
bis-N-benzyl- and N-benzhydrylaminomethane-
bis-phosphonous acid. These authors reported the
exclusive formation of one diastereoisomeric form
but did not point out its configuration.
In this paper, we would like to present re-
sults from our studies on the addition of hy-
pophosphorous acid to terephthalic N-aliphatic
and N-aromatic Schiff bases and the synthesis of
several new 1,4-phenylene-bis-aminomethane-bis-
phosphonous acids.
INTRODUCTION
Studies on the addition of phosphites to symmet-
rical bis-Schiff bases were performed previously,
where particular attention was directed to reactions
This work is dedicated to my mentor Professor Romuald
Skowron´ski of the University of Lꢀ o´dz´, Lꢀ o´dz´, Poland on the oc-
casion of his 80th birthday.
Correspondence to: Jaroslꢀaw Lewkowski; e-mail: jlewkow@uni.
lodz.pl.
Contract grant sponsor: Polish Ministry of Higher Education
and Science.
c
ꢀ
2008 Wiley Periodicals, Inc.
283

284 Lewkowski and Rybarczyk
TABLE 1 Diastereomeric Composition of Products
RESULTS AND DISCUSSION
Schiff bases 2a–h were prepared following the pub-
lished procedure [6] by the condensation of cor-
responding amines with terephthalic aldehyde 1
in methanol at room temperature. Corresponding
imines were obtained in quantitative yields.
Number of
Diastereoisomers
Diastereomeric
Acid
R
Ratio
3a
3b
3c
3d
3e
3f
CH2Ph
CH2Fur
C(CH3)3
CHPh2
p-MeOC6H4
p-MeC6H4
m-MeOC6H4
m-MeC6H4
1
2
1
1
1
2
2
2
–
1:1
–
–
–
5:2
2:1
3:1
The
preparation
of
terephthalic
bis-
aminophosphonous acids 3a–h has been performed
adopting the general procedure reported by Baylis
et al. [11]. Reactions were carried out in boiling
acetonitrile for 5 h, and subsequently mixtures
were left overnight to stir at room temperature
(Scheme 1).
3g
3h
following cases: N-benzyl (3a), N-tert-butyl (3c), N-
benzhydryl (3d), and N-p-methoxyphenyl (3e). But
pairs of diastereoisomers were formed for cases: N-
m-methoxyphenyl (3f), N-p-methylphenyl (3g), and
N-m-methylphenyl (3h), in effect, which was rather
expected as addition of dialkyl phosphites to the
Schiff bases 2f–h led to both diastereomeric forms
[8]. In the case of the N-furfuryl-substituted product
(3b), both diastereomers were formed in a 1:1 ratio
(Table 1)
The novel phosphonous acids were obtained in
moderate yields varying from 40%–90%, which was
more then expected, since several authors [2–5] sug-
gested much lower conversion rates for additions to
two azomethine groups.
In general, two individual diastereoisomeric
forms might be expected for the title compounds:
a meso form and a racemic mixture. However, it
was proven in papers [2–10] that the addition of
dialkyl or diaryl phosphites to N-alkyl terephthalic
Schiff bases led to the exclusive formation of one di-
astereoisomeric form. Our previous study [6–9] re-
vealed that this diastereoisomer was the meso form.
On the other hand, the addition of dialkyl or diaryl
phosphites to N-aryl terephthalic Schiff bases led
exclusively either to the formation of the meso form
or to both diastereomeric forms, which depended
on the nature of the aryl substituent [8,9]. Our find-
ings are consistent with reports by Barycki et al. [5]:
these authors observed the exclusive formation of
one diastereoisomeric form for the addition of hy-
pophosphorous acid to N-benzyl terephthalic Schiff
base.
To determine the configuration of the
aminophosphonous acids 3a and 3c–e, which
occurred as pure but hitherto unknown diastere-
omeric forms, we prepared the chiral salts of acid
3e with (S)-α-methylbenzylamine by simply mixing
both components in methanol (Scheme 2).
1
1
We expected one set of H NMR and 31P{ H}
NMR signals for the meso form, whereas the racemic
mixture should give rise to two signal sets. Since
NMR spectra of this salt exhibited one set of signals
only, the exclusive formation of the meso form in the
reaction of hypophosphorous acid with terephthalic
Schiff bases is deduced unequivocally.
In our previous reports [6,8], the hypothetical
reasons were proposed for the highly stereoselec-
tive addition of dialkyl phosphites to achiral tereph-
thalic Schiff bases. This model may be also well
adapted to the case of the similar addition of hy-
pophosphorous acid. According to this hypothesis,
the reaction is controlled kinetically. The key step is
the formation of an active complex 6, consisting of
two molecules of iminoester 5, and two molecules of
phosphite linked to each other with hydrogen bonds
(Scheme 3), which forces the attack of the hypophos-
phorous acid molecule from one strictly defined side.
Therefore, when the possibility for the formation
of such a dimer is lower, the formation of both di-
astereoisomeric forms is expected. In the case of ad-
dition of dialkyl phosphites to the N-furfuryl tereph-
thalic Schiff base, the diaminophosphonic derivative
was formed in 100% diastereospecifity, whereas the
addition of hypophosphorous acid to this Schiff base
After analyzing all eight aminophosphonous
acids 3a–h, we realized that the addition reaction is
not diastereospecific for all cases. The exclusive for-
mation of one diastereoisomer was observed for the
SCHEME 1
Heteroatom Chemistry DOI 10.1002/hc

Stereochemical Aspects of the Hypophosphorous Acid Addition to Terephthalic Schiff Bases 285
SCHEME 2
SCHEME 3
led to the formation of both diastereoisomers in a 1:1
ratio.
These findings demonstrate that the influence
of the chiral substituent attached to nitrogen is
competing with the phenomenon discussed above,
determining the stereochemistry for additions of
hypophosphorous acid to terephthalic Schiff bases.
Intriguing stereochemical problems will encourage
forthcoming studies.
Since previous studies [12] showed that the ad-
dition of hypophosphorous acid to chiral (R)-N-α-
methylbenzyl Schiff bases is diastereoselective to
100% [12], we performed analogous addition to the
bifunctional N-(R)-α-methylbenzyl Schiff base 2i de-
rived from terephthalic aldehyde.
Using those Schiff bases, we expected to
obtain exclusively the (S, S) diastereoisomer 3i,
but in practice a mixture of all three possi-
ble diastereoisomers of 1,4-phenylene-bis-(N-(R)-α-
methyl-benzylaminomethanephosphonous) acid ex-
hibited a 4:1:1 ratio for 3i, 3iꢁ, and 3iꢁꢁ and a total
yield of 97% (Scheme 4).
EXPERIMENTAL
All solvents were routinely distilled prior to use. Hy-
pophosphorous acid 50% (Aldrich, Poznan´, Poland)
was dehydrated following the published procedure
[10]. Amines and terephthalic aldehyde (Aldrich)
were used as received. Schiff bases 2a–i were
SCHEME 4
Heteroatom Chemistry DOI 10.1002/hc

286 Lewkowski and Rybarczyk
1
31P { H} NMR (NaOD/D2O, 81 MHz): δ 29.66. Anal.
prepared following the previously published proce-
dure [6,8]. NMR spectra were recorded on a Var-
ian Gemini 200 BB apparatus operating at 200 MHz
(1H NMR) with internal TMS standard and 81 MHz
Calcd for C16H30N2O4P2: C, 51.06; H, 8.03; N, 7.44.
Found: C, 50.86; H, 7.93; N, 7.23.
1
(31P{ H} NMR) with external 85% H3PO4 standard.
1,4-Phenylene-bis-(N-benzhdrylaminomethanephos-
Elemental analyses were made in the Center for
Molecular and Macromolecular Science of the Polish
Academy of Science in Lꢀ o´dz´.
phonous) Acid (3d). Y = 20% (1.19 g); mp: 242–
245◦C. H NMR (DMSO, 200 MHz): δ 8.21 (s, C6H4,
1
1
4H); 7.35 (m, C6H5, 20H); 6.74 (d, JPH = 524.0 Hz,
2
PH, 2H); 5.71 (s, CHPh2, 2H); 5.02 (d, JPH = –17.8
Hz, PCH, 2H). 31P { H} NMR (DMSO, 81 MHz): δ
1
1,4-Phenylene-bis-aminomethanephosphonous
Acids (3a–i). General Procedure
23.35. Anal. Calcd for C34H34N2O4P2: C, 68.45; H,
5.74; N, 4.70. Found: C, 68.21; H, 5.72; N, 4.77.
Terephthalic aldehyde (10 mmol, 1.34 g) was dis-
solved in 30 mL of methanol, and the appropriate
amine (20 mmol) was added. The mixture was stirred
overnight at room temperature, then it was evap-
orated, redissolved in dichloromethane, dried over
MgSO4, filtered, and evaporated. The residue, which
was the pure Schiff base, was dissolved in 40 mL of
acetonitrile, and hypophosphorous acid (20 mmol,
1.32 g) was added. The mixture was refluxed for 5 h
and then stirred overnight at room temperature. The
precipitated solid was collected by filtration, washed
with cold water then cold methanol to give almost
pure acids 3a–i. Compounds 3d and 3h–i were ad-
ditionally purified by dissolving in aqueous NaOH
solution and precipitating by acidification.
1,4-Phenylene-bis-(N-p-methoxyphenylamino-
methanephosphonous) Acid (3e). Y = 77% (3.67 g);
mp: 183–186◦C. 1H NMR (DMSO, 200 MHz): δ
7.27 (s, C6H4, 4H); 6.58 (m, p-C6H4, 8H); 6.87 (d,
2
1 JPH = 526.5 Hz, PH, 2H); 4.42 (d, JPH = –17.0 Hz,
1
PCH, 2H); 3.46 (s, CH3, 6H). 31P { H} NMR (DMSO,
81 MHz): δ 24.82. Anal. Calcd for C22H26N2O6P2: C,
55.47; H, 5.50; N, 5.88. Found: C, 55.17; H, 5.40; N,
5.72.
1,4-Phenylene-bis-(N-p-methylphenylamino-
methanephosphonous) Acid (3f). Y = 54% (2.40 g);
mp: 138–140◦C. 1H NMR (DMSO, 200 MHz): δ
7.31 (s, C6H4, 4H); 6.75 (m, p-C6H4, 4H); 6.53 (m,
1
p-C6H4, 4H); 6.87 (d, JPH = 526.5 Hz, PH, 2H); 4.52
1,4-Phenylene-bis-(N-benzylaminomethanephos-
phonous) Acid (3a). Y = 89% (3.95 g); mp 235–
238◦C (lit. [5] 243–246◦C). 1H NMR (NaOD/D2O, 200
MHz): δ 7.12 (s, C6H4, 4H); 7.04 (m, C6H5, 10H); 6.67
(d, 2 JPH = –17.3 Hz, PCH, 2H); 2.07 (s, CH3, 6H). 31
P
1
{ H} NMR (DMSO, 81 MHz): δ 25.07 and 24.91,
(5:2). Anal. Calcd for C22H26N2O4P2: C, 59.46; H,
5.90; N, 6.30. Found: C, 59.05; H, 5.97; N, 6.09.
1
2
(d, JPH = 522.0 Hz, PH, 2H); 3.52 (d, JPH = –17.4
2
Hz, PCH, 2H); 3.50 and 3.31 (2d, JHH = –13.2 Hz,
CH2Ph, 4H). 31P { H} NMR (NaOD/D2O, 81 MHz):
1
1,4-Phenylene-bis-(N-m-methoxyphenylamino-
methanephosphonous) Acid (3g). Y = 98% (4.67
g); mp: 236–239◦C. 1H NMR (DMSO, 200 MHz):
δ7.37 (s, C6H4, 4H); 6.80 (m, m-C6H4, 2H); 6.28
(m, m-C6H4, 4H); 6.17 (m, m-C6H4, 2H); 7.00 (d,
δ 28.31. Anal. Calcd for C22H26N2O4P2: C, 59.46; H,
5.90; N, 6.30. Found: C, 59.19; H, 5.66; N, 6.11.
1,4-Phenylene-bis-(N-furfurylaminomethanephos-
2
1 JPH = 543.2 Hz, PH, 2H); 4.75 (d, JPH = –16.9 Hz,
phonous) Acid (3b). Y = 58% (1.40 g); mp: 240–
1
PCH, 2H); 3.57 (s, CH3, 6H). 31P { H} NMR (DMSO,
1
243◦C. H NMR (NaOD/D2O, 200 MHz): δ 7.50 (d,
J = 1.4 Hz, CH5fur, 2H); 7.45 (s, C6H4, 4H); 6.45 (d,
81 MHz): δ 24.60 and 24.35, (2:1). Anal. Calcd for
C22H26N2O6P2: C, 55.47; H, 5.50; N, 5.88. Found: C,
55.30; H, 5.39; N, 5.70.
J = 3.0 Hz, CH3fur, 2H); 6.39 (m, CHf4ur, 2H); 7.05
1
2
(d, JPH = 549.0 Hz, PH, 2H); 3.55 (d, JPH = –15.5
2
Hz, PCH, 2H); 3.60 and 3.44 (2d, JHH = –14.5 Hz,
CH2Ph, 4H). 31P { H} NMR (NaOD/D2O, 81 MHz):
1,4-Phenylene-bis-(N-m-methylphenylamino-
methanephosphonous) Acid (3h). Y = 49% (2.20
g); mp: 124–126◦C. 1H NMR (DMSO, 200 MHz):
δ 7.39 (s, C6H4, 4H); 6.85 (dd, J = 7.6 and 7.2 Hz,
m-C6H4, 2H); 6.56 (s, m-C6H4, 2H); 6.49 (d, J = 7.6,
m-C6H4, 2H); 6.35 (d, J = 7.2, m-C6H4, 2H); 7.01 (2d,
1
δ 28.19 and 28.09. Anal. Calcd for C18H22N2O6P2: C,
50.95; H, 5.23; N, 6.60. Found: C, 50.66; H, 5.05; N,
6.63.
1,4-Phenylene-bis-(N-tert-butylaminomethanephos-
1
phonous) Acid (3c). Y = 57% (2.14 g); mp: 259–
1 JPH = 545.0 Hz, PH, 2H); 6.83 (2d, JPH = 536.0 Hz,
1
260◦C. H NMR (NaOD/D2O, 200 MHz): δ 7.31 (s,
PH, 2H); 4.78 (d, 2 JPH = –17.6 Hz, PCH, 2H); 2.08 (s,
1
1
C6H4, 4H); 6.75 (d, JPH = 520.9 Hz, PH, 2H); 3.84
CH3, 6H). 31P { H} NMR (DMSO, 81 MHz): δ 24.93
(d, 2 JPH = –18.0 Hz, PCH, 2H); 0.92 (s, (CH3)3, 18H).
and 24.55 (3:1). Anal. Calcd for C22H26N2O4P2: C,
Heteroatom Chemistry DOI 10.1002/hc

Stereochemical Aspects of the Hypophosphorous Acid Addition to Terephthalic Schiff Bases 287
3
1
1.60 (d, JHH = 6.3 Hz, CH3CH, 4H). 31P { H} NMR
59.46; H, 5.90; N, 6.30. Found: C, 59.76; H, 6.08; N,
5.95.
(CD3OD, 81 MHz): δ 24.68.
1,4-Phenylene-bis-(N-(R)-α-methylbenzylamino-
methanephosphonous) Acid (3i). Y = 97% (4.58 g);
mp: 238–241◦C. 1H NMR (NaOD/D2O, 200 MHz):
δ 7.02 (s, C6H4, 4H); 6.90 (m, C6H5, 10H); 6.76
REFERENCES
[1] (a) Pudovik, A. N.; Pudovik, D. A. J Gen Chem USSR
1966, 36, 1471–1476; (b) Zh Obshch Khim 1966, 36,
1467–1472.
[2] Failla, S.; Finocchiaro, P. Phosphorus Sulfur Silicon
1993, 85, 65–72.
[3] Failla, S.; Finocchiaro, P.; Ha¨gele, G.; Rapisardi, R.
Phosphorus Sulfur Silicon 1993, 82, 79–90.
[4] Failla, S.; Finocchiaro, P. Phosphorus Sulfur Silicon
1995, 107, 79–86.
[5] Barycki, J.; Gancarz, R.; Milewska, M.; Tyka, R. Phos-
phorus Sulfur Silicon 1995, 105, 117–122.
[6] Lewkowski, J.; Rzez´niczak, M.; Skowron´ski, R.
Heteroat Chem 2000, 11, 144–151.
1
2
(d, JPH = 521.7 Hz, PH, 2H); 3.71 (d, JPH = –15.9
3
Hz, PCH, 2H); 3.51 (q, JHH = 6.3 Hz, CH3CH, 4H);
3
1
1.11 (d, JHH = 6.3 Hz, CH3CH, 4H). 31P { H} NMR
(NaOD/D2O, 81 MHz): δ 28.61; 28.07; 27.10 (4:1:1).
Anal. Calcd for C24H30N2O4P2: C, 61.01; H, 6.40; N,
5.93. Found: C, 60.98; H, 6.23; N, 6.28.
1,4-Phenylene-bis-(N-p-methoxyphenylamino-
methanephosphonous) Acid Bis-(S)-α-methyl-
benzyl-ammonium Salt (4e)
[7] Lewkowski, J.; Skowron´ski, R. Heteroat Chem 2001,
12, 27–32.
[8] Lewkowski, J. Phosphorus Sulfur Silicon 2005, 180,
179–195.
[9] Lewkowski, J.; Stronka-Lewkowska, E. Phosphorus
Sulfur Silicon 2006, 181, 1323–1330.
[10] Kukhar, V. P.; Hudson, H. R. (Eds.). Aminophospho-
nic and Aminophosphinic Acids. Chemistry and Bio-
logical Activity; Wiley: Chichester, UK, 2000; pp. 217–
284.
[11] Baylis, E. K.; Campbell, C. D.; Dingwall, J. G. J Chem
Soc, Perkin Trans I 1984, 2845–2852.
The acid 3e (1 mmol, 0.48 g) was dissolved in 5 mL
of methanol-d4, (R)-α-methylbenzylamine (2 mmol,
0.24 g) was added, and the mixture was stirred at
room temperature for 24 h. Then, an appropriate
sample was taken for NMR measurements.
1H NMR (CD3OD, 200 MHz): δ 7.45 (m, C6H5,
10H); 7.39 (s, C6H4, 4H); 6.65 and 6.54 (AAꢁXXꢁ sys-
1
tem, J = 9.0 Hz, p-C6H4, 4H); 6.87 (d, JPH = 518.3
Hz, PH, 2H); 4.35 (d, 2 JPH = –17.8 Hz, PCH, 2H); 3,74
[12] Hamilton, R.; Walker, B.; Walker, B. J. Tetrahedron
Lett 1995, 36, 4451–4454.
3
(q, JHH = 6.5 Hz, CH3CH, 4H); 3.67 (s, CH3, 6H);
Heteroatom Chemistry DOI 10.1002/hc