Addition of hypophosphorous acid to N,N'-terephthalylidene-bis[1- (alkoxycarbonyl)alkylamines]

Article abstract of DOI:10.1080/10426500903005456

The preparation of 1,4-phenylene-bis[1-(alkoxycarbonyl)alkylamino- methanephosphonous acids] by the addition of hypophosphorous acid to terephthalylidene-bis[1-(alkoxycar bonyl)alkylamines] is described. Despite expectations, no chiral assistance of the a

Full text of DOI:10.1080/10426500903005456

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Phosphorus, Sulfur, and Silicon and the
Related Elements
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Addition of Hypophosphorous Acid
to N,N′-Terephthalylidene-bis[1-
(alkoxycarbonyl)alkylamines]
Jarosław Lewkowski a & Marek Dzięgielewski a
a Department of Organic Chemistry , University of Łódź , Łódź,
Poland
Published online: 23 Mar 2010.
To cite this article: Jarosław Lewkowski & Marek Dzięgielewski (2010) Addition of Hypophosphorous
Acid to N,N′-Terephthalylidene-bis[1-(alkoxycarbonyl)alkylamines], Phosphorus, Sulfur, and Silicon
and the Related Elements, 185:4, 838-841, DOI: 10.1080/10426500903005456
To link to this article: http://dx.doi.org/10.1080/10426500903005456
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Phosphorus, Sulfur, and Silicon, 185:838–841, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500903005456
ADDITION OF HYPOPHOSPHOROUS ACID
TO N,Nꢁ-TEREPHTHALYLIDENE-BIS[1-
(ALKOXYCARBONYL)ALKYLAMINES]
Jarosław Lewkowski and Marek Dziegielewski
ꢀ
Department of Organic Chemistry, University of Ło´dz´, Ło´dz´, Poland
The preparation of 1,4-phenylene-bis[1-(alkoxycarbonyl)alkylamino-methanephosphonous
acids] by the addition of hypophosphorous acid to terephthalylidene-bis[1-(alkoxycar
bonyl)alkylamines] is described. Despite expectations, no chiral assistance of the amino
acid ester moiety is observed.
Keywords Amino acid esters; azomethine bond; chiral assistance; chiral terephthalic imines;
hypophosphorous acid
INTRODUCTION
The addition of hypophosphorous acid to terephthalic Schiff bases was stereoselective
in a majority of cases. The addition of hypophosphorous acid to achiral N-alkyl terephthalic
imines has been reported1,2 to be diastereoselective to 100% and to lead to a meso-form,
while the reaction performed on N-aryl imines has been noted to depend on the nature of
a substituent at the aromatic ring.2 Similar results have been reported for the addition of
dialkyl phosphites to achiral N-alkyl and N-aryl terephthalic Schiff bases.1,3–7
The addition of dialkyl phosphites as well as hypophosphorous acid to a chiral N-
(R)-α-methylbenzyl Schiff base led to the formation of all three possible diastereoisomers.
This was rather unexpected in the case of the addition of hypophosphorous acid, because
the addition of hypophosphorous acid to chiral mono (R)-N-α-methylbenzyl Schiff bases
was demonstrated to be diastereoselective to 100%,8,9 and we hoped that the influence of
the chiral substituent at nitrogen would work in this case also. But evidently, that influence
was in competition with the phenomenon determining the stereochemistry of the addition
to terephthalic Schiff bases.
That is why we have reached for more efficient chiral auxiliaries, i.e., l-α-amino
acid esters. We supposed that their chiral assistance would force the system to form one
diastereoisomer, which was necessary for further synthesis of some macrocyclic systems.
Received 23 March 2009; accepted 27 April 2009.
Financial support of the Polish Ministry of Science and Higher Education is kindly acknowledged.
Address correspondence to Prof. Jarosław Lewkowski, Department of Organic Chemistry, University of
Ło´dz´, Narutowicza 68 90-136, Ło´dz´, Poland. E-mail: jlewkow@uni.lodz.pl
838

ADDITION OF HYPOPHOSPHOROUS ACID
839
RESULTS AND DISCUSSION
We have chosen three model amino acid esters: l-alanine methyl ester, l-
phenylalanine ethyl ester, and l-leucine methyl ester and prepared their imines 2a–c
with terephthalic aldehyde. Imines 2a–h were prepared following a modification of the
commonly known procedure for the condensation of corresponding hydrochlorides of
amino acid esters with terephthalic aldehyde 1 in methanol in the presence of triethylamine
at room temperature. After precipitation of the formed triethylamine hydrochloride from
dichloromethane-hexane, the imines were obtained in almost quantitative yields.
The preparation of terephthalic bis-aminophosphonous acids 3a–c has been per-
formed based on the previously published procedure.2 Reactions were carried out in boiling
acetonitrile for 5 h and subsequent stirring overnight at room temperature (Scheme 1). The
acids were obtained as powder solids in moderate yields fluctuating around 45%, which
was expected, as Barycki et al.1 suggested much lower conversion rates for the addition to
two azomethine groups.
O
H
NR
RHN
P
CHO
OH
H3PO2
MeCN
RNH2
MeOH
CHO
OH
H
NR
RHN
P
O
2a-c
1
3a-c
COOMe
COOEt
COOMe
a: R =
;
b: R =
; c: R =
HC
HC
HC
CH3
CH2Ph
Scheme 1
Unfortunately, the 1H and 31P NMR spectroscopy demonstrated that each of all three
acids 3a–c occurred as a mixture of all three possible diastereoisomeric forms in a 2:1:1
ratio; therefore no chiral assistance occurred. Evidently, the chiral assistance of l-α-amino
acid esters interferes with the “natural” stereochemistry of the addition to terephthalic
imines, as was demonstrated in the case of addition to N-α-methylbenzyl Schiff bases.2
The problem is depicted in Scheme 2. Considering the formation of intermediate 4a–c,
the occurrence of which we have postulated in a case of nonchiral Schiff bases,2 the
“natural” action within the complex 4a–c is in competition with the action of the amino
acid chiral moiety, which may force the attack of the hypophosphorous acid molecule from
the completely opposite direction. Therefore, the resultant stereoselectivity became zero,
and the formation of the stoichiometrically equal amounts of all possible diastereoisomers
occurred. The phenomenon is obvious from the 31P NMR spectra. In the case of the leucine
(3c) and phenylalanine (3b) derivatives, the magnetic nonequivalence of two phosphorus
nuclei has been demonstrated for two of the three diastereoisomers, as their 31P NMR

840
J. LEWKOWSKI AND M. DZIEGIELEWSKI
ꢀ
signals occurred as two-peak systems but not as single peaks, which was rather expected.
However, such a phenomenon has not been noticed in the case of the alanine derivative 3a.
H
H
H
HO
HO
O
P
H
HO
P
R
MeOOC
H
P
MeOOC
CH
O
N
O
COOMe
COOMe
HO
P
CH
R
N
O
C
N
H
R
H
H
H
H
H
COOMe
P
H
N
C
N
CH
R
O
OH
O
H
R
MeOOC
O
P
N
CH
P
P
H
HO
O
OH
R
H
HO
H
H
H
3a-c
All three possible
4a-c
diastereoisomeric forms
Scheme 2
EXPERIMENTAL
All solvents (POCh-Poland) were routinely distilled and dried prior to use. Hy-
pophosphorous acid 50% (Aldrich) was dehydrated following the published procedure.2
Amino acid ester hydrochlorides 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) and 81 MHz (31P NMR). Elemental analyses were performed in the Centre for
Molecular and Macromolecular Science of the Polish Academy of Science in Ło´dz´, Poland.
Preparation of 1,4-Phenylene-bis[1-(alkoxycarbonyl)alkylamino]-
methanephosphonous acids] 3a–c: General Procedure
In a 250-mL flask, terephthalic aldehyde (1.34 g, 10 mmol) was dissolved in methanol,
then amino acid ester hydrochloride (20 mmol) and triethylamine (20 mmol) were added.
The mixture was stirred at room temperature for 24 h, the solvent was removed in vacuo,
and the residue was dissolved in dichloromethane. To this solution, hexane was added
portionwise until white precipitate stopped occurring. The white precipitate was filtered
off and discarded, and the filtrate was evaporated to give the corresponding imine. The
imine (5 mmol) was dissolved in acetonitrile, hypophosphorous acid (0.66 g, 10 mmol)
was added, and the mixture was refluxed for 5 h. Then the solvent was removed in vacuo to
afford the crude acid, which was purified by dissolving in aqueous sodium hydroxide and
subsequent precipitation with hydrochloric acid.
1,4-Phenylene-bis[1-(methoxycarbonyl)ethylaminomethanephosphon
ous acid] (3a). Yield: 0.85 g (39%); Mp: 101–105◦C. Calcd. for C16H26N2O8P2: C,
1
44.04; H, 6.01; N, 6.42. Found: C, 43.92; H, 5.87; N, 6.47. H NMR (NaOD/D2O, 200
MHz): δ 7.26 (s, C6H4, 4H); 6.97 and 6.80 (2d, 1JPH = 518.4 and 506.4 Hz, PH, 2H); 3.77
2
and 3.65 (2d, JPH = 15.1 and 15.4 Hz, PCH, 2H); 3.28 (s, OCH3, 6H); 3.15 (q, J = 6.5
Hz, CHCH3, 2H); 1.12 (d, J = 6.5 Hz, CHCH3, 6H). 31P NMR (NaOD/D2O, 81 MHz): δ
27.96; 26.31; 26.29 (2:1:1).

ADDITION OF HYPOPHOSPHOROUS ACID
841
1,4-Phenylene-bis[1-(ethoxycarbonyl)-2-phenylethylaminomethanepho
sphonous acid] (3b). Yield: 1.42 g (46%); Mp: 159–163◦C. Calcd. for C30H38N2O8P2:
C, 58.44; H, 6.21; N, 4.54. Found: C, 58.43; H, 5.98; N, 4.18. 1H NMR (NaOD/D2O, 200
1
MHz): δ 7.15 (s, C6H4, 4H); 7.09-6.92 (m, PhH, 10H); 6.64 and 6.63 (2d, JPH = 522.6
Hz, PH, 2H); 3.77 and 3.65 (2d, 2JPH = 15.1 and 15.4 Hz, PCH, 2H); 3.49 (q, J = 7.1 Hz,
OCH2CH3, 4H); 2.95 (m, CHCH2Ph, 2H); 2.81-2.69 (m, CHCH2Ph, PCH, 6H); 1.03 (t, J
= 7.1 Hz, OCH2CH3, 6H). 31P NMR (NaOD/D2O, 81 MHz): δ 27.40; 27.15; 27.08; 26.10;
25.81 (4:1:1:1:1).
1,4-Phenylene-bis[1-(methoxycarbonyl)isopentylamino)methanephos
phonous acid] (3c). Yield: 1.22 g (47%); Mp: 155–158◦C. Calcd. for C22H38N2O8P2:
C, 50.77; H, 7.36; N, 5.38. Found: C, 51.92; H, 7.48; N, 5.05. 1H NMR (NaOD/D2O, 200
1
MHz): δ 7.22 (s, C6H4, 4H); 6.93, 6.75 and 6.68 (3d, JPH = 518.4 and 520.4 and 523.1
Hz, PH, 2H); 3.69 and 3.53 (2d, 2JPH = 14.2 and 17.6 Hz, PCH, 2H); 3.23 (s, OCH3, 6H);
3.14 (t, J = 5.7 Hz, CHCH2, 2H); 2.81 (dd, J = 5.7 and 6.0 Hz, CHCH2, 4H); 1.32 (m,
CH(CH3)2, 2H); 0.67 (d, J = 5.4 Hz, CH(CH3)2, 12H). 31P NMR (NaOD/D2O, 81 MHz):
δ 28.10; 28.02; 27.95; 26.70; 26.64 (4:1:1:1:1).
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(1995).
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4. S. Failla, P. Finocchiaro, G. Haegele, and R. Rapisardi, Phosphorus, Sulfur, and Silicon, 82, 79
(1993).
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