Dual stereochemical control in reaction of di- and trialkyl phosphites with aldimines

Article abstract of DOI:10.1007/s11176-005-0502-9

Stereochemistry of addition of di- and trialkyl phosphites to C=N compounds was investigated. Reactions of achiral dialkyl phosphites with chiral aldimines as well as that of chiral di-(1R,2S,5R)-menthyl phosphite with achiral aldimines result in low dias

Full text of DOI:10.1007/s11176-005-0502-9

Russian Journal of General Chemistry, Vol. 75, No. 11, 2005, pp. 1735 1743. Translated from Zhurnal Obshchei Khimii, Vol. 75, No. 11, 2005,
pp. 1818 1826.
Original Russian Text Copyright
2005 by Kachkovskii, Andrushko, Sheiko, Kolodyazhnyi.
Dual Stereochemical Control in Reaction of Di-
and Trialkyl Phosphites with Aldimines
G. A. Kachkovskii, N. V. Andrushko, S. Yu. Sheiko, and O. I. Kolodyazhnyi
Institute of Bioorganic Chemistry and Petrochemistry, Ukrainian National Academy of Sciences, Kiev, Ukraine
Received December 15, 2004
Abstract Stereochemistry of addition of di- and trialkyl phosphites to C=N compounds was investigated.
Reactions of achiral dialkyl phosphites with chiral aldimines as well as that of chiral di-(1R,2S,5R)-menthyl
phosphite with achiral aldimines result in low diastereomeric enrichment of the addition compound. Reaction
stereoselectivity increased when supplementary chiral inductor was introduced to the reaction system. Reac-
tion of di-(1R,2S,5R)-menthyl phosphite with (S)- -methylbenzylbenzaldimine proceeds as concerted asym-
metric induction to form practically one diastereomer of N-substituted aminophosphonic acid. However, reac-
tion of di-(1R,2S,5R)-menthyl phosphite with (R)- -methylbenzylbenzaldimine proceeded as not concerted
asymmetric induction, and diastereomeric enrichment of the product was low. By chemical extrapolation,
absolute configuration of compounds formed was established. Tri-(1R,2S,5R)-menthyl phosphite reacts with
C=N compounds in the presence of boron trifluoride etherate to form aminophosphonic acid derivatives with
the absolute configuration opposite to that appearing in the reaction of di-(1R,2S,5R)-menthyl phosphite with
the same C=N compounds.
A prospective route allowing significant enhancing
stereoselectivity of organic reactions is the method of
multiple asymmetric induction, a stereochemical
process controlled by more than one chiral inductor.
Earlier we reported on the fact that appropriate choice
of chiral inductors with certain configuration allowed
to increase stereoselectivity in reaction of dialkyl
phosphites with carbonyl compounds [3]. Now we
applied this method to enhance stereoselectivity in the
reaction of phosphorous esters with C=N compounds
on the example of chiral di-(1R,2S,5R)-menthyl- and
tri(1R,2S,5R)-menthyl phosphites and of di-(1S)-endo-
bornyl phosphite with chiral Schiff bases, proceeding
under dual asymmetric control.
chiral inductors acted to the same direction (concerted
dual asymmetric induction). For example, chiral di-
(1R,2S,5R)-menthyl phosphite reacted with chiral
(S)- -methylbenzylbenzaldimine on heating to 80 C
to form practically one (1R,2S)-diastereomer of
N-substituted aminophosphonic acid diester (IIIa) (de
92 96%). Stereoselectivity did not increase when
both the chiral inductors acted to opposite directions,
that is, in the case of not concerted dual asymmetric
induction. Thus, reaction of di-(1R,2S,5R)-menthyl
phosphite with (R)- -methylbenzylbenzaldimine was
less stereoselective: diastereomeric enrichment of the
reaction product (IVa) with (1S,2R) absolute con-
figuration was 75% or less. Reaction of di-(1S)-endo-
bornyl)] phosphite with chiral -methylbenzylbenzal-
dimines leading to diastereomerically enriched amino-
phosphonic acid derivatives (V, VI) proceeded si-
milarly.
Diastereoselective addition of trialkyl phosphites
to Schiff bases has not been studied before our inves-
tigations. Earlier we reported on diastereoselective
addition of chiral dialkyl phosphites to Schiff bases
[4 6]. Thus, reaction of chiral di-(1R,2S,5R)-menthyl
phosphite with achiral benzylbenzaldimine as well as
that of achiral diethyl phosphite with chiral (S)- -
methylbenzylbenzaldimine controlled stereochemi-
cally by one asymmetric inductor resulted in 30 45%
diastereomeric enrichment of aminophosphonic acid
diesters (I, II) only [7, 8].
The reaction stereoselectivity depends on the nature
of substituents in the aromatic ring of Schiff bases.
As seen from results exposed in Table 1, electron
acceptor substituents in aromatic ring reduced reaction
stereoselectivity while electron-donors increased it.
For example, the highest diastereoselectivity was
acieved with compounds (IIIa IIIc) possessing
4-MeO, 4-Me2N and H in their rings. Compounds
(IIId IIIf) with acceptors of electros F, Br and NO2
showed low stereoselectivity.
When two asymmetric inductors were introduced
to the of chiral phosphite addition to C=N compound
the reaction stereoselectivity increased when both the
1070-3632/05/7511-1735 2005 Pleiades Publishing, Inc.

1736
KACHKOVSKII et al.
O
MntO
O
EtO
EtO
Ph
P
Ph
P
MntO
C
C
H
NHCH2Ph
H
NHCH(Me)Ph-(S)
I, de 40%
II, de 45%
PhCH=NCH2Ph
R = Mnt
(S)-PhCH=NCH(Me)Ph
R = Et
O
MntO
MntO
O
MntO
MntO
Ph
Ar
P
P
C
C
H
H
NHCH(Me)Ph-(S)
NHCH(Me)Ph-(R)
IIIa IIIf, (RS)
IVa IVf, (SR)
O
H
RO
RO
(S)-ArCH=NCH(Me)Ph
(R)-ArCH=NCH(Me)Ph
P
R = Mnt
R = Mnt
(S)-PhCH=NCH(Me)Ph
(R)-PhCH=NCH(Me)Ph
R = Brn
R = Brn
O
C
O
BrnO
P
BrnO
BrnO
BrnO
Ph
Ph
P
C
H
NHCH(Me)Ph-(R)
H
NHCH(Me)Ph-(S)
V, (RS)
VI, (SR)
CH3
R = Et; Mnt = (1R,2S,5R)-menth-1-yl =
; Brn = (1S)-endo-bornyl =
; Ar = Ph (a), 4-C6H4OMe
CH3
H3C
H
(b), 4-C6H4NMe2 (c), 4-C6H4NO2 (d), 4-C6H4F (e), 4-C6H4Br (f)
Trialkyl phosphites, triethyl phosphite and tri-
(1R,2S,5R)-menthyl phosphite in particular, reacted
with aldimines in the presence of boron trifluoride
etherate to form boron trifluoride complex (VII), as
was registered by NMR spectrum. Treatment of the
complex (VII) with water led to its decomposition
with quantitative formation of aminophosphonic acid
dietster (VIII). Reaction of tri(1R,2S,5R)-menthyl
phosphite with achiral benzylbenzaldimine controlled
by only one chiral inductor proceeded with low stereo-
selectivity (de 30%). Also, low stereoselectivity oc-
curred in the reaction of triethyl phosphite with chiral
(S)- or (R)- -methylbenzylbenzaldimines (de 40%).
tion of trialkyl phosphites with C=N compounds,
stereoselectivity increased. Thus, addition of tri-
(1R,2S,5R)-menthyl phosphite to (S)- -methylbenzyl-
benzaldimine in the presence of equimolar amount of
boron trifluoride etherate resulted in N-substituted
aminophosphonate diastereomers with de >70%.
It is noteworthy that reaction of tri-(1R,2S,5R)-
menthyl phosphite and di-(1R,2S,5R)-menthyl phos-
phite with Schiff bases differ in steric results and led
to diastereomers with opposite absolute configuration
of -carbon atom. While reaction of tri-(1R,2S,5R)-
menthyl phosphite with (S)- methylbenzylbenzal-
dimine resulted predominantly in formation of (1S,2S)-
When two chiral inductors were involved to reac-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 11 2005

DUAL STEREOCHEMICAL CONTROL IN REACTION
1737
Table 1. Reaction of dialkyl phosphates with -methylbenzylaldimines
Comp. no.
R
Ar
Imine configuration
P, ppm
Diastereomeric ratio
IIIa
IVa
IIIb
IVb
IIIc
IVc
IIId
IVd
IIIe
IVe
IIIf
IVf
V
Mnt
Mnt
Mnt
Mnt
Mnt
Mnt
Mnt
Mnt
Mnt
Mnt
Mnt
Mnt
Brn
Brn
Ph
Ph
(S)
(R)
(S)
(R)
(S)
(R)
(S)
(R)
(S)
(R)
(S)
(R)
(S)
(R)
21.93 (21.42)a
21.88 (21.58)
22.49 (21.87)
22.36 (22.10)
23.06 (22.29)
23.10 (22.95)
20.35 (20.07)
20.49 (19.94)
21.86 (21.43)
21.80 (21.79)
21.30 (21.13)
21.23 (20.74)
25.15 (24.92)
24.20 (24.99)
96: 4
75: 25
94: 6
78: 22
93: 7
75: 25
85: 15
70: 30
88: 12
75: 25
86: 14
74: 26
93: 7
C6H4OMe-4
C6H4OMe-4
C6H4NMe2-4
C6H4NMe2-4
C6H4NO2-4
C6H4NO2-4
4-FC6H4
4-FC6H4
4-BrC6H4
4-BrC6H4
Ph
VI
Ph
80: 20
a
In parentheses
of minor stereoisomer.
Et2O BF3
P
Ar
(R*O)3P/BF3
H
Ph
N
H
R
Ar
O
O
NHCH(R)Ph
Ph
H
F
N+
F
R*O
H
H
P
Ph
Ph
B
VIIIa, VIIIb
F
R*O
NCH(R)Ph
R*O
BF3
P
H
H2O
(R*O)3P
Ar
R*O
VIIa, VIIb
R = Me, H; R* = Mnt (a), Et (b).
-(N-1-phenylethyl)aminobenzylphosphonate (VIIIa),
dimenthyl phosphite reacted with (S)- -methylbenzyl-
benzaldimine to form (1R,2S)- -(N-1-phenethyl)-
aminobenzylphosphonate (IIIa).
compounds with chiral phosphorous di- and triesters
can be explained by formation of complexes of these
compounds with boron trifluoride. Stereochemical
analysis of reaction of the imino compounds with
phosphorous esters by means of MOPAC-8 package
shows that conformation of imino compound with
Difference in steric results of reaction of imino
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 11 2005

1738
KACHKOVSKII et al.
Me
Me
H
H
O
O
NH
H
H
NH
Ph
O
Me
Ph
(MntO)2P(O)H
(MntO)3P
BF3
MntO
P
MntO
H
P
H
Ph
Ph
N
Ph
Ph
MntO
(S,S)-VIIIa
(R,S)-IIIa
phenyl groups in diastereo-zerro plane (Fig. 1a) cor-
responds to the energy minimum. Therefore carbon
atom of C=N group is attacked at diastereofacial side
Re where diastereogenic center posses hydrogen atom,
the less substituent by size, resulting in (1R,2S)
configuration of aminophosphonate. Presence of
charged BF3 group at iminium carbon atom in the
complex of imino compound with boron trifluoride
makes preferable the configuration with methyl group
in diastereo-zerro plane, resulting in attack at C=N
carbon atom by reagent at Si diastereofacial side. This
lead to formation of (1S,2S)-aminophosphonate
(Fig. 1b).
31P NMR spectra of reaction mixtures confirm
difference of compounds (S,S)-VIIIa and (R,S)-IIIa.
Figure 2 shows that these reactions lead to predo-
minate formation of different diastereomers. For
further evidence we mixed both the reaction mixtures
and found that signals of corresponding diastereomers
in 31P NMR spectra coincided completely.
multiplets of CH2 and CH groups at 1.0 2.0 ppm,
two septets of magnetically nonequivalent methyne
protons in isopropyl groups of menthyls at
1.9
2.0 ppm. Doublet signal at 4.2 ppm corresponds to
the proton of CHP group, signal of NH groups ap-
pears as a multiplet, CHN proton gives quadruplet at
3.95 ppm, magnetically nonequivalent OCH protons
in menthyl groups induce a multiplet at 4.2 ppm,
signals of aromatic protons fall to the region of
7.25 ppm.
Absolute configuration of compounds III and VIII
was established by their transformation into -amino-
benzylphosphonic acids (S)-XI and (R)-XI whose
optical rotations and absolute configurations has been
determined earlier [8, 9]. For this purpose, menthyl or
bornyl groups in compounds III VI were removed
by hydrolysis with a solution of concentrated hydro-
chloric acid in dioxane (1:1) on heating to 80 C.
Reaction progress was monitored by 31P NMR spectra
and TLC. Under such conditions, reaction completed
in 18 24 h in the case of R = (1R,2S,5R)-Mnt and in
48 72 h for R = endo-Brn, with formation of phos-
phonic acids X in a high yield with no indication to
destruction, reorganization of the molecule backbone
or racemization. At higher concentration of hydro-
chloric acid, reaction duration shortened but yields
decreased. Thus, hydrolysis of di-(1R,2S,5R)-menthyl
(R)-(N-1-phenylethyl)aminomethylphosphonate (IIIa)
with the solution of hydrochloric acid in dioxane at
100 C yielded 40% only of N-substituted aminophos-
phonic acid. As a result, we obtained enantiomerically
pure (1R,2S)- and (1S,2R)-phenyl-(N-1-phenylethyl)-
Structure and composition of compounds was con-
firmed by elemental analysis, spectroscopic investiga-
tions and chemical transformations. Chemical shifts
of the studied compounds fall to the range of 20
2P2 ppm. Reaction products possessing two asym-
metric centers exist as two optically active (1S)- and
(1R)-diastereomers. Diastereomeric ratio of com-
pounds was measured my means of 31P NMR spectra
by integral intensities of the signals of different
1
stereoisomers. In H NMR spectra we detected signals
of magnetically nonequivalent methyl groups in
menthyl fragments as six doublets at 0.6 1.00 ppm,
(a)
(b)
F
Re
Re
F
B
Ph
Ph
H
N
N+
Ph F
H
H
Ph
Me
H
Me
Si
Si
Fig. 1. Stereochemical models of reaction: (a) dimenthyl phosphite with (S)- -methylbenzylbenzaldimine; (b) trimenthyl
phosphite with the boron trifluoride (S)- methylbenzylbenzaldimine complex.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 11 2005

DUAL STEREOCHEMICAL CONTROL IN REACTION
1739
aminomethylphosphonic acids (X and XII) which
were isolated as hydrochlorides. The -aminophos-
phonic acid X and XII N-derivatives appeared as
crystalline compounds insoluble in organic solvents,
merely soluble in water or DMSO. The N-substituted
-aminophosphonic acids were purified by crystalliza-
tion from water. -Methylbenzyl group at nitrogen
atom in compounds X and XII was removed by
treatment with gaseous hydrogen over palladium on
charcoal. We obtained homochiral stereoisomers
(S)-XI and (R)-XI, whose configurations were estab-
lished by comparison with earlier described -amino-
benzylphosphonic acid enantiomers by their optical
rotation angles [8]. The optical rotation angle of
-aminobenzylphosphonic acid hydrochloride (R)-XI
was found equal to [ ]2D0 = +15 (c 2, DMSO), that of
-aminobenzylphosphonic acid hydrochloride (S)-XI
had opposite sign, [ ]D20
=
15 (c 2, DMSO).
Ar
Ph
Ar
HCl/dioxane
(S,R)-III
Pd/c H2
(HO)2P(O)
(HO)2P(O)
Me
(HO)2P(O)
N
H
NH2
NH2
H
H
H
(S)-XI
(S,R)-Xa, Xb
Ar
Ph
Ar
Pd/c H2
HCl/dioxane
(R,S)-III
(HO)2P(O)
N
H
Me
H
H
H
(R,S)-XIIa, XIIb
(R)-XI
Ar = Ph (a), 4-C6H4OMe.
Structure of unsubstituted aminophosphonic acids
was confirmed by spectroscopy. Thus, 31P NMR spec-
aminophosphonates are formed with high stereoselec-
tivity (ratio of diasteremers is 95:5 or higher). Thus,
available chiral di- and trialkyl phosphates can be
successfully used as starting material for asymmetric
synthesis of organophosphorus compounds, including
synthesis of enantiomerically pure - and -sub-
stituted alkylphosphonic acid derivatives [10, 11].
trum of compound X contained only one peak with
1
phosphorus chemical shift
14 ppm. In its H NMR
P
spectrum together with the signals of PCH group and
aromatic protons we observed signal of NH group at
2.3 2.50 ppm.
As a result of this investigation we found that
(1) aminophosphonic acids prepared from dimenthyl
phosphite (or dibornyl phosphite) and (S)- -methyl-
benzylbenzaldimine have (1R,2S) configuration;
(2) aminophosphonic acids from dimenthyl phosphite
(or dibornyl phosphite) and (R)- methylbenzylbenz-
aldimine have (1R,2R) configuration; (3) aminophos-
phonic acids from trimenthyl phosphite and (S)- -
methylbenzylbenzaldimine have (1S,2S) configuration;
(4) aminophosphonic acids from trimenthyl phosphite
and (R)- -methylbenzylbenzaldimine have (1R,2R)
configuration.
3
2
1
22
21
20
19 P, ppm
High yield and high optical purity of the reaction
products give rise of application this procedure for
preparation multigram amounts of enantiomerically
pure -aminophosphonic acids without fractional
crystallization or chromatography. Reaction requires
application of inexpensive menthol or borneol as
parent reagent. Under developed reaction conditions
31
1
Fig. 2. P { H} NMR spectra of diastereomeric mix-
tures formed in the reactions: (1) (S)- -methylbenzyl-
benzaldimine with di[(1R,2S,5R)-menthyl phosphite;
(2) (S)- -methylbenzylbenzaldimine with tri-(1R,2S,5R)-
menthyl phosphite; (3) spectrum of mixed above dia-
stereomeric mixtures.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 11 2005

1740
KACHKOVSKII et al.
EXPERIMENTAL
hexane stereochemically pure diastereomer was ob-
tained. Yield 40%, mp 132.5 C (hexane), [ ]2D0 88.9
1
Melting points are not corrected. NMR spectra are
registered on a Varian VXR 300 spectrometer at 300
(1H) and 126.16 MHz (31P), and a JEOL instrument
(90 MHz). All chemical shifts are given in (ppm)
(c 1, toluene). H NMR spectrum (CDCl3), , ppm (J,
3
Hz): 0.49 d (3H, CH3, JHH 6.5); 0.63 d (3H, CH3,
3
3JHH 6.5); 0.80 d (3H, CH3, JHH 6.5); 0.87 d (3H,
3
3
CH3, JHH 6.5); 0.88 d (3H, CH3, JHH 6.5); 0.93 d
1
3
scale. H chemical shifts are given relatively Me4Si as
(3H, CH3, JHH 6.5); 0.75 1.6 m (16H, CH2 + CH);
1.28 d (3H, CH3CHN, JHH 6.4); 2.1 m [1H,
an internal reference. 31P NMR spectra are measured
relatively to external 85% H3PO4. For column
chromatography Silica gel 60 m (Merck), thin layer
chromatography was conducted on Silufol UV
(Chemapol, Praga).
3
CH(CH3)2]; 2.2 m (1H, CH(CH3)2); 2.25 m (1H, NH);
3
2
3.82 q (1H, NCH, JHH 6.4); 4.2 d (1H, CHP, JHP
16.7); 4.3 m (2H, OCH); 7.25 m (10H, ArH). 31P
{1H} NMR spectrum (DMSO-d6, P, ppm): 21.88.
Found, %: P 5.34. C35H54NO3P. Calculated, %:
P 5.45.
All experiments were performed under argon, sol-
vents were distilled under inert atmosphere over the
following during reagents: diethyl ether, hexane,
heptane, benzene and carbon tetrachloride over P2O5,
methanol and triethylamine over sodium, ethyl acetate
over CaCl2. [( )-(S)- -methylbenzylamine, [(+)-(R)-
-methylbenzylamine, (1R,2S,5R)-menthol, endo-
borneol were taken from Merk and used without ad-
ditional purification. For removing water admixture,
(1R,2S,5R)-menthol was distilled in a vacuum. Com-
pounds II IV were described by us earlier [2, 3].
Di-(1R,2S,5R)-menthyl (R)-(4-methoxyphenyl)-
(S)-(N-1-ethylphenyl)aminomethylphosphonate
(IIIb) prepared similarly to compound IIIa. Yield
64%, mp 124 C (acetonitrile), [ ]2D0 72 (c 1.0,
1
toluene). H NMR spectrum (CDCl3), , ppm (J, Hz):
3
3
0.72 d (3H, CH3, JHH 6.5); 0.76 d (3H, CH3, JHH
3
6.5); 0.78 d (3H, CH3, JHH 6.5); 0.80 d (3H, CH3,
3JHH 6.5); 0.87 d (3H, CH3, JHH 6.5); 0.89 d (3H,
3
3
CH3, JHH 6.5); 1.1 1.6 m (16H, CH2 + CH); 1.27
3
d (3H, CH3CHN, JHH 6.4); 2.06 m [1H, CH(CH3)2];
Di-(1R,2S,5R)-menthyl (R)-phenyl-(S)-(N-1-
phenylethyl)aminomethylphosphonate (IIIa). To
3.5 g (0.1 mol) of (1R,2S,5R)-menthyl phosphite at
0oC 2.09 g (0.10 mol) of (S)- methylbenzylbenzal-
dimine was added, and reaction mixture was heated
for 4 h at 80 C. After cooling to room temperature the
mixture crystallized. 31P NMR spectrum showed
2.2 m [1H, CH(CH3)2]; 2.25 m (1H, NH); 3.79 with
3
(3H, OCH3); 3.81 q (1H, CHN, JHH 6.4); 4.03 d (1H,
2
PCH, JPH 16.7); 4.05 m (1H, OCH); 4.25 m (1H,
3
OCH); 6.84 d (2H, ArH, JHH 8.6); 7.19 7.32 m (7H,
ArH). 31P {1H} NMR spectrum (DMSO-d6, P, ppm):
22.49. Found, %: P 5.07. C36H56NO4P. Calculated, %:
P 5.18.
presence of two signals,
21.93 and 21.42 ppm. By
P
crystallization from hexane or acetonitrile stereo-
chemically pure (R,S)-diastereomer was isolated.
Yield 60%, mp 128 C (acetone), [ ]2D0 68.0 (c 1,
Di-(1R,2S,5R)-menthyl (S)-4-methoxyphenyl-
(R)-(N-1-phenylethyl)aminomethylphosphonate
(IVb) prepared similarly to compound IVa. Yield
60%, mp 118 118.7 C (acetonitrile), [ ]2D0 46.7 (c
1
toluene). H NMR spectrum (CDCl3), , ppm (J, Hz):
3
3
1
0.72 d (3H, CH3, JHH 6.5); 0.74 d (3 H, CH3, JHH
1.0, toluene). H NMR spectrum (CDCl3), , ppm (J,
3
3
3
6.5); 0.76 d (3H, CH3, JHH 6.5); 0.77 d (3 H, CH3,
Hz): 0.66 d (3H, CH3, J 6.6 Hz); 0.7 d (3H, CH3, J
3JHH 6.5); 0.86 d (3 H, CH3, JHH 6.5); 0.89 d (3H,
3
3
3
6.6); 0.73 d (3H, CH3, J 6.6); 0.81 d (3H, CH3, J
6.6); 0.83 d (3H, CH3, J 6.6,); 0.9 1.6 m (14H,
3
3
CH3, JHH 6.5); 0.8 1.6 m (16H, CH2 + CH); 1.28 d
(3H, CH3CHN, JHH 6.4); 2.1 m (1H, CH(CH3)2);
3
CH2 + CH); 1.21 d (3H, CH3CH, JHH 6.6); 2.00 m
[1H, CH(CH3)2]; 2.1 m [1H, CH(CH3)2]; 3.73 s (3H,
OCH3), 3.8 m (1H, CHN), 3.95 d (1H, PCH, JPH
21.00), 4.05 m (1H, OCH), 4.2 m (1H, OCH), 7.1
7.2 m (9H, C6H5 + C6H4), 31P {1H} NMR spectrum
( , ppm, CDCl3): 23.16. Found, %: P 5.11.
C3P6H56NO4P. Calculated, %: P 5.18.
2.2 m [1H, CH(CH3)2]; 2.25 m (1H, NH); 3.82 q (1H,
3
2
NCH, JHH 6.4); 3.98 d (1H, CHP, JHP 16.7); 4.1 m
(1H, CHO); 4.3 m (1H, CHO); 7.2 7.4 m (10H, ArH).
31P {1H} NMR spectrum (DMSO-d6, P, ppm): 21.93.
Found, %: P 5.34, N 2.47. C35H54NO3P. Calculated,
%: P 5.46, N 2.47.
Di-(1R,2S,5R)-menthyl (S)-phenyl-(R)-(N-1-
phenylethyl)aminomethylphosphonate (IVa). To
3.5 g (0.1 mol) of di-(1R,2S,5R)-menthyl phosphite at
0 C, 2.09 g (0.10 mol) of (R)- methylbenzylbenzald-
imine was added. Reaction mixture was kept for 4 h
at 80 C. 31P NMR spectrum showed presence of two
Di-(1R,2S,5R)-menthyl (S)-(4-methoxyphenyl)-
(R)-(N-1-phenylethyl)aminomethylphosphonate
(IIIc) prepared similarly to compound IIIa. Yield
70%, mp 140 C (acetonitrile), [ ]2D0 82.45 (c 1.0,
1
chloroform). H NMR spectrum (CDCl3), , ppm (J,
3
Hz): 0.69 d (3H, CH3, J 6.6); 0.77 d (3J 6.6, 3H,
signals,
21.80, 21.58. By crystallization from
CH3); 0.81 d (3J 6.6, 3H, CH3); 0.87 d (3J 6.6, 3H,
P
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 11 2005

DUAL STEREOCHEMICAL CONTROL IN REACTION
1741
CH3); 0.89 d (3J 6.6, 3H, CH3); 0.91 d (3J 6.6, 3H,
CH3); 1.1 1.7 m (14H, CH2 + CH); 1.27 d (3H,
CH3CH, JHH 6.6); 2.94 s (6H, NCH3), 3.83 q (1H,
d6, , ppm): 109.52. Found (%): P 5.30. C35H53
FNO3P. Calculated, %: P 5.29.
Di-(1R,2S,5R)-menthyl (S)-(4-fluorophenyl)-(R)-
(N-1-phenylethyl)aminomethylphosphonate (IVe)
prepared similarly to compound IVa. Yield 55%,
CHN, JHH 6.4), 4.07 m (1H, CHO), 4.01 d (2JPH
21.00, 1H, PCH), 4.29 m (1H, CHO), 6.67 d (H,
C6H4), 7.17 7.3 m (H, C6H5 + C6H4). 31P NMR spec-
1
mp 131 C (acetonitrile). H NMR spectrum (CDCl3),
3
trum (DMSO-d6,
ppm): 23.06. Found, %: P 5.10.
P
, ppm (J, Hz): 0.54 d (3H, CH3, JHH 6.5); 0.69 d
3
3
C37H59N2O3P. Calculated, %: P 5.07.
(3H, CH3, JHH 6.5); 0.81 d (3H, CH3, JHH 6.5);
3
3
0.88 d (3H, CH3, JHH 6.5); 0.89 d (3H, CH3, JHH
6.5); 0.94 d (3H, CH3, JHH 6.5); 0.95 1.7 m (16H,
Di-(1R,2S,5R)-menthyl (R)-(4-dimethylamino-
phenyl)-(S)-(N-1-phenylethyl)aminomethylphos-
phonate (IVc) prepared similarly to compound IVa.
3
CH2 + CH); 2.00 2.15 m [2H, (CH3)2CH]; 1.28 d
3
(3H, CH3CHN, JHH 6.4); 2.49 m (1H, NH); 3.82 q
Yield 50%, mp 125 C (acetonitrile), [ ]2D0 35.22 (c
3
2
(1H, NCH, JHH 6.4); 4.05 d (1H, CHP, JHP 16.7);
4.24 m (1H, OCH); 4.27 m (1H, OCH); 6.98 d.d (2H,
ArH); 7.16 7.28 m (7H, ArH). 31P {1H} NMR spec-
trum (DMSO-d6, , ppm): 21.80.
1
1.0, chloroform). H NMR spectrum (CDCl3), , ppm
1
(J, Hz): H NMR spectrum, (CDCl3), , ppm: 0.69 d
(3J 6.6, 3H, CH3); 0.77 d (3J 6.6, 3H, CH3); 0.81 d
(3J 6.6, 3H, CH3); 0.87 d (3J 6.6, 3H, CH3); 0.89 d (3J
6.6, 3H, CH3); 0.91 d (3J 6.6, 3H, CH3); 1.1 2.2 m
(14H, CH2 + CH); 1.27 d (3H, CH3CH, JHH 6.6);
2.94 s (6H, NCH3), 3.83 q (1H, CHN, JHH 6.4),
4.07 m (1H, CHO), 4.01 d (2JPH 21.00, 1H, PCH),
4.29 m (1H, CHO), 6.67 d (2H, C6H4), 7.17 7.3 m
(7H, C6H5 + C6H4). 31P NMR spectrum (DMSO-d6,
, ppm): 22.92.
Di-(1R,2S,5R)-menthyl (R)-(4-bromophenyl)-
(S)-(N-1-phenylethyl)aminomethylphosphonate
(IIIf) prepared similarly to compound IIIa. Yield
56%, mp 96 C (acetonitrile), [ ]2D0 77.96 (c 1.0,
1
chloroform). H NMR spectrum (CDCl3), , ppm (J,
3
Hz): 0.76 d (3H, CH3, JHH 6.5); 0.78 d (3H, CH3,
3
3JHH 6.5); 0.88 d (3H, CH3, JHH 6.5); 0.89 d (3H,
3
3
CH3, JHH 6.5); 0.90 d (3H, CH3, JHH 6.5); 0.93 d
3
Di-(1R,2S,5R)-menthyl (R)-(4-nitrophenyl)-(S)-
(N-1-phenylethyl)aminomethylphosphonate (IIId)
prepared similarly to compound IIIa. Isolated as
yellow crystalline substance consisted of two diastereo-
mers that we failed to separate by column chromato-
graphy or crystallization. Yield 90%, 31P NMR spec-
(3H, CH3, JHH 6.5); 0.8 1.7 m (16H, CH2 + CH);
1.32 d (3H, CH3CHN, JHH 6.4); 2.07 m [2H,
CH(CH3)2]; 2.21 m (1H, NH); 3.81 q (1H, NCH, 3JHH
3
2
6.4); 4.00 d (1H, CHP, JPH 16.7); 4.12 m (1H,
OCH); 4.26 m (1H, OCH); 7.20 7.32 m (7H, ArH);
3
7.41 d (2H, ArH, JHH 8.2). 31P {1H} NMR spectrum
trum ( , ppm, CDCl3): 20.35; 20.07.
P
(DMSO-d6, , ppm): 21.30.
Di-(1R,2S,5R)-menthyl (S)-(4-nitrophenyl)-(R)-
(N-1-phenylethyl)aminomethylphosphonate (IVd)
prepared similarly to compound IIIa. Isolated as
Di-(1R,2S,5R)-menthyl (S)-(4-bromophenyl)-
(R)-(N-1-phenylethyl)aminomethylphosphonate
(IVf) prepared similarly to compound IIIa. Yield 56%,
yellow crystalline substance consisted of two diastereo- mp 96 C (acetonitrile), [ ]2D0 77.96 (c 1.0, chloro-
1
mers that we failed to separate by column chromato-
graphy or crystallization. Yield 90%, 31P NMR spec-
trum ( , ppm, CDCl3): 20.49; 19.94.
form). H NMR spectrum (CDCl3), , ppm (J, Hz):
3
3
0.76 d (3H, CH3, JHH 6.5); 0.78 d (3H, CH3, JHH
3
6.5); 0.88 d (3H, CH3, JHH 6.5); 0.89 d (3H, CH3,
3JHH 6.5); 0.90 d (3H, CH3, JHH 6.5); 0.93 d (3H,
3
3
Di-(1R,2S,5R)-menthyl (R)-(4-fluorophenyl)-(S)-
(N-1-phenylethyl)aminomethylphosphonate (IIIe)
prepared similarly to compound IIIa. Yield 68%, mp
CH3, JHH 6.5); 0.8 1.7 m (16H, CH2 + CH); 1.32 d
(3H, CH3CHN, JHH 6.4); 2.07 m [2H, CH(CH3)2];
2.21 m (1H, NH); 3.81 q (1H, NCH, 3JHH 6.4); 4.00 d
3
1
122 C (acetonitrile). H NMR spectrum (CDCl3), ,
2
(1H, CHP, JPH 16.7); 4.12 m (1H, OCH); 4.26 m
3
ppm (J, Hz): 0.77 d (3H, CH3, JHH 6.5); 0.78 d (3H,
(1H, OCH); 7.20 7.32 m (7H, ArH); 7.41 d (2H, ArH,
3
3
CH3, JHH 6.5); 0.79 d (3H, CH3, JHH 6.5); 0.88 d
3JHH 8.2). 31P {1H} NMR spectrum (DMSO-d6,
,
3
3
P
(3H, CH3, JHH 6.5); 0.89 d (3H, CH3, JHH 6.5);
0.90 d (3H, CH3, JHH 6.5); 0.95 1.7 m (16H, CH2 +
CH); 1.30 d (3H, CH3CHN, JHH 6.4); 2.00 2.15 m
ppm): 21.30.
3
3
Di-(1R)-endo-bornyl (R)-phenyl-(S)-(N-1-
phenylethyl)aminomethylphosphonate (V) prepared
similarly to compound IIIa. Yield 60%, mp 124
127 C (acetonitrile). A mixture of two diastereomers.
1H NMR spectrum (CDCl3), , ppm (J, Hz): 0.74 s
(3H, CH3); 0.76 s (3H, CH3); 0.84 s (3H, CH3);
[2H, (CH3)2CH]; 2.9 m (1H, NH); 3.71 q (1H, NCH,
2
3JHH 6.4); 4.07 d (1H, CHP, JHP 16.7); 4.12 m (1H,
OCH); 4.27 m (1H, OCH); 6.98 d.d (2H, ArH); 7.25
7.36 m (7H, ArH). 31P {1H} NMR spectrum (DMSO-
d6, , ppm): 21.86. 19F {1H} NMR spectrum (DMSO-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 11 2005

1742
KACHKOVSKII et al.
0.87 s (3H, CH3); 0.88 s (6H, CH3); 1.33 d (3H,
removed. Aminophosphonic acid hydrochloride pre-
cipitated on cooling as colorless crystals. Yield 75%,
mp 241 C (EtOH + H2O). [ ]2D0 15 (c 1, 0.1 N
3
CHCH3, JHH 7); 0.8 1.8 m (16H, CH2); 3.54 q (1H,
3
3
CHNH, JHH 6.4); 3.73 d (1H, JHH 23, CHP); 4.38 m
1
(2H, OCH); 7.17 7.31 m (10 H, ArH). 31P {1H}
KOH). H NMR spectrum (DMSO), , ppm (J, Hz):
7.35 m (10H, C6H5); 3.74 4.07 m (3H, NCH +
NMR spectrum ( , ppm, CDCl3): 25.15, 24.92.
P
NCH3+); 3.48 s (NH2+). 31P NMR spectrum (DMSO-d6,
P, ppm): 7.87. Found, %: Cl 10.60; P 9.50. C15H19
ClNO3P. Calculated, %: Cl 10.82; P 9.45.
Di-(1R)-endo-bornyl (S)-phenyl-(R)-(N-1-
phenylethyl)aminomethylphosphonate (VI) pre-
pared similarly to compound IIIa. Yield 70%, mp
135 137 C (acetonitrile). 1H NMR spectrum (CDCl3),
, ppm (J, Hz): 0.66 s (3H, CH3); 0.67 s (3H, CH3);
0.75 s (3H, CH3); 0.76 c (3H, CH3); 0.78 s (6H, CH3);
(S)-Phenyl-(R)-(N-1-phenylethyl)aminomethyl-
phosphonic acid (XIIa). To a solution of 1 g of
phosphonate IVa in 60 ml of dioxane 30 ml of con-
centrated hydrochloric acid was added. Solution ob-
tained was heated at 80 C for 70 h. Then solvent was
evaporated in a vacuum and residue was dissolved in
25 ml of boiling water. Insoluble compound was
isolated. Aminophosphonic acid hydrochloride pre-
cipitated on cooling as colorless crystals, mp 241 C
(EtOH + H2O). [ ]2D0 +15 (c 1, 1 N aqueous NaOH).
1H NMR spectrum (DMSO), , ppm(J, Hz): 7.35 m
(10H, C6H5); 3.74 4.07 m (3H, NCH + NCH2); 3.48 s
(NH+2). 31P NMR spectrum (DMSO-d6, P, ppm): 7.87.
3
1.21 d (3H, NCHCH3, JHH 6.4); 0.8?1.8 m (12H,
CH2); 1.85 m (1H, NH); 2.11 m (1H, CH-bridge);
2.27 m (1H, CH-bridge); 3.68 q (1H, CHN, 3JHH 6.4);
2
4.01 d (1H, CHP, JPH 17.0); 4.33 m (1H, OCH);
4.60 m (1H, OCH); 7.17 7.31 m (10H, ArH). 31P
{1H} NMR spectrum (CDCl3, P, ppm): 24.40.
Reaction of tri-(1R,2S,5R)-menthyl phosphite
with (S)- -methylbenzylbenzaldimine. Di(1R,2S,-
5R)-menthyl (S)-phenyl-(S)-(N-1-phenylethyl)-
aminomethylphosphonate (IXa). To a solution of
2.4 g (4.8 mmol) of tri-(1R,2S,5R)-menthyl phosphite
and 1 g (4.8 mmol of (S)- -methylbenzylbenzald-
imine in 40 ml of absolute methylene chloride 0.7 g
(4.8 mmol) of boron trifluoride etherate was added
and mixture was left for 6 days at room temperature.
Solvent was then evaporated in a vacuum, oily residue
was treated with water and product was extracted with
methylene chloride. Extract was dried over Na2SO4
solvent was evaporated.The product contained two
(R)-Methoxyphenyl-(S)-(N-1-phenylethyl)-
aminomethylphosphonic acid (Xb). To a solution of
1.93 g (0.0032 mol) of phosphonate IIIb in 26 ml of
dioxane 22.5 ml of concentrated hydrochloric acid
was added dropwise. Solution obtained was heated
49 h at 75 C. Then solvent was evaporated in a
vacuum and product was extracted by boiling in 15 ml
of distilled water. Insoluble resin-like part of the
product was removed. Aqueous solution was con-
centrated to volume of 5 ml and on cooling in a re-
frigerator aminophosphonic acid hydrochloride pre-
cipitated as colorless crystals. The precipitate was
separated and dried. Yield 32.17%. [ ]2D0 14.5 (c 1,
diastereomers,
21.42 and 21.93 ppm. The mixture
was purified byP column chromatography with ethyl
acetate hexane in 1:8 ratio as eluent, Rf 0.15. 1.64 g
of product was isolated as oil which crystallized in a
few days. Yield 60%, mp 73 75 C, [ ]2D0 96.62 (c
1
chloroform). H NMR spectrum (DMSO), , ppm (J,
1
1.0, chloroform). H NMR spectrum (CDCl3), , ppm
Hz): 1.24 s (3H, CH3CHPh); 3.5 m (5H, OCH3 +
NH+2), 3.89 m (2H, CHP + CHPh), 6.53 m (2H, C6H4),
7.02 m (7H, C6H5 + C6H4). 31P {1H} NMR spectrum
( , ppm, water dioxane): 12.18.
(J, Hz): 0.54 d (3J 6.6, 3H, CH3); 0.69 d (3J 6.6, 3H,
CH3); 0.83 d (3J 6.6, 3H, CH3); 0.88 d (3J 6.6, 3H,
CH3); 0.9 d (3J 6.6, 3H, CH3); 0.95 d (3J 6.6, 3H,
CH3); 1.34 m (4H, CH + CH2); 1.68 m (4H, CH +
CH2); 2.11 2.35 m (8H, CH + CH2); 3.59 q (1H,
CHN, JHH 6.4); 3.68 d (1H, JHP 22, CHP); 4.10 m
(1H, OCH); 4.20 m (1H, OCH); 4.1 br (1H, NH);
7.19 7.33 m (10H, C6H5). 31P NMR spectrum
(DMSO-d6, P, ppm): 21.42.
(S)-Methoxyphenyl-(R)-(N-1-phenylethyl)-
aminomethylphosphonic acid (XIIb). To a solution
of 1.98 g (0.0033 mol) of phosphonate IVb in 26 ml
of dioxane 23.5 ml of concentrated hydrochloric acid
was added. Solution obtained was heated at 75 C for
60 h. Then solvent was evaporated and product was
extracted by boiling in 25 ml of distilled water. Tar
was removed and aqueous solution was concentrated
to volume of 5 ml. Aminophosphonic acid precipi-
tated on cooling as colorless crystals.The precipitate
was separated and dried. Yield 49%. [ ]2D0 18.46 (c
1, chloroform). 31P {1H} NMR spectrum (DMSO-d6,
P, ppm): 10.69.
(R)-Phenyl-(S)-(N-1-phenylethyl)aminomethyl-
phosphonic acid (Xa). To a solution of 1 g of phos-
phonate IIIa in 60 ml of dioxane 30 ml of concen-
trated hydrochloric acid was added. Solution obtained
was heated at 80 C for 70 h. Then solvent was
evaporated in a vacuum and residue was dissolved in
25 ml of boiling water. Insoluble substance was
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DUAL STEREOCHEMICAL CONTROL IN REACTION
(S)- -Aminobenzylphosphonic acid (S)-XI. To a
1743
REFERENCES
solution of 0.3 g of phosphonic acid Xa in 50 ml of
water 300 mg of palladium on charcoal was added and
gaseous hydrogen was passed through the solution for
24 h. The catalyst was then filtered off and solvent
was evaporated in a vacuum. Residue was -amino-
phosphonic acid in the form of hydrochloride. Yield
90%, mp 226 C, [ ]2D0 15 (c 2, 1 N aqueous NaOH),
which corresponded to earlier described ( )-(S)-
1. Kolodiazhnyi, O.I., Tetrahedron, 2003, vol. 59,
no. 32, p. 5923.
2. Kolodiazhnyi, O.I., Sheiko, S.Yu., Guliaiko, I.V., and
Gryshkun, E.V., Phosphorus, Sulfur, Silicon and Relat.
Elem., 2002, vol. 177, nos. 8 9, p. 2269.
3. Kolodiazhnyi, O.I and Sheiko, S.Yu., Zh. Obshch.
Khim., 2001, vol. 71, no. 7, p. 977.
4. Kolodiazhnyi, O.I., Grishkun, E.V., Sheiko, S., De-
mchuk, O., Thoennessen, H., Jones, P., and Schmutz-
ler, R., Tetrahedron: Asymmetry, 1998, vol. 9, no. 10,
p. 1645.
1
phenyl(amino)methylphosphonic acid [8, 9]. H NMR
spectrum (D2O), , ppm (J, Hz): 7.28 m (5H, C6H5);
4.25 d (1H, PCH, JHP 17).
5. Kolodiazhnyi, O.I., Sheiko, O., and Grishkun, E.V.,
Heteroatom. Chem., 2000, vol. 11, no. 2, p. 138.
6. Kolodiazhnyi, O.I., Grishkun, E.V., Sheiko, S.Yu., and
Demchuk, O., Izv. Ross. Akad. Nauk, Ser. Khim.,
1998, vol. 9, no. 11, p. 1588.
7. Gilmore, W.F. and McBride, H.A., J. Am. Chem. Soc.,
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8. Blazis, V.J., Koeller, K.J., and Spilling, S.D., Tetra-
hedron: Asymmetry, 1994, vol. 5, no. 4, p. 499.
9. Kafarski, P., Lejczak, B. and Szewczyk, J., Can. J.
Chem., 1983, vol. 61, p. 2425.
(R)- -Aminobenzylphosphonic acid (R)-XI. To a
solution of 0.3 g of phosphonic acid XIIa in 50 ml of
water 300 mg of palladium on charcoal was added and
gaseous hydrogen was passed through the solution for
24 h. The catalyst was filtered off and solvent was
evaporated in a vacuum. In residue, we obtained
-aminophosphonic acid hydrochloride. Yield 90%,
mp 226 C, [ ]2D0 +15 (c 2, in 1 N aqueous NaOH),
which corresponded to earlier described (+)-(R)-
1
phenyl(amino)methylphosphonic acid [8, 9]. H NMR
spectrum (D2O), , ppm (J, Hz): 4.25 d (JHP 17 Hz,
10. Kolodiazhnyi, O.I., Tetrahedron: Asymmetry, 1998,
vol. 9, no. 8, p. 1279.
1H, PCH); 7.28 s (5H, C6H5).
11. Sheiko, S.Yu., Diss. Thesis, Kiev, 2002.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 75 No. 11 2005